Sex Hormones and Hormone Therapy during COVID-19 Pandemic: Implications for Patients with Cancer

Abstract

The novel coronavirus disease 2019 (COVID-19) shows a wide spectrum of clinical presentations, severity, and fatality rates. The reason older patients and males show increased risk of severe disease and death remains uncertain. Sex hormones, such as estradiol, progesterone, and testosterone, might be implicated in the age-dependent and sex-specific severity of COVID-19. High testosterone levels could upregulate transmembrane serine protease 2 (TMPRSS2), facilitating the entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into host cells via angiotensin-converting enzyme 2 (ACE2). Data from patients with prostate cancer treated with androgen-deprivation therapy seem to confirm this hypothesis. Clinical studies on TMPRSS2 inhibitors, such as camostat, nafamostat, and bromhexine, are ongoing. Antiandrogens, such as bicalutamide and enzalutamide, are also under investigation. Conversely, other studies suggest that the immune modulating properties of androgens could protect from the unfavorable cytokine storm, and that low testosterone levels might be associated with a worse prognosis in patients with COVID-19. Some evidence also supports the notion that estrogens and progesterone might exert a protective effect on females, through direct antiviral activity or immune-mediated mechanisms, thus explaining the higher COVID-19 severity in post-menopausal women. In this perspective, we discuss the available evidence on sex hormones and hormone therapy in patients infected with SARS-CoV-2, and we highlight the possible implications for cancer patients, who can receive hormonal therapies during their treatment plans.

Keywords: ACE2; COVID-19; SARS-CoV-2; TMPRSS2; androgen-deprivation therapy; androgens; camostat; estrogens; progesterone; tamoxifen; testosterone.

Figure 1

The role of sex hormones and hormone therapies in modulating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) entry in host cells and immune response. (A) A proposed model suggests that androgens can upregulate the activity of transmembrane serine protease 2 (TMPRSS2), which is necessary for the SARS-CoV-2 spike protein priming; several TMPRSS2 inhibitors are under investigation in clinical trials. In vitro data also suggest that estrogens might downregulate the angiotensin-converting enzyme 2 (ACE2) expression, which is used by SARS-CoV-2 for host cell entry. (B) Androgens (blue arrows), estrogens (pink arrows), and progesterone (yellow arrows) can activate and inhibit several components of the immune response against SARS-CoV-2, affecting the clinical course and disease severity of patients with COVID-19. TGFβ—transforming growth factor-beta; IL—interleukin; Th-1—T helper 1; Th-2—T helper 2; T reg—T regulatory cells; TNF—tumor necrosis factor; MDSC—myeloid-derived suppressor cells; DCs—dendritic cells; INOS—inducible nitric oxide synthase; NO—nitric oxide; NF-κB—nuclear factor kappa-light-chain-enhancer of activated B cells.