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Worse progression of COVID-19 in men: Is testosterone a key factor?
Giagulli, VA, Guastamacchia, E, Magrone, T, Jirillo, E, Lisco, G, De Pergola, G, Triggiani, V
Andrology. 2021;(1):53-64
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Abstract
BACKGROUND The novel severe acute respiratory syndrome coronavirus (SARS-CoV-2) disease 2019 (COVID-19) seems to have a worse clinical course among infected men compared with women, thus highlighting concerns about gender predisposition to serious prognosis. Therefore, androgens, particularly testosterone (T), could be suspected as playing a critical role in driving this excess of risk. However, gonadal function in critically ill men is actually unknown, mainly because serum T concentration is not routinely measured in clinical practice, even more in this clinical context. OBJECTIVE To overview on possible mechanisms by which serum T levels could affect the progression of COVID-19 in men. METHODS Authors searched PubMed/MEDLINE, Web of Science, EMBASE, Cochrane Library, Google, and institutional websites for medical subject headings terms and free text words referred to "SARS-CoV-2," "COVID-19," "testosterone," "male hypogonadism," "gender" "immune system," "obesity," "thrombosis" until May 19th 2020. RESULTS T, co-regulating the expression of angiotensin-converting enzyme 2 and transmembrane protease serine 2 in host cells, may facilitate SARS-CoV-2 internalization. Instead, low serum T levels may predispose to endothelial dysfunction, thrombosis and defective immune response, leading to both impaired viral clearance and systemic inflammation. Obesity, one of the leading causes of severe prognosis in infected patients, is strictly associated with functional hypogonadism, and may consistently strengthen the aforementioned alterations, ultimately predisposing to serious respiratory and systemic consequences. DISCUSSION AND CONCLUSION T in comparison to estrogen may predispose men to a widespread COVID-19 infection. Low serum levels of T, which should be supposed to characterize the hormonal milieu in seriously ill individuals, may predispose men, especially elderly men, to poor prognosis or death. Further studies are needed to confirm these pathophysiological assumptions and to promptly identify adequate therapeutic strategies.
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Low testosterone levels and high estradiol to testosterone ratio are associated with hyperinflammatory state and mortality in hospitalized men with COVID-19.
Infante, M, Pieri, M, Lupisella, S, D'Amore, L, Bernardini, S, Fabbri, A, Iannetta, M, Andreoni, M, Morello, M
European review for medical and pharmacological sciences. 2021;(19):5889-5903
Abstract
OBJECTIVE Evidence supports a sex disparity in clinical outcomes of COVID-19 patients, with men exhibiting higher mortality rates compared to women. We aimed to test the correlation between serum levels of sex hormones [total testosterone, estradiol (E2), estradiol to testosterone (E2/T) ratio, progesterone), prolactin and 25-hydroxyvitamin D [25(OH)D] and markers of inflammation, coagulation and sepsis at admission in hospitalized men with COVID-19. PATIENTS AND METHODS We conducted an exploratory retrospective study including symptomatic men with confirmed SARS-CoV-2 infection who were consecutively admitted to our Institution between April 1 and May 31, 2020. RESULTS Patients were divided into survivors (n=20) and non-survivors (n=39). As compared to survivors, non-survivors showed significantly higher median neutrophil-to-lymphocyte ratio (NLR) values, D-dimer and procalcitonin (PCT) levels, along with significantly lower median 25(OH)D levels and total testosterone levels. Non-survivors exhibited significantly higher median values of E2/T ratio (a marker of aromatase activity). Spearman's correlation analysis revealed that total testosterone levels were significantly and inversely correlated with NLR, high-sensitivity C-reactive protein (hsCRP), interleukin-6, D-dimer and PCT. Conversely, E2/T ratio values were significantly and positively correlated with the aforementioned markers and with white blood cell (WBC) count. In a multivariate analysis performed by a logistic regression model after adjusting for major confounders (age, body mass index, hypertension and cardiovascular disease, diabetes mellitus and malignancy), total testosterone levels were significantly and inversely associated with risk of COVID-19-related in-hospital mortality. CONCLUSIONS Low total testosterone levels and elevated E2/T ratio values at admission are associated with hyperinflammatory state in hospitalized men with COVID-19. Low total testosterone levels at admission represent an independent risk factor for in-hospital mortality in such patients. Therefore, total testosterone and E2/T ratio may serve as prognostic markers of disease severity in this population.