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DOI: 10.1055/a-1954-5605
Androgens’ Role in Severity and Mortality Rates of COVID-19
Abstract
By the end of December 2019 new corona virus began to spread from Wuhan, China and caused a worldwide pandemic. COVID-19 deaths and prevalence represented sex discrepant patterns with higher rate of deaths and infection in males than females which could be justified by androgen-mediated mechanisms. This review aimed to assess the role of androgens in COVID-19 severity and mortality. Androgens increase expressions of Type II transmembrane Serine Protease (TMPRSS2) and Angiotensin Converting Enzyme 2 (ACE2), which both facilitate new corona virus entry into host cell and their expression is higher in young males than females. According to observational studies, prevalence of COVID-19 infections and deaths was more in androgenic alopecic patients than patients without androgenic alopecia. The COVID-19 mortality rates in aged men (>60 years) were substantially higher than aged females and even young males caused by high inflammatory activities such as cytokine storm due to hypogonadism in this population. Use of anti-androgen and TMPRSS2 inhibitor drugs considerably modified COVID-19 symptoms. Androgen deprivation therapy also improved COVID-19 symptoms in prostate cancer: overall the role of androgens in severity of COVID-19 and its associated mortality seemed to be very important. So, more studies in variety of populations are required to define the absolute role of androgens.
Publikationsverlauf
Eingereicht: 20. Dezember 2021
Angenommen nach Revision: 04. Oktober 2022
Accepted Manuscript online:
04. Oktober 2022
Artikel online veröffentlicht:
21. November 2022
© 2022. Thieme. All rights reserved.
Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany
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References
- 1 Li L-q, Huang T, Wang Y-q. et al. COVID-19 patients' clinical characteristics, discharge rate, and fatality rate of meta-analysis. J Med Virol 2020; 92: 577-583
- 2 Li X, Xu S, Yu M. et al. Risk factors for severity and mortality in adult COVID-19 inpatients in Wuhan. J Allergy Clin Immunol 2020; 146: 110-118
- 3 Robinson DP, Lorenzo ME, Jian W. et al. Elevated 17β-estradiol protects females from influenza A virus pathogenesis by suppressing inflammatory responses. PLoS Pathog 2011; 7: e1002149
- 4 Ortona E, Pierdominici M, Maselli A. et al. Sex-based differences in autoimmune diseases. Ann Istitut Sup Sanita 2016; 52: 205-212
- 5 Iaccarino G, Grassi G, Borghi C. et al. Gender differences in predictors of intensive care units admission among COVID-19 patients: the results of the SARS-RAS study of the Italian society of hypertension. PLoS One 2020; 15: e0237297
- 6 Goren A, Vaño-Galván S, Wambier CG. et al. A preliminary observation: male pattern hair loss among hospitalized COVID-19 patients in Spain – a potential clue to the role of androgens in COVID-19 severity. J Cosmet Dermatol 2020; 19: 1545-1547
- 7 Mauvais-Jarvis F. Do anti-androgens have potential as therapeutics for COVID-19?. Endocrinology 2021; 162 bqab114 DOI: 10.1210/endocr/bqab114.
- 8 Manning JT, Fink B. Understanding COVID-19: digit ratio (2D: 4D) and sex differences in national case fatality rates. Early Hum Develop 2020; 146: 105074
- 9 Vahedian-Azimi A, Pourhoseingholi MA, Saberi M. et al. 23 Gender susceptibility to COVID-19 mortality: androgens as the usual suspects?. Adv Exp Med Biol 2021; 1321: 261-264
- 10 Sharma G, Volgman AS, Michos ED. Sex differences in mortality from COVID-19 pandemic: are men vulnerable and women protected?. J Am Coll Cardiol Case Rep 2020; 2: 1407-1410
- 11 Ghandehari S, Matusov Y, Pepkowitz S. et al. Progesterone in addition to standard of care vs standard of care alone in the treatment of men hospitalized with moderate to severe COVID-19: a randomized, controlled pilot trial. Chest 2021; 160: 74-84
- 12 Breithaupt-Faloppa AC, Correia CDJ, Prado CM. et al. 17β-Estradiol, a potential ally to alleviate SARS-CoV-2 infection. Clinics (Sao Paulo) 2020; 75: e1980 DOI: 10.6061/clinics/2020/e1980.
- 13 Dambha-Miller H, Hinton W, Joy M. et al. Mortality in COVID-19 amongst women on hormone replacement therapy or combined oral contraception: a cohort study. Fam Pract 2022; cmac041 DOI: 10.1093/fampra/cmac041.
- 14 Salonia A, Pontillo M, Capogrosso P. et al. Severely low testosterone in males with COVID-19: A case-control study. Andrology 2021; 9: 1043-1052
- 15 Kumar N, Zuo Y, Yalavarthi S. et al. SARS-CoV-2 spike protein S1-mediated endothelial injury and pro-inflammatory state is amplified by dihydrotestosterone and prevented by mineralocorticoid antagonism. Viruses 2021; 13: 2209
- 16 Peng Z, Shu B. Zhang Yet al. Endothelial response to pathophysiological stress. Arterioscler Throm Vasc Biol 2019; 39: e233-e243
- 17 Karkin K, En Alma. Erectile dysfunction and testosterone levels prior to COVID-19 disease: what is the relationship?. Arch Ital Urol Androl 2021; 93: 460-464
- 18 Gheblawi M, Wang K, Viveiros A. et al. Angiotensin-converting enzyme 2: SARS-CoV-2 receptor and regulator of the renin-angiotensin system: celebrating the 20th anniversary of the discovery of ACE2. Circ Res 2020; 126: 1456-1474
- 19 Jia H. Pulmonary angiotensin-converting enzyme 2 (ACE2) and inflammatory lung disease. Shock 2016; 46: 239-248
- 20 Kalidhindi RSR, Borkar NA, Ambhore NS. et al. Sex steroids skew ACE2 expression in human airway: a contributing factor to sex differences in COVID-19?. Am J Physiol Lung Cell Mol Physiol 2020; 319: L843-L847
- 21 Guy J, Lambert D, Warner F. et al. Membrane-associated zinc peptidase families: comparing ACE and ACE2. Biochim Biophys Acta 2005; 1751: 2-8
- 22 Hoffmann M, Kleine-Weber H, Schroeder S. et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 2020; 181: 271-80, e8
- 23 Douglas GC, O’Bryan MK, Hedger MP. et al. The novel angiotensin-converting enzyme (ACE) homolog, ACE2, is selectively expressed by adult Leydig cells of the testis. Endocrinology 2004; 145: 4703-4711
- 24 Li L, Li Y, Sottas C. et al. Directing differentiation of human induced pluripotent stem cells toward androgen-producing Leydig cells rather than adrenal cells. Proc Natl Acad Sci U S A 2019; 116: 23274-23283
- 25 Walls AC, Park Y-J, Tortorici MA. et al. Function, and antigenicity of the SARS-CoV-2 spike glycoprotein. Cell 2020; 181: 281-292
- 26 Millet JK, Whittaker GR. Host cell proteases: critical determinants of coronavirus tropism and pathogenesis. Virus Res 2015; 202: 120-134
- 27 Walls AC, Tortorici MA, Snijder J. et al. Tectonic conformational changes of a coronavirus spike glycoprotein promote membrane fusion. Proc Natl Acad Sci U S A 2017; 114: 11157-11162
- 28 Lin B, Ferguson C, White JT. et al. Prostate-localized and androgen-regulated expression of the membrane-bound serine protease TMPRSS2. Cancer Res 1999; 59: 4180-4184
- 29 Jacquinet E, Rao NV, Rao GV. et al. Cloning and characterization of the cDNA and gene for human epitheliasin. Eur J Biochem 2001; 268: 2687-2699
- 30 Ambrosino I, Barbagelata E, Ortona E. et al. Gender differences in patients with COVID-19: a narrative review. Monaldi Arch Chest Dis 2020; 90 DOI: 10.4081/monaldi.2020.1389.
- 31 Mehra MR, Desai SS, Kuy S. et al. Cardiovascular disease, drug therapy, and mortality in Covid-19. N Eng. J Med 2020; 382: e102
- 32 Kuba K, Imai Y, Rao S. et al. A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus – induced lung injury. Nat Med 2005; 11: 875-879
- 33 Dai M, Liu D, Liu M. et al. Patients with cancer appear more vulnerable to SARS-CoV-2: a multicenter study during the COVID-19 outbreak. Cancer Discov 2020; 10: 783-791
- 34 Kim TS, Heinlein C, Hackman RC. et al. Phenotypic analysis of mice lacking the Tmprss2-encoded protease. Mol Cell Biol 2006; 26: 965-975
- 35 Iwata-Yoshikawa N, Okamura T, Shimizu Y. et al. TMPRSS2 contributes to virus spread and immunopathology in the airways of murine models after coronavirus infection. J Virol 2019; 93: e01815-e01818
- 36 Li F, Han M, Dai P. et al. Distinct mechanisms for TMPRSS2 expression explain organ-specific inhibition of SARS-CoV-2 infection by enzalutamide. Nat Commun 2021; 12: 1-14
- 37 Zhao H, Lu L, Peng Z. et al. SARS-CoV-2 Omicron variant shows less efficient replication and fusion activity when compared with Delta variant in TMPRSS2-expressed cells. Emerg. Microb Infect 2022; 11: 277-283
- 38 Meng B, Abdullahi A, Ferreira IA. Altered TMPRSS2 usage by SARS-CoV-2 Omicron impacts infectivity and fusogenicity. Nature 2022; 603: 706-714
- 39 Yeap BB, Marriott RJ, Manning L. et al. Higher premorbid serum testosterone predicts COVID-19-related mortality risk in men. Eur J Endocrinol 2022; 187: 159-170
- 40 Cadegiani F, Lin EM, Goren A. et al. Expression of concern: potential risk for developing severe COVID-19 disease among anabolic steroid users. BMJ Case Rep CP 2021; 14: e241572
- 41 Brooke G, Bevan C. The role of androgen receptor mutations in prostate cancer progression. Curr Genom 2009; 10: 18-25
- 42 Tan ME, Li J, Xu HE. et al. Androgen receptor: structure, role in prostate cancer and drug discovery. Acta Pharmacol Sinica 2015; 36: 3-23
- 43 Clinckemalie L, Spans L, Dubois V. et al. Androgen regulation of the TMPRSS2 gene and the effect of a SNP in an androgen response element. Mol Endocrinol 2013; 27: 2028-2040
- 44 Cano LQ, Lavery DN, Sin S. et al. The co-chaperone p23 promotes prostate cancer motility and metastasis. Mol Oncol 2015; 9: 295-308
- 45 Mikkonen L, Pihlajamaa P, Sahu B. et al. Androgen receptor and androgen-dependent gene expression in lung. Mol Cell Endocrinol 2010; 317: 14-24
- 46 Yoon G, Kim JY, Choi YK. et al. Direct activation of TGF-β1 transcription by androgen and androgen receptor complex in Huh7 human hepatoma cells and its tumor in nude mice. J Cell Biochem 2006; 97: 393-411
- 47 Jeong Y, Xie Y, Lee W. et al. Research resource: diagnostic and therapeutic potential of nuclear receptor expression in lung cancer. Mol Endocrinol 2012; 26: 1443-1454
- 48 Leach D, Mohr A, Giotis E. et al. The antiandrogen enzalutamide downregulates TMPRSS2 and reduces cellular entry of SARS-CoV-2 in human lung cells. Nat Commun 2021; 12: 1-12
- 49 Wang X-M, Mannan R, Xiao L. et al. Characterization of SARS-CoV-2 and host entry factors distribution in a COVID-19 autopsy series. Commun Med 2021; 1: 1-10
- 50 McCoy J, Wambier CG, Herrera S. et al. Androgen receptor genetic variant predicts COVID-19 disease severity: a prospective longitudinal study of hospitalized COVID-19 male patients. J Eur Acad Dermatol Venereol 2021; 35: e15-e17
- 51 Velavan TP, Pallerla SR, Rüter J. et al. Host genetic factors determining COVID-19 susceptibility and severity. EBioMed 2021; 72: 103629
- 52 Kaufman JM, Vermeulen A. The decline of androgen levels in elderly men and its clinical and therapeutic implications. Endocr Rev 2005; 26: 833-876
- 53 Wu FC, Tajar A, Pye SR. et al. Hypothalamic-pituitary-testicular axis disruptions in older men are differentially linked to age and modifiable risk factors: the European male aging study. J Clin Endocrinol Metab 2008; 93: 2737-2745
- 54 Tajar A, Forti G, O’Neill TW. et al. Characteristics of secondary, primary, and compensated hypogonadism in aging men: evidence from the European male ageing study. J Clin Endocrinol Metab 2010; 95: 1810-1818
- 55 Travison TG, Araujo AB, O’Donnell AB. et al. A population-level decline in serum testosterone levels in American men. J Clin Endocrinol Metab 2007; 92: 196-202
- 56 Harman SM, Metter EJ, Tobin JD. et al. Longitudinal effects of aging on serum total and free testosterone levels in healthy men. J Clin Endocrinol Metab 2001; 86: 724-731
- 57 Carcaillon L, Blanco C, Alonso-Bouzon C. et al. Sex differences in the association between serum levels of testosterone and frailty in an elderly population: the Toledo study for healthy aging. PLoS One 2012; 7: e32401
- 58 Saad F, Gooren LJ. The role of testosterone in the etiology and treatment of obesity, the metabolic syndrome, and diabetes mellitus type 2. J Obes 2011; 471584 DOI: 10.1155/2011/471584.. Epub 2010 Aug 10
- 59 Laouali N, Brailly-Tabard S, Helmer C. et al. Testosterone and all-cause mortality in older men: the role of metabolic syndrome. J Endocr Soc 2018; 2: 322-335
- 60 Corona G, Rastrelli G, Monami M. et al. Body weight loss reverts obesity-associated hypogonadotropic hypogonadism: a systematic review and meta-analysis. Eur J Endocrinol 2013; 168: 829-843
- 61 Basaria S, Muller DC, Carducci MA. et al. Hyperglycemia and insulin resistance in men with prostate carcinoma who receive androgen-deprivation therapy. Cancer 2006; 106: 581-588
- 62 Smith MR. Changes in fat and lean body mass during androgen-deprivation therapy for prostate cancer. Urology 2004; 63: 742-745
- 63 Smith MR, Lee H, Nathan DM. Insulin sensitivity during combined androgen blockade for prostate cancer. J Clin Endocrinol Metab 2006; 91: 1305-1308
- 64 Muraleedharan V, Jones TH. Testosterone and the metabolic syndrome. Therap Adv Endocrinol Metab 2010; 1: 207-223
- 65 Yandi H, Dong Y, Huafen Z. et al. Lower testosterone levels predict increasing severity and worse outcomes of hepatitis B virus-related acute-on-chronic liver failure in males. BMC Gastroenterol (Web) 2021; 21: 1-11
- 66 Muraleedharan V, Jones TH. Testosterone and the metabolic syndrome. Therap Adv Endocrinol Metab 2010; 1: 207-223
- 67 Burger HG. Androgen production in women. Fertil Steril 2002; 77: 3-5
- 68 Davison SL, Bell R, Donath S, Montalto J, Davis SR. Androgen levels in adult females: changes with age, menopause, and oophorectomy. J Clin Endocrinol Metab 2005; 90: 3847-3853
- 69 Morley JE, Perry HM. Androgens and women at the menopause and beyond. J Gerontol Ser A 2003; 58: M409-M416
- 70 Zumoff B, Strain GW, Miller LK. et al. Twenty-four-hour mean plasma testosterone concentration declines with age in normal premenopausal women. J Clin Endocrinol Metab 1995; 80: 1429-1430
- 71 Kim C, Harlow SD, Zheng H. et al. Changes in androstenedione, dehydroepiandrosterone, testosterone, estradiol, and estrone over the menopausal transition. Women Midlife Health 2017; 3: 1-9
- 72 Shifren JL, Gass ML. Group NRfCCoMWW. The north American menopause society recommendations for clinical care of midlife women. Menopause 2014; 21: 1038-1062
- 73 Papadopoulos V, Li L, Samplaski M. Why does COVID-19 kill more elderly men than women? Is there a role for testosterone?. Andrology 2021; 9: 65-72
- 74 Potluri T, Fink AL, Sylvia KE. et al. Age-associated changes in the impact of sex steroids on influenza vaccine responses in males and females. NPJ Vacc 2019; 4: 1-12
- 75 vom Steeg LG, Klein SL. SeXX matters in infectious disease pathogenesis. PLoS Pathogens 2016; 12: e1005374
- 76 Ershler WB, Keller ET. Age-associated increased interleukin-6 gene expression, late-life diseases, and frailty. Ann Rev Med 2000; 51: 245-270
- 77 Wikby A, Nilsson B-O, Forsey R. et al. The immune risk phenotype is associated with IL-6 in the terminal decline stage: findings from the Swedish NONA immune longitudinal study of very late life functioning. Mech Ageing Develop 2006; 127: 695-704
- 78 Thompson WW, Shay DK, Weintraub E. et al. Mortality associated with influenza and respiratory syncytial virus in the United States. JAMA 2003; 289: 179-186
- 79 Reed C, Chaves SS, Daily Kirley P. et al. Estimating influenza disease burden from population-based surveillance data in the United States. PLoS One 2015; 10: e0118369
- 80 Wong KC, Luscombe GM, Hawke C. Influenza infections in Australia 2009–2015: is there a combined effect of age and sex on susceptibility to virus subtypes?. BMC Infect Dis 2019; 19: 1-10
- 81 Eshima N, Tokumaru O, Hara S. et al. Sex-and age-related differences in morbidity rates of 2009 pandemic influenza A H1N1 virus of swine origin in Japan. PLoS One 2011; 6: e19409
- 82 Moncada I. Testosterone and men’s quality of life. Aging Male 2006; 9: 189-193
- 83 Muehlenbein MP, Bribiescas RG. Testosterone-mediated immune functions and male life histories. Am J Hum Biol 2005; 17: 527-558
- 84 Vom Steeg LG, Attreed SE, Zirkin B. et al. Testosterone treatment of aged male mice improves some but not all aspects of age-associated increases in influenza severity. Cell Immunol 2019; 345: 103988
- 85 Bereshchenko O, Bruscoli S, Riccardi C. Glucocorticoids, sex hormones, and immunity. Front Immunol 2018; 9: 1332
- 86 Klein SL, Flanagan KL. Sex differences in immune responses. Nat Rev Immunol 2016; 16: 626-638
- 87 Traish A, Bolanos J, Nair S. et al. Do androgens modulate the pathophysiological pathways of inflammation? Appraising the contemporary evidence. J Clin Med 2018; 7: 549
- 88 Nakashima A, Ohkido I, Yokoyama K. et al. Associations between low serum testosterone and all-cause mortality and infection-related hospitalization in male hemodialysis patients: a prospective cohort study. Kidney Int Rep 2017; 2: 1160-1168
- 89 Vom Steeg LG, Vermillion MS, Hall OJ. et al. Age and testosterone mediate influenza pathogenesis in male mice. Am J Physiol Lung Cell Mol Physiol 2016; 311: L1234-L1244
- 90 Furman D, Hejblum BP, Simon N. et al. Systems analysis of sex differences reveals an immunosuppressive role for testosterone in the response to influenza vaccination. Proc Natl Acad Sci 2014; 111: 869-874
- 91 Bobjer J, Katrinaki M, Tsatsanis C. et al. Negative association between testosterone concentration and inflammatory markers in young men: a nested cross-sectional study. PLoS One 2013; 8: e61466
- 92 Maggio M, Basaria S, Ble A. et al. Correlation between testosterone and the inflammatory marker soluble interleukin-6 receptor in older men. J Clin Endocrinol Metab 2006; 91: 345-347
- 93 Tsigos C, Papanicolaou DA, Kyrou I. et al. Dose-dependent effects of recombinant human interleukin-6 on glucose regulation. J Clin Endocrinol Metab 1997; 82: 4167-4170
- 94 Malkin CJ, Pugh PJ, Jones RD. et al. The effect of testosterone replacement on endogenous inflammatory cytokines and lipid profiles in hypogonadal men. J Clin Endocrinol Metab 2004; 89: 3313-3138
- 95 Corrales J, Almeida M, Burgo R. et al. Androgen-replacement therapy depresses the ex vivo production of inflammatory cytokines by circulating antigen-presenting cells in aging type-2 diabetic men with partial androgen deficiency. J Endocrinol 2006; 189: 595-604
- 96 Bianchi VE. The anti-inflammatory effects of testosterone. J Endocr Soc 2019; 3: 91-107
- 97 Mehta P, McAuley DF, Brown M. et al. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet 2020; 395: 1033-1034
- 98 Ansariniya H, Seifati SM, Zaker E. et al. Comparison of immune response between SARS, MERS, and COVID-19 infection, perspective on vaccine design and development. BioMed Res Int 2021; 8870425 DOI: 10.1155/2021/8870425.
- 99 Michot J-M, Albiges L, Chaput N. et al. Tocilizumab, an anti-IL6 receptor antibody, to treat Covid-19-related respiratory failure. A case report. Ann Oncol 2020; 31: 961-964
- 100 Chi Z, Zhao W, Jia-Wen L. et al. The cytokine release syndrome (CRS) of severe COVID-19 and interleukin-6 receptor (IL-6R) antagonist tocilizumab man be the key to reduce the mortality. https://www ncbi nlm nih gov/pmc/articles/PMC7118634/pdf/main pdf 2020
- 101 Fox WJU, Brahmer JR, Chen DS. et al. Correction: Insights from immuno-oncology: the society for immunotherapy of cancer statement on access to IL-6-targeting therapies for COVID-19. J Immunother 2020; 13: e000878corr1
- 102 Liu Y, Sun W, Li J. et al. Clinical features and progression of acute respiratory distress syndrome in coronavirus disease 2019. MedRxiv 2020; DOI: 10.1101/2020.02.17.20024166.
- 103 Akbaş T, Deyneli O, Sönmez FT. et al. The pituitary-gonadal-thyroid and lactotroph axes in critically ill patients. Endokrynol Polska 2016; 67: 305-312
- 104 Vanhorebeek I, Langouche L, Van den Berghe G. Endocrine aspects of acute and prolonged critical illness. Nat Clin Pract Endocrinol Metab 2006; 2: 20-31
- 105 Nierman DM, Mechanick JI. Hypotestosteronemia in chronically critically ill men. Crit Care Med 1999; 27: 2418-2421
- 106 Van den Berghe G, Weekers F, Baxter RC. et al. Five-day pulsatile gonadotropin-releasing hormone administration unveils combined hypothalamic-pituitary-gonadal defects underlying profound hypoandrogenism in men with prolonged critical illness. J Clin Endocrinol Metab 2001; 86: 3217-3226
- 107 Iglesias P, Prado F, Macias MC. et al. Hypogonadism in aged hospitalized male patients: prevalence and clinical outcome. J Endocrinol Invest 2014; 37: 135-141
- 108 Iglesias P, Prado F, Ridruejo E. et al. Hypogonadism and mortality in aged hospitalized male patients: a 5-year prospective observational study. Exp Clin Endocrinol Diabetes 2015; 123: 589-593
- 109 Nasir N, Jamil B, Siddiqui S. et al. Mortality in sepsis and its relationship with gender. Pakistan J Med Sci 2015; 31: 1201
- 110 Bech A, Van Leeuwen H, De Boer H. Etiology of low testosterone levels in male patients with severe sepsis requiring mechanical ventilation. Crit Care 2013; 17: 1-200
- 111 Christeff N, Benassayag C, Carli-Vielle C. et al. Elevated oestrogen and reduced testosterone levels in the serum of male septic shock patients. J Steroid Biochem 1988; 29: 435-440
- 112 Stanojcic M, Finnerty CC, Jeschke MG. Anabolic and anticatabolic agents in critical care. Curr Opin Crit Care 2016; 22: 325
- 113 Heffernan DS, Dossett LA, Lightfoot MA. et al. Gender and ARDS in critically injured adults: a prospective study. J Trauma 2011; 71: 878
- 114 Fuseini H, Newcomb DC. Mechanisms driving gender differences in asthma. Curr Allergy Asthma Rep 2017; 17: 1-9
- 115 Dhindsa S, Champion C, Deol E. et al. Association of male hypogonadism with risk of hospitalization for COVID-19. JAMA Network Open 2022; 5: e2229747-e
- 116 Marinelli L, Beccuti G, Zavattaro M. et al. Testosterone as a biomarker of adverse clinical outcomes in SARS-CoV-2 pneumonia. Biomedicines 2022; 10: 820
- 117 Lanser L, Burkert FR, Thommes L. et al. Testosterone deficiency is a risk factor for severe COVID-19. Front Endocrinol 2021; 12: 694083
- 118 Salonia A, Pontillo M, Capogrosso P. et al. Severely low testosterone in males with COVID-19: A case-control study. Andrology 2021; 9: 1043-1052
- 119 Toscano-Guerra E, Gallo MM, Arrese-Muñoz I. et al. Recovery of serum testosterone levels is an accurate predictor of survival from COVID-19 in male patients. BMC Med 2022; 20: 1-18
- 120 Ruan Y, Hu B, Liu Z. et al. No detection of SARS-CoV-2 from urine, expressed prostatic secretions, and semen in 74 recovered COVID-19 male patients: a perspective and urogenital evaluation. Andrology 2021; 9: 99-106
- 121 Leach DA, Mohr A, Giotis ES. et al. The antiandrogen enzalutamide downregulates TMPRSS2 and reduces cellular entry of SARS-CoV-2 in human lung cells. Nat Commun 2021; 12: 4068
- 122 Baratchian M, McManus JM, Berk M. et al. Sex, androgens and regulation of pulmonary AR, TMPRSS2 and ACE2. bioRxiv 2020; DOI: 10.1101/2020.04.21.051201.
- 123 Baratchian M, McManus JM, Berk MP. et al. Androgen regulation of pulmonary AR, TMPRSS2 and ACE2 with implications for sex-discordant COVID-19 outcomes. Sci Rep 2021; 11: 11130
- 124 Deng Q, Rasool RU, Russell RM. et al. Targeting androgen regulation of TMPRSS2 and ACE2 as a therapeutic strategy to combat COVID-19. iScience 2021; 24: 102254
- 125 Wang SC, Chen Y, Wang YC. et al. Tannic acid suppresses SARS-CoV-2 as a dual inhibitor of the viral main protease and the cellular TMPRSS2 protease. Am J Cancer Res 2020; 10: 4538-4546
- 126 McCoy J, Cadegiani FA, Wambier CG. 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: e243-e246
- 127 Cadegiani FA, Zimerman RA, Fonseca DN. et al. Final results of a randomized, placebo-controlled, two-arm, parallel clinical trial of proxalutamide for hospitalized COVID-19 patients: a multiregional, joint analysis of the proxa-rescue androCoV trial. Cureus 2021; 13: e 20691 DOI: 10.7759/cureus.20691.
- 128 McCoy J, Goren A, Cadegiani FA. et al. Proxalutamide reduces the rate of hospitalization for COVID-19 male outpatients: a randomized double-blinded placebo-controlled trial. Front Med (Lausanne) 2021; 8: 668698
- 129 Cadegiani FA, Goren A, Wambier CG. et al. Proxalutamide improves inflammatory, immunologic, and thrombogenic markers in mild-to-moderate COVID-19 males and females: an exploratory analysis of a randomized, double-blinded, placebo-controlled trial early antiandrogen therapy (EAT) with proxalutamide (The EAT-Proxa Biochemical AndroCoV-Trial). medRxiv 2021; DOI: 10.1101/2021.07.24.21261047.
- 130 Cadegiani FA, Fonseca DN, Correia MN. et al. Proxalutamide (GT0918) improves lung injury in hospitalized COVID-19 patients – an analysis of the radiological findings of the proxa-rescue androCoVtrial. medRxiv 2021; DOI: 10.1101/2021.07.01.21259656.
- 131 Cadegiani FA, McCoy J, Gustavo Wambier C. et al. Proxalutamide significantly accelerates viral clearance and reduces time to clinical remission in patients with mild to moderate COVID-19: results from a randomized, double-blinded, placebo-controlled trial. Cureus 2021; 13: e13492
- 132 Zimerman RA, Fonseca DN, Correia MN. et al. Proxalutamide (GT0918) reduction of mortality rate in hospitalized COVID-19 patients depends on treatment duration – an exploratory analysis of the proxa-rescue androCoV trial. . medRxiv 2021; DOI: 10.1101/2021.06.28.21259661.
- 133 Barnette KG, Gordon MS, Rodriguez D. et al. Oral sabizabulin for high-risk, hospitalized adults with Covid-19: interim analysis. N Engl J Med Evidence 2022; 1: EVIDoa2200145
- 134 Markowski MC, Tutrone RF, Eisenberger MA. et al. VERU-111, an oral cytoskeleton disruptor, to treat men with metastatic castration-resistant prostate cancer (mCRPC) who failed an androgen receptor targeting agent. J Clin Oncol 2021; 39: 5056
- 135 Cadegiani FA, McCoy J, Wambier CG. et al. 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; 13: e13047
- 136 Zarehoseinzade E, Allami A, Ahmadi M. et al. Finasteride in hospitalized adult males with COVID-19: a risk factor for severity of the disease or an adjunct treatment: a randomized controlled clinical trial. Med J Islam Rep Iran 2021; 35: 30
- 137 Cadegiani FA, Goren A, Wambier CG. et al. An open-label prospective observational study of antiandrogen and non-antiandrogen early pharmacological approaches in females with mild-to-moderate COVID-19. The pre-androCoV female trial. medRxiv 2020; DOI: 10.1101/2020.10.05.20206870.
- 138 Nickols NG, Mi Z, DeMatt E. et al. Effect of Androgen suppression on clinical outcomes in hospitalized men with COVID-19: the HITCH randomized clinical trial. JAMA Network Open 2022; 5: e227852-e
- 139 Kuderer NM, Choueiri TK, Shah DP. et al. Clinical impact of COVID-19 on patients with cancer (CCC19): a cohort study. Lancet 2020; 395: 1907-1918
- 140 Mou R, Jin X, Li W. et al. Prostate cancer: a risk factor for COVID-19 in males?: a protocol for systematic review and meta analysis. Medicine (Baltimore) 2020; 99: e22591
- 141 Lucas JM, Heinlein C, Kim T. et al. The androgen-regulated protease TMPRSS2 activates a proteolytic cascade involving components of the tumor microenvironment and promotes prostate cancer metastasis. TMPRSS2 influences prostate cancer metastasis. Cancer Discov 2014; 4: 1310-1325
- 142 Perner S, Mosquera J-M, Demichelis F. et al. TMPRSS2-ERG fusion prostate cancer: an early molecular event associated with invasion. Am J Surg Pathol 2007; 31: 882-888
- 143 Kizilkan Y, Senel S, Ozercan AY. et al. Evaluating the anxiety and depression status of prostate cancer patients whose operations were postponed because of the COVID-19 pandemic. Int J Clin Pract 2021; 75: e14278
- 144 Crawford ED, Heidenreich A, Lawrentschuk N. et al. Androgen-targeted therapy in men with prostate cancer: evolving practice and future considerations. Prostate Cancer Prost Dis. 2019; 22: 24-38
- 145 Ghafoor R, Ali SM, Patil A. et al. Association of androgenetic alopecia and severity of coronavirus disease 2019. J Cosmet Dermatol 2022; 21: 874-879
- 146 Goren A, Wambier CG, Herrera S. et al. Anti-androgens may protect against severe COVID-19 outcomes: results from a prospective cohort study of 77 hospitalized men. J Eur Acad Dermatol Venereol 2021; 35: e13-e15
- 147 Subramanian A, Anand A, Adderley NJ. et al. Increased COVID-19 infections in women with polycystic ovary syndrome: a population-based study. Eur J Endocrinol 2021; 184: 637-645
- 148 Cadegiani F, Lim R, Goren A. et al. Clinical symptoms of hyperandrogenic women diagnosed with COVID-19. J Eur Acad Dermatol Venereol 2021; 35: e101-e104
- 149 Di Stasi V, Rastrelli G, Inglese F. et al. Higher testosterone is associated with increased inflammatory markers in women with SARS-CoV-2 pneumonia: preliminary results from an observational study. J Endocrinol Invest 2022; 45: 639-648
- 150 Desai A, Sachdeva S, Parekh T. et al. COVID-19 and cancer: lessons from a pooled meta-analysis. JCO Global Oncol 2020; 6: 557-559
- 151 Sica A, Massarotti M. Myeloid suppressor cells in cancer and autoimmunity. J Autoimmun 2017; 85: 117-125
- 152 Liang W, Guan W, Chen R. et al. Cancer patients in SARS-CoV-2 infection: a nationwide analysis in China. Lancet Oncol 2020; 21: 335-337
- 153 Experton B, Tetteh HA, Lurie N. et al. A predictive model for severe COVID-19 in the medicare population: a tool for prioritizing primary and booster COVID-19 vaccination. Biology 2021; 10: 1185
- 154 Lucas JM, Heinlein C, Kim T. et al. The androgen-regulated protease TMPRSS2 activates a proteolytic cascade involving components of the tumor microenvironment and promotes prostate cancer metastasis. Cancer Discov 2014; 4: 1310-1325
- 155 Kizilkan Y, Senel S, Ozercan AY. et al. Evaluating the anxiety and depression status of prostate cancer patients whose operations were postponed because of the COVID-19 pandemic. Int J Clin Pract 2021; e14278
- 156 Nuhn P, De Bono JS, Fizazi K. et al. Update on systemic prostate cancer therapies: management of metastatic castration-resistant prostate cancer in the era of precision oncology. Eur Urol 2019; 75: 88-99
- 157 Bennani NN, Bennani-Baiti IM. Androgen deprivation therapy may constitute a more effective COVID-19 prophylactic than therapeutic strategy. Ann Oncol 2020; 31: 1585-1586
- 158 Bahmad HF, Abou-Kheir W. Crosstalk between COVID-19 and prostate cancer. Prostate Cancer Prostat Dis 2020; 23: 561-563
- 159 Montopoli 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: 1040-1045
- 160 Patel VG, Zhong X, Liaw B. et al. Does androgen deprivation therapy protect against severe complications from COVID-19?. Ann Oncol 2020; 31: 1419-1420
- 161 Lee K, Heberer K, Gao A. et al. A population-level analysis of the protective effects of androgen deprivation therapy against COVID-19 disease incidence and severity. Front Med (Lausanne) 2022; 9: 774773
- 162 Jiménez-Alcaide E, García-Fuentes C, Hernández V. et al. Influence of androgen deprivation therapy on the severity of COVID-19 in prostate cancer patients. Prostate 2021; 81: 1349-1354
- 163 Gedeborg R, Styrke J, Loeb S. et al. Androgen deprivation therapy and excess mortality in men with prostate cancer during the initial phase of the COVID-19 pandemic. PLoS One 2021; 16: e0255966
- 164 Pozzilli P, Lenzi A. Testosterone, a key hormone in the context of COVID-19 pandemic [Commentary]. Metabolism 2020; 108: 154252
- 165 Cattrini C, Bersanelli M, Latocca MM. et al. Sex hormones and hormone therapy during COVID-19 pandemic: implications for patients with cancer. Cancers 2020; 12: 2325