Androgen sensitivity gateway to COVID-19 disease severity

Abstract

In this communication, we present arguments for androgen sensitivity as a likely determinant of COVID-19 disease severity. The androgen sensitivity model explains why males are more likely to develop severe symptoms while children are ostensibly resistant to infection. Further, the model explains the difference in COVID-19 mortality rates among different ethnicities. Androgen sensitivity is determined by genetic variants of the androgen receptor. The androgen receptor regulates transcription of the transmembrane protease, serine 2 (TMPRSS2), which is required for SARS-CoV-2 infectivity. TMPRSS2 primes the Spike protein of the virus, which has two consequences: diminishing viral recognition by neutralizing antibodies and activating SARS-CoV-2 for virus-cell fusion. Genetic variants that have been associated with androgenetic alopecia, prostate cancer, benign prostatic hyperplasia and polycystic ovary syndrome could be associated with host susceptibility. In addition to theoretical epidemiological and molecular mechanisms, there are reports of high rates of androgenetic alopecia of from hospitalized COVID-19 patients due to severe symptoms. Androgen sensitivity is a likely determinant of COVID-19 disease severity. We believe that the evidence presented in this communication warrants the initiation of trials using anti-androgen agents.

Keywords: COVID-19; SARS-CoV-2; TMPRSS2; alopecia; androgens; anti-androgen; clinical trial; pandemic.

FIGURE 1

Androgen pathway in COVID‐19 infection. Red arrows show the steps that are targeted by androgen blockers, which include: GnRH analogs (Degarelix, Goserelin, Leuprolide, Leuprorelin, Nafarelin), which stop LH secretion and induce chemical castration. Dutasteride and Finasteride are 5‐alpha‐reductase inhibitors, which are safe for men and women after menopause, because dihydrotestosterone (DHT) is the most potent intrinsic androgen hormone. Testosterone is regarded as the main androgen hormone, its production in inhibited by ketoconazole, an inhibitor of steroidogenesis. Androgen receptor inhibitors may be steroidal, such as Abiraterone, Cyproterone, Nomegestrol, or Spironolactone; or nonsteroidal (Apalutamide, Bicalutamide, Darolutamide, Enzalutamide, Flutamide, and Nilutamide). TMPRSS2 blockers include Bromhexine, Camostat, and Nafamostat

FIGURE 2

Proposal of host vulnerability stratification following the androgen‐driven COVID‐19 hypothesis, subjects with increased androgen receptor activity through androgen receptor gene polymorphism or through hyperactivation by androgen hormones would be predisposed to increased viral infectivity and cumulative viral load, which would reflect on pronounced symptoms and transmissibility from cell lining of the airways and digestive tract. A spectrum of androgenic activity would imply in polar pauciviral COVID‐19 (e.g., children < 7), with null airway/fecal transmission potential, women with normal androgen activity would have low transmission potential (borderline pauciviral COVID‐19), male teenagers and adults would have high transmission potential (borderline multiviral COVID‐19), and infected individuals with abnormally high androgen receptor activity (genetic or acquired) would represent the multiviral COVID‐19 pole of the spectrum, with extremely high transmission

FIGURE 3

Gross testosterone levels per gender, from birth to 85 years of age. Note peak in newborn males, and increase in testosterone levels in both genders after puberty. There is a subtle decrease in testosterone levels with aging. Adapted from: “Sex‐specific genetic architecture of human disease,” C. Ober et al., 2008, Nature Reviews. Genetics, 9(12), 911–922

FIGURE 4

Steroidogenesis. Enzyme activities that reduce androgen steroid levels: 21‐hydroxylase and aromatase (red boxes). 21‐Hydroxylase deficiency causes increased production of androgen hormones in females. Male patients who take external androgens may accumulate dihydrotestosterone, particularly when combined with aromatase inhibitors. (Figure source: Wikimedia commons)