key: cord-0896156-74flzssx
authors: Kazybay, Bexultan; Xie, Yingqiu
title: Re: Herjan J.T. Coelingh Bennink, Jean-Michel Foidart, Frans M.J. Debruyne. Treatment of Serious COVID-19 with Testosterone Suppression and High-dose Estrogen Therapy. Eur Urol. In press. https://doi.org/10.1016/j.eururo.2021.06.024
date: 2021-08-17
journal: Eur Urol
DOI: 10.1016/j.eururo.2021.08.004
sha: 3aeed79c66240521f6cfa7ac9fe64f2b254f018c
doc_id: 896156
cord_uid: 74flzssx

nan

This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Bennink et al [1] have proposed clinical treatment of COVID-19 with androgen deprivation therapy using high-dose estrogen (ADET) in combination with the gonadotropin-releasing hormone antagonists degarelix and transdermal estradiol for both male and female patients. The proposal is based on the hypothesis that the therapy will have an antiandrogen effect in suppressing ACE2 and TMPRSS2, key proteins involved in SARS-CoV-2 viral cell entry, while increasing estrogen levels to reduce inflammation and cytokine production, immune complications that are linked to COVID-19.

The study needs to consider several factors before starting clinical trials, including age and sex restrictions, potent hormonal side-effects, and the efficacy of degarelix. First, we suggest setting the age criterion for patients to >60 yr, as this approach was previously used for prostate cancer patients with a mean age of 74 yr (range 59-85 yr) [2] . Because both androgen deprivation therapy (ADT) and ADET have not been tested in female patients and women have 10-to 20-fold lower testosterone levels in comparison to men [1] , we suggest more valid evidence and reasons to justify the use of the proposed therapy for female patients to prevent a decrease in quality of life. According to Rhee et al [3] , ADT has a wide range of serious adverse effects. It is associated with higher risk of hypercholesterolemia, myocardial infarction, diabetes, and renal impairment. As ADET might also cause obesity, gynecomastia, sexual dysfunction, and depression [3] , the mental health and quality of life of male patients needs to be taken into consideration as well. Similarly, use of high-dose estrogen in severe COVID-19 cases is also controversial, as several studies indicate that it has prothrombotic and procoagulation effects, with possible links to ventricular arrhythmias and sudden cardiac arrest [4] . As Bennink et al suggest using combination therapy, such treatment may pose a serious risk to the health of hospitalized COVID-19 patients who are already in a critical condition. A randomized clinical trial by Sayyid at al [5] involving 39 patients with prostate cancer demonstrated that degarelix had little effect on testosterone and luteinizing hormone levels, in contrast to luteinizing hormone-releasing hormone (LHRH) agonists, which are traditionally used for ADT. According to the results, the mean testosterone level for the degarelix versus LHRH agonist groups was 11.59 versus 13.03 nmol/L at baseline, and 1.57 versus 1.40 nmol/l in week 4. The study also revealed no significant difference for weeks 8 and 12. Thus, the use of degarelix is also questionable. We appreciate the proposal by Bennink and colleagues [1] to use hormonal treatment as a novel therapy for hospitalized COVID-19 patients. However, we have concerns regarding the condition of patients in this trial, the rationale for evaluating the risks of ADET side-effects, and the contradiction in using degarelix as one of the therapy agents. We recommend considering these issues for a better study design and approach, such as specific COVID-19targeted nonhormonal therapy.

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

The authors have nothing to disclose.

Treatment of Serious COVID-19 with testosterone suppression and high-dose estrogen therapy

Estetrol cotreatment of androgen deprivation therapy in infiltrating or metastatic, castration-sensitive prostate cancer: a randomized, double-blind, phase II trial (PCombi)

Adverse effects of androgen-deprivation therapy in prostate cancer and their management

The protective role of estrogen and estrogen receptors in cardiovascular disease and the controversial use of estrogen therapy

A phase II, randomized, open-label study of neoadjuvant degarelix versus LHRH agonist in prostate cancer patients prior to radical prostatectomy

We thank Nazarbayev University for providing the opportunity to carry out this research. Yingqiu Xie has received research funding from the Nazarbayev University Faculty-Development Competitive Research Grants Program (ID 16797152 and ID 16796808).J o u r n a l P r e -p r o o f