Commentary: Testosterone, a key hormone in the context of COVID-19 pandemic
Authors: Paolo Pozzilli, Andrea Lenzi
Journal: Metabolism (2020)

Daily data show that entire population with SARS-CoV2 is 58% made of males [1Zhou F. Yu T. Du R. et al.Clinical course and risk factors for mortality of adult in patients with COVID-19 in Wuhan, China: a retrospective cohort study.Lancet. 2020; https://doi.org/10.1016/S0140-6736(20)30566-3Abstract Full Text Full Text PDF Scopus (18524) Google Scholar, 2Team TNCPERE The epidemiological characteristics of an outbreak of 2019 Novel Coronavirus Diseases (COVID-19) in China.China CDC Wkly. 2020; https://doi.org/10.3760/cma.j.issn.0254-6450.2020.02.003Crossref Scopus (2331) Google Scholar, 3Guan W. Liang W. Zhao Y. et al.Comorbidity and its impact on 1590 patients with Covid-19 in China: a nationwide analysis.Eur Respir J. 2020; https://doi.org/10.1183/13993003.00547-2020Crossref Scopus (8) Google Scholar]. The difference in the number of cases reported by gender increases progressively in favor of male subjects up to the age group ≥60–69 (66.6%) and ≥70–79 (66.1%), with the exception of the 20–29 years and 30–39 years group in which the number of female subjects it is slightly higher. Furthermore, higher lethality is in favor of male subjects in all age groups. Deaths among 30–39ys are 82.4% males; among 40-49ys are 73.1% males; among 50-59ys are 78.5% males; among 60-69ys are 79.7% males; among 70-79ys are 79.6% males; among 80-89ys are 66.9% males [[4]Walter L.A. McGregor A.J. Sex- and gender-specific observations and implications for COVID-19.West J Emerg Med. 2020; https://doi.org/10.5811/westjem.2020.4.47536Crossref Scopus (86) Google Scholar]. The initial clinical manifestation of COVID-19 is pneumonia, although gastrointestinal symptoms and asymptomatic infections are described, the latter has not yet been definitely assessed [[5]Chan J.F.W. Yuan S. Kok K.H. et al.A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster.Lancet. 2020; https://doi.org/10.1016/S0140-6736(20)30154-9Abstract Full Text Full Text PDF Scopus (6148) Google Scholar]. The infection can progress to severe disease with dyspnoea and chest symptoms corresponding to pneumonia in the second or third week of a symptomatic infection. Clinical data show decreased oxygen saturation, changes visible through chest X-rays and other imaging techniques. Furthermore, lymphopenia appears to be common, and an increase of inflammatory markers (C-reactive protein and pro-inflammatory cytokines) has been reported [[6]Velavan T.P. Meyer C.G. The COVID-19 epidemic.Trop Med Int Heal. 2020; https://doi.org/10.1111/tmi.13383Crossref PubMed Scopus (1597) Google Scholar]. It is well established that plasma testosterone concentration is reduced by age and comorbidities like obesity, diabetes and obstructive sleep apnea (OSA) [[7]Bhasin S. Brito J.P. Cunningham G.R. et al.Testosterone therapy in men with hypogonadism: an endocrine society clinical practice guideline.J Clin Endocrinol Metab. 2018; 103: 1715-1744Crossref PubMed Scopus (931) Google Scholar], all comorbidities highly prevalent in COVID-19 patients [[8]Van Vliet M. Spruit M.A. Verleden G. et al.Hypogonadism, quadriceps weakness, and exercise intolerance in chronic obstructive pulmonary disease.Am J Respir Crit Care Med. 2005; 172: 1105-1111Crossref PubMed Scopus (112) Google Scholar]. Several studies have shown that in men with chronic obstructive pulmonary disease (COPD) hypogonadism is associated with a prevalence ranging between 22% and 69% [[9]Balasubramanian V. Naing S. Hypogonadism in chronic obstructive pulmonary disease: incidence and effects.Curr Opin Pulm Med. 2012; 18: 112-117Crossref PubMed Scopus (54) Google Scholar]. In this context low testosterone levels can cause a reduction of respiratory muscles activity and overall strength and exercise capacity [[10]Montanõ L.M. Espinoza J. Flores-Soto E. Chávez J. Perusquiá M. Androgens are bronchoactive drugs that act by relaxing airway smooth muscle and preventing bronchospasm.J Endocrinol. 2014; 222: 1-13Crossref PubMed Scopus (48) Google Scholar], whilst normal circulating testosterone levels show a protective effect on several respiratory outcomes (i.e. forced expiratory volume in one second-FEV1, and forced vital capacity - FVC) [[11]Mohan S.S. Knuiman M.W. Divitini M.L. et al.Higher serum testosterone and dihydrotestosterone, but not oestradiol, are independently associated with favourable indices of lung function in community-dwelling mem.Clin Endocrinol (Oxf). 2015; 83: 268-276Crossref PubMed Scopus (47) Google Scholar]. A randomized controlled trial reported an improvement in peak oxygen consumption in men receiving testosterone replacement therapy [[12]Caminiti G. Volterrani M. Iellamo F. et al.Effect of long-acting testosterone treatment on functional exercise capacity, skeletal muscle performance, insulin resistance, and baroreflex sensitivity in elderly patients with chronic heart failure. A double-blind, placebo-controlled, randomized study.J Am Coll Cardiol. 2009; 54: 919-927Crossref PubMed Scopus (403) Google Scholar]. SARS-CoV2 infects lung alveolar epithelial cells using as an entry receptor the angiotensin-converting enzyme II (ACE2) [[13]Leung J.M. Yang C.X. Tam A. et al.ACE-2 expression in the small airway epithelia of smokers and COPD patients: implications for COVID-19. medRxiv, 2020https://doi.org/10.1101/2020.03.18.20038455Crossref Google Scholar]. ACE2 plays a role in lung protection and therefore viral binding to this receptor may deregulate a lung protective pathway [[14]Li G. He X. Zhang L. Ran Q. Wang J. Xiong A. et al.Assessing ACE2 expression patterns in lung tissues in the pathogenesis of COVID-19.J Autoimmun. Apr 13 2020; : 102463https://doi.org/10.1016/j.jaut.2020.102463Crossref PubMed Scopus (209) Google Scholar]. Interestingly, studies showed that ACE2 is a constitutive product of adult-type Leydig cells [[15]Douglas G.C. O'Bryan M.K. Hedger M.P. et al.The novel Angiotensin-Converting Enzyme (ACE) homolog, ACE2, is selectively expressed by adult Leydig cells of the testis.Endocrinology. 2004; 145: 4703-4711Crossref PubMed Scopus (223) Google Scholar], thus implying a role in testicular function and suggesting a possible involvement of testicle in COVID-19 infected patients, a factor which may affect testosterone secretion. Pro-inflammatory cytokines have a central role in the progression of COVID-19 infection. Reduction of cytokine activity and/or their receptors (anti-cytokine therapy), can be useful for treatment. In this context testosterone may downregulate inflammation. As a matter of fact, several studies carried out both in animals and humans showed that hypogonadism is associated with increased pro-inflammatory cytokines and that testosterone treatment reduces IL-1β, IL-6, and TNF-α [[16]Mohamad N.V. Wong S.K. Wan Hasan W.N. et al.The relationship between circulating testosterone and inflammatory cytokines in men.Aging Male. 2019; 22: 129-140Crossref PubMed Scopus (174) Google Scholar]. Furthermore, the association between an increase of pro-inflammatory state and decline in testosterone is often observed in aging men [[17]Maggio M. Basaria S. Ceda G.P. et al.The relationship between testosterone and molecular markers of inflammation in older men.J Endocrinol Invest. 2005; 28: 116-119Crossref PubMed Google Scholar] and in men with stable coronary artery disease [[18]Nettleship J.E. Pugh P.J. Channer K.S. Jones T. Jones R.D. Inverse relationship between serum levels of interleukin-1β and testosterone in men with stable coronary artery disease.Horm Metab Res. 2007; 39: 366-371Crossref PubMed Scopus (68) Google Scholar]. Based on the above considerations, the hypothesis arises that testosterone may have a role in the cascade of events leading to progression of COVID-19 infection due to the cytokine storm. Suppression of ACE2 expression by inflammatory cytokines accompanied by the decrease of androgens and estrogens of the elderly, may establish a negative correlation between ACE2 expression and COVID-19 mortality [[19]Chen J. Jiang Q. Xia X. Liu K. Yu Z. Tao W. et al.Individual variation of the SARS-CoV2 receptor ACE2 gene expression and regulation.2020Google Scholar]. Measuring testosterone levels may be recommended at the time of an identified COVID-19 positive patient. At present data on testosterone can be collected systematically at one or more institutions. If values are low, use of testosterone may be considered to reduce the associated pulmonary syndrome, thus preventing progression to severe COVID-19 disease where pro-inflammatory cytokines play a major role. In a further selection of patients for testosterone treatment, avoidance of enrolling patients in whom therapy with the hormone is contraindicated, should be taken into account. A proper randomized trial with testosterone should be then designed. As opposed to what mentioned earlier, stands the testosterone-driven COVID-19 theory [[20]Wambier C.G. Goren A. SARS-COV-2 infection is likely to be androgen mediated.J Am Acad Dermatol. 2020; (Journal pre-proof)https://doi.org/10.1016/j.jaad.2020.04.032https://doi.org/10.1016/j.jaad.2020.04.032Abstract Full Text Full Text PDF Scopus (164) Google Scholar]. This is based on the androgen receptor activation of the transcription of a transmembrane protease, serine 2 (TMPRSS2), exploring possible implications in risk stratification and transmissibility of COVID-19 infection [[21]Lukassen S. Lorenz Chua R. Trefzer T. et al.SARS-CoV-2 receptor ACE2 and TMPRSS2 are primarily expressed in bronchial transient secretory cells.EMBO J. 2020; https://doi.org/10.15252/embj.20105114Crossref PubMed Scopus (701) Google Scholar]. Although other proteases were described to activate the COVID-19 spikes in vitro, only TMPRSS2 activity is regarded as essential for viral spread and pathogenesis in the infected hosts [[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; https://doi.org/10.1016/j.cell.2020.02.052Abstract Full Text Full Text PDF PubMed Scopus (13243) Google Scholar]. TMPRSS2 may also cleave ACE2 for augmented viral entry [[23]Heurich A. Hofmann-Winkler H. Gierer S. Liepold T. Jahn O. Pohlmann S. TMPRSS2 and ADAM17 cleave ACE2 differentially and only proteolysis by TMPRSS2 augments entry driven by the severe acute respiratory syndrome coronavirus spike protein.J Virol. 2014; 88: 1293-1307Crossref PubMed Scopus (634) Google Scholar]. Androgen receptor activity has been considered a requirement for the transcription of TMPRSS2 gene as no other known TMPRSS2 gene promoter has been reported to exert the same action in humans [[24]Lucas J.M. 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: 1310-1325Crossref PubMed Scopus (342) Google Scholar,[25]National Institutes of Health. TMPRSS2 transmembrane serine protease 2 [Homo sapiens (human)] Gene ID: 7113. Gene ID: 7113, updated on 13-Mar-2020.Google Scholar]. The modulation of TMPRSS2 expression by testosterone has been suggested to contribute to male predominance of COVID-19 infection [[26]Stopsack K.H. Mucci L.A. Antonarakis E.S. Nelson P.S. Kantoff P.W. TMPRSS2 and COVID-19: serendipity or opportunity for intervention?.Cancer Discov. 2020; https://doi.org/10.1158/2159-8290.CD-20-0451Crossref PubMed Scopus (286) Google Scholar]. Finally, TMPRSS2 is both the most frequently altered gene in primary prostate cancer and a critical factor enabling cellular infection by SARS-CoV-2 [[24]Lucas J.M. 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: 1310-1325Crossref PubMed Scopus (342) Google Scholar]. The hyper adrogenic phenotype could explain the COVID-19 positivity in those few young males with severe COVID-19 infection [[27]Guan W. Ni Z. Hu Y. et al.Clinical characteristics of coronavirus disease 2019 in China.N Engl J Med. 2020; https://doi.org/10.1056/nejmoa2002032Crossref Google Scholar], possibly with shorter AR CAG lengths, who are at greater risk of developing prostate cancer because higher receptor transcription activity [[28]Bennett C.L. Price D.K. Kim S. et al.Racial variation in CAG repeat lengths within the androgen receptor gene among prostate cancer patients of lower socioeconomic status.J Clin Oncol. 2002; 20: 3599-3604Crossref PubMed Scopus (84) Google Scholar]. A role for TMPRSS2 variants and its expression levels in modulating COVID-19 severity has been suggested, leading to foster a rapid experimental validation on large cohorts of patients with different clinical manifestations of COVID-19 infection [[29]Asselta R. Paraboschi E.M. Mantovani A. Duga S. ACE2 and TMPRSS2 variants and expression as candidates to sex and country differences in COVID-19 severity in Italy. Prepr from medRxiv bioRxiv.2020: 1-20https://doi.org/10.1101/2020.03.30.20047878Google Scholar]. Since TMPRSS2 are expressed also at pulmonary level, the use of TMPRSS2 inhibitors, currently used for prostate cancer, represent an appealing target for prevention or treatment of COVID-19 pneumonia [[21]Lukassen S. Lorenz Chua R. Trefzer T. et al.SARS-CoV-2 receptor ACE2 and TMPRSS2 are primarily expressed in bronchial transient secretory cells.EMBO J. 2020; https://doi.org/10.15252/embj.20105114Crossref PubMed Scopus (701) Google Scholar,[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; https://doi.org/10.1016/j.cell.2020.02.052Abstract Full Text Full Text PDF PubMed Scopus (13243) Google Scholar]. Studies are required to validate this hypothesis and to evaluate the therapeutic and prophylactic potential of drugs that temporarily target androgen activity, such as androgen receptor inhibitors, steroidogenesis inhibitors and 5-alpha reductase inhibitors [[20]Wambier C.G. Goren A. SARS-COV-2 infection is likely to be androgen mediated.J Am Acad Dermatol. 2020; (Journal pre-proof)https://doi.org/10.1016/j.jaad.2020.04.032https://doi.org/10.1016/j.jaad.2020.04.032Abstract Full Text Full Text PDF Scopus (164) Google Scholar]. The elucidation of the role of testosterone in the battle towards COVID-19 infection turns out to be an urgent need. None.