key: cord-028721-x6f26ahr
authors: Nistal, Manuel; Paniagua, Ricardo
title: Non-neoplastic diseases of the testis
date: 2020-06-22
journal: Urologic Surgical Pathology
DOI: 10.1016/b978-0-323-01970-5.50014-2
sha: 
doc_id: 28721
cord_uid: x6f26ahr

nan

Testicular biopsy 665

Infertility and chromosomal anomalies 686

Other syndromes associated with hypergonadotropic hypogonadism 692

Secondary idiopathic hypogonadism 694

Hypogonadism secondary to endocrine gland dysfunction 697

Infertility secondary to physical and chemical agents 705

Infertility in patients with spinal cord injury 708

Orchitis 708

Histiocytosis with testicular involvement 712

Non-neoplastic diseases of the testis Manuel Nistal, Ricardo Paniagua CHAPTER 12 Embryology and anatomy of the testis Embryology

Sexual differentiation is the result of complex genetic and endocrine mechanisms that are closely associated with the development of both the genitourinary system and the adrenal glands. Formation of the bipotential gonad and, subsequently, of the ovaries and testes, depends on gene expression in both sex and autosomal chromosomes. Testes secrete steroid and peptidic hormones that are necessary for the development of inner and outer male genitalia. These hormonal actions are mediated by specifi c receptors that are transcriptional regulators. Alteration of these genetic events leads to sexual dimorphism involving the inner and outer genitalia, and can also hinder the development of other organs. 1 Chromosomal gender is established at fecundation with formation of an egg with either a 46XY (male) or a 46XX (female) karyotype. Each chromosomal constitution initiates a cascade of genetic events leading to the development of female (ovaries) or male (testes) gonads (gonadal gender). Hormonal secretions from the ovaries or testes are essential for the development of external genitalia (phenotypic gender). The relationship between the individual and the environment determines the social gender.

There are multiple genes involved in the formation of the undifferentiated gonad. The two most important for the proper formation of the bipotential gonad are WT1 (Wilms' tumor gene) and NR5A1 ( Fig. 12-1 ).

WT1 contains 10 exons located on chromosome 11p13, with two alternative splicing loci in introns 5 and 9. Intron 9 splicing can lead to the inclusion or exclusion of three amino acids (KTS: lysine, threonine and serine), giving rise to KTS+ or KTS− isoforms. An adequate KTS+/KTS− balance is crucial for normal expression of the gene. Translation of this gene may generate up to 24 isoforms with several zinc-fi nger domains. This gene is expressed mainly in the kidneys and gonads, and mediates the transition from stroma to epithelium and morphogenetic differentiation (inhibits those genes that encode proliferative factors and activates those that enhance epithelial differentiation). WT1 gene anomalies lead to a wide variety of phenotypes; deletions are associated with minimal genitourinary alterations and predisposition to develop Wilms' tumor. [2] [3] [4] Missense heterozygous mutations give rise to Denys-Drash syndrome (complete or partial 46XY gonadal dysgenesis, renal disease of early onset with diffuse mesangial sclerosis, and Wilms' tumor (OMIM 19408) ). 5 Loss of the KTS+ isoform accounts for Frasier's syndrome (46XY gonadal dysgenesis, renal disease of late onset and absence of Wilms' tumor (OMIM 136680)). 6 NR5A1 gene product is termed SF-1 (steroidogenic factor 1). The gene has seven exons in chromosome 9q33.3, and is expressed in the urogenital ridge that forms the gonads and adrenal glands. SF-1 promotes the expression of the anti-müllerian hormone (AMH) and joins elements that regulate upstream the AMH gene. SF-1 is fi rst detected in the developing Sertoli cells of sex cords, but later is mainly localized in Leydig cells. 7 A heterozygous deletion causes a female phenotype in patients with 46XY, adrenal failure during the fi rst weeks of extrauterine life, persistence of normal müllerian structures, and gonads consisting of poorly differentiated tubules embedded in abundant connective tissue. These patients do not respond to hCG stimulation. 8 In 46XX patients, ovarian development is not modifi ed by SF-1 mutations, and they present with adrenal failure only. 9 LIM-1 is another gene involved in the formation of the bipotential gonad and kidneys. It was recently identifi ed in mice that bore homozygous deletions and presented alterations in both organs. 10 FGF-9 (fi broblastic growth factor 9) has also been related to gonadal development.

Both gonosomal and autosomal genes mediate the progression of the bipotential gonad toward testicular differentiation. The signal is triggered by the SRY gene on the distal portion of the short arm of the Y chromosome (sexdetermining region of the Y chromosome; Yp11.3), also called TDF (testis determining factor gene). 11 This gene stimulates the differentiation of Sertoli cell precursors and germ cells, is responsible for the production of the anti-müllerian hormone, 12 and regulates other genes of the downstream cascade. These are either activated or inhibited by other genes in such a way that dozens of genes are involved in testicular differentiation. 13 The SRY gene contains a single exon that encodes a 204 amino acid protein whose central part (79 amino acids) encodes a DNA-binding domain termed HMG (high mobil- ity group). Immunohistochemical studies have demonstrated expression of the SRY gene in the nuclei of both Sertoli cells and germ cells, 14 suggesting that this gene acts in somatic cells of genital ridge and germ cells. SRY works with the AMH promoter gene and also regulates steroidogenic hormone expression. 15 SRY mutations produce pure gonadal dysgenesis (Swyer's syndrome) or true hermaphroditism; the karyotype of patients with the male phenotype lacking Y chromosome is either 46XX SRY+ (80%) or 46XX SRY− (20%), and all have male external genitalia, testes, azoospermia and no müllerian structures. Some 46XX SRYpatients have SOX-9 duplication. 16 Following discovery of the SRY gene, the knowledge about genes involved in gonadal formation advanced experimentally with knockout mice and the study of human syndromes. Now, there are numerous reported genes (including SOX-8, SOX-9, DAX-1, LHX-9, LIM-1 and DMRT-1) that encode associated transcription factors.

SOX-8 and SOX-9 (SRYY box 8 and 9 or SRY HMG-BOX gene 9 ) are related to autosomal genes. SOX-9 is on chromosome 17q24,3q25,1 and is expressed after SRY expression in the same cell type (the pre-Sertoli cell). 17 This gene is also essential for the development of the cartilaginous extracellular matrix. In the mouse gonad, SOX-9 inhibits testicular development or Sertoli cell marker expression, and the gonad acquires an ovarian pattern. 18 SOX-9 haploinsufficiency (loss of a functional allele) causes camptomelic dysplasia (a syndrome characterized by abnormal formation of cartilage) and a 46XY constitution with female phenotype, 17, 19 whereas SOX-9 duplication results in 46XX patients with male phenotype. 20 SOX-8 is other cofactor in AMH regulation and acts by protein-protein interaction with SF-1. Experimental models show that SOX-9 dysfunction results in replacement by SOX-8 expression via a feedback mechanism. 21 DAX-1 (dosage-sensitive sex-reversal, adrenal hyperplasia, X-linked) gene is involved in the development of testes, ovaries, and adrenal glands. DAX-1, on X chromosome, is expressed during ovarian formation and inhibited by SRY during testicular formation. Duplication of the DAX-1 region in Xp21 results in 46XY gonadal dysgenesis. 22, 23 Conversely, DAX-1 mutations decrease gene expression, resulting in absence of adrenal cortex and hypogonadotropic hypogonadism; 10 testicular determination is normal.

Deletions in chromosomes 9p 24 and 10q 25 are associated with the female phenotype in 46XY individuals. Chromosome 9p deletions are also associated with facial malformations, premature closure of the frontal suture, hydronephrosis, and delayed development. Deletions of two genes (DMRT1 and DMRT2) on chromosome 9p24.3 may be found in 46XY females. Terminal deletions in chromosome 10q are associated with genital malformations, multiple phenotypic anomalies, and mental retardation.

In the fourth week of gestation, the urogenital ridges appear as two parallel prominences along the posterior abdominal wall. These give rise to two important pairs of structures: the genital ridges arising from the medial prominences, and the mesonephric ridges from the lateral prominences.

The genital ridges are the fi rst primordium of the gonad and stand out as a pair of prominences about the midline. In 30-32-day embryos, each genital ridge is lateral to the aorta and medial to the mesonephric duct ( Fig. 12-2) . The celomic epithelium forming the genital ridges grows as cordlike structures to create the primary sex cords. Immediately beneath the celomic epithelium there are several mesonephric ductuli and glomeruli ( Fig. 12-3) .

The origin of the gonadal blastema results from the junction of two cell types: epithelial cells from the celomic epithelium and mesenchymal cells from the mesonephric region, 26,27 although experimental data are confl icting. One of the earliest effects of SRY expression is induction of mesonephric cell migration toward the genital ridge. 28, 29 Histochemical studies revealed that an early event is also disruption of the celomic epithelium basal lamina, permitting the migration of these epithelial cells inside the gonad. If chromosomal constitution is XY, these cells give rise to Sertoli cells. 30 Cells derived from the celomic epithelium are recognized by their pale cytoplasm, large size, Embryology and anatomy of the testis The rete testis originates from mesonephric remnants of sex cords that are in continuity with the seminiferous cords. The connection between the testis and the mesonephros becomes progressively thinner ( Fig. 12-4) . The testis has a round transversal section, and remains located between two suspensory ligaments: the cranial and the caudal, the latter of which gives rise to the gubernaculum.

The development of the urogenital tract begins at the stage of the undifferentiated gonad, with the appearance of two different pairs of ducts: the wolffi an and the müllerian.

The wolffi an ducts are formed in the mesonephros in the third week of gestation, when the cranial region of the segmented intermediate mesoderm gives rise to 10 pairs of tubules (the nephric tubules) that are metamerically arranged. These tubules form the pronephros. On each side of the body, the tubules converge to form a longitudinal duct that opens in the celomic cavity. In the fourth week, the pronephros disappears and is replaced by another tubular system (derived from the intermediate mesoderm, which is not segmented) that forms the mesonephros. The medial ends of the mesonephric tubules do not open to the celomic cavity but are connected to glomeruli at one end and the wolffi an duct at the other. At the end of the second month of gestation, the mesonephros is replaced by the metanephros or defi nitive kidney. However, in the male, the most caudal mesonephric tubules and the wolffi an duct persist. The former give rise to the ductuli efferentes, and the latter forms the ductus epididymidis, the ductus deferens, the seminal vesicle, and the ejaculatory duct.

Both müllerian ducts originate from a longitudinal invagination of the celomic epithelium in the anterolateral aspect of the genital ridge. The cranial end of each duct is a funnel that opens in the celomic cavity. Each duct runs parallel and lateral to the respective wolffi an duct and, as they pass caudally, the müllerian duct crosses over the wolffi an duct and lies medial to it. Finally, the two müllerian ducts fuse into the uterovaginal duct. This elongates caudally up to the posterior and ovoid euchromatic nucleus. The cells of mesonephric origin are darker and have a mesenchymal pattern.

Initially, the genital ridges are devoid of germ cells. In the third week, primordial germ cells appear in the extraembryonal mesoderm lining the posterior wall of the yolk sac near the allantoic evagination. They are ovoid, measuring 12-14 µm in diameter, and are easily detected histochemically by a high content of alkaline phosphatase. The nuclei are spherical and possess one or two prominent central nucleoli. The cytoplasm contains mitochondria with tubular cristae, lysosomes, microfi laments, lipid inclusions, numerous ribosomes, and abundant glycogen granules. Attracted by chemotactic factors, the primordial germ cells migrate along the mesenchyma of the mesentery and reach the genital ridge by 32-35 days.

The seminiferous cords arise from the gonadal blastema. 31,32 Many germ cells reach the seminiferous cords, but some degenerate during migration. The seminiferous cords are delimited from the stroma by a basement membrane 33 and lose their connection to the celomic epithelium, which reduces its depth to one or two cell layers only. The intercordal mesenchyma, composed chiefl y of cells that migrated from the mesonephric stroma, differentiate later into myoid cells, Leydig cells, fi broblasts, and blood vessels. 34 Up to the sixth week, the gonads appear similar, although the incipient testes have more numerous blood vessels, more abundant stroma, 35 and a higher total DNA content, suggesting more rapid growth.

Sertoli cells arise from somatic sex cord cells. These cells differentiate at the end of the seventh week from the somatic cells in the cords, develop adherent junctions between them and a basal lamina on the other cord surface, and begin to express AMH. 36 In the eighth week, Leydig cells differentiate from the intercordal gonadal blastema, 37 and immunohistochemical detection of 3β-HSD is apparently the fi rst step in this process. Leydig cell development peaks during the 18th week, and numbers subsequently decrease progressively. 38 aspect of the urogenital sinus, forming the müllerian tubercle. The wolffi an ducts terminate at either side of this tubercle.

The remaining structures of the male genital system are derived from the urogenital sinus. Epithelium with endodermal origin forms the prostate, the urethra, and the bulbourethral and periurethral glands. The primitive urogenital sinus derives from the cloaca, a structure that appears at the end of the fi rst month and which consists of a dilation of the terminal portion of the primitive posterior intestine. The cloaca is closed by the cloacal membrane. In the third week, mesenchyma proliferates in the outer aspect of the cloacal membrane to form the cloacal folds and the cloacal eminence. In the sixth week, the cloacal folds enlarge to form the genital (or urethral) tubercle. External to the genital folds, another mesenchymal thickening develops into the genital prominences or genital swellings.

In the fi fth week, a septum forms, dividing the cloaca into two compartments. The anterior compartment is the primitive urogenital sinus that is covered by the urogenital membrane. The posterior compartment is the anorectal canal, covered by the anal membrane. The primitive urogenital sinus then divides into two new compartments: superior and inferior. The superior compartment is the vesicourethral canal that later forms the urinary bladder and the urethra. The inferior compartment is the defi nitive urogenital sinus that will develop later according to the gender.

The development of the male genital system is directly infl uenced by the action of multiple hormones, including anti-müllerian hormone (AMH), dihydrotestosterone (derived from testosterone), and the pituitary hormones folliclestimulating hormone (FSH) and luteinizing hormone (LH) .

AMH (müllerian inhibitory substance; MIS), 39 secreted by the Sertoli cells, is a glycoprotein polymer consisting of two identical 72 kDa subunits linked by disulfi de bonds. [40] [41] [42] It belongs to the TGF-β family and is synthesized as a 560 amino-acid precursor protein with proteolytic cleavage at 109 amino acids from the C terminal. Cleavage is necessary to activate the hormone. AMH is encoded by a 2.75 kb gene that comprises fi ve exons and is located on the p13.2 region of chromosome 19. AMH is secreted by somatic cells only in both sexes: Sertoli cells in males and granulosa cells in females. It is detected by 6-7 weeks of gonadal development (8-9 weeks of gestation), probably as soon as germ cells make contact with pre-Sertoli cells, a week before the müllerian ducts lose their responsiveness. 43, 44 AMH is at high concentration in the second trimester, but drops precipitously in the third trimester. 45 Levels rise again during the fi rst year after birth, are detectable during infancy and childhood, and fi nally drop defi nitively to undetectable levels at the onset of puberty. The secreted amount of AMH is inversely correlated to the degree of Sertoli cell maturation.

AMH regulation is incompletely understood. Its expression is controlled by steroidogenic factor 1 (SF-1), also called Ad4BP, 46 which is an orphan nuclear receptor that acts as a transcriptional regulator of all steroidogenic genes. AMH regulates SRY expression, which in Sertoli cells is detected immediately before AMH expression. 47 During puberty, AMH is negatively regulated by androgens. 48 AMH acts on the testis, genital tract, and extragenital structures. It causes involution of the ipsilateral müllerian duct. Action begins at the caudal testicular pole and progresses rapidly. In adults, remnants of the müllerian ducts include the appendix testis at the cranial end and the prostatic utricle (verumontanum) at the caudal end. AMH also stimulates development of the tunica albuginea, formed by insertion of mesenchyma between the celomic epithelium and primordial sex cords. This mesenchyma is also the origin of collagenized connective tissue, with deposition of collagen fi bers in several layers that parallel the testicular surface. 49 AMH also hinders the entry of spermatogonia in meiosis. 50 The best-known function of AMH in the extragonadal system is the maturation of fetal lungs. 51 Testosterone is synthesized by the Leydig cells. These fi rst appear among the sex cords in the eighth week of gestation, and their number increases to 48 million per pair of testes by the 16th week, 52 occupying about 50% of the testicular volume ( Fig. 12-6 ). The relative number of Leydig cells decreases from the 16th to the 24th week, owing to rapid enlargement of the testis during this period. However, the absolute number of Leydig cells remains constant. From the 24th week to birth, the number of Leydig cells decreases to 18 million per pair of testes. Testosterone synthesis begins after the 56th day of gestation.

Testosterone secretion is regulated by hCG and LH concentrations. hCG peaks between weeks 11 and 17 and drops markedly thereafter; hCG-dependent testosterone is the most important determinant of genital differentiation. Wolffian duct differentiation occurs only as a response to the testosterone secreted by the ipsilateral testis. This secretion stimulates differentiation of the ductus epididymidis, ductus deferens, and seminal vesicle. Anomalies in androgen synthesis lead to incomplete masculinization and cryptorchidism.

Dihydrotestosterone (DHT) derives from testosterone by the action of the enzyme 5α-reductase and is responsible for differentiation of the prostate and the development of the external genitalia, male urethra, penis and scrotum. It induces fusion of the labioscrotal folds in the middle plane to form the scrotum and the middle scrotal raphe. The urethral folds become fused to form the penile urethra. The genital tubercle enlarges to form the glans penis. An ectodermal invagination of the glans tip forms the terminal portion of the urethra. The urogenital sinus gives rise to the urinary bladder, prostatic urethra, and prostate. 53 The initial effects of DHT (labioscrotal fusion) occur on approximately day 70; the urethral groove is closed on about day 74; and the external genitalia are completely developed by week 20.

The actions of these hormones occur at precise moments in development. Failure in the amount or timing of secretion or in the responsiveness of target tissues causes most of the malformations found in intersex conditions. 52 FSH and LH both play an important role in the last months of gestation. LH appears in the fetal circulation during the 10th week and peaks by the 18th, decreasing progressively and slowly thereafter until birth. LH chiefl y regulates androgen production during the second half of fetal life. FSH is an essential mitogen for Sertoli cells that reach the highest mitotic ratio at the end of fetal life ( Fig. 12-7) . 54, 55 Testicular descent Testicular descent is the result of hormonal and mechanical actions that are not fully understood. Three steps are recognized: nephric displacement, transabdominal descent, and inguinal descent. In nephric displacement, the gonad detaches from the metanephros in the seventh week of gestation. Transabdominal descent occurs in the 12th week and consists of the displacement of the testis towards the deep inguinal ring. Inguinal descent occurs between the seventh month and birth. 56 Clinically, the term testicular descent often refers only to this last step, in which the testis passes from the abdominal cavity to the scrotum. Testicular descent is directed by the gubernaculum testis, a structure that appears in the sixth week as an elongate condensation of mesenchymal cells extending from the genital ridge to the presumptive inguinal region. 57, 58 At this level in the abdominal wall, the gubernaculum cells persist as a simple mesenchyma while the remaining abdominal wall cells differentiate into muscle. These mesenchymal cells give rise to the inguinal canal. Thus, the testis lies on a continuous column of mesenchyma limited by the cranial testicular ligament in the upper pole and by the plica gubernaculi that joins the testis to the future scrotal region in the inferior pole. The periphery of this mesenchymal tissue is invaded by the processus vaginalis, which develops from a peritoneal pouch that grows into this mesenchyma. Once the inguinal canal and the plica gubernaculi are formed, development slows. In the seventh month the processus vaginalis undergoes active growth, the cremasteric muscle develops from the mesenchyma outside the processus vaginalis, and the distal end of the gubernaculum enlarges markedly. Gubernacular enlargement occurs from the 16th to the 24th weeks of gestation period and is caused by hyperplasia, hypertrophy, and the absorption of a great volume of water by the glycosaminoglycans of the matrix. 59 The tissue is reminiscent of Wharton's jelly of the umbilical cord. By this time, the testis-epididymis complex is pear-shaped and its largest component is the gubernaculum. The testis and epididymis slide through the inguinal canal behind the gubernaculum. Simultaneously, development of the processus vaginalis is completed and the gubernaculum begins to shorten, the epididymis develops further, and the testicular blood vessels and vas deferens lengthen. 60 Testicular descent is a complex process integrating several essential factors, including normal function of the hypothalamopituitary-testicular axis, normal development of abdominal musculature, gubernaculum and the processus vaginalis, 61, 62 and a testis with normal endocrine function.

The critical role of normal hormonal function is supported by clinical and experimental observations: destruction of the hypophysis in laboratory animals impedes testicular descent; anencephalic fetuses usually have undescended testes; many cryptorchid patients have transitory neonatal hypogonadotropic hypogonadism; and some undescended testes descend after treatment with human chorionic gonadotropin or gonadotropin-releasing hormone. Adequate intra-abdominal pressure is another requisite. 63, 64 In the prune-belly syndrome, bilateral cryptorchidism is associated with urologic malformations and absence of the abdominal wall musculature. In a variant of this syndrome, termed pseudo-prune-belly syndrome, there is a positive correlation between the development of the abdominal wall musculature and testicular descent. Development of the processus vaginalis also plays a critical role in testicular descent. This structure grows within the gubernaculum; if it is partially replaced by fi brous tissue, the testis will follow other directions in its descent and end in an ectopic location. If fi brous tissue completely replaces the gubernaculum, the processus vaginalis and cremasteric muscle fail to develop fully, and descent of the testis is mechanically blocked. 62 The hormonal requirements for testicular descent are not clear. 65 The most important factor in transabdominal descent is the androgen-independent peptide insulin-like factor 3 (INSF-3), a member of the relaxin-insulin family that is produced by fetal Leydig cells. This peptide stimulates gubernaculum cells to initiate gubernaculum swelling, a necessary step for the initiation of testicular descent. 66 Mutations in INSL-3 gene or its receptors LGRB-8 (leucine-rich repeatcontaining G protein-coupled receptor 8) or GREAT (G protein-coupled receptor affecting testicular descent) interfere with transabdominal descent and cause cryptorchidism. 67, 68 AMH and androgens are also involved in the gubernaculum swelling reaction; androgens also facilitate regression of the cranial suspensory ligament.

Uncertainty exists regarding the mechanism of inguinoscrotal descent and its hormonal control. Androgens and the genitofemoral nerve are two factors strongly implicated in these processes. The role of androgens on the gubernaculum is very limited, because this structure has neither muscular cells 69 nor androgen receptors at the time of testicular descent. Androgenic effects are explained by the hypothesis of the genitofemoral nerve. 70 Androgens appear to act on the nucleus of the genitofemoral nerve in the spinal cord rather than directly on the gubernacula, producing masculinization of the neurons that form this nucleus 71 (these neurons are much more numerous in males than in females) and secreting great amounts of calcitonin gene-related peptide (CGRP). In rats, CGRP causes rapid rhythmic contractions of the gubernaculum and it has been suggested that the gubernaculum might have embryonic cardiac muscle cells. However, it is also possible that CGRP acts on the cremasteric muscle that develops within the gubernaculum and is innervated by the genitofemoral nerve. This hypothesis is supported by the observation of neurogenic atrophy of this muscle in cryptorchid patients. 72 Other factors involved in testicular descent are estrogens and epidermal growth factor (EGF). During the fi rst trimester of gestation, mothers of cryptorchid infants have free estradiol serum concentrations that are signifi cantly higher than those of controls. 73 Experimental studies have shown that estradiol diminishes gubernacular swelling and stabilizes müllerian ducts. It has been proposed that estradiol inhibits the cell proliferation that causes gubernaculum swelling. 74, 75 EGF may facilitate testicular descent throughout the placental-gonadal axis. Maternal EGF levels increase just before fetal masculinization occurs. 76 The placenta has an elevated concentration of EGF receptors, and placental stimulation by EGF might stimulate hCG production, which may also stimulate fetal Leydig cells to produce androgens; hypothetically, these and/or other factors may determine testicular descent.

After birth, the gubernaculum and processus vaginalis regress. The gubernaculum is replaced by fi brous tissue that forms the scrotal ligament. The cephalic segment of the processus vaginalis atrophies after testicular descent. An exaggerated resorption of the processus vaginalis with pulling up of the testis may induce a testis that had descended normally to ascend, resulting in cryptorchidism. 77

From birth to puberty the testis is a dynamic structure, an important consideration in interpreting biopsies from children. All testicular components undergo waves of proliferation and differentiation prior to puberty. 78 Three waves of germ cell proliferation occur: during the neonatal period, infancy, and puberty. 79 The last gives rise to complete spermatogenesis. There also are three waves of Leydig cell proliferation (fetal, neonatal, and pubertal); the last corresponds to the pubertal wave of germ cell proliferation.

The testis at birth

The newborn testis has a volume of about 0.57 mL 80 and is covered by a thin tunica albuginea from which the intratesticular septa arise. These divide the testis into lobules containing the seminiferous tubules and testicular interstitium ( Fig. 12-8) . The seminiferous tubules measure 60-65 µm in diameter, with no apparent lumina, and are fi lled with Sertoli cells and germ cells. Sertoli cells are the most abundant, with 26-28 cells per tubular cross-section ( Fig. 12-9) . 81 They form a pseudostratifi ed cellular layer and have elongated to oval nuclei with darker chromatin than that of mature Sertoli cells, as well as one or two small peripheral nucleoli. The cytoplasm contains abundant rough endoplasmic reticulum, several Golgi complexes and numerous vimentin fi laments, and expresses inhibin B (Fig. 12-10) . No specialized intercellular junctions appear between Sertoli cells, but desmosome-like junctions are present between Sertoli cells and germ cells. 82 Two types of germ cell are present at birth: gonocytes and spermatogonia. Gonocytes are usually located near the center of the tubules, with voluminous nuclei and large central nucleoli. 82 Gonocyte migration is probably facilitated by cell adhesion molecules such as P cadherin, which is expressed by Sertoli cells of immature testes. 83 Spermatogonia are mainly located on the basal lamina, and possess smaller nuclei and less cytoplasm than gonocytes; the nucleoli are peripheral and very small. At birth, most spermatogonia correspond to the adult type A (see discussion on the adult testis below) ( Fig. 12-11) .

The testicular interstitium contains fetal Leydig cells that resemble adult Leydig cells but lack Reinke's crystalloids ( Fig. 12-12) . 84, 85 Additionally, mast cells, macrophages, and hematopoietic cell are present. 86 The fi rst wave of testicular development occurs during the neonatal period and involves germ cells and Leydig cells. These changes are caused by a signifi cant increase in secretion of both FSH and LH during the third postnatal month. 87-89 Testicular weight and volume increase. LH stimulates the Leydig cells to produce testosterone, 90,91 which stimulates the transformation of gonocytes to spermatogonia of the Ad type ( Fig. 12-13) . Afterwards, some of these In some normal testes at this age, meiotic primary spermatocytes and round spermatids are observed ( Fig. 12-15 ). This spermatogenic attempt fails and many degenerate germ cells may be present. 94, 95 The testis continues to produce AMH (by Sertoli cells) 96 and inhibin B. 97 AMH modulates the number and function of Leydig cells by regulating differentiation of their mesenchymal precursors and the expression of steroidogenic enzymes. 98 Inhibin B plays a role in FSH inactivation during infancy.

The cause of this second wave of germ cell proliferation is unknown; there is no elevation of FSH or LH serum concentrations between 6 months and 10 years of life. After the sixth year, there is a slight increase in adrenal androgens, but testicular testosterone levels increase only after the 10th year. 99, 100 By the third year, most Leydig cells have degenerated: from a peak of about 18 million at birth, only 60 000 remain by the age of 6 years. At this age, testosterone levels Embryology and anatomy of the testis divide to form Ap spermatogonia (see discussion on the adult testis below). Six months after birth, gonocytes are absent, coinciding with the loss of fetal germ cell markers (placental alkaline phosphatase and c-kit).

Paraganglia are often observed in epididymides and spermatic cords from newborns. This is not surprising, as paraganglia are the main source of catecholamine before birth ( Fig. 12-14) . 92 The testis in infancy From the sixth month to approximately the second half of the third year of life, the testis is in a resting period; this quiescence is broken by the second wave of germ cell proliferation. 93 The number of Ap spermatogonia increases, and B spermatogonia (derived from Ap spermatogonia) appear. are similar to those of girls, 99 and most androgens are of adrenal origin.

At about 9 years of age, the third and defi nitive wave of spermatogenesis begins, 101 coinciding with a signifi cant elevation of LH. This is followed by additional increases in the level of this hormone between 13 and 15 years of age. LH induces fi broblast-like Leydig cell precursors to differentiate into mature Leydig cells. 102 By the end of puberty, the population of Leydig cells per testis has risen to about 786 million. 103 Leydig cells secrete androgens, which, together with the rise in FSH between 11 and 14 years of age, cause Sertoli cell maturation, germ cell development, and the appearance of tubular lumina ( Fig. 12-16) , 103 increasing the size of the testes between the ages of 11.5 and 12.5 years of life. 104 At 13.5 years, before the testis reaches adult size, spermatozoa are present, secondary sex characteristics are completely developed, and the epiphyses close. 105 

Testicular biopsy in children is useful for diagnosing those with ambiguous genitalia, a history of leukemia or lymphoma whose testes underwent a rapid enlargement, or precocious testicular maturation of unknown cause. In other situations, the value of testicular biopsy is less established. For example, the value of biopsy of cryptorchid testes during orchidopexy is controversial. Evaluation of biopsies of the prepubertal testis should involve the assessment of several features, including tunica albuginea thickness, mean tubular diameter, and the number of germ cells, Sertoli cells, and Leydig cells.

The most frequent anomalies of the tunica albuginea include thin, poorly collagenized tunica albuginea with abnormal tubules typical of testicular dysgenesis (see the section on male pseudohermaphrodites with müllerian remnants, below); well-collagenized tunica albuginea containing ectopic seminiferous tubules, a frequent fi nding in cryptorchidism; and poorly collagenized tunica albuginea containing ovocytes characteristic of true hermaphroditic ovotestes.

The mean tubular diameter is an excellent indicator of the development of the seminiferous epithelium. In the prepubertal testis, tubular diameter depends principally on the Sertoli cells and thus indicates whether they are adequately stimulated by FSH. Tubular diameter varies throughout, being smallest in the end of the third year of life, slowly enlarging up to 9 years of age, and rapidly enlarging thereafter up to 15 years ( Fig. 12-17) .

The most frequent abnormality in the prepubertal testis is a low mean tubular diameter. This is seen in undescended testes as well as in hypogonadotropic or hypergonadotropic hypogonadism. In the latter, the lesion results from anomalous Sertoli cell responsiveness to FSH. 106 There are three levels of severity of low tubular diameter: slight tubular hypoplasia (up to 10% reduction in relation to the diameter normal for the age); marked tubular hypoplasia (from 10% to 30% reduction); and severe tubular hypoplasia (more than 30% reduction). Many testicular biopsies show malformed seminiferous tubules that vary from straight or branched tubules up to ring-shaped. These are megatubules formed by either tight spiral or bell-shaped tubules. The presence of these malformations suggests the child will be infertile in adulthood.

Diffuse increase in mean tubular diameter may be unilateral or bilateral. Unilateral increase is found in monorchidism (compensatory testicular hypertrophy) and some testes that are contralateral to cryptorchid testes. Most frequently, diffuse enlargement occurs with benign idiopathic macroorchidism or macroorchidism associated with fragile X chromosome, familial testotoxicosis, hypothyroidism, or different forms of precocious puberty. Focal increases in mean tubular diameter are usually associated with precocious maturation of the seminiferous epithelium layers, and occur at the periphery of some Sertoli cell and Leydig cell tumors.

Germ cells can be counted in two ways: calculation of the number of cells per tubular cross-section, or determination of the tubular fertility index. The former counts the number of germ cells in a light microscopic fi eld and divides this by the number of cross-sectioned tubules in the same fi eld. In the fi rst 6 months of postnatal life the normal testis has two germ cells per cross-sectioned tubule. This number drops to 1.5 at the end of the fi rst year and to 0.5 at the end of the third year. The number of germ cells increases to 1.8 cells at the age of 3-4 years, which coincides with the appearance of spermatocytes in some tubules.

The tubular fertility index refl ects the percentage of tubular sections containing germ cells. In newborns, 68% of tubular sections contain at least one germ cell. From birth to 3 years this decreases to 50%, followed by a progressive increase to 100% at puberty. 93 If the numbers of gonocytes and spermatogonia are calculated separately, it is possible to determine when the transformation of gonocytes to spermatogonia occurs. The most accurate measure is calculation of total germ cell numbers per testis. This is more diffi cult because it requires morphometric assessment of intratubular volume and careful clinical measurement of the three axes of the testis.

Congenital decrease of germ cells occurs in numerous conditions, including trisomies 13, 18, and 21, some forms of primary hypogonadism such as Klinefelter's syndrome, anencephaly, many cryptorchid testes, and in patients with posterior urethral valves and severe obstruction of the urinary ducts. 107 An increased number of germ cells may be seen at the periphery of germ cell tumor, gonadal-stromal tumor, and paratesticular sarcoma. At the periphery of Leydig cell tumor, seminiferous tubular cellular maturation may be complete.

Three levels of severity of germinal hypoplasia are recognized: slight (tubular fertility index >50), marked (tubular fertility index between 50 and 30), and severe (tubular fertility index <30) ( Fig. 12-17 ). Marked and severe germinal hypoplasia is usually associated with marked or severe tubular hypoplasia, in most cases resulting from tubular dysgenesis. It also is useful to determine whether the seminiferous tubules devoid of germ cells are randomly distributed. If they are grouped, they probably belong to the same lobule or group of lobules that never will develop normally.

Other germ cells observed are multinucleate or hypertrophied spermatogonia and gonocyte-like cells; these latter may require immunohistochemical studies to exclude intratubular germ cell neoplasia.

The number of Sertoli cells per tubular cross-section varies during childhood as a result of slow proliferation from 4 years to 12 years 108 and the redistribution of Sertoli cells as the seminiferous tubules become longer and broader. The pseudostratifi ed cellular pattern characteristic of Sertoli cells at birth changes slowly to a columnar pattern at puberty . Testicular biopsies may reveal hypoplasia or hyperplasia of Sertoli cells; hyperplasia is usually pronounced and a sign of tubular dysgenesis, often detected during the fi rst year of life or the beginning of puberty. 109 Some biopsies reveal one or several tubular sections containing Sertoli cells with eosinophilic and granular cytoplasm that is positive to CD68 and α 1 -antitrypsin. These oncocytic changes are the result of lysosomal accumulation. 110 

Calculation of Leydig cell numbers during childhood is diffi cult because at this age the population is scant. 102 Semi-thin sections or immunohistochemistry to detect testosteronecontaining cells may be helpful. 111 Selection of the appropriate denominator to express the Leydig cell population is another problem. The most frequent measures are Leydig cell number per tubular section, per unit area, or total number per testis. 104 Low numbers of Leydig cell are observed in undescended testes, hypogonadotropic hypogonadism, some variants of male pseudohermaphroditism caused by a defect in the LH receptor, and in anencephalic fetuses. High numbers of Leydig cells occur in congenital Leydig cell hyperplasia, 112 triploid fetuses, 113 variants of precocious puberty, several syndromes such as leprechaunism and Beckwith-Wiederman syndrome, and in most male pseudohermaphroditisms.

An apparent increase in loose connective tissue is found in patients with marked tubular hypoplasia; in addition, disordered thick fusiform cell bundles are seen in patients with androgen insensitivity. Other alterations include the presence of excessively developed lymphatic vessels (lymphangiectasis), focal hematopoiesis, leukemic infi ltration, and the presence of cells similar to those of the adrenal cortex (tumors of the adrenogenital syndrome).

Embryology and anatomy of the testis 

The adult testis is an egg-shaped organ that hangs in the scrotum from the spermatic cord, the retroepididymal surface, and the scrotal ligament. Mean weight in Caucasian men is 21.6 ± 0.4 g for the right testis and 20 ± 0.4 g for the left. Mean testicular diameter is 4.6 cm (range, 3.6-5.5 cm) for the longest axis and 2.6 cm (range, 2.1-3.2 cm) for the shortest. [114] [115] [116] [117] Testicular volume varies from 15 to 25 mL.

The tunica albuginea and interlobular septa make up the connective tissue framework of the testis. The tunica albuginea consists of three connective tissue layers and an outer surface covered by mesothelium. From the outer to the inner layers, the amount of collagen fi bers decreases while the number of cells increases. The fi bers and cells in the two outermost layers form planes parallel to the testicular surface; cell types include fi broblasts, myofi broblasts, and mast cells.

Myofi broblasts are more numerous in the posterior portion of the testis. The thickness of the tunica albuginea increases with age from 400-450 µm in young men to more than 900 µm in elderly men. 118 It acts as a semipermeable membrane that produces the fl uid of the vaginal cavity. The presence of many contractile cells showing high concentrations of GMP suggests that the tunica albuginea undergoes impulses of contraction and relaxation. These cells might regulate testicular size 119 and favor the transport of spermatozoa into the epididymis. 120 The innermost layer, the tunica vasculosa, consists of loose connective tissue containing blood and lymphatic vessels. The interlobular septa consist of fi brous connective tissue with blood vessels supplying the testicular parenchyma. The interlobular septa divide the testis into approximately 250 pyramidal lobules with their bases at the tunica albuginea and vertices at the mediastinum testis. Each lobule contains two to four seminiferous tubules and numerous Leydig cells. 121

Adult seminiferous tubules are 180-200 µm in diameter and 30-80 cm long. The total combined length of the seminiferous tubules is about 540 m (range, 299-981 m). 122 They are highly convoluted and tightly packed within the lobules. The seminiferous tubules comprise about 80% of testicular volume. The tubular lining of germ cells and Sertoli cells is surrounded by a lamina propria (tunica propria) ( Fig.  12-18 ).

Sertoli cells are columnar cells that extend from the basal lamina to the tubular lumen, with 10-12 cells per crosssectioned tubule. They are easily identifi ed by their nuclear characteristics. The nucleus is located near the basal lamina and has a triangular shape with indented outline, pale chromatin, and a large central nucleolus ( Fig. 12-19 ). Charcot-Böttcher's crystals and lipid droplets often are visible in the cytoplasm. [123] [124] [125] [126] Ultrastructurally, Sertoli cells have characteristic nucleoli, plasma membranes, and cytoplasmic components. The nucleolus has a tripartite structure with a round fi brillar center, a compact granular portion, and a three-dimensional net composed of intermingled fi brillar and granular portions. [127] [128] [129] The plasma membrane has two types of intercellular junction which develop at puberty: junctions between adjacent Sertoli cells, and junctions between Sertoli cells and germ cells. 130 The inter-Sertoli cell junctions are tightjunction complexes. The adjacent cytoplasm has numerous actin fi laments and parallel-arranged smooth endoplasmic reticula cisternae. In adjacent plasma membranes there are adhesion molecules, including connexin-43. Between the plasma membrane and the adjacent endoplasmic reticulum cisterna there are many molecules, including those required for actin fi lament anchorage, vinculin, zonula occludens-1, plakoglobin, and radixin. The inter-Sertoli cell junctions are the morphologic basis for the blood-testis barrier and divide the seminiferous epithelium into two compartments: the basal compartment (which contains spermatogonia and newly formed primary spermatocytes) and the adluminal compartment (which contains meiotic primary spermatocytes, secondary spermatocytes and spermatids). These junctions permit each compartment to have its own microenvironment for spermatogenic development. [131] [132] [133] The Sertoli cell-germ cell junctions persist from the primary spermatocyte stage through spermatozoon release. These junctions are desmosomes and gap-type junctions. The adhesion among Sertoli cells and germ cells is mediated by N-cadherin. These junctions have also occasionally been observed between spermatogonia. 134 Sertoli cell cytoplasm contains abundant smooth endoplasmic reticulum, elongated mitochondria, annulate lamellae, lysosomes, residual bodies, glycogen granules, microtubules, vimentin fi laments around the nucleus , 135 actin fi laments in both inter-Sertoli cell junctions and ectoplasmic specializations that surround germ cells, 136 lipid droplets in amounts that vary with the seminiferous tubular cycle, 137 Charcot-Böttcher crystals (structures several micrometers long, formed of multiple parallel laminae of protein), and scant rough endoplasmic reticulum and ribosomes. 138 The number of Sertoli cells decreases with age, from about 250 million per testis in young men to 125 million in men over 50 years. 139, 140 There is a positive correlation between the number of Sertoli cells and daily sperm production. 141 Sertoli cells are the target of FSH 142, 143 and androgen action ( Fig. 12 -21) . 144 In adulthood, they produce testicular fl uid through an active transport mechanism, and synthesize multiple products to ensure the nutrition, proliferation and maturation of germ cells, to stimulate other cells such as Leydig cells and peritubular cells, 145 and to contribute to hormonal regulation (inhibin secretion) (Table 12 -1). The transport of small molecules (<600-700 Da) such as pyruvate, lactate, and probably choline from the Sertoli cell, to germ cells occurs through gap junctions. Large or small soluble molecules are transported by proteins that are synthesized by the Sertoli cell, and include androgen-binding protein, transferrin, ceruloplas-Embryology and anatomy of the testis min, sulfated glycoproteins, α 2 -macroglobulin, and γ-glutamyl transpeptidase. 146 Activin and inhibin are Sertoli cell-secreted proteins that induce the proliferation and differentiation of germ cells. Whereas activin stimulates FSH production and, subsequently, spermatogonial proliferation, inhibin B inhibits FSH secretion, and is an important marker of spermatogenesis. 147 Other Sertoli cell secretions are interleukins, mainly IL-1, 148 and growth factors such as transforming growth factor-β (TGF-β), insulin growth factors 1 and 2 (IGF-1 and IGF-2), and seminiferous growth factor (SGF) or stem cell factor (SCF). Some of these growth factors, such as TGF-α, TGF-β, and IGF-1, are involved in the regulation of Leydig cell function. Other secreted substances include clusterin, the steroid 3-α-4-pregnen-20-one (3HP), and prostaglandin D synthase (Table 12-2) . Sertoli cells are also involved in migration of differentiating germ cells towards the tubular lumen. This movement leads to a continuous remodeling of the plasma membrane and requires synthesis of several proteases, including urokinase, tissue-type plasminogen activator, cyclic protein 2, collagenase IV, other metalloproteins, and several antiproteases, such as cystatin C, tissue inhibitor of metalloproteinase type 2, and α 2 -macroglobulin. 149 The Sertoli cell also regulates germ cell apoptosis by the production of Fas-ligand, which binds to the Fas-ligand receptor (APO-1, CD95) in germ cell plasma membranes. In addition, Sertoli cells possess receptors for several factors such as the nerve growth factor (NGF) produced by spermatocytes and young spermatids, emphasizing the complexity of the Sertoli cell-germ cell relationship. Sertoli cells also produce some steroid hormones (estradiol and testosterone) and several components of the seminiferous tubule wall, including laminin, type IV collagen, and heparin sulfate-rich proteoglycans.

The germ cells of the adult testis include spermatogonia, primary and secondary spermatocytes, and spermatids . Spermatogonia There are two types of spermatogonia: A and B. Type A are about 12 µm in diameter, rest on the basal lamina, and are surrounded by the cytoplasm of the adjacent Sertoli cells. The nuclei of type A spermatogonia are spherical, contain several peripheral nucleoli, and have four different patterns: Ad (dark), Ap (pale), Al (long), and Ac (cloudy). 150, 151 The cytoplasm of these spermatogonia contains a moderate number of ribosomes, small ovoid mitochondria joined by electron-dense bars, and Lubarsch's crystals. These are several micrometers long and are composed of numerous 8-15 nm parallel fi laments intermingled with ribosome-like granules.

Ad spermatogonia are thought to be stem cells in spermatogenesis. Some of them replicate DNA and, during replication, acquire the Al pattern. Afterwards, they divide to make another Ad (maintaining the stem cell reservoir) and an Ap spermatogonium. During replication, Ap spermatogonia become Ac and then divide to form two type B spermatogonia. [152] [153] [154] Type B spermatogonia are the most numerous, and their contact with the basal lamina is less extensive than that of Ultrastructural studies show coarse chromatin masses in which synaptonemal complexes and sex pairs may be present. The nucleolus acquires a peculiar appearance, with segregation of the fi brillar and granular portions. Associated with the nucleolus is the round body that contains proteins but no nucleic acids. 128 In the pachytene spermatocyte, homologous chromosomes are completely paired, and on electron microscopy the chromatin masses appear larger and less numerous than in the zygotene spermatocyte. In the diplotene spermatocyte, paired homologous chromosomes begin to separate and remain joined by the points of interchange (chiasmata); neither synaptonemal complexes nor sex pairs are observed. The diakinesis spermatocyte shows maximal chromosome shortening and the chiasmata begin to resolve by displacement towards the chromosomal ends. The nuclear envelope and the nucleolus disintegrate. The spermatocyte completes the other phases of the fi rst meiotic division (metaphase, anaphase and telophase), forming two secondary spermatocytes; the fi rst meiotic division lasts 24 days. 156 Secondary spermatocytes are haploid cells, smaller than primary spermatocytes, and show coarse chromatin granules and abundant rough endoplasmic reticulum cisternae. 157 These cells rapidly undergo the second meiotic division and within 8 hours give rise to two spermatids. The newly formed spermatids differ from secondary spermatocytes, having smaller nuclei with homogeneously distributed chromatin. Spermiogenesis The transformation of spermatids into spermatozoa is called spermiogenesis. During this process pronounced changes occur in the nucleus and cytoplasm. 158 The nucleus becomes progressively darker and elongated. 159 The cytoplasm develops the acrosome and fl agellum, 160 the mitochondria cluster around the fi rst portion of the spermatozoon tail, and the remaining cytoplasm is phagocytosed by Sertoli cells. 161, 162 By electron microscopy, there are four tran-sient stages of spermatid development: Golgi, cap, acrosome, and maturation. These correspond to those defi ned by light microscopy of nuclear morphology: Sa, Sb, Sb 1 , Sb 2 , Sc, Sd 1 and Sd 2 . 163, 164 These phases may be grouped as early (or round) spermatids that comprise the stages with round nuclei (Sa and Sb), and as late (or elongated) spermatids that comprise the stages with elongated nuclei (Sc and Sd). Mature spermatids (Sd 2 ) are the spermatozoa that are released into the tubular lumen (spermiation). All the germ cells derived from the same stem cell remain interconnected by cytoplasmic bridges that ensure synchronous maturation during the spermatogenic process. 165 Cycle of the seminiferous epithelium At fi rst glance, the arrangement of the germ cells in the seminiferous tubules appears disorderly. However, closer study reveals that these cells are grouped into six successive associations, designated I-VI. In contrast to other mammals, in humans the volume occupied by each association is small, so that several associations may be observed in the same tubular cross-section. Stereological studies have shown that the successive associations are organized helically along the length of the seminiferous tubule. 126, [165] [166] [167] Each association persists for a specifi c number of days (I, 4.8 days; II, 3.1 days; III, 1 day; IV, 1.2 days; V, 5 days; and VI, 0.8 days), and each successively transforms into the following one. Finally, at the end of association VI, the cycle is repeated; the spermatogenic process requires 4.6 cycles. 168 Because each cycle lasts 15.9 days, the transformation of spermatogonium into spermatozoon takes 74 days (Fig. 12-22) .

The succession of different associations probably depends on cyclic Sertoli cell activity. Cyclic changes in the mitochondria, rough endoplasmic reticulum, Golgi complex, lysosomes, and lipid droplets have been reported. [169] [170] [171] This cyclic activity is probably regulated by germ cell signals. 172 The yield of human spermatogenesis is lower than that of Embryology and anatomy of the testis 

The six different germ cell associations of the seminiferous tubules and the sequence of spermatogenesis. Completion of spermatogenesis requires more than four cycles and lasts for approximately 74 days. Each association is indicated by Roman numerals with its corresponding duration. Ad: dark type of A spermatogonia; Ap: pale type of a spermatogonia; B: B spermatogonia; I: interphase primary spermatocyte; L: leptotene primary spermatocyte; Z: zygotene primary spermatocyte; P: pachytene primary spermatocyte; II: secondary spermatocyte (only in stage VI). S a , S b1 , S b2 , S c , S d1 , and S d2 represent the progressive stages of spermatid differentiation into spermatozoa. most mammalian species, including primates, with maximal cell degeneration occurring at the end of meiosis. 173 

The seminiferous tubule is surrounded by a 6 µm thick lamina propria (tunica propria) consisting of a basement membrane, myofi broblasts, fi broblasts, collagen and elastic fi bers, and extracellular matrix. 174, 175 The basement membrane measures 100-200 nm in thickness, and displays three layers: lamina lucida (beneath the Sertoli cells), lamina densa (basal lamina), and lamina reticularis (a discontinuous layer containing fi bers). The basal lamina contains laminin, type IV collagen, entactin (nidogen), and heparan sulfate. 176 External to the basal lamina there are fi ve to seven layers of fl attened, elongated peritubular cells that have important secretory functions (Table 12-3) . 177 The cells forming the three to fi ve innermost layers are myofi broblasts containing numerous actin, myosin, and desmin fi laments. These cells play an important role in the rhythmic tubular contractions that propel spermatozoa toward the rete testis. 178, 179 The two outermost cell layers consist of fi broblasts without desmin fi laments, and with less actin and myosin than the myofi broblasts.

Collagen fi bers are present among the peritubular cells and are abundant between the basal lamina and the peritubular cells. Elastic fi bers are located mainly at the periphery of peritubular cells. Because elastic fi bers appear at puberty, their absence in adults is a sign of tubular immaturity or dysgenesis. 180 The extracellular matrix contains proteoglycans and fi bronectin. In addition, the tubular wall contains capillaries and Leydig cells. These are very similar to the interstitial Leydig cells and are named peritubular Leydig cells.

The most important functions of myofi broblasts are contraction of seminiferous tubules and control of Sertoli cells. 181 Myofi broblasts have α and β adrenergic and muscarinic receptors. 182 Contractility depends on several factors produced in the testis (endothelin-1, vasopressin, oxytocin, and TGF-β) and prostaglandins. Relaxation can be facilitated by the NO/cGMP system because myofi broblasts are also able to synthesize nitric oxide. Sertoli cell control by myofibroblasts is facilitated by the production of P-Mod-S, which activates aromatase activity, inhibin production, and the secretion of androgen-binding protein and transferrin.

The interstitium between the seminiferous tubules contain Leydig cells, macrophages, neuron-like cells, mast cells, blood vessels, lymphatic vessels, and nerves, accounting for 12-20% of testicular volume. 183 

The most numerous connective tissue cells are fi broblasts and myofi broblasts. The former are also known as interstitial dendritic cells or CD34-positive stromal cells. They display a network around the seminiferous tubules and Leydig cells, and also form the outermost layers of the tubular wall. 184 This distribution begins in fetal life. Some of these cells are in contact with typical macrophages, so it has been suggested that they might be involved in immune surveillance. Myofibroblasts, in addition to their presence in the inner layer of the tubular wall, are numerous in the tunica albuginea.

Leydig cells are distributed single or in clusters, and form about 3.8% of testicular volume. Most are in the testicular interstitium, although they may also be found in the tubular tunica propria, mediastinum testis, tunica albuginea, epididymis, and spermatic cord. Extratesticular Leydig cells are usually seen within or near nerve trunks. [185] [186] [187] Leydig cells have spherical eccentric nuclei with one or two eccentric nucleoli and prominent nuclear lamina. The cytoplasm is abundant, eosinophilic, and contains lipid droplets and lipofuscin granules (residual bodies) ( Fig. 12-23 ). Reinke's crystalloids are found only in the Leydig cells of adults and, although it was believed that these crystals were present exclusively in humans, they have also been observed in the wild bush rat. Reinke's crystalloids are up to 20 µm long and 2-3 µm wide, consisting of a complicated meshwork of 5 nm fi laments with a trigonal lattice arrangement. Depending on the plane of section, three basic aspects of this lattice can be discerned. Frequently, the crystalloids display pale lines, con- sidered to be potential planes of cleavage. The fi laments are grouped into 19 nm-wide hexagons visible on cross-section.

In some areas there are aggregates of electron-dense, rodshaped structures. Some Leydig cells contain other types of paracrystalline inclusion, the most common of which consists of multiple parallel-folded laminae. 188 Leydig cells contain abundant well-developed smooth endoplasmic reticulum, pleomorphic mitochondria with tubular cristae, lysosomes, and peroxisomes. Leydig cells react with antibodies to S100 protein and neuron-specifi c enolase. 189 Leydig cells immunoreact to LH receptors, 3-β-hydroxysteroid dehydrogenase (3-β-ΗSD), relaxin-like factor, 190 inhibin, and ghrelin. 191 Relaxin-like factor, also known as insulin-like factor 3 (INSF-3), is a peptide that is involved in testicular descent and can be found in serum. Its concentration is a maker of the Leydig cell functional status. As occurs with testosterone, INSF-3 production is associated with that of LH. 192 Leydig cells immunoreact with calretinin, a 29 kDa calcium-binding protein that has a buffering effect to avoid abnormal increases in intracellular calcium. 193 Calretinin is a more sensitive marker than inhibin, albeit less specifi c ( Fig.  12-24) . 194 Leydig cells also contain VEGF and its two receptors (Flt-1 and KDR), and endothelin and its two receptors (α and β). VEGF and endothelin are involved in paracrine and autocrine control of Leydig cells. Leydig cells near seminiferous tubules show immunoreactivity for glial fi brillar acid protein (GFAP) 195 (Fig. 12-24 ). The demonstration of several substances that are characteristic of nerve cells, such as substance P, neurofi lament triplet proteins (NF-L, NF-M and NF-H), and the ultrastructural observation of microtubules, intermediate fi laments, and clear and dense core vesicles, qualifi es Leydig cells for inclusion within the family of the diffuse endocrine system or paraneurons. 196, 197 Leydig cells of the adult testis originate from fi broblastic precursor cells at puberty under LH stimulation. 198 Experimental studies in rats have shown that adult Leydig cells differentiate from peritubular cells (myofi broblasts and blood capillary pericytes). Precursor Leydig cells are reminiscent of neural stem cells because they express nestin and eventually acquire properties of neurons and glial cells. 199 The human testis contains about 200 million Leydig cells. This number decreases with age: the testes of 60-year-old men contain about half as many as those of 20-year-old men. [202] [203] Mitotic fi gures are seen occasionally in normal Leydig cells. 204 Leydig cells are the target cell of LH, in response to which they produce testosterone and other androgens necessary for the maintenance of spermatogenesis and many structures of the male genital tract, as well as other tissues such as bone, muscle, and skin. [205] [206] [207] [208] Testosterone acts on the Sertoli cells, either directly 209 or via the P-mod-S factor secreted by the myofi broblasts in the tunica propria. [210] [211] [212] Leydig cells also secrete numerous non-steroidal factors, including oxytocin, which acts on myofi broblasts and stimulates seminiferous tubule contraction; β endorphin, which inhibits Sertoli cell proliferation and function; EGF, which regulates spermatogenesis; and other factors with less known actions, such as angiotensin, pro-opiomelanocortin, and α-melanotropic stimulating hormone (Table 12-4) . Together with Sertoli cells, peritubular cells, and endothelial cells, Leydig cells produce nitric oxide, which has a relaxing effect on smooth muscle. 213 Leydig cells are associated with cholinergic and adrenergic nerve fi bers. 186 Varicosities containing synaptic vesicles in the proximity of Leydig cells and nerve endings in direct contact with Leydig cells have been reported, although the functional signifi cance of this innervation is unknown. 214, 215 Macrophages, neuron-like cells, and mast cells Macrophages are a normal component of the testis 216-218 and can be classifi ed into two groups: resident and activated. Resident macrophages are an essential cell type of the testicular interstitium (about 25% of interstitial cells in mouse testis). 219 In young adult men, there is one macrophage per 10-15 Leydig cells, and this number increases with age. Macrophages are closely related to Leydig cells and play a role in proliferation and differentiation of Leydig cell fi broblastic precursors. 220 Interaction between macrophages and Leydig cells is an example of paracrine function. In the rat, testicular macrophages produce 25-hydroxycholesterol (25-HC) and express 25-hydroxylase, which transforms cholesterol into 25-HC. 221,222 Activated macrophages produce interleukins 1 and 6 (IL-1 and IL-6), tumor necrotizing factor-α (TNF-α), and transforming growth factor-α (TGF-α).

Immunohistochemical techniques have demonstrated neuron-like cells in the testicular interstitium. 223 These cells are an important source of intratesticular cate-cholamines, which appear to be increased in some disorders such as the Sertoli cell-only syndrome, and hypospermatogenesis.

Mast cells are a normal component of the testicular interstitium, where they are often found near blood vessels. Their number increases in several diseases. 224

The testis is supplied by the testicular artery, which arises from the abdominal aorta. In the spermatic cord, the testicular artery gives rise to two or three branches that obliquely penetrate the tunica albuginea testis and to multiple branches that run along the intralobular septa of the testis. 225 These centripetal arteries lead to the mediastinum testis. Along their course, the centripetal arteries give off branches that abruptly reverse direction; these are called centrifugal arteries. At puberty, both the centripetal and the centrifugal arteries develop a pronounced spiral architecture. 226,227 The centrifugal arteries develop additional branches in the testicular interstitium, giving rise to arterioles and capillaries that form intertubular plexuses, some of which are apposed to the tunica propria. 228, 229 Capillaries are of the continuous type, except for the seminiferous tubule capillaries, which are partially fenestrated, 230 and their endothelial cells are similar to those of brain capillaries, with scant pinocytosis, intercellular junctions of the fascia adherens type, and low permeability. The mediastinum testis is poorly vascularized.

The inner two-thirds of the testicular parenchyma is drained by veins that follow the interlobular septa to the mediastinum testis (centripetal veins). The outer third is drained by veins that lead to the tunica albuginea (centrifugal veins). Both centripetal and centrifugal veins join to form the pampiniform plexus, which drains the testis via the spermatic cord.

Lymphatic vessels are poorly developed in the testis and limited to the tunica vasculosa and interlobular septa, 231 where they accompany arterioles and venules. Prelymphatic vessels have been reported in the interstitium and probably drain interstitial fl uid into the true interlobular lymphatic vessels.

Efferent innervation of the testis is mainly supplied by neurons of the pelvic ganglia, where contralateral and bilateral neural connections occur. Postganglionic nerve fi bers enter the testis via the pelvic nerves, extend throughout the tunica vasculosa, and follow the interlobular septa to reach the interstitium. These nerve fi bers end in the wall of arterioles, the wall of seminiferous tubules, and the Leydig cells. 232 Adrenergic nerve fi bers innervate the tunica albuginea and the blood vessels of the tunica vasculosa. 233 Peptidergic nerve endings are uncommon. Afferent nerve endings form corpuscles similar to those of Meissner and Pacini in the tunica albuginea.

The rete testis is a network of channels and cavities that connects the seminiferous tubules with the ductuli efferentes. Differences in the confi guration and size of channels and cavities distinguish three portions of the rete testis: septal (intralobular), composed of the tubuli recti; mediastinal, composed of a network of interconnected channels; and extratesticular, composed of dilated cavities (up to 3 mm in diameter) termed the bullae retis.

The tubuli recti are short tubules (0.5-1 mm long) that connect the seminiferous tubules to the mediastinal rete, although some seminiferous tubules may connect directly to the mediastinal rete, principally those in the central region of the testis. The tubuli recti are lined by cuboidal epithelium. There are approximately 1500 tubuli recti (or their analogous seminiferous tubule segments). The tubuli recti in the cranial, central, and anterior testis are perpendicular to the mediastinal rete testis channel into which they drain, and those in the caudal testicular region are parallel to their respective channels. The transitional segments between the seminiferous tubules and the tubuli recti are formed by modifi ed Sertoli cells. 234 The epithelium of the mediastinal rete testis consists of fl attened cells interspersed with small areas of columnar cells. Both cell types have single centrally located cilia and numerous microvilli on their free surfaces, and contain keratin and vimentin fi laments. 235 There are interdigitations between adjacent cells. The epithelium rests on a basal lamina, surrounded by a layer of myofi broblasts and a more peripheral layer of fi broblasts and collagen and elastic fi bers.

The rete channels and cavities are traversed by the chordae rete, columns from 15 µm to 100 µm long and from 5 µm to 40 µm wide, arranged obliquely to the long axis of the cavity. The chordae consist of fi brous connective tissue with fi broblasts and are covered by fl attened epithelium; the widest contain capillaries. The rete testis probably has the following functions: damping differences in pressure between the seminiferous tubules and ductuli efferentes; reabsorption of protein and potassium from tubular fl uid; and, occasionally, phagocytosis of spermatozoa.

Anorchidism refers to the absence of one (monorchidism) or both testes (testicular regression syndrome). Monorchidism is estimated to occur in about 4.5% of cryptorchid testes, 236 40% of the testes that are impalpable in physical examination, 237 or 1 in 5000 males. Bilateral anorchidism occurs in approximately 1 in 20 000 males. 238 Monorchidism The hormonal pattern in prepubertal patients with monorchidism does not differ from that of normal children, whereas children lacking both testes have elevated levels of gonadotropins and fail to respond to stimulation with hCG. [238] [239] [240] Although the hCG stimulation test is often positive in children with bilateral cryptorchidism, it is negative in some children with bilateral intra-abdominal cryptorchidism and this further complicates the differential diagnosis between anorchidism and cryptorchidism. 241 For unknown reasons, the left testis is more frequently absent (68.7%) than the right. In such cases the contralateral scrotal testis undergoes compensatory hypertrophy and its volume increases to more than 2 mL. 242 Compensatory hypertrophy has also been reported in association with abdominal cryptorchid testis. 243 The absence of testicular parenchyma should be confi rmed before diagnosing monorchidism. At exploration, the fi nding of a vas deferens ending near or in a hypoplastic epididymis is not suffi cient for the diagnosis of monorchidism. The only acceptable fi nding is blind-ending spermatic vessels. If inguinoscrotal exploration fails to identify these vessels, intra-abdominal exploration is required to insure against an undescended testis and avoid the development of a testicular tumor. 224 All remnants found at exploration should be removed. 245 Testicular regression syndrome Testicular regression syndrome refers to a variety of conditions, including agonadism, anorchidism, testicular agenesis, rudimentary testes, hypoplastic testes, and embryonal testicular dysgenesis. 246 Each of these syndromes shares a complete absence or involution of both testes 247 but differ in the time of testicular disappearance during development. The most frequently observed are Swyer's syndrome (see discussion on gonadal dysgenesis below), true agonadism, rudimentary testes, bilateral anorchidism, vanishing testes syndrome, and Leydig cell-only syndrome (Table 12-5) . True agonadism (46XY gonadal agenesis syndrome) Patients with true agonadism have ambiguous external genitalia, fusion of the labia, and a short vagina, refl ecting very early testicular regression (between the eighth and 12th weeks of embryonal development). The internal genitalia consist of a uterus and two uterine tubes, although both müllerian and wolffi an derivatives may be absent. No gonads (not even in an ectopic location) are found. Patients are phenotypically girls, and the male gender may be discovered only at the time of referral for other symptoms. 248 Both sporadic and familial cases with associated extragenital anomalies have been reported. In some cases the cause is a heterozygous mutation of WT1. 249 In most familial cases inheritance is either recessive autonomic or X-linked, and the cause seems to be either unknown anomalies in the WT1 gene or known anomalies in other genes involved in development. 250 A SRY molecular defect has never been observed. 251 Agonadism may be associ-ated with several syndromes, including those of PAGOD (hypoplasia of lungs and pulmonary artery, agonadism, omphalocele/diaphragmatic defect, dextrocardia), 252 Kennerknecht, 253 Seckel, 254 and CHARGE. 255 Rudimentary testes syndrome Patients with rudimentary testes have a normal male phenotype. Müllerian remnants are absent and wolffi an derivatives usually are found. The testes are cryptorchid and very small, less than 0.5 cm long. Seminiferous tubules are few ( Fig. 12-25 ). The testicular regression occurs between the 14th and 20th weeks of gestation. This syndrome has been reported in several members of the same family, 256 suggesting genetic transmission, but this is not a constant feature. 257, 258 Congenital bilateral anorchidism Congenital bilateral anorchidism occurs in 1 in 20 000 newborns. The patients have male external genitalia, but the internal genitalia consist only of normal wolffi an derivatives without müllerian derivatives, suggesting that the testes were present and functionally active up to approximately the 20th week of gestation. Patients have male external genitalia with hypoplasia of both the scrotum and penis. The karyotype is the normal male. The disorder may be associated with other malformations, such as anal atresia, rectourethral and rectovaginal fi stula, and urinary exstrophy. Patients diagnosed at adulthood have male phenotype, androgen insuffi ciency symptoms, and elevated levels of both FSH and LH. 259, 260 Familial incidence in some cases suggests SRY gene mutation, but this has not been confi rmed. 261, 262 Vanishing testes syndrome This term refers to the disappearance of one or both testes between the last months of intrauterine life and the beginning of puberty. [263] [264] [265] As testicular regression occurs after the seventh month, exploration fi nds the vas deferens in the inguinal canal or high in the scrotum; it may be accompanied by the epididymis and, less frequently, by testicular remnants consisting of small groups of seminiferous tubules ( Fig. 12-26 ). Patients lacking both testes develop hypergonadotropic hypogonadism after puberty, with gynecomastia, infantile phallus, hypoplastic scrotum, and impalpable prostate. The condition is usually secondary to a perinatal scrotal torsion, 266 although rarely there is a genetic cause. 267, 268 Leydig cell-only syndrome Patients with Leydig cell-only syndrome have agonadism without eunuchoidism and a normal male phenotype, although meticulous surgical exploration fails to fi nd testicular remnants. Study of serial sections from the spermatic cord reveals clusters of Leydig cells. 269 Detection of testosterone in spermatic vein blood indicates that these ectopic Leydig cells are functionally active and synthesize testosterone in amounts suffi cient to induce a rudimentary male phenotype but insuffi cient to support the complete development of secondary sex characteristics.

The morphology of spermatic cord remnants is similar in monorchidism and testicular regression syndrome occurring after the 20th week of gestation. [270] [271] [272] Grossly, a small, fi rm mass is found at the end of the cord ( Fig. 12-27 ). Histologic examination reveals vas deferens, epididymis, or small groups of seminiferous tubules in 69-83% of cases. 273 Vas deferens is the most constant fi nding (79%), followed by epididymis (36%) and seminiferous tubules (5-13%). The spermatic vessels are abnormally small in 83% of cases. 245, 274 Areas of dystrophic calcifi cation, hemosiderin deposition, and giant cell reaction may be found within the mass in place of the testis. Other fi ndings include arterial and venous vessels (88%), fat (44%), and nerves that may resemble traumatic neuroma (56%). The minimal requirement to diagnose vanishing testis is to fi nd either a vascularized fi brous nodule with calcifi cation or hemosiderin, or a fi brous nodule with cord elements. 275 It has been proposed that removal of the testicular nubbin in this syndrome may not be required because the percentage of seminiferous tubules is very low and the presence of germ cells low, and thus the probability of a tumor is minimal. 276, 277 The general recommendation is scrotal exploration as a fi rst step, reserving laparoscopy for cases in which either the atrophic remnant cannot be identifi ed during scrotal exploration or has a patent vaginal process. 266 

The histologic fi ndings suggest that most cases of unilateral and bilateral anorchidism are produced during the fetal period after the testis has inhibited the müllerian ducts and induced differentiation of wolffi an duct derivatives. Two hypotheses account for the disappearance of the testes: primary anomaly of the gonad; and atrophy secondary to a vascular lesion such as thrombosis or intrauterine torsion. The presence of macrophages with hemosiderin and dystrophic calcifi cation supports the latter. Absence of one testis may be associated with malformations of the urogenital system, such as absence of the kidney, cystic seminal vesicles, and ipsilateral renal dysgenesis. 278, 279 

This clinical term refers to diverse conditions (Klinefelter's syndrome, hypogonadotropic hypogonadism, rudimentary testes syndrome, bilateral cryptorchidism, etc.) that share small testicular size. 280, 281 A peculiar case is presented by some patients with Kenny-Caffey syndrome: short stature, cortical thickening and medullary stenosis of long bones, delayed closure of anterior fontanelles, hypoparathyroidism, and several ocular alterations. FSH serum levels are elevated, but only in some cases, whereas LH and testosterone are normal. Adult testes are small, with seminiferous tubules showing complete but diminished spermatogenesis. Leydig are hyperplastic. Unlike patients with the rudimentary testes syndrome, microorchidism patients have a normal-sized penis and no epididymal or prostatic atrophy. 282

Polyorchidism is a rare condition, with approximately 100 reported cases. 283, 284 It was fi rst described in a postmortem study in 1880, 285 and the fi rst case treated surgically and confi rmed histologically was reported in 1895. 286 Although three testes are the most common, 287 four testes have been reported in six patients, [288] [289] [290] [291] [292] and fi ve in one case but without histologic confi rmation. 293 Age of diagnosis varies from newborn to 74 years, with a mean of 17 years. Testicular duplication is usually an incidental fi nding during surgery for inguinal hernia, cryptorchidism, or testicular torsion, but has also been detected in patients with infertility or unexplained fertility after bilateral vasectomy. 294 The extra testis is often intrascrotal (75%) and less frequently inguinal (20%), abdominal, 295 or retroperitoneal (5%). 296, 297 Duplication is three times more frequent on the left than on the right. 298 High-resolution ultrasound is the appropriate diagnostic technique. 284, 299 Testicular maldescent (40%), inguinal hernia (30%), hydrocele, varicocele, and contralateral cryptorchidism are the most frequently associated anomalies. [300] [301] [302] Testicular torsion (13%) 303 and testicular cancer (5.4%) are occasional complications. Although the extra testis may be histologically normal, 304-306 usually it is not, 300, 307 and displays lesions such as Sertoli cell-only tubules, hypospermatogenesis, or maturation arrest. The lack of spermatogenesis has been attributed to the anomalous location of the testis and the absence of communication between the testis and excretory ducts. 308 The embryologic origin of polyorchidism remains uncertain, and the following have been proposed to account for the variety of fi ndings in different cases ( Fig. 12-28 The clinical differential diagnosis of polyorchidism includes most of pathologic conditions that enlarge the scrotum and spermatic cords: spermatocele, hydrocele, cysts and tumors of the spermatic cord, crossed testicular ectopia, adrenal cortical ectopia, and splenogonadal fusion. Orchidectomy used to be the treatment of choice for all atrophic and non-scrotal testes. Today, most surgeons undertake fi xation of the testis to the scrotal pouch and the re-creation of a 'simple testis' if it is permitted by the anatomical condition and malignancy has been precluded. This treatment may allow spermatogenesis as well as additional psychologic and cosmetic benefi ts. 313 Intrascrotal rhabdomyosarcoma, testicular teratoma, and seminoma have been reported in patients with polyorchidism. 314, 315 

Macro-orchidism may be uni-or bilateral and be associated with chromosomal anomalies or endocrine alterations. An increase in the testicular parenchyma occurs in several conditions, 316 including congenital Leydig cell hyperplasia, compensatory hypertrophy, benign idiopathic macroorchidism, bilateral megalotestes with low gonadotropins, fragile X chromosome, and the testicular hypertrophy observed in juvenile hypothyroidism.

Congenital Leydig cell hyperplasia is uncommon and may be diffuse or nodular. The diagnosis of diffuse Leydig cell hyperplasia requires quantifi cation of Leydig cells by morphometry, using normal newborn testes as controls ( Fig.  12-29 ). Nodular Leydig cell hyperplasia is characterized by the presence of non-encapsulated Leydig cell nodules in the mediastinum testis, adjacent testicular parenchyma and connective tissue among the ductuli efferentes ( Fig. 12-30) .

The differential diagnosis of nodular Leydig cell hyperplasia includes intratesticular adrenal rests and bilateral Leydig cell tumor. Except for patients with adrenogenital syndrome, intratesticular adrenal rests are rare. These rests are encapsulated, with the exception of the adrenogenital tumors, and consist of radially arranged cells with vesicular nuclei and small nucleoli displacing the rete testis or seminiferous tubules. Leydig cell tumors may be bilateral, poorly circumscribed, and surrounded by testicular parenchyma, features making it diffi cult to distinguish from Leydig cell hyper-plasia. However, Leydig cell tumors are rarely congenital, whereas those occurring at infancy often induce precocious maturation of the adjacent seminiferous tubules and early macrogenitosomia.

Leydig cell hyperplasia is caused by large quantities of hCG entering the fetal circulation. Diabetic mothers, particularly those with hypertension, may develop hyperplacentosis; the resulting edema in the placental villi alters the vascular permeability and allows the passage of hCG to the fetus. Congenital Leydig cell hyperplasia decreases rapidly during the fi rst months of postnatal life, after maternal human chorionic gonadotropin is gone. Combined diffuse and nodular Leydig cell hyperplasia occurs in several malformative syndromes, such as Beckwith-Wiederman, leprechaunism, triploid fetuses, fetuses with Rh isoimmunization, 317 and in several complications of pregnancy.

Compensatory hypertrophy has been observed in monorchidism, 318 cryptorchidism 319 ( Fig. 12-31) , varicocele, 320 and after testicular injury. Hypertrophy persists and may increase during childhood and puberty, but ceases thereafter; the hypertrophied testis then becomes normal or remains slightly enlarged. 321, 322 The degree of hypertrophy is determined by three factors: the volume of the remaining testicular parenchyma, the age at which the injury occurred, and the functional ability of the descended testis. 323 Compensatory hypertrophy results from an alteration in the hypophyseal hormonal feedback mechanism, followed by an increase in secretion of FSH, evidence that the contralateral testis is normal. In monorchidism, the testis is initially normal. 237 When a 50% reduction of testicular mass occurs (probably before birth), the endocrine feedback changes and the resulting secretion of FSH (before or immediately after birth) causes accelerated growth of the contralateral testis. In cryptorchidism, the reduction in testicular mass is less severe than in monorchidism, and the scrotal testis may also be abnormal, inducing a lesser compensatory hypertrophy. Compen- satory hypertrophy develops between birth and 3 years of age, and the testis may reach a volume twice normal when the other testis is absent. 243

Some prepubertal and pubertal patients have pronounced unilateral 324 or bilateral [325] [326] [327] testicular hypertrophy in the absence of other pathologic fi ndings. This probably results from hormonal receptivity in the testicular parenchyma. Morphometric studies have shown that the testicular enlargement is chiefl y due to an increase in the length of the seminiferous tubules, although increases in tubular diameter and Sertoli cell numbers have also been observed. Elevated FSH serum levels, reported in some cases, or hyperactive FSH receptors might be the cause of the excessive Sertoli cell proliferation and the lengthening and thickening of seminiferous tubules. [328] [329] [330] In addition, Leydig cell hyperplasia and defi cient spermatogenesis are frequent fi ndings in adult life. As the development of the two testes may be asynchronous during puberty, some unilateral macroorchidisms may represent cases in which these differences are unusually exaggerated.

About 2% of adults with fertility problems have enlarged testes, with volumes over 25 mL, and low levels of FSH, LH, testosterone, prolactin, and estradiol. 331 Despite the important hormonal changes, sperm concentrations and total numbers of spermatozoa are higher than normal. Low FSH levels may be attributable to increased inhibin secretion because the number of Sertoli cells is elevated in these testes, but no explanation for the reduction in the other hormone levels has been found.

Fragile X chromosome is the best-known form of inherited mental retardation, with an incidence of 1 in 1500 males and 1 in 2500 females. 332 In addition to facial dysmorphia (large ears, prognathism, high forehead, and arched palate), macroorchidism (Martin-Bell syndrome) is often an associated fi nding. [333] [334] [335] [336] [337] The impaired gene (FMR1 gene) is mapped to Xq27,3 which is genetically fragile. The gene alteration is due to a lengthening of a trinucleotide CGG repeat that results in FMR1 gene silencing. If the CGG sequence is repeated fewer than 200 times, the disorder is considered a premutation and males show no symptoms; if the number of repetitions exceeds 200, mutation is complete and all show the disorder. [338] [339] [340] In men with this syndrome, the average testicular volume is more than 70 mL (four times greater than normal). The penis also is larger than normal, and both anomalies are apparent in infancy. The scrotum is also enlarged and prematurely pigmented. This precocious genital development is diffi cult to explain because the hypothalamopituitary axis is normal, but it may be caused by increased sensitivity to stimulation by FSH. 341 Testicular biopsies from adults may be normal or show interstitial edema and hypospermatogenesis ( Fig. 12-32) . Usually, there is normal testicular parenchyma with focal reduced spermatogenesis and Sertoli cell hyperplasia ( Fig.  12 -33) or tubules containing only immature Sertoli cells. Morphometry indicates that testicular enlargement is chiefl y the result of lengthening of seminiferous tubules. 328 The low number of spermatids is attributed to atrophy caused by compression of the seminiferous epithelium by marked increase in intratubular fl uid. 342 Meiotic anomalies have been excluded. 343 The fragile X syndrome is second in frequency only to Down's syndrome as a cause of mental retardation. [344] [345] [346] However, this chromosomal anomaly is not always associated with mental retardation or macroorchidism, and there are men with fragile X syndrome who are otherwise normal. 347 The terms 'fragile X-negative Martin-Bell syndrome' or 'mental retardation-macro-orchidism' refer to X-linked (MRMO) or XLMR+MO patients who have the Martin-Bell syndrome phenotype but do not present the fragile X site. The gene responsible for this disorder is mapped to Xq12-q21. 348 starts. 353, 358, 359 The etiopathogenesis has been explained by three hypotheses: an increase in gonadotropin secretion caused by TRH stimulation of gonadotropic cells; 360,361 a direct TSH effect on the testis due to the structural similarity between TSH receptors and FSH receptors present in the testis; 362 and a lack of steroid hormones that are required for testicular maturation (in their absence, Sertoli cell proliferation is excessive, giving rise to testicular enlargement). [363] [364] [365] [366] Precocious puberty Precocious puberty is defi ned by onset of secondary sex characteristics at a chronologic age that is below the mean middle age for the population. For practical purposes, this is considered to be before 8 years of age in girls and 9 years in boys. The incidence is estimated at between 1 in 5000 and 1 in 10 000, with a female:male ratio higher than 20 : 1. In boys, the fi rst symptom is rapid testicular enlargement followed by growth of pubic and axillary hair, enlargement of the penis, and acceleration of skeletal growth. 367 According to hypothalamopituitary-gonadal axis function, precocious puberty can be classifi ed into three groups: central or gonadotropin-dependent, which results from the activation of this axis; peripheral or gonadotropinindependent, mediated by sex steroid hormones secreted by the testis or adrenal glands; and a mixed group that fi rst appears as peripheral precocious puberty and thereafter, because of the secondary response of the hypothalamus, becomes gonadotropin dependent.

Other possible causes of precocious puberty are hypoprolactinemia, pituitary tumor, and alteration of testicular steroid metabolism. Central precocious puberty (CPP) Central precocious puberty, also known as true precocious puberty, is isosexual. It is the most common form of precocious puberty in girls and accounts for more than 50% of cases in boys. The age of presentation is between 4 and 10 years. 368 The cause is only known in 60% of cases; most are related to lesions in the central nervous system, whereas the others are usually idiopathic.

Lesions in the central nervous system that causes CPP share alterations of specifi c areas, including the posterior hypothalamus (eminencia media and tuber cinereum), mammillary bodies, the bottom of the third ventricle, or the pineal gland. 369 

Testicular hypertrophy appears associated with FSH-secreting pituitary adenoma, 349 hyperprolactinemia, hypoprolactinemia, and hypothyroidism. 350, 351 The most frequent association of testicular hypertrophy is with hypothyroidism. Children with hypothyroidism often show testicular enlargement without virilization. 350 About 80% have macroorchidism, 352 most have elevated FSH levels, and half have increased LH levels. 353, 354 Testosterone levels are normal during infancy. The response of FSH and LH to GnRH is altered and no pulsatile LH release occurs ( Fig. 12-34 ). 355 Testicular biopsies before puberty show an accelerated development of the testis with pubertal maturation of seminiferous tubules but not Leydig cells. Testicular biopsies in untreated adults show tubular and interstitial hyalinization with few Leydig cells. 356, 357 Testicular size in this type of macroorchidism diminishes as soon as the substitutive therapy • Hereditary diseases as neurofi bromatosis and tuberous sclerosis. Children with type I neurofi bromatosis often have also optic pathway tumors. • Cerebral irradiation, as occurs in hypothalamopituitary selective irradiation, 378 prophylactic irradiation in children with acute lymphoblastic leukemia, 379 and irradiation of cerebral tumor that is far from the hypothalamopituitary region.

The diagnosis of central precocious puberty is easy if the hormonal fi ndings show elevated gonadotropin levels (both basal values and in response to GnRH), associated with high testosterone levels and an increase in either LH/FSH ratio or in LH and FSH values after stimulation with GnRH agonists. However, in some cases it is necessary to measure nocturnal LH secretion to fi nd secretion pulses before a dynamic test can reveal the pubertal pattern.

Knowledge of the etiology in males has improved with the use of CT and MRI. 380, 381 One of the most important contributions of these techniques is the fi nding of a high number of hamartomas in children with precocious puberty. [382] [383] [384] These lesions, also known as gangliocytomas, consist of abnormally located neurons and glial cells. Lesions are usually multiple, small, and located on the hypothalamus between the anterior part of the mammillary body and the posterior part of the tuber cinereum. These neurons contain LHRH-positive neurosecretory granules, suggesting that this hormone can be released into the blood draining the hypophyseal portal system and reach the gonadotropic cells. 385 Precocious puberty owing to cerebral tumors usually occurs with advanced stage of the tumor, preceded by cerebral symptoms such as hydrocephaly, papillary edema, or psychic alterations. The same occurs when precocious puberty results from cerebral infl ammation or cerebral malformation.

Although pineal gland tumor is rare in children, 30% produce precocious puberty, principally in boys. This tumor is usually a teratoma or non-parenchymatous tumor that destroys the pineal gland, hindering its antigonadotropic action and initiating puberty. 386 In contrast, pinealocytederived tumor secretes great amounts of melatonin that delay the onset of puberty. Peripheral precocious puberty (PPP) Peripheral precocious puberty is also known as precocious pseudopuberty. It may be caused by a primary testicular disorder, a lesion in other endocrine glands, or hormonal treatment. Primary testicular disorders causing precocious pseudopuberty include familial testotoxicosis, functioning testicular tumor, excessive aromatase activity, or Leydig cell hyperplasia with focal spermatogenesis. The principal secondary anomalies include adrenal cortical anomaly (congenital adrenal hyperplasia, virilizing tumor of the adrenal, and Nelson's syndrome), and lesion secondary to hCG-secreting tumor (hepatoblastoma accounts for half of precocious pseudopuberty cases, and testicular germ cell tumor and the tumors of the retroperitoneum, mediastinum, and pineal gland are responsible for the other half of cases). 387 Familial testotoxicosis: gonadotropin-independent precocious puberty (GIPP) or familial male-limited precocious puberty (FMPP) Familial testotoxicosis is a form of male sexual precocity characterized by early differentiation of Leydig cells and the initiation of spermatogenesis in the absence of stimulation by pituitary gonadotropin. This is a primary testicular abnormality with autosomal dominant inheritance. 388, 389 Ultrastructural studies confi rm an adult Leydig cell pattern and complete spermatogenesis, although many spermatids are abnormal. 390 The cause of familial testotoxicosis is a constitutive activating mutation of the LH receptor gene. 391 This gene comprises 11 exons and has been mapped to 2p21. Hormonal measurements show elevated serum levels of testosterone, and low levels of dihydroepiandrosterone sulfate, androstenedione, 17-hydroxyprogesterone, gonadotropin-releasing hormone (GRH), and LH, as well as absence of a pulsatile pattern. In addition, serum levels of inhibin B appear elevated before the normal age of onset of puberty. 392 In some patients, a mutation in LH receptor induces Leydig cell adenoma. 393 Precocious puberty secondary to functioning testicular tumor A syndrome of precocious puberty can be the result of different tumors, including Leydig cell tumor, sex cord tumor, adrenal cortex virilizing carcinoma, and extratesticular hCG-secreting germ cell tumor.

Leydig cell tumor may cause precocious puberty. The testis is enlarged owing to tumor growth and maturation of the seminiferous tubules adjacent to the tumor; such maturation results from androgen secretion by tumor cells (Fig. 12-35) . In most cases, the contralateral testis is not enlarged. 394, 395 Sex cord tumor with annular tubules and large cell calcifying Sertoli cell tumor may give rise to precocious pseudopuberty that is isosexual (development of musculature and axillary and pubic hair) and heterosexual (gynecomastia). This precocious testicular maturation and the development of the tumor itself cause testicular enlargement. It has been suggested that tumor cells stimulate Leydig cells to produce androgens that are aromatized to estrogens by the tumor cells themselves, thus accounting for the clinical symptoms. These tumors are frequently observed in Peutz-Jeghers syndrome 396,397 and Carney's complex. 398 Most infants with adrenal cortex virilizing tumors have small testes, but some cases of testicular hypertrophy have also been observed. 399 Testicular development in these cases is attributed to adrenal androgenic action on seminiferous tubules. 400 In untreated (or maltreated) congenital adrenal hyperplasia, both testes can be enlarged because they contain growing masses of adrenal cortex-like cells. 401 A similar condition is observed in Nelson's syndrome.

Testicular enlargement is modest in paraneoplastic precocious pseudopuberty secondary to hepatoblastoma 402 or extratesticular hCG-secreting germ cell tumor, although nodular or diffuse precocious maturation has been occasionally reported. 403 Precocious pseudopuberty secondary to excessive aromatase activity Biosynthesis of C18 estrogens from C19 androgens occurs by three consecutive oxidative reactions that are catalyzed by an enzymatic complex known as estrogen synthetase or aromatase. 404 This complex has two components: P450 arom (a product from the CYP19 gene located on 15p21.1), 405 which joins C19 substrate and catalyzes the insertion of oxygen in C19 to form C18 estrogens; and NADPH-cytochrome P450 reductase, a ubiquitous fl avoprotein that conveys reducing equivalents to any form of cytochrome P450 it meets.

Aromatase is in the endoplasmic reticulum of estrogensynthesizing cells and expressed in placenta, ovarian granulosa, Sertoli cells, Leydig cells, adipose tissue, and several central nervous system regions, including the hypothalamus, amygdala, and hippocampus. Excessive aromatase causes excessive conversion of androgens to estrogen, 406 and is a heterogeneous genetic disorder with an autosomal dominant inheritance. The disorder leads to heterosexual precocious pseudopuberty with gynecomastia in males, and to isosexual precocity and macromastia in females. Ultimately, patient stature is short because of the potent ability of androgens to accelerate epiphyseal closure. Most males are fertile and have normal libido. 407 Generally, the inhibitory estrogenic effect on testicular function is less than that observed with estrogen-producing tumors or in patients treated with exogen estrogens.

Excessive aromatase caused by P450 mutation induces alterations in both males and females. In females lacking estrogens owing to desmolase defi ciency, excessive aromatase leads to pseudohermaphroditism and progressive virilization at puberty; conversely, pubertal development is normal in males. In children, FSH and LH levels and gonadotropin response to GnRH are normal, suggesting that the role of estrogens in pituitary regulation is weak during infancy. 408 In both genders, epiphyseal closure is delayed and a eunuchoid habitus results. Adult males have small testes, severe oligozoospermia, and complete asthenozoospermia; FSH and LH levels are high, testosterone levels are normal, and serum estrogen levels are very low.

All patients with excessive aromatase have short stature, with continuing linear growth into adulthood, unfused epiphyses, osteoporosis, bilateral genu valgum, and eunuchoid proportions. The testes show macroorchidism with normal testicular consistency in some cases, 409 and are small with severe oligozoospermia and 100% immotile spermatozoa in other cases. 410 A syndrome similar to that of excessive aromatase production is found in patients with estrogen resistance caused by disruptive mutations of the ER gene. These patients show macroorchidism, elevated testosterone levels, and increased levels of FSH, LH, estradiol, and estrona. 411 Precocious pseudopuberty secondary to Leydig cell hyperplasia with focal spermatogenesis This entity can present with clinical symptoms similar to those of a functioning Leydig cell tumor; this is a precocious pseudopuberty with ipsilateral testicular enlargement. 412 The testes contains hypertrophic Leydig cell nests in association with normal spermatogenesis. No tumoral mass is seen. Leydig cells do not contain Reinke's crystalloids and do not compress the seminiferous tubules. There is a clear delimitation between tubules with spermatogenesis and infantile immature tubules. The differential diagnosis between this entity and Leydig cell tumor with precocious pseudopuberty is based on the histological pattern. Open excisional testicular biopsy is recommended; if there is Leydig cell tumor, or the diagnosis by frozen section is not conclusive, removal is advisable. 413 There are no data to suggest that this hyperplasia might develop into Leydig cell tumor. Mixed precocious puberty The best known form is the McCune-Albright syndrome (MAS), characterized by the association of 'coffee and milk' pigmentary lesions in the skin, bone lesions (polyostotic fi brous dysplasia), enlarged testes, prepubertal size of the penis, and absence of pubic and axillary hair. Although testicular enlargement is usually bilateral, unilateral macroorchidism may be the fi rst symptom. 414 An interesting fi nding is that the onset of testicular maturation is induced by the testis itself, which produces steroid secretion due to autonomous hyperfunction of Sertoli cells without evidence of Leydig cell involvement. 415 This secretion causes early maturation of the hypothalamopituitary-testicular axis and, subsequently, true precocious puberty. 416 Serum levels of testosterone are low, but those of inhibin B and AMH are abnormally increased. This syndrome is caused by mutations that activate the GNAS-1 gene, which encodes the α subunit of the trimeric G-protein.

Because mutations are lethal in the uterus, those subjects producing AMH bear a mosaicism chromosomal constitution for this defi ciency.

A testis is ectopic when it is in a location outside the normal path of descent. Unlike cryptorchid testes, ectopic testes are nearly normal in size and are accompanied by a spermatic cord that is normal or even longer than normal, and by a normal scrotum. 417 Testicular ectopia is classifi ed according to location; [418] [419] [420] [421] [422] in decreasing order of frequency, the major types are:

• Interstitial or inguinal superfi cial ectopia. This is the most frequent form and may be confused with inguinal cryptorchidism. After passing through the outer genital opening, the testis ascends to the anterosuperior iliac spine and remains on the aponeurosis of the major oblique muscle. These testes often are more nearly normal histologically than are cryptorchid testes. • Femoral or crural ectopia. After passing through the inguinal canal, the testis lodges in the high crural cone in Scarpa's triangle. • Perineal. The testis is located between the raphe and the genitocrural fold. • Transverse or crossed ectopia. Both testes descend through the same inguinal canal and lodge in the same scrotal pouch. Each possesses its own vascular supply, epididymis, and vas deferens. In addition, there is ipsilateral hernia. [423] [424] [425] [426] [427] [428] [429] [430] Between 20% and 40% of patients with this ectopia have persistent müllerian duct syndrome [431] [432] and show a high incidence of testicular germ cell tumor. 433 • Pubopenile ectopia. The ectopic testis is on the back of the penis near the symphysis pubis. 434 • Pelvic ectopia. The testis is in the pelvis, usually in the depth of Douglas' cul-de-sac. • Other unusual testicular ectopias include retroumbilical, craniolateral to the inner inguinal opening between the outer and inner oblique muscles, and subumbilical. 435 Rarely, the testis and its spermatic cord may protrude through a defect in the scrotal skin, a condition called testicular exstrophy. 436 The term testicular dislocation refers to testes that secondarily disappear from the scrotum and lodge around the superfi cial inguinal ring, within the inguinal ring, or inside the abdominal cavity as a result of testicular trauma. The formation of canalicular and intra-abdominal dislocation requires the presence of previous inguinal hernia. 437 

Testicular fusion is a rare anomaly characterized by fusion of the testes to form a single structure, usually in the midline. Each has its own epididymis and vas deferens. This anomaly is often associated with other malformations, such as fusion of the adrenal glands or horseshoe kidney.

Cystic dysplasia of the testis is a congenital lesion characterized by cystic transformation of an excessively developed rete testis that may extend to the tunica albuginea of the opposite pole. 438 To date, fewer than 40 cases have been reported. 439, 440 The seminiferous tubules may be dilated and atrophic; this is more evident after puberty. Ultrasound images are characteristic. 441, 442 Cysts arise in the septal and mediastinal rete testis ( Fig. 12 -36); they are interconnected and contain acellular, eosinophilic, periodic acid-Schiffpositive material. They are lined by cuboidal cells that resemble those of the normal rete testis. [443] [444] [445] The connective tissue between the cysts is scant and histologically similar to the interstitial connective tissue. There may be small groups of cysts limited to the region of the mediastinum testis, or cysts extending throughout the entire testis. In extensive cases, residual seminiferous tubules occupy only a small crescent beneath the tunica albuginea and the testis is grossly spongy. Cystic dysplasia occurs in normally descended and cryptorchid testes in children and adults, and may affect one or both testes. 446 In adults, the residual parenchyma often shows complete tubular sclerosis or hypospermatogenesis with intratubular accumulation of spermatozoa and Leydig cell pseudohyperplasia.

In most cases the epididymis is altered. 447 The head of the epididymis is small and contains few ductuli efferentes with irregular, usually dilated lumina. The ductus epididymidis is dilated, has an atrophic epithelium, and thick connective tissue replaces the muscular layer ( Fig. 12-37) .

Testicular cystic dysplasia is frequently associated with severe anomalies of the urinary system. Renal agenesis, [446] [447] [448] [449] renal dysplasia, 446 hydroureter, and urethral stenosis 450 have been reported ipsilateral to cystic dysplasia. The clinical differential diagnosis should consider all cystic testicular lesions impairing prepubertal testes, including epidermoid cyst, cystic teratoma, juvenile granulosa cell tumor, testicular lymphangiectasis, and simple cyst of the testis. 451 The presence of ipsilateral renal anomalies during ultrasound exploration provides an important diagnostic clue. 452 Previously, orchidectomy was the treatment of choice, but testis-sparing surgery 453 is now recommended. 454, 455 The etiology and pathogenesis of cystic dysplasia are uncertain. Given that the rete testis is a mesonephric derivative and most of the associated renal malformations are apparently caused by failure in the induction of renal blastema by the mesonephros, cystic dysplasia is considered to be the result of an abnormal mesonephros.

During childhood, the normal rete testis has no lumina, and these form during puberty. The adult rete testis is a conduit for the passage of tubular fl uid and spermatozoa and also actively reabsorbs part of this fl uid while adding ions, proteins and steroids to it. Malfunction of the rete testis cells may cause the formation of excessive fl uid of abnormal composition, resulting in a condition morphologically similar to cystic dysplasia of the rete testis induced in fowl by sodium intoxication or the administration of the saltretaining hormone deoxycorticosterone acetate.

Gonadoblastoid testicular dysplasia refers to an abnormally differentiated testicular parenchyma beneath the tunica albuginea. 456 The anomaly consists of large tubular or nodular structures within a dense stroma, reminiscent of ovarian stroma ( Fig. 12-38 ). Each structure is composed of three cell types: cells with vesicular nuclei and vacuolated cytoplasm; cells with hyperchromatic nuclei; and germ cell-like cells. The former two types are arranged at the periphery, forming a pseudostratifi ed epithelium. The third type resembles fetal spermatogonia and are fewer in number. These structures contain eosinophilic, periodic acid-Schiff-positive material, similar to Call-Exner bodies ( Fig. 12-39 ). There may be continuity between these structures and normal seminiferous tubules. The differential diagnosis includes conditions showing anomalous seminiferous tubules at the gonadal periphery, including testicular dysgenesis and gonadoblastoma. Testicular dysgenesis also presents tubular or cord-like structures, but these are differentiated (some form true seminiferous tubules) and may also be present within a poorly collagenized tunica albuginea; patients with testicular dysgenesis are male pseudohermaphrodites with müllerian remnants. Gonadoblastoma usually appears in a streak gonad or dysgenetic gonad and contains granulosa-Sertoli cells and germ cells that are similar to those of dysgerminoma or seminoma; these cells are absent in gonadoblastoid testicular dysplasia. Several cases with this disorder have been reported in patients with Walker-Warburg syndrome. 457, 458 

This disorder refers to the presence, in an adult testis, of one or several foci of infantile (immature) seminiferous tubules. Each group of tubules appears well delimited but unencapsulated. Nodule size varies from microscopic to 5 mm. On section, each nodule is distinguished by its whitish color. Sertoli cell nodule is found in most adult cryptorchid testes, regardless of when the testes descended. It is also present in 22% of normal scrotal testes in some series, 459 and is an occasional fi nding in males with idiopathic infertility.

The seminiferous tubules have a prepubertal diameter and may be anastomotic. The epithelium is columnar or pseudostratifi ed, devoid of lumina, and usually consists only of Sertoli cells ( Fig. 12-40 ). The cells have elongated hyperchromatic nuclei with one or several peripherally placed small nucleoli. 459 The interstitium varies from scant to well collagenized. Leydig cells are usually absent in these areas and, if present, their numbers are low. Study of serial sections reveals continuity between some of these tubules and normal tubules. Sertoli cell nodule changes with advancing age. The Sertoli cells produce large amounts of basal lamina that protrudes inside the hypoplastic tubules. In transverse and oblique sections, these protrusions might be misinterpreted as intratubular accumulations of basal lamina material ( Fig. 12-41 ). This material can undergo calcifi cation to form microliths. Immunohistochemical study reveals two basic components of the basal lamina (collagen IV and laminin), confi rming its extracellular origin; the protrusions consist mainly of laminin, whereas collagen IV delimits the outer profi le of the seminiferous tubules. So, while the amount of collagen IV is uniform around the tubules, the depth of laminin varies within the same tubule.

Tubular hypoplasia is assumed to be a primary testicular lesion, and refers to the presence of seminiferous tubules that are unable to undergo pubertal development despite the same hormonal stimuli of adjacent normal tubules. This dysgenesis includes immature Sertoli cell pattern, low inhibin secretion, absence of androgen receptors, 460 and lack of maturation of peritubular myoid cells that fail to synthesize elastic fi bers. The presence of hypoplastic zones in a testicular biopsy is an adverse prognostic sign for fertility.

The differential diagnosis includes tubular hamartoma in androgen insensitivity syndrome, sex cord tumor with annular tubules, and mixed atrophy of the testis. Tubular hamartoma in androgen insensitivity syndrome is multiple, similar to the hypoplastic zones of tubular hypoplasia; however, the Sertoli-like cells of hamartoma have spherical nuclei (rather of elongated nuclei), form a cuboidal epithelium, and contain numerous Leydig cells among the tubules (see Androgen insensitivity syndrome, below). Sex cord tumor with annular tubules may present with multiple foci of intratubular neoplasia, similar in distribution to that of hypoplastic zones; however, sex cord tumor appears in undescended testes, and in patients with Peutz-Jeghers syndrome, and consists of cuboidal or spherical cells that express cytokeratins that are not expressed in hypoplastic tubules.

It is possible that hypoplastic tubules contain some germ cells that may be spermatogonia or gonocytes. There are scant spermatogonia that fail to display signs of maturation or proliferation. Also, some of the tubules contain intratubular undifferentiated germ cell neoplasia that usually also appears in the adjacent, non-hypoplastic seminiferous tubules. The histologic picture is similar to that of gonadoblastoma, but such a tumor can be easily excluded because it arises in malformed gonads (gonadal dysgenesis and testicular dysgenesis) characteristic of intersex stages, unlike patients with tubular hypoplasia.

Congenital testicular lymphangiectasis is characterized by abnormal and excessive development of lymphatic vessels in the tunica albuginea, mediastinum testis, interlobular septa, and testicular interstitium. [461] [462] [463] Ultrastructurally these dilated vessels are similar to normal lymphatic capillaries, although some are markedly dilated and the testicular interstitium is slightly edematous ( Fig. 12-42 ). Testicular lymphangiectasis occurs in both cryptorchid and scrotal testes; in one of the latter cases, the patient had Noonan's syndrome. The disease does not seem to affect the seminiferous tubules, and low numbers of spermatogonia and reduced tubular diameters are observed only in cryptorchid testes. The epididymis and spermatic cord are not affected, and congenital testicular lymphangiectasis is not associated with pulmonary, intestinal, or systemic lymphangiectasis. During fetal life, lymphatic vessels are visible only immediately beneath the tunica albuginea and in the interlobular septa. 464 During childhood, the number and size of the septal lymphatic vessels decreases; 465 by adulthood they are inconspicuous. 466 In lymphangiectasis, the septal lymphatic vessels are large and often massively dilated. Testicular lymphangiectasis occurs only in the childhood testis, suggesting that these dilated vessels undergo involution at puberty or that pubertal development of the seminiferous tubules masks the lymphangiectasis. One exceptional case of epididymal lymphangiectasis, with dilated epididymal blood vessels, was reported in a 59-year-old man. 467 The vessels distort the architecture of the ductuli efferentes, which in turn become irregularly dilated by mechanical compression.

Other hamartomas of the testis include hamartoma of the rete testis and smooth muscle hamartoma. Hamartoma of the rete testis is a disordered proliferation of tubular structures in a loose connective tissue. 468 Cystic transformation of the rete testis associated with proliferation of smooth muscle cells and abundant myxoid stroma was reported in a 26-year-old man. 469 Smooth muscle hamartoma is located in the inferior testicular pole, the cauda of the epididymis, and the proximal segment of the vas deferens ( Fig. 12-43) , 470 and is similar to that reported in the digestive and respiratory tracts. 471, 472 Smooth muscle hyperplasia also occurs in the androgen insensitivity syndrome, forming nodules up to 1 cm in diameter. The muscular proliferation is located in the lower testicular pole, and involves the tunica albuginea and adjacent soft tissues.

This infrequent fi nding has been observed in newborns and consists of gonadal blastema in otherwise normal testes. The blastema is located in the vicinity of the upper testicular pole, near the implantation of the caput of the epididymis, displays a crescent shape, and extends throughout the depth of the tunica albuginea and the adjacent testicular parenchyma.

The blastema consists of epithelial cords of cells or solid masses in continuity with the mesothelium (Fig. 12-44 ). These cells are intermingled with others that are larger, with pale cytoplasm, vesicular nuclei, and prominent nucleoli. The blastematous epithelial cells display immunoreactivity for vimentin, laminin, type IV collagen, and cytokeratin; the expression of the latter in the most superfi cial cells is similar to that of mesothelial cells and decreases in intensity in the deeper cells. This suggests that these may be pre-Sertoli cells. The cord-like structures are delimited by laminin and type IV collagen. The second larger cell type is immunoreactive for placenta-like alkaline phosphatase (PLAP) on the surface, suggesting that it is related to the gonocyte. Leydig cells have not been observed among the cords of gonadal blastema.

The differential diagnosis of gonadal blastema ectopia is with ovotestes. The small size of the gonocytes distinguishes them from ovocytes, which are several times larger. In addition, no intersex condition is observed.

The presence of seminiferous tubules within the tunica albuginea is rare and usually an incidental histologic fi nding. 473 Ectopic tubules are present in approximately 0.8% of pediatric autopsies and 0.3% of adult autopsies. The lower inci- dence in adults may be explained by proportionally less sampling. The lesion ranges from microscopic size to a few millimeters in diameter, and may be visible as minute bulges in which multiple small vesicles protrude through a thin tunica albuginea. 474 Histologically there are groups of seminiferous tubules in the tunica albuginea, sometimes accompanied by Leydig cells. In children, the ectopic tubules appear normal ( Fig. 12-45 ), whereas in adults they are usually slightly dilated, although some may be hyalinized. Serial sections reveal continuity with the intraparenchymatous seminiferous tubules.

Ectopia of the seminiferous tubule is probably congenital, although it has been found in elderly men. 475 It does not appear to be the result of trauma. The malformation probably arises in the sixth week of gestation, when the primordial sex cords have formed and are branching toward the gonadal surface, and the developing testes is covered by only one to three layers of celomic epithelium. Later, the tunica albuginea forms around the sex cords and under the celomic epithelium. Failure of insertion of the tunica albuginea between the sex cords and celomic epithelium may entrap seminiferous tubules.

Ectopia differs from testicular dysgenesis, a distinctive form of male pseudohermaphroditism with müllerian remnants. Numerous features, characteristic of ectopic seminiferous tubules, distinguish it from other conditions, including normal thickness and collagenization of the tunica albuginea, absence of interstitial tissue resembling ovarian stroma (characteristic of testicular dysgenesis), and clear delimitation of the tunica albuginea and testicular parenchyma (see discussion on male pseudohermaphroditism with müllerian remnants, below).

In a unique case, there were multiple clusters of seminiferous tubules in the wall of a hernia sac that accompanied an undescended testis removed from an adult man. The ectopic tubules were not surrounded by tunica albuginea and were similar to those in cryptorchid testicular parenchyma with only dysgenetic Sertoli cells.

Leydig cells occur normally in the testicular interstitium (interstitial Leydig cells) and in the wall of the seminiferous tubules (peritubular Leydig cells). However, clusters of Leydig cells are often observed in other locations in the testis, or in the epididymis or spermatic cord. 476 Ectopic Leydig cells may be found in the interlobular septa, 477-479 rete testis, tunica albuginea, [480] [481] [482] or within hyalinized seminiferous tubules. 478, [483] [484] [485] Intratubular Leydig cells are found only in tubules with advanced atrophy and marked thickening of the tunica propria, including the tubules in adult cryptorchid testes, those of men with Klinefelter's syndrome, and in some other primary hypogonadisms ( Fig. 12-46 ). Immunohistochemical studies suggest that the endocrine function of these Leydig cells is low. 486 Several theories have been offered to account for these ectopic cells, including in situ differentiation, migration from the testicular interstitium, and trapping of peritubular Leydig cells in the tunica propria during its thickening. 487 Leydig cells are commonly found in the epididymis 487 and spermatic cord; 488,489 26 of 64 autopsies had such foci. 490 Extratesticular Leydig cells usually form small groups within or adjacent to nerves ( Fig. 12-47) . 477, 490 The occurrence of ectopic Leydig cells in the albuginea, epididymis, or spermatic cord may account for the rare cases of Leydig cell tumor in these paratesticular structures. Ectopic Leydig cells should not be misinterpreted as tumor cells (infi ltration or metastasis) when malignancy of a testicular Leydig cell tumor is suspected.

Other rare forms of ectopia are found within and outside the testis. Intratesticular ectopia includes adrenal cortical ectopia, osseous and adipose tissue heterotopia, and ectopia of the ductus epididymidis. Extratesticular ectopia includes splenic ectopia (splenogonadal fusion), hepatic ectopia (hepatotes- Adrenal cortical ectopia may be important in two conditions that develop tumoral masses: adrenogenital syndrome and Nelson's syndrome. Tumors in adrenogenital syndrome appear in 8.2% of patients with congenital adrenal hyperplasia, appearing as bilateral testicular masses of synchronous growth. These tumors consist of well delimited but non-encapsulated yellow nodules, several centimeters long, composed of large microvacuolated cells. The cause seems to be prolonged stimulation by elevated ACTH secretion. The differential diagnosis includes Leydig cell tumor. The diagnosis of tumors in adrenogenital syndrome is supported by a family or personal history of salt-lost syndrome or hypertension, demonstration of 11 β-hydroxysteroids (a specifi c marker for adrenal cortex) in spermatic vein blood, or a rapid positive response of tumor to corticoid treatment. Nelson's syndrome occurs in patients who, after adrenalectomy for treatment of Cushing's syndrome, develop an ACTH-secreting pituitary adenoma. These patients may develop testicular tumor growth similar to that in adrenogenital syndrome. Most Nelson's syndrome tumors do not respond to dexametasone treatment.

Cartilaginous heterotopia may be found in the caput of the epididymis and has been attributed to metaplasia of metanephric rests. Osseous heterotopia (testicular osteoma) is a metaplasia occurring in areas of the testicular parenchyma with fi brosis or ischemia. 491 Adipose metaplasia is frequent in undescended testis, elderly men, and those with Cowden's syndrome ( Fig. 12-48 ). 492 Groups of tubular formations that resembles the epididymis have been reported inside the testicular parenchyma in testes with marked tubular atrophy, and probably represent a rare form of metaplasia. 493

Testicular descent is not always complete at birth, and about 3.2% of full-term newborns have incompletely descended testes. Most of these descend within 3 months, and only 0.8% of infants have incompletely descended testes 12 months after birth. Spontaneous testicular descent is exceptional after the fi rst year. In recent decades, a signifi cant increase in the incidence of cryptorchidism has been detected. 494 Only 5% of patients with impalpable testes are actually devoid of testes. Other causes include true cryptorchidism, testicular ectopia, and retractile testes. True cryptorchidism includes abdominal, inguinal, and high scrotal testes that cannot be moved to the scrotum. Ectopic testes are those located out of the normal path of testicular descent; the most frequent site is the superfi cial inguinal pouch. Other rare locations of ectopia include the abdominal wall, the upper thigh, the perineum, and the base of the penis. Retractile testes may be moved to the scrotum at exploration and account for about one third of undescended testes.

Patients with true cryptorchidism account for about 25% of cases of empty scrotum. These testes most frequently are found in the inguinal canal or upper scrotum; arrest within the abdomen is less frequent. Cryptorchidism is slightly more frequent on the right than the left, and in approximately 18% of cases is bilateral. There is a family history of cryptorchidism in 14% of cases. 495 The cryptorchid testis is usually smaller than the contralateral one, and this difference is often discernible at 6 months of age. 496 One-third of cryptorchid testes are soft.

Several conditions are predictive of high risk of cryptorchidism, including increased maternal age, maternal obesity, pregnancy toxemia, bleeding during late pregnancy, and smoking, tallness, subfertility antecedents, cesarean birth, low birthweight, preterm newborn, twin birth, hypospadias 497 and other congenital malformations, and children born from September to November, and in May and June. 498, 499 Of these associations, low birth weight seems to be the most important. 500 There are two types of cryptorchidism: congenital and acquired.

This cryptorchidism is caused by anomalies in anatomic development or hormonal mechanisms involved in testicular descent (described above). Impalpable undescended testes are infrequent because the transabdominal phase follows the simple mechanism of relative movement of the testis, whereas displacement of the ovary is more complex. 501 Conversely, palpable undescended testes are more frequent because the second phase of testicular descent is more complex. Unilateral cryptorchidism may be caused by androgen failure, which leads to either an ipsilateral lesion in the development of genitofemoral nerve neurons or a defect in CGRP release that hinders normal migration of the gubernaculum.

A normally descended testis may become cryptorchid and locate even in the abdominal cavity. Two categories of acquired undescended testis have been described.

The postoperative trapped testis 502 is a normally descended testis that leaves the scrotal pouch after surgery owing to an inguinal hernia or hydrocele. [503] [504] [505] This iatrogenic cryptorchidism occurs in 1.2% of children after herniotomy. Adherence of the testis or the cremasteric muscle to the surgical incision causes testicular ascent when the incision heals and undergoes retraction.

Spontaneous ascent from unknown causes. Various mechanisms have been proposed, including inability of the spermatic blood vessels to grow adequately, 506 anomalous insertion of the gubernaculum, 507 failure in reabsorption of the vaginal process 508, 509 and failure in postnatal elongation of the spermatic cord. 510, 511 The spermatic cord measures 4-5 cm at birth and reaches 8-10 cm at 10 years of age. This growth does not occur if the peritoneal-vaginal duct has become a fi brous remnant. The cause might be a defect in postnatal CGRP release by the genitofemoral nerve. 501, 512, 513 Pathogenesis The most frequent fi ndings in congenital and acquired cryptorchidism at infancy are decreased germ cell numbers and diminished tubular diameter. 514, 515 There are multiple causes of testicular maldescent, including anatomical anomalies of the gubernaculum testis, hormonal dysfunction (hypogonadotropic hypogonadism), mechanical impairment (insuffi cient intra-abdominal pressure, short spermatic cord, underdeveloped processus vaginalis), dysgenetic (primary anomaly of the testis), and heredity.

Most cryptorchidism appears to be caused by either a defi cit of fetal androgens or an excess of maternal estrogens. Androgen insuffi ciency seems to be slight and transient because anomalies other than hypoplasia of the epididymis are not seen. Elevated maternal estrogens level could cause diminution of FSH secretion by the fetal pituitary, inducing low müllerian-inhibiting hormone production that would hinder testicular descent. 516 Three mechanisms seem to be involved in the process:

• Primary testicular anomaly. Cryptorchid testes may bear an anomalous germ cell population, as suggested many years ago. 517 More than 40% of cryptorchid patients have a marked decrease in the tubular fertility index, 518 In the normal testis there is transient formation of spermatocytes at 4-5 years of age. This meiotic attempt is probably an androgenic event that does not occur in cryptorchid testes and agrees with the characteristic low numbers of spermatogonia in the prepubertal age. 523 

Prepubertal testes Undescended testes are usually smaller than the contralateral ones. This difference is already significant at 6 months of age. 524, 525 Although there have been a number of biopsy studies in the fi rst years of life, there is no agreement about the severity of damage or the time of its onset. 523, 526, 527 Based on the tubular fertility index (TFI) and mean tubular diameter (MTD), most testicular biopsies from cryptorchid testes of children can be classifi ed into one of three groups:

• Type I (testes with slight alterations). The tubular fertility index is higher than 50, and the mean tubular diameter is normal or slightly (<10%) decreased. Approximately 31% of cryptorchid testes are in this group ( Fig. 12-49 ). • Type II (testes with marked germinal hypoplasia). Tubular fertility index is between 30 and 50, and mean tubular diameter is 10-30% lower than normal. The spermatogonia are distributed irregularly and most are in tubular sections that are grouped in the same testicular lobule. These testes comprise approximately 29% of cryptorchid testes ( Fig. 12-50 ). 528 • Type III (testes with severe germinal hypoplasia). Tubular fertility index is less than 30, and mean tubular diameter less than 30% of normal. Many of the spermatogonia are giant with dark nuclei (Fig. 12 -51). These testes often contain ring-shaped tubules, induced by increased temperature. 527 Testes with type II or III lesions bear variable degrees of dysgenesis that, in addition to germ cells, involve Sertoli cells, peritubular myofibroblasts, and Leydig cells. The dysgenesis of these other cell types is evident only after puberty. In about 25% of cases the contralateral scrotal testis also has histologic lesions of variable severity. This fi nding supports the hypothesis of a bilateral defect in many cases of unilateral cryptorchidism. Microdeletions in the long arm of the Y chromosome are present in 27% of patients with corrected unilateral cryptorchidism who present with azoospermia or severe oligospermia. 530 These fi ndings are similar to those observed in patients with azoospermia or severe idiopathic oligospermia. Unilateral cryptorchidism with a normal contralateral testis could be due to an end-organ failure. 531 In cryptorchidism secondary to spontaneous ascent, lesions are similar to megatubules (with or without eosinophilic bodies or microliths) ( Fig. 12-52) , and focal granular changes in the Sertoli cells ( Fig. 12-53 ). The testicular interstitium is wide and edematous. These comprise about 40% of cryptorchid testes.

About 8% of tests with type I lesions show many multinucleated spermatogonia (with three or more nuclei) ( Fig. 12-54 ). 529 The seminiferous tubules of testes with types II or III lesions have a thickened lamina propria during childhood and, at puberty, Sertoli cell hyperplasia. 526 Patients with bilateral cryptorchidism have a higher incidence of type II and III lesions than those with unilateral cryptorchidism.

Type I lesions are comparable to those seen in experimental cryptorchidism; normal testes in which lesions were those of congenital cryptorchidism, whereas in cryptorchidism secondary to herniotomy, germ cell depletion is slight 532 and becomes important only after 5 years of age. 533 Adult testes Most pubertal and adult cryptorchid testes have anomalies in all testicular structures. The seminiferous tubules have decreased diameters and defi cient spermatogenesis. In decreasing order of frequency, the most common germ cell lesions are tubules with Sertoli cell and spermatogonia-only pattern; tubules with Sertoli cells (dysgenetic) only; tubular hyalinization; and mixed atrophy. The lamina propria has scant elastic fi bers and increased collagen fi bers. 534 Sertoli cells are present in increased numbers and do not mature normally except in tubules with germ cells (Fig. 12-55 ). 528, 535 Often, groups of tubules containing only Sertoli cells with a prepubertal pattern (very small diameter and total absence of maturation) are present and are considered hypoplastic, dysgenetic, or hamartomatous. Areas of apparent Leydig cell hyperplasia are frequent, and many of these cells contain vacuolated lipid-laden cytoplasm ( Fig. 12-56 ).

The rete testis is hypoplastic in most cases and is lined by columnar epithelium with rare areas of fl attened cells. Cystic dilation is common, and adenomatous hyperplasia has been found in some cases. Near the rete testis, the testicular parenchyma frequently contains metaplastic fat. In some cryptorchid testes, several tubular segments are destroyed by infl ammation that probably has an autoimmune cause (focal orchitis). 536 Epididymal tubules are poorly developed and peritubular tissue is immature.

Blood fl ow is associated with testicular histology. For example, testicular volume, histologic pattern, and testicular artery resistive index are lower in undescended testes than in controls, and testicular artery resistive index is inversely proportional to testicular histology score in undescended testes. 537 There is also an apparent correlation between testicular size, spermiogram, and hormone levels. Assuming that a signifi cant reduction in testicular size (>12 mL) is only observed in 9.3% of cases, and that serum levels of FSH, LH, and testosterone are normal, an inverse correlation is seen between FSH and testicular volume, sperm concentration, sperm motility, and normally shaped sperm. In addition, there is a direct relation between testicular volume and sperm concentration, sperm motility, and normally shaped sperm. These fi ndings indicate the cause of tubular impairment in young men operated on in childhood for cryptorchidism. 538

Obstructed testes are located in the superfi cial inguinal pouch (Denis-Browne pouch) and are considered ectopic by some authors and cryptorchid by others. 539, 540 Histologic studies reveal that most obstructed testes bear the same lesions as true cryptorchid testes. Type I lesions are observed in half, type II in more than one-third, and the remainder show type III lesions. The higher proportion of type I lesions suggests a better prognosis than in true cryptorchid testes.

Some authors assume that retractile testes are normal and exclude them from studies of cryptorchidism. 541, 542 However, these testes may present important lesions and many consider them to be a form of cryptorchidism. [543] [544] [545] Retractile testes may not always be movable to the lower scrotum (70-75 mm from the pubic tubercle) and in 50% of cases are smaller than scrotal testes. Approximately 50% of retractile testes remain high after age 6 years, when cremasteric activity declines. 546 Retractile testes have a 32% risk of becoming ascending or acquired undescended testes. The risk is higher in boys younger than 7 years, or when the spermatic cord is tight or inelastic. 547 During childhood, tubular diameter and tubular fertility index decrease. 544 Adults with retractile testes that descended spontaneously but late may be fertile 548 or infertile. 549 Usually there is germ cell atrophy that varies in severity from lobule to lobule. 544 Regular examination of retractile testes is advisable during childhood and, if complete testicular descent does not occur, orchidopexy is indicated.

Most cryptorchid patients have a patent processus vaginalis, and 65-75% have a hernia sac, although most hernias are not clinically visible. Urologic anomalies are present in 10.5% of patients, the most frequent being hypospadias, complete duplication of the urinary tract, non-obstructive ureteral dilatation, kidney malrotation, and posterior urethral valves. Cryptorchidism is more frequent in patients with microcephaly, myelomeningocele, bifi d spine, omphalocele, gastroschisis, micropenis, and imperforate anus. Cryptorchidism may appear isolated or associated with congenital anomalies, endocrine dysfunction, chromosomal disorders, or intersex conditions. Thus, cryptorchidism is found in the Kallmann, Prader-Willi, Klinefelter, Noonan, Smith-Lemli-Opitz, Aarskog-Scott, Rubinstein-Taybi, prune belly, and caudal regression syndromes, anomalies of the androgen receptor, absence of anti-müllerian hormone, CHARGE association, and trisomies 13, 18, and 21.

Sperm excretory duct anomalies occur in 9-36% of cryptorchid patients, 550, 551 and are classifi ed into three types: 552 • Ductal fusion anomalies (25% of cases). These consist of anomalous fusion of the caput of the epididymis to the testis or segmental atresia of the epididymis and vas deferens. This is chiefl y associated with intraabdominal or high scrotal cryptorchid testes. • Ductal suspension anomalies (59% of cases). The caput of the epididymis is attached to the testis, whereas the corpus and the cauda of the epididymis are separated from the testis by a mesentery. A variant consists of an excessively long cauda of the epididymis that descends along the inguinal duct to the scrotum. • Anomalies associated with absent or vanishing testes (16% of cases).

Cryptorchidism is part of the testicular dysgenesis syndrome. This consists of abnormal testicular development that predisposes to cryptorchidism, hypospadias, spermatogenetic alterations, and testicular cancer. The association of these disorders with cryptorchidism has been corroborated by numerous clinical, epidemiological and genetic studies. The least severe form of this syndrome is a defect in spermatogenesis; the most severe is testicular cancer. A constellation of histologic lesions is common in the testes of men with testicular dysgenesis; these lesions include Sertoli cellonly pattern, mixed atrophy, hypoplastic tubules (Sertoli cell nodules), microlithiasis, malformed tubules, granular changes in Sertoli cells, nodular Leydig cell hyperplasia, and intratubular germ cell neoplasia. It is assumed that there is a prenatal development of the lesions as a result of several genetic, environmental, or endocrine disruptor factors that would interfere with the estrogen/androgen ratio. [553] [554] [555] [556] 

The main complications of cryptorchidism are testicular cancer, infertility, testicular torsion, and psychological problems.

Approximately 0.8% of 1-year-old males have cryptorchidism, and about 10% of testicular cancer patients had cryptorchidism. The risk of testicular cancer in cryptorchid males is four to10 times higher than that of the general population. Testes with elevated number of multinucleated spermatogonia seem to have a higher risk of cancer and adulthood. 557 About 5% of biopsies in children contain cells similar to those seen in undifferentiated intratubular germ cell neoplasia, and these cells may evolve toward germ cell tumor ( Fig.  12-57 ). 558 The most frequent tumor in undescended testes is seminoma. 559, 560 Regardless of timing, orchidopexy does not reduce the risk of cancer, although it facilitates early detection as the intrascrotal testis is palpable. One in fi ve testicular tumors arises in properly descended testes contralateral to cryptorchid testes, suggesting that there is a primary bilateral testicular anomaly in cryptorchidism. Intra-abdominal testes also have a higher incidence of tumors. 560 Infertility Infertility is the most frequent problem caused by cryptorchidism. In a series of patients with infertility, nearly 9% had cryptorchidism. 561 Infertility is infl uenced by several factors, including bilaterality, number of germ cells, location and size of the testis, and age at time of orchidopexy. The most important risk factors are bilaterality and germ cell number. Only 16% 562 to 25% 563 of men with bilateral cryptorchidism have normal sperm counts (20 million/mL or more). The highest sperm counts occur with testes in the superfi cial inguinal pouch. Patients with bilaterally impalpable testes are usually azoospermic. 563 Fertility rates in unilateral cryptorchidism vary from 25% to 81%. 564 The number of germ cells per cross-sectioned tubule is the most important prognostic factor. Patients with no increase in inhibin B during the postoperative period usually have a low number of spermatogonia per cross-sectioned tubule and a low tubular fertility index. In unilateral cryptorchidism, fertility depends on the number of spermatogonia in the contralateral testis. However, if the number of germ cells per cross-sectioned tubule in the cryptorchid testis is lower than 1% of normal, the risk of infertility is 33%. In bilateral cryptorchidism the risk of infertility rises from 75% to 100% when one or both testes have less than 1% of germ cells per cross-sectioned tubule. Neither the preoperative location of the testis in patients with unilateral cryptorchidism nor the small size of the testis at the time of orchidopexy is relevant for fertility. [565] [566] [567] An important fertility factor is the permeability of sperm excretory ducts. The age at orchidopexy may also infl uence fertility, although this has not been proven. In patients over 4 years of age orchidopexy does not enhance fertility. 568, 569 Benefi t of testicular biopsy in patients with cryptorchidism Testicular biopsies of infantile testes at orchidopexy are useful for determining baseline germ cell status and whether surgery should be completed with hormonal treatment. 570 However, even if biopsy supplies important data, it is not considered a routine procedure.

Even in the best cases when the number of spermatogonia is nearly normal, spermatogenesis may never occur owing to defi cient spermatogonium development during childhood, failure of spermatogenesis at puberty, and, if complete spermatogenesis occurs, this might be associated with obstruction of sperm excretory ducts.

In childhood, the chance of a biopsy fi nding an occult cancer or precancer is low because intratubular germ cell neoplasia is not diffusely distributed throughout the testis. Testicular biopsy is recommended in patients with intra-abdominal testes, abnormal external genitalia, or abnormal karyotype. 571 The situation is different in adults because intratubular germ cell neoplasia is present in 2-3% of cases and is diffuse. 572, 573 When intratubular germ cell neoplasia is detected in a child, further examination of the testis and rebiopsy after puberty are recommended. 574 In adults, if intratubular germ cell neoplasia is unilateral orchidectomy should be performed, but if it is bilateral, radiation may be used to eradicate the neoplasia while maintaining Leydig cell function. 575

Testicular microlithiasis (TM) is characterized by the presence of numerous calcifi cations diffusely distributed throughout the testicular parenchyma. The number and size of the calcifi cations often is great enough to be detected radiographically or by ultrasound. 576 Isolated microliths have been reported in undescended testes, prepubertal Klinefelter's syndrome, male pseudohermaphroditism, and otherwise normal children and patients studied for other diseases. 577 In adults, microliths are frequently observed in cryptorchid and ex-cryptorchid testes, 578 seminiferous tubules located at the periphery of germ cell tumor, 579 infertile patients, [580] [581] [582] and in some patients complaining of orchialgia 583, 584 or testicular asymmetry. 585 Testicular microlithiasis occurs in 0.3% of cryptorchid testes and is slightly more common in prepubertal than adult testes. In adults, it usually is diagnosed when men seek help for infertility, pain, or testicular asymmetry. 581 Microlithiasis has been observed in 1.4-2% of testicular echographies of different disorders. 586, 587 In infertile patients the incidence is slightly higher. Microlithiasis is present in 35% of testis having a malignant tumor. 588 Ultrasound studies reveal two types of microlithiasis: classic TM, in which the number of microliths is fi ve or more; and limited TM, when there are fewer than fi ve microliths ( Fig. 12-58 ). The incidences of TM in these studies are lower than 1% in infants, 5.6% in the general population aged between 18 and 35 years (bilateral in 66% of patients showing microliths, 589 0.68-4.1% in patients with other disorders, 586,587,590-592 from 4.6% 593 to 20% 594 in subfertile patients, 9.52% in ex-cryptorchid testes, 595 and more than 30% in adult testes with germ cell tumors). 588,596-599 Several cases of testicular microlithiasis have also been observed in infant testes with germ cell tumor or gonadal stroma tumor. 600, 601 The incidence is higher in whites than in blacks.

Pain is the most common clinical symptom in patients without a palpable testicular mass, and has been attributed to dilation of seminiferous tubules secondary to obstruction by microliths.

Microliths are made by hydroxyapatite, according to X-ray diffraction studies 602 and Raman spectroscopy. 603 In the prepubertal testis, microliths are surrounded by a double layer of Sertoli cells and measure up to 300 µm in diameter. When they are very large, the seminiferous epithelium may be destroyed and the microlith is surrounded by peritubular cells (Fig. 12-59 ). Testes with microliths have subnormal mean tubular diameters and tubular fertility index. 604 In adult testes with microliths there is incomplete spermatogenesis. Some seminiferous tubules with microliths are cystically dilated (Fig. 12-60 ). Microliths arise as extratubular eosinophilic bodies that mineralize and pass into the tubular lumina. 605 Microlithiasis may be a disorder of the tunica propria. Also, testicular microlithiasis is occasionally associated with pulmonary microlithiasis and with calcifi cations in the parasympathetic nervous system. 606, 607 The association of microlithiasis and testicular cancer is controversial. 608, 609 Although the development of testicular cancer has been observed in several patients whose testicular microlithiasis had been previously diagnosed by ultrasound studies, [610] [611] [612] [613] [614] it is also thought that patients with testicular microlithiasis not associated with other disorder do not require any follow-up. 615 When microlithiasis is associated with infertility the incidence of cancer varies according to the unilaterality or bilaterality of microlithiasis: 594 subfertile patients with unilateral microlithiasis show no intratubular germ cell neoplasia, whereas this is present in 20% of those with bilateral microlithiasis. The risk of malignancy is higher in classic than in limited TM. 616 The nexus between microlithiasis and cancer does not seem to be the predisposition of one disorder towards the other but rather the predisposition of both to develop in abnormal testes. This may also explain the association between microlithiasis and infertility.

Yearly ultrasound examination, perhaps with testicular biopsy, is recommended in those with testicular microlithiasis associated with cryptorchidism, infertility, atrophic testes, or contralateral testis bearing germ cell tumor. 617 Microlithiasis also occurs in the rete testis or sperm excretory ducts. Epididymal rupture and extravasation of microliths into the interductal tissue may cause a histiocytic reaction resembling malakoplakia ( Fig. 12-61 ). The disorder is asymptomatic and not associated with testicular cancer. 618 

Gonadal dysgenesis refers to disorders characterized by amenorrhea and streak gonads in phenotypically female patients. In adults, streak gonads are elongated masses of fi brous tissue resembling ovarian stroma ( Fig. 12-62 ). They may contain hilar cells and rete or epithelial cords with variable degrees of maturation, and may result from failure in gonad formation, failure of gonadal differentiation to ovary, or failure of gonadal differentiation to testis. Some streak gonads contain a few ovocytes or primordial follicles, but all germ cells disappear at puberty. Patients with streak gonads have a hypoplastic uterus and fallopian tubes. Four types of gonadal dysgenesis have been described: 46XY pure, 46XX pure, 45X0, and mixed.

46XY gonadal dysgenesis (Swyer's syndrome) is characterized by female phenotype, absence of Turnerian stigmata, and female external genitalia, sometimes with fused labia majora, a hypertrophic clitoris, and hypospadias. The breasts develop at puberty. Sexual infantilism persists in adulthood, and eunuchoidism and amenorrhea appear. These patients have elevated serum gonadotropin levels and low serum estradiol.

There are two types of gonadal dysgenesis: complete and incomplete. Patients with the complete type have female external genitalia and classic streak gonads, although cases with ovarian tissue have been reported. The cause is unknown in about 80% of cases, 619 and is due to alterations in the SRY gene in the remainder (a mutation in 10-15% of cases, and a SRY deletion as a result of an aberrant X/Y interchange in 10-15%). 620 The consequence of failure is very early gonadal alteration (sixth to eighth week of gestation). With the subsequent absence of müllerian inhibiting factor, testosterone, and dihydrotestosterone, a female phenotype develops.

Patients with incomplete 46XY gonadal dysgenesis have ambiguous external genitalia and variable degree of development of the müllerian and wolffi an structures. Although they have streak gonads, testicular development is usually observed. This gonadal dysgenesis does not seem to be caused by SRY alterations. 621 These fi ndings suggest that in the fi rst type ovarian differentiation was canceled, and that in the second type testicular differentiation failed. The fi rst is similar to the gonad of 45X0 Turner's syndrome, whereas the second resembles the gonad of mixed gonadal dysgenesis. 622 The clitoromegaly may be caused by androgens secreted by hyperplastic Leydig cells in the streak gonad.

Some patients with 46XY gonadal dysgenesis present with extragonadal anomalies and multiple syndromes, including camptomelic dysplasia and renal disorder, 623 myotonic dystrophy and terminal renal disease, 624 without 631 facial anomalies or short stature, 632 renal insufficiency and Wilms' tumor (Denys-Drash syndrome), the combination of cleft palate, micrognathia, kyphosis, scoliosis, and clubfoot (Gardner-Silengo-Wachtel syndrome or genitopalatocardiac syndrome), 633 pterygium multiple syndrome, 634 Graves' disease, 635, 636 and congenital universalis alopecia, microcephaly, cutis marmorata, and short stature. 637, 638 Most cases are sporadic, 639 although the syndrome has been reported in several members of the same family, [640] [641] [642] [643] and several forms of inheritance (X-linked, autosomal recessive, and male-limited autosomal dominant) have been proposed. 644 In addition to infertility, patients with 46XY gonadal dysgenesis have a high risk of germ cell tumor. This risk is about 5% in the fi rst decade of life, and 25-30% overall, [645] [646] [647] [648] and, thus, prophylactic gonadectomy is recommended.

Patients with 46XX gonadal dysgenesis have normal stature, female phenotype, well-developed external genitalia, and hypoplastic ovaries rather than streak gonads ( Fig. 12-65 ). The anomaly is usually detected when patients present with primary amenorrhea or infertility. This syndrome is sporadic and familial, and it may be linked to recessive autosomal inheritance. 649, 650 Patients have no predisposition to gonadal neoplasia. Associated somatic anomalies such as neurosensory hearing loss (Perrault's syndrome) are rare.

Some familial cases have shown a balanced translocation of the X chromosome (from the long arm to the short arm) 651, 652 or between chromosomes 1 and 11. 653 Because the development of ovarian follicles requires FSH, mutations have been sought in the FSHR gene. Mutations have been detected in familial cases and also in unrelated patients, 654, 655 whereas other patients have shown no mutations in this gene. 656 The incidence of tumors in these patients is very low, and the most common is dysgerminoma. [657] [658] [659] 

This is one of the most common chromosomal anomalies (from 1/2500 to 1/5000 in female newborns), 660 although 99% of zygotes with this karyotype are aborted in the fi rst stages of embryonal development. 661 Patients with 45XO gonadal dysgenesis have characteristic stigmata of Turner's syndrome, including short stature, pterygium coli, lymphedema, and cardiac malformations. The external genitalia are female and infantile; the gonads are typical streak gonads. Today, Turner's syndrome is defi ned by the combination of physical features and the complete or partial absence of one of both X chromosomes, frequently associated with mosaicism. Turnerian stigmata may be classifi ed into four groups: 662 skeletal anomalies such as cubitus valgus, shortening of the fourth metacarpal and Madelund's deformity characteristic of Leri-Weill dyschondrosteosis; soft tissue anomalies such as webbed neck, low posterior hair line, and puffy hands and feet; visceral anomalies such as aortic coarctation, horseshoe kidney, polycystic kidney, urethral stenosis and vesicourethral refl ux; and miscellaneous anomalies such as nevus pigmentosus. 663 During embryonic life, these gonads show normal germ cell numbers up to the third month, when germ cell proliferation ceases. 665, 666 Ovogenesis stops in meiosis I, usually before the pachytene stage. The cause seems to be generalized meiotic pairing errors with the start of an apoptotic mechanism to avoid the formation of abnormal gametes. 667 Massive apoptosis of ovocytes occurs between the 15th and the 20th weeks. 668 Surviving germ cells disappear throughout fetal life, and their numbers at birth are usually low ( Fig.  12-66 ). 669 Patients with mosaicism have fewer anomalies than pure 45X0 individuals; 12% have menstruation (compared to 3% of pure 45X0 patients), and 18% have breast development (compared to 5% of pure 45X0 patients). In 10-20% of 45X0 patients the SRY gene is demonstrable by in-situ hybridization. It has been proposed that patients with SRY expression should undergo gonadectomy, because this gene is also a marker of gonadoblastoma. 670 These patients may develop gonadoblastoma, dysgerminoma, and mixed germ cell tumor. 670, 671 

Mixed gonadal dysgenesis is characterized by the presence of a streak gonad and a contralateral testis (often cryptorchid) or streak testis (see discussion on male pseudohermaphroditism with müllerian remnants, below).

True hermaphroditism is a disorder of gonadal differentiation characterized by the presence in the same individual of both testicular and ovarian tissue. This condition is rare and usually diffi cult to diagnose, so only 25% of male hermaphrodites are diagnosed before age 20. 672 Failure to recognize this disorder may lead to surgical intervention for hernia repair or orchidopexy. Most hermaphrodites raised as males display symptoms for the fi rst time at puberty because of breast development 673 (95% of hermaphrodites have some degree of gynecomastia), periodic hematuria 674 (if they have a uterus ending in the urinary tract), or cryptorchidism. 675 Hermaphrodites raised as females initially present with irregular menstruation or clitoromegaly. True hermaphroditism should be suspected in all children with ambiguous sex characteristics ( Fig. 12-67 ). The gonads of these patients are ovotestes, ovaries, or testes, with all possible combinations. 676 True hermaphroditism can be (1) unilateral, if there are both testicular and ovarian tissues (forming one ovotestes or two separated gonads) on one side, and a testis or an ovary in the other side; if there is no gonadal tissue in this latter side, unilateral hermaphroditism is incomplete; (2) bilateral, if testicular and ovarian tissues are present on both sides of the body; and (3) alternate, if there is a testis on one side, and an ovary on the other side.

Ovotestis is the most frequent gonadal type in true hermaphroditism. It is more frequent on the right side and is located in the abdomen (50% of cases), labioscrotal folds, inguinal canal, or the external inguinal ring. The ovotestis has a bilobated or ovoid shape ( Fig. 12-68 ). In the bilobated ovotestis the testis and ovary are connected by a pedicle, whereas in the ovoid ovotestis the ovarian tissue forms a crescent capping the testicular parenchyma. The proportion of ovary to testis varies widely ( Fig. 12-69 ). At adulthood, the ovarian follicles mature and corpora lutea or corpora albicantia may be seen. The seminiferous tubules rarely develop complete spermatogenesis. The interstitium usually contains Leydig cells. Ovotestis is associated with a fallopian tube in 65% of cases, and with a vas deferens in the remainder. If the patient has ovotestis/ovary, a completely developed uterus is present. If the patient has bilateral ovotestis (13%), uterine agenesis is frequent (Fig. 12-70 ). 677 The testis of hermaphrodites is most often on the right side (60%) and is located anywhere from the abdomen to the scrotum. These testes have low tubular fertility indices during childhood. After puberty, the seminiferous tubules remain small, often containing only dysgenetic Sertoli cells, similar to the tubules of cryptorchid testes. Incomplete spermatogenesis has been reported, but complete spermatogenesis is exceptional. The ovary of hermaphrodites is most frequently on the left side (63%) and usually is hypoplastic with few primordial follicles. However, in occasional patients the ovary is histologically and functionally normal.

The most frequent karyotype is 46XX (60%), followed by several mosaicisms (33%) which, in decreasing order of frequency, are 46XX/46XY, 46XY/47XXY, 45X0/46XY, 46XX/47XXY. The 46XY karyotype is the least common (7%). There is variation in the incidence of some karyotypes around the world. Mosaicism is found in 40.5% of European cases, but in only 21% of North America cases. Conversely, most African true hermaphrodites (97%) have 46XX karyotype. The karyotype 46XY is rare and its frequency is similar in Europe, Asia, and North America. 678, 679 Most cases are sporadic, and families with several affected members also have 46XX males. This fi nding suggests that both genetic anomalies are alternative forms of a single genetic defect. 680 The following mechanisms 681, 682 have been proposed to explain the occurrence of testicular parenchyma: true hermaphroditism 46XX, a hidden mosaicism with a cell line having a Y chromosome; transfer from a Y chromosome fragment (including SRY gene) to the X chromosome; autosomal mutation of variable penetrance; and X-linked mutation coupled with rare X inactivation or X mutation that permits testicular differentiation in the absence of SRY. Some 46XX hermaphrodites with SRY-negative leukocytes are positive for this gene in DNA from the testicular parenchyma in the ovotestis. 683 Over 22 pregnancies in true hermaphrodites have been reported, 684 in contrast to the exceptional cases of paternity. Ovules may arise from the ovotestes or the ovary.

Management of true hermaphroditism depends on the patient's age at the time of diagnosis, the nature and location of the gonads, and the developmental stage of the external genitalia. Although bilateral castration may be justifi ed in order to avoid the risk of neoplasia, gonadal preservation may be desirable until adulthood. In this case, if the patient is raised as a girl, puberty will occur spontaneously and there is a small chance of fertility. 685 However, the high risk of malignancy (estimated at 4.6%) should be taken into account. The most frequent tumors are gonadoblastoma, dysgerminoma, and yolk sac tumor. 676 The risk of cancer may be reduced if some precautions are taken, including removal of the testis if it has not descended and surveillance of the residual gonad with periodic ultrasound studies, especially in cases of chromosomal mosaicisms.

Normal male development requires adequate differentiation of the testes in the fetal period, synthesis and secretion of testicular hormones, and proper response of target organs to these hormones. Anti-müllerian hormone produced by Sertoli cells inhibits the development of müllerian derivatives that would otherwise form the uterus and fallopian tubes. Testosterone produced by Leydig cells stimulates differentiation of the wolffi an ducts into male genital ducts. The conversion of testosterone into dihydrotestosterone by the enzyme 5α-reductase ensures the development of male external genitalia. Alterations in these processes may cause male pseudohermaphroditism.

Androgen synthesis defi ciencies These autosomal recessive syndromes are characterized by an error in testosterone synthesis that results in incomplete or absent virilization. Cholesterol is the source for the synthesis of androgens, estrogens, and other steroid hormones through multiple steps. First, the steroidogenic acute regulatory protein (StAR) generates cholesterol into mitochondria; StAR gene mutations cause congenital lipoid adrenal hyperplasia. Second, within mitochondria, the cholesterol sidechain cleavage enzyme P450scc transforms cholesterol into pregnenolone; a disorder in this enzyme is rare because it is highly lethal in embryonic life. Third, pregnenolone undergoes 17α-hydroxylation by microsomal P450c17; defi ciency in 17α-hydroxylase causes female sexual infantilism and hypertension. Fourth, 17-OH-pregnenolone is converted into DHEA by 17,20-lyase activity of P450c17. The ratio of 17,20-lyase to 17α-hydroxylase activity of P450c17 determines the ratio of C21 to C19 steroids produced. The ratio is regulated by at least three factors, including the electrondonating protein P450 oxidoreductase (POR), cytochrome b5, and serine phosphorylation of P450c17. Mutations in POR are present in the Antley-Bixler skeletal dysplasia syndrome as well as a variant of polycystic ovarian syndrome. Figure 12 -71 shows the enzymes involved in the abovementioned steps. The enzyme 3β-hydroxysteroid dehydrogenase transforms DHEA to androstenedione, and the enzymatic complex called aromatase transforms androstenedione into estrone and testosterone into estradiol.

In some patients cholesterol synthesis is also impaired, and congenital adrenal hyperplasia is superimposed on androgen defi ciency. Defi cient testosterone synthesis may result from abnormalities in the enzymes involved in pregnenolone formation (congenital lipoid adrenal hyperplasia), including 3β hydroxysteroid dehydrogenase, 17αhydroxylase, 17,20-desmolase, and 17β-hydroxysteroid dehydrogenase ( Fig. 12-71 ).

Congenital lipoid adrenal hyperplasia is the most severe form of congenital adrenal hyperplasia. 686 The disorder is characterized by a defi cit in steroid hormone synthesis in the adrenal cortex and gonads, producing a female phenotype with severe salt-loss syndrome. Conversion of cholesterol to pregnenolone requires the enzymes 20α-hydroxylase, 20,22desmolase, and 22α-hydroxylase. Failure of any of these leads to defi cits in cortisol, aldosterone, and testosterone. 687 The enzymatic defect is usually is caused by a defi cit in the steroidogenic acute regulatory (StAR) protein; in other cases, the defi cit is in P450ssc. The mitochondrial protein StAR promotes cholesterol transfer from the outer to inner mitochondrial membrane, where cholesterol serves as a substrate for P450scc and initiates steroidogenesis. More than 35 different mutations in the StAR gene have been identifi ed. 690 As a result, cholesterol is not converted to pregnenolone, which is required for the synthesis of mineralocorticoids, glucocorticoids, and sex hormones.

The disorder is rare in most countries, but is common in Japan, Korea, and the Arabian countries. 691, 692 Patients usually present with salt-losing crisis in the fi rst 2 months of life. 693, 694 In most cases, males have female or ambiguous external genitalia and a blind-sac vagina, hypoplastic wolffi an derivatives, absence of müllerian structures, and cryptorchidism. 695 The adrenals usually appear enlarged and contain lipid accumulations, 696,697 but these diminish with age and the adrenals shrink. In the testes, lipid accumulations may be present or absent in Leydig cells 686, 696, [698] [699] [700] [701] [702] or Sertoli cells. 703 An 8-year-old child had partially hyalinized seminiferous tubules with Sertoli cell-only pattern. 704 The testes of pubertal patients are usually normal for age. 701, 702 Intratubular germ cell neoplasia has been reported in one case. 705 Most patients die from adrenal insuffi ciency. Survivors have female phenotype 704 and require the administration of glucocorticoids, mineralocorticoids, and gonadal steroids. 703 3β-Hydroxysteroid dehydrogenase defi ciency Patients with this defect have two main problems: salt-loss syndrome produced by reduced aldosterone secretion, and incomplete virilization. 706 At puberty, virilization increases and gynecomastia develops. 707, 708 The enzyme 3BHSD catalyzes the conversion of 5-3βhydroxysteroids such as pregnenolone, 17-hydroxypregnenolone, and dehydroepiandrosterone into respectively 4-3β-ketosteroid, progesterone, 17-hydroxyprogesterone, and androstenedione. 709 There are two 3BHSD genes located on the p11-p13 region of chromosome 1. The type I gene is expressed in the placenta, kidney, and skin, whereas the type II gene 3BHSD is expressed only in the gonads and adrenal glands. Complete absence of the 3BHSD gene is lethal; therefore, most reported cases have only partial 3BHSD deficits. [710] [711] [712] It is assumed that these defi cits account for 10% of cases of congenital adrenal hyperplasia.

The classic form of salt-losing 3BHSD defi cit is diagnosed in the fi rst months of life because of insuffi cient aldosterone synthesis and subsequent loss of salt. The other 3BHSD defi cit, without salt loss, is due to mutations in the type II 3BHSD gene 708 and its diagnosis may be delayed until puberty.

Severe forms of 3BHSD defi ciency are associated with defi cits in aldosterone, cortisol, and estradiol. Symptoms may vary widely, as enzymatic activity in the adrenal gland is not the same as in the testis. Most patients show salt loss and adrenal crisis; they have incomplete masculinization and may develop spontaneous puberty and gynecomastia. 706, 707, 713 Patients with mild forms have normal genitalia and normal mineralocorticoid levels. Some patients have only hypospadias 714 or micropenis. 715 The testes are smaller and softer than normal. 17α-Hydroxylase defi ciency The cause of defi cits in the enzymes 17α-hydroxylase and 17,20-lyase are mutations of the CYP17 gene that encodes cytochrome P450c17. 716 The CYP17 gene is located on chromosome 10q24-q25, 717 and 50 different mutations have been described. 718 P450c17 catalyzes the 17α-hydroxylation of pregnenolone to 17OHpregnenolone and of progesterone to 17α-OH-progesterone. This enzyme also catalyzes 17,20-lyase activity, transforming 17OH-pregnenolone to DHEA. The classic form of 17αhydroxylase defi cit is caused by severe defi ciencies in CYP17; less severe defects give rise to the isolated 17,20-lyase defi cit. 17α-Hydroxylase defi cit impairs the synthesis of both cortisol and testosterone. 719 Low cortisol levels stimulate ACTH secretion, causing hypersecretion of aldosterone precursors and the development of hypokalemic hypertension and male pseudohermaphroditism in males. 720 Patients usually have hypospadias and develop gynecomastia at puberty. 721 

The enzyme 17,20-desmolase cleaves the side chain of 17-hydroxypregnenolone and 17hydroxyprogesterone to form dehydroepiandrosterone and androstenedione, respectively. Varying degrees of 17,20desmolase defi ciency are seen, resulting in varied development of external genitalia, ranging from female phenotype to virilization with microphallus, bifi d scrotum, and perineal hypospadias. In childhood, the testes contain reduced numbers of spermatogonia (Figs 12-72, 12-73) . 722, 723 The cause may be mutations in one of the genetic loci encoding P450c17, fl avoprotein OR or b5. 724 17β-Hydroxysteroid dehydrogenase defi ciency This enzyme transforms androstenedione into testosterone and also converts estrone into estradiol. The enzymatic defects are sexlinked. Most patients have female phenotype at birth and are raised as girls, but at puberty undergo virilization. 725 One or both testes may be cryptorchid or are located in the labia majora. Normal spermatogenesis has never been observed. The most common testicular patterns are hypoplasia or absence of germ cells and Leydig cell hyperplasia. 726 The germ cell injury was initially attributed to cryptorchidism, but it is now thought to be a primary testicular lesion because even very young patients lack germ cells. 727 This defi cit is due to mutations in the HSD17B3 gene located on 9q22. 728, 729 Leydig cell hypoplasia This variant of male pseudohermaphroditism is defi ned by insuffi cient testosterone secretion 422 and the following characteristics: predominance of female external genitalia; absence of male secondary sex characteristics at puberty; absence of uterus and fallopian tubes and the presence of epididymis and vas deferens; 46XY karyotype; lack of response to human chorionic gonadotropin stimulation; absence of an enzymatic defect in testosterone synthesis; and small undescended testes that are gray and mucous on section. [730] [731] [732] [733] Age at diagnosis varies from 4 months to 35 years. The syndrome is sporadic and familial. 734, 735 The best-known cause of Leydig cell hypoplasia is inactivating mutation of the LH receptor in these cells. [736] [737] [738] During fetal life, there is an inadequate response to placental hCG initially and to pituitary LH subsequently. Phenotypes vary widely according to the presence of complete or partial loss of receptor function. These changes range from male pseudohermaphroditism with female external genitalia (type I of Leydig cell hypoplasia) to male phenotype with micropenis, hypospadias, pubertal delay, and primary hypogonadism (type II of Leydig cell hypoplasia).

In type I hypoplasia, the testes contain small seminiferous tubules with Sertoli cells, spermatogonia, and thickened basement membranes. Leydig cells are rare or absent, in contrast to Leydig cell hyperplasia seen in other types of male pseudohermaphroditism, such as those arising from defects in androgen synthesis or androgen action on peripheral tissues. 739, 740 Leydig cell hypoplasia accounts for low serum testosterone levels, lack of virilization, and lack of spermatogenesis. The absence of müllerian derivatives suggests a normal function of Sertoli cells, which synthesize müllerian inhibiting factor. In type II hypoplasia, adult testes show maturation arrest of spermatogonia and a few incompletely differentiated Leydig cells. 741, 742 

Resistance to androgen stimulation is the cause of several syndromes with phenotypes varying from complete testicular feminization 743 to normal male. 744, 745 These syndromes are caused by partial or complete lack of response of the target organs to androgens 746 due to the absence, diminution, or impairment of androgen receptors or postreceptor anomaly. 740 The gene for the androgen receptor is located on the X chromosome (Xq11-q12), and X-linked transmission occurs in two-thirds of cases. The karyotype is usually 46XY, but 47XXY and several mosaicisms have been observed. 747 These syndromes affect 1 : 20 000-1 : 40 000 newborns. The diverse phenotypes associated with androgen insensitivity may be classifi ed as: complete androgen insensitivity syndrome (CAIS) or testicular feminization syndrome; partial androgen insensitivity syndrome (PAIS) or partial testicular feminization syndrome, which includes the syndromes of Lubs, Gilbert-Dreyfus, Reifenstein, and Rossewater; and mild androgen insensitivity syndrome (MAIS), infertile men with light androgen insensitivity, and Kennedy's disease. Complete androgen insensitivity syndrome (complete testicular feminization syndrome) This form of male pseudohermaphroditism is characterized by female phenotype with testes. Complete testicular feminization syndrome is rarely diagnosed during childhood except in patients who present with hernia, inguinal tumor, or with a family history of pseudohermaphroditism. Primary amenorrhea is the principal presentation in adults.

The testes may be in the abdomen, inguinal canal, or labia majora, and during the fi rst year of life may be normal histologically except for reduced tubular diameter and low tubular fertility index. After the fi rst year, decreased germ cell numbers become evident and the few remaining spermatogonia are concentrated in clusters of seminiferous tubules. The testicular interstitium contains numerous spindle cells arranged in bundles, and during the fi rst year of life has Leydig cells with abundant eosinophilic or vacuolated cytoplasm. At puberty, patients have female external genitalia, a short blind-ended vagina, feminine breast development; and scarce pubic and axillary hair. Serum testosterone is at the normal male level and LH is markedly increased.

In adults, the testes vary in size from small to large, are tan-brown, and contain small seminiferous tubules without lumina which usually contain only Sertoli cells. 748, 749 In one-third of patients both Sertoli cells and spermatogonia are present. 750 Ultrastructurally, Sertoli cells lack Charcot-Böttcher crystals and annulated lamellae; inter-Sertoli cell specialized junctions are not well developed, and in cryofracture studies the arrangement of membrane particles has an immature pattern. 751 Leydig cells are abundant, but few contain Reinke's crystalloids. Often, there are areas resembling ovarian stroma in the testicular interstitium.

In about two-thirds of cases the testes contain grossly visible white nodules that stand out from the surrounding testicular parenchyma (Figs 12-74, 21-75). Histologically, the nodules consist of clusters of small seminiferous tubules with immature Sertoli cells, hyalinized lamina propria, numerous Leydig cells, and an absence of elastic fi bers ( Fig.  12-76) . These have been referred to as Sertoli-Leydig cell hamartoma. About 25% of testes have Sertoli cell adenoma, sometimes very large, consisting of tubules resembling infantile testis but lacking in germ cells and peritubular myofi broblasts. No Leydig cells are present between the tubules (Figs 12-77, 12-78). 752 Other benign tumors include Sertoli cell tumor (large cell calcifying Sertoli cell tumor and sex cord tumor with annular tubules), Leydig cell tumor, leiomyoma, and fi broma. 746 Approximately 60% of cases have small cystic structures closely apposed to the testes, and about 80% of patients have thick bundles of smooth muscle fi bers resembling myo- metrium near the testis. True myometrium has been demonstrated in only one case. Hypoplastic fallopian tubes are present in about one-third of cases. In about 70% of patients the epididymis and vas deferens are rudimentary; the only explanation for this is residual activity of the mutated androgen receptor. 753 Approximately 10% of testes from patients with testicular feminization syndrome develop cancer. The frequency increases with age, but tumors rarely appear before puberty. These tumors include intratubular germ cell neoplasia ( Fig. 12-79) , 749 several types of germ cell tumor, 750, 754 and sex cord tumor. 441 Thus, the gonads should be removed immediately after puberty. 755 Partial androgen insensitivity syndrome (partial testicular feminization syndrome) The phenotype of patients with partial testicular feminization varies from normal female to normal male. The disorder includes four classic syndromes:

Lubs' syndrome, 756 characterized by partial fusion of labioscrotal folds, a defi nitive introitus, clitoromegaly, pubic and axillary hair, and poor breast development; 757 Gilbert-Dreyfus syndrome, characterized by progressively greater male phenotypic features that include small phallus, hypospadias, incomplete development of wolffi an derivatives, and gynecomastia; 758 Reifenstein's syndrome, characterized by hypospadias, weak or absent virilization, testicular atrophy, gynecomastia, azoospermia, and infertility; 759 and Rosewater-Gwinup-Hamwi syndrome, characterized by infertile men whose only abnormal feature is gynecomastia. 760 Mild androgen insensitivity syndrome Spermatogenesis requires high levels of intratesticular testosterone. A minor form of androgen insensitivity may be observed in some patients with male phenotype who present with infertility. 761 The frequency of androgen resistance among azoospermic and oligozoospermic men is estimated at about 19% 762 or lower. 763, 764 Some patients have lost exon 4 765 or mutated exons 6 764 or 7. 766 Kennedy's disease Kennedy's disease (spinal and bulbar muscular atrophy, SBMA) is an X-linked recessive disorder of the adult male 767,768 characterized by loss of motor neurons in the spinal cord and brain stem and associated with less important loss of sensory neurons and atrophy caused by skeletal muscle denervation. 767, 769 Disease onset around 20 years of age includes muscular weakness, cramps, and fasciculations. 770 In most cases the male reproductive system is impaired. [770] [771] [772] The testes may be normal in the initial stages of the disease, and many patients are fertile; however, with progression, there is onset of secondary testicular atrophy and gynecomastia. Testosterone levels are decreased in some cases.

The disease results from mutations in the fi rst exon of the androgen receptor (AR) gene. 773 The SMBA gene, located on Xq11-12, has expansion of a repetitive CAG sequence in exon A. The number of CAG repeats is 21 (range, 17-26) in control men and more than 40 in men with Kennedy's disease. 768, [774] [775] [776] [777] 

This disorder is a variant of male pseudohermaphroditism caused by a lack of the enzyme 5α-reductase with failure of conversion of testosterone to dihydrotestosterone. 778 In patients with the 46XY karyotype there are two isoenzymes: isoenzyme 1 is encoded by the gene SRD5A, located on 5p15, and isoenzyme 2 is encoded by the gene SRD5A2 on 2p23. Most reported cases result from defects in SRD5A2. 779 Many mutations in different exons have been reported. [780] [781] [782] [783] [784] During childhood, patients have a clitoriform penis, bifi d scrotum, urogenital sinus, and testes in the inguinal canal or labioscrotal folds (Fig. 12-80) . Müllerian derivatives are absent. At puberty they acquire the male phenotype, with development of the penis and scrotum. Adults have erections, ejaculations, and normal libido, scant body hair and a thin beard, a very small prostate, and lack of temporal hairline recession (male pattern baldness). Serum levels of FSH, LH, and testosterone are increased, but dihydrotestosterone is decreased. 785, 786 The disorder is autosomal recessive and has been observed in many consanguineous families from the Dominican Republic. 787

This group of male pseudohermaphrodites is characterized by the presence of müllerian derivatives and unilateral or bilateral testicular dysgenesis. These two features depend on anti-müllerian hormone gene mutations and end-organ insensitivity. [788] [789] [790] [791] In normal development, anti-müllerian hormone is responsible for inhibition of the ipsilateral müllerian ducts and collagenization of the tunica albuginea. Patients with defi cient secretion of this hormone may also have androgen defi ciency. Three variants of defective müllerian duct regression have been reported: mixed gonadal dysgenesis, dysgenetic male pseudohermaphroditism, and persistent müllerian duct syndrome.

Mixed gonadal dysgenesis (asymmetric gonadal differentiation) is characterized by the presence of a testis on one side of the body and a streak gonad on the other. 792 If the gonads are intra-abdominal, the labioscrotal folds may appear as either normal labia or empty scrotal sacs (Fig. 12-81 ). In the former, the syndrome cannot be recognized in the newborn unless a peniform clitoris is present. If the gonad is descended, it is usually a testis. Müllerian derivatives such as fallopian tubes are usually associated with streak gonad (95% of cases), but may also be associated with testicular tissue (74%). Ipsilateral to the testis there is one epididymis and one vas deferens. On the contralateral side, no gonad or a streak gonad and a fallopian tube are present. A hypoplastic uterus and a poorly developed vagina are frequent fi ndings.

This syndrome accounts for about 15% of intersex conditions. Some patients are raised as males, although their external genitalia are usually ambiguous as a result of fetal virilization. The penis is clitoriform, and the urethra opens in the perineum. Most have cryptorchid testes and are raised as girls, becoming virilized at puberty. Infertility is a common symptom. 793 The etiology is heterogeneous: 794 one-third of patients have turnerian features, in accordance with the presence of the 45X0/46XY karyotype in more than 50% of patients. Other observed karyotypes are 46XY and 45X0/47XYY. Approximately 81% of patients have one Y chromosome. Mutation in the SRY gene has not been found. 795 The testes can show two different patterns: testicular dysgenesis and streak testis. Testicular dysgenesis is characterized by a tunica albuginea that varies in width and is reminiscent of ovarian stroma by the storiform distribution of cells and fi bers; there are also malformed seminiferous tubules (Fig.  12-82 ) that are small, usually lack lumina, and contain only immature Sertoli cells. In adults, spermatogenesis has been observed occasionally. The testicular interstitium contains increased numbers of Leydig cells.

Streak testes are complex gonads in which testicular dysgenesis is associated with a fi brous streak. Most of the gonad consists of a testis showing the characteristic lesions of testicular dysgenesis. In a pole of the gonad, or in continuity with it, there is a fi brous streak whose structure may correspond to any of the varieties mentioned above (Fig. 12-83 ). This peculiar gonad can also be observed in some dysgenetic male pseudohermaphrodites as well as in the persistent mül- lerian duct syndrome. In these cases, the streak contains no ovocytes. Light microscopy indicates a wide spectrum of testicular lesions, ranging from those of patients with 46XY pure gonadal dysgenesis to true hermaphroditism. Differentiation of the ovocyte-containing streak testis and ovotestis remains controversial. 796, 797 The testes in mixed gonadal dysgenesis are incapable of müllerian duct inhibition and allow complete differentiation of wolffi an derivatives, virilization of external genitalia, and, in most cases, testicular descent. The risk of germ cell neoplasia reaches 50% in the third decade of life, usually beginning with gonadoblastoma. The testes should be removed after puberty.

Dysgenetic male pseudohermaphroditism is a disorder of sexual differentiation characterized by bilateral dysgenetic testes or streak testis, persistent müllerian structures, and cryptorchidism. This syndrome is considered a variant of mixed gonadal dysgenesis ( Fig. 12-84) . 791, 798 The karyotype may be 46XY or 45X0/46XY, and turnerian stigmata may be present. The uterus and fallopian tubes are present and both are usually hypoplastic (Fig. 12-85 ). 799 The testes show lesions characteristic of testicular dysgenesis, with few germ cells during childhood (Fig. 12-85) . 799 In adults, spermatogenesis is poorly developed and the testicular interstitium shows Leydig cell hyperplasia. About 25% of patients develop gonadoblastoma. 800

Persistent müllerian duct syndrome has many names, including male with uterus, tubular hermaphroditism, persistent oviduct syndrome, and hernia uteri inguinalis. 801 It is a rare form of pseudohermaphroditism, with müllerian derivatives in an otherwise phenotypically normal male, and is the most characteristic form of isolated anti-müllerian hormone defi ciency.

The molecular basis of this syndrome is heterogeneous. Three hypotheses have been proposed, including a defect in anti-müllerian hormone synthesis, caused by mutation in the anti-müllerian hormone gene (45% of cases); resistance of target organs to this hormone, caused by mutation in the receptor II for this hormone (39% of cases); and failure in the action of this hormone immediately before the eighth week of gestation (16% of cases). 802 Although the external genitalia are male, one (35% of cases) or both testes (75% of cases) are cryptorchid. The syndrome usually also includes inguinal hernia contralateral to the undescended testis, with a uterus and fallopian tubes within the hernia sac (Figs 12-86, 12-87) . 803 Several cases with transverse testicular ectopia and persistent müllerian duct structures have been reported. 804, 805 Patients usually have inguinal hernia, but others have cryptorchidism, infertility, 806 and testicular tumor. 807 In childhood, the testes have a low tubular fertility index and decreased tubular diameter. In adults, the tunica albu- ginea is variably thickened, contains connective tissue resembling ovarian stroma, and may contain tubular structures -alterations typical of testicular dysgenesis. The seminiferous tubules are usually atrophic and hyalinized. Tubules with reduced spermatogenesis or patterns suggesting mixed atrophy (seminiferous tubules with spermatogenesis intermingled with Sertoli cell-only tubules) have also been reported. The Leydig cells appear hyperplastic. Azoospermia or oligozoospermia are common, and paternity is exceptional. 808 The syndrome is sporadic or familial, with autosomal recessive or X-linked inheritance. 809, 810 These patients have a higher risk of testicular tumor than that attributed to cryptorchidism, 811 and all types of germ cell tumor have been observed. 812, 813 Other forms of male pseudohermaphroditism Of the dysmorphic syndromes associated with incomplete virilization of external genitalia, the best-known are those of RSH, Denys-Drash, WAGR, Opiz, camptomelic dysplasia, ATR-X, Gardner-Silengo-Wachtel, Meckel, branchioskeletal-genital, Down's, and other trisomies.

RSH (Smith-Lemli-Opitz) syndrome is a malformative recessive autosomal syndrome caused by mutations in the gene encoding for 7-dehydrocholesterol reductase (DHCR7), responsible for the synthesis of cholesterol from its immediate precursor 7-dehydrocholesterol. [814] [815] [816] The disorder is common in Europe and rare in other countries. 817 The most severe form is lethal before birth. Fetuses show postaxial oligodactyly (instead of polydactyly) and sometimes severe hydrops. 818 Non-lethal forms are characterized after birth by severe growth failure; a semi-obtunded state; absence of psychomotor development; microcephaly; congenital cataracts; peculiar facies; broad anteriorly rugose alveolar ridges with cleft palate, edema of the nape of the neck, and unilobulate lungs; male pseudohermaphroditism or female external genitalia in 46,XY patients; postaxial polydactyly of the hands and feet; congenital heart defects; and renal anomalies. 819 Hepatic and renal insuffi ciencies are frequent. 820 The less severe forms in the male have genital anomalies (70%) varying from normal genitalia to severe hypospadias with or without cryptorchidism, and numerous small anomalies whose collection characterizes the syndrome. Most patients also show mental retardation and severe behavioral problems. 821 The DHCR7 gene maps to chromosome 11q12-13. Its product is a microsomal, membrane-bound protein. Many different missense, nonsense, and splice-site mutations as well as duplications and deletions have been reported. [822] [823] [824] [825] [826] [827] Prenatal diagnosis is possible by relating ultrasound and cytogenetic studies and carrying out a biochemical analysis in the second trimester in those pregnant women who have low levels or no conjugated estriol. 828 In Denys-Drash syndrome, male pseudohermaphroditism is associated with nephroblastoma and renal insufficiency. 829 The pseudohermaphroditism is usually either mixed gonadal dysgenesis, dysgenetic male pseudohermaphroditism, 46XY pure gonadal dysgenesis, or true hermaphroditism. 830 The most common nephropathy is diffuse mesangial sclerosis. 831 Most patients have mutations in the WT-1 gene, 832 which is expressed in the genital ridge in the sixth week of gestation and gives rise to either streak gonads or testicular dysgenesis, but, if a delay in testicular determination occurs, normal testes are formed. 833 The term WAGR syndrome refers to Wilms' tumor, aniridia, genital anomalies, and mental retardation. Prevalence is estimated at between 0.75% and 2% of Wilms' tumor patients. The syndrome is related to the syndrome of Denys-Drash and that of Frasier (a variety of 46,XY gonadal dysgenesis). 834, 835 All have in common mutations in the WT-1 gene located on chromosome 11 (11p13).

WT-1 product is a transcription factor expressed in different tissues that participates in embryogenesis and cell differentiation. Mutations lead to the production of an anomalous protein that causes alterations in renal function, gonadal anomalies, and the loss of tumor suppressor function. Six variants of alleles have been described: isolated Wilms' tumor, mesothelioma, isolated diffuse mesangial sclerosis, Denis-Drash syndrome, Frasier syndrome, and WAGR syndrome. Frasier syndrome is caused by mutations in the donor zone of the intron 9 link, with the subsequent loss of the +KTS isoform (the patient has an imbalance in KTS isoforms), whereas large deletions or loss of genetic material that comprises the WT-1 gene and other contiguous genes (PAX6 or AN) lead to the WAGR syndrome. 836, 837 Patients with Opitz's syndrome are mainly boys with hypertelorism and, in the severe forms, unilateral or bilateral lip cleft, laryngeal cleft, severe dysphagia with more or less life-threatening aspiration, hypospadias and, occasionally, imperforate anus. The most important internal anomalies are those in the tracheobronchial tree, cardiovascular system (defects in cardiac septation), and gallbladder, with a subjacent defect of the developing embryonal ventral midline. The syndrome is genetically heterogeneous and consists of two entities that were described as different in the past: ADOS, or autosomal dominant Opitz syndrome or G syn- drome 838 with a mutated gene that maps to 22q11.2; and XLOS, or X-linked Opitz syndrome or BBB syndrome 839 with a mutated gene that maps to Xp22.3. 840, 841 Camptomelic dysplasia is an autosomal dominant syndrome with multiple osseous malformations. Patients have 46XY karyotype and external genitalia that are ambiguous or female. Gonadal histology varies from testes to dysgenetic ovaries with primary follicles. The cause is a haploinsufficiency of SOX9, located on 17q. 842 The incidence of gonadoblastoma is low.

ATR-X syndrome is characterized by mild α-thalassemia, mental retardation, facial dysmorphism, and hypospadias. 843, 844 The disorder is X-linked, and is caused by mutation in the ART-X gene (synonymous XNP, HX2). 845

Testicular biopsy to diagnose infertility began in the 1940s, 846, 847 and most of the diagnostic terms used today were created then. 848 These terms are usually descriptive and, except for a few (normal testes, Sertoli cell-only tubules, tubular hyalinization, for example), do not specify the degree of tubular abnormality that is evaluated by each pathologist subjectively. The terms maturation arrest and hypospermatogenesis have been applied to biopsies in more than 50% of cases of infertility, 849-851 but the criteria for these vary widely among pathologists.

Two forms of maturation arrest have been described: spermatogenic arrest, and spermatocytic arrest, or its equivalent, meiotic arrest. True spermatogenic arrest is rare because germ cell maturation usually does not arrest at the level of a defi ned germ cell type. 852 To avoid confusion the term irregular hypospermatogenesis has been proposed 853 for testicular biopsies with decreased numbers of germ cells, subclassifi ed as slight, moderate, or severe. However, this diagnosis is of little help to clinicians. The reported frequency of spermatocytic (meiotic) arrest in infertile men varies from 12% 854 to 32.1% 855 and is present in one or both testes of about 18% of oligozoospermic or azoospermic patients. 856 If observed in only one testis, the contralateral testis may show histologic changes ranging from normal spermatogenesis to hyalinized tubules.

Disorganization of the seminiferous tubular cell layers is another frequent diagnosis in testicular biopsies, 848,857,858 but this term is rejected by many pathologists. Actual disorganization of the seminiferous tubular cells is unlikely and has not been demonstrated in ultrastructural studies. In most cases, the apparent disorganization is an artifact induced by handling or fi xation. 859, 860 The term tubular blockage was introduced by Meinhard and co-workers 858 for testes with at least 50% of seminiferous tubules devoid of a central lumen and showing spatial disorganization of germ cells. This morphology was found in 28% of testicular biopsies from infertile men, mainly those with obstructive azoospermia. 861 Although this appearance can result from improper fi xation, 862 the accumulation of Sertoli cells and immature germ cells in the centers of tubules suggests a specifi c lesion, a variant of germ cell sloughing.

Diagnostic confusion decreased the interest and trust of urologists and andrologists in the study of testicular biopsies. Subsequent studies attempted to correlate semen spermatozoa concentration with testicular size and biochemical fi ndings such as serum levels of FSH, and testicular biopsies were undertaken in only a limited number of oligozoospermic and azoospermic patients. 859, 862, 863 However, these studies were also discouraging because FSH was found to correlate poorly with numbers of spermatozoa in the semen but better with numbers of spermatogonia in the seminiferous tubules, 864 and normal numbers of spermatozoa can be produced by relatively small testes whereas some large testes have no spermatogenesis. In recent years, serum levels of inhibin B have been shown to have a positive correlation with spermatozoon numbers and serum FSH level. 865, 866 The development of morphometry caused a resurgence of interest in biopsies. Many semiquantitative 853,867-869 and quantitative [870] [871] [872] [873] [874] [875] studies were carried out. The greatest achievements of these studies were enhancement of the reproducibility of results and better evaluation of the reversibility of lesions. Morphometry emerged as the best method to objectively evaluate the seminiferous tubular cells. 876 The scoring method of Johnsen, 868 estimation of the germ cell/ Sertoli cell ratio for each germ cell type, 871 and calculation of germ cell number per unit length of seminiferous tubules 870 are reliable and useful.

Several methods are available to evaluate the Leydig cell population, including the mean number of cells per seminiferous tubule and per cell cluster; the mean number of Leydig cell clusters per seminiferous tubule; the ratio of Leydig cell area to seminiferous tubule area; 877 and the ratio of Leydig cells to Sertoli cells. 878 These methods have shown that the appearance of Leydig cell hyperplasia described in many conditions is false, and that true Leydig cell hyperplasia is extremely rare.

Optimal interpretation of testicular biopsies depends on the surgical technique by which the tissue sample is taken, the care and delicacy with which the specimen is manipulated, and proper fi xation and processing of the tissue. The size of the biopsy should not be greater than a grain of rice: that is, no diameter should be greater than 3 mm. This amounts to about 0.12% of testicular volume (normal volume is approximately 20 mL). The biopsy should be bilateral because in more than 28% of patients the fi ndings differ between the testes. At the time of biopsy, the testicular axes should be measured as the basis of quantitative studies. The tissue should be taken opposite to the rete testis through a 4-5 mm incision in the tunica albuginea. This parenchyma herniates through the incision and can be carefully snipped off. If only light microscopy is to be performed, the specimen should be fi xed in Bouin's fl uid for 24 hours. If electron microscopy is indicated, a small biopsy fragment should be fi xed in glutaraldehyde-osmium tetroxide or a similar fi xative. To perform meiotic studies, testicular biopsy should be processed by air-drying or surface-spreading methods. The examination of testicular biopsies includes qualitative and quantitative evaluation of the testis and correlation between the biopsy and spermiogram.

Light microscopy immediately reveals whether the lesion is focal or diffuse. If focal, the percentage of tubules showing each lesion (Sertoli cell-only, hyalinization, tubular hypoplasia, etc.) should be calculated. It is useful to evaluate elastic fi bers with a special stain because this highlights groups of small tubules that may be missed with hematoxylin and eosin. A minimum of 30 cross-sectioned tubules should be studied (this is usually possible when fi ve or six histological sections are available). The diameter of each tubule should be measured, and the number of spermatogonia, primary spermatocytes, young spermatids (also called round spermatids or S a + S b spermatids), mature spermatids (also called elongated or S c + S d spermatids), Sertoli cells, and, in some cases, peritubular cells counted. The presence of tubular diverticula, 879 

The most frequently observed lesions are Sertoli cell-only tubules, tubular hyalinization, alterations in spermatogenesis in either the adluminal or the basal compartments of seminiferous tubules, and mixed tubular atrophy.

Sertoli cell-only syndrome includes all azoospermias in which the seminiferous epithelium consists only of Sertoli cells. To better understand this syndrome, it is necessary to consider the morphological and functional changes induced in the Sertoli cell by hypophyseal gonadotropin secretion during puberty. During childhood, Sertoli cells are pseudostratifi ed and their nuclei are dark, small, and round or elongated, with regular outlines and one or two small peripherally placed nucleoli. The cytoplasm lacks specialized organelles. 881 Adult Sertoli cells have characteristically pale, triangular nuclei with irregular, indented outlines. The nucleoli are large and have tripartite structures. The cytoplasm contains abundant smooth endoplasmic reticulum and specialized structures, including annulate lamellae, Charcot-Böttcher crystals, and specialized junctional complexes with other Sertoli cells. The pubertal increase in length and width of the seminiferous tubules replaces the infantile pseudostratifi ed pattern with a simple columnar distribution.

Five variants of the Sertoli cell-only syndrome are identifi ed by Sertoli cell morphology, the degree of development of the seminiferous tubules, and the presence or absence of interstitial lesions. 882 These variants are designated by the appearance of the predominant Sertoli cell population: immature Sertoli cells, dysgenetic Sertoli cells, adult Sertoli cells, involuting Sertoli cells, and dedifferentiated Sertoli cells (Fig. 12-88) . Each type is associated with other tubular and interstitial alterations (Table 12-7) .

The most frequent types of Sertoli cell-only syndrome in infertility patients are dysgenetic Sertoli cells, adult Sertoli cells, and involuting Sertoli cells. The clinical manifestations are similar, including normal external genitalia, welldeveloped secondary male characteristics, azoospermia, elevated serum FSH level, normal or elevated serum LH level, and normal or slightly low testosterone. These clinical and histologic features were long thought to constitute a single syndrome, Del Castillo's syndrome, but recent ultrastructural, histochemical, immunohistochemical, and cytogenetic studies have shown that this results from a variety of syndromes that may have primary or secondary causes (Table  12-7) . [883] [884] [885] [886] [887] Some patients with the adult or dysgenetic Sertoli cellonly syndrome variants have a few spermatozoa in their spermiograms. This discrepancy between oligozoospermia and the biopsy histology is caused by the presence of some seminiferous tubules with complete spermatogenesis elsewhere in the testicular parenchyma. Sertoli cell-only syndrome with immature Sertoli cells Sertoli cells in adult testes with this variant of Sertoli cell-only syndrome have an immature prepubertal appearance with pseudostratifi cation. The number of cells per cross-sectioned tubule is greater than normal. Other tubular and interstitial features suggest immaturity, including small tubular diame-ters (<80 µm), tubules lacking central lumina, thin lamina propria lacking elastic fi bers, and interstitium lacking mature Leydig cells. [888] [889] [890] This syndrome is caused by a defi ciency of both FSH and LH which begins in childhood and is responsible for the lack of maturation of the Sertoli cells, tubular walls, and interstitium. Subsequently, there is no renewal or differentiation of germ cells, and these eventually disappear. When these patients are treated with hormones, the biopsy may show some degree of spermatogenesis or thickening and hyalinization of the tubular basement membrane. Sertoli cell-only syndrome with dysgenetic Sertoli cells Dysgenetic Sertoli cells begin pubertal differentiation but variably deviate from normal maturation, so that the morphology of dysgenetic Sertoli cells differs among tubules and even among Sertoli cells within the same tubule. Nuclei usually have both mature features (pale chromatin and a centrally located, tripartite nucleolus) and features of immaturity (ovoid or round shape; regular outline; and small, dense chromatin granules) (Fig. 12-89) . 891 In addition to vimentin, Sertoli cells immunoexpress anti-müllerian hormone (AMH) 892 and cytokeratin 18. 893 Immunoreaction to these two substances is assumed to be a sign of immaturity, as under normal conditions it is not detected after puberty.

Other signs of immaturity are poor development of the hematotesticular barrier 894 and the absence of tubular lumina. Tubular lumina are very small or absent in most dysgenetic Sertoli cell-containing tubules, because the ability to produce testicular fl uid is greatly reduced. Sertoli cell numbers per cross-sectioned tubule are very high, and mean tubular diameter is lower than 120 µm. The tubular walls have few elastic fi bers, 534 and most tubules show a variable degree of tunica propria hyalinization.

Completely hyalinized tubules are frequent. The testicular interstitium contains a variable number of Leydig cells (normal, decreased, or apparently increased), many of which are pleomorphic with abundant paracrystalline inclusions. 895, 896 Most patients have normal or slightly subnormal testosterone level and elevated levels of FSH and LH. This syndrome can be observed in men with cryptorchid testes, at the periphery of germ cell tumors, in men with idiopathic infertility, 897 and in men with Y chromosome anomalies. 898 Sertoli cell-only syndrome with mature Sertoli cells In this variant, most Sertoli cells appear mature but are present in increased numbers (14 ± 0.8 per cross-sectioned tubule). The seminiferous tubules have small diameters, but are still larger than in the two variants described above, and central lumina are visible. The cytoplasm contains abundant vacuoles that communicate with the tubular lumina ( Fig. 12-90 ). The lateral cell surfaces have many unfolding and extensive specialized junctions with other Sertoli cells (from the basement membrane to the apical cytoplasmic portion). Lipid droplets, usually derived from phagocytosis of spermatid tubulobulbar complexes and dead germ cells, are scant. 884 Vimentin fi laments are abundant in the basal and perinuclear cytoplasm. 899 The lamina propria is normal or slightly thickened. Leydig cells are normal.

Serum testosterone level is normal or nearly normal, and FSH and LH levels are elevated. [900] [901] [902] This syndrome is probably caused by failure of migration of primordial germ cells from the primitive yolk sac to the gonadal ridge. 903 This failure may be due to a deletion in the AZFa region in Yq11 904 or a mutation in the genes that encodes c-KIT or its ligand (stem cell factor), responsible for migration, proliferation, and survival of germ cells.

Testes with this variant of Sertoli cell-only syndrome have numerous changes. Sertoli cell nuclei may have lobulated shapes with irregular outlines, coarse chromatin granules, and inconspicuous nucleoli. Seminiferous tubules have central lumina, decreased diameters, and variable thickening of the basement membrane (Fig. 12-91) . Elastic fi bers are present in normal or diminished amounts. Leydig cells are variably involuted.

This syndrome may be a primary disorder or secondary to irradiation or cytotoxic therapy, such as cancer chemotherapy or treatment for nephrotic syndrome. 905 It is not usually possible to determine the etiology from the biopsy fi ndings alone. Changes in the tubular walls are more pronounced in patients with a history of cyclophosphamide treatment, combination chemotherapy, or radiotherapy. The testicular interstitium may be fi brotic in patients treated with cis-platinum or cyclophosphamide. 906 Some syndromes with involuting Sertoli cells, mainly those associated with decreased number of elastic fi bers, probably express a primary testicular anomaly with involuting and dysgenetic Sertoli cells within the same tubule.

The presence of immature-appearing Sertoli cells in The tubular wall is thickened and contains elastic fi bers, increased amounts of collagen fi bers, and elevated numbers of peritubular cells as a result of tubular shortening. Mean tubular diameter is markedly decreased to less than 90 µm. The testicular interstitium contains few Leydig cells, and these appear dedifferentiated or contain an increased amount of lipofuscin.

This variant has been observed in surgical specimens from patients receiving androgen deprivation therapy for prostatic cancer, estrogen treatment for transsexuality, and cancer chemotherapy with cis-platinum. There is a correlation between the degree of Sertoli cell dedifferentiation and the dose and timing of treatment with estrogens or anti-androgens. Brief treatment induces germ cell loss and inconspicuous Sertoli cell changes; long-term treatment causes pronounced Sertoli cell changes, including initial nuclear rounding followed by nuclear elongation and the development of dark chromatin masses. 907 Eventually, the nuclei come to resemble those of infantile Sertoli cells, including pseudostratifi cation. At the same time, the tubules become hyalinized and peritubular cells increase whereas Leydig cells disappear. 908, 909 Estrogens act on the pituitary by inhibiting LH secretion, and on Leydig cells. 910 The action of gonadotropin-releasing hormone agonist analogs is only on the pituitary, whereas cis-platinum acts only on the testis. The most common causes of tubular hyalinization include dysgenetic hyalinization, hormonal defi cit, ischemia, obstruction, infl ammation, and physical or chemical agents. The differential diagnosis is given in Table 12 -8. Dysgenetic hyalinization Dysgenetic hyalinization is a diffuse lesion in which most tubules are uniformly hyalinized (Fig.  12-92) . Tubules lack seminiferous tubular cells and have a reduced number of peritubular cells. The few preserved tubules usually contain only Sertoli cells, although rarely a few with spermatogenesis are present. Dysgenetic hyalinization is seen in Klinefelter's syndrome, testes that remain cryptorchid through puberty, and some hypergonadotropic hypogonadisms associated with myopathy. Focal lesions are seen in mixed atrophy of the testis.

Tubular hyalinization is pronounced in Klinefelter's syndrome, and from infancy the seminiferous tubules are small, containing reduced numbers of Sertoli cells and few or no spermatogonia. At puberty, the dysgenetic Sertoli cells fail to Infertility mature and soon disappear. The tubules collapse, giving the appearance of phantom tubules. 911 Peritubular cells fail to differentiate and their number is low. 912 They form a discontinuous ring around the hyalinized tubules and are incapable of synthesizing elastic fi bers and other components of the lamina propria. Dysgenesis also involves the interstitium: Leydig cells exhibit a characteristic adenomatous pattern, although their total number is decreased. The morphology of the Leydig cell is not uniform, and there are shrunken, normal, and large forms. Most contain reduced amounts of lipofuscin granules and lipid droplets. Reinke's crystalloids are uncommon, and paracrystalline inclusions are abundant. 896 In spite of the hyperplastic adenomatous appearance of the Leydig cells, testosterone secretion is markedly decreased, and the resulting hypogonadism is the most important clinical feature of Klinefelter's syndrome.

Tubular hyalinization in the cryptorchid testis is also dysgenetic. However, in contrast to the atrophic collapse seen in Klinefelter's syndrome, cross-sections of the hyalinized tubules in cryptorchidism are targetoid. This results from the arrangement of the peritubular cells into two layers, suggesting an atrophic process that has evolved over a longer period than in Klinefelter's syndrome, or a lower degree of dysgenesis. 913 Elastic fi bers are diminished. 534 In the interstitium Leydig cells appear hyperplastic, forming large aggregates, although their absolute numbers are decreased. Leydig cell pleomorphism is less intense than in Klinefelter's syndrome. Many Leydig cells have abundant vacuolated cytoplasm. Whereas tubular hyalinization in Klinefelter's syndrome is secondary to the effect of pubertal gonadotropin secretion on dysgenetic tubules, tubular hyalinization in cryptorchidism probably results from the effect of increased temperature on the dysgenetic tubules. However, other mechanisms are also involved in cryptorchid tubular hyalinization, including obstruction of sperm excretory ducts (anomalies in these ducts are frequent in cryptorchidism) and ischemia (principally in testes that could only be incompletely descended by surgery). Hyalinization caused by hormonal defi cit Hormonal defi cit causes diffuse tubular hyalinization, although the tubules may be recognized for a time as cellular cords surrounded by hyaline material. Sertoli cell, a few spermatogonia, and rare primary spermatocytes may be identifi ed in these cords. When hyalinization is complete, only the elastic fi bers in the lamina propria indicate the structure of the previously normal adult testis. Peritubular myofi broblasts decrease in number and form a ring at the periphery of the lamina propria. Leydig cells disappear as hyalinization progresses, and the few that remain have pyknotic nuclei and shrunken cytoplasm with abundant lipofuscin granules.

This process manifests clinically as postpubertal hypogonadotropic hypogonadism and is usually caused by a lesion in or near the pituitary, such as pituitary adenoma, craniopharyngioma, and trauma to the cranial base or sella turcica (see discussion on hypogonadotropic hypogonadism in this chapter). Ischemic hyalinization Ischemic atrophy is usually caused by torsion of the spermatic cord, vascular injury during inguinal surgery, 914 polyarteritis nodosa, and severe arteriosclerosis. 915 Except for cases caused by torsion of the cord, these patients usually are not referred to infertility clinics.

Torsion of the spermatic cord often is not listed as a cause in large series of infertile patients. However, follow-up of men with torsion reveals marked alteration in their spermiograms. Several hypotheses have been offered to explain the low number of sperm produced by the contralateral normal testis; the most promising include response to the release of antigens by the ischemic testis, and primary lesions of the contralateral testis 916 (see discussion on testicular torsion in this chapter). Testicular anoxia caused by torsion rapidly produces severe lesions that are irreversible without adequate treatment. Eight hours after torsion, there is intense hemorrhagic infarction of the seminiferous tubular cells. Chronic anoxia leads to tubular hyalinization and loss of Leydig cells (Fig.  12-93) .

Testicular atrophy secondary to inguinal hernia surgery occurs in 0.03-0.5% of patents in the fi rst repair, and in 0.8-5% in surgery for recurrent hernia. Atrophy is most fre- Postobstructive hyalinization Obstruction of sperm excretory ducts may cause atrophy of seminiferous tubules. In order to produce tubular hyalinization, the obstruction must be close to the testis because the ductuli efferentes in the caput epididymis absorb about 90% of tubular fl uid and protect the testis from excessive intratubular pressure. Obstructive tubular hyalinization is usually focal and secondary to varicocele and other disorders involving dilation of the channels of the rete testis. These may be congenital, as in epididymis-testis dissociation, or acquired, as in rete testis dilation secondary to epididymal atrophy caused by arteritis, arteriosclerosis, or androgen insuffi ciency. Obstructive tubular hyalinization also occurs in the seminiferous tubules at the periphery of the testis in patients who have had orchitis. 917 Obstructive hyalinization has a mosaic distribution: lobules of completely hyalinized tubules are intermingled with lobules of normal tubules (Fig. 12-94 ). The diameter of the hyalinized tubules is not as small as in other causes of hyalinization, and the tubules occasionally contain Sertoli cells. In the centers of many of the tubules there is a small lumen or vacuole, the latter in the cytoplasm of a residual Sertoli cell. 918 The lamina propria is thick and contains hypertrophic peritubular cells and abundant extracellular material. Finally, the peritubular cells dedifferentiate and only fi broblasts remain. 919 The interstitium contains a normal number of Leydig cells forming small clusters, some of which are among hyalinized tubules. This is not seen in other patterns such as ischemic hyalinization. In addition, dilated veins with eccentrically hyalinized walls can be seen in testes associated with varicocele. This lobular pattern of tubular atrophy causes a peculiar ultrasound image which has been described as a striated pattern. 920, 921 Postinfl ammatory hyalinization Many infections of the testis cause irreversible lesions in the seminiferous tubules. In bacterial infection the epididymis is usually involved, resulting in obstructive azoospermia. In viral infection the testis is often affected, even without symptoms. Two types of viral orchitis often cause infertility, including mumps orchitis and Coxsackie B orchitis. Tubular atrophy caused by viral infection has a mosaic topography in which hyalinized and normal tubules are intermingled. In fully hyalinized tubules, the only recognizable cells are peritubular cells that form an incomplete, peripheral ring around the hyalinized material. The presence of elastic fi bers in these tubules distinguishes this from dysgenetic hyalinization. Leydig cells form clusters of variable size, but their total number is normal. In bacterial infection the pattern of tubular hyalinization is variable.

Tubular atrophy of unknown etiology may be caused by an autoimmune response. This appears to occur in hypogonadism associated with disorders in other endocrine glands, such as Addison's disease associated with gonadal insufficiency; adrenal-thyroid-gonadal insuffi ciency; and the association of diabetes, hypogonadism, adrenal insuffi ciency, and hypothyroidism. The testicular lesions are morphologically similar to those seen in the seminiferous tubules at the periphery of germ cell tumor and in testes with burn-out germinal cancer. In the initial stages of hyalinization associated with germ cell neoplasm, the tubules are small, contain intratubular germ cell neoplasia and dedifferentiating Sertoli cells, and the lamina propria is infi ltrated by macrophages, lymphocytes, and plasma cells. In the fi nal stages, the intratubular cells have degenerated, the infl ammation has disappeared, and the seminiferous tubules are replaced by areas of hypocellular or acellular fi brosis (Fig. 12-95) . It should be noted that autoimmune hyalinization is not the most common type of hyalinization associated with testicular tumors: the obstructive, ischemic, and dysgenetic variants are more common.

Radiation and a wide variety of chemicals cause tubular hyalinization. Lengthy cancer chemotherapy combined with Infertility radiotherapy invariably causes hyalinization. Children's testes are more sensitive to radiation than those of adults. Radiation for testicular leukemia frequently causes tubular hyalinization. In addition, radiation induces dense interstitial fi brosis and loss of peritubular cells, obscuring the borders between the interstitium and the tubules. This makes the tubules hard to see in hematoxylin-eosin-stained sections. Leydig cells are atrophic and decreased in number. Ischemia secondary to radiation-induced vascular injury also contributes to hyalinization.

In tubular hyalinization associated with cancer chemotherapy, in addition to the direct toxicity of drugs on seminiferous tubular cells (see discussion on Sertoli cell-only syndrome with involuting Sertoli cells in this chapter), nutritional defi ciencies cause hypogonadotropic hypogonadism. 922, 923 

Histophysiological studies have distinguished two compartments in the seminiferous tubules: basal and adluminal. The blood-testis barrier separates these, and each contains different cell types with diverse hormonal and nutritional requirements. On this basis, lesions may be classifi ed as involving only the adluminal compartment or both the basal and the adluminal compartments. The following discussion of spermatogenic lesions uses this new concept of tubular pathophysiology, conserving as much as possible of the classic terminology.

This category includes all infertile testes with normal numbers of spermatogonia per cross-sectioned tubule, normal or decreased numbers of spermatocytes and young spermatids, and variable numbers of adult spermatids. A descriptive term for this disorder is immature germ cell sloughing.

A few immature germ cells are normally found in the lumina of the seminiferous tubules, 923 a fi nding that correlates with their presence in the ejaculates of fertile men. 924 When these cells make up more than 4% of the cells in the ejaculate, it is abnormal and the result of premature sloughing of spermatids and, in some cases, of spermatocytes. 925, 926 Some authors have attempted to establish a correlation between the number of sloughed immature germ cells and the severity of lesions of the seminiferous tubules using light 927 and electron 928 microscopy.

Lesions in the adluminal compartment are classifi ed according to the most abundant type of germ cell whose maturation is arrested and which then sloughs: young spermatids, late primary spermatocytes, or early primary spermatocytes ( Fig. 12-96) . Young spermatid sloughing Young spermatid sloughing is present when the ratio of elongated (S c + S d ) spermatids to round (S a + S b ) spermatids is lower than normal. The implication of this pattern is that many round spermatids are incapable of further differentiation and are sloughed ( Fig.  12-97) . Late primary spermatocyte sloughing In this condition, spermatogenesis develops normally up to the level of interphase primary spermatocytes, and these are present in normal numbers. Afterwards, these spermatocytes degenerate without achieving meiosis and slough into the tubular lumen. All types of spermatid are greatly reduced in number. When biopsies of these testes are not properly fi xed, the seminiferous tubules may have a target-like appearance, with numerous cells in the lumen. This appearance sometimes has been referred to as tubular blockage. Another descriptive term, spermatogenic arrest, also has been applied to this morphology. The latter term is inadequate in most cases, because some spermatids are present, and the number of primary spermatocytes is usually not increased as would occur if the transformation of spermatocyte into spermatid were blocked (Fig. 12-98 ). Late spermatocyte sloughing is a more accurate term for this condition and is preferred. Primary spermatocyte sloughing occurs at the pachytene or diplotene stage of meiosis.

Early primary spermatocyte sloughing This lesion is characterized by the presence of a normal number of spermatogonia and decreased numbers of primary spermatocytes (Fig. 12-99 ). The seminiferous tubules may contain a few spermatids.

The term early primary spermatocyte sloughing does not necessarily imply an early meiotic lesion, which is quite rare. 856, 926 Rather, it refers to the sloughing of newly formed spermatocytes. The Sertoli cells may show vacuolation of the apical cytoplasm as an expression of germ cell loss. This lesion is more severe than that in testes with late primary spermatocyte sloughing, and is considered to result from failure of the Sertoli cells to maintain the adluminal compartment.

Etiology The mechanisms causing adluminal compartment lesions can be classifi ed into obstructive and nonobstructive. Obstruction is present in more than 70% of cases, and is characterized by variability of involvement among lobules and the presence of at least two of the following abnormalities: enlargement of tubular diameter and a lumen with remarkable differences among lobules; Sertoli cells with adherens germ cells protruding into the lumen, giving an indented outline; intense apical vacuolation of Sertoli cell cytoplasm; accumulation of spermatozoa in the lumen of some tubules; or number of spermatids S c + S d is higher that that of S a + S b (see Testicular lesions resulting from obstruction of sperm excretory ducts). 929 The three levels of severity of adluminal compartment lesions emphasized by the terms young spermatid sloughing, later primary spermatocytes sloughing, and early primary spermatocyte sloughing, depend on the degree (total or partial) of obstruction and the level of sperm excretory duct obstruction: as the obstruction gets nearer to the testis, the greater the severity. Obstruction may be extratesticular (epididymis, vas deferens, and ejaculatory ducts) or intratesticular (rete testis or any level of the seminiferous tubule length). The most frequent causes of extratesticular excretory duct obstruction are vasectomy, infl ammation (epididymitis, prostatitis), mucoviscidosis (congenital bilateral absence of vas deferens), and testis-epididymis dissociation.

Rete testis obstruction. Varicocele is the most frequent cause of obstruction of the rete testis. More than 50% of testes with Varicocele patients also often have spermatozoa with characteristically elongated heads with thin bases. 930 Initially, abnormalities are confi ned to the testis ipsilateral to the varicocele, but eventually both testes are affected, although abnormalities are more severe in the ipsilateral testis. Elevated pressure in the pampiniform plexus is transmitted to the veins within the testes, principally to the centripetal veins that cross the testicular mediastinum and drain most of the testicular parenchyma ( Fig. 12-100 ). 931 The dilated centripetal veins compress the intratesticular sperm excretory ducts, explaining the mosaic distribution of the tubular lesions. 932 Seminiferous tubule obstruction. Obstruction at the level of the seminiferous tubules can be dysgenetic or post-orchitic. A dysgenetic cause may be suspected in specimens with a mosaic distribution of lesions and seminiferous tubules with small diameters, thickened lamina propria, and an unusual seminiferous tubular cell layer consisting of cuboidal Sertoli cells and spermatozoa that clog the lumina (Fig. 12-101) . The diagnosis is confi rmed if study of serial sections demonstrates continuity between these tubules and those with conserved spermatogenesis. The structure of seminiferous tubules has been observed with scanning microscopy at such points of continuity. 858, 933 Tubular stenosis appears to be due to a primary anomaly of Sertoli cells and peritubular cells.

Post-orchitic obstruction should be suspected in cases of tubular atrophy with a mosaic pattern without dysgenetic tubules or varicocele. Some patients have a history of orchitis associated with parotiditis; 934 in others the only fi ndings are oligozoospermia and small testes. Testicular biopsy, sampling only the testicular periphery, reveals only the consequences of obstruction, lesions similar to those observed with varicocele. However, some postinfl ammatory changes should also be present, including hyalinized tubules, dilated tubules lined by cuboidal Sertoli cells, or complete spermatogenesis. Occasionally, there is modest perivascular or peritubular infl ammation and angiectasis. 935, 936 About 30% of testes with lesions in the adluminal compartment have no obstruction, and most have primary anomalies of germ cells. This claim is supported by the following: pronounced decrease of germ cell type when the preceding type is greatly increased in number; normal correlation between the number of mature spermatids in biopsy and number of spermatozoa in the spermiogram; and the presence of numerous malformed germ cells in the adluminal compartment.

Decrease in the number of a germ cell type may be so important that spermatogenesis is arrested, with subsequent azoospermia. In some cases, maturation arrest is only partial and results in severe oligozoospermia. This maturation arrest is observed mainly in primary spermatocytes and young spermatids.

Primary spermatocyte sloughing may also be owing to meiotic anomalies ( Fig. 12-102 ). The observation of increased numbers of spermatocytes arrested in preleptotene-leptotene 926 or, more frequently, pachytene 856 suggests the diagnosis. The lesion is always bilateral. Spermatocytes arrested in pachytene are usually increased in size and later degenerate. In addition, some spermatids have large, diploid, spherical, hyperchromatic nuclei. The anomaly does not always affect all spermatocytes, and then a higher number of spermatids are produced. 856 Young spermatid sloughing not associated with obstruction may be due to either meiotic anomalies or defective spermiogenesis. The former gives rises to the appearance of many multinucleate, polyploid, hyperchromatic young spermatids. In the second cause, young spermatids are incapable of transforming into mature spermatids, and only round spermatids appear in the ejaculate. 

Lesions in the basal and adluminal compartments of seminiferous tubules are the most frequent histological fi ndings in testicular biopsies from infertile men. These testes may be classifi ed into two major subgroups: hypospermatogenesis and spermatogonial maturation arrest ( Fig.  12-103) . Hypospermatogenesis: Types and etiology Hypospermatogenesis is defi ned as a reduced number of spermatogonia and primary spermatocytes, with primary spermatocytes outnumbering the spermatogonia. Most seminiferous tubules contain few spermatids. About 8% of patients with hypospermatogenesis have focal tubular hyalinization. 937 Two variants of hypospermatogenesis have been quantitatively distinguished: pure hypospermatogenesis, and hypospermatogenesis associated with sloughing of primary spermatocytes.

Pure hypospermatogenesis is defi ned as a proportionate decrease in the number of all types of germ cell. The number of spermatogonia per cross-sectioned tubule is less than 17 and usually more than 10. The number of primary spermatocytes is equal to or higher than that of spermatogonia. The number of round spermatids is higher than that of primary spermatocytes, and the number of elongated spermatids is similar to that of spermatogonia ( Fig.  12-104) .

Hypospermatogenesis associated with primary spermatocyte sloughing is characterized by two features: low numbers of spermatogonia and primary spermatocytes (with spermatocytes more numerous than spermatogonia), and degeneration and sloughing of many primary spermatocytes. The remaining spermatocytes give rise to the few spermatids observed in the tubules (Fig. 12-105) .

Etiology of hypospermatogenesis. Hypospermatogenesis may result from hormonal dysfunction, congenital germ cell defi ciency, Sertoli cell dysfunction, Leydig cell dysfunction, Infertility androgen insensitivity, exposure to chemical or physical agents, and vascular malfunction. Hormonal dysregulation. Although complete spermatogenesis may be observed in men with low levels of FSH and LH, the production of a normal number of spermatozoa requires normal gonadotropin levels. Hypospermatogenesis has been reported in patients with abnormal pulsatile secretion of FSH and LH, 938 low gonadotropin secretion, 939 biologically inactive gonadotropins, mutation in the gonadotropin β subunit, 940 inactivating mutation of FSH receptor gene, 941 hyperprolactinemia, and adrenal and thyroid dysfunction (see discussion on hypogonadisms secondary to endocrine gland dysfunction in this chapter).

Congenital germ cell defi ciency. Biopsy of cryptorchid patients after orchidopexy reveals that spermatogonia proliferation is decreased and germ cell development is insufficient in adulthood even if the number of spermatogonia was normal in infancy. Is it likely that this poorly understood primary anomaly of germ cells is present in some cases of hypospermatogenesis.

Sertoli cell dysfunction. For many years, primary germ cell defi ciency was considered the most common cause of hypospermatogenesis; today, it is known that Sertoli cell failure is the cause of many cases of germ cell defi ciency. This conclusion is based on several fi ndings. Sertoli cells in many infertile patients are markedly abnormal, with an increase in the number of glycogen granules 942 and acid phosphatase activity; 884 a decrease in the number of lipid droplets; and alterations in the cytoskeleton, 943 the nucleus, 944 and cytoplasmic organelles. 945 In some cases Sertoli cells have abnormal maturation, with elongated nuclei containing coarse clumped chromatin instead of triangular-shaped nuclei with pale chromatin. Anomalies in Sertoli cell FSH receptors may be present in idiopathic oligozoospermia associated with elevated levels of FSH. 946 Serum inhibin B concentration may be used as a marker to estimate Sertoli cell function. 947 Leydig cell dysfunction. Testosterone synthesis by Leydig cells is necessary for normal spermatogenesis, 948 and abnormal Leydig cell function is a frequent fi nding in idiopathic oligozoospermia. [949] [950] [951] Leydig cell dysfunction should be suspected when the cells appear diffusely hyperplastic. Patients have elevated serum LH level with depletion of rapid-release testosterone, revealing a lack of early response of Leydig cells to gonadotropin-releasing hormone stimulation. The ratio of testosterone to LH in the plasma indicates the degree of Leydig cell dysfunction. Decreased ratio with normal testosterone level suggests compensated dysfunction. Patients with a ratio of less than 1 : 5 and normal other parameters may have complete spermatogenesis. 951 Androgen insensitivity. Some patients with severe oligozoospermia or azoospermia have a defect in androgen receptor responsiveness, similar to that in Reifenstein's syndrome. [952] [953] [954] The abnormality may arise from a genetic defect in the eight exons that code for this receptor, mapped to Xq11-12, 955 or from post-translational errors. 956, 957 This defect is also referred to as infertile male syndrome and mild androgen insensitivity, and the patients have male phenotype with somatic features of slight androgen defi cit. 958 Histologically, the testis is similar to that observed with Leydig cell dysfunction or mixed atrophy, although the mechanism causing the Leydig cell hyperplasia is quite different (Fig.  12-106) . Peripheral resistance to testosterone action alters regulation of the hypothalamohypophyseal-testicular axis, and LH and testosterone levels are elevated. Androgen insensitivity causes between 10% 959 and 40% 960 of all cases of severe oligozoospermia or azoospermia. In such cases spermatogenesis improves with the administration of tamoxifen citrate, 960 clomiphene citrate, or androgen therapy. 961, 962 Calculation of the index of androgen insensitivity can be helpful: plasma LH (mIU/mL) × plasma testosterone levels (ng/mL). In patients with androgen insensitivity, the index is higher than 200 (normal is about 102). Physical and chemical agents. The number of chemicals implicated in infertility increases daily. A detailed history is invaluable in evaluating these patients. The same is true of physical agents such as prolonged exposure to heat, ionizing radiation, or microwave radiation. 963 Etiology of hypospermatogenesis associated with primary spermatocyte sloughing. Most testes with primary spermatocyte sloughing have varicocele, and this is commonly associated with infertility. [964] [965] [966] [967] Varicocele is found in 15% of the general population, and is present in 30-40% of infertile men. The mechanism by which varicocele affects fertility is unknown. Clinical varicocele may occur without a testicular lesion (or only phlebectasis), and subclinical varicocele may be associated with severe spermatogenic lesions. Increased testicular temperature 968, 969 and compression of intratesticular sperm excretory ducts by dilated veins 932 are the most plausible mechanisms. In other cases, primary spermatocyte sloughing results from anomalies of primary spermatocytes and spermatids, suggesting a meiotic anomaly. Finally, in some patients the cause may be the presence of involuting Sertoli cells. Spermatogonial maturation arrest Spermatogonial maturation arrest is a disorder defi ned by the presence of fewer than 17 spermatogonia per cross-sectioned tubule and even fewer primary spermatocytes. Spermatids are usually absent. There have been attempts to correlate the etiology of spermatogonial maturation arrest with the Sertoli cell type present. 970 Immature Sertoli cells are characteristic of hypogonadotropic hypogonadism and some syndromes with androgen insensitivity (Fig. 12-107) . Mature Sertoli cells, if their presence is unilateral, are observed in varicocele, epididymitis, and ipsilateral testicular traumatism, but if they appear in both testes the etiology is unknown. Involuting Sertoli cells are usually present bilaterally; some cases are idiopathic, whereas others are associated with a history of alcoholism or chemotherapy. Dedifferentiated Sertoli cells are found in spermatogonial maturation arrest caused by gonadotropin inhibition in treatment with estrogen, -releasing hormone agonist, or anti-androgen. 971 

Mixed atrophy is a descriptive term for the coexistence, in the same testis, of tubules containing only Sertoli cells and tubules with complete or incomplete spermatogenesis. 972 This disorder includes patchy failure of spermatogenesis and partial del Castillo's syndrome.

The extent of Sertoli cell-only tubules varies widely. Tubules with spermatogenesis may be normal or partially atrophic. Tubular hyalinization is occasionally seen (Fig.  12-108) . Mixed atrophy is more common than suggested by the literature, and many cases are included under other diagnoses, such as 'hypospermatogenesis with a severe germ cell depletion in such a way that some Sertoli cell-only tubules are seen,' 859 and 'Sertoli cell-only syndromes with focal spermatogenesis.' 973 Serial sections from testes with mixed atrophy reveal that the two different types of tubule are grouped according to their histologic pattern, suggesting that the distribution is by testicular lobules. In cases of mixed atrophy, the percentage of tubules with spermatogenesis, the degree of spermatogenic development in the tubules, and the type of Sertoli cell present should be reported. Correlation of the fi rst two with the spermiogram gives an indication of prognosis, and the Sertoli cell types identifi es the nature (primary or secondary) of the lesion. 974 Mixed atrophy (probably primary) is observed in idiopathic infertility, cryptorchidism (even if orchidopexy was done at infancy, in both the cryptorchid and the contralateral descended testis), retractile testes, macroorchidism, intravaginal torsion of the spermatic cord (in both twisted and contralateral testis), and chromosomal anomalies such as Down's syndrome, 47/XYY karyotype, 46/XX karyotype, Infertility giant Y chromosome, Klinefelter's syndrome with chromosomal mosaicism, partial androgen insensitivity, and some male pseudohermaphrodites. Secondary mixed atrophy may be seen in patients undergoing chemotherapy, corticoid therapy, 975 or in those with a history of viral orchitis.

In addition to anomalies in the seminiferous tubules, examination of the biopsy should include a description of the morphology of the germ cells.

Giant spermatogonia are a normal component of the seminiferous epithelium. These cells may be altered spermatogonia in the S or G 2 phases of the cell cycle. They rest on the basal lamina and have pale cytoplasm and an ovoid nucleus measuring at least 13 µm in diameter. The frequency of these cells in normal and infertile men is about 0.65 cells per 50 cross-sectioned tubules, although their number is usually higher in mixed atrophy. These cells should not be mistaken for intratubular germ cell neoplasia; they are also present in normal numbers in tubules at the periphery of germ cell tumor ( Fig. 12-109 ). 976 

Multinucleate spermatogonia are a common fi nding in cryptorchid testes that were surgically corrected, infertile patients, and old men. Nuclei of both Ad and Ap spermatogonial types may be seen within the same cell.

Normally, spermatogonia are present only in the transition zone between the seminiferous tubule basal layer and the tubuli recti. Dislocated spermatogonia have been found throughout the testis in old age, 977 in infertile patients with a variety of lesions, after long-term estrogen therapy, 978 and in seminiferous tubules with intratubular germ cell neoplasia. 979 

Megalospermatocytes are large primary spermatocytes arrested in the leptotene stage ( Fig. 12-110) 980 that exhibit asynapsis of chromosomes. 981 Joined by cytoplasmic bridges, they form small groups. These cells may be clones of synchronously degenerating spermatocytes. 982 They are frequently found in elderly men and are a non-specifi c fi nding in infertile patients.

The presence of spermatids with multiple nuclei (from 2 to 86) is frequent is old age. 983 Similar cells with fewer nuclei have also been reported in infertility due to cryptorchidism, 984 hyperprolactinemia, and idiopathic infertility ( Fig.  12-111 ).

There are at least four teratozoospermic syndromes that may be easily identifi ed by testicular biopsy, although in most the diagnosis previously relied on morphologic study of the spermiogram: (1) round-headed spermatids (characteristic of spermatozoa lacking acrosomes) (Fig. 12-112) , (2) S c + S d spermatids with a very elongated head (characteristic of varicocele) (Fig. 12-113) , (3) macrocephalic S c + S d spermatids whose DNA content suggests an anomaly in the fi rst meiotic division, and (4) S c + S d spermatids with voluminous eosinophilic cytoplasmic droplets (syndrome of spermatozoa with short thick fl agella 985 or fi brous sheath dysplasia).

In some patients, S a + S b spermatids rest in these initial phases of spermiogenesis and eventually become sloughed in the tubular lumina. 986 In other testes there are macrocephalic S c and S d spermatids with anomalous DNA content, suggesting an anomaly in the fi rst meiotic division.

Ultrastructural study of spermatozoa is sometimes necessary to determine the cause of male infertility. A number of mor-phologically abnormal spermatozoa are present in all semen samples, including those from fertile men, but abnormal spermatozoa are very numerous in infertile patients. Ultrastructural study is advised in all cases of asthenozoospermia, in teratozoospermia when the number of spermatozoa showing the same morphological anomaly is high, and in cases with apparently normal spermatozoa that fail to fertilize in vitro. 987 The classifi cation of ultrastructural anomalies in spermatozoa is based on light microscopy fi ndings 988 of lesions in the head and tail. Anomalies of the spermatozoal head These are defi ned by changes in the shape of the head, and usually involve both the nucleus and the acrosome. Some anomalies, such as pear-shaped, candle-shaped, or egg-shaped heads, 989,990 are regarded as minor variants of normal. More signifi cant abnormalities are the elongated, microcephalic, macrocephalic, and crater-defect forms.

The most frequent abnormal head shape is elongated with a narrow base (tapered head spermatozoa). This anomaly is frequently associated with varicocele. 991 Microcephalic spermatozoa have spherical (globozoospermia) or irregularly shaped heads. The former have spherical nuclei with poorly condensed chromatin and lack acrosomes, postacrosomal sheaths, and a nuclear ring (Fig.  12-114 ). Most cases are sporadic, but this lesion was also reported in two pairs of infertile brothers. 992, 993 Microcephalic spermatozoa with irregularly shaped heads have small and irregularly shaped acrosomes that usually are not in contact with the nucleus. This anomaly may be congenital, as in Aarskog-Scott syndrome, 994 or secondary to heat exposure or hashish smoking. In both types of microcephaly loss of connection between the acrosomal vesicle and the spermatozoal head is attributed to a defi ciency in basic proteins of the sperm perinuclear theca that promotes nuclear envelope organization and adhesion of the acrosomal vesicle. 995 Acrosin is reduced or absent in spermatozoa lacking acrosomes and those with small acrosomes. 996 Motility may be Infertility normal. The occurrence of aneuploidy 997 and disomy of sex chromosomes 998, 999 in some cases should be evaluated before performing intracytoplasmic sperm injection (ICSI).

The cause of round-headed spermatozoa might be the lack of Golgi-associated protein known in male mice as Golgi-associated PDZ-and coiled-coil motif-containing protein (GOPC). This protein is principally localized in the trans-Golgi region in round spermatids, and its loss produces globozoospermia. The primary defect consists of an inability of acrosomal vesicles to fuse to each other to create the acrosome. 1000 Macrocephalic spermatozoa (macronuclear spermatozoa) have enlarged, irregularly shaped heads and defi cient chromatin condensation. There are two types (multiple tails 1001, 1002 and afl agellate), both of which have abnormal DNA content (many are tetraploid), suggesting a meiotic anomaly. 1003, 1004 Irregularly shaped spermatozoa are characterized by irregularity in the shape of the nucleus or acrosome. 1005 In the crater defect syndrome, there is invagination of the nuclear envelope in which the acrosome penetrates. The tail is morphologically normal, and motility is only slightly reduced. In spermatozoa with spoon-shaped nuclei, the defect is probably genetic. Other anomalies include double-headed spermatozoa with two nuclei sharing a single acrosome. 1006 Anomalies in the spermatozoal tail Spermatozoal tail anomalies are classifi ed as generalized anomalies of the tail or anomalies in defi ned tail components, such as the connecting piece, the axoneme, or the periaxonemal structure. 1007 Generalized anomalies in the tail Cytoplasmic remnants. The presence of cytoplasmic droplets is normal during spermiogenesis. An elevated number of spermatozoa with cytoplasmic droplets in semen is associated with premature sloughing of spermatozoa, as occurs in varicocele, and should not be misinterpreted as spermatozoa with excess residual cytoplasm. 1008 These spermatozoa are very often abnormal and the residual cytoplasm may be located around the intermediate piece or surrounding the head. These spermatozoa also have other fl agellar anomalies.

Bent tail. A bend in the tail may occur at the level of the connecting piece or the intermediate piece. In bends of the connecting piece, the tail is laterally implanted and forms an angle with a nucleus that displays a thin base. Bends of the intermediate piece are associated with cytoplasmic droplets, malposition of mitochondria, and loss of the parallel arrangement of the dense outer fi bers.

Coiled tail. Spermatozoa with a coiled tail are a frequent fi nding in centrifuged semen, but they may also be a true abnormality. These spermatozoa have a perinuclear cytoplasmic remnant containing a fl agellum that is coiled around the nucleus and along the middle or principal pieces (Fig.  12-115 ). This is frequently associated with abnormalities of the periaxonemal structures.

Tail stump (short-tail spermatozoa). The presence of many spermatozoa with short, thick tails in semen represents a well-defi ned teratozoospermic syndrome. 1009 Ultrastructural examination reveals hypertrophy and hyperplasia of the fi brous sheath, 1010 hence this syndrome has also been termed 'fi brous sheath dysplasia.' 1011 Additional axonemal malformations, including absence of the central pair of microtu-bules ( Fig. 12-116) 1012 and, less frequently, lack of dynein arms, are observed in 50% of cases. About 24% of patients have respiratory disease, such as rhinosinusitis, bronchitis, and bronchiectasis from an early age. Similar fi ndings have been reported in the cilia of the upper respiratory tract, and thus a relationship between fi brous sheath dysplasia and immotile cilia syndrome has been assumed. Clinical presentation may be sporadic or familial. The cause of fi brous sheath dysplasia and the subsequent lack of motility in these spermatozoa is probably related to the occurrence of deletions in Akap3 and Akap4 genes, as well as the absence of Akp4 protein in the fi brous sheath. 1013 Multiple tails. The presence of more than two tails is associated with macrocephalic spermatozoa. 1014 Sperm tail agenesis. Teratozoospermia with 100% sperm tail agenesis has been reported in patients with a high degree of consanguinity. These spermatozoa also have defects in chromatin condensation and residual cytoplasmic droplets. 1015 Anomalies of the connecting piece Anomalies of the connecting piece are classifi ed as acephalic spermatozoa, defi cient organization of the connecting piece, and separation between the head and the tail.

Acephalic spermatozoa are known as 'pin-headed,' although they lack a true head; the small cephalic knob-like thickening is actually a cytoplasmic droplet with a variable degree of mitochondrial organization giving rise to a variable degree of motility. 1016 This anomaly is due to an early failure in spermiogenesis. It may be familial in some cases. 1017, 1018 Spermatozoa with defi cient organization of the connecting piece have narrowing at this level, with loss of alignment of the head and fl agellum axes. Spermatozoa with a separated head and fl agellum, known as decapitated and decaudated spermatozoa, are also the result of an anomaly in spermiogenesis, but the separation between heads and tails can occur during spermiation or at any level of the sperm excretory ducts. 1019, 1020 Anomalies in axoneme Abnormalities of the axoneme are classifi ed as numerical anomalies, microtubular ectopia, and immotile cilia syndrome.

The most common numerical anomalies are the absence of one or both microtubules of the central pair and complete lack of the axoneme. Spermatozoa lacking the central microtubule pair also lack the central sheath and are immotile, although they are normal by light microscopy. Familial cases have been reported. 1021 This anomaly may be associated with ciliary dyskinesia. 1022 Immotile cilia syndrome (primary ciliary dyskinesia) 1023 refers to patients having low mucociliary clearance associated with otitis, sinusitis, bronchitis, bronchiectasis, and immotile spermatozoa. Most patients have the same defect in the axoneme and cilia of the respiratory mucosa. The frequency of this syndrome is estimated at between 1 in 20 000 and 1 in 60 000 men. Clinical symptoms consist of reduced clearance of ciliary mucus in the airway, with onset at infancy. In order to prevent the later development of bronchiectasis, ultrastructural study of the respiratory mucosa is advisable if other disorders have been excluded, including cystic fi brosis, allergy and other immune disorders, α 1antitrypsin defi ciency, and cardiovascular and metabolic diseases. 1024 The most frequent anomalies of this syndrome are the absence of microtubule doublets and peripheral junctions, the central microtubule pair, the outer dynein arms, the central junctions, the two dynein arms, and the inner dynein arm plus the peripheral junctions ( Fig. 12-117) . Spermatozoa lacking the two dynein arms or the peripheral junctions are immotile. Reduced motility is seen in spermatozoa with only one dynein arm. Kartagener's syndrome is a variant of the immotile cilia syndrome characterized by the classic triad of situs inversus, bronchiectasis, and chronic sinusitis. The syndrome has autosomal recessive inheritance 1025 and is found in 20-25% of patients with situs inversus. 1026 Anomalies in periaxonemal structures Periaxonemal abnormalities include mitochondrial sheath defects, 1027 malposition of the annulus, alteration in number, shape, or length of the outer dense fi bers, and absence, thickening, or disruption of the fi brous sheath. 1011, 1028 Many cases of asthenozoospermia, present in 30% of infertile men, may be attributable to defi cient mitochondrial function, possibly caused by mutations in their DNA. 1029 Abnormalities of the dense fi bers are associated with deficient motility. Abnormalities of the fi brous sheath include, in addition to the abovementioned dysplasia of the fi brous sheath, absence of the fi brous sheath, and redundant fi brous sheath material associated with a defi cit or lack of mitochondria. 1030 The three defects are probably inherited.

The incidence of intratubular germ cell neoplasia (IGCN) in infertile patient is 0.4% in England, 1031 0.7% in Spain, 1932 0.73% in Germany, 1033 and 1.1% in Denmark. 1034 A higher risk occurs in patients with severe oligozoospermia (fewer than 10 million spermatozoa per milliliter), azoospermia associated with unilaterally or bilaterally diminished testicular volume, 1035 a history of testicular maldescent, 1036, 1037 or unilateral testicular cancer. 1038 The cells of IGCN are located in seminiferous tubules with decreased tubular diameter and lacking spermatogenesis. These cells are large and have pale cytoplasm and large and irregularly outlined nuclei, with one or several prominent nucleoli. They stain intensely with periodic acid-Schiff and express placenta-like alkaline phosphatase, c-kit, and the cell adhesion molecule CD44. 1039

A reduction in the number or absence of Leydig cells is infrequent in infertility, and only occurs in hypogonadotropic hypogonadism secondary to LH defi cit and in patients Infertility with biologically inactive LH. Leydig cell hyperplasia is very common, 1040 and has been observed in Klinefelter's syndrome, cryptorchidism, male pseudohermaphroditism, minor androgen insensitivity, infertility secondary to Leydig cell dysfunction, varicocele, after treatment with 5αreductase inhibitors or non-steroidal anti-androgens, and in some elderly men. Such hyperplasia may give rise to hypoechoic or hyperechoic images that may be misdiagnosed as tumor. 1041

There is a close relationship between testicular dysfunction and elevated mast cell numbers in the testis. An increase in interstitial and peritubular mast cells occasionally occurs in infertile patients. 1042, 1043 This increase is higher than that observed in infl ammatory or neoplastic process. 1044 Daily administration of ketotifen, an antihistamine-like drug with a mast cell-stabilizing effect, signifi cantly improves the spermiogram parameters in some patients. 1045

For effective therapy, it is important to know whether or not the azoospermia or oligozoospermia is the result of obstruction. 863, 1046 Obstructive azoospermia and oligozoospermia Azoospermia caused by obstruction is usually easily diagnosed, but this determination is more diffi cult with oligozoospermia. Obstruction of the ductal system should be suspected when there are more than 20 mature spermatids (S c + S d ) per cross-sectioned tubule and fewer than 10 million spermatozoa in the spermiogram (Fig. 12-118) . 1047, 1048 Obstructive azoospermia is implicated in 7.4-14.3% of cases of male infertility.

Obstruction is classifi ed as proximal, distal, and mixed, according to the distance from the testis to the point of obstruction in the ductal system. Proximal obstruction Obstruction is considered proximal when the lesion lies between the seminiferous tubules and the distal end of the ampulla of the vas deferens. Epididymal obstruction, principally of the caput-corpus transition zone, accounts for 66% of cases. Rarely, there is a defective connection between the rete testis and epididymal ductuli efferentes. Because the seminal vesicles are normal, men with proximal obstruction have a normal volume of semen (the testicular contribution to semen is about 5% of the total volume). When obstruction is in the cauda of the epididymis, epididymal markers, including carnitine, glycerophosphorylcholine and α-glycosidase are low. 1049 The nearer the obstruction is to the caput of the epididymis, the higher the level of these markers. Distal obstruction Distal obstruction is located between the ampulla of the vas deferens and the junction of the ejaculatory ducts and urethra. These patients present with sacral, perineal, or scrotal pain on ejaculation. Rectal examination often reveals enlarged seminal vesicles. The volume of semen is low and consists of watery fl uid that fails to coagulate. Seminal vesicle secretions are lacking. The concentration of prostatic secretions, such as acid phosphatase and citric acid, is increased owing to the lack of semen dilution. Vasography may help in diagnosis, as higher segments fail to fi ll. 1050 Transrectal ultrasonography is the most accurate imaging modality for the diagnosis of ejaculatory duct obstruction. Needle aspiration of seminal vesicle fl uid may show spermatozoa that have entered the seminal vesicles by refl ux. Mixed obstruction Mixed obstruction refers to lack of patency of the vas deferens or the epididymis and alterations in the ejaculatory ducts or seminal vesicles (low ejaculate volume, and absence of fructose). The most frequent cause is mucoviscidosis. One-third of patients with congenital bilateral absence of the vas deferens have agenesis or hypoplasia of the seminal vesicles. The cause of epididymal obstruction in patients with anomalies of the prostate-vesiculo-deferential junctions is diffi cult to determine. Etiology of obstructive azoospermia Obstructive azoospermia may be caused by congenital or acquired lesions. Congenital azoospermia The most frequent anomalies associated with congenital azoospermia are testis-epididymis dissociation, epididymal malformation in cryptorchidism, bilateral absence of the vas deferens, congenital unilateral absence of the vas deferens associated with pathology of the contralateral testis or its sperm excretory ducts, seminal vesicle agenesis, and ejaculatory duct obstruction (Table  12-9) .

Agenesis of all mesonephric duct derivatives. Agenesis of all mesonephric duct derivatives is a rare disorder that gives rise to varied anatomical anomalies, depending on the stage of embryonic development at which the mesonephric duct derivatives disappear. If failure occurs before the fourth week the ipsilateral kidney and ureter are absent, although the testis may be present, or there may be other renal anomalies. If failure occurs in the fourth week, and the ureteral bud is already formed, the ureter and kidney may develop normally. If failure occurs between the fourth and the 13th weeks, there is a variable constellation of anomalies that most frequently include normal development of the testis and globus major and hypoplasia of the other excretory duct segments, or agenesis of an excretory duct segment (epididymis, vas deferens, or seminal vesicle). Epididymal anomalies. The most frequent epididymal anomalies are absence of the epididymis, testis-epididymis dissociation, defective connection of the vas deferens and epididymis, epididymal cyst, and anatomical abnormalities of the epididymis.

Complete absence of the epididymis is frequent in monorchidism and anorchidism. The epididymis is replaced by a small mass of cellular connective tissue with abundant blood vessels at the blind end of the vas deferens.

Partial absence of the epididymis is more frequent than complete absence. Absence of the corpus of the epididymis gives rise to a characteristic malformation called bilobated epididymis. This varies from simple strangulation to complete separation of the caput and cauda. These anomalies are often associated with absence of the vas deferens.

Testis-epididymis dissociation is found in 1% of cases of obstructive azoospermia and is usually associated with cryptorchidism.

Defects in connection between the ductuli efferentes and the ductus epididymidis are rarely complete. In the incomplete form, some of the fi ve to 30 ductuli efferentes in the epididymis are short and end blindly.

Epididymal cysts usually arise from blind-ended ductuli efferentes and contain spermatozoa. These spermatoceles retain their epithelial lining, although it becomes atrophic ( Fig. 12-119 ). Spermatozoa may be obtained from these cysts. Some epididymal cysts arise from embryonic remnants, do not contain spermatozoa, and are lined by columnar or pseudostratifi ed epithelium. Wolffi an cyst, unlike müllerian cyst, is immunoreactive in the apical border of epithelial cells with CD10. 1051 Cyst lined by clear cells with or without papillae raises concern for von Hippel-Lindau disease. 1052 Large epididymal cyst requires removal and must be excised with great care to avoid damaging the ductuli efferentes and resulting in obstruction. Epididymal cyst is present in about 5% of males, and the incidence is high (21%) in those exposed to diethylstilbestrol during gestation. The incidence of epididymal cyst in those with hepatorenal polycystosis is similar to that in the general population. 1053 Anomalies in epididymal confi guration, altering its shape and location, are frequent in men with cryptorchidism and uncommon with descended testes. The most common malformations are elongated epididymis, angulated epididymis, and free epididymis. Elongated epididymis is found in approximately 68% of undescended testes. The length of the epididymis may be several times that of the testis, and, in abdominal or inguinal cryptorchidism, the epididymis extends several centimeters below the testis. Angulated epididymis is characterized by a long epididymis that has a sharp bend in the corpus with or without stenosis. With free epididymis, all or part of the epididymis is unattached to the testis. The most common variant is epididymis with free cauda.

Vas deferens anomalies. The most frequent anomalies are of the vas deferens are congenital absence, segmental aplasia, ectopia, duplication, diverticula, and crossed dystopia. 1054 Congenital absence is defi ned as unilateral or bilateral absence of either the whole vas deferens or only a segment. Obviously, azoospermia occurs with bilateral absence. The frequency of this malformation varies among populations. At autopsy, the prevalence is 0.5%, but the clinical incidence Infertility is 1-1.3% in infertile men 1055 and 10-25% in patients with obstructive azoospermia. Unilateral complete absence is three times more frequent than bilateral absence, and absence of only a segment is even more frequent. The affected segment may be absent or reduced to a fi brous cord. Absence of the vas deferens may be associated with other malformations of the sperm excretory ducts or urinary system. The most frequent malformations of the excretory ducts are absence of the ejaculatory ducts (33% of cases) and, less frequently, absence of the seminal vesicles. About 71% of patients with bilateral absence of the vas deferens have partial aplasia of the epididymis. The most frequent malformations of the urinary system are absence of the ipsilateral kidney and other renal anomalies. Complete or partial absence of the vas deferens occurs frequently in patients with cystic fi brosis. Persistent mesonephric duct consists of the ureter joined to the vas deferens, forming a single duct that opens in an ectopic orifi ce between the trigone and the verumontanum. This malformation may be associated with cystic transformation or absence of the seminal vesicle. The kidney may be normal or dysplastic.

Anomalies of seminal vesicle and ejaculatory duct. The most frequent anomalies are agenesis of the seminal vesicles or ejaculatory ducts, cyst of the seminal vesicle, and ectopic opening of the ureter into the seminal vesicle. The last is the most common and often is associated with ipsilateral renal dysplasia. Acquired azoospermia Infl ammation and trauma are the main causes of acquired azoospermia. Epididymitis is a frequent cause; Chlamydia trachomatis 1056, 1057 and Escherichia coli are the most common infectious causes in developed countries. 1958 Infections with Neisseria gonorrheae and mycobacteria are also implicated, and non-specifi c epididymitis is important. 1059 Apart from elective vasectomy, the most frequent traumatic causes of azoospermia are surgical accidents during herniorrhaphy in chidren, 1060 orchidopexy, varicocelectomy, hydrocelectomy, deferentography, 1061 and removal of epididymal cyst. Obstructive azoospermia may also result from blockage of the ejaculatory ducts following transurethral resection, or as a result of chronic urethral catheterization.

Lesions of the testis and epididymis may result from obstructed sperm excretory ducts, depending on the location, origin (congenital or acquired), and duration of the obstruction. Location of obstruction Obstruction at the level of the ampulla of the vas deferens, seminal vesicles, or ejaculatory ducts does not usually cause signifi cant lesions in the testis or epididymis. More proximal obstruction at the level of the vas deferens, epididymis, or testis-epididymis junction usually causes severe lesions in both the sperm excretory ducts and the testicular parenchyma. Obstruction of the vas deferens causes increased pressure within the ductus epididymis. As a result, epididymal lumina dilate, the epithelium atrophies, and fl uid containing few spermatozoa and some spermiophages accumulates in the lumen (Fig. 12-120) . The most dilated epididymal segment is the caput. The ductuli efferentes often become cystically dilated and fi lled with spermatozoa and macrophages. From reabsorption and lysosomal degradation of this protein-rich fl uid, the epithelium accumulates lipofuscin granules or aquires apical eosinophilic granules (Paneth cell-like change). 1062 Rupture of the vas deferens gives rise to microgranulomas and ceroid granuloma (Fig. 12-121 ). Macrophages and lymphocytes are often present in the intertubular connective tissue. 1063 The most frequent testicular lesions in proximal obstruction involve the adluminal compartment, and are the result of the negative effect of hydrostatic pressure on the seminiferous tubular cell layers and, in particular, on the Sertoli cell (Figs 12-122-12-124) . Etiology of obstruction Obstruction secondary to congenital absence of the vas deferens usually causes little testicular injury, mainly dilation of the seminiferous tubules and an increase in the number of mature (S c + S d ) spermatids. 1064 Lesions resulting from vasectomy are more important. Increased intraluminal pressure in the epididymis 1065 may give rise to pain (late post-vasectomy syndrome). 1066 Testicular lesions depend on the surgical technique used: they are slight if the proximal end of the vas deferens is not ligated or sperm granuloma forms at the site of vasectomy. The spermatogenic rhythm in the testis is slower than before vasectomy, and lesions characteristic of testicular obstruction develop, including thickening of the lamina propria and fi brosis of the interstitium. 1067, 1068 In testicular obstruction secondary to herniorrhaphy in infancy, testicular lesions are mild. Testicular lesions may be important if the epididymis is damaged by hydrocelectomy, and consist mainly of primary spermatocyte sloughing. In addition to these lesions, hyalinized tubules may be observed when obstruction is caused by infl ammation.

In acquired obstruction the testicular lesions worsen with time. Obstruction in the caput of the epididymis leads to disappearance of all germ cells in the adluminal compartment of seminiferous tubules. The tubules become dilated and Sertoli cells appear vacuolated. Testicular alterations after vasectomy may not be related to the duration of the obstruction but rather to the initial injury, and may disappear with time as the intraluminal pressure decreases. 1069 However, if a signifi cant amount of time has elapsed after vasectomy, the possibility of attaining a normal spermiogram with vasovasostomy is very low. Vasal patency is restored in most cases of reanastomosis, but paternity rates are markedly lower (25-51%) 1069 than normal (85%). 1070 

Some azoospermic patients have testicular biopsy with minimal histologic abnormality or minor tubular dilation without detectable excretory duct obstruction. These fi ndings are characteristic of two main conditions: Young's syndrome, and alterations in spermatozoal transport. Young's syndrome Young's syndrome is defi ned by the following constellation of fi ndings: azoospermia, sinusitis, bronchitis or bronchiectasis, and normal spermatozoal fl agella. 1071 The incidence is probably higher than that recorded in the literature, and Young's syndrome should be suspected in all patients with obstructive azoospermia without a history of epididymitis or scrotal trauma. These patients have a lesion at the junction of the caput and corpus of the epididymis that gives the epididymis a characteristic gross appearance. The caput of the epididymis is distended, the ductuli efferentes contain yellowish fl uid and numerous spermatozoa, and the remaining epididymal segments are normal. The ductus epididymidis is blocked by thick fl uid. 1072 Young's syndrome should be distinguished from other causes of infertility also associated with chronic sinusitis and pulmonary infections, including ciliary dyskinesia and cystic fi brosis. Ciliary dyskinesia consists of morphological, biochemical, and functional alterations in cilia and fl agella, and includes Infertility several diseases such as the immotile cilia syndrome, Kartagener's syndrome, and miscellaneous syndromes characterized by imperfectly defi ned abnormalities of cilia and fl agella. 1073 In Young's syndrome, sinusitis and pulmonary infections develop in childhood and stabilize or improve in adolescence; in other conditions, the pulmonary damage increases with age and the cilia and fl agella are ultrastructurally abnormal. 1074 Alterations in spermatozoon transport Normally, spermatozoa detach from the Sertoli cells and are transported through the intratesticular and extratesticular excretory ducts, where they are stored, mainly in the cauda of the epididymis, and fi nally released from the corpus by ejaculation or eliminated by phagocytosis. Only about 50% of spermatozoa are ejaculated. Whereas the release of spermatozoa from the corpus is intermittent, their transport through the sperm excretory ducts is continuous. Transport is accomplished by the myofi broblasts in the wall of the seminiferous tubules and ductuli efferentes and the smooth muscle cells in the wall of the ductus epididymidis and vas deferens. These cells cause peristaltic contraction, propelling spermatozoa along the length of the epididymis in a mean of 12 days (range, 1-21 days). The walls of the seminiferous tubules and extratesticular excretory ducts are under hormonal and neural control. The myofi broblasts in the seminiferous tubules have oxytocinic, α 1 -β-adrenergic, and muscarinic receptors. Unmyelinated nerve fi bers penetrate the tubular lamina propria, pass among the myofi broblasts, and end near the Sertoli cells. 1075 Along their length these nerve fi bers have varicosities containing sympathetic vesicles.

The ductus epididymis is innervated by sympathetic adrenergic nerve fi bers that end among the smooth muscle cells. Several hormones, including oxytocin, endothelin-1, vasopressin, and prostaglandins, act on the musculature of the ductus epididymis. The peristaltic contractions begin in the caput and propagate toward the cauda. The frequency and amplitude of contractions vary from region to region, being higher in frequency near the caput and of maximal amplitude in the initial portion of the cauda. The progressive increase in amplitude parallels the progressive increase in thickness of the muscular wall and the requirement for greater force to propel the fl uid as it becomes progressively more viscous with a higher concentration of spermatozoa. The distal portion of the cauda is unusually at rest because it is the main reservoir of spermatozoa between ejaculations. Several times daily, vigorous contractions of the distal cauda impel the spermatozoa from the cauda toward the vas deferens. 1076 Several drugs that favor contraction of the muscular wall (α 1 blocking and F 2α prostaglandins) have been successfully used in the treatment of alterations in the spermatozoon transport. 1077

Knowledge of the incidence of chromosomal abnormalities in male infertility has progressed in parallel with advances in technology: karyotypic studies in peripheral blood, meiotic and chromosomal studies of testicular biopsies, analysis of chromosomes in spermatozoa, and analysis of DNA in blood and spermatozoa for the detection of chromosome Y deletions. 1078 The incidence of chromosomal anomalies in infertile men is 2.2-6.6%, whereas in the general population it is lower than 0.5%. The frequency of chromosomal abnormalities increases with the decrease in number of spermatozoa in the ejaculate. 1079

Klinefelter's syndrome Genetic and clinical aspects Klinefelter's syndrome is characterized by an abnormal number of X chromosomes and primary gonadal insuffi ciency. The original description was of a man with eunuchoidism, gynecomastia, small testes, mental retardation, and elevated level of serum gonadotropins. 1080 The frequency of this syndrome varies according to the population studied: 1 in 1000 to 1 in 1400 surviving newborns; 1 in 100 patients in mental institution; 3.4 in 100 infertile men; and 11% of patients who are azoospermic. 1081 In 80% of cases, the karyotype is 47XXY. The remaining 20% have chromosomal mosaicism with at least two X chromosomes. The most common are XY/XXY, XY/XXXY, XX/ XXY, XXY/XX/XY, XY/XO/XXY, XX/XXY/XXXY, and XXXY/ XXXXY. The 47XXY lesion is due to non-disjunction in sex chromosome migration during the fi rst or second meiotic division of the spermatocyte or ovule, or during the fi rst meiotic division of the zygote. 1082 Study of the Xg antigen in blood revealed that the extra X chromosome is from the mother in 73% of cases. Advanced maternal age increases the incidence of children with the 47XXY karyotype.

In 47XXY patients, the most common clinical fi ndings are: 1083 • Eunuchoid phenotype with increased stature.

The increased height is due to a disproportionate lengthening of the lower extremities. The ratio of span to height is less than 1. • Incomplete virilization. This is variable and ranges from normal development to absence of secondary sex characteristics. • Gynecomastia, usually bilateral, present in 50% of patients. • Mental retardation.

Other commonly associated conditions include chronic bronchitis; varicose veins; cervical rib; kyphosis; scoliosis or pectus excavatum; and a high incidence of hypothalamic, hypophyseal, thyroid, and pancreatic dysfunction. 1084 The external genitalia usually are normally developed. The testes are usually less than 2.5 cm long, although in some cases of chromosomal mosaicism they are of normal size. 1085 The incidence of cryptorchidism is low in 47XXY patients but increased in mosaicism. 1086 Supernumerary X-chromosome material is associated with a reduction of gray matter in the left temporal lobule, a fi nding correlated with verbal and language defi cits. 1087 Histologically, the testes show the classic picture of tubular dysgenesis with small hyalinized seminiferous tubules lacking elastic fi bers and pseudoadenomatous clustering of Leydig cells (Figs 12-125, 12-126 ). 1080 Most biopsies show some tubules with a few Sertoli cells. 1088 These cells may be dysgenetic (pseudostratifi ed distribution of nuclei that are dark and elongate and contain small peripherally placed nucleoli in tubules without apparent lumina). Sex chromatin may only be observed in dysgenetic Sertoli cells. 1089 This suggests that either there is testicular mosaicism of the X chromosome, or that both X chromosomes are heterochromatinized. In mosaicism, Sertoli cell-only tubules may be more numerous than hyalinized ones.

The reduced testicular volume gives an appearance of Leydig cell hyperplasia, 1090 although quantitative studies have shown that the total number of Leydig cells is lower than normal. 1091 Many of the Leydig cells are pleomorphic and some are multivacuolated. Immature fi broblast-like Leydig cells may be present. The abnormally differentiated Leydig cells have nuclei with coarse masses of dense chromatin, deep unfolding of the nuclear envelope, multiple paracrystalline inclusions instead of Reinke's crystalloids, multilayered concentric cisternae of smooth endoplasmic reticulum, large masses of microfi laments, and scant lipid droplets. 1092 Sex chromatin is apparent in 40-70% of Leydig cells. Leydig cell function is insuffi cient and androgen levels are less than 50% of normal. Basal FSH and LH are markedly increased. 1084, 1093, 1094 In a few patients the testicular damage is less severe, with some tubules showing spermatogenesis and less prominence of Leydig cells. 1095 Exceptionally, complete spermatogenesis and even paternity have been reported. 1096 The XY/XXY karyotype is the most frequent variant of Klinefelter's syndrome with chromosomal mosaicism. In this condition, the clinical abnormalities may be attenuated. Gynecomastia is present in 33% of cases, compared to a frequency of 55% in men with the 47XXY karyotype. Azoospermia is found in 50% of cases (93% in XXY men). The testes are larger and spermatogenesis is more developed in men with XXY ( Fig. 12-127) . Patients with the 47XXY karyotype who have spermatozoa in seminiferous tubules are bearers of 46XY spermatogonia and also of 47XXY spermatogonia, whereas those who have no spermatozoa have 47XXY spermatogonia only; these 47XXY spermatogonia may include some spermatozoa with 23X or 23Y chromosomal complement, elevated numbers of both 24XY and 24XX spermatozoa, and also a high frequency of spermatozoa with 21 disomy; this could be an important risk for gonosomy 1097 and also for trisomy 21. 1098 Genetic counseling is advisable in patients seeking intracytoplasmic sperm injection therapy. Genetic diagnosis before implantation of the zygote or prenatal diagnosis have been recommended, except for parents who assume the risk of gonosomy. 

The incidence of the 48XXYY karyotype is estimated to be 0.04 per 1000 live births. [1099] [1100] [1101] [1102] This karyotype may be associated with aggressive character, antisocial behavior, more severe mental retardation, and a higher frequency of congenital malformations than the 47XXY karyotype. Men with the 48XXYY karyotype also have characteristic dermatoglyphics with an increase in arches, a decrease in total fi nger ridge count, and ulnar triradiuses associated with changes in the hypothenar region. 1103 Concentric lamellae of smooth endoplasmic reticulum in Leydig cells are a characteristic fi nding (Fig. 12-128 ). 1104 Men with the 48XXXY or 49XXXYY karyotype often have skeletal malformations, principally radioulnar synostosis, and cryptorchidism. 1105 In addition to the characteristic symptoms of 47XXY Klinefelter's syndrome, 1106 men with the 49XXXXY karyotype have other abnormalities, including severe mental retardation, hypoplasia of external genitalia, cardiac malformations, radioulnar synostosis, microcephaly, and a high arched palate. 1107 Association of Klinefelter's syndrome with malignancy Patients with Klinefelter's syndrome have a higher incidence of malignancy than the general population. The association was fi rst discovered with breast carcinoma, 1108 which had an incidence 20 times greater than in the general male population, 1109 and is related to hormonal stimulation. 1110 Although testicular germ cell tumor is rare in these patients, 1111 extragonadal germ cell tumor is 30-40 times more frequent than in the general population. Most occur in the mediastinum (about 71%) and are less frequent in the pineal gland, central nervous system, and retroperitoneum. The most frequent types are teratoma and choriocarcinoma; embryonal carcinoma and seminoma are rare. [1112] [1113] [1114] The extragonadal origin of germ cell tumors has been attributed to abnormal germ cell migration from the yolk sac. The high incidence has been attributed to elevated hormone levels and chromosomal anomaly. 1115 In a patient with the XY/XXY chromosomal mosaic and bronchogenic carcinoma, cultured XXY fi broblasts transformed three times more frequently when exposed to SV40 virus than did fi broblasts from normal men. 1116 Other tumors reported in patients with Klinefelter's syndrome (lymphoma, leukemia, bronchogenic carcinoma, urothelial carcinoma of the bladder, adrenal carcinoma, prostatic adenocarcinoma, testicular Leydig cell tumor, and epidermoid cyst) do not appear to have a higher incidence than in the general population. [1117] [1118] [1119] [1120] Occurrence of Klinefelter's syndrome in childhood Early identifi cation of this syndrome is possible with systematic cytogenetic study of newborns with positive sex chromatin or mental retardation. 1121 Several clinical symptoms suggest Klinefelter's syndrome. Initial symptoms include decreased muscle tone, delayed speech, and poor language skills with an increased incidence of reading diffi culties and dyslexia. 1122 Later, there may be recognition of mental retardation, 1123 psychiatric problems, excessive stature for age, disproportionately long legs, micropenis, and small testes. [1124] [1125] [1126] [1127] Androgen defi ciency is an early fi nding. 1128 Testicular biopsy reveals scant or absent germ cells. Quantitative studies indicate that the number of germ cells in 47XXY fetuses is signifi cantly lower than in normal 46XY fetuses. The seminiferous tubules have reduced diameter, particularly those devoid of germ cells. The number of Sertoli cells per cross-sectioned tubule is reduced. Megatubules, ring-shaped tubules, and intratubular eosinophilic bodies are common (Fig. 12-129) . In some cases of Klinefelter's syndrome associated with Down's syndrome, tubular hyalinization is observed in childhood. 1129 The interstitium is wide and contains few Leydig cell precursors. If one testis is undescended, its histology does not differ from that of the contralateral testis. The testicular pattern remains constant through childhood. 1130 At puberty, before maturation of the tunica propria occurs, the seminiferous tubules rapidly hyalinize and Leydig cell precursors differentiate into Leydig cells. 1131 Association of Klinefelter's syndrome with precocious puberty Although precocious puberty is not a characteristic fi nding in Klinefelter's syndrome, karyotyping in older boys with mental retardation, gynecomastia, small testes, and precocious puberty is advisable. In most cases, the cause of precocious puberty is a hCG-secreting germ cell tumor in the mediastinum. 1132 Infrequently, precocious puberty is idiopathic, and only in isolated cases is there a hamartoma in the third ventricle. 1133 

Klinefelter's syndrome is often associated with pituitary disorders such as panhypopituitarism 1134 or incomplete hypopituitarism. 1135 Defi cits in FSH, 1136 LH, 1137 or both 1138, 1139 have been reported. The cause of this association is unknown, and diverse etiologies such as trauma, immunologic disorders, and genetic defi ciencies have been postulated. Alternatively, it may be due to exhaustion of pituitary gonadotropin-secreting cells after years of gonadotropin-releasing hormone stimulation. 1135 In patients defi cient in both gonadotropins, testicular biopsy shows diffuse tubular hyalinization and a marked reduction in or absence of Leydig cells. The histological picture is similar to that of hypogonadotropic hypogonadism occurring after puberty, except for the presence of isolated tubules containing only dysgenetic Sertoli cells and absence of elastic fi bers in the hyalinized tubular wall (Fig.  12-130) . 1139 Biopsy of patients with a defi cit only in FSH is similar to that of the dysgenetic Sertoli cell variant of the Sertoli cell-only syndrome, although some hyalinized tubules are present. The testicular biopsy of patients defi cient only in LH resembles that of men with classic 47XXY Klinefelter's syndrome. 46XX males The 46XX karyotype may be present in three phenotypes: male phenotype, including normal external genitalia; male pseudohermaphrodites, with a variable degree of ambiguity in external genitalia, ranging from hypospadias to micropenis; and true male hermaphrodites. 46XX males with male phenotype and normal external genitalia Men with the 46XX karyotype having male phenotype and normal external genitalia have clinical features similar to those of Klinefelter's syndrome, including small testes, small or normal penis, azoospermia, gynecomastia, and minimal development of secondary sex characteristics. However, these men have harmonious body proportions, normal or slightly low stature, and normal intelligence. 1140 The incidence of 46XX males varies from 1 : 10 000 to 1 : 25 000 live births, accounting for about 0.2% of infertile men. 1141, 1142 Males with 46XX karyotype have hypergonadotropic hypogonadism with elevated serum levels of FSH and, to a lesser degree, elevated LH, with normal or slightly decreased testosterone. Familial cases have been reported. 1143 During childhood, biopsy of 46XX males reveals decreased numbers of germ cells. 1144, 1145 Biopsies from adults show one of three patterns: histology similar to that of 47XXY men, including diffuse tubular hyalinization with prominent Leydig cells; 1146 Sertoli cell-only tubules; 1147, 1148 and both patterns intermingled with less prominent Leydig cells. The last is the most frequent ( Fig. 12-131) . Ultrastructural studies reveal an increase in intermediate fi laments, absence of annulate lamellae in Sertoli cells, 1149 absence of Reinke's crystalloids, and abundance of intracytoplasmic and intranuclear paracrystalline inclusions in Leydig cells. 1147 46XX males with ambiguous external genitalia Some patients with the 46XX karyotype have ambiguous external genitalia or hypospadias and are assumed to have a variation of male pseudohermaphroditism. 1150 These males, together with true hermaphrodites, may be found in the same family, suggesting that both disorders are different manifestations of the same genetic defect.

The origin of 46XX males may be diffi cult to determine. However, as testicular differentiation requires genes located on the Y chromosome, 46XX males have been classifi ed by cytogenetics as those having the SRY gene, those lacking the SRY gene, and XX/XY mosaicism. Males with the SRY gene comprise 80% of 46XX males. 1151 It is likely that this occurs when the genetic material from Infertility the short arm of the Y chromosome is translocated to the X chromosome. 1152 During paternal meiosis, the homolog pseudoautosomal regions of chromosomes X and Y interchange the terminal portions of their short arms, giving rise to an X chromosome with the SRY gene but lacking the azoospermia factor. [1153] [1154] [1155] [1156] [1157] [1158] Alternatively, the SRY region may be inserted in an autosome. 1159 Most 46XX patients who are SRY positive have a normal male phenotype. About 10% of 46XX males are SRY negative and most have ambiguous genitalia. Some patients have a normal male phenotype 1161 and only infertility. 1162 Although SRY is assumed to be the most important regulator factor of testicular determination, these patients may have mutation of one of the downstream non-Y testis-determining genes. [1163] [1164] [1165] [1166] About 10% of 46XX males have XX/XY mosaicism or other karyotype with the chromosomal complement Y. In these cases, detection of the specifi c DNA sequences of Y chromosome may be diffi cult because this chromosome may be only in some tissues and in a small number of cells. 1160 47XYY syndrome The 47XYY syndrome was fi rst described in 1961 in the father of a girl with Down's syndrome. 1167 The only clinical fi ndings were excessive height and pustular acne. Study of other cases suggests that these men are predisposed to a psychopathic personality and antisocial behavior, although most have a normal personality and are socially adapted. The incidence of 47XYY patients is estimated to be 0.01% of the general population, 0.7-0.9% of men in prison, and 1.8% of sexual homicide criminals. 1168 The extra Y chromosome originates from non-disjunction during the paternal second meiotic division.

In the past decade, many cases have been diagnosed prenatally. From birth, the patients have weight, stature and cephalic circumference above mean values and a higher risk for delayed language and/or motor development. About 50% of children have psychological and psychiatric problems such as autism; although their intelligence is normal, many patients are referred to special education programs. 1169 As adults, they have normal external genitalia and secondary sex characteristics. Fertility is reduced, 1170 although many have been fathers. Usually, testicular biopsy reveals mixed atrophy characterized by tubules with spermatogenesis associated with Sertoli cell-only tubules (Fig. 12-132) . 1171, 1172 Those tubules with spermatogenesis may show normal spermatogenesis or have lesions in the adluminal or basal compartments. In these tubules, many XXY spermatocytes degenerate during meiosis. About 64 % of pachytene cells have three sex chromosomes. 1173 The number of normal spermatozoa in the ejaculate is low. There is a high incidence of both YY and XY spermatozoa and disomy 18.

The variability in germ cell development is apparently due to elimination of germ cells that could not pair their sex chromosomes during the fi rst or second meiotic divisions 1174 or, later, during the round spermatid stage. 1175 Spermatocytes that succeed in forming trivalent chromosomes are initially viable. 1176 The ultimate trivalent chromosome segregation yields aneuploid and euploid cells in equal numbers. Sertoli cell-only tubules are attributed to either spermatogonial damage by substances released from degenerated spermatocytes 1177 or absence of testicular colonization by primordial germ cells. These men have normal serum levels of testosterone and LH. The latter may be slightly increased in 47XYY men with severe spermatogenic alterations. 1178 47XYY men with mosaicism (47XYY/46XY) have a higher risk of fathering children with hyperdiploid chromosomal constitution, and spermatozoa should be studied genetically to evaluate the risk of intracytoplasmic sperm injection. 1179 Men with three and four Y chromosomes have been reported. Men with the 48XYYY karyotype are tall and have normal male phenotype, slight mental retardation, azoospermia and, during childhood, frequent infections of the upper respiratory tract. 1180 Testicular biopsy shows Sertoli cell-only tubules, severe hyalinization of tubular basement membrane, and diffuse Leydig cell hyperplasia. The chromosomal complement of parents can be normal. 1181 Men with 49XYYYY also have no signifi cant phenotypic abnormalities (except for cases of chromosomal mosaicism). Slight mental retardation, infertility, and antisocial behavior are the most signifi cant clinical fi ndings. 1182 Rarely patients have facial dysmorphism and various skeletal abnormalities. 1183 

The Y chromosome is essential for gender determination and spermatogenesis, and abnormalities often lead to infertility. The relationship between Y chromosome abnormalities and infertility is best understood in azoospermic men with alterations in Yq11, the distal region of the euchromatic part of the long Y arm, the location of a male fertility gene complex called azoospermia factor. Infertility may result from deletion of any of four subregions in which the azoospermia factor has been divided (AZFa, AZFb, AZFc and AZFd). 1184, 1185 The best-known Y chromosome genes involved in spermatogenesis are RBM. DAZ, DFFRY, CDY, SMCY, and ZFY. Six different partial deletions of this region have been found in azoospermic patients (Table 12- Monocentric deleted Yq chromosome Partial deletion of the distal portion of the Yq11 euchromatic region is associated with azoospermia owing to loss of the azoospermia factor. These men have normal external genitalia except for small testes, 1187 normal testosterone and LH serum levels, and increased FSH serum level. The most frequent histological fi nding is Sertoli cell-only pattern, although many other patterns have been reported. 1188 The number of Leydig cells is normal or increased. These fi ndings suggest that the azoospermia factor is required for early spermatogenesis. 1189 If the breakpoint of Yq11 is proximal to the centromere, patients are short because the gene that controls stature is close to that for the azoospermia factor. 1190 Dicentric Yq isochromosomes Sterility is frequent in men with dicentric Yq isochromosomes. 1191 This anomaly is usually associated with a 45X cell line. The proportion of this line varies between patients and between cell types (fi broblasts or lymphocytes). When the point of breakage and fusion of the two Y chromosomes is in the distal region Yq11, and the second centromere is inactivated, the Y isochromosome is normal in size but does not stain with quinacrine, and thus is called non-fl uorescent Y chromosome (Ynf). As the breakpoint is in the Yq11 region, the azoospermia factor function is altered. Development of external genitalia varies from ambiguous to normal, and is probably related to the extent of XO present. 1192 Testicular biopsies are similar to those of men with monocentric deleted Yq chromosomes (Fig.  12-133) . 1193, 1194 Ring Y chromosome Men with ring Y chromosomes have normal male phenotype, azoospermia, and, in some cases, short stature. Most have mosaic karyotype with a 45X line. In some cases, testicular biopsy resembles that of men with monocentric deleted Yq chromosome, but in others there is premeiotic arrest of spermatocyte maturation. 1195 This is attributed to diffi culty in pairing the X and Y chromosomes during meiosis. Many patients have deletion of some AZF regions. 1196, 1197 Y/Y translocation chromosome Patients with this anomaly have small soft testes and primary spermatocyte maturation arrest owing to defective pairing of the X and Y chromosomes. The karyotype may be mosaic with a 45X line. 1198 Translocation of Y chromosome to X chromosome Most frequently this translocation is cytogenetically undetectable, and patients present with infertility and are found to have 46XX karyotype. 1199 The phenotype is similar to that of men with Klinefelter's syndrome except for shorter stature, absence of mental retardation, and smaller teeth. Testicular biopsy shows Sertoli cell-only pattern. Men with cytogenetically detectable translocations have short stature, small testes, tubular hyalinization, and prominent clustered Leydig cells similar to Klinefelter's syndrome. 

Autosomal translocation of Y chromosome Translocation of the distal heterochromatic portion of the Y chromosome to the short arm of an acrocentric chromosome occurs occasionally. The most frequent are translocations to chromosomes 5, 18, 13, 15, and 22. The fertility of these men depends on the point of breakage. 1200, 1201 If this occurs in the Yq12 heterochromatic region, the patient has a male phenotype and is fertile. If the point of breakage is in the Yq11 region, the patient is infertile and has small testes. Seminiferous tubules may show only Sertoli cells, spermatogenetic arrest in early stages of meiosis, or an infantile pattern. 1202, 1203 Interstitial microdeletion in Yq11 Yq11 microdeletion is the most frequent congenital cause of infertility. The frequency of Y chromosome microdeletion in infertile patients varies widely (1-35%). 1204 In azoospermic men, the frequency is between 18% 1205 and 37%. 1206 In oligozoospermic males the incidence drops. Most microdeletions are in the AZFc subregion. 1207, 1208 Testicular biopsy shows only Sertoli cells, maturation arrest, or mixed atrophy. There is no correlation between site of AZF subregion alteration and histological pattern. 1209 There is no exact correlation between genotype and phenotype, 1209 but most microdeletions in AZFa are associated with azoospermia, most microdeletions in AZFb are associated with maturation arrest, and most microdeletions of AZFc are associated with spermatid maturation arrest or mixed testicular atrophy. Partial deletion of AZFc has a mild effect on fertility. 1210

External genitalia in 46XY patients with duplication of distal Xp vary from male, ambiguous, to female, and gonadal dysgenesis is frequent. If the patient has male genitalia, these are usually hypoplastic with hypogonadotropic hypogonadism and, frequently, multiple congenital anomalies and mental retardation. 1211 Males with translocation of the X chromosome to an autosome may have disturbed spermatogenesis with subfertility or infertility. 1212,1213 47XXX males show mental retardation, gynecomastia, normal stature, hypoplastic scrotum, a well-confi gured but small penis, small testes, and poorly developed pubic hair. Serum testosterone levels are very low. Seminiferous tubules appear severely hyalinized. 47XXX males result from an abnormal X-Y interchange during paternal meiosis and X-X non-disjunction during maternal meiosis. 1214

There have been many reports on the relationship between autosomal anomalies and infertility, although the causes are not fully understood because the same anomaly is associated with infertility in some patients but not in others.

Robertsonian translocations are found in 0.7% of infertile men (8.5% higher than in the normal population) and are more frequent in oligozoospermic than in azoospermic men. The most frequent translocations are 13;14 and 14;21.

The incidence of reciprocal translocations in infertile patients is 0.5% (0.1% in the general population) and increases to 0.8% in patients with azoospermia or severe oligozoospermia. 1215 The most frequent in infertile men are 11;22 and 17;21.

Paracentric and pericentric inversions (except for the pericentric inversion of the heterochromatic region in chromosome 9) are eight times greater in infertile patients (0.16%) than in the general population. The highest risk for infertility occurs in the pericentric inversion of chromosome 1. 1216, 1217 The most common testicular lesions in men with autosomal anomalies are spermatogonial maturation arrest, primary spermatocyte sloughing sometimes associated with hypospermatogenesis, and Sertoli cell-only pattern. 1218

The only autosomal anomaly with prolonged survival is Down's syndrome. In addition to trisomy of chromosome 21 and the characteristic appearance, patients with Down's syndrome usually have cryptorchidism, small testes, hypoplasia of the penis and scrotum, and hypospadias. 1219 Adults have oligozoospermia or azoospermia secondary to primary testicular defi ciency. Levels of FSH and LH are elevated, but testosterone is normal or slightly diminished. 1220 Isolated cases of paternity have been reported. 1221, 1222 In utero, there is marked delay in germ cell development. 1223 Histologic studies of prepubertal testes at autopsy reveal decreased tubular diameter and tubular fertility index. Eosinophilic bodies or microliths may be present in some tubules (Fig. 12-134 ). Adult testes have defi cient spermatogenesis and mixed atrophy, with some tubules showing complete spermatogenesis and others containing Sertoli cellonly pattern. 1224

Hypergonadotropic hypogonadism is found in several myopathies (myotonic dystrophy and progressive muscular Fig. 12-134 Prepubertal testis in Down's syndrome. There are megatubules, ring-shaped tubules, and small tubules. Germ cell number is very low in all these tubules. Eosinophilic bodies or microliths are present in some tubules. dystrophy) and dermopathies (Bloom's, Rothmund-Thomson, Werner's, Cockayne's, and Tay's syndromes), with testicular histology that resembles that of Klinefelter's syndrome. Hypogonadism is also observed in Noonan's syndrome, cerebellar ataxia (with milder testicular lesions), and a miscellaneous group of syndromes with variable histological fi ndings. 1225 Myotonic dystrophy accounts for approximately 30% of men with muscular disorders, and about 80% have testicular atrophy. The estimated incidence is 1 in 8000 live births. The abnormality involves the distal muscles of the extremities. In addition, patients may have premature baldness, posterior subcapsular cataracts, cardiac conduction defects, impotence, gynecomastia (rarely), and dementia (at later stages). Myotonic dystrophy is an autosomal dominant inherited disease with variable penetrance. Two loci are associated with the disease phenotype: DM1 in 19q13.3, and DM2 in chromosome 3. Mutation in DM1 results in a serine/threonine protein kinase defi ciency that causes expansion of a CTG repeat (from 50 to several hundred repeats) located on the 3′-untranslated region of the dystrophy myotonic-protein kinase gene. The number of repeats is positively correlated to severity of the disease and negatively correlated to age of clinical onset. [1226] [1227] [1228] DM2 is caused by a mutation in 3q21.3 of the ZNF9 gene and accounts for CCTG-repeat expansion (from 75 to 11 000 repeats) in intron 1 of this gene. The common clinical symptoms are due to gain of function of RNA mechanism in CUG and CCUG repeats altering cellular function, including alternative splicing of various genes. 1229 The severity of the disease increases in the successive generations. 1230 The number of CTG repeats is not associated with male subfertility. 1231 Hypogonadism is hypergonadotropic in most cases and is not related to the number of CTG repeats. 1232 Testicular lesions probably begin late because 65% of patients are fathers. Testicular biopsy shows different degrees of severity, ranging from nearly normal to fully hyalinized seminiferous tubules, with the number of Leydig cells varying from increased to decreased. In some patients the hypogonadism is hypogonadotropic, and the testes show an infantile pattern. Infertility may be the fi rst symptom of myotonic dystrophy. 1233 Progressive muscular dystrophy is a multisystemic X-linked disease. It is usually associated with gonadal atrophy caused by a defective locus in chromosome 19. Patients rarely live more than 20 years. The incidence is approximately 1 in 4000 live births. In both Duchenne and Becker forms the cause is a defect in the dystrophin gene. 1234, 1235 Bloom's, Rothmund-Thomson, and Werner's syndromes are caused by a homozygous defect in human RECEQ helicases in chromosome 15. Of the fi ve members of this gene family (RECQ1, BLM, WRN, RECQ4, and RECQ5), three produce autosomal recessive inherited diseases. Mutations of BLM have been identifi ed in patients with Bloom's syndrome, WRN has been shown to be mutated in Werner's syndrome, and mutations of RecQ4 have been associated with Rothmund-Thomson syndrome. 1236, 1237 Despite the close genetic origin of the three syndromes, symptoms are very different. Bloom's syndrome is characterized by short stature, narrow face with prominent nose, facial 'patchy' skin color changes that become more marked with sun light exposure, and increased susceptibility to respiratory diseases, cancer and leukemia. Severe oligozoospermia and azoospermia are common. Leydig cell function is conserved. 1238 Rothmund-Thomson syndrome presents with poikiloderma, juvenile cataracts, sparse hair, short stature, skeletal defects, dystrophic teeth and nails, and hypogonadism. These patients are predisposed to cancer and osteogenic sarcoma. 1239 Werner's syndrome (progeria) is characterized by short stature, prematurely graying hair, baldness, cataracts, atrophy and calcifi cation of muscle and fat, wrinkling of the skin, keratosis, osteoporosis, telangiectasis, atheroma, diabetes mellitus, gynecomastia, and hypergonadotropic hypogonadism. The lifespan of fi broblasts and other cells is shortened in this syndrome. The mutation is in the RECQ3 helicase gene.

Cockayne's syndrome is a rare autosomal recessive neurodegenerative disorder. Signs and symptoms include infantile failure to thrive, short stature, poorly developed trunk, premature aging, neurological alterations, retinitis pigmentosa, optic atrophy, cataract, deafness, microcephaly, micrognathia, photosensitivity, delayed eruption of primary teeth, congenital absence of some permanent teeth, partial macrodontia, atrophy of the alveolar process and caries, limited articular movements in elbows, knees, and fi ngers, 1240 abnormally small eccrine glands, 1241 and hypergonadotropic hypogonadism. It may be caused by two gene mutations: CNK1 (ERCC8) and ERCC6, located respectively on chromosomes 5 and 10, and causing two variations of Cockayne's syndrome, including CS-A, secondary to a ERCC8 mutation, and CS-B with ERCC6 mutation. CS-B patients have hypersensitivity to ultraviolet light secondary to a DNA repair defect. 1242 Tay's syndrome (trichothiodystrophy) has two presentations: IBSD (ichthyosis, brittle hair, impaired intelligence, short stature) and IBISD (photosensitivity, ichthyosis, brittle hair, impaired intelligence, short stature). In both forms, patients have decreased fertility. One case of hypergonadotropic hypogonadism has been reported. 1243 Noonan's syndrome is characterized by multiple malformations reminiscent of Turner's syndrome, including short statute, pterygium coli, and cubitus valgus, although there is normal male karyotype. The disease has an incidence of 1 in 1000 to 1 in 2500 live births and autosomal dominant inheritance, with sporadic occurrence in about 50% of cases. A locus for dominant forms has been mapped to 12q24.1. 1244 Mutation in PTPN11 (protein-tyrosine phosphatase, nonreceptor-type 11) accounts for half of cases, although similar germline mutations also cause Leopard's syndrome and certain pediatric hematopoietic malignancies. 1245 Cryptorchidism is present in about 70% of cases and is usually bilateral. During childhood, testicular biopsy shows a low tubular fertility index. Puberty is often delayed, and, at adulthood, hypogonadotropic or hypergonadotropic hypogonadism occurs. Ultrastructural studies reveal morphologic anomalies in germ cells. 1246 Although spermatogenesis is generally impaired, some patients have been fertile (Fig.  12-135) .

Cerebellar atrophy may be associated with hypogonadism. Patients are infertile and have moderate ataxia without endocrine disorder. Infertility is due to morphological abnormalities of spermatozoa caused by decreased expression of MAP2 (the most important microtubule-associated protein), and a defect in erythroid ankyrin. 1247, 1248 Many other syndromes also present with primary hypogonadism. The best known are Alström's, Weinstein's, Borjenson-Forssman-Lehmann, Marinesco-Sjögren, Richards-Rundle, Robinow's, and Silver-Russell syndromes.

Hypogonadotropic hypogonadism or hypogonadism of hypothalamo-hypophyseal origin is classifi ed according to whether the hypothalamo-hypophyseal failure occurs before or after puberty. Eunuchoidism, present only in the former group, is the basis of the distinction. The most frequent types of hypogonadism caused by hypothalamo-hypophyseal failure are those caused by a defi cit of gonadotropinreleasing hormone, bioinactive FSH and LH, defi cit in growth hormone, those associated with Prader-Willi syndrome, and Laurence-Moon-Rozabal-Bardet-Biedl syndrome.

The onset and maintenance of the hypothalamo-hypophyseal-gonadal axis is due to pulsatile gonadotropin-releasing hormone (GnRH) secretion by neurons of the nucleus arcuatus hypothalamus, with release into the pituitary portal system and subsequent stimulation of gonadotropinreleasing hormone receptors on the surface of gonadotropinsecreting cells. The GnRH gene is located on 4q13. 1249 Patients with GnRH defi cit have partial or complete absence of GnRH-induced pulsatile LH secretion, and normalization of pituitary and gonadal secretions after exogenous GnRH administration. Imaging studies of the hypothalamo-hypophyseal region are normal. Clinical symptoms vary with age at presentation (congenital or acquired) and severity (complete or partial defi cit). Clinical presentations include delayed puberty, idiopathic hypogonadotropic hypogonadism (isolated gonadotropin defi cit), Kallmann's syndrome, isolated FSH defi cit, and isolated LH defi cit (fertile eunuch syndrome).

Constitutional delayed puberty is assumed to be a minor form of GnRH defi cit, 1250 and is characterized by delayed sexual maturation in otherwise healthy males. Patients are short and usually have a family history of delayed puberty. Puberty usually begins at 13-14 years of age and progresses over 2 years. If a 14-year-old boy has not begun pubertal changes (testicular enlargement, growth in height, and development of secondary sex characteristics), delayed puberty should be suspected. 1251 Simple pubertal delay that is overcome naturally in a short time without treatment must be distinguished from hypogonadotropic hypogonadism. The latter should be suspected when any of the following symptoms are present in the patient or his family: a midline defect, anosmia, or pubic hair without testicular development. Hormone assays may also assist in diagnosis. If a patient between 16 and 18 years old has prepubertal gonadotropin levels, he probably has hypogonadotropic hypogonadism.

A variant of hypogonadotropic hypogonadism, isolated gonadotropin defi cit is characterized by defects in the synthesis or release of FSH and LH; other hypophyseal functions are normal. Patients have eunuchoid phenotype, with small testes and penis, scanty body hair and beard, a high-pitched voice, and poorly developed muscles. Presentation may be sporadic, autosomal dominant, autosomal recessive, or Xlinked. The cause might be a mutation in the GnRH receptor gene. 1252 Patients have very low levels of FSH, LH, testosterone, and estrogen. Clomiphene citrate treatment fails to stimulate hormonal secretion. 1253 Pulsatile administration of GnRH is useful to promote both androgen production and spermatogenesis. The LH-Leydig cell-testosterone axis is normal in most cases, but normalization of the FSH-Sertoli cell-inhibin axis is not achieved in all cases. Basal inhibin levels higher than 60 pg/mL and absence of cryptorchidism are favorable predictor factors for the acquisition of normal testicular size and acceptable spermatogenesis. 1254 Testicular biopsy reveals an immature pattern. The seminiferous tubules have neither lumina nor elastic fi bers (Fig.  12-136 ). Sertoli cells are immature, and no differentiated Leydig cells are seen. Spermatogonia are rare. In some patients the pattern is similar to that of Sertoli cell-only testes with immature Sertoli cells. 1255

Hypogonadism associated with anosmia is also known as Maestre de San Juan, 1256 Kallman, 1257 abnormalities include olfactory bulb agenesis, cryptorchidism, mental retardation, color blindness, facial asymmetry, nerve deafness, epilepsy, shortening of the fourth metacarpal, tarsal navicular fi brous dysplasia, familial cerebellar ataxia, diabetes mellitus, hyperlipidemia, gynecomastia, cleft lip, maxillary or palate, unilateral renal aplasia, and cardiovascular abnormalities. The syndrome may be Xlinked or autosomal. The gene for the X-linked form is mapped to Xp22.3 and may have different mutations (termed Kal-X, KALIG-1, and ADMLX), complete deletion, and point mutations. This gene encodes the protein anosmina-1, which is similar to other nerve cell adhesion molecules and is involved in axonal growth and development. KAL protein, secreted by mitral cells, permits the passage of olfactory neurons into the olfactory bulbs and is lacking in Kallmann's syndrome. This failure also inhibits migration of neuroblasts from the olfactory epithelium to the hypothalamus to form GnRH-secreting neurons. 1259 The autosomal dominant presentation (occurring in 10% of cases) is due to loss of function of fi broblastic growth factor receptor 1 (FGFR1). 1260 Interaction between KAL1 and FGFR1 is required for neuronal migration. 1261 Patients are classifi ed into two groups according to the partial or complete absence of GnRH. Partial absence of GnRH is diagnosed by the presence of spontaneous pulses of LH, FSH, and testosterone during a 24-hour period. Complete absence is diagnosed by the absence of spontaneous pulses of LH, FSH, and testosterone during a 24-hour period. These patients show an increase in FSH only after GnRH administration. 1262 Testes are histologically infantile; the tubules have a small diameter, lack lumina, and contain immature Sertoli cells and isolated spermatogonia. 1263 The interstitium is wide and consists of acellular connective tissue with no recognizable Leydig cell precursors (Fig.  12-137 ). 1264 Autopsy studies in patients with anosmia and hypogonadism reveal agenesis of the olfactory bulbs that may be partial or complete and unilateral or bilateral, together with an apparently normal hypophysis and normal or hypoplastic hypothalamus. This syndrome is the least severe form of holoprosencephaly-hypopituitarism complex, a spectrum of developmental anomalies associated with impaired midline cleavage of the embryonic forebrain, aplasia of the olfactory bulbs and tracts, and midline dysplasia of the face. Testicular seminoma has been reported in a patient with anosmia with hypogonadotropic hypogonadism. 1265

This rare syndrome is characterized by azoospermia or oligozoospermia in normally virilized patients with normal sexual potency. Serum levels of LH and testosterone are normal, but FSH levels are very low or undetectable. The clomiphene stimulation test gives variable results. The GnRH test induces a normal response only of LH. Mutations in the FSH-β gene are exceptional. 1266, 1267 Testicular biopsy shows maturation arrest at the spermatocyte level, hypospermatogenesis, or partial Sertoli cell-only pattern. 1268 Gonadotropin treatment increases spermatozoal numbers in most cases, and fertility may be induced.

Isolated LH defi ciency, also known as Pasqualini's or fertile eunuch syndrome, 1269, 1270 is characterized by hypogonadism secondary to LH defi cit with preservation of spermatogenesis. Patients have eunuchoid habitus, small testes, decreased libido, female distribution of pubic hair, and a high-pitched voice. Other frequent fi ndings include gynecomastia, anosmia, ocular lesions, and pituitary tumor. 1271 FSH level is normal, but LH and testosterone levels are very low. Mutations in the LH-β subunit gene 1272 and the GnRH receptor have been reported. 1273 

The clomiphene test is usually negative, and GnRH stimulation increases LH and, to a lesser degree, FSH. Testicular biopsy shows seminiferous tubules with normal or slightly decreased diameters and complete spermatogenesis; however, the number of all germ cell types is below normal. Leydig cells are rare or absent (Fig. 12-138) . Maintenance of spermatogenesis in the absence of Leydig cells and serum testosterone can only be explained by assuming the occurrence of testosterone secretion suffi cient for spermatogenesis but not to be detectable in the blood.

In addition to adequate hypothalamic function, spermatogenesis requires that FSH and LH are biologically active. LH is a heterodimer, composed of two subunits: α (common to FSH and LH) and β (specifi c for LH). The genes for the β subunit are on 19q13.32. If both alleles are mutated for this subunit, the LH produced in biologically inactive although it may be detectable in standard hormone assay. Homozygous patients have elevated serum level of LH and low testosterone levels, lack of puberty, and infantile testes. Heterozygous patients are only infertile. 1274 Patients with mutation in the β subunit of the FSH gene are oligozoospermic or azoospermic. 1275

Activating and inactivating mutations of gonadotropin receptor genes have been reported. Activating mutation of the LH/human chorionic gonadotropin receptor gene causes familial precocious puberty (see discussion on familial testotoxicosis, below). Inactivating mutation of this gene causes male pseudohermaphroditism (see discussion on Leydig cell hypoplasia in this chapter).

Inactivating mutation of the FSH receptor gene produces only mild spermatogenetic lesions, emphasizing the relative value assumed for FSH in spermatogenesis. Activating muta-tion of this gene gives rise to spermatogenesis even in the absence of pituitary function.

Patients with isolated growth hormone defi cit and those with resistance to growth hormone action may have delayed puberty and hypogonadotropic hypogonadism. 1276 Some patients with spermatogenetic maturation arrest or idiopathic oligozoospermia have a relative defi cit of growth hormone. This hormone probably acts on the testis by stimulating local secretion of insulin-like growth factor-1, which cooperates with testosterone.

Prader-Willi syndrome is characterized by hypogonadism, obesity, muscular hypotonia, mental and physical retardation, and acromicria. 1277 Other frequent fi ndings include strabismus and non-insulin-dependent diabetes mellitus. The incidence is estimated at between 1 in 12 000 and 1 in 15 000 newborns in 25 000 live births, and is higher in males. Patients have low serum levels of LH, testosterone, estradiol, and inhibin B, and high levels of FSH. These hormonal fi ndings suggest the occurrence of a mixed form of central (low LH) and peripheral (low inhibin B and high FSH) hypogonadism. 1278 The penis and testes are hypoplastic, and cryptorchidism is present in about 70% of cases (bilateral in 45% of cases) (Fig. 12-139 ). 1279 During infancy and childhood, the testes have reduced tubular diameters; adults have an infantile pattern. 1280 This syndrome is caused by an anomaly of chromosome 15, usually in the 15p11-12 band. Other chromosomal anomalies include Robertsonian translocations, reciprocal translocations, small supernumerary metacentric chromosomes, and partial deletion of the long arm of chromosome 15.

This syndrome is a pleiotropic disorder characterized by obesity, infantilism, short stature, diabetes insipidus, mental retardation, retinitis pigmentosa, polydactyly, and syndactyly. It is more frequent in males than in females. Men with this syndrome are infertile, and about 74% show hypogonadism. The testes are prepubertal, the scrotum is hypoplastic or bifi d, and the penis is small. Cryptorchidism is found in 42% of males, and is bilateral in 28%. At least 11 genes responsible for this syndrome have been cloned, and it is probable that additional genes are involved. The function of the products of these gene is to mediate and regulate microtubule-based transport processes. 1281, 1282 Hypogonadotropic hypogonadism associated with dermatologic diseases Several dermatopathies are associated with hypogonadotropic hypogonadism, including ichthyosis and Johnson's neuroectodermic syndrome. Most cases of ichthyosis associated with hypogonadism are X-linked. About 15% of these patients have cryptorchidism, small testes, micropenis, and high risk of testicular cancer. The cause is a defective microsomal enzyme, steroid sulfatase, causing the accumulation of cholesterol sulfate that hinders sloughing of the cornifi ed layer of the epidermis. The gene responsible for this enzyme is mapped to Xp22,3. Some of these patients also have anosmia or hyposmia owing to involvement of the neighboring genes, causing a contiguous gene defect. 1283 Johnson-McMillin neuroectodermic syndrome is a rare autosomal dominant disorder characterized by alopecia, hypogonadotropic hypogonadism, anosmia or hyposmia, deafness, prominent ears, microtia and/or atresia of the external auditory meatus, and a pronounced tendency to dental caries. 1284

Hypogonadism associated with ataxia is rare. Most patients are the offspring of a consanguineous marriage. Inheritance is autosomal recessive. The most frequent syndromes are Louis-Bar's syndrome (ataxia-telangiectasia) and Friedreich's ataxia.

Ataxia-telangiectasia is the most common inherited ataxia and is characterized by cerebellar ataxia that starts in infancy and develops progressively; mucocutaneous telangiectasis; anomalies of the immune system that cause pulmonary infection; hypersensitivity to ionizing radiation owing to impairment of DNA repair; and a high risk of lymphoid neoplasia. The gene responsible is on 11q22-q23.1. 1285 This ataxia results from inactivation of the A-T mutated (ATM) kinase, a critical protein kinase that regulates the response to DNA double-strand breaks by selective phosphorylation of a variety of substrates. 1286 Friedreich's ataxia is a neurodegenerative disorder characterized by degeneration of dorsal root ganglia and spinocerebellar tracts. Hypertrophic myocardiopathy is also observed in many of these patients. The incidence is estimated at 1 in 40 000 children. It is caused by defects in the gene encoding frataxin, a protein required for vesicular traffi c in cell and synaptic transmission. 1287 About 95% of patients are homozygous for an unstable trinucleoid (GAA) expansion in intron 18 of STM7 on 9q13. The normal gene has up to 35 or 40 triplet repeats, whereas patients with this ataxia carry 70 to more than 1000 GAA triplets. 1288 The normal gene has seven to 22 GAA repeats, whereas the mutated gene has over 120 repeats. The extent of the expanded allele is directly proportional to the severity of disease, early onset of disease, and development of cardiac abnormalities.

Other ataxias associated with hypogonadism are Kearns-Sayre, Boucher-Neuhauser, and Gordon-Holmes syndromes.

Hypogonadotropic hypogonadism may also be present in Carpenter's, Biemond's, Fraser's, and Moebius' syndromes, and in patients with mental retardation.

Maintenance of spermatogenesis requires the harmonious cooperation of several endocrine glands and proper functioning of other tissues. Symptomatic endocrinopathy is present in only 1.7% of infertile men, but over 9% of infertile patients have abnormalities in their endocrine studies. 1289 Hypogonadism may be present in disorders involving the hypothalamus-hypophysis, thyroid, adrenals, pancreas, liver, kidney, and gastrointestinal tract, and may be associated with AIDS, chronic anemia, obesity, lysosomal and peroxisomal diseases, and neoplasia. Hypogonadotropic hypogonadism can also be found in some (usually women) who perform rigorous sports (long-distance runners, swimmers, dancers, and rhythmic gymnasts). 1290

Hypopituitarism Hypogonadism may result from destruction of the hypothalamus or hypophysis by primary or secondary hypothalamic tumor; granulomatous disease ( Fig. 12-140 ); fracture Infertility of the cranial base; radiotherapy for malignancy of the nasopharynx, central nervous system, or the eye orbit; pituitary adenoma and cyst; aneurysm of the inner carotid artery; and chronic and nutritional disease. Many of these processes cause panhypopituitarism with varied symptoms. 1291 Clinical manifestations of hypogonadism in patients with pituitary lesions vary according to time of onset (childhood, or after puberty). In prepubertal hypopituitarism the testes retain an infantile appearance into adulthood, and there is rarely proliferation of spermatogonia and the development of primary spermatocytes. Biopsy shows variable hyalinization of tubules. In postpubertal hypopituitarism the appearance ranges from complete spermatogenesis to tubular hyalinization ( Fig. 12-141) . The presence of elastic fi bers in tubular walls indicates that pubertal maturation occurred before the development of hypopituitarism. Leydig cells have pyknotic nuclei and retracted cytoplasm with abundant lipofuscin. In some patients, recovery of spermatogenesis occurs after administration of human chorionic gonadotropin. 1292 There are cases in which pituitary adenoma secretes both FSH and LH, inducing testosterone hypersecretion and an elevated sperm count. 1293 FSH-secreting pituitary adenoma associated with large testes and increased serum inhibin concentration has been reported. 1294 Hyperprolactinemia Prolactin inhibits GnRH secretion and hence FSH and LH secretion. In addition, prolactin has a direct inhibitory effect on androgens in target tissues. In men, hyperprolactinemia causes impairment of spermatogenesis, impotence, loss of libido, and depressed serum testosterone. 1295 Some patients seek treatment because of oligozoospermia and infertility. Hyperprolactinemia is also associated with dysfunction of prolactin receptors. 1296 Spermiograms usually show oligozoospermia and an elevated level of fructose, 1287 although not all males with hyperprolactinemia have subnormal testicular function. 1298 Testicular biopsy reveals variable testicular atrophy. The most frequent lesion is in the tubular adluminal compartment, with degenerative changes in the apical cytoplasm of Sertoli cells, sloughing of young spermatids, 1297 and increased lipid droplets in Leydig cells. 1299 In boys, two different conditions associated with abnormal prolactin secretion have been reported: hyperprolactinemia, testicular enlargement, and primary hypothyroidism; and prolactin defi ciency, obesity, and enlarged testes.

Infertility caused by thyroid gland malfunction is rare but reversible. It accounts for about 0.5% of male infertility Testicular function is impaired more by hypo-than by hyperthyroidism. Patients with hyperthyroidism may have gynecomastia, impotence, and infertility. Levels of FSH and LH serum are normal or increased, with elevated sex hormonebinding globulin, increased testosterone concentration, reduced non-sex hormone-binding globulin-bound testosterone, and little or no change in free testosterone. 1300, 1301 In Graves' disease there is a pronounced inhibition of gonadal steroidogenesis. 1302 In patients with hyperthyroidism, spermatozoa may be normal or reduced in number, and in both cases progressive motility is low.

Prepubertal hypothyroidism may impair testicular function by causing precocious or delayed puberty. In delayed puberty, hypothyroidism leads to hypogonadotropic hypogonadism, with testes showing incomplete maturation arrest and, in severe myxedematous hypothyroidism, hydrocele. 1303 In experimental hypothyroidism, testicular enlargement is frequently associated with increased spermatid production. 1304 Primary hypothyroidism in adults causes hypergonadotropic, hypogonadotropic, or normogonadotropic hypogonadism, 1305 but testicular function is rarely impaired and patients are usually infertile. 1306 The cause of testicular damage is decreased gonadotropins or hyperprolactinemia. 1307 Children with hypothyroidism usually have precocious pseudopuberty. 1308

About 11% of infertile patients reportedly have subclinical adrenal dysfunction, but the true incidence is probably lower. Adrenal disorders most frequently associated with infertility are adrenal hypoplasia, adrenal hyperplasia, and adrenal carcinoma.

Congenital adrenal hypoplasia with hypogonadotropic hypogonadism is an X-linked recessive disorder that gives rise to adrenal insuffi ciency in the fi rst months of life. In later presentations, patients have cryptorchidism and delayed puberty. 1309 The responsible gene, DAX1 on Xp21, is expressed in the adrenals, testes, pituitary, and hypothalamus. The resulting hypogonadism may be either pure or mixed (hypophyseal and testicular). In the last case, hypogonadism is partial. 1310 Testicular biopsy from one adult with adrenal hypoplasia showed an apparent primary lesion, including tubules with dysgenetic Sertoli cells and others with spermatogonial maturation arrest in associated with hypertrophy and hyperplasia of Leydig cells. 1311 

Infertility is frequent in patients with minor forms of congenital adrenal hyperplasia. Those with defi ciency of 21hydroxylase 1312 or 11β-hydroxylase usually have complete spermatogenesis but with reduced numbers of all germ cells. The characteristic histologic fi nding is decreased numbers of Leydig cells. [1313] [1314] [1315] [1316] In untreated patients, the testes become enlarged by 'tumors' of the adrenogenital syndrome that consist of cells similar to adrenal cortical cells ( Fig.  12-142 ). [1316] [1317] [1318] [1319] Adrenal cortical carcinoma Adrenal carcinoma is often associated with excessive secretion of several hormones, causing hyperaldosteronism, Cushing's syndrome, virilization, or feminization. Virilizing tumors in infancy have their own characteristics, which differ from those of the same adult tumors as the infantile form may be associated with other disorders, such as hemihypertrophy and Beckwith-Wiederman syndrome, may be included in the spectrum of 'families with cancer predisposition' (mutations in p53 gene), and produce precocious pseudopuberty syndrome. In adults, adrenal carcinoma may cause marked spermatogenic depletion owing to the conversion of large amounts of dehydroepiandrosterone produced by the tumor into estrogen. Feminizing tumor in infancy causes gynecomastia and pubic hair development. 1320 Feminizing tumor presents more striking clinical characteristics, including progressive loss of secondary sex characteristics and feminization due to elevated estrogen. Testicular atrophy results from the inhibitory effect of estrogen on pituitary gonadotropins. Similar symptoms may be observed in patients with prostatic carcinoma treated with estrogens ( Fig.  12-143 ) and in other conditions with excessive estrogen production, such as Sertoli cell or Leydig cell tumor.

Patients with Cushing's syndrome or diseases that require long-term corticoid therapy, such as ulcerous colitis, rheumatoid arthritis, or asthma, have reversible reduction of fertility. The explanation for this is that most testicular receptors for corticoids are in Leydig cells, and thus glucocorticoids are powerful inhibitors of testosterone synthesis.

Alterations in the carbohydrate, lipid and protein metabolism characteristic of diabetes mellitus involve the genital system, although most diabetic patients are fertile. Gonadal impairment depends on the type of diabetes and the time of disease onset (infancy and childhood, puberty, or adulthood). 1321, 1322 Testicular lesions in newborns with diabetic mothers are discussed in the section on congenital anomalies of the testis. 317 Puberty may be delayed in diabetic patients, although the cause is unknown. Other gonadal alterations appear at puberty, and diabetic men who have not been adequately treated may be infertile and have sexual dysfunction. Serum levels of FSH, LH, and testosterone are decreased. 1323 Spermiograms reveal low numbers and poor motility of spermatozoa. 1324 Prolactin levels are increased and testosterone levels low or near normal.

The seminiferous tubules have reduced diameters, thickening of the lamina propria, and alterations in the adluminal compartment. These consist of degenerative changes in the Sertoli cell apical cytoplasm and sloughing of immature germ cells. The major lesion is in the interstitial connective tissue and Leydig cells. Small interstitial blood vessels show diabetic microangiopathy characterized by enlargement and duplication of the basal lamina, pericyte degeneration, and endothelial cell alterations. The number of fi broblasts Infertility and the amount of collagen and ground substance in the interstitial connective tissue are increased. 1325 Leydig cells are decreased in number and show increased amounts of lipid droplets and lysosomes, accounting for the reduced function of these cells.

The tubular lesions are attributed to low serum testosterone, probably owing to defi cient Leydig cell stimulation by insulin (or a decrease in insulin-dependent FSH) and abnormal carbohydrate metabolism of Sertoli cells. Sexual dysfunction is present in more than half of patients and consists of impotence, decreased libido, disorders of intercourse, and retrograde ejaculation. The causes of impotence are multiple, including microangiopathy and macroangiopathy, hormonal defi ciencies, psychological factors, and autonomic neuropathy affecting the parasympathetic system. Neuropathy is probably chiefl y responsible for erectile failure in diabetic men. 1326 Alterations in sperm excretory ducts may be associated with diabetes. The most frequent are enlarged seminal vesicles and calcifi cation of both seminal vesicles and vasa deferentia. Calcifi cations are found in the muscular layers and display a concentric arrangement (Fig. 12-144 ). 1327

Although cystic fi brosis (mucoviscidosis) was recognized as a disease prior to 1940, its effects on the male genital system were not recognized until the 1970s. This may be explained by improvements in medical care during childhood, allowing the survival of many patients to adulthood, and the recognition of cystic fi brosis in patients who had been diagnosed with chronic bronchitis and hepatic or digestive dysfunction. In the US, cystic fi brosis is the most lethal congenital disease, with a prevalence of 1 in 2500 children, and a carrier status of 1 in 25 white men. 1328 Lesions in sperm excretory ducts involve (in decreasing order of frequency) the vas deferens (congenital bilateral absence, unilateral absence), ejaculatory ducts (bilateral obstruction), epididymis (diffuse or segmental hypoplasia), and seminal vesicles (incomplete development). Thus, it appears that most patients with cystic fi brosis have infertility due to obstruction. 1329, 1330 Histologic studies in children, even at an early age, reveal that the vas deferens and ductus epididymis are absent or reduced to small ductuli with reduced or absent lumina and thin, poorly muscular walls (Fig. 12-145 ). The testes are normal during childhood, but show hypospermatogenesis and spermatid malformations by adulthood. The spermiogram is characteristic of obstructive azoospermia, with acid pH, decreased semen volume and fructose concentration, and increased citric acid and acid phosphatase. 1331 The disease is a genetic disorder with autosomal recessive inheritance. The impaired gene (cystic fi brosis gene) is on chromosome 7 (7q31), 1332 and encodes a protein termed cystic fi brosis transmembrane regulator (CFTR). Alterations in this protein cause cystic fi brosis. Although more than 800 mutations of this gene have been identifi ed, 1333 the most frequent mutation in Caucasians is D-F508, responsible for 70% of cases. Congenital bilateral obstructive azoospermia secondary to bilateral absence of the vas deferens, even in the absence of other symptoms, is often a forme fruste of cystic fi brosis. 1334 Before initiating treatment for infertility, the possibility that the patient is a carrier of the cystic fi brosis gene should be evaluated. 1335 Malformation of the genital system plays the most important role in infertility in cystic fi brosis. 1336 The lesions begin in the 10th week of gestation, when the wolffi an duct forms the sperm excretory ducts. 1337 Variable penetrance of the cystic fi brosis gene accounts for the diversity of malformations affecting different regions of the male genital system.

The liver has a primary role in metabolism, detoxifi cation, and excretion of sex steroid hormones. Chronic hepatic failure damages the hypothalamo-hypophyseal-testicular axis, and subsequently all related endocrine glands. Hypogonadism is frequent in the fi nal stages of severe chronic liver diseases, including alcoholism, non-alcoholic liver disease, and hemochromatosis.

The association of testicular atrophy with gynecomastia and hepatic cirrhosis is well known and is referred to as Silvestrini-Corda syndrome. 1338, 1339 Alcohol has a direct toxic effect on Leydig cells. Acute alcoholic intoxication suppresses serum testosterone in voluntary non-alcoholic men and laboratory animals. Chronic alcohol ingestion, even in the absence of cirrhosis, causes hypogonadism, with symptoms of Leydig cell failure, including testicular atrophy, infertility, decreased libido, impotence, and reduced size of the prostate and seminal vesicles. 1340 Chronic alcoholic patients with cirrhosis also have symptoms of hyperestrogenism, including gynecomastia, female escutcheon, and female fat distribution pattern.

Most chronic alcoholic men, with or without cirrhosis, have signifi cant testicular lesions. The seminiferous tubules have reduced diameters, thickened lamina propria, and decreased or absent germ cells. Leydig cells are reduced in number and contain abundant lipofuscin granules ( Fig. 12-146 ). The epididymis becomes atrophic, mainly in the ductuli efferentes, owing to androgen deprivation. The epithelium of the rete testis becomes cuboidal or columnar due to estrogens. The spermiogram correlates with the variability of histologic fi ndings, usually showing a marked reduction in the number and motility of spermatozoa and an increase in the percentage of morphologically abnormal spermatozoa. 1341, 1342 About 20% of patients initially have an increase in serum testosterone; with advanced disease, testosterone level decreases. The initial increase is due to an elevation in sex hormone-binding globulin concentration and reduced testosterone metabolism by the liver. 1343 Serum estrogen level also increases owing to increased conversion of testos-terone into estrogen in peripheral adipose and muscular tissue. 1344 

Non-alcoholic liver disease impairs gonadal function according to the severity of the disease. 1345 Patients have decreased levels of total and biologically active free testosterone. Hormonal alterations are not as severe as in alcoholic patients, emphasizing the direct action of alcohol on Leydig cells. In α 1 -antitrypsin defi ciency testicular function and fertility are conserved; only in advanced stages of the disease do minor biochemical alterations occur. 1346 In Alagille's syndrome (intrahepatic biliary duct hypoplasia), hypogonadism is associated with cholestasis, frequent vertebral, cardiac, and facial malformations, and mental retardation. Hypogonadism is manifest by small testes, delayed puberty, and, in adults, lack of germ cell development.

Hereditary hemochromatosis is the most frequent genetic disease in the northern hemisphere and results from excessive iron absorption and accumulation in multiple tissue and organs, leading to cirrhosis, diabetes, hypogonadism, and arthralgia. Four types of hereditary hemochromatosis have been reported. 1347 Type 1, the most frequent, is caused by mutation in the HFE gene (C282Y), leading to increased intestinal absorption of iron, supersaturation of iron deposits, and damage in multiples organs. The type I hereditary hemochromatosis gene (HFE) is located on the short arm of chromosome 6, 1348,1349 is present in 85-100% of hemochromatosis patients with northern European ancestry, and its protein product is mainly expressed in the epithelium of Lieberkühn crypts. This protein interacts with the transferrin receptor, reducing its affi nity for iron-bound transferrin; therefore, HFE becomes a negative regulator of transferrinbound iron uptake. Type 2 gene is a juvenile form that expresses before the age of 30 years in both sexes, and is associated with severe cardiomyopathy and hypogonadism. 1350 The type 2 hemochromatosis locus is on chromosome 1q21, but this gene has not yet been isolated. 1351, 1352 Type 3 is on chromosome 7q22, impairs the transferrin 2 receptor, and its consequences are similar to those of type 1 receptor defect. Type 4 is autosomal dominant, on 2q32, and affects the basolateral iron carrier ferroportin 1, resulting in iron deposition in macrophages. Types 1, 2, and 3 have recessive autosomal inheritance and show a similar distribution pattern of iron deposits. In these three types, alteration of gonadal function has also been reported.

Iron homeostasis depends on many genes that act in a coordinated manner, and their exact function is not well known. It is assumed that normal individuals absorb 1-2 mg/day of iron, whereas homozygous patients with hereditary hemochromatosis absorb up to 3-4 mg/day. Once iron deposits become saturated (cells of liver, pancreas, hypophysis, heart, adrenals, and gastric mucosa), the toxic effects of iron cause dysfunction of the liver (cirrhosis and cancer in 5-10% of patients), the pancreas (diabetes in 80% of patients), the heart (myocardiopathy), musculoskeletal system (arthritis), and hypophysis (hypogonadism) (Fig.  12-147) . 

Hypogonadism may be the fi rst sign of disease when it starts in adult life. 1353 With age, hypogonadism becomes hypogonadotropic, with low serum levels of testosterone, LH, and FSH in more than 40% of patients, 1354 except if early treatment is initiated. 1355 The most frequent fi ndings are testicular atrophy with diminished tubular diameter, tubular wall thickening, a progressive decrease in spermatogenesis, and increased lipofuscin granules in Leydig cells. The cause of these testicular disorders might be preferential deposition of iron in gonadotropic cells. 1356 Iron deposits are not observed in the testis. Hypogonadism decreases after aggressive therapy. 1357

Polycystic renal disease in adults is a dominant autosomal disorder that appears with 1 in 1000 frequency in the general population. Patients with this disease comprise 10% of end-stage renal failure cases. 1358 Infertility is common, even before the beginning of renal insuffi ciency. Oligoteratozoospermia and necrospermia are frequent fi ndings. 1359, 1360 Serum levels of FSH, LH, prolactin, testosterone, and estradiol remain normal for a long time before the onset of renal insuffi ciency. The causes of spermiogram alterations have been related to partial obstruction of ejaculatory ducts (based on fi nding cystic dilations in seminal vesicles in 60% of patients) or seminal vesicle cyst. 1361 The incidence of these two disorders in patients with polycystic renal disease is very high compared to andrological patients without this disease (5.2%). 1362

Chronic renal insuffi ciency is associated with disturbed endocrine function in the pituitary, thyroid, parathyroids, and testes. The associated sexual dysfunction consists of erectile impotence, diminution of libido and semen volume, oligozoospermia or azoospermia, and infertility. In children, skeletal development and puberty are delayed. 1363 Hormonal studies reveal elevated levels of FSH, LH, and prolactin, but testosterone levels are low. 1364 Testicular biopsy shows seminiferous tubules with reduced diameters and reduced or absent germ cells (Fig. 12-148) . 1365, 1366 The interstitium contains a normal number of Leydig cells and increased numbers of macrophages. Additionally, patients with chronic renal insuffi ciency due to glomerulonephritis have thickening of the tubular lamina propria and decreased number of Leydig cells. Patients with end-stage renal disease who undergo dialysis show calcifi cations in several organs and tissues, including the male genital system (epididymidis, tunica albuginea, and cavernous tissue) in 87% of cases, and, in isolated cases, calcifi cation of the testicular parenchyma and microlithiasis. 1367 Elevated serum levels of phosphorus, increased calciumphosphorus product, severe hyperparathyroidism secondary to other disorders, older age, and prolonged time on dialysis contribute to this disorder. Uremic calcifi cation is a cell-mediated process in which elevated levels of TGF, vitamin K-dependent proteins such as osteocalcin and atherocalcin, and defects in calcium-regulatory proteins such as fetuin are implicated. 1368 When these patients are dialyzed, accumulations of urate and oxalate crystals are deposited in the rete testes and ductuli efferentes. These crystals are deposited beneath the epithelium and often sloughed into the lumen. Reactive changes in the rete testis, including cystic transformation, are frequent (see Disorders of the rete testis). 1369 The cause of gonadal dysfunction is unclear and probably involves several factors, including impaired testicular steroidogenesis, 1370 reduced clearance of pituitary hormones, 1371 and secretory defects of the pituitary and hypothalamus. 1372 Dialysis does not improve testicular function. The response to renal transplantation is not immediate and is related to the glomerular fi ltration rate. Patients with rates lower than 50 mL/min develop atrophy of the seminiferous tubular cells. 1370 

Hypogonadism is a frequent fi nding in men with celiac disease, and results in clinical symptoms in 5-10% of untreated patients. Celiac disease causes infertility in some cases. Spermiograms show reduced motility and numerous morphologic anomalies in spermatozoa. Hormonal studies show elevated serum FSH levels in more than 25% of men with celiac disease. LH also is increased in more than 50% of these men. The response of FSH and LH to GnRH stimulation is excessive. The cause of this pituitary derangement is unknown. Sperm anomalies are not always corrected by a gluten-free diet. Studies in patients with ulcerative colitis and regional enteritis reveal a low sperm count, impaired motility, and ultrastructural alterations, including nuclear pleomorphism and chromatin malcondensation and decondensation. Zinc defi cit may be responsible for these alterations in Crohn's disease. 1373 The alterations apparently are related to the extent of the intestinal lesions and the severity of symptoms. 1374 Patients with ulcerative colitis treated with salazopyrine, 1375 mesalazine 1376 or fasalazine 1377 present with signifi cant impairment of spermatogenesis and subfertility. Spermiogram parameters improve when treatment ceases.

More than 17% of HIV-infected men have hypogonadism, 1378 which can be observed even in those whose viral replication is under control and show normal numbers of CD4 lymphocytes. Patients frequently develop 'early andropause,' marked by dysregulation of the hypothalamopituitary-testicular axis. 1379 Hypogonadism is more frequent in HIV-infected men with wasting syndrome, and therefore these patients should undergo screening for hypogonadism and, if necessary, physiologic androgen replacement therapy. [1380] [1381] [1382] [1383] The incidence of hypogonadism in males with AIDS is estimated to be 50%. 1384, 1385 According to autopsy studies this increases to 100% in the 3-24 months prior to death. 1386 Histological studies reveal that 28% have complete but quantitatively abnormal spermatogenesis, and the remainder have spermatocytic arrest or Sertoli cell-only pattern.

Patients with chronic anemia requiring multiple transfusions develop iron deposits in the pituitary and polyglandular insuffi ciency, with atrophy of the thyroid, adrenals, and testes ( Fig. 12-149) . The most frequent conditions are βthalassemia and sickle cell anemia (see Fig. 12-119) .

β-Thalassemia is an autosomal dominant disease with three types: thalassemia trait (heterozygous β-thalassemia), intermediate thalassemia, and major β-thalassemia. The cause is mutation in the β-globin gene resulting in ineffective erythropoiesis, hemolysis, and anemia. Nearly 20% of patients with major thalassemia have delayed puberty, [1387] [1388] [1389] and 69% have hypogonadotropic hypogonadism. 1390 Gonadal dysfunction persists in most patients after healing of the thalassemia. 1391 Sickle cell anemia is an autosomal recessive disorder with a constellation of fi ndings resulting from abnormal synthesis of hemoglobin, with over 90% of hemoglobin being type A. Most patients have hypogonadotropic hypogonadism. 1392

The majority of people in developed countries are currently overweight, and the incidence of obesity seems to be increasing. Infertility is frequently associated with obesity. Very obese males have increased levels of serum estradiol and decreased levels of free testosterone and inhibin B. 1393 Testosterone reduction is not followed by a compensatory increase in gonadotropins, resulting in hypogonadotropic hypogonadism. 1394, 1395 Testicular abnormalities begin with the adluminal compartment and later involve the basal compartment; also, there are Leydig cell atrophy, cuboidal metaplasia of the rete testis, and epididymal atrophy.

There are three types of autoimmune polyglandular insufficiency syndrome. Type I is defi ned by the presence of at least two of three characteristic features: Addison's disease, hypoparathyroidism, and chronic mucocutaneous candidiasis. The AIRE gene (autoimmune regulator), responsible for type l disease, is on 21q22.3, 1396,1397 and the disorder is recessive autosomal. Hypergonadotropic hypogonadism is frequent. 1398 Patients with type I syndrome have antibodies against many autoantigens, intracellular enzymes including the P450 side-chain cleavage enzyme, 17α-hydroxylase 1399, 1400 and 21-hydroxylase, glutamic acid decarboxylase 65, aromatic L-amino acid decarboxylase, tyrosine phosphataselike protein IA-2, tryptophan hydroxylase (TPH), tyrosine hydroxylase, and cytochrome P450 1A2. 1401 Type II autoimmune polyglandular syndrome is characterized by the presence of diabetes mellitus, hyperthyroid- Infertility ism, Hashimoto's thyroiditis, Addison's disease, vitiligo, alopecia, pernicious anemia, and hypogonadism (listed in decreasing order of frequency). Type III syndrome includes thyroiditis, diabetes mellitus, pernicious anemia, and vitiligo or alopecia. About 14% of patients have hypogonadism owing to autoimmune destruction of the testis or pituitary gonadotropin-secreting cells (Fig. 12-150) . 1402, 1403 

There are at least four diseases caused by metabolic deposits in lysosomes or peroxisomes associated with testicular alterations, including Fabry's disease, adrenal leukodystrophy, Wolman's disease, and cystinosis.

Fabry's disease is an X-linked metabolic disorder characterized by intralysosomal deposits of globotriaosylceramide (Gb3) owing to α-galactosidase defi ciency. Clinical symptoms begin with painful neuropathy and progressive renal, cardiovascular, and cerebrovascular dysfunction. All endocrine glands may accumulate Gb3 as a result of welldeveloped vasculature and low rate of cell proliferation. 1404 Testes and sperm excretory ducts are always damaged. Some alterations, including those of endothelial cells, smooth muscle cells, and fi broblasts, are non-specifi c; others, such as those of myofi broblasts, Leydig cells, and epididymal epithelium, are specifi c (Figs 12-151, 12-152 ). Spermatogenesis is defi cient. 1405 Enzyme replacement therapy with recombinant human α-galactosidase eliminates existing glycosphingolipid deposits and blocks new ones, and is thus recommended for implementation as soon as possible after diagnosis. [1406] [1407] [1408] Adrenoleukodystrophy (adrenal testicular myeloneuropathy) This disorder is caused by mutation in the adrenoleukodystrophy gene on Xq28. 1409 Mutation at this site produces three peroxisomal diseases: adrenoleukodystrophy, adrenomyeloneuropathy, and Addison's disease.

Adrenoleukodystrophy is characterized by progressive demyelinization of the central nervous system, usually in children and young adults, often with adrenal insuffi ciency and testicular failure. Peroxisomal β-oxidation is defi cient and, as a result, very long-chain fatty acids accumulate inside peroxisomes in many tissues, causing the signs and symptoms of the disease. 1410, 1411 Adrenomyeloneuropathy begins at a later age (about 30 years) with progressive paraparesis, peripheral neuropathy, and adrenal cortical failure. Males usually have gonadal dysfunction with oligozoospermia or azoospermia and hypergonadotropic hypogonadism. 1412 Testicular atrophy develops slowly, the seminiferous epithelium disappear, and Leydig cells contain characteristic cytoplasmic lamellar inclusions, with similar inclusions in adrenal cortical cells and cerebral cells. 1413 

Wolman's disease is a rare inherited lysosomal disease characterized by a defi cit in acid lipase/cholesteryl ester hydrolase. The genetic mutation has been mapped to 10q23.2-q23.3. 1414 Complete enzymatic defi ciency (Wolman's disease) causes death in infancy as a result of the accumulation of cholesterol esters and triglycerides in numerous organs such as the liver, adrenal cortex, and intestines. 1415 Partial defi ciency is known as cholesteryl ester storage disease, and the testis accumulates triglycerides and cholesterol in Leydig cells and, to a lesser degree, in interstitial macrophages. Delayed disruption of spermatogenesis by this storage disease probably accounts for the frequent lack of fertility problems in men with this disease. 1416 Early treatment of children with Wolman's disease by transplantation of umbilical cord blood-derived stem cells may successfully restore acid lipase level in some. 1417 

Cystinosis is an autosomal recessive metabolopathy characterized by alterations in cystine transport from the lysosomes to the cytosol that results in intralysosomal accumulation of cystine. There are several genes responsible, all on chromosome 17p13. Cystine storage occurs in all body tissues. Deposits in the renal parenchyma cause the main complication of cystinosis, namely renal insuffi ciency (nephropathic cystinosis). Patients also develop hypergonadotropic hypogonadism. Testicular involvement may be massive, with interstitial macrophages fi lled with cystine crystals that are visible by polarized light. 1418 

Niemann-Pick disease consists of a heterogeneous group of inherited recessive autosomal diseases characterized by deposition of lipids in macrophages and other tissues. There are four reported types (A, B, C, D). The most common, type A, results from excessive storage of sphingomyelin owing to a mutation in the acid sphingomyelin gene that encodes a lysosomal hydrolase, located on 11p15.1-4 region. 1419 Interstitial macrophages in the testes have wide eosinophilic, granular cytoplasm. Ultrastructural studies reveal a large number of lysosomes fi lled with laminate bodies.

Physical and chemical agents may impair testicular function by direct action on the pituitary, the testis, or the sperm excretory ducts. In the pituitary, damage to gonadotropic cells may be caused by estrogen. In the testes, gonadotoxic agents may selectively impair a select cell type, but later, global dysfunction occurs. For example, there is direct toxicity to Sertoli cells by phthalates used as plasticizers, nitroaromatic compounds intermediate in the production of dyes and explosives, and γ-diketones used as solvents. Direct toxicity on spermatogenesis is seen wtih ionizing radiation. Many drugs that impair epididymal fl uid or spermatozoon transport damage sperm excretory ducts, with subsequent loss of fertility. 1420

The relationship between infertility or subfertility and certain professions or exposures to environmental agents is well known. 1421 Adverse effects of the following agents on spermatogenesis has been demonstrated: organic solvents such as chlorinated solvents, aromatic solvents and varnishes, degreasers, thinners, and adhesives; this is also the case with carbon disulfi de exposure; pesticides such as DDT, linuron, and polychlorinated biphenyls; 1422 heavy metals such as lead, cadmium, mercury, and copper; industrial wastes such as dioxins and ethylene dibromide; phthalates and polyvinyl chloride; oral contraceptives; exposure to radiation or high temperature; and recreational drugs and doping. There is also a long list of potentially harmful agents that disrupt testicular function. 1423

Carbon disulfi de is used as a solvent in the production of rayon. Continuous exposure is toxic to the nervous system, and causes a decrease in spermatogenesis and libido and an increase in FSH and LH serum levels. 1424, 1425 Dibromochloropropane Dibromochloropropane is used as a soil fumigant to control nematodes. Lengthy exposure causes oligozoospermia, azoospermia, increased FSH and LH levels, and Y-chromosome non-dysjunction. 1426 

Of the two natural forms of lead, organic and inorganic, the inorganic form is more dangerous. Exposure to inorganic lead by workers in smelting, battery, and stained-glass plants causes direct spermatogenic damage. 1427 Patients have asthenospermia, teratozoospermia, and oligozoospermia. 1428, 1429 Oral contraceptive manufacture Workers in pharmaceutical plants using synthetic estrogens and progestins develop hyperestrogenism with gynecomastia, decreased libido, and impotence. 1430 Neonatal exposure of males to diethylstilbestrol may induce cryptorchidism, testicular hypoplasia, epididymal cyst, and severe anomalies in semen production. 1431

There is increasing evidence to suggest that estrogen-like effects are produced by a variety of naturally occurring estrogens (so-called phytoestrogens) and numerous synthetic compounds such as phthalates, 1432 pesticides, 1433 and polychlorinated biphenyls. 1434 The principal methods of contact with potential endocrine-disrupting compounds is dietary ingestion of milk, fi sh, meat, fruits and vegetables, or environmental exposure. 1435 The increasing incidence of cryptorchidism, hypospadias, testicular cancer, and poor semen quality may be related to the negative infl uence of environmental factors on the testis during fetal life. The term 'testicular dysgenesis syndrome' has been proposed to designate this constellation of putative syndromes. 1436 Estrogen exposure in utero may disrupt development of the testes and the entire male reproductive tract. Estrogen may hinder FSH secretion by the fetal pituitary, and also interfere with subsequent Sertoli cell proliferation, and hence the secretion of AMH required for the regression of müllerian ducts. Persistence of müllerian derivatives is associated with lack of testicular descent. Changes in AMH secretion may also account for altered germ cell proliferation during fetal life. Exposure to high concentrations of estrogen might compromise testosterone production as well as masculinization of external genitalia (hypospadias) and inguinal descent of the testis (cryptorchidism). Abnormal development of Sertoli cells and low germ cell numbers could cause diminished spermatozoon production and infertility. 1437 

Marijuana decreases sperm density and motility and increases the number of morphologically abnormal spermatozoa. 1438 Cocaine induces apoptosis in the rat testis ( Fig. 12-153 ). 1439 About 20% of injection drug users have low serum testosterone levels. Consumption of more than 80 g alcohol per day adversely affects spermatogenesis in two-thirds of patients. 1440 Women smoking more than 20 cigarettes per day have fertility problems, neonatal and perinatal mortality, miscarriage, and congenital malformations. 1441 Abuse of anabolic steroids by athletes causes hypogonadotropic hypogonadism and transient azoospermia. 1442 

Ionizing radiation causes alterations in spermatogenesis and hormonal regulation of the testes. Some patients recover fertility a few years after exposure. 1443 The effects of non-ionizing radiation are less severe; however, reduced libido and reduced numbers of spermatozoa have been reported in men exposed to microwaves. 1444 Heat Normal intratesticular temperature is 31-33°C, about 4-6°C lower than core body temperature. Conditions causing higher testicular temperature, such as varicocele and cryptorchidism, also cause testicular damage, with decreased numbers of spermatozoa and an elevated percentage of sper-matozoa with abnormal forms and low motility. 1445, 1446 Primary spermatocytes at the end of the pachytene stage are most sensitive to heat. The mechanism by which heat produces testicular lesions is unknown; hyperthermia affects the activity of enzymes such as ornithine decarboxylase 1447 and carnitine acetyl transferase, 1448 both necessary for metabolism and proliferation of the seminiferous tubular cells. 1449 The synthesis of DNA and RNA by germ cells also depends on temperature. DNA synthesis by spermatogonia and preleptotene primary spermatocytes is higher at 31°C than at 37°C. RNA and protein synthesis are normal at temperatures between 28°C and 37°C, but decrease markedly at 40°C. 1450

Testicular trauma is especially frequent among athletes. Trauma results in a wide variety of lesions, including contusion with or without hematocele, rupture, dislocation, and eventually spermatogenetic alteration that may lead to infertility. Dislocation involves the displacement of one or both testes to a non-scrotal location 1451, 1452 such as the inguinal canal, abdominal cavity, acetabular area, or distant locations such as the perineum, subcutaneous tissues, or superfi cial to the outer oblique fascia. 1453, 1454 Spermatogenetic recovery by orchidopexy has been successfully performed up to 13 years after bilateral traumatic dislocation. 1455

Sexual dysfunction is found in 25-50% of patients who are treated for cancer. 1456 Testicular cancer, Hodgkin's disease, and leukemia are the most frequent malignancies during the reproductive years. Therefore, preservation of fertility requires careful selection of less gonadotoxic therapeutic regimens; if paternity is planned, cryopreservation of semen before treatment may be considered. The most destructive treatments for gonadal function are radiation therapy and alkylating agents. 1457 

The testicular parenchyma is one of the most radiosensitive tissues of the body, and the germ cells are the most radiosensitive cells of the testis. Experimental irradiation of volunteers with a single dose revealed that late spermatogonia (Ap and B) are more radiosensitive than early (Ad) spermatogonia. Ap and B spermatogonia may be destroyed with doses as low as 0.3 Gy (1 Gy = 100 rad), whereas Ad spermatogonia tolerate doses higher than 4 Gy. Type A spermatogonia, spermatids, and spermatozoa are respectively 100, 200, and 10 000 times less radiosensitive than B spermatogonia. Doses higher than 6 Gy produce a Sertoli cellonly pattern. Leydig cells tolerate up to 8 Gy and Sertoli cells up to 60 Gy, although Sertoli cells show ultrastructural alterations and increased phagocytosis of germ cell remnants after low doses of radiation.

Even with optimal protection, the contralateral testis absorbs from 0.2 to 1.4 Gy in adjuvant therapy for rectal cancer 1458 or when the opposite testis is irradiated, 1459 a dose suffi cient to cause temporary azoospermia. Likewise, irradiation of iliac or inguinal lymph nodes for Hodgkin's disease or other forms of lymphoma exposes the testes to about 5 Gy. 1460 Restoration of testicular function is time-dependent, 1461 requiring at least 2 years. 1462 Fertility in thyroid cancer patients who received radioiodine-131 ( 131 I) therapy decreases briefl y, but infertility is not permanent. 1463 Electromagnetic radiation from cell phones impairs spermatozoon motility according to one study. 1464 Prepubertal testes also are sensitive to radiation therapy. Patients treated for Wilms' tumor may have delayed puberty and, at adulthood, oligoospermia or azoospermia with elevated levels of FSH; this fi nding suggests that Leydig cells are also damaged. A special case is that of children with acute lymphoblastic leukemia involving the testis. Radiotherapy with doses of 20-25 Gy, either alone or with chemotherapy, causes irreversible damage to the seminiferous tubules and Leydig cells. These patients develop azoospermia and hypogonadotropic hypogonadism with low serum testosterone ( Fig. 12-154 ).

Widespread use of cytotoxic chemotherapy has created a number of adverse side effects, including gonadotoxicity. Combination chemotherapy makes it diffi cult to ascertain which specifi c agent is responsible for azoospermia and Leydig cell dysfunction. Comparative studies of chemotherapy for acute lymphoblastic leukemia, 1465 extragonadal solid tumors, 1466 Hodgkin's disease, 1467 Ewing's sarcoma, and other soft tissue sarcomas 1468 in children and pubertal boys have shown that alkylating agents cause the most severe testicular damage. Alkylating agents destroy the seminiferous tubular cells and induce tubular atrophy, shrinking the testis and increasing FSH serum concentration. 1469 These agents also impair Leydig cell function, causing low testosterone, normal or elevated serum levels of LH, and an exaggerated response of LH to GnRH administration. 1470 Testicular damage may be increased by combination with other agents (Fig. 12-155 ).

Cyclophosphamide appears to be responsible for the greatest number of permanent or temporary cases of azoospermia after chemotherapy. This agent acts directly on the spermatogenic stem cells, 1468 and recovery depends on the number of surviving cells. In children, cyclophosphamide reduces seminiferous tubule diameter and germ cell numbers; in the residual spermatogonia nuclei are enlarged. Puberty may progress, even during treatment, and the adult testis may show a Sertoli cell-only pattern. 1465 In adults, cyclophosphamide treatment may cause irreversible testicular damage. Administered alone, a dose of 20 000 mg/m 2 produces permanent azoospermia in 50% of men. If cyclophosphamide is administered with doxorubicin, vincristine, dacarbazine, or dactinomycin (drugs that alone do not cause azoospermia), doses of 7500 mg/m 2 cause azoospermia in 50% of patients. Fludarabine, used for the treatment of chronic lymphocytic leukemia, produces testicular damage with diminution of ejaculate volume, oligozoospermia, increase in serum levels of FSH and LH, and decreased testosterone level. DNA in spermatozoa is markedly abnormal, an effect that persists for several months. 1471 Procarbazine, used to treat Hodgkin's disease, causes permanent azoospermia in 30% of patients, even when not combined with alkylating agents. 1472 Patients treated with a combination of cyclophosphamide and procarbazine in the COPP protocol (cyclophosphamide, vincristine, procarbazine, and prednisone) do not recover spermatogenesis even if the cyclophosphamide dose does not exceed 4800 mg/m 2 .

Chemotherapy without both alkylating agents and procarbazine, such as the ABVD (dexorubicin, bleomycin, vinblastine and dacarbazine) or VBM (vinblastine, bleomycin and methotrexate) regimens, produces reversible azoospermia in 36% of patients. The alternating use of MOPP (mechlorethamine, vincristine, procarbazine and prednisone) and Fig. 12-154 Testis from a 26-year-old patient who, at the age of 9 years, underwent surgery followed by radiotherapy for paratesticular rhabdomyosarcoma. The testicular biopsy shows post-irradiation lesions, including germ cell aplasia and peritubular and interstitial fi brosis. 

ABVD treatments causes testicular dysfunction in 87% of patients, but spermatogenesis recovers in 40%. 1473 Patients with germ cell cancer who received chemotherapy with BEP regimens (cisplatinum, etoposide, and bleomycin) become azoospermic 7-8 weeks after starting treatment. When the total doses reaches 600 mg/m 2 , infertility is irreversible; at lower dosages, fertility might be recovered over a period of about 2 (50% of patients) to 5 (80%) years, 1474 although a high percentage of spermatozoa with DNA abnormalities persists. 1475 An important consideration in patients with testicular cancer or Hodgkin's disease is the existence of testicular dysfunction before treatment. In some series 1476 dysfunction is present at diagnosis in more than 50% of patients; its cause is unknown. Proposed mechanisms include primary germ cell defi ciency, release of toxic substances by tumor cells, and alteration in the hypothalamo-hypophysealtesticular axis.

Sexual function is often lost in patients who undergo bilateral retroperitoneal lymph node dissection for nonseminomatous testicular cancer. Up to 90% lose antegrade ejaculation, although libido, erection, and orgasm are normal. Loss of antegrade ejaculation results from the removal of or injury to sympathetic ganglia and the hypogastric nervous plexus during surgery. Unilateral surgery, especially if the left side is not operated on, reduces this complication. 1477, 1478 Hypospermatogenesis sometimes occurs after surgery for rectal cancer, perhaps due to vascular compromise.

Spinal cord injury is a frequent fi nding, with more than 10 000 cases annually in the US, mostly in young adults. 1479 Fertility is impaired in 90% of males with spinal cord injury. The major sexual dysfunctions in these patients are the lack of erection and ejaculation and poor semen quality. [1480] [1481] [1482] [1483] [1484] [1485] Failure of ejaculation occurs in 95% of patients. Semen may be obtained by means of vibratory stimulation of the penis or electroejaculation in more than 90%, but its quality is low, with increased numbers of dead spermatozoa, markedly low motility, and reduced fertilization rate. [1486] [1487] [1488] Possible explanations include genitourinary tract infection, endocrine anomaly, and impaired spermatogenesis. Recurrent infection occurs in 60-70% of patients. Compared to controls, a signifi cant increase in the numbers of neutrophils and macrophages occurs, with a marked increase in the production of reactive oxygen species. 1489, 1490 This fi nding and the presence of elevated cytokine levels 1491 are assumed to be involved in pathogenesis. Endocrine anomalies are transient, and hormonal levels return to normal after a few months. More than 50% of patients have abnormalities of the adluminal compartment of the seminiferous tubules, with variable degrees of immature germ cell sloughing; 1482 in 50% of patients the number of mature spermatids per cross-sectioned tubule is less than 10 (normal >21).

Possible etiologies include an increase in testicular temperature due to vascular dilation, or an alteration in scrotal thermoregulation secondary to impaired sympathetic innervation from prolonged wheelchair restraint; alteration in sperm transport secondary to nerve injury, resulting in sperm stagnation in seminal vesicles, a hostile environment that normally is devoid of spermatozoa; 1493 and abnormal composition of seminal fl uid, causing deterioration of spermatozoa that in the epididymis and ductus deferens had good motility. 1494 More than 25% of patients with spinal cord injury have brown-tinged semen in some ejaculations. 1495 Although the cause is unknown, it might be related to seminal vesicle dysfunction.

When spermatozoa cannot be obtained by electroejaculation or vibratory stimulation, vasal aspiration or testicular biopsy are recommended. Most patients have at least a few mature spermatids in some seminiferous tubules; therefore, testicular sperm extraction followed by intracytoplasmic sperm injection is a reasonable consideration in azoospermic patients. 1492

Infectious agents may reach the testis and epididymis through blood vessels, lymphatics, sperm excretory ducts, or directly from a superfi cial wound. Infection transmitted through the blood mainly affects the testis and causes orchitis, whereas infection ascending through the sperm excretory ducts usually causes epididymitis. Acute infl ammation is accompanied by enlargement of the testis or epididymis. The tunica albuginea is covered by a fi brinous exudate, and the testicular parenchyma is yellow or brown. Bacterial infection may cause abscess. In some cases the infection begins to heal, with the deposition of granulation tissue and fi brosis; in others, the infection may persist as an active process for a long time, resulting in chronic orchidoepididymitis.

The most frequent causes of viral orchidoepididymitis are mumps virus and Coxsackie B virus. Other viral infections that occasionally cause acute orchitis include infl uenza, infectious mononucleosis, echovirus, lymphocytic choriomeningitis, adenovirus, coronavirus, bat salivary gland virus, smallpox, varicella, vaccinia, rubella, dengue, and phlebotomous fever. Subclinical orchitis probably occurs during other viral infections (Fig. 12-156) .

Before vaccination was commonly used, mumps orchidoepididymitis complicated 14-35% of adult mumps cases and was bilateral in 20-25% of cases. Nevertheless, miniepidemics still occasionally occur. 1496, 1497 As expected, the incidence remains high in countries where vaccination is not obligatory. 1498 In about 85% of cases of mumps orchitis the epididymis is also involved, but epididymal involvement alone is rare. 1499 Clinical symptoms of orchitis usually appear 4-6 days after symptoms of parotiditis, but orchitis may also appear without parotid involvement. 1500 Testicular involvement is multifocal, and consists of acute infl ammation of the interstitium and seminiferous tubules. The tubular lining is destroyed, and eventually only hyalinized tubules and clusters of Leydig cells remain. 1501 With time, the testes shrink and become soft. If the infection is bilateral the patient is usually infertile, with severe oligozoospermia or azoospermia, although biopsy may reveal the presence of mature spermatids in some tubules, allowing sperm extraction for paternity. 1502 If only one testis was affected, the sperm concentration may be normal or slightly decreased and fertility is maintained. Occasionally the testicular damage is so severe that testicular endocrine function is impaired, causing hypergonadotropic hypogonadism, with low testosterone levels and regression of secondary sex characteristics. Mumps orchidoepididymitis is infrequent in childhood.

Most bacterial orchitis is associated with bacterial epididymitis. Orchitis secondary to suppurative epididymitis caused by Escherichia coli is most common. 1503 On light microscopy, the tubules are effaced by intense acute infl ammation. Chronic orchitis with microabscesses is caused by E. coli, streptococci, staphylococci, pneumococci, Salmonella enteritidis, 1504 and Actinomyces israeli. 1505, 1506 In some cases of chronic bacterial orchitis, the testis contains an infl ammatory infi ltrate consisting of numerous histiocytes with foamy cytoplasm (xanthogranulomatous orchitis) (Fig. 12-157) , 1507 similar to that of idiopathic granulomatous orchitis but lacking intratubular giant cells. Rarely, as in Whipple's disease, large numbers of bacilli are present in histiocytes in the interstitium, vascular walls, and seminiferous tubules.

The most frequent complications of pyogenic bacterial orchidoepididymitis are scrotal pyocele and chronic draining scrotal sinus. Small fragments of testicular parenchyma may be eliminated through the scrotal skin, known clinically as fungus testis. Another complication is testicular infarct, resulting from compression or thrombosis of the veins of the spermatic cord, in the scrotal neck, or the superfi cial inguinal ring.

Most cases of chronic orchidoepididymitis are associated with granulomas in the testis. Specifi c causes may require special stains, cultures, or serologic tests, and include tuberculosis, syphilis, leprosy, brucellosis, mycoses, and parasitic diseases. In sarcoidosis and idiopathic granulomatous orchitis, the agent is unknown.

The incidence of tuberculous orchidoepididymitis declined after the development of effective antibiotics, but it has recently undergone a resurgence among people who have emigrated from countries with a high incidence of the disease and the increasing population of immunologically compromised patients.

Most cases of tuberculous orchidoepididymitis are associated with involvement elsewhere in the genitourinary system. 1508 Tuberculous epididymitis is usually the result of ascent from tuberculous prostatitis, which in turn is often secondary to renal or pulmonary tuberculosis. The pattern of spread is different in children: more than half have advanced pulmonary tuberculosis, and the testis is infected through the blood. 1509 More than 50% of patients with renal tuberculosis develop tuberculous epididymitis, and orchitis occurs in approximately 3% of patients with genital tuberculosis, usually secondary to epididymal tuberculosis. It has been suggested that some cases of tuberculous orchidoepididymitis are sexually transmitted. 1510 Tuberculous orchidoepididymitis occurs mainly in adults: 72% of patients are older than 35 years, and 18% are over 65 years. The signs and symptoms may be mild, consisting only of testicular enlargement and scrotal pain. In such cases, fever is infrequent and constitutional symptoms may be absent. 1511 Histologically, there are typical caseating and noncaseating granulomas that destroy the seminiferous tubules 

and interstitium (Figs 12-158, 12-159 ). In immunosuppressed patients, the granulomas consist of epithelioid histiocytes and a few lymphocytes with rare giant cells. Acid-fast bacilli tend to be more numerous in immunosuppressed patients. Similar lesions may be observed in orchidoepididymitis caused by bacillus Calmette-Guérin, which is usually used for intravesical instillation in patients with vesicular urothelial carcinoma. 1512 Syphilis Syphilitic orchitis may be congenital or acquired. In congenital orchitis, both testes are enlarged at birth. The histological fi ndings are similar to those of the interstitial orchitis of acquired syphilis. If diagnosis is delayed until puberty, the testis often shows retraction and fi brosis. In adults, acquired orchitis is a complication of the tertiary stage of syphilis and has two characteristic histologic patterns: interstitial infl ammation and gumma.

Early in the disease, patients with interstitial orchitis have painless enlargement. Grossly, the parenchyma is gray with translucent areas. Histologically, plasma cells are abundant. The infl ammation begins in the mediastinum testis and testicular septa, later extending through the parenchyma as the seminiferous tubules lose their cellular lining and undergo sclerosis. Initially, the arteries show an obliterans type of endarteritis. Small gummas may be observed. Eventually, the infl ammation subsides and is replaced by fi brosis. The epididymis is usually not affected.

Gummatous orchitis is characterized by the presence of one or several well-delineated grossly gray-yellow zones of necrosis. 1513 Histologically, ghostly silhouettes of seminiferous tubules are visible within the gumma, surrounded by infl ammation consisting of lymphocytes, plasma cells, and scattered giant cells. In most cases spirochetes may be demonstrated histochemically with Warthin-Starry silver stain, but the most specifi c diagnostic technique is genetic testing.

The testis may be infected in patients with lepromatous or borderline leprosy. Frequent involvement of the testis in lepromatous leprosy results from the low intrascrotal temperature that promotes growth of the bacilli. Orchitis is usually bilateral, although the degree of involvement may differ between the testes. Occasionally, testicular involvement may be the sole indication of the infection, and the diagnosis may be made by testicular biopsy. 1514 The histologic fi ndings in the testis vary with the duration of the infection. Initially, there is perivascular lymphocytic infl ammation and interstitial macrophages that contain numerous acid-fast bacilli. Later, the seminiferous tubules undergo atrophy, the Leydig cells cluster, and blood vessels show endarteritis obliterans. Finally, the testis is replaced by fi brous tissue with a few lymphocytes and macrophages containing acid-fast bacilli. Most patients with lepromatous leprosy are infertile, even if the orchitis was clinically mild. 1515, 1516 Brucellosis Brucellosis is common in some parts of the world, including the Middle East. 1517, 1518 Orchitis occurs in some patients and may be the fi rst sign of disease. Brucellosis should be suspected when testicular enlargement occurs in patients with undulating fever, malaise, sweats, weight loss, and headache. 1519 Occasionally this may mimic testicular tumor. Histologically, there is a dense lymphohistiocytic infl ammation with occasional non-caseating granulomas in the interstitium. The seminiferous tubules are infi ltrated by infl ammatory cells and undergo atrophy. Diagnosis is made by clinical and laboratory fi ndings, including blood culture, the Bengal rose test, and high brucella agglutination titers, 1520, 1521 or by real-time polymerase chain reaction assay of urine. 1522

Sarcoidosis is a systemic granulomatous disease of unknown etiology that preferentially affects young black adults. The genitourinary tract is involved in only 0.5% of clinical cases and 5% of autopsy cases. Fewer than 30 cases of primary epididymal involvement have been reported, and about 12 of these also involved the testis. 1523, 1524 Isolated testicular involvement is exceptional. 1523, 1525, 1526 Testicular sarcoidosis is usually unilateral and nodular. 947 It is often asymptomatic and found at autopsy. 1527 The testis contains non-caseating granulomas similar to sarcoid granulomas at other locations. Before diagnosing testicular sarcoidosis, other granulomatous lesions should be excluded, including tuberculosis, sperm granuloma, granulomatous orchitis, and seminoma. Seminoma often has an intense sarcoid-like reaction, and examination of multiple histologic sections may be necessary to fi nd diagnostic foci of seminoma. An association of mediastinal sarcoidosis and testicular cancer has been reported. 1528 Genital involvement of sarcoidosis may be the cause of intermittent azoospermia that benefi ts from corticoid therapy. 1529

Malakoplakia is a chronic infl ammatory disease that was initially described in the bladder 1530 and subsequently in many other organs. The testes (alone or together with the epididymis) are involved in 12% of cases involving the urogenital system. 1531, 1532 Grossly, the testes are enlarged and have a brown-yellow parenchymous discoloration, 1533 often with abscesses. Malakoplakia causes tubular destruction that is associated with a dense infi ltrate of macrophages with granular eosinophilic cytoplasm that often contains Michaelis-Gutmann bodies (Fig. 12-160) . 1534, 1535 The differential diagnosis includes idiopathic granulomatous orchitis and Leydig cell tumor. Infl ammation in idiopathic granulomatous orchitis includes intratubular multinucleate giant cells; in malakoplakia it is diffi cult to identify the tubular outlines, and giant cells are usually absent. Leydig cell tumor is not usually associated with infl ammation, but may contain mononucleated or binucleated cells with abundant eosinophilic cytoplasm. Reinke's crystalloids are identifi ed in up to 40% of cases of Leydig cell tumor but absent in malakoplakia, and Michaelis-Gutmann bodies are absent.

Fungal orchitis is rare; most cases are associated with blastomycosis, coccidiomycosis, histoplasmosis, and cryptococcocis. 1536 The genital tract may be involved in widespread blastomycosis. In decreasing order, the organs most frequently affected are the prostate, epididymis, testis, and seminal vesicles. Grossly, there often are small abscesses that may have caseous centers. Fungi measuring 8-15 µm in diameter with double refringent contours are present in the giant cells in granulomas and stain positively with periodic acid-Schiff and methenamine silver stains.

Coccidioidomycosis is endemic in California, the southwestern United States, and Mexico, and may present as epididymal disease after remission of systemic symptoms. 1537 The granulomas are similar to those of tuberculosis and contain 30-60 µm sporangia with endospores that stain with periodic acid-Schiff. Dissemination of histoplasmosis and cryptococcosis frequently occurs after steroid therapy and may give rise to granulomatous orchitis with extensive necrosis. 1538 Histoplasma capsulatum measures 1-5 µm in diameter and may be demonstrated with silver stain. Cryptococcus is identifi ed by its thick wall that stains with mucicarmine.

Most parasites that reach the genital tract, such as Phyllaria and Schistosoma, are in the spermatic cord, and testicular lesions are secondary to vascular injury. 1539 Testicular infection has also been reported in patients with visceral leishmaniasis, congenital and acquired toxoplasmosis ( Fig.  12-161) , 1540 Echinococcus infection, 1541 and orchitis due to Trichomonas vaginalis. 

Idiopathic granulomatous orchitis is a chronic infl ammatory condition of older adults (mean, 59.2 years). The most prominent clinical symptom is testicular enlargement, suggesting malignancy. 1542 Most patients have a history of scrotal trauma, 66% have symptoms of urinary tract infection with negative cultures, and 40% have sperm granuloma in the epididymis. An autoimmune etiology has been suggested.

The testis is enlarged, with a nodular cut surface and areas of necrosis or infarction. There are two histologic forms, according to whether the lesion is predominantly in the tubules (tubular orchitis) or the interstitium (interstitial orchitis). In tubular orchitis, germ cells degenerate and the Sertoli cells have vacuolated cytoplasm and vesicular nuclei. Plasma cells and lymphocytes infi ltrate the walls of the seminiferous tubules, forming concentric rings. Multinucleated giant cells are present in the tubular lumina and sometimes in the interstitium (Fig. 12-162 ). Vascular thrombosis and arteritis are common. In interstitial orchitis, the infl ammation is predominantly interstitial. Ultimately, tubular atrophy and interstitial fi brosis prevail in both forms, which may arise from different immune mechanisms. 1543 Tubular orchitis histologically resembles experimental orchitis caused by injection of serum from animals with orchitis, whereas interstitial orchitis resembles orchitis produced by the transfer of cells from immunized animals.

The differential diagnosis of idiopathic granulomatous orchitis is infectious orchitis caused by bacteria, spirochetes, fungi, or parasites. A useful clue in the tubular form is the presence of giant cells within seminiferous tubules.

The occurrence of focal lymphoid cell infi ltrates in the testicular interstitium is common in infertile patients, 1544, 1545 patients who have undergone surgery for bilateral inguinal hernia, 1546 vasectomized patients who developed post-infection obstruction, 1547 after testicular piercing, 1548 and cryptorchidism. 1549 Infl ammatory infi ltrates usually involve the seminiferous tubules, and this suggests the disorder is due to an immunologic response (Fig. 12-163 ).

Pseudolymphoma is a benign reactive process with a lymphoid cell proliferation so intense that it may be mistaken for lymphoma. Testicular pseudolymphoma consists of infl ammatory infi ltrates with numerous lymphocytes and plasma cells that partially or totally destroy testicular parenchyma. 1550, 1551 The differential diagnosis includes lymphoma, various forms of orchitis, and seminoma. The diagnosis of lymphoma may be excluded by the lack of atypia and polyclonal nature of the infl ammation. Syphilitic orchitis also contains a plasma cell-rich infl ammatory infi ltrate, but pseudolymphoma does not have other characteristic features of syphilitic orchitis, such as endarteritis obliterans; spirochetes cannot be demonstrated by special stains. The lack of granulomas or signifi cant numbers of macrophages, together with the negative results of specifi c histochemical stains, also helps to exclude idiopathic granulomatous orchitis, tuberculosis, leprosy, sarcoidosis, and fungal infection. Finally, although the presence of a prominent infl ammatory infi ltrate and, in many cases, numerous lymphoid follicles, may suggest the diagnosis of seminoma, the presence of seminoma cells should be easily demonstrated with Best's carmine stain, periodic acid-Schiff, or placenta-like alkaline phosphatase. The term plasma cell granuloma 1152 refers to a reactive process characterized by the presence of polyclonal adult plasma cells that are absent in testicular plasmacytoma. 1553

Sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease) is a benign proliferation of macrophages that uniquely contain numerous lymphocytes in their cytoplasm. The disease was reported in a kidney and testis of a patient in remission from malignant lymphoma in association with monoclonal IgA gammopathy, 1554 and in a second patient with diabetes mellitus who had been previously treated for pulmonary tuberculosis. 1555 Increased numbers of interstitial macrophages may also be observed in more than two-thirds of autopsies from adult patients, but the cause is unknown. One condition associated with this disorder is treatment with hydroxyethylstarch plasma expander. In this lesion, the interstitial macrophages stand out by virtue of their large size and multivacuolated cytoplasm, suggesting thesaurosis. There is no evidence of mucin glycoproteins, proteoglycans, starch, lipids, glycogen, or foreign body material. Most patients have no clinical symptoms other than pruritus and persistent erythrema. 1556

Epididymitis nodosa is a proliferation of small irregular ducts whose epithelium lacks the characteristic features of the epididymal epithelium. The disorder is associated with infl ammation and fi brosis, similar to vasitis nodosa. 1557

In several tissues, including the testis, amiodarone is concentrated up to 300 times its plasma level, 1558 causing testicular atrophy and increased serum levels of FSH and LH in some patients. 1559 The incidence of epididymitis during amiodarone therapy varies from 3% to 11%, 1560, 1561 and more than 35 cases (in several cases involvement was bilateral) have been reported, although there are probably many others. 1562, 1563 The disorder may occur at any age. 1564 When amiodarone dosage is reduced to 300 mg/day the epididymitis heals within a few weeks. 1565 Autopsy studies show focal areas of fi brosis and lymphoid cell infi ltrates not related to infection. Recognition is important to avoid unnecessary antibiotics or aggressive surgery.

This term describes a lesion located in the epididymal head characterized by non-infectious necrosis with polypoid masses of infl amed granulation tissue in peripheral ductal structures. Granulomas containing multinucleated giant cells present within efferent ductuli or form sperm microgranulomas with ductal neoformation similar to that of epididymitis nodosa. The cause is unknown, but may result from ischemia. 1566

The terms 'testicular calculus' and 'stone in the testis' have been used to describe a lesion characterized by the presence of nodular testicular calcifi cation that is not related to ischemia, orchitis, vasculitis, hematoma, or tumor. 1567, 1568 

The testicular arteries may be affected by systemic disorders such as Schönlein-Henoch purpura, 1569 Wegener's disease, 1570, 1571 Kogan's disease, 1572 Behçet's disease, 1573 relapsing polychondritis, rheumatoid arthritis, and dermatomyositis, but the most frequent involvement is with polyarteritis nodosa. 1574 Approximately 80% of patients with polyarteritis nodosa have testicular or epididymal involvement, 1575 but only 2-18% are diagnosed during life. Rarely, testicular or epididymal polyarteritis nodosa is the fi rst manifestation of the disease. In these cases the symptoms may suggest orchitis, epididymitis, testicular torsion, or tumor. [1576] [1577] [1578] The testis usually shows arterial lesions in different stages of evolution, including fi brinoid necrosis, infl ammatory reaction, thrombosis, or aneurysm. The parenchyma initially has zones of infarction ( Fig. 12-164 ). Histologic and immunohistochemical fi ndings similar to those of polyarteritis nodosa may occasionally be observed in the testis or the epididymis without lesions elsewhere; this condition is referred to as isolated arteritis of the testis and epididymis, 1579 and differs from classic polyarteritis by a lack of vascular thrombosis, aneurysm, or infarct. The etiology of isolated arteritis is unknown, but the prognosis is excellent. 1580 The histologic fi ndings of necrotizing arteritis in the testis or epididymis should be followed by clinical, hematologic, and biochemical studies to exclude systemic arteritis. 1581, 1582 

Torsion of the spermatic cord is the most frequent cause of testicular infarct, followed by trauma, incarcerated inguinal hernia, epididymitis, and vasculitis.

Spermatic cord torsion is a surgical emergency. If repair is delayed more than 8 hours, testicular viability is usually compromised. This disorder may appear at any age, but the Other testicular and epididymal lesions peaks of maximal incidence are the perinatal period and puberty. 1583 Factors that predispose to testicular torsion are anatomical anomalies in testicular suspension and abnormal position of the testis. Many men with testicular torsion have an abnormally high refl ection of the tunica vaginalis, giving rise to the deformity known as 'bell-clapper.' Other anomalies include elongated mesorchium, separation between the epididymis and testis, and absent or very elongated gubernaculum. The frequency of testicular torsion is higher in cryptorchid and retractile testes than in normal testes.

There are two classic anatomic forms of testicular torsion: high (supravaginal or extravaginal) and low (intravaginal). Each appears at a different age. Extravaginal torsion typically occurs in infancy and childhood, whereas intravaginal torsion is more frequent at puberty and adulthood.

Neonatal torsion is bilateral in 12-21% of cases. 1584 Most torsion observed on the fi rst of life is intrauterine. 1585 Pubertal and adult torsion causes testicular pain that may radiate to the abdomen or other sites. About 36% of patients have a previous history of pain or swelling in one or both testes. The differential diagnosis includes all causes of acute scrotum. 1586, 1587 Torsion causes hemorrhagic infarction of the testis ( Fig.  12-165 ). In old neonatal torsion, the histological fi ndings are so advanced that only collagenized tissue containing calcium and hemosiderin deposits is seen. In adults, three degrees of histological lesion may be distinguished. 1588 Degree I (26.5% of adult twisted testes) is characterized by edema, vascular congestion, and focal hemorrhage. Seminiferous tubules are dilated, with sloughed immature germ cells, apical vacuolation of Sertoli cells, and dilated lymphatic vessels. 1589 Degree II (26.5% of testes) has pronounced interstitial hemorrhage and sloughing of all germ cell types in the seminiferous tubules. The lesion is more severe in the center of the testis, and thus biopsy might provide erroneous information (Fig. 12-166 ). Degree III lesions (45% of testes) are characterized by necrosis of the seminiferous tubular cell layers. There is often a correlation between the time interval of torsion and the degree of the histologic lesion. 1590 Degree I appears in torsion of less than 4 hours' duration, degree II in torsion of between 4 and 8 hours, and degree III in torsion of more than 12 hours. Nevertheless, there are some exceptions that could probably be related, among other factors, to the number of twists in the torsed spermatic cord (degrees of testicular rotation). The testicular salvage rate, defi ned as testicular growth and development that refl ects the age of the patient and the contralateral testis, is around 50% in all cases of testicular torsion. 1591 Testes that do not bleed into the albugineal incision within 10 minutes are assumed to be non-viable and should be removed. 1592 Little attention has been paid to intermittent testicular torsion. Early orchiopexy may save these testes, but after surgery, the testis becomes small and excessively mobile, and most have the bell-clapper deformity. 1593 Seminiferous tubules are devoid of germ cells and have hyalinized walls.

Some adults with untreated testicular torsion develop lipomembranous fat necrosis of the spermatic cord. 1594 Patients seek help for pain in the high scrotum. At this level, there is a small nodule that corresponds to remnants of the twisted testis. The epididymis and proximal spermatic cord characteristically contain fat necrosis (Fig. 12-167) .

Adults with prior spermatic cord torsion often consult for infertility. The mechanism causing spermiogram alteration is controversial, and three hypotheses have been proposed:

• Autoimmune process. It has been suggested that the ischemic injury breaks the blood-testis barrier, and antigens released from the necrotic germ cells activate macrophages and lymphocytes in the interstitium, stimulating the formation of antibodies against these antigens. These antibodies that enter in the blood circulation may presumably damage the contralateral testis. 1595 • Alterations in microcirculation. After testicular torsion, blood fl ow decreases in the contralateral testis, causing an increase in the characteristic products of hypoxia, such as lactic acid and hypoxanthine. 1596 Intense apoptosis involving mainly spermatocytes I and II has been observed. 1597 Long-term effects are yet unknown. • Primary testicular lesions. Many twisted testes have lesions that cannot be formed in a few hours, such as hypoplastic tubules, microlithiasis, and focal spermatogenesis. In addition, more than half of biopsies of the contralateral testis show marked spermatogenetic lesions. 1598 These fi ndings suggest that torsion occurs in testes with congenital lesions.

Trauma 1599 and lesions of the vessels of the spermatic cord may also cause testicular infarct. Ischemic atrophy is a risk of inguinal surgery, including herniorrhaphy, varicocelectomy, hydrocelectomy, and descent of cryptorchid testis ( Fig. 12-168 ). The incidence of atrophy after inguinal herniorrhaphy varies from 0.06% in primary herniorrhaphy 1600 to 7.9% after surgery for recurrent herna, 1601 depending on the diffi culty and extent of the hernia. Atrophy occurs in some cases of thrombosis of the vena cava or spermatic artery. 1602 Focal infarction of the testis is associated with polycythemia, sickle cell disease, trauma, 1603, 1604 and laparoscopic inguinal hernia repair. Focal infarction may also be spontaneous. Clinical symptoms of testicular infarct mimic testicular tumor. Color Doppler ultrasound reveals the diagnosis in most cases. 1605

Cystic malformation of the tunica albuginea and testicular parenchyma was fi rst described in the 19th century, 1606 and was long considered rare and mainly present in the tunica albuginea. 1607, 1608 With the systematic use of ultrasonography, the incidence of cysts has been found to be much higher: 1609 non-neoplastic cysts are found in 2.1% 1610 to 9.8% 1611 of testes. 1612, 1613 Cyst of the tunica albuginea is usually an incidental fi nding in patients in the fi fth or sixth decade of life. It is located in the anterolateral aspect of the testis and may be unilocular or multilocular, 1614 ranging from 2 to 4 mm and containing clear fl uid without spermatozoa. The cyst may be embedded within the connective tissue of the tunica albuginea, protrude from the inner surface of the tunica albuginea into the testicular parenchyma, or protrude from the outer surface forming a blue lump in the tunica albuginea. The epithelium lining the cyst may be simple columnar or stratifi ed cuboidal, and is supported by a thin layer of collagenized connective tissue. The columnar epithelium usually includes some ciliated cells, 1615 and the cuboidal epithelium is composed of two layers of non-ciliated cells (Fig.  12-169) .

Cyst of the rete testis is identifi ed by a distinctive epithelial lining of areas of fl attened cells intermingled with areas of tall columnar cells. Spermatozoa are frequently found within the cyst, 1616 and hence the cyst is also called intratesticular spermatocele. 1617 It may be associated with cystic transformation of the rete testis and multiple epididymal cysts. Rete testis cyst is not always attached to the rete and may be found at a distance.

Simple cyst of the testis constitutes the remaining intraparenchymal cyst. It is usually lined by cuboidal epithelium and contains no spermatozoa. 1618, 1619 Simple cyst ranges Other testicular diseases from 2 nm to 18 mm in diameter. 1620, 1621 The disorders occurs at any age, from 5 months to 80 years, with a bimodal distribution with peaks at 8 month and 60 years. 1622 It may occur bilaterally, 1623 and may present as two cysts in the same testis. 1624 Origin of the three types of testicular cyst is uncertain. Previously, traumatic 1625 and infl ammatory 1626 origins were attributed to tunica albuginea cyst, but most now believe that they are derived from embryonal remnants of the mesonephric ducts 1615, 1627 or mesothelial cells embedded in the tunica albuginea during embryogenesis. 1614, 1628, 1629 Simple cyst of the testis may also have a mesothelial origin, but it is possible that some arise from ectopic rete testis epithelium. These cysts are unrelated to epidermoid cyst, differing in the ultrasonographic 1630,1631 and histologic features (see discussion on cystic dysplasia and testicular tumors in the section on hamartomatous testicular lesions). Ultrasound studies indicate that testicular cyst has little potential for growth. 1630,1632 Currently, excision is recommended only in children when the cyst may impair testicular development. 1633 

Dysgenesis of the rete testis is characterized by inadequate maturation and persistence of infantile or pubertal characteristics in adults. 1634 This disorder is frequent in undescended adult testes. The lesion involves the rete testis segments referred to as septal, mediastinal, and extratesticular. There is poor development of the cavities and their epithelial lining, which becomes cuboidal or columnar instead of fl attened with areas of columnar cells. The lumina of the rete testis cavities may be completely absent (simple hypoplasia) or, conversely, undergo microcystic dilation (cystic hypoplasia). In a few cases, the rete testis develops papillary, cribriform, or tubular formations (adenomatous hyperplasia).

The epithelium of the rete testis is usually fl attened, with scattered areas of columnar cells. In estrogen-treated patients, those with chronic hepatic insuffi ciency, functioning tumor that secretes estrogens or human chorionic gonadotropin, and other disorders that are described as hyperplasia of the rete testis it may undergo diffuse transformation into tall columnar epithelium. Except for the latter group, metaplasia of the rete testis seems to be an estrogen-dependent process, and estrogen receptors are present in the rete testis epithelium. 1635

Acquired cystic transformation of the rete testis is common, and its incidence increases with age and associated disorders. 1636 Ultrasound 1637 Ultrasound ,1638 and magnetic resonance 1639 studies reveal characteristic images that may suggest malignancy. The lesion has three forms: simple, associated with epithelial metaplasia, and with crystalline deposits.

Simple cystic transformation consists of dilated cavities with normal epithelium. It results from obstruction of the epididymis or the initial portion of the vas deferens due to ischemia (aging men); compression by epididymal and spermatic cord tumor, or by congestive veins in varicocele; infl ammation in patients with previous epididymitis; malformation (testis-epididymis dissociation, malformed epididymis and absence of the vas deferens); 1640 or iatrogenic causes (surgery for epididymoectomy or removal of epididymal cyst) (Fig. 12-170) . 1641 Cystic transformation with epithelial metaplasia is a frequent fi nding at autopsy. 1369 Its development is probably due to the concurrence of sperm excretory duct obstruction and conditions involved in increased serum estrogen levels, such as chronic liver insuffi ciency. Another possible cause is infl ammation involving the rete testis.

Cystic transformation with crystalline deposits has also been called cystic transformation of the rete testis secondary to renal insuffi ciency. 1642 It is a bilateral lesion of adult testes characterized by the concurrence of three fi ndings: cystic transformation of the rete testis, cuboidal or columnar metaplasia of its epithelium, and the presence of urate and oxalate crystalline deposits that may be recognized by polarized light. The lesion is pathognomonic of dialyzed patients with chronic renal insuffi ciency. Crystalline deposits are initially formed beneath the epithelia of the rete testis and ductuli efferentes; later they protrude into the lumina, where they are fi nally released. Infl ammation is absent or slight, although a few giant cells and small fi brotic areas are often seen (Figs 12-171, 12-172 ).

This lesion is characterized by diffuse or nodular proliferation of tubular or papillary structures that are derived from the rete testis 1643 and are observed in cryptorchid or normally descended testes. Cases have been reported in newborns, children, and adults. 1644 Adenomatous hyperplasia in newborn and infantile testes consists of enlargement of the mediastinum testis by cordlike or tubular structures derived from the rete testis. The lesion may extend up to one-third of testicular volume. Despite excessive development of the rete testis, the normal connections with seminiferous tubules and efferent ductuli remain. Presentation may be unilateral or bilateral. Unilateral presentation is associated with cryptorchidism or vanishing testis. Bilateral cases may also present with bilateral renal dysplasia. Efferent ductuli may show luminal dilation and irregular outlines. The etiopathogenesis might be similar to that of cystic dysplasia of the testis. 1644 Adenomatous hyperplasia in adults is usually an incidental fi nding at autopsy, 1645 in cryptorchid testes, 1646 or in testes with germ cell tumor. The rete testis epithelium forms nonencapsulated nodular outgrowths or a diffuse pattern. Nodule size may be large enough to suggest tumor. The epithelium consists of cuboidal cells with ovoid nuclei, deep nuclear folds, and peripheral nucleoli. Atypias and mitotic fi gures are lacking (Fig. 12-173) . The ultrastructure and immunophenotype of the epithelium are similar to those of the normal rete testis. Spermatozoa may be seen inside the cavities in some cases, suggesting that such a proliferation is connected with the seminiferous tubules. Most of the testes show a certain degree of seminiferous tubular atrophy.

In incidental autopsy cases the etiology is unknown, although it may be related to hormonal or chemical agent effects. [1647] [1648] [1649] In cryptorchid testes and with many testicular tumors, the most probable cause is a primary anomaly that is part of the testicular dysgenesis syndrome. 1650 Adenomatous hyperplasia should be distinguished from three entities: rete testis pseudohyperplasia, which appears in atrophic testes; primary rete testis tumor; and metastasis of adenocarcinoma. In pseudohyperplasia, lesions are focal, microscopic, and usually located in the septal rete, although the mediastinal rete shows few or no alterations. Benign rete testis tumor such as adenoma (solid and papillary variants) Fig. 12-171 Changes in the rete testis associated with dialysis. Dilation of the rete testis and initial portion of the ductuli efferentes can be observed. Crystalline structures, mainly rhomboidal in shape, accumulate inside and outside the tubules. Other testicular diseases and cystoadenoma are isolated and focal, 1651 whereas rete testis hyperplasia is diffuse. Adenocarcinoma of the rete testis is a tumor that displays numerous mitotic fi gures and infi ltrates adjacent structures. 1652 Metastasis of prostatic adenocarcinoma may be excluded because these metastases alter the rete testis architecture and are immunoreactive for prostatic acid phosphatase and PSA.

This reactive lesion is characterized by the presence of intracytoplasmic accumulation of hyaline eosinophilic globules in the epithelial cells of the rete testis. The epithelium may be hyperplastic, but does not contain mitotic fi gures or nuclear atypia. The globules are up to 15 µm in diameter ( Fig. 12-174 ). This lesion is associated with tumor and infl ammatory processes occurring near the mediastinum testis, and can be observed in association with 75% of mixed testicular germ cell tumors, 47% of seminomas, and 20% of non-germ cell testicular tumors, such as epididymal tumor that infi ltrates the testis (adenomatoid tumor). 1653 Yolk sac tumor infi ltrating the rete testis may closely resemble this type of rete testis hyperplasia. Positive immunoreactions for α-fetoprotein and placenta-like alkaline phosphatase, as well as nuclear atypia, are helpful to distinguish germ cell neoplasia from this rete testis hyperplasia. 1654

This lesion, described as nodular proliferation of calcifying connective tissue in the rete testis, is characterized by the presence of multiple nodules that originate from the rete testis lining and subjacent connective tissue, protruding into the channels of the rete testis. These consist of cellular connective tissue covered by several layers of a fi brin-like material, which in turn is covered by rete testis epithelium. The nodules may be totally or partially calcifi ed (Fig. 12-175 ). 1655 The lesion is an incidental fi nding at autopsy in patients with impaired peripheral perfusion.

Selective location of the lesion in the walls of the cavities and chordae rete testis is probably related to poor vascularization of these structures. The etiopathogenetic mechanism may be anoxia, necrosis, fi brin deposition, proliferation of connective tissue, or dystrophic calcifi cation. The intracavitary growth of the lesion might be due to the lower intracavitary pressure and also to the stiff structure of the mediastinum testis. 

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Development of Leydig cells in the normal human testis. A cytological, cytochemical and quantitative study

A quantitative morphology study of human Leydig cells from birth to adulthood

Testicular volume during adolescence. Cross-sectional and longitudinal studies

Testicular volumes of adolescent

Clinical measurement of the testes in boys and men

Testicular histology in fetuses with the prune belly syndrome and posterior urethral valves

Proliferation of Sertoli cells during development of the human testis assessed by stereological methods

Hyperplasia and the immature appearance of Sertoli cells in primary testicular disorders

Granular transformation of Sertoli cells in testicular disorders

A quantitative morphological study of human Leydig cells from birth to adulthood

Congenital Leydig cell hyperplasia

Morphologic anomalies in triploid liveborn fetuses

Objective measurement of testicular volume by ultrasonography: evaluation of the technique and comparison with orchidometer estimates

Ethnic differences. Variation in human testis size

Testicular size: The effects of ageing, malnutrition, and illness

Testicular size: assesment and clinical importance

Studies of the participation of the tunica albuginea and rete testis (TA and RT) in the quantitative structure of human testis

Postnatal development and differentiation of contractile cells within the rabbit testis

The tunica albuginea of the human testis is characterized by complex contraction and relaxation activities regulated by cyclic GMP

Histology of the normal testis

A method for determining the relative total lenght of the tubules in the testis

The fi ne structure of Sertoli cells in the human testis

Some observations on the fi ne structure of the Sertoli cell in the human testis

On the morphology of the human Sertoli cell

Organization and morphogenesis of the human seminiferous epithelium

The mammalian spermatozoon

Ultrastructural observations on nucleoli and related structures during human spermatogenesis

Ultrastructure of the nucleus of human Sertoli cells in normal and pathological testes

Cell-cell communication in the testis

The fi ne structure of the monkey (Macaca) Sertoli cell and its role in maintaining the blood-testis barrier

Electron microscopic observations on the structural components of the blood testis barrier

Sertoli cell junctions: morphological and functional correlates

Morphological and functional evidence for Sertoli-germ cell relationship

The testis

Evidence that vinculin is codistributed with actin bundles in ectoplasmic ('junctional') specializations of mammalian Sertoli cells

Changes in the lipid inclusion/ Sertoli cell cytoplasm area ratio during the cycle of the human seminiferous epithelium

Fine structure of the Sertoli cell of the human testis

Testicular involution in elderly men: comparison of histologic quantitative studies with hormone patterns

Multinucleate Sertoli cells in aged human testes

Infl uence of age on sperm production and testicular weights in men

Localization of folliclestimulating hormone (FSH) immunoreactivity and hormone receptor mRNA in testicular tissue of infertile men

Role of FSH in male gonadal function

Androgen receptor distribution in adult human testis

The paracrine role of Sertoli cells on Leydig cell function

Receptormediated endocytosis of testicular transferrin by germinal cells of the rat testis

Regulation of inhibin production in the human male and its clinical applications

Human testis cytosol an ovarian follicular fl uid contain high amounts of interleukin-1-like factor(s)

Cell interactions during the seminiferous epithelial cycle

Quantitative differences between variants of A spermatogonia in man

The ultrastructure of the four types of human spermatogonia

Decrease in the number of Ap and Ad spermatogonia and the Ap/Ad ratio with advancing age

Quantifi cation of cell types throughout the cycle of the human seminiferous epithelium and their DNA content

Normal and abnormal spermatogonia in the human testis

Development of the endoplasmic reticulum during human spermatogenesis

Kinetics of the germinal epithelium in man

Atlas of human spermatogenesis

Ultrastructural features of human spermiogenesis

Morphogenetic factors infl uencing the shape of the sperm head

The fi ne structure and development of the neck region of the mammalian spermatozoon

Morphogenesis and fate of the residual body in human spermiogenesis

The phagocytic function of Sertoli cells. A morphological, biochemical, and endocrinological study of lysosomes and acid phosphatase localization in the rat testis

Renewal of spermatogonia in man

Ultrastructural observations on the differentiation of spermatids in man

Further observations on the numbers of spermatogonia, spermatocytes and spermatids connected by intercellular bridges in the mammalian testis

Evidence of a wave of spermatogenesis in the human testis

Computeraided threedimensional reconstructions of the arrangement of primary spermatocytes in human seminiferous tubules

The cycle of the seminiferous epithelium in man

Morphometrical analysis of Sertoli cell ultrastructure during the seminiferous epithelial cycle in rats

Stage-specifi c signals in germ line differentiation control of Sertoli cell phagocytic activity by spermatogenic cells

Changes in the lipid inclusions/ Sertoli cell cytoplasm area ratio during the cycle of the Sertoli cell of the human seminiferous epithelium

Interaction between germ cells and Sertoli cells in the testis

Apoptosis of male germ cells, a generalized or a cell typespecifi c phenomenon?

Ultrastructure and function of the lamina propia of mammalian seminiferous tubules

The peritubular tissue in the normal and pathological human testis: an ultrastructural study

Basement membrane regulation of Sertoli cells

The lamina propia of vertebrate seminiferous tubules: A comparative light and electron microscopic investigation

Contractile cells in human seminiferous tubules

Peritubular myoid cells of human and rat testis are smooth muscle cells that contain desmin-type intermediate fi laments

Elastic tissue in the limiting membrane of the human seminiferous tubules

The biology of myofi broblasts

Evidence for contractility of the human seminiferous tubule confi rmed by its response to noradrenaline and acetylcholine

Agerelated variations in seminiferous tubules in men. A stereologic evaluation

Distribution and role of CD34-positive stromal cells and myofi broblasts in human normal testicular stroma

Giant interstitial cells and extraparenchimal interstitial cells of the human testis

Morphological relationship between testicular nerves and Leydig cells in man

Sertoli cells and Leydig cells in man

Ultrastructure of Leydig cells in human ageins testes

Neuron-specifi c enolase-like inmunoreactivity in human Leydig cells

Relaxin-like factor: a highly specifi c and constitutive new marker for Leydig cells in the human testis

Ghrelin and reproduction: a novel signal linking energy status and fertility

A novel circulating hormone of testis origin in humans

Calretinin is expressed in the Leydig cells of rat testis

Calretinin, a more sensitive but less specifi c marker than α-inhibin for ovarian sex cord-stromal neoplasms: an immunohistochemical study of 215 cases

Barrier properties of testis microvessels

The Leydig cell of the human testis -a new member of the diffuse neuroendocrine system

Sertoli and Leydig cells of the human testis express neurofi lament triplet proteins

Isolation of human Leydig cell mesenchymal precursors from patients with the androgen insensitivity syndrome: testosterone production and response to human chorionic gonadotropin stimulation in culture

Progenitor cells of the testosterone-producing Leydig cells revealed

Attrition of the human Leydig cell population with advancing age

Effect of ageing on the volume, structure and total Leydig cell content of human testis

Stereological analysis of Leydig cell ultrastructure in aged humans

Multinucleate Leydig cells in normal human testes

Mitosis in adult human Leydig cells

Leydig cell numbers, daily sperm production and serum gonadotropin levels in ageing men

Agerelated change in numbers of other interstitial cells in testes of adult men: evidence bearing on the fate of Leydig cells lost with increasing age

Testosterone and spermatogenesis. Identifi cation of stage-specifi c, androgen-regulated proteins secreted by adult rat seminiferous tubules

Regulation of the semininiferous epithelium

Changes in surface area and number of Leydig cells in relation to the 6 stages of the cycle of the human seminiferous epithelium

Actions of the testicular paracrine factor (P-Mod-S) on Sertoli cell transferrin secretion througout pubertal development

Diaphragmatic hernia in Denys-Drash syndrome

Sex reversal and diaphragmatic hernia in phenotypically female sibs with normal XY chromosomes

Clinical expression and SRY gene analysis in XY subjets lacking gonadal tissue

PAGOD syndrome: eighth case and comparison to animal models of congenital vitamin A defi ciency

Familial occurrence of agonadism and multiple internal malformations in phenotypically normal girls with 46,XY and 46,XX karyotypes, respectively: a new autosomal recessive syndrome

Low birth-weight, microcephalic malformation syndrome in a 46,XX girl and her 46,XY sister with agonadism: third report of the Kennerknecht syndrome or autosomal recessive Seckel-like syndrome with previously undescribed genital anomalies

Agonadism in a 46,XY patient with CHARGE association

The syndrome of rudimentary testes: occurrence in live siblings

Identical twins discordant for the 'rudimentary testes' syndrome

Rudimentary testes syndrome revisited

Congenital anorchism: diagnostic and therapeutic aspects

Congenital bilateral anorchia: clinical, hormonal and imaging study in 12 cases

PCR analysis and sequencing of the SRY sex determining gene in four patients with bilateral congenital anorchia

Is bilateral congenital anorchia genetically determined?

The vanishing testis syndrome. Indications for conservative therapy

The vanishing testis

The vanishing testis

Is the vanished testis always a scrotal event?

Bilateral anorchia: discordance in monozygotic twins

An analysis of the genetic factors involved in testicular descent in a cohort of 14 male patients with anorchia

Report of 11 cases with discussion of etiology and pathogenesis

Hyperplasia of spermatic cord nerves: a sign of testicular absence

Signifi cance of testicular biopsies in cryptorchidism in children

Human monorchism: A clinicopathological study of unilateral absent testes in 65 boys

Testicular regression syndrome a pathological study of 77 cases

Testicular regression syndrome: a clinical and pathologic study of 11 cases

Laparoscopic and histologic evaluation of the inguinal vanishing testis

Histological evaluation of the testicular nubbin in the vanishing testis syndrome

Ureteral ectopia into cystic seminal vesicle with ipsilateral renal dysgenesis and monorchia

Renal and testicular agenesis in a patient with Darier's disease

Findings: small testicles

Klinefelter's syndrome diagnosed three years after surgery for mediastinal teratoma

Kenny-Caffey syndrome and microorchidism

Polyorchidism: case report and review of literature

Polyorchidism: sonographic and magnetic resonance image fi ndings

A case of supernumerary testis

Polyorchidism presenting as retractile testes

Polyorchidism: evaluation by MR

Polyorchidism: An unusual case

Polyorchidism: a strange anomaly with unsuspected properties

Bilateral double by testis: evaluation magnetic resonance imaging

One man with fi ve testes: report of case

Triorchidism with normal spermatogenesis: an unusual cause for failure of vasectomy

Abdominal polyorchidism: a case report and review of the literature

Ultrasound of polyorchidism: Case report and literature review

Sonographic features of polyorchidism

Polyorchidism: Case report and literature review

Polyorchidism discovered as testicular torsion associated with undescended atrophic contralateral testis. A surgical solution

Revisión y aportación de un nuevo caso

Polyorchidism discovered as testicular torsion

Polyorchidism with normal spermatogenesis

Polyorchidism with normal spermatogenesis

Polyorchidism with normal spermatogenesis and equal sized testes. A theory of embryonal development

Testiculo supernumerario. Comunicación de un caso y revisión de la literatura

Polyorchidism: case report and review of the literature

Polyorchidism: a case report

Polyorchidism: report of a case

Polyorchidism in a newborn: case report and review of the literature

Polyorchidism: A case report and review of the literature

Polyorchidism and seminoma in a child

A case of polyorchidism with testicular teratoma

Signifi cance of testicular size measurement in andrology. II Correlation of testicular size with testicular function

Congenital Leydig cell hyperplasia

Evidence in favor of the mechanical (intrauterine torsion) theory over the endocrinopathy (cryptorchidism) theory in the pathogenesis of testicular agenesis

Compensatory hypertrophy of testicle in unilateral cnyptorchidism

Impact of varicocele on testicular volume in young men: signifi cance of compensatory hypertrophy of contralateral testis

Plasma LH and FSH response to LRH in boys with compensatory testicular hypertrophy

Followup of boys with unilateral compensatory testicular hypertrophy

Testicular volume during adolencence

Unilateral testicular hypertrophy: An apparently benign occurrence without cryptorchidism

Benign bilateral testicular enlargement

Benign macroorchidism in a pubescent boy

Idiopathic macroorchidism

Macro-orchidism: light and electron microscopic study of four cases

Idiopathic benign bilateral testicular enlargement in a pubertal boy: a case report and review of literature

Macroorchidism: a case report

Endocrine and spermatological characteristics of 135 patients with bilateral megalotestis

The Fragile X premutation: new insights and clinical consequences

A marker X chromosome

A pedigree of mental defect showing sex-linkage

X-linked mental retardation associated with macroorchidism

Inherited congenital normofunctional testicular hyperplasia and mental defi ciency. A corroborative study

X-linked mental defi ciency megalotestes syndrome

Xlinked mental retardation with macroorchidism and the fragile site at Xq 27 or 28

Familial-X-linked mental retardation with a marker X chromosome and its relationship to macroorchidism

A recognizable syndrome of sex-linked mental retardation, large testes and marker X chromosome

Gonadal function in men with the Martin-Bell (fragile X) syndrome

Spermatogenesis in two patients with the fragile X syndrome. I. Histology: light and electron microscopy

Spermatogenesis in two patients with the fragile X syndrome

X-linked mental retardation and an X-chromosome marker

Population incidence and segregation ratios in Martin-Bell syndrome

Study of a family with a fragile site of the X chromosome at Xq 27-28 without mental retardation

Testicular size in fetal fragile X syndrome

A family with mental retardation, variable macrocephaly and macroorchidism, and linkage to Xq12-q21

Testicular enlargement and elevated serum inhibin concentrations occur in patients with pituitary macroadenomas secreting follicle stimulating hormone

Juvenile hypothyroidism with testicular enlargement

Hipotiroidismo y maduración testicular precoz

Thyroid hormone and male gonadal function

Sexual maturation in juvenile hypothyroidism

Hypothalamic-pituitary gonadal axis in boys with primary hypothyroidism and macroorchidism

Thyroid hormones: their role in testicular steroidogenesis

Male hypogonadism in hypothyroidism: A study of six cases

Macroorchidism and testicular fi brosis associated with autoimmune thyroiditis

Juvenile hypothyroidism and precocious testicular maturation

Acquired hypothyroidism with muscular hypertrophy and precocious testicular enlargement

Regulation of gonadotropin-releasing hormone (GnRH) gene expression in hypothalamic neuronal cells

Hypothyroidism-induced macroorchidism: Use of a gonadotropin-hormone agonist to understand its mechanism and augment adult stature

A potential novel mechanism for precocious puberty in juvenile hypothyroidism

High neonatal triiodothironine levels reduce the period of Sertoli cell proliferation and accelerate tubular lumen formation in the rat testis, and increase serum inhibin levels

Increased numbers of Sertoli and germ cells in adult rat testes induced by synergistic action of transient neonatal hypothyroidism and neonatal hemicastration

Tri-iodothyronine directly affects rat Sertoli cell proliferation and differentiation

Neonatal hypothyroidism causes delayed Sertoli cell maturation in rats treated with propylthiouracil: evidence that the Sertoli cell controls testis growth

Central precocious puberty. An overview of diagnosis, treatment, and outcome

Precocious puberty

Precocious puberty

Sexual precocity

Precocious puberty caused by a suprasellar arachnoid cyst. Analysis of 6 cases

The endocrine spectrum of arachnoid cysts in childhood

Growth, puberty and hypothalamicpituitary function in children with suprasellar arachnoid cyst

Aspects étiologiques cliniques et biologiques des pubertés précoces d'origine centrale

Precocious puberty following severe head trauma

Precocious puberty after traumatic brain injury

Endocrine disorder as the only sign of chronic 'nonhypertensive' hydrocephalus

Precocious puberty after hypothalamic and pituitary irradiation in young children

Precocious and premature puberty associated with treatment of acute lymphoblastic leukaemia

Endocrine function and morphological fi ndings in patients with disorders of the hypothalamopituitary area: a study with magnetic resonance

The radiological approach to precocious puberty

MR imaging features in hypothalamic hamartoma: a report of three cases and review of literature

Boys with precocious puberty due to hypothalamic hamartoma: reproductive axis after discontinuation of gonadotropinreleasing hormone analog therapy

Etiology of central precocious puberty in males: the results of the Italian Study Group for Physiopathology of Puberty

Hypothalamic hamartoma: a source References of luteinizing-hormone-releasing factor in precocious puberty

Mixed germ cell tumour of the pineal region: a case report

hCG-secreting pineal teratoma causing precocious puberty: report of two patients and review of the literature

Puberty without gonadotropins: A unique mechanism of sexual development

Gonadotropinindependent familial sexual precocity with premature Leydig and germinal cell maturation (familial testotoxicosis): Effects of a patent luteinizing hormone-releasing factor agonist and metroxyprogesterone acetate therapy in four cases

Testicular changes in gonadotropin-independent familial male sexual precocity. Familial testotoxicosis

Gonadotropin-independent precocious puberty due to luteinizing hormone receptor mutations in Brazillian boys: A novel constitutively activating mutation in the fi rst transmembrane helix

Activating mutations in the LH receptor gene: a human model of non FSH-dependent inhibin production and germ cell maturation

Mutational analysis of the luteinizing hormone receptor gene in two individuals with Leydig cell tumors

Tumor de células de Leydig con pseudopubertad precoz

Leydig cell tumor in a child with spermatocyte maturation and no pseudoprecocious puberty

An aromatase-producing sex-cord tumor resulting in prepubertal gynecomastia

Sertoli cell tumour in a boy with Peutz-Jeghers syndrome

Carney complex: the complex of mixomas, spotty pigmentation, endocrine overactivity, and schwannomas

Virilising adrenal cortical tumours in children

Virilizing adrenal cortical carcinoma with hypertrophy of spermatic tubules in childhood

Bilateral testicular tumours in congenital adrenal hyperplasia: A continuing diagnostic and therapeutic dilemma

Hepatoblastoma presenting as isosexual precocity. The clinical importance of histologic and serologic parameters

Gonadotropin-secreting pineal teratoma causing precocious puberty

The P450 gene superfamily: updated listing of all genes and recommended nomenclature for the chromosomal loci

Human aromatase: cDNA cloning, Southern blot analysis, and assignment of the gene to chromosome 15

Familial hyperestrogenism in both sexes: clinical, hormonal, and molecular studies of two siblings

The aromatase excess syndrome is associated with feminization of both sexes and autosomal dominant transmission of aberrant P450 aromatase gene transcription

Aromatase defi ciency caused by a novel P450arom gene mutation: impact of absent estrogen production on serum gonadotropin concentration in a boy

Aromatase defi ciency in male and female siblings caused by a novel mutation and the physiological role of estrogens

Effect of testosterone and estradiol in a man with aromatase defi ciency

Estrogen: consequences and implications of human mutations in synthesis and action

Primary testicular abnormalities causing precocious puberty Leydig cell tumor, Leydig cell hyperplasia, and adrenal rest tumor

Focal lobular spermatogenesis and pubertal acceleration associated with ipsilateral Leydig cell hyperplasia

McCune-Albright syndrome in a boy may present with a monolateral macroorchidism as an early and isolated clinical manifestation

Macroorchidism due to autonomous hyperfunction of Sertoli cells and G(s)alpha gene mutation: an unusual expression of McCune-Albright syndrome in a prepubertal boy

McCune-Albright syndrome in a male child: A clinical and endocrinologic enigma

Anomalies of the testicle

Preperitoneal ectopic testis: a case report

Ectopia epidídimo-perineal

Testículo ectópico perineal

Perineal testicle

Crossed ectopic testis: a case report and review of the literature

Crossed ectopic testis. Case report and review

Transverse testicular ectopia

Crossed ectopic testis with common vas deferens

Crossed testicular ectopia detected by laparoscopy

Transverse testicular ectopia: a case report

Crossed testicular ectopia in association with double incomplete testicular descent

Two rare genital abnormalities: Crossed testicular and scrototesticular ectopia

Transverse testicular ectopia associated with persistent Müllerian duct syndrome. A case report

The persistent müllerian duct syndrome: a rare cause of cryptorchidism

Mixed germ cell tumor after bilateral orchidopexy in persistent Müllerian duct syndrome with transverse testicular ectopia

Two rare cases of ectopic testes

Subumbilical ectopic testis

Exstrophy of the testis

Testicular dislocation after scrotal trauma

Cystic dysplasia of the testis: a unique anomaly studied by microdissection

Cystic dysplasia of the rete testis. Case report

Cystic dysplasia of the rete testis associated to cryptorchidism: a case report

Cystic dysplasia of the testis: sonographic and pathologic fi ndings

Cystic testicular lesions in the pediatric population

The human rete testis

The rete testis in man: Ultrastructural aspects

The mammalian rete testis. A morphological examination

Cystic displasia of the testis: light and electron microscopic study of three cases

Cystic dysplasia of the testis associated with multicystic dysplasia of the kidney

Ectasia of the rete testis with ipsilateral renal agenesis

Cystic dysplasia of the testis

Cystic dysplasia of testis

Coffi n CM. Cystic testicular lesions in the pediatric population

Cystic dysplasia of the testis with ipsilateral renal agenesis. A case report and review of the literature

Conservative managemet of cystic dysplasia of the testis

Testicular cystic dysplasia: evaluation of 3 new cases treated without surgery

Cystic dysplasia of rete testis associated with ipsilateral renal agenesis. Case report

Fetal gonadoblastoid testicular dysplasia

Gonadoblastoid testicular dysplasia in Walker-Warburg syndrome

Fetal gonadoblastoid testicular dysplasia: a focal failure of testicular development

Frequency of so-called hypoplastic or dysgenetic zones in scrotal and otherwise normal testes

Androgen receptor expression in Sertoli cells as a function of seminiferous tubule maturation in the human cryptorchid testis

Congenital testicular lymphangiectasis

Congenital testicular lymphangiectasis in Noonan's syndrome

Congenital testicular lymphangiectasis in children with otherwise normal testes

Macromicroscopischeskoe is sledavanie vnutriorgannoi limfaticheskoi sistemy muzhskoi polovoi zhelezy [Macro/ microscopic study of intraorgan lymphatic system of male gonad in man

Distribution and fi ne structure of the lymphatic system in the human testis

Lymph vascular system of the interstitial tissue of the testis as revealed by electron microscopy

Epididymal lymphangiectasis

Tumors and cysts of the paratesticular region

Complex multilocular cystic lesion of rete testis, accompanied by smooth muscle hyperplasia, mimicking intratesticular Leydig cell neoplasm

Smooth muscle hyperplasia of the testicular adnexa clinically mimicking neoplasia. Clinicopathologic study of sixteen cases

Myoepithelial hamartoma of the small bowel: report of a case

Focal muscular hyperplasia of the trachea

Ectopic seminiferous tubules in the tunica albuginea of normal and dysgenetic testes

Pseudocysts of the tunica albuginea: Benign invasion by testicular tubules

Development of the testis from birth to puberty

Testosterone immunoexpression in human Leydig cells of the tunica albugiena testis and spermatic cord. A quantitative study in normal fetuses, young adults, elderly men and patients with cryptorchidism

Giant interstitial cells and extraparenchymal interstitial cells of the human testis

The infi ltrative activity of Leydig cells

Relation of Leydig cells in the human testicle to the tubules and testicular function

A histological study of extraparenchymal Leydig-like cells

Über die Zwischenzellen des Hodens

Zur pathologischen Anatomie der Leydig Zelle

Leydig cells within the lamina propria of seminiferous tubules in four patients with azoospermia

Ectopic Leydig cells in seminiferous tubules of an infertile human male with a chromosomal aberration

Leydig cells within the spermatogenic seminiferous tubules

Immunohistochemical and quantitative study of interstitial and intratubular Leydig cells in normal men, cryptorchidism, and Klinefelter's syndrome

Über das Verhalten von Hoden und Nebenhoden bei angeborenem Fehlen des Ductus deferens, zugleich zur Frage des Vorkommens von Zwischenzellen in menschliche Nebenhoden

Sur l'existence de glands sympathicotropes dans l'ovaire et le testicule humains; leur rapport avec la glande interstitielle du testicule

Zur Ultrastrusktur der Leydigzellen im Funiculus spermaticus des Menschen

Histogenesis of human extraparenchymal Leydig cells

Presentación de un caso y revisión de la literatura

Testicular lipomatosis in Cowden's syndrome

Age-related epididymis-like intratesticular structures: benign lesions of Wolffi an origin that can be misdiagnosed as testicular tumors

Male reproductive disorders in humans and prenatal indicators of estrogen exposure. A review of published epidemiological studies

Testicular cancers occurring in brothers with cryptorchism

Anatomical, morphological and volumetric analysis: a review of 759 cases of testicular maldescent

Risk factor patterns for cryptorchidism and hypospadias

Cryptorchidism: a registry based study in Sweden on some factors of some possible etiological importance

Maternal and neonatal risk factors for cryptorchidism

Risk factors for cryptorchidism and hypospadias

Abnormalities of testicular descent

Surgical outcome of orchidopexy II. Trapped and ascending testes

Iatrogenic cryptorchidism resulting from hernia repair

Iatrogenic ascent of the testis: an under-recognized complication of inguinal hernia operation in children

Iatrogenic ascent of the testis: an underrecognized complication of inguinal hernia operation in children

Testicular descent and ascent in the fi rst year of life

Late presentation of cryptorchidism: The etiology of testicular re-ascent

Ascent of the testis: fact or fi ction

Incomplete disappearance of the processus vaginalis as a cause of ascending testis

Undescended testis: congenital or acquired?

Spontaneous ascent of the testis

Acquired undescended testis

Does proximal genitofemoral nerve division induce testicular maldescent or ascent in the rat?

Association between testicular microlithiasis, testicular cancer, cryptorchidism and history of ascending testis

The ascending testis and the testis undescended since birth share the same histopathology

Elevated placental estradiol: a possible etiological factor of human cryptorchidism

Histologic observations in cryptorchidism: the congenital germinal-cell defi ciency of the undescended testis

Histologic classifi cation of undescended testes

Cytophotometric DNA quantifi cation in human spermatogonia of cryptorchid testes

Early postnatal testicular maldevelopment in cryptorchidism

Hormonal treatment of cryptorchidism -hCG or GnRH -a multicentre study

Busereline treatment of cryptorchidism: a randomized, double-blind, placebo-controlled study

Abnormal germ cell development in cryptorchidism

Anatomical, morphological and volumetric analysis: A review of 759 cases of testicular maldescent

Impact of early orchidopexy on testicular growth

Effi cacy of orchiopexy by patient age 1 year for cryptorchidism

Clinical and histopathologic evaluation of operated maldescended testes after luteinizing hormonereleasing hormone treatment

Bilateral prepubertad testicular biopsias predict signifi cance of cryptorchisism-associated mixed testicular atrophy, and allow assessment of fertility

Multinucleated spermatogonia in cryptorchid boys: a possible association with an increased risk of testicular malignancy

Y chromosome microdeletions in cryptorchidism and idiopathic infertility

An unusual subset of cryptorchidism: possible end organ failure

Ascent of the testis in children

Impaired germ cells in secondary cryptorchid testis after herniotomy

Elastic fi bers in tunica propria of undescended and contralateral scrotal testes from cryptorchid patients

Hyperplasia and the immature appearance of Sertoli cells in primary testicular disorders

Focal orchitis in undescended testes: discussion of pathogenetic mechanisms of tubular atrophy

Undescended testes in adults: clinical signifi cance of resistive index values of the testicular artery measured by Doppler ultrasound as a predictor of testicular histology

Testicular function in men treated in childhood for undescended testes

Histologic lesions in undescended ectopic obstructed testes

Is a testis located at the superfi cial inguinal pouch (Denis Browne pouch) comparable to a true cryptorchid testis?

Histologic maldevelopment of unilaterally cryptorchid testes and their descended partners

Anatomical, morphological and volumetric analysis: a review of 759 cases of testicular maldescent

Les testicules oscillants. forme degradée de cryptorchidie?

Infertility in adult males with retractile testes

Changes in the volume and histology of retractile testes in prepubertal boys

The retractile testis

Retractile testis -is it really a normal variant?

Bilateral retractile testes -subsequent effects on fertility

Effect of cryptorchidism and retractile testes on male factor infertility: a multicenter, retrospective, chart review

Epididymal anomalies associated with hydrocele/hernia and cryptorchidism: implications regarding testicular descent

Congenital deformities of the testis and epididymis

Signifi cance of epididymal and ductal anomalies associated with undescended testis

Insulin-like factor 3 gene mutations in testicular dysgenesis syndrome: clinical and functional characterization

Testicular dysgenesis syndrome: possible role of endocrine disrupters

Ethnic differences in occurrence of TDS -genetics and/or environment?

Granular changes in Sertoli cells in children and pubertal patients

Erythropoietin may reduce the risk of germ cell loss in boys with cryptorchidism

Early orchiopexy: prepubertal intratubular germ cell neoplasia and fertility outcome

Testicular cancer and cryptorchidism

Cryptorchidism and testicular neoplasia

Testicular maldescent and infertility

Histology of testicular biopsies taken at operation for bilateral maldescended testes in relation to fertility in adulthood

Semen analysis in patients operated on for impalpable testes

Fertility in cryptorchidism: an overview in 1987

Paternity and hormone levels after unilateral cryptorchidism: association with pretreatment testicular location

No relationship of testicular size at orchiopexy with fertility in men who previously had unilateral cryptorchidism

Fertility potential: a comparison of intra-abdominal and intracanalicular testes by age groups in children

Surgical mangeament of undescended testis: retrospective study of potential fertility in 274 cases

orchiopexy and infertility: a critical long-term retrospective analysis

The importance of mini-puberty for fertility in cryptorchidism

Cryptorchidism: aspects of fertility References and neoplasms. A study including data of 1,335 consecutive boys who underwent testicular biopsy simultaneously with surgery for cryptorchidism

Experience of screening for carcinoma-in-situ of the testis among young men with surgically corrected maldescended testes

Distribution of carcinoma-in-situ in testes from infertile men

Carcinoma-in-situ of the testis: aneuploid cells in semen

Cryptorchidism and testicular neoplasia

Testicular microlithiasis: sonographic features with pathologic correlation

Testicular microlithiasis in a child with torsion of the appendix testis

Testicular microlithiasis occurring in a postorchidopexy testis

Microcalcifi cations in testicular malignancy: diagnostic tool in occult tumor?

Testicular microlithiasis with sterility

Testicular microlithiasis in male infertility

Microlitiasis testicular asociada a infertilidad

Painful testicular lithiasis

Testicular microlithiasis: diagnosis associated with orchialgia

Idiopathic testicular microlithiasis. Ultrastructural study

Testicular microlithiasis in a UK population: its incidence, associations and follow-up

Testicular microlithiasis is associated with testicular pathology

Testicular microlithiasis -a possibly premalignant condition

The prevalence of testicular microlithiasis in an asymptomatic population of men 18 to 35 years old

Testicular microlithiasis: prevalence and tumor risk in a population referred for scrotal sonography

Testicular calcifi cation and microlithiasis: association with primary intra-testicular malignancy in 3,477 patients

Testicular microlithiasis, a premalignant condition: prevalence, histopathologic fi ndings, and relation to testicular tumor

Seminal profi le of subjects with testicular microlithiasis and testicular calcifi cations

Bilateral testicular microlithiasis predicts the presence of the precursor of testicular germ cell tumors in subfertile men

Testicular nicrolithiasis and cryptorchidism: ultrasound analysis after orchidopexy

Testicular microlithiasis. a benign condition with a malignant association

Testicular microlithiasis: a review and its association with testicular cancer

Testicular microlithiasis heralding mixed germ cell tumor of the testis in a boy

Signifi cance of testicular microlithiasis

Yolk sac tumor and testicular microlithiasis

Testicular microlithiasis in children: sonographic features and clinical implications

Identifi cation of seminiferous tubule aberrations and a low incidence of testicular microliths associated with the development of azoospermia

Raman spectroscopic analysis identifi es testicular microlithiasis as intratubular hydroxyapatite

Testicular calcifi cation in a 4-year-old boy

The origin of testicular microliths

Testicular microlithiasis in 2 children with bilateral cryptorchidism

Pulmonary alveolar microlithiasis with involvement of the sympathetic nervous system and gonads

Testicular microlithiasis and concomitant testicular intraepithelial neoplasia

Increased risk of carcinoma in situ in patients with testicular germ cell cancer with ultrasonic microlithiasis in the contralateral testicle

Testicular carcinoma in a patient with previously demostrated testicular microlithiasis

Testicular microlithiasis and subsequent development of metastatic germ cell tumor

Detection of testicular microlithiasis by sonography

The interval of development of testicular carcinoma in a patient with previously demonstrated testicular microlithiasis

Surveillance of testicular microlithiasis? Results of an UK based national questionnaire survey

Testicular microlithiasis: US follow-up

Testicular microlithiasis as a predictor of intratubular germ cell neoplasia

Microlithiasis of the epididymis and the rete testis

Three novel SRY mutations in XY gonadal dysgenesis and the enigma of XY dysgenesis cases without SRY mutations

A novel postzygotic nonsense mutation in SRY in familial XY gonadal dysgenesis

Mutations in SRY and WT1 genes required for gonadal development are not responsible for XY partial gonadal dysgenesis

Pathology of 46,XY pure gonadal dysgenesis: absence of testis differentiation associated with mutations in the testis-determining factor

XY gonadal dysgenesis: Genetic heterogeneity based upon clinical observations, H-Y antigen status and segregations analysis

Chronic renal disease, myotonic dystrophy, and gonadoblastoma in XY gonadal dysgenesis

Renal failure with XY gonadal dysgenesis: Report of the second case

A syndrome of chronic renal failure and XY gonadal dysgenesis in young phenotypic females without genital ambiguity

Atypical presentation of Denys-Drash syndrome in a female with a novel WT1 gene mutation

Molecular analysis of Frasier syndrome: mutation in the WT1 gene in a girl with gonadal dysgenesis and nephronophthisis

Frasier syndrome: a rare syndrome with WT1 gene mutation in pediatric urology

XY siblings with inadequate virilization and CNS defi ciency

Testicular dysgenesis and mental retardation in two incompletely masculinized XYsiblings

Analysis of the testisdetermining gene SRY in patients with XY gonadal dysgenesis

The Gardner-Silengo-Wachtel or genitor-palato-cardiac syndrome: Male pseudohermaphroditism with micrognathia, cleft palate, and conotruncal cardiac defects

XY gonadal dysgenesis associated with a multiple pterygium syndrome phenotype

XY pure gonadal dysgenesis: a case with Graves' disease

A case of gonadal dysgenesis, breast development, Graves' disease, and low bone mass

Alopecia universalis congenita, XY gonadal dysgenesis and laryngomalacia: a novel malformation syndrome

Alopecia congenita universalis, microcephaly, cutis marmorata, short stature and XY gonadal dysgenesis: variable expression of El-Shanti syndrome

Syndromal (and nonsyndromal) forms of male pseudohermaphroditism

Familial ovarian dysgerminomas (Swyer syndrome) in females associated with

A new familial syndrome of 46 XY gonadal dysgenesis with anomalies of ectodermal and mesodermal structural

Familial XY gonadal dysgenesis

Familial XY gonadal dysgenesis

XY gonadal dysgenesis: Genetic heterogeneity based upon clinical observations, H-Y antigen status and segregations analysis

The X linked recessive form of XY gonadal dysgenesis with high incidende of gonadal cell tumors: Clinical and genetic studies

The relationship of neoplasia to disorders of abnormal sexual diferentiation

XY gonadal dysgenesis: evidence for autosomal dominant transmission in a large kindred

Gonadoblastomas in 5 patients with 46XY gonadal dysgenesis

Familial 46,XX gonadal dysgenesis

Pure gonadal dysgenesis XX and XY: observations in fi fteen patients

Gonadal dysgenesis in a patient with an X; 3 translocation: case report and review

Gonadal dysgenesis, intra-X chromosomal insertion, and possible position effect in an otherwise normal female

Ovarian dysgenesis with balanced autosomal translocation

A novel mutation in the FSH receptor inhibiting signal transduction and causing primary ovarian failure

A novel loss of function mutation in exon 10 of the FSH receptor gene causing hypergonadotropic hypogonadism: clinical and molecular characteristics

No evidence of mutations in the follicle-stimulating hormone receptor gene in Mexican women with 46,XX pure gonadal dysgenesis

Dysgerminoma and gonadal dysgenesis in a 46,XX female with no evidence of Y chromosomal DNA

Dysgerminoma with syncytiotrophoblastic giant cells References arising from 46,XX pure gonadal dysgenesis

Familial dysgerminoma associated with 46, XX pure gonadal dysgenesis

Prenatal and postnatal prevalence of Turner's syndrome: a registry study

The distribution of chromosomal genotypes associated with Turner's syndrome: livebirth prevalence and evidence for dismissed fetal mortality and severity in genotypes associated with structural X abnomalities or mosaicism

Primary ovarian failure

Turner syndrome and female sex chromosome aberrations: deduction of the principal factors involved in the development of clinical features

Turner's syndrome

The anatomy and histology of XO human embryos and fetuses

Principles of reproductive embryology

Mammalian MutS homologue 5 is required for chromosome pairing in meiosis

Accelerated germ cell apoptosis in sex chromosome aneuploid fetal human gonads

Sex chromosomes and sexlinked genes

Gonadal mixed germ cell tumor combined with a large hemangiomatous lesion in a patient with Turner's syndrome and 45,X/46,X, + mar karyotype

Gonadoblastoma and Turner syndrome

A review of 41 cases with observations on testicular histology and function

True hermaphroditism presenting as bilateral gynecomastia in an adolescent phenotypic male

Aetiological diagnosis of male sex ambiguity: a collaborative study

Seminoma in a 46 XX true hermaphrodite with positive H-Y antigen. A case report

The gonads of human true hermaphrodites

True hermaphroditism. Clinical morphological and cytogenetic aspects

True hermaphroditism: geographical distribution, clinical fi ndings, chromosomes and gonadal histology

True hermaprhoditism: clinical features, genetic variants and gonadal histology

Hormonal and molecular genetic fundings in 46, XX subjects with sexual ambiguity and testicular differentiation

Familial 46XX males coexisting with familial 46,XX true hermaphrodites in same pedigree

Partially delected SRY gene confi ned to testicular tissue in a 46,XX true hermaphrodite without SRY in leukocytic DNA

Pregnancy in a woman with a Y chromosome after removal of an ovarian dysgerminoma

Preservation of gonadal function in true hermaphroditism

Das syndrom des Pseudohermaphroditismus masculinus bei kongenitaler Nebennierensiden-Hyperplasie ohne Androgenüberproduktion

A novel compound heterozygous mutation in the steroidogenic acute regulatory protein gene in a patient with congenital lipoid adrenal hyperplasia

Molecular and structural analysis of two novel StAR mutation in patients with lipoid congenital adrenal hyperplasia

A novel mutation L260P of the steroidogenic acute regulatory protein gene in three unrelated patients of Swiss ancestry with congenital lipoid adrenal hyperplasia

Mutations in the steroidogenic acute regulatory protein (StAR) in six patients with congenital lipoid adrenal hyperplasia

Disorders of androgen synthesis -from cholesterol to dehydroepiandrosterone

A genetic isolate of congenital lipoid adrenal hyperplasia with atypical clinical fi ndings

Phenotypic variations in lipoid congenital adrenal hyperplasia

Abnormal sex differentiation

Prenatal diagnosis of congenital lipoid adrenal hyperplasia

Targeted disruption of the mouse gene encoding steroidogenic acute regulatory protein provides insights into congenital lipoid adrenal hyperplasia

An autopsy case of congenital lipoid hyperplasia of the adrenal cortex

Gonadal development and grown in 46,XX and 46,XY individuals with P450scc defi ciency (congenital lipoid adrenal hyperplasia)

New developments in congenital lipoid adrenal hyperplasia and steroidogenic acute regulatory protein

Zur Morphologie und Genese der kongenitalen Nebennierenrindenhyperplasie beim männlichen scheinzwitter

The testicular lesion and sexual differentiation in congenital lipoid adrenal hyperplasia

Congenital adrenal lipoid hyperplasia due to defi cient cholesterol side-chain cleavage activity (20,22-desmolase) in a patient treated for 18 years

Congenital lipoid adrenal hyperplasia in a eight-year-old phenotype female

Gonadal histology with testicular carcinoma in situ in a 15-year old 46,XY female patient with a premature termination in the steroidogenic acute regulatory protein causing congenital lipoid adrenal hyperplasia

Unusual steroid pattern in congenital adrenal hyperplasia: defi ciency of 3β-hydroxydehydrogenase

Pubertal boy with the 3β-hydroxysteroid dehydrogenase defect

Characterization of two novel homozygous missense mutations involving codon 6 and 259 of type II 3β-hydroxysteroid dehydrogenase (3βHSD) gene causing, respectively, nonsalt-wasting and salt-wasting 3βHSD defi ciency disorder

Disorders of sexual differentiation

Congenital adrenal hyperplasia due to point mutations in the type II 3β-hydroxysteroid dehydrogenase gene

Molecular basis of congenital adrenal hyperplasia due to 3β-hydroxysteroid dehydrogenase defi ciency

Detection and functional characterization of the novel missense mutation Y254D in type II 3β-hydroxysteroid dehydrogenase (3βHSD) gene of a female patient with nonsalt-losing 3βHSD defi ciency

Nonsalt-losing congenital adrenal hyperplasia due to 3β-hydroxysteroid dehydrogenase defi ciency with normal glomerulosa function

Defects of the testosterone biosynthetic pathway in boys with hypospadias

Abnormalities of adrenal steroidogenesis in Chilean boys with micropenis

Mutation of proline 409 to arginine in the meander region of cytochrome p450c17 causes severe 17 alpha-hydroxylase defi ciency

Localization of the human CYP17 gene (cytochrome P450 (17 alpha)) to 10q24.3 by fl uorescence 'in situ' hybridization and simultaneous chromosome banding

A novel point mutation in P450c17 (CYP17) causing combined 17alpha-hydroxylase/17,20-lyase defi ciency

Towards a unifying mechanism for CYP17 mutations that cause isolated 17,20-lyase defi ciency

17 alpha-hydroxylation defi ciency in man

Endocrine studies in male pseudohermaphroditism in childhood and adolescence

desmolase defi ciency

Male pseudohermaphroditism consistent with 17-20 desmolase defi ciency

Pitfalls in characterizing P450c17 mutations associated with isolated 17,20-lyase defi ciency

Severe 46,XY virilization defi cit due to 17β-hydroxysteroid dehydrogenase defi ciency

17 ketosteroid reductase defi ciency in an adult patient without gynecomastia but with female psychosexual orientation

Absent spermatogenesis despite early bilateral orchidopexy in 17-ketoreductase defi ciency

Substitution mutation C268Y causes 17β-hydroxysteroid dehydrogenase 3 defi ciency

Novel insertion frameshift mutation of the LH receptor gene: problematic clinical distinction of Leydig cell hypoplasia from enzyme defects primarily affecting testosterone biosynthesis

Leydig cell hypoplasia: A cause of male pseudohermaphroditism

Leydig cell hypoplasia causing male pseudohermaphroditism: diagnosis 13 year after prepubertal castration

Leydig cell hypofunction resulting in male pseudohermaphroditism

A case of male pseudohemaphroditism associated with elevated LH, normal FSH and low testosterone possibly due to the secretion of an abnormal LH molecula

Inherited male pseudohermaphroditism due to gonadotropin irresponsiveness

A clinico-genetic investigation of Leydig cell hypoplasia

Naturally occurring mutations of the luteinizing hormone receptor gene affecting reproduction

Leydig cell hypoplasia due to inactivation of luteinizing hormone receptor by a novel homozygous nonsense truncation mutation in the seventh transmembrane domain

Biological effect of a novel mutation in the third leucine-rich repeat of human luteinizing hormone References receptor

Familial incomplete male pseudohermaphroditism, type I. Evidence for androgen resistance and variable clinical manifestations in a family with the Reifenstein syndrome

Quantitative receptor defects in families with androgen resistance; failure of stabilization of the fi broblast cytosol androgen receptor

Leydig cell hypoplasia determining familial hypergonadotropic hypogonadism

Male pseudohermaphroditism resulting from Leydig cell hypoplasia

The syndrome of testicular feminization in male pseudohermaphrodites

The molecular bases of androgen insensitivity

Molecular basis of androgen insensitivity

The androgen insensitivity syndrome (testicular feminization). A clnicopathologic study of 43 cases

A case of complete testicular feminization and 47 XXY karyotype

Morphometry and histology of gonads from twelve children and adolescents with the androgen insensitivity (testicular feminization) syndrome

Testicular carcinoma in situ in children with the androgen insensitivity (testicular feminization) syndrome

Síndrome de feminización testicular completa

Inmunohistochemical and ultrastructural study of Sertoli cells in androgen insensitivity

Androgen receptor gene mutation associated with complete androgen insensitivity syndrome and Sertoli cell adenoma

Residual activity of mutant androgen receptors explains wolffi an duct development in the complete androgen insensitivity syndrome

Bilateral testicular tumors in androgen insensitivity syndrome

Puberty in subjects with complete androgen insensitivity syndrome

Familial male pseudohermaphroditism with labial testes and partial feminization: endocrine studies and genetic aspects

Altered hypothalamic-pituitarytesticular function in incomplete testicular feminization syndrome

Etude d'un cas familial d'androgynoïdisme avec hypospadias grave, gynécomastie et hyperoestrogénie

Hereditary familial hypogonadism

Familial gynecomastia

Androgens and fertility

Variable androgen receptor levels in infertile men

Frecuency of androgen insensitivity in infertile phenotypically normal men

Analysis of the transactivation domain of the androgen receptor in patients with male infertility

Evidence for partial deletion in the androgen receptor gene in a phenotypic male with azoospermia

Preserved male fertility despite decreased androgen sensitivity caused by a mutation in the ligand-binding domain of the androgen receptor gene

Progressive proximal spinal and bulbar muscular atrophy of late onset. A sex-linked recessive trait

Founder effect in spinal and bulbar muscular atrophy (SBMA)

X-linked recessive bulbospinal neuronopathy: a clinicopathological study

X-linked recessive bulbospinal neuronopathy: a report of ten cases

X-Linked spinal and bulbar muscular atrophy of late onset. A separate type of motor neuron disease?

A family with adult spinal and bulbar muscular atrophy, X-linked inheritance and associated testicular failure

Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy

Meiotic stability and genotypephenotype correlation of the tricucleotide repeat in X-linked spinal and bulbar muscular atrophy

The length and location of CAG trinucleotide repeats in the androgen receptor N-terminal domain affect transactivation function

Abnormal androgen receptor binding affi nity in subjects with Kennedy's disease (spinal and bulbar muscular atrophy)

Molecular pathology of the androgen receptor in male (in)fertility

Steroid 5 alpha-reductase defi ciency in man. An inherited form of male pseudohermaphroditism

Identifi cation of missense mutations in the SRD5A2 gene from patients with steroid 5alpha-reductase 2 defi ciency

Deletion of steroid 5 alpha reductase 2 gene in male pseudohermaphroditism

Steroid 5 alpha-reductase 2 defi ciency

Molecular study of the 5

alpha-reductase type 2 gene in three european families with 5 alphareductase defi ciency

5alpha-reductase 2 gene mutations in three unrelated patients of Greek Cypriot origin: identifi cation of an ancestral founder effect

A novel frameshift mutation in the 5alpha-reductase type 2 gene in Korean sisters with male pseudohermaphroditism

Testosterone and epitestosterone metabolism of single hairs in 5 patients with 5 alpha-reductasedefi ciency

Male pseudohermaphroditism due to 5 alpha-reductase defi ciency

Male pseudohermaphroditism due to steroid 5 alpha-reductase defi ciency

Persistence of müllerian ducts in male pseudohermaphroditism, and its relationship to cryptorchidism

Anti-Müllerian hormone and intersex states

Anti-Müllerian hormone, the Jost factor

The persistent müllerian duct syndrome: a rare cause of cryptorchidism

Hermaphroditism with atypical or 'mixed' gonadal dysgenesis. Relationship to gonadal neoplasm

Mixed gonadal dysgenesis

Penoscrotal hypospadias and coarctation of the aorta with mixed gonadal dysgenesis

Molecular analysis of SRY gene in patients with mixed gonadal dysgenesis

Dysgenesis of testicular and streak gonads in the syndrome of mixed gonadal dysgenesis. Perspective derived from a clinicopathologic analysis of twentyone cases

Clinical and pathologic spectrum of 46,XY gonadal dysgenesis: its relevance to the understanding of sex differentiation

Dysgenetic male pseudohermaphroditism

Morphometry and histology of gonads from 13 children with dysgenetic male pseudohermaphroditism

Testicular pathology in 46,XY dysgenetic male pseudohermaphroditism: an approach to pathogenesis of testis cancer

Hernia uteri inguinalis beim Manne

Persistence of müllerian derivatives in males

Persistent müllerian duct syndrome. Review and report of 3 cases

Familial persistent müllerian duct syndrome

Persistent müllerian duct syndrome in a man with transverse testicular ectopia

Persistent müllerian structures in infertile male

Male pseudohermaphroditism with persistent müllerian and wolffi an structures complicated by intraabdominal seminoma

Persistence of müllerian derivatives in males

Familial persistent müllerian duct syndrome

Variants of the anti-müllerian hormone gene in a compound heterozygote with the persistent müllerian duct syndrome and his family

Diffuse intratubular undifferentiated germ cell tumor in both testes of a male subject with a uterus and ipsilateral testicular dysgenesis

Testicular tumor in patient with persistent müllerian duct syndrome

A case of bilateral seminoma in the setting of persistent müllerian duct syndrome

RSH/Smith-Lemli-Opitz syndrome: mutations and metabolic morphogenesis

Atypical case of Smith-Lemli-Opitz syndrome: implications for diagnosis

Genetic disorders of cholesterol biosynthesis in mice and humans

Frequency gradients of DHCR7 mutations in patients with Smith-Lemli-Opitz syndrome in Europe: evidence for different origins of common mutations

Prenatal death in Smith-Lemli-Opitz/RSH syndrome

Antenatal manifestations of Smith-Lemli-Opitz (RSH) syndrome: a retrospective survey of 30 cases

Levels of unconjugated estriol and other maternal serum markers in pregnancies with Smith-Lemli-Opitz (RSH) syndrome fetuses

Syndromal (and nonsyndromal) forms of male pseudohermaphroditism

Mutations in the delta7-steroid reductase gene in patients with the Smith-Lemli-Opitz syndrome

Molecular cloning and expression of the human delta7-sterol reductase

Mutations in the human sterol delta7 reductase gene at 11q12-13 cause Smith-Lemli-Opitz syndrome

Smith-Lemli-Opitz syndrome is caused by mutations in the 7-dehydrocholesterol reductase gene

Opitz syndrome: a multiple congenital anomaly/mental retardation syndrome due to an inborn error of cholesterol biosynthesis

Mutation analysis and description of sixteen RSH/Smith-Lemli-Opitz syndrome patients: polymerase chain reaction-based assays to simplify genotyping

Recognition of Smith-Lemli-Opitz syndrome (RSH) in the fetus: utility of ultrasonography and biochemical analysis in pregnancies with low maternal serum estriol

A syndrome of pseudohermaphroditism, Wilms' tumor, hypertension and degenerative renal disease

Association between Wilms' tumor and gonadal dysgenesis

Glomerulonephritis associated with male pseudohermaphroditism and nephroblastoma

Twenty-four new cases of WT1 germline mutations and review of the literature: genotype/phenotype correlations for Wilms' tumor development

Nephrogenic rests in Wilms' tumor patients with the Drash syndrome

Frasier syndrome, part of the Denys Drash continuum or simply a WT1 gene associated disorder of intersex and nephropathy?

Frasier syndrome: a rare syndrome with WT1 gene mutation in pediatric urology

Mutation in the PAX6 gene in twenty patients with aniridia

WAGR syndrome: a clinical review of 54 cases

The G syndrome of multiple congenital anomalies

The BBB syndrome: familial telecanthus with associated congenital anomalies

Mig12, a novel Opitz syndrome gene product partner, is expressed in the embryonic ventral midline and co-operates with Mid1 to bundle and stabilize microtubules

Xlinked Opitz G/BBB syndrome: identifi cation of a novel mutation and prenatal diagnosis in a Korean family

Genetic study of SOX9 in a case of campomelic dysplasia

Molecularclinical spectrum of the ATR-X syndrome

A new detection method for ATRX gene mutations using a mismatch-specifi c endonuclease

Prenatal diagnosis of ATR-X syndrome in a fetus with a new G>T splicing mutation in the XNP/ATR-X gene

Testicular biopsy, its value in male sterility

Testicular biopsy. Further studies in male infertility

Interpretation of testicular biopsy

Testicular biopsy in the evolution of male infertility

Testicular causes of infertility

Pretesticular causes of infertility

A quantitative approach to the classifi cation of hypospermatogenesis in testicular biopsies for infertility

Testicular biopsy for infertility: a review of sixty-eight cases with a simplifi ed histologic classifi cation of lesions

Testicular biopsy in azoospermia: a review of the last ten years. Experience of over 800 cases

Posttesticular causes of infertility

Histopathology and ultrastructure of meiotic arrest in human spermatogenesis

Refl ections on testicular biopsy

Testicular biopsy in evaluation of male infertility

Testicular biopsy in the study of male infertility. Its current usefulness, histologic techniques, and prospects for the future

Testicular biopsy of azoospermic men with vas deferens malformation using two different techniques

Ultrastructural studies on testicular biopsies from eighteen cases of hypospermatogenesis

Serum and seminal gonadotropins in normal and infertile men: correlations with sperm count, prolactinemia, and seminal prolactin

The relationship of biopsy evaluations and testicular measurements to overall daily sperm production in human testes

The relationship between germinal cells and serum FSH levels in males with infertility

Inhibin B as a serum marker of spermatogenesis: correlation to differences in sperm concentration and follicle-stimulating hormone levels

Danish men

Inhibin B is a better marker of spermatogenesis than other hormones in the evaluation of male factor infertility

The correlation between sperm count and testicular biopsy using a new scoring system

Testicular biopsy score count -a method for registration of spermatogenesis in human testes: Normal values and results in 335 hypogonadal males

Statistical study of a semiquantitative evaluation of testicular biopsies

A method for quantitative analysis of human seminiferous epithelium

Quantitation of the cells of the seminiferous epithelium of human testis employing Sertoli cells as a constant

Quantifi cation of human seminiferous epithelium. III Histological studies in 44 infertile men with normal chromosome complements

Quantifi cation of human seminiferous epithelium. 4. Histological studies in 17 men with numerical and structural autosomal aberrations

Quantifi cation of human seminiferous epithelium. I Histological studies in twenty-one fertile men with normal chromosome complements

Quantitative analysis of the seminiferous epithelium in human testicular biopsies, and the relation of spermatogenesis to sperm density

Quantifi cation of the human Sertoli cell population: its distribution, relation to germ cell numbers, and age related decline

Quantitation of Leydig cells in testicular biopsies of oligospermic men with varicocele

A method for the quantifi cation of Leydig cells in man

Seminiferous tubule hypercurvature: a newly recognized common syndrome of human male infertility

Branching of seminiferous tubules associated with hypofertility and chronic respiratory infection

Morphological and histometric study on the human Sertoli cells from birth to the onset of puberty

Sertoli cell types in Sertoli-cell-only syndrome: relationships between Sertoli cell morphology and aetiology

Pathophysiological observations of Sertoli cells in patients with germinal aplasia or severe germ cell depletion. Ultrastructural fi ndings and hormone levels

Morphological evidence for two types of idiopathic 'Sertoli-cell-only' syndrome

Enzyme histochemical studies on the pathological changes in human Sertoli cells

Behaviour of glycogen and related enzymes in the Sertoli cell syndrome

Hypoplasia túbulo intersticial difusa (hipogonadismo hipogonadotrópico)

Leydig cell differentiation induced by stimulation with HCG and HMG in two patients affected with hypogonadotropic hypogonadism

The fi ne structure of the immature human testis in hypogonadotrophic hypogonadism

Hyperplasia and the immature appearance of Sertoli cells in primary testicular disorders

Immunohistochemical detection of immature Sertoli cell markers in testicular tissue of infertile adult men: a preliminary study

Maturation phenotype of Sertoli cells in testicular biopsies of azoospermic men

The human blood-testis barrier in impaired spermatogenesis

Reversion of the differentiated phenotype and maturation block in Sertoli cells in pathological human testis

Leydig cell types in primary testicular disorders

Ectopic testis and the undescended testis: a histological comparison

Short arm dicentric Y chromosome in a sterile man: a case report

Intermediate fi laments in Sertoli cells

Urinary gonadotropins in the Sertoli-cell-only syndrome

Impaired Leydig cell function in vitro in testicular tissue from human males with 'Sertoli cell only' syndrome

Testicular FSH and HCG receptors in Sertoli-cell-only syndrome

Syndrome produced by absence of the germinal epithelium without impairment of the Sertoli or Leydig cells

AZFa deletions in Sertoli cell-only syndrome: a retrospective study

Sertoli cell only syndrome in 1982

Return of spermatogenesis after stopping cyclophosphamide therapy

Evidence for testicular impairment after long-term treatment with a luteinizing hormone-releasing hormone agonist in elderly men

Effects of estrogens on the testis of transsexuals: a pathological and immunocytochemical study

Response of the human testis to long-term estrogen treatment: Morphology of Sertoli cells, Leydig cells and spermatogonial stem cells

Depressed testosterone release from testicular tissue in vitro after withdrawal of oestrogen treatment in patients with prostatic carcinoma

Tubular hyalinization in human testes

The peritubular myofi broblasts in the testes from normal men and men with Klinefelter's syndrome. A quantitative, ultrastructural, and immunohistochemical study

Laminin, type IV collagen, and fi bronectin in normal References and cryptorchid human testes. An immunohistochemical study

Testicular atrophy as a sequela of inguinal herniorrhaphy

Testis epididymis, and spermatic cord in elderly men. Correlation of angiographic and histologic studies with systemic arteriosclerosis

Primary testicular lesions in the twisted testis

Infl ammation and infestation of the testis and paratesticular structures

Quantitative testicular biopsy in congenital and acquired genital obstruction

The peritubular myoid cells in the testes from men with varicocele. An ultrastructural, immunohistochemical and quantitative study

Striated pattern of the testicle on ultrasound: an appearance of testicular fi brosis

Clinical importance of a unilateral striated pattern seen on sonography of the testicle

Suppressive effects of 1,2-dibromo-3-3-chloropropane on human spermatogenesis

Signifi cance of testicular exfoliation in male infecundity

Laboratory manual for the examination of human semen and semen-cervical mucus interaction

Zytologische Klassifi kation in reifer Keimzellen im Luftgetrockneten Ejakulatanstrich beim spermatologische Syndrom der vermehrten Desquamation von Zellen der Spermatogenese (VDZS)

Transformed spermatocytes constituting the ejaculate of an infertile man

Studies on the differentiation of round cells in the human ejaculate

Diagnostic value of differential quantifi cation of spermatids in obstructive azoospermia

Seminal cytology in the presence of varicocele

The pathophysiology of varicocele in male infertility

Obstruction of the tubuli recti and ductuli efferentes by dilated veins in the testes of men with varicocele and its possible role in causing atrophy of the seminiferous tubules

Scanning electron microscopic study on the shape of infertile seminiferous tubules: A hypothesis of pathogenesis of idiopathic male infertility

The histopathology of acute mumps orchitis

An azoospermic man with a double-strand DNA break-processing defi ciency in the spermatocyte nuclei: case report

Association of three isoforms of the meiotic BOULE gene with spermatogenic failure in infertile men

Abnormal germ cell exfoliation in semen of hypogonadotrophic patients during a hCG treatment

Altered luteinizing hormone pulsatility in infertile patients with idiopathic oligoasthenozoospermia

Differential effect of luteinizing hormone-releasing hormone infusion on testicular steroids in normal men and patients with idiopathic oligospermia

Molecular heterogeneity of serum follicle-stimulating hormone in hypogonadal patients before and during androgen replacement therapy and in normal men

Men homozygous for an inactivating mutation of the folliclestimulating-hormone (FSH) receptor gene present variable suppression of spermatogenesis and fertility

Klassifi zierung tubulärer Hodenatrophien bei Sterilitätabklärungen

Testicular ultrastructure in infertile men

Ultrastructure of the nucleus of human Sertoli cells in normal and pathological testes

Evaluation of the ultrastructural changes in the human Sertoli cell in testicular disorders and the relationship of the changes to the levels of serum FSH

Abnormality of testicular FSH receptors in infertile men

Signifi cance of inhibin in reproductive pathophysiology and current clinical applications

Placebo-controlled trial of high-dose mesterolone treatment of idiopathic male infertility

Impaired Leydig cell function in infertile men: a study of 357 idiopathic infertile men and 318 proven fertile controls

Leydig and Sertoli cell function in normal and oligospermic males: a preliminary report

Leydig cell function in infertile men with idiopathic oligospermic infertility

Androgen insensitivity as a cause of infertility in otherwise normal men

The frequency of androgen receptor defi ciency in infertile men

Malignant sex cord stromal tumor in a patient with the androgen insensitivity syndrome

A new point mutation of the androgen receptor gene in a patient with partial androgen resistance and severe oligozoospermia

The use of clomiphene citrate in the treatment of azoospermia secondary to incomplete androgen resistance

Evidence for a partial deletion in the androgen receptor gene in a phenotypic male with azoospermia

Androgen insensitivity and male infertility

Frequency of androgen insensitivity infertile phenotypically normal men

Improvement of spermatogenesis after treatment with the antiestrogen tamoxifen in a man with the incomplete androgen insensitivity syndrome

A controlled comparison of the effi cacy of clomiphene citrate in male infertility

Pregnancy after hormonal correction of severe spermatogenic defect due to a mutation in androgen receptor gene

Occupational exposures associated with male reproductive dysfunction

Ultrastructural surface characteristics of seminiferous tubules from men with varicocele

Signifi cance of testicular size measurement in andrology. II. Correlation of testicular size with testicular function

Deterioration of semen parameters over time in men with untreated varicocele: evidence of progressive testicular damage

Quantitative evaluation of testicular biopsies in varicocele

Testis biopsy in subfertile men with varicocele

Testicular changes in subfertile males with varicocele

Classifi cation of several types of maturational arrest of spermatogonia according to Sertoli cell morphology: an approach to aetiology

Prostate cancer. Primary hormonal treatment

Focal atrophy of the seminiferous tubule in the human testis

Quantitative and ultrastructural study on germinal epithelium in testicular biopsies with 'mixed atrophy

Proliferation and functional maturation of Sertoli cells, and their relevance to disorders of testis function in adulthood

Return of spermatogenesis after stopping cyclophosphamide therapy

The frequency and morphology of 'giant spermatogonia' in the human testis

Seminiferous tubule involution in elderly men

Pattern of compartmentation in human seminiferous tubules showing dislocation of spermatogonia

Dislocated type-A spermatogonia in human seminiferous tubules

Intercellular bridges between megalospermatocytes in the human testis

Megalospermatocytes in the human testis exhibit asynapsis of chromosomes

Megalospermatocytes: indicators of disturbed meiosis in man

Multinucleate spermatids in aging human testes

Unusual incidence of binucleate spermatids in human cryptorchidism

Testicular and epididymal pathology

Spermatogenetic arrest with inhibition of acrosome and sperm tail development

Recent advances in human sperm pathology

Anomalies morphologiques du spermatozoide humain. Propositions pour un système de classifi cation

Morphologische Studien an abnormen Spermatiden und Spermatozoen des Menschen

Classifi cation of abnormalities in human spermatids based on recent advances in ultrastructural research on spermatid differentiation

Morphology of spermatozoa in fertile man with and without varicocele

On round headed human spermatozoa

Morphogenesis of round headed human spermatozoa lacking acrosomes in a case of severe teratozoospermia

Sperm acrosome defects in a patient with Aarskog-Scott syndrome

Failure of differentiation of the nuclear-perinuclear skeletal complex in the round-headed human spermatozoa

Human sperm acrosin activity with relation to semen parameters and acrosomal ultrastructure

Chromosome aneuploidy in the spermatozoa of two men with globozoospermia

Sperm chromosome aneuploidy analysis in a man with globozoospermia

Round head' sperm defect. Ultrastructural and meiotic segregation study

Lack of acrosome formation in mice lacking a Golgi protein

Human infertility due to production of multiple-tailed References spermatozoa with excessive amounts of DNA

Multi-tailed spermatozoa in a case with asthenospermia and teratospermia

Human spermatozoa with large heads and multiple fl agella: a quantitative ultrastructural study of 6 cases

Chromosomal analysis of spermatozoa with normal-sized heads in two infertile patients with macrocephalic sperm head syndrome

Crater defect in human spermatozoa

Ultrastructural study of human binucleate spermatids

Ultrastructural abnormalities of human spermatozoa

Cytoplasmic droplets: the good, the bad or just confusing?

Absence de la paire centrale du complexe axonemique dans une tératospermie avec fl agelles courts et épais

Asthenozoospermie totale avec anomalie ultrastructurale du fl agelle dans deux frères stériles

Dysplasia of the fi brous sheath. An ultrastructural defect of human spermatozoa associated with sperm immotility and primary sterility

Tail stump spermatozoa: morphogenesis of the defect. An ultrastructural study of sperm and testicular biopsy

Gene deletions in an infertile man with sperm fi brous sheath dysplasia

Multi-tailed spermatozoa in a case with asthenospermia and teratospermia

Sperm tail agenesis in a case of consanguinity

Ultrastructural study of the decapitates sperm defect in a infertile man

Morphogenesis of the decapitated and decaudated sperm defect in two brothers

Acephalic spermatozoa and abnormal development of the head-neck attachment: a human syndrome of genetic origin

Sperm structure and its relevance to infertility

Decapitated and decaudated spermatozoa in man, and pathogenesis based on the ultrastructure

Assisted reproduction for infertile patients with 9 + 0 immotile spermatozoa associated with autosomal dominant polycystic kidney disease

Spermatozoa and cilia lacking axoneme in an infertile man

Lack of dynein arms in immotile human spermatozoa

Diagnostic approach to primary ciliary dyskinesia: a review

Primary ciliary dyskinesia: a review

Anomalies of lateralization in man: a case of total situs inversus

Stiff-tail-oder Mittelstück-Syndrom

Pour development of outer dense fi bres as a mayor cause of tail abnormalities in the spermatozoa of asthenoteratozoospermic men

Human mtDNA haplogroups associated with high or reduced spermatozoa motility

Male infertility and mitochondrial DNA

Carcinoma in situ in testicular biopsies from men presenting with infertility

Carcinoma in situ of the testis in infertile men. A histological, immunocytochemical and cytophotometric study of DNA content

Early testicular cancer in severe oligozoospermia

Carcinoma-insitu of the testis: possible origin from gonocytes and precursor of all types of germ cell tumours except spermatocytoma

Male subfertility. Continuing diagnostic and therapeutic measures

Testicular cancer risk in boys with maldescended testis: A cohort study

Seminoma discovered in two males undergoing successful testicular sperm extraction for intracytoplasmic sperm injection

Screening for carcinoma in situ of the contralateral testis in patients with germinal testicular cancer

The incidence of seminoma and expression of cell adhesion CD44 in cryptorchid boys and infertile men

A novel androgen receptor mutation resulting in complete androgen insensitivity syndrome and bilateral Leydig cell hyperplasia

Leydig cell hyperplasia mimicking testicular neoplasm

Increased mast cells in the limiting membrane of seminiferous tubules in the testes of patients with idiopathic infertility

Testicular mast cell heterogeneity in idiopathic male infertility

Mast cells in testicular lesions

Ketotifen improves sperm motility and sperm morphology in male patients with leukocytospermia and unexplained infertility

An attempt to explain occurrence of patent reproductive tract in azoospermic males with tubular spermatogenesis

Quantitative analysis of testicular biopsy: determination of partial obstruction and prediction of sperm count after surgery for obstruction

Correlation between spermatozoon numbers in spermiogram and seminiferous epithelium histology in testicular biopsies from subfertile men

Alpha-1,4-glucosidase activity and the presence of germinal epithelium cells in the semen for differential diagnosis of obstructive and nonobstructive azoospermia

Ejaculatory duct obstruction in subfertile males: analysis of 87 patients

Paratesticular cysts with benign epithelial proliferations of wolffi an origin

Von Hippel-Lindau disease

Prevalence of epididymal, seminal vesicle, prostate, and testicular cysts in autosomal dominant polycystic kidney disease

Congenital anomalies of the vas deferens, epididymis, and seminal vesicles

Etiologic factors in 1294 consecutive cases of male infertility

Male fertility and positive chlamydial serology. A study of 61 fertile and 82 subfertile men

Relationship of bacteriologic characteristics to semen indices in men attending an infertility clinic

Treatment of bacterial urinary tract infections: presence and future

Relationship of azoospermia to inguinal surgery

Coarse granular cytoplasmic change of the epididymis. An immunohistochemical and ultrastructural study

Histology of the epididymis in men with obstructive infertility

Quantitative testicular biopsy in spinal cord injured men: comparison to fertile controls

Some gross observations of the epididymides following vasectomy: a clinical study

Chronic testicular pain following vasectomy

Quantitative pathologic changes in the human testis after vasectomy. A controlled study

Consequences of vasectomy: an immunological and histological study related to subsequent fertility

The status of vasectomy reversals

A fi fteen-year study of alterations in semen quality occurring after vasectomy reversal

Surgical treatment of male infertility

Young's syndrome: obstructive azoospermia and chronic sinopulmonary infections

Respiratory tract disease and obstructive azoospermia

Obstructive azoospermia: respiratory function tests, electron microscopy and the results of surgery

Varicose axon bearing 'synaptic' vesicles on the basal lamina of the human seminiferous tubules

Oxytocin mediates the estrogendependent contractile activity of endothelin-1 in human and rabbit epididymis

Comparison of the effectiveness of placebo and alpha-blocker therapy for the treatment of idiopathic oligozoospermia

Screening for abnormalities of chromosomes X, Y, and 18 and for diploidy in spermatozoa from infertile men participating in an vitro fertilization-intracytoplasmic sperm injection program

Cytogenetic study of 435 subfertile men: incidence and clinical features

Syndrome characterized by gynecomastia, aspermatogenesis without aleydigism and increased excretion of follicle-stimulating hormone

Infertility in the Klinefelter syndrome

Control of meiotic process

Klinefelter syndrome

Endocrine features of Klinefelter's syndrome

Clinical and diagnostic features of patients with suspected Klinefelter syndrome

Clinical and therapeutic experiences with Klinefelter's syndrome

Brain morphology in Klinefelter syndrome: extra X chromosome and testosterone supplementation

Their fi ne structure in three cases of Klinefelter's syndrome

Dimorphism in sex chromatin pattern of Sertoli cells in adults with Klinefelter'ssyndrome: correlation with two types of 'Sertoli-cell-only' tubes

Leydig cell counts in chromatin-positive Klinefelter's syndrome

Quantitative and ultrastructural study of Leydig cells in Klinefelter'ssyndrome

Etude en microscopie électronique de References la cellule de Leydig dans la maladie de Klinefelter en périodes pre, per et postpubertaires

Testicular function in Klinefelter's syndrome

Testosterone and δ4 androstenedione in the saliva of patients with Klinefelter's syndrome

Fine structure of spermatogenesis in Klinefelter's syndrome

Spermatogenesis in Klinefelter's syndrome

PDG in 47,XXY Klinefelter's syndrome patients

Risk of trisomy 21 in offspring of patients with Klinefelter's syndrome

A new chromosome constitution in Klinefelter's syndrome

A male with XXYY chromosomes

Do the 48 XXYY males have a characteristic phenotype?

Genetics and endocrine fi ndings in a 48 XXYY male

Dermatoglyphics associated with the XXYY chromosome complement

Ultrastructure of Leydig cells in Klinefelter's syndrome with 48 XXYY karyotype

Primary amentia and microorchidism associated with an XXXY sex-chromosome constitution

49,XXXXY syndrome with diabetes mellitus

A child with 49 chromosomes

Carcinoma of the male breast in association with Klinefelter's syndrome

Male breast cancer

Klinefelter's syndrome and breast cancer

Seminoma in Klinefelter's syndrome with 47 XXY, 15s+ karyotype

Klinefelter's syndrome and mediastinal teratoma

Extragonadal germ cell tumor in the retrovesical region associated with Klinefelter's syndrome: A case report and review of literature

Primary mediastinal embryonal carcinoma in association with Klinefelter's syndrome

The malignant potential of the dysgenetic germ cell in Klinefelter's syndrome

Simian papovavirus 40 transformation of cells from cancer patient with XY/XXY mosaic Klinefelter's syndrome

Isolated primary aldosteronism in a patient with adrenal carcinoma and XY/XXY Klinefelter's syndrome

Acute leukemia following a malignant teratoma in a child with Klinefelter's syndrome

Hematologic malignancies and Klinefelter syndrome. A chance association?

Prostate cancer in Klinefelter syndrome during hormonal replacement therapy

The prepubertal testicular lesion in chromatin-positive Klinefelter's syndrome (primary micro-orchidism). As seen in mentally handicapped children

Mental development in polysomy X Klinefelter syndrome (47,XXY; 48,XXXY): effects of incomplete X inactivation

Klinefelter syndrome is a common cause for mental retardation of unknown etiology among prepubertal males

Growth and body proportions in 54 boys and men with Klinefelter's syndrome

Disorders of sex differentiation

Klinefelter syndrome

Klinefelter syndrome and its variants: an update and review for the primary pediatrician

Early androgen defi ciency in infants and young boys with 47,XXY Klinefelter syndrome

Klinefelter's syndrome in a ten month old mongolian idiot

Síndrome de Klinefelter's XXY en el periodo prepuberal. Estudio de ocho observaciones

Natural history of seminiferous tubule degeneration in Klinefelter syndrome

Klinefelter syndrome and mediastinal germ cell tumors

Central precocious puberty in 48,XXYY Klinefelter syndrome variant

A case of Klinefelter's syndrome with acquired hypopituitarism

Klinefelter's syndrome with hypogonadotropic hypogonadism

Chromatinpositive Klinefelter's syndrome with undetectable peripheral FSH levels

A case of hypogonadotrophic hypogonadism with an XY/XXY chromosome mosaicism

Klinefelter's syndrome with hypogonadotrophic hypogonadism

XXY Klinefelter's syndrome with low FSH and LH levels and absence of Leydig cells

A case of XX-male syndrome

45X/46XX boy with hypospadias: case report

XX sex chromosomes in a human male. First case

XX sex reversal, palmoplantar keratoderma, and predisposition to squamous cell carcinoma: genetic analysis in one family

Analytic review: Nature and origin of males with XX sex chromosomes

Leydig cell ultrastructure in an XX male

Varón con cariotipo 46 XX

Ultrastructure of testicular biopsy from an XX male

Le testicule chez l'homme 46, XX: A propos d'une observation ultrastructural

Ultrastructure of the testis in an XX male with normal plasma testosterone

Sex determination and sex reversal: genotype, phenotype, dogma and semantics

Clinical case of the month. A male with 46,XX karyotype

X-Y chromosomal interchange in the etiology of true hermaphroditism and of XX Klinefelter's syndrome

A possible etiology of the infertile 46 XX male subject

Deletion mapping of the testis determining locus with DNA probes in 46 XX males and 46 XY and 46 X dic (Y) females

DNA hybridization study using Yspecifi c probes in an XX-male

Localization of the sex-determining region-Y gene in XX males

XX male: clinical, hormonal/ genetic fi ndings

A comparative genomic hybridization study in a 46,XX male

An XX male with the sexdetermining region Y gene inserted in the long arm of chromosome 16

Deoxyribonucleic acid and cytological detection of Y-containing cells in a XX hypospadic boy with polyorchidism

XX males without SRY gene and with infertility

SRY-negative 46,XX male with normal genitals, complete masculinization and infertility

Genotype-phenotype correlations in XX males and their bearing on current theories of sex determination

A regulatory cascade hypothesis for mammalian sex determination: SRY represses a negative regulator of male development

XX sex reversal with partial duplication of chromosome arm 22q

Clinical, hormonal and cytogenetic evaluation of 46,XX males and review of the literature

XYY human male

XYY chromosome abnormality in sexual homicide perpetrators

The XYY syndrome: a follow-up study on 38 boys

Testicular function in XYY men

Quantifi cation of human seminiferous epithelium. II. Histological studies in eight 47, XYY men

Persistence of two Y chromosomes through meiotic prophase and metaphase I in an XYY man

From spermatocytes to spermatozoa in an infertile XYY male

Sex chromosome pairing and male fertility

The role of unpaired sex chromosomes in spermatogenetic failure

Evidence for an association between univalent Y chromosomes and spermatocyte loss in XYY mice and men

Meiosis in XYY men

Pituitary gonadotrophins and 17-ketosteroids in patients with the XYY syndrome

Analysis of the sex chromosome constitution of sperm in men with a 47,XYY mosaic karyotype by fl uorescence in situ hybridization

A male subject with 3 Y chromosomes (48,XYYY): A case report

Triple-Y syndrome following ICSI treatment in a couple with normal chromosomes: case report

49 XYYYY. A case report

Tetrasomy Y by structural rearrangement: clinical report

Human Y chromosome function in male germ cell development (review)

Defi ning regions of the Ychromosome reponsible for male infertility and identifi cation of a fourth AZF region (AZFd) by Ychromosome microdeletion

Characterization of novel genes in AZF regions

Localization of factors controlling spermatogenesis in the nonfl uorescent portion of the human Y chromosome long arm

Severe oligozoospermia resulting from deletions of References azoospermia factor gene on Y chromosome

Yq deletion and failure of spermatogenesis

Yq deletion with short stature, abnormal male development, and schizoid character disorder

FISH characterization of a dicentric Yq (p11.32) isochromosome in an azoospermic male

The Y chromosome, Part B. Clinical aspects of Y chromosome abnormalities

Short arm dicentric Y chromosome with associated statural defect in a sterile man

Four new cases of dicentric Y chromosomes

Meiotic studies on a subfertile patient with a ring Y chromosome

Mosaic ring Y chromosome in two normal healthy men with azoospermia

Ring (Y) in two azoospermic men

The Y chromosome Part B: Clinical aspects of Y chromosome abnormalities

An abnormal terminal X-Y interchange accounts for most but not all cases of human XX maleness

Cytogenetic, molecular and testicular tissue studies in an infertile 45,X male carrying an unbalanced (Y; 22) translocation: case report

Unique t(Y; 1)(q12; q12) reciprocal translocation with loss of the heterochromatic region of chromosome 1 in a male with azoospermia due to meiotic arrest: a case report

Y; autosome translocations and mosaicism in the aetiology of 45,X maleness: assignment of fertility factor to distal Yq ll

Characterization of a (Y; 4) translocation by DNA hybridization

Genome analysis: From sequence to function

Submicroscopic delections in the Y chromosome of infertile men

Y-chromosome deletions in idiopathic severe testiculopathies

Prevalence of Y chromosome microdelections in oligospermic and azoospermic candidates for intracytoplasmic sperm injection

Y-chromosome microdeletions and recurrent pregnancy loss

Molecular scanning of Yq 11 (interval 6) in men with Sertoli-cellonly syndrome

Y chromosome variants and male reproductive function

A duplication of distal Xp associated with hypogonadotrophic hypogonadism, hypoplastic external genitalia, mental retardation, and multiple congenital abnormalities

The behavior of sex chromosomes in two human Xautosome translocations: failure of extensive -inactivation spreading

ICSI and the transmission of Xautosomal translocation: a threegeneration evaluation of X; 20 translocation: case report

XXX male: a clinical and molecular study

Chromosome complements in 695 sperm from three men heterozygous for reciprocal translocations and a review of the literature

Analysis of sperm chromosome complements from a man heterozygous for a pericentric inversion of chromosome 1

An excess of chromosome 1 breakpoints in male infertility

Unbalanced chromosomal translocation associated with Sertoli-cell-only histology

Urological manifestations of Down syndrome

Hormone profi les and contralateral testicular histology in Down's syndrome with unilateral testicular tumor

Down syndrome and male fertility: PCR-derived fi ngerprinting, serological and andrological investigations

Successful pregnancy and delivery from frozen-thawed embryos after intracytoplasmic sperm injection using round-headed spermatozoa and assisted oocyte activation in a globozoospermic patient with mosaic Down syndrome

Maturation delay of germ cells in fetuses with trisomy 21 results in increased risk for the development of testicular germ cell tumors

Down syndrome in the male. Reproductive pathology and meiotic studies

Hypogonadism due to primary testicular failure

Correlation between CTG trinucleotide repeat length and frequency of severe congenital myotonic dystrophy

Size of the unstable CTG repeat sequence in relation to phenotype and prenatal transmission in myotonic dystrophy

Relationship between parenteral trinucleotide CTG repeat length and severity of myotonic dystrophy in offspring

Myotonic dystrophy: clinical and molecular parallels between myotonic dystrophy type 1 and type 2

Infl uence of sex of the transmitting parent as well as of parental allele size on the CTG expansion in myotonic dystrophy (DM)

CTG amplifi cation in the DM1PK gene is not associated with idiopathic male subfertility

Correlations between individual clinical manifestations and CTG repeat amplifi cation in myotonic dystrophy

Increasing infertility in myotonia dystrophica Curschmann-Steinert. A case report

Dystrophin characterization in muscle biopsies from Duchenne and Becker muscular dystrophy patients

Dystrophin, its interactions with other proteins, and implications for muscular dystrophy

Cloning of two new human helicase genes of the RECQ family: biological signifi cance of multiple species in higher eukaryotes

Positional cloning of the Werner's syndrome gene

Chromosomal breakage in human spermatozoa, a heterozygous effect of the Bloom syndrome mutation

RECQL4-defi cient cells are hypersensitive to oxidative stress/ damage: Insights for osteosarcoma prevalence and heterogeneity in Rothmund-Thomson syndrome

Cockayne's syndrome with unusual retinal involvement (report of one family)

Eccrine sweat gland anatomy in cockayne syndrome: a possible diagnostic aid

Cockayne's syndrome: a case report. Literature review

Trichothiodystrophy associated with photosensitivity, gonadal failure, and striking osteosclerosis

Mapping a gene for Noonan syndrome to the long arm of chromosome 12

Noonan syndrome and related disorders: genetics and pathogenesis

Testicular biopsy and hormonal study in a male with Noonan's Syndrome

Purkinje cell degeneration associated with erythroid ankyrin defi ciency in nb/nb mice

Ataxia and male sterility (AMS) mouse. A new genetic variant exhibiting degeneration and loss of cerebellar Purkinje cells and spermatic cells

Molecular structure of the human gonadotropin-releasing hormone receptor gene

Gonadotropin-Releasing hormone defi ciency in the human (idiopathic hypogonadotropic hypogonadism and Kallmann's syndrome): pathophysiological and genetic considerations

Algunos aspectos del eunucoidismo hipogonadotrópico

Complete hypogonadotropic hypogonadism associated with a novel inactivating mutation of the gonadotropin-releasing hormone receptor

Synchronization of augmented luteinizing hormone secretion with sleep during puberty

Predictors of outcome of longterm GnRH therapy in men with idiopathic hypogonadotropic hypogonadism

Hypogonadism due to secondary testicular failure

Falta total de nervios olfatorios con anosmia en un individuo en quien existía una atrofi a congénita de los testículos y miembro viril

The genetic aspects of primary eunuchoidism

La dysplasie olfacto-génitale

Polysialic acid facilitates migration of luteinizing hormonereleasing hormone neurons on vomeronasal axons

Mechanisms of disease: Insights into X-linked and autosomal-dominant Kallmann syndrome

Mutations in fi broblast growth factor receptor 1 cause Kallmann syndrome with a wide spectrum of reproductive phenotypes

Pulsatile gonadotropin-releasing therapy in male patients with Kallmann's syndrome or constitutional delay of puberty

Hipogonadismo hipogonadotrópico con anosmia

Electron microscopic studies of testes in Kallmann syndrome

Seminoma in hypogonadotropic hypogonadism associated with anosmia (Kallmann's syndrome)

Clinical and hormonal features of selective follicle-stimulating hormone (FSH) defi ciency due to FSH βsubunit gene mutations in both sexes

Human FSH β subunit gene is highly conserved

Isolated folliclestimulating hormone defi ciency in men: successful long-term gonadotropin therapy

Síndrome hipoandrogénico con gametogénesis conservada: clasifi cación de la insufi ciencia testicular

Hypoandrogenic syndrome with spermatogenesis

A syndrome of eunuchoidism with spermatogenesis, normal urinary FSH, and low-normal ICSH ('fertile eunuchs')

Fertile eunuch syndrome with the mutations (Trp8Arg and Ile15Thr) in the β subunit of luteinizing hormone

The fertile eunuch variant of idiopathic hypogonadotropic hypogonadism: spontaneous reversal associated with a homozygous mutation in the gonadotropinreleasing hormone receptor

Hypogonadism caused by a single amino acid substitution in the β subunit of luteinzing hormone

FSH β gene mutations in a female with partial breast development and a male sibling with normal puberty and azoospermia

Gonadal function and response to growth hormone (GH) in boys with isolated GH defi ciency and to GH and gonadotropins in boys with multiple pituitary hormone defi ciencies

Ein syndrom von Adipositas, Kleinwuchs, Kryptorchismus, und Oligophrenie nach myotonieartigen Zustand in Neugeborenenalter

Hypothalamic and gonadal components of hypogonadism in boys with Prader-Labhart-Willi syndrome

Cryptorchidism in the Prader-Willi syndrome

Síndrome de Prader-Willi

A fi fth locus for Bardet-Biedl syndrome maps to chromosome 2q31

Bardet-Biedl syndrome: an emerging pathomechanism of intracellular transport

An atypical contiguous gene syndrome: molecular studies in a family with Xlinked Kallmann's syndrome and Xlinked ichthyosis

Johnson-McMillin syndrome: report of a new case with novel features

A single ataxia telangiectasia gene with a product similar to PI-3 kinase

Ataxiatelangiectasia and related diseases

The Friedreich's ataxia gene encodes a novel phosphatidylinositol-4-phosphatase 5-kinase

Friedreich ataxia: Detection of GAA repeat expansions and frataxin point mutations

Endocrine evaluation of infertile men

Idiopathic hypogonadotropic hypogonadism in a male runner is reversed by clomiphene citrate

Endocrine function after spontaneous infarction of the human pituitary

Acquired hypogonadotropic hypogonadism presenting as decreased seminal volume

Gonadotropin-secreting pituitary adenoma with concomitant hypersecretion of testosterone and elevated sperm count. Treatment with LRH agonists

Testicular enlargement and elevated serum inhibin concentrations occur in patients with pituitary macroadenomas secreting follicle stimulating hormone

The impotent couple: low desire

Immunohistochemical detection of prolactin and its receptors in human testis

Ultrastructural lesions in testes from hyperprolactinemic men

Infl uence of serum prolactin on semen characteristics and sperm function

Return of gonadal function in men with prolactin-secreting tumors

Serum levels of free and bound testosterone in hyperthyroidism

Testicular function in hyperthyroidism

Graves'autoimmune serum inhibits gonadal steroidogenesis. Development of a Leydig cell bioassay to identify broad spectrum anti-endocrine autoantibodies

Male hypogonodism in hypothyroidism: A study of six cases

Male reproductive function in relation with thyroid alterations

Testicular dysfunction in men with primary hypothyroidism; reversal of hypogonadotropic hypogonadism with replacement thyroxine

Primary hypothyroidism and human spermatogenesis

Serum hormones and seminal parameters in males with thyroid disturbance

Thyroid function and puberty

Prepubertal diagnosis of X-linked congenital adrenal hypoplasia presenting after infancy

X-linked adrenal hypoplasia congenita and hypogonadotropic hypogonadism: report on new mutation of the DAX-1 gene in two siblings

X-linked adrenal hypoplasia congenita: a mutation in DAX1 expands the phenotypic spectrum in males and females

Genotyping of congenital adrenal hyperplasia due to 21-hydroxylase defi ciency presenting as male infertility: Case report and literature review

Male infertility due to congenital adrenal hyperplasia: testicular biopsy fi ndings, hormonal evaluation, and therapeutic results in three patients

Adrenal rest tumors of the testes

Bilateral testicular adrenal rests in a patient with 11-hydroxylase defi cient congenital adrenal hyperplasia

Infertility caused by bilateral testicular masses secondary to congenital adrenal hyperplasia (21-hydroxylase defi ciency)

Elevated 17-hydroxyprogesterone and testosterone in a newborn with 3β-hydroxysteroid dehydrogenase defi ciency. N Eng l

Congenital 17 alfa-hydroxylase defi ciency: A clinico-pathologic study

Bilateral tumors of the testis in 21-alpha hydroxylase defi ciency without adrenal hyperplasia

Estrogen secreting adrenal adenocarcinoma in an 18-month-old boy: aromatase activity, protein expression, mRNA and utilization of gonadal type promoter

Diabetes mellitus/male infertility

Growth, puberty, and fi nal height in children with type 1 diabetes

Insulin-dependent diabetes affects testicular function by FSHand LH-linked mechanisms

Semen characteristics and diabetes mellitus: signifi cance of insulin in male infertility

Interstitial compartment pathology and spermatogenic disruption in testes from impotent diabetic men

Autonomic neuropathy and sexual impotence in diabetic patients: Analisis of cardiovascular refl exes

Mutation analysis for heterozygote detection and the prenatal diagnosis of cystic fi brosis

CFTR gene mutations and male infertility

Infertility in male patients with cystic fi brosis

Anomalies du sperme, des defferents et de l'epididyme dans la mucoviscidose

A mutation in the second nucleotide binding fold of the cystic fi brosis gene

Cystic fi brosis in infertility: screening before assisted reproduction: opinion

Autosomal recessive hereditary congenital aplasia of the vasa deferentia in four siblings

Congenital bilateral absence of the vas deferens. A primary genital form of cystic fi brosis

Congenital mesonephric defects in male infants with mucoviscidosis

Genital abnormalities in male patients with cystic fi brosis

La reviviscenza mammaria nell'uomo affecto da cirrosi del Laennec

Sulla c.d. reviviscenza della mammella maschile nella cirrosi epatica (nota preventiva)

Hypogonadism in alcoholic liver direase: evidence for a double defect

Effect of chronic alcoholism on semenstudies on lipid profi les

Alterations of testicular morphology in alcoholic disease

Differential binding of testosterone and oestradiol to isoforms of sex hormone binding glolulim: selective alteration of estradiol binding in cirrhosis

Group for Liver Diseases. Serum testosterone concentration in men with alcoholic cirrhosis: background for variation

Sexual function and testosterone levels in men with nonalcoholic liver disease

Testicular function and fertility in men with homozygous alpha-1 antitrypsin defi ciency

Hereditary hemochromatosis

Haemochromatosis and HLA-H

A novel MHC class 1-like gene is mutated in patients with hereditary haemochromatosis

Clinical and molecular aspects of juvenile hemochromatosis in Saguenay

Juvenile hemochromatosis locus maps to chromosome 1q

Juvenile hemochromatosis

A 24-year-old patient with decreased libido and erectile dysfunction as initial manifestations of hemochromatosis

Endocrine complications of genetic hemochromatosis

Hypogonadism in hereditary hemochromatosis

The anterior pituitary in hemochromatosis

Reversibility of hypogonadotropic hypogonadism in a patient with the juvenile form of hemochromatosis

Polycystic kidney disease and infertility: case report and literature review

Infertility in adults with References polycystic kidney disease

Male infertility and adult polycystic kidney disease are associated with necrospermia

Seminal vesicle cysts and infertility in autosomal dominant polycystic kidney disease

Clinical relevance of scrotal and transrectal ultrasonography in andrological patients

Testosterone esters advance skeletal maturation more than growth in short boys with chronic renal failure and delayed puberty

Discordant elevation of the common alpha subunit of the glycoprotein hormones compared to β subunits in serum of uremic patients

The pituitary testicular axis in men with chronic renal failure

Pathology of endocrine organs in chronic renal failure. An autopsy analysis of 66 patients

Calcifi cation of the epididymis and the tunica albuginea of the corpora cavernosa in patients on maintenance hemodialysis

Novel insights into uremic vascular calcifi cation: role of matrix Gla protein and alpha-2-heremans Schmid glycoprotein/fetuin

Cystic transformation and calcium oxalate deposits in rete testis and efferent ducts in dialysis patients

Gonadal dysfunction in uremic men. A study of the hypothalamo-pituitarytesticular axis before and after renal transplantation

Pathogenesis of endocrine abnormalities in uremia

Hypothalamic-pituitary function in uremia

Zinc defi ciency in men with Crohn's disease may contribute to poor sperm function and male infertility

Sperm nucleomalacia in men with infl amatory bowel disease

The effects of sulphasalazine on human male fertility potencial and seminal prostaglandins

Mesalazineinduced reversible infertility in a young male

Sulphasalazine and 5-aminosalicylic acid in long-term treatment of ulcerative colitis: report on tolerance and side-effects

Testosterone replacement for hypogonadism: clinical fi ndings and best practices

HIV-associated hypogonadism

Hypogonadism and wasting in the era of HAART in HIV-infected patients

Prevalence of hypogonadism among men with weight loss related to human immunodefi ciency virus infection who were receiving highly active antiretroviral therapy

Loss of lean body mass and muscle mass correlates with androgen levels in hypogonadal men with acquired immunodefi ciency syndrome and wasting

Effects of hypogonadism and testosterone administration on depression indices in HIV-infected men

Gonadal hormone levels in injection drug users

Endocrine disorders in men infected with human immunodefi ciency virus

Testicular pathologic changes and the pituitary-testicular axis during human immunodefi ciency virus infection

Adrenal and testicular function in boys affected by thalassemia

Italian Working Group on Endocrine Complications in Non-Endocrine Diseases. Impact of long-term iron chelation therapy on growth and endocrine functions in thalassaemia

Pubertal evaluation of adolescent boys with β-thalassemia major and delayed puberty

Prevalence of growth and puberty failure with respect to growth hormone and gonadotropins secretion in βthalassemia major

Growth and puberty and its management in thalassaemia

Spontaneous and GnRHprovoked gonadotropin secretion and testosterone response to human chorionic gonadotropin in adolescent boys with thalassaemia major and delayed puberty

Inhibin B in men with severe obesity and after weight reduction following gastroplasty

Obesity and reproductive disorders: a review

Obesity, fat distribution and infertility

Mutational analysis of the autoimmune regulator (AIRE) gene in sporadic autoimmune Addison's disease can reveal patients with unidentifi ed autoimmune polyendocrine syndrome type l

Autoimmune regulator (AIRE) gene on chromosome 21: implications for autoimmune polyendocrinopathycandidiasis-ectodermal dystrophy (APECED) any more common manifestations of endocrine autoimmunity

Adrenal and gonadal autoimmune diseases

Identifi cation by molecular cloning of an autoantigen associated with Addison's disease as steroid 17 alphahydroxylase

Two different cytochrome p450 enzymes are the adrenal antigens in autoimmune polyendocrine syndrome type I and Addison's disease

Prevalence and clinical associations of 10 defi ned autoantibodies in autoimmune polyendocrine syndrome type I

Polyglandular autoinmune syndromes

Isolated gonadotrope failure in the polyglandular autoimmune syndrome

Endocrine dysfunction in patients with Fabry disease

Testicular and epididymal involvement in Fabry's disease

Safety and effi cacy of recombinant human alpha-galactosidase A replacement therapy in Fabry's disease

Fabry disease, an underrecognized multisystemic disorder: expert recommendations for diagnosis, management, and enzyme replacement therapy

Enzyme replacement therapy and renal function in 201 patients with Fabry disease

Putative X-linked adrenoleukodystrophy gene shares unexpected homology with ABC transporters

Gonadal mosaicism in a family with adreno-leukodystrophy. Molecular diagnosis of carrier status among daughters of a gonadal mosaic when direct detection of the mutation is not possible

X-linked adrenoleukodystrophy: role of very long-chain acyl-CoA synthetases

Adrenal and testicular function in 14 patients with adrenoleukodystrophy or adrenomyeloneuropathy

The testis in adreno-leukodystrophy

In situ localization of the genetic locus encoding the lysosomal acid lipase/cholesteryl esterase (LIPA) defi cient in Wolman disease to chromosome 10q23.2-q23.3

Enfermedad de Wolman. Estudio anatomopatológico de dos observaciones

Autopsy report of an adult case with a long-standing subclinical course complicated by accelerated atherosclerosis and liver carcinoma

Successful treatment of Wolman disease by unrelated umbilical cord blood transplantation

Pituitary-testicular function in nephropathic cystinosis

Lysosomal diseases

Environmental infl uences on male reproductive health

Occupational exposures associated with male reproductive dysfunction

Semen quality in fertile US men in relation to geographical area and pesticide exposure

Semen quality of workers occupationally exposed to hydrocarbons

Semen quality in workers exposed to carbon disulfi de compared to a control group from the same plant

Endocrinologic studies in men exposed occupationally to carbon disulfi de

Y-chromosomal nondysjunction in dibromochloropropane exposed workmen

Inorganic lead exposure in battery and paint factory: effect on human sperm structure and functional activity

Reproductive ability of workmen occupationally exposed to lead

Endocrine and reproductive dysfunction in men associated with occupational inorganic lead intoxication

Occupational exposure to synthetic estrogens: some methodological problems

Association of diethylstilbestrol exposure in utero with cryptorchidism, testicular hypoplasia and semen abnormalities

Altered semen quality in relation to urinary concentrations of phthalate monoester and oxidative metabolites

Current use of pesticides in Poland and the risk of reproductive disorders

The environment and male fertility: recent research on emerging chemicals and semen quality

Exposure to exogenous estrogens in food: possible impact on human development and health

Testicular dysgenesis syndrome; an increasingly common developmental disorder with environmental aspects

Environmental infl uences on male reproduction

Effects of delta-9-tetrahydrocannabinol, the primary psychoactive cannabinoid in marijuana, on human sperm function in vitro

Effect of cocaine on germ cell apoptosis in rats at different ages

Effect of chronic alcoholism on male fertility hormones and semen quality

Effect of smoking on semen parameters of men attending an infertility clinic

Concomitant abuse of anabolic androgenic steroids and human chorionic gonadotrophin impairs spermatogenesis in power athletes

The infl uence of radiation on fertility in man

Gonadal function in workmen with long term exposure to microwaves

Effects of artifi cial cryptorchidism on sperm morphology

Spermatogenic arrest in men with testicular hyperthermia

The effect of hyperthermia on ornithine decarboxylase activity in different rat tissue

Effects of L-acetylcarnitine (LAC) on the post-injury recovery of mouse spermatogenesis monitored by fl ow cytometry. Recovery after hyperthermic treatment

The role of carnitine in spermatozoa metabolism. Substrate induced elevations in the acetylation state of carnitine and coenzyme A in bovine and monkey spermatozoa

In vitro temperature sensitivity of DNA, RNA, and protein synthesis throughout puberty in human testis

Traumatic dislocation of testes and bladder rupture

Report of 2 new cases and review of the literature

Traumatic dislocation of testis

Traumatic testicular dislocation a review of 36 cases

Restoration of spermatogenesis by orchiopexy 13 years after bilateral traumatic testicular dislocation

Sexuality and fertility in long-term survivors of testicular cancer

Fertility and pregnancy after treatment for cancer during childhood or adolescence

Male gonadal dose in adjuvant 3-d-pelvic irradiation after anterior resection of rectal cancer. Infl uence to fertility

Recovery from aspermia induced by low-dose radiation in seminoma patients

Aspermia following lower truncal irradiation in Hodgkin's disease

Testicular function in eight patients with seminoma after unilateral orchidectomy and radiotherapy

Paternity after irradiation for testicular cancer

Gonadal function in patients with differentiated thyroid cancer treated with (131)I

Effects of electromagnetic radiation from a cellular phone on human sperm motility: an in vitro study

Development of the seminiferous epithelium during and after treatment for acute lymphoblastic leukemia in childhood

Gonadal effects of cancer therapy in boys

The effects of different cumulative doses of chemotherapy on testicular function

Impact of cyclophosphamide on long-term reduction in sperm count in men treated with combination chemotherapy for Ewing and soft tissue sarcomas

Sertoli cell inactivation by cytotoxic damage to the human testis after cancer chemotherapy

Leydig cell dysfunction and gynaecomastia in adult males treated with alkylating agents

Testicular and sperm DNA damage after treatment with fl udarabine for chronic lymphocytic leukaemia

1473. van den Berg H, Furstner F, van den Bos C, Behrendt H. Decreasing the number of MOPP courses reduces gonadal damage in survivors of childhood Hodgkin disease

Effects of the chemotherapy cocktail used to treat testicular cancer on sperm chromatin integrity

Sperm integrity pre-and postchemotherapy in men with testicular germ cell cancer

Testicular dysfunction in Hodgkin's disease before and after treatment

Posttreatment fertility in patients with testicular cancer. Part 1

Sexual function after bilateral retroperitoneal lymph node dissection for nonseminomatous testicular cancer

Sexual dysfunction and electroejaculation in men with spinal cord injury: review

Infertilty in the spinal cord injuried male

Reproductive biology of paraplegics: Results of semen collection, testicular biopsy and serum hormone evaluation

Auto-immunity to spermatozoa and quality of semen in men with spinal cord injury

Histological and hormonal testicular changes in spinal cord patients

Male fertility and sexual function after spinal cord injury

Current trends in the treatment of infertility in men with spinal cord injury

Spermatogenese bei Patienten mit traumatischer Querschnittähmung

Deep scrotal temperature and the effect on it of clothing, air, temperature, activity, posture and paraplegia

Neurological correlations of ejaculation and testicular size in men with a complete spinal cord section

Leukocytes in semen from men with spinal cord injuries

Leukocyte subtypes in electroejaculates of spinal cord injured men

Infl ammatory cytokine concentrations are elevated in seminal plasma of men with spinal cord injuries

Testis biopsy fi ndings in the spinal cord injured patient

Seminal vesicle aspiration in spinal cord injured men: insight into poor sperm quality

Sperm motility from the vas deferens of spinal cord injured men is higher than from the ejaculate

Brown-colored semen in men with spinal cord injury

Mumps orchitis: report of a mini-epidemic

Mumps orchitis

Mumps -an underestimated disease

Mumps orchitis among soldiers: frequency, effect on sperm quality, and sperm antibodies

Mumps orchitis: symptoms and treatment possibilities

Pathology of mumps orchitis

Successful testicular sperm extraction and fertilization in an azoospermic man with postpubertal mumps orchitis

Infl ammation of the testis, epididymis, peritesticular membranes and scrotum

Orchitis and testicular abscess formation caused by non-typhoid salmonellosis

Disseminated actinomycosis presenting as a testicular mass. A case report

Primary testicular actinomycosis mimicking metastatic tumor

Xanthogranulomatous funiculitis and orchiepididymitis: report of 2 cases with immunohistochemical study and literature review

Tuberculous epididymitis occurring 35 years after renal tuberculosis

Tuberculous epididymitis as a cause of testicular pseudomalignancy in two young children

Tuberculous epididymo-orchitis. Diagnosis by fi ne needle aspiration

Tuberculous epididymo-orchitis. A case report

Epididymo-orchitis caused by intravesically instillated bacillus Calmette-Guérin: genetically proven using a multiplex polymerase chain reaction method

Gumma of testis

Lepromatous leprosy presenting as orchitis

Clinicopathological study of testicular involvement in leprosy

Genital manifestations of tropical diseases

Human brucellosis in Northern Saudi Arabia

Epididymoorchitis due to brucellosis in central Anatolia

Brucellar orchiepididymitis in acute brucellosis

Brucella orchitis: a rare cause of testicular enlargement

Orquioepididimitis brucelosa: A propósito de un caso

Rapid diagnosis of Brucella epididymo-orchitis by realtime polymerase chain reaction assay in urine samples

Epididymal sarcoidosis

Sarcoidosis with bilateral epididymal and testicular lesions

Sarcoidosis presenting as a testicular mass

Sarcoid of the testis

Genitourinary involvement of systemic sarcoidosis confi ned to testicle

Seminoma and sarcoidosis: an unusual association

Intermittent azoospermia associated with epididymal sarcoidosis

Ueber Einschlüsse in Blastumoren

A case of malacoplakia of the epididymis associated with trauma

Epididymo-testicular malacoplakiaa case report

An unusual case of malakoplakia involving the testis and prostate

Testicular malacoplakia

Septate junctions between digestive vacuoles in human malakoplakia

Genitourinary tract involvement with systemic mycosis

Coccidioidomycosis of the epididymis and testis

Cryptococcal epididymoorchitis complicating steroid therapy for releasing polychondritis

Schistosomal epididymitis

Alveolar echinococcosis with involvement of the ureter and testes

Idiopathic granulomatous orchitis: pathologic study of one case

Experimental allergic orchitis in mice. Histopathological and immunological studies

Immunological phenomena observed in the testis and their possible role in infertility

Immunocompetent cells in human testis in health and disease

Sympathetic autoimmune orchitis

Testicular obstruction: clinicopathological studies

Hypoechoic Lesion found on testicular ultrasound after testicular piercing

Focal orchitis in undescended testes: discussion of pathogenetic mechanisms of tubular atrophy

Pseudolymphoma of the testis

Plasma cell granuloma of the testis: unusual localization

Testicular plasmacytoma: report of a case and review of the literature

Sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease): report of a patient with isolated renotesticular involvement after cure of non-Hodgkin's lymphoma

Rosai-Dorfman disease of the testis: an unusual entity that mimics testicular malignancy

Persistent erythema and pruritus, with a confl uent histiocytic skin infi ltrate, following the use of a hydroxyethylstarch plasma expander

Epididymitis nodosa. An epididymal lesion analogous to vasitis nodosa

Amiodarone in testis and semen

Testicular dysfunction with amiodarone use

Non-infectious epididymitis associated with amiodarone therapy

Amiodaroneinduced epididymitis: report of a new case and literature review of 12 cases

Amiodarone-induced sterile epididymitis

Recurrent bilateral amiodarone induced epididymitis

Amiodarone induced epididymitis in children

Amiodarone-induced epididymitis

Granulomatous epididymal lesion of possible ischemic origin

A stone in the testicle

Testicular calculus

Orchitis mimicking testicular torsion in Henoch-Schönlein's purpura

Wegener's granulomatosis involving the urogenital tract

Testicular infarction in a 12-year-old boy with Wegener's granulomatosis

Cogan's syndrome: 18 cases and a review of the literature

Recurrent epididymo-orchitis in patients with Behçet's disease

Isolated polyarteritis nodosa of the male reproductive system

Testicular mass as presenting symptom of isolated polyarteritis nodosa

Testicular lesions of periarteritis nodosa, with special reference to diagnosis

Polyarteritis nodosa presenting as acute orchitis: A case report and review of the literature

Isolated epididymal vasculitis

Limited polyarteritis nodosa of the male and female reproductive systems: diagnostic and therapeutic approach

Polyarteritis nodosa masquerading as a primary testicular neoplasm. A case report and review of the literature

Testicular vasculitis: Implication for systemic disease

Torsión del cordón espermático. A propósito de 87 nuevos casos. Revisión de la literatura

Controversies of perinatal torsion of the spermatic cord: a review, survey and recommendations

Prenatal testicular torsion: ultrasonographic features, management and histopathological fi ndings

Torsion of the testis

Testicular torsion in a 68-year-old man

Testicular torsion: simple grading for histological evaluation of tissues damage

Primary testicular lesions in the twisted testis

Torsión testicular antes de 6 horas

Late postoperative results in males treated for testicular torsion during childhood

Testicular tissue bleeding as an indicator of gonadal salvageability in testicular torsion surgery

Intermittent testicular torsion

Lipomembranous fat necrosis in three cases of testicular torsion

Immunologic aspects of testicular torsion: detection of antisperm antibodies in contralateral testicle

Ipsilateral and contralateral testicular biochemical acute changes after unilateral testicular torsion and detorsion

Increased apoptosis in the contralateral testes of patients with testicular torsion as a factor for infertility

Unilateral testicular torsion: abnormal histological fi ndings in the contralateral testis. Cause or effect?

Testicular injury. Late results of semen analyses after orchiectomy

Testicular atrophy as a sequela of inguinal hernioplasty

Cooper's ligament repair for adult growing hernias

Spontaneous thrombosis of left spermatic vein: Report of 2 cases

Postsurgical focal testicular infarct

Localised infarction of the testis

Acute segmental testicular infarction: differentiation from tumour using high frequency colour Doppler ultrasound

Observations on the structure and diseases of the testis

Cysts of the testicle

Tunica albuginea cyst: rare testicular mass

High-resolution sonography of scrotal contents in asymptomatic subjects

The high incidence of benign testicular tumors

Testicular cysts. US fi ndings

Benign intrascrotal lesions

Sonography of benign intrascrotal lesions

Cysts of the testicular parenchyma and tunica albuginea

Efferent ductule cyst of tunica albuginea

Simple cyst of the rete testis

Intratesticular spermatocele

Simple cyst of the testis: case report and review of literature

Congenital simple cysts of the testis: a hitherto undescribed lesion

Intratesticular cysts

Testicular cysts: Differentiation with US and clinical fi ndings

Simple testicular cyst: A rare cause of scrotal swelling in infancy

Bilateral intratesticular cysts. A specifi c entity

Cysts of the tunica albuginea (cysts of the testis)

Cysts of the tunica albuginea testis

Nonneoplastic cystic lesions of the tunica albuginea: an electron microscopic and clinical study of 2 cases

Cysts of the tunica albuginea: report of 4 cases and review of the literature

Cysts of the tunica albuginea: a report of 3 cases with a review of the literature

High resolution ultrasonography in the diagnosis of simple intratesticular cysts

Simple testicular cyst diagnosed preoperatively by ultrasound

Surveillance strategy for intratesticular cysts: preliminary report

Simple cysts of the testis in children: Preoperative diagnosis by ultrasound and excision with testicular preservation

Rete testis dysgenesis. A characteristic lesion of undescended testes

Estrogen receptor alpha has a functional role in the mouse rete testis and efferent ductules

Cystic transformation of the rete testis

Tubular ectasia of the rete testis: an ultrasound diagnosis

Cystic ectasia of the rete testis

Pronounced cystic transformation of the rete testis. MRI appearance

The diversity of reproductive tract abnormalities in males with cystic fi brosis

Postsurgical changes in the testis: a diagnostic dilemma

Acquired cystic transformation of the rete testis secondary to renal failure

Adenomatous hyperplasia of the rete testis

Adenomatous hyperplasia of the rete testis. A review and report of new cases

Displasia quística del testículo: anomalia en la diferenciación del parénquima testicular por probable fallo en la conexión entre los conductos de origen mesonéfrico y los cordones testiculares

Adenomatous hyperplasia of the References rete testis: report of two cases

Glandular changes in the rete testis: metastatic tumour or adenomatous hyperplasia? [Letter

Tumors and cysts of the paratesticular region

Adenomatous hyperplasia of the rete testis. A clinicopathologic study of nine cases

Primary testicular lesions are associated with testicular germ cell tumors of adult men

Adénome du rete testis

Adenocarcinoma of the rete testis: case report, ultrastructural observations, and clinicopathologic correlates

Infarcted adenomatoid tumor: a report of fi ve cases of a facet of a benign neoplasm that may cause diagnostic diffi culty

Rete testis hyperplasia with hyaline globule formation. A lesion simulating yolk sac tumor

Nodular proliferation of calcifying connective tissue in the rete testis: A study of three cases