Hormones and COVID-19

We read with interest the recent study of Dr Taleen A. MacArthur and colleagues1MacArthur T.A. Goswami J. Ramachandran D. et al.Estradiol and dihydrotestosterone levels in COVID-19 patients.Mayo Clin Proc. 2023; 98: 559-568Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar from Mayo Clinic regarding hormone levels in their patients with coronavirus disease 2019 (COVID-19) compared with healthy volunteers, and we share their interest that hormones may have an impact on prognosis in this potentially fatal viral infection. Testosterone may influence the expression of molecular targets that the COVID-19 uses to enter human cells,2Cadegiani F.A. McCoy J. Gustavo Wambier C. Goren A. Early antiandrogen therapy with dutasteride reduces viral shedding, inflammatory responses, and time-to-remission in males with COVID-19: a randomized, double-blind, placebo-controlled interventional trial (EAT-DUTA AndroCoV Trial – Biochemical).Cureus. 2021; 13e13047Google Scholar,3La Vignera S. Cannarella R. Condorelli R.A. Torre F. Aversa A. Calogero A.E. Sex-specific SARS-CoV-2 mortality: among hormone-modulated ACE2 expression, risk of venous thromboembolism and hypovitaminosis D.Int J Mol Sci. 2020; 21: 2948Crossref PubMed Scopus (166) Google Scholar which may explain why worldwide there is a higher incidence and mortality of this disease in men compared with women.4Borges do Nascimento I.J. Cacic N. Abdulazeem H.M. et al.Novel Coronavirus Infection (COVID-19) in humans: a scoping review and meta-analysis.J Clin Med. 2020; 9: 941Crossref PubMed Scopus (354) Google Scholar, 5Grasselli G. Zangrillo A. Zanella A. et al.Baseline characteristics and outcomes of 1591 patients infected with SARS-CoV-2 admitted to ICUs of the Lombardy Region, Italy.JAMA. 2020; 323: 1574-1581Crossref PubMed Scopus (3650) Google Scholar, 6Jin J.M. Bai P. He W. et al.Gender differences in patients with COVID-19: focus on severity and mortality.Front Public Health. 2020; 8: 152Crossref PubMed Scopus (1315) Google Scholar Men receiving androgen deprivation therapy have demonstrated lower risk of COVID-19 infection,7Montopoli M. Zumerle S. Vettor R. et al.Androgen-deprivation therapies for prostate cancer and risk of infection by SARS-CoV-2: a population-based study (N = 4532).Ann Oncol. 2020; 31: 1040-1045Abstract Full Text Full Text PDF PubMed Scopus (398) Google Scholar milder symptoms,8McCoy J. Cadegiani F.A. Wambier C.G. et al.5-alpha-reductase inhibitors are associated with reduced frequency of COVID-19 symptoms in males with androgenetic alopecia.J Eur Acad Dermatol Venereol. 2021; 35 (Published correction appears in J Eur Acad Dermatol Venereol. 2021;35(7):1595.): e243-e246Crossref PubMed Scopus (32) Google Scholar and reduced viral shedding and inflammatory markers compared with men with COVID-19 receiving placebo.2Cadegiani F.A. McCoy J. Gustavo Wambier C. Goren A. Early antiandrogen therapy with dutasteride reduces viral shedding, inflammatory responses, and time-to-remission in males with COVID-19: a randomized, double-blind, placebo-controlled interventional trial (EAT-DUTA AndroCoV Trial – Biochemical).Cureus. 2021; 13e13047Google Scholar It has been suggested that testosterone therapy may be discontinued in men with COVID-19 and that androgen deprivation therapy may be considered to reduce the severity of COVID-19 disease in men.9Cannarella R. Calogero A.E. Condorelli R.A. Aversa A. La Vignera S. Systemic effects of the hormonal treatment of male hypogonadism with preliminary indications for the management of COVID-19 patients.Ther Adv Endocrinol Metab. 2020; 112042018820966438Crossref Scopus (4) Google Scholar However, a retrospective study found no difference in hospital or intensive care admission, ventilator use, venous thromboembolism, or death in COVID-19 patients regardless of testosterone therapy.10Rambhatla A. Bronkema C.J. Corsi N. et al.COVID-19 infection in men on testosterone replacement therapy.J Sex Med. 2021; 18: 215-218Crossref PubMed Scopus (23) Google Scholar Further study is required to determine the potential risks or benefits of testosterone in men diagnosed with COVID-19. The evidence for estrogen in COVID-19 may be considerably stronger than that for testosterone. In fact, the impact of estradiol (E2) on the acquisition and course of infections with COVID-19 is of great importance, and this original research adds to the body of knowledge on this topic. Although the term sex hormone is the common terminology applied to E2, it would be far more accurate to consider E2 a “life hormone” as its role in modulating the function of numerous enzymes, peptides, fatty acid signaling agents, and neurotransmitters is now expansive and involves all organ systems. The body-wide effects of E2 extend to the immune system, facilitating optimal potential for survival of both mother and fetus, as pregnancy is a unique state of immune functioning. In addition, survival from trauma and infections is imperative for species survival, more so for females than for males, as females must survive pregnancy, nurse the young, and raise them to sexual maturity, multiple times during a lifetime. To that end, females have evolved with a more robust immune system than males. All immune cells, innate and adaptive, have various estrogen receptors, and the initiation and resolution of the inflammatory processes involve E2 modulation. Indeed, E2 is a key factor in rapid and effective response to a pathogen while controlling the degree of inflammatory response and facilitating the resolution and healing phase.11Kovats S. Estrogen receptors regulate innate immune cells and signaling pathways.Cell Immunol. 2015; 294: 63-69Crossref PubMed Scopus (610) Google Scholar It has long been documented that females survive more successfully after infections and trauma, except during pregnancy, a time during which there are significant immune modifications and a distinctly different hormonal status, with estriol (E3) being the dominant estrogen along with large quantities of progesterone produced. In addition to the significant role played by E2 in the female immune response, there is a contribution to the success of the female immune system by the presence of 2 X chromosomes, which are active for a time during embryonic life, and during that time, there is genetic programming occurring that results in the development of the female immune system being distinct from that of males. Females are programmed to have a greater number of immune cells, a greater innate immune response, and a more robust antibody response. Even after the deactivation of 1 X chromosome in each cell, approximately 15% of the genes remain active on this “deactivated” X chromosome, most of which are involved in immune functions.12Schurz H. Salie M. Tromp G. Hoal E.G. Kinnear C.J. Moller M. The X chromosome and sex-specific effects in infectious disease susceptibility.Hum Genomics. 2019; 13: 2Crossref PubMed Scopus (220) Google Scholar Understanding the foundations of the female immune system, inclusive of the dual roles of E2 and genetics, allows the thoughtful consideration of the potential benefits of E2 supplementation in menopausal women to potentiate the ongoing ability of the female immune system to maintain optimal capability to effectively deal with pathogens and trauma in the aging female, offering a greater opportunity for continued survival and healthy longevity, whether or not there is an ongoing pandemic. The lessons learned from this and other studies undertaken during the COVID-19 pandemic, confirming the female immune advantage and the benefits of E2, are applicable for all women, at all stages of life.13Harding A.T. Heaton N.S. The impact of estrogens and their receptors on immunity and inflammation during infection.Cancers (Basel). 2022; 14: 909Crossref PubMed Scopus (21) Google Scholar Congratulations to MacArthur and colleagues1MacArthur T.A. Goswami J. Ramachandran D. et al.Estradiol and dihydrotestosterone levels in COVID-19 patients.Mayo Clin Proc. 2023; 98: 559-568Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar for raising awareness of the potential of hormones and, potentially, hormone replacement therapy to have an impact on COVID-19. The authors report no competing interests. Dr Lavie, associate editor of the journal, had no role in the editorial review of or decision to publish this article. In Reply — Hormones and COVID-19Mayo Clinic ProceedingsVol. 98Issue 7PreviewWe thank Dr Elagizi and colleagues for taking the time to review our recent publication in Mayo Clinic Proceedings.1 We appreciate the thoughtful and well-researched reply, and we very sincerely appreciate the support of our work and findings. We agree that further study into potential hormonal advantages in COVID-19 as well as in other pathologic conditions, including trauma, is warranted and may open doors for alternative therapeutic and prophylactic opportunities in the future that can be tailored to specific patient populations. Full-Text PDF