Background The recent emergence of COVID-19 poses a global health emergency. One of the most frequently reported data is sex-related severity and mortality: according to the last available analysis on 239,709 patients in Italy, lethality is 17.7% in men and 10.8% in women, with 59% of total deaths being men. Interestingly, the infection rate is lower in males than in females, with 45.8% and 54.2% of positive cases, respectively, suggesting that gender-related factor may worsen disease evolution. A tentative hypothesis to explain these findings is the role of angiotensin-converting enzyme 2 (ACE2) and serine protease TMPRSS2 involved in viral infection. Purpose In this review, we summarize the available evidence pointing to gender-related differences in ACE2 and TMPRSS2 expression, from both genetic and endocrine points of view. Results Altogether, available evidence points toward two not-mutually exclusive mechanisms in gender susceptibility to COVID-19 by sex hormonal regulation of ACE2 and TMPRSS2. On one hand, ACE2 expression could be increased in women, either by estrogens or constitutively by X chromosome inactivation escape or by reduced methylation, providing a larger reservoir of ACE2 to maintain the fundamental equilibrium of RAS regulatory axis. On the other, low levels of androgens in women may keep at low levels TMPRSS2 expression, representing a further protective factor for the development of COVID-19 infection, despite the increased expression of ACE2, which represents the Trojan horse for SARS-CoV-2 entry. Conclusions Both mechanisms consistently point to the role of sex hormones and sex chromosomes in the differential severity and lethality of COVID-19 in men and women.

This work was supported by the Italian Ministry of University and Research (grant no. 2009AMPA9C to C.F.) and Padova University (grant 2010 to A.D.R.). The authors have no competing interests to declare.

No external funding was either sought or obtained for this study. There are no conflicts of interest to be declared.

Background Considerable attention has been paid to perfluoroalkyl compounds (PFCs) because of their worldwide presence in humans, wildlife, and environment. A wide variety of toxicological effects is well supported in animals, including testicular toxicity and male infertility. For these reasons, the understanding of epidemiological associations and of the molecular mechanisms involved in the endocrine-disrupting properties of PFCs on human reproductive health is a major concern. Objective To investigate the relationship between PFC exposure and male reproductive health. Design This study was performed within a screening protocol to evaluate male reproductive health in high schools. Patients This is a cross-sectional study on 212 exposed males from the Veneto region, one of the four areas worldwide heavily polluted with PFCs, and 171 nonexposed controls. Main Outcome Measures Anthropometrics, seminal parameters, and sex hormones were measured in young males from exposed areas compared with age-matched controls. We also performed biochemical studies in established experimental models. Results We found that increased levels of PFCs in plasma and seminal fluid positively correlate with circulating testosterone (T) and with a reduction of semen quality, testicular volume, penile length, and anogenital distance. Experimental evidence points toward an antagonistic action of perfluorooctanoic acid on the binding of T to androgen receptor (AR) in a gene reporter assay, a competition assay on an AR-coated surface plasmon resonance chip, and an AR nuclear translocation assay. Discussion This study documents that PFCs have a substantial impact on human health as they interfere with hormonal pathways, potentially leading to male infertility.

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