A repeated observation that disease severity and mortality rate of Covid-19 is significantly higher in male rather than female sufferers [1] has led researchers to investigate the role of sex hormones in disease progression. Recent reports of case series from China [2], Germany [3] and Italy [4] have highlighted strong associations between serum testosterone levels, inflammatory cytokines, disease progression and clinical outcomes in male Covid-19 patients, independent of patient age and comorbidities. In a cohort of 31 Italian male hospital inpatients, a significant stepwise decline in calculated free (cFT) and total testosterone (TT) levels was strongly correlated with need for escalation of care from general ward based to specialist respiratory and intensive care [4]. There was significant negative correlation between both total and free testosterone with inflammatory markers such as neutrophil count, LDH and PCT, CRP and ferritin and a positive correlation with lymphocyte count. The probability of being transferred to the ICU or dying below and above a TT level of 5 nmol/L was 14.18% [8.89–17.03] vs 0.60% [0.12–3.32] (p < 0.0001) and 12.40% [6.77–16.43] vs 0.39% [0.07–2.26] (p < 0.0001) respectively. Similar observations were made in a cohort of 45 German patients with approximately 70% having low testosterone on admission to ICU with 7 of the 9 subsequent mortalities having significantly reduced TT levels [3].
Low testosterone levels in men admitted to hospital with acute illness have previously been described in published data and have similarly been directly associated with risk of admission to intensive care and severity of disease, as measured by likelihood of development of ARDS, length of ICU stay and mortality [5]. Expert commentators have however put forward hypothesise for disease-specific processes to suggest a potentially causative effect of low testosterone on adverse clinical outcomes in Covid-19. One theory is that low testosterone levels could theoretically be detrimental because of the role of testosterone in inducing the angiotensin-converting enzyme 2 (ACE2) expression, which is an important lung protective enzyme.
Further research is needed to define the cause and effect relationship between testosterone and severe acute illness from Covid-19; however, the importance of low testosterone as a prognostic marker of severe disease is clear and as yet underrecognised in men with Covid-19. We call for wider screening of testosterone levels in men admitted to hospital with symptoms of Covid-19 as a strategy to identify those at highest risk of severe disease leading to ICU admission and mortality.
Acknowledgements
Not Applicable.
Authors’ contributions
SR and EOB both drafted the manuscript and were responsible for the decision to submit for publication. The authors read and approved the final manuscript.
Funding
Not applicable
Availability of data and materials
Not applicable
Ethics approval and consent to participate
Not applicable
Consent for publication
Not applicable
Competing interests
SR and EOB are employees of Besins Healthcare, who manufacture and commercialise testosterone replacement therapies.
Footnotes
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
References
- 1.Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020;395(10229):1054–62. 10.1016/S0140-6736(20)30566-3. [DOI] [PMC free article] [PubMed]
- 2.Ma L, Xie W, Li D, Shi L, Mao Y, Xiong Y, et al. Effect of SARS-CoV-2 infection upon male gonadal function: a single center-based study. medRxiv. 2020. https://www.medrxiv.org/content/10.1101/2020.03.21.20037267v2.
- 3.Schroeder M, Tuku B, Jarczak D, Nierhaus A, Bai T, Jacobsen H, et al. The majority of male patients with COVID-19 present low testosterone levels on admission to Intensive Care in Hamburg, Germany: a retrospective cohort study. medRxiv. 2020. https://www.medrxiv.org/content/10.1101/2020.05.07.20073817v1.
- 4.Rastrelli G, Di Stasi V, Inglese F, et al. Low testosterone levels predict clinical adverse outcomes in SARS-CoV-2 pneumonia patients. Andrology. 2020;10.1111/andr.12821. 10.1111/andr.12821. [DOI] [PMC free article] [PubMed]
- 5.Iglesias P, Prado F, Macías MC, et al. Hypogonadism in aged hospitalized male patients: prevalence and clinical outcome. J Endocrinol Invest. 2014;37(2):135–41. 10.1007/s40618-013-0009-x. [DOI] [PubMed]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
Not applicable