Role of testosterone in COVID-19 patients – A double-edged sword?
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7494488/
Abstract
COVID-19 affects males twice as frequently as females with significantly increased severity and mortality. Current data suggest a direct correlation between the lower level of serum testosterone, inflammatory cytokines, disease severity, and poor clinical outcomes among male patients with COVID-19. The gradual decline in total and free testosterone levels has a direct correlation with serious pulmonary complications requiring advanced care (ICU, ventilators, ECMO, etc.). SARS-CoV-2 utilizes Angiotensin-Converting Enzyme II (ACE2) for entry in the host cell, and Transmembrane Protease, Serine 2 (TMPRSS2) to prime spike protein of SARS-CoV-2. Testosterone induces ACE-2 expression, a critical pulmonary protective enzyme. Low testosterone levels in males have a direct correlation with the high probability of ICU admission and the worse disease outcome (ARDS, duration of ICU stay, mortality). On the contrary, however, high testosterone levels can lead to thrombosis which is also one of the fatal manifestations in COVID-19 patients. A critical evaluation of the serum testosterone and its relevance to COVID-19 is warranted to re-evaluate strategies to effectively triage, prioritize, and manage high-risk patients for ICU admission, survival outcomes, targeted solutions, and operational algorithms.
Introduction
Coronavirus disease 2019 (COVID-19) affects men significantly more than women [SUP]
[1][/SUP][SUP], [/SUP][SUP]
[2][/SUP]. Male patients with COVID-19 are reported to die at twice the rate of females when they contract the virus [SUP]
[3][/SUP]. Lower levels of testosterone result in the upregulation of ACE2 and TMPRSS2 receptors, facilitating SARS-CoV-1 entry into the alveolar cells, and deregulating a lung-protective pathway [SUP]
[4][/SUP]. Decreased testosterone levels in critically ill males negatively affect endothelial cell functioning, promote defective immune response, impair the ability to clear the virus, and promote systemic inflammation. Obesity among males also generates more pro-inflammatory cytokines important in cell signaling, emanating in increased vulnerability, severe disease, and worst outcome. Lower serum testosterone level is a poor prognostic indicator for patients with COVID-19 by deregulating pulmonary protective pathways [SUP]
[5][/SUP][SUP], [/SUP][SUP]
[6][/SUP].
Thereby we hypothesize that low testosterone levels in males have a direct correlation with the severity of disease and a worse outcome in COVID-19.
https://www.frontiersin.org/articles/10.3389/fendo.2021.607179/full
High Testosterone Impact on COVID-19 Severity—The TMPRSS2 Connection
TMPRSS2 is a cell-surface protein expressed by the epithelial cells of specific tissues including those in the aero-digestive tract. It is a member of the type II Transmembrane Serine Proteases (TTSPs) family that are involved in multiple physiological and pathological processes, including viral infections and cancer, although its exact physiological role is still under investigation.
TMPRSS2 transcription is regulated by the androgen receptor (AR) (
37). Specifically, AR activity is considered a requirement for the transcription of the
TMPRSS2 gene because no other known
TMPRSS2 gene promoter has been described in humans to date (
37).
The human AR, located on the X chromosome, functions as a steroid hormone–activated transcription factor, which signals through classical and non-classical signaling pathways (ligand-dependent and independent actions) (
38,
39). Androgens can work along three known paths, by intracellular conversion of serum testosterone into dihydrotestosterone (DHT), by testosterone itself, or by intracellular conversion of testosterone to estradiol through aromatization. The AR has widespread expression in many cells and tissues with a diverse range of biological actions involving the development and maintenance of the reproductive, musculoskeletal, cardiovascular, immune, neural, and haemopoietic systems (
39,
40).
Androgen receptor expression is low prior to pubertal maturation and may contribute to the low incidence of severe COVID-19 infection in children (
41,
42). In addition, the lower rate of severe COVID-19 infection in female patients may be attributed to lower AR expression (
43,
44). AR contains two polymorphic nucleotide repeats, GGN and CAG, encoding for glycine and glutamine, respectively (
45). Several mutations or polymorphisms have been described in the gene encoding the AR in a variety of diseases or among various ethnic groups. Some of these mutations/polymorphisms are associated with functional changes in the AR expression and mutations in or around the receptor (
46–
48). Testosterone’s biological action is dependent on the length of the CAG repeat of the androgen receptor gene (
49).
Androgen mediated expression of ACE2 and TMPRSS2 may explain the gender difference in COVID-19 disease severity and mortality (
50). Furthermore, the frequency of genetic variations in the AR differs by ethnicity, which may suggest a possible explanation for the wide differences in COVID-19 severity and mortality rates between countries and between different ethnic backgrounds in the same country (
51,
52).
Various experimental data in mammalian animal models, as well as in numerous, unrelated clinical manifestations, in diverse in-vivo as well as human clinical settings, support the interplay between SARS-CoV-2 and sex hormones, specifically testosterone and AR, most likely
via the cell host TMPRSSE2.
In animal models, ACE and ACE2 activity in cardiac cells were significantly higher in male compared to female rats, whereas orchiectomy decreased the activity of these enzymes and ovariectomy increased ACE2 but did not change ACE activity (
53). In addition, androgen administration to a lung adenocarcinoma cell line up regulated the TMPRSS2 transcript more than two-fold, accompanied by an androgen dependent loading of the AR protein onto the TMPRSS2 enhancer (
54). Furthermore, TMPRSS2 inhibition or knock down has been shown to reduce SARS-CoV infection
in vitro (
33).
Just recently, in-vitro studies employing human embryonic stem cell-derived cardiac cells and lung organoids have substantiated that testosterone regulates SARS-CoV-2 development, intensifying its severity in men. Furthermore, the pharmacological dampening of testosterone activity by inhibitors of 5 alpha reductases can reduce ACE2 levels in the target cells, leading to the decay of SARS CoV-2 infectivity (
55).
In the clinical setting, recent preliminary studies suggest a high incidence of androgenic (androgenetic) alopecia among male and female patients hospitalized due to severe COVID-19 (
56,
57). Androgenic alopecia, often referred to as male pattern (scalp) hair loss, is the most common form of hair loss among men and is associated with AR polymorphism (
58). In one small-scale study, clinically significant androgenic alopecia was shown to complicate 71% of males with COVID-19 as compared to 31-57% in literature controls (
57).
The androgen-dependency of TMPRSS2 activity is normally expressed at its highest level in the prostate epithelium, as evidenced by several fold abundance compared to all other body tissues (
59,
60). While the physiological role of TMPRSS2 is still under investigation, it is significantly up regulated in men with a prostatic disease, including those with prostate cancers (
37). Elevated free testosterone was recently shown in a large scale study to be associated with COVID-19 complications in this subgroup of men (
55).
Men with metastatic prostatic cancer are usually treated with androgen-deprivation therapies to control the disease. It is noteworthy that these therapies substantially decrease the levels of TMPRSS2. While cancer patients have an increased risk of SARS-CoV-2 compared to non-cancer patients, it has been recently shown by two independent preliminary studies that prostate cancer patients receiving androgen-deprivation therapies are partially protected from SARS-CoV-2 infections (
61,
62), supporting further the deleterious role of androgens in the pathogenesis of COVID-19. The active controversy surrounding this topic in contemporary literature calls for well-designed targeted studies to substantiate the potential protective effects of androgen-deprivation therapy.
A more recent prospective longitudinal study of hospitalized males with COVID-19 suggested that longer AR CAG repeats are associated with a more severe form of the disease, supporting the active role of testosterone in the pathogenesis of the complicated disease (
63).
Furthermore, there is evidence that AR has an impact on furin and other members of the convertase proprotein family in prostate cancer, which may support an alternative role for testosterone in the pathogenesis of COVID-19 (
64,
65). This two-pronged position of testosterone to employ either TMPRSS2 or furin to intensify the virulence of SARS-CoV-2 warrants investigation in targeted studies.
Further to the AR genetic disparities among various ethnic populations, other natural candidate genetic polymorphisms related to
ACE2, TMPRSS2, or FURIN genes, as well as other host invasion genes such as
DPP4 or PCSK3, which have been shown to differ among different population ancestries, may also provide a supplementary explanation for COVID-19 pandemic spread and progression (
66–
68). It is possible that the presence of different
ACE2, TMPRSS2, FURIN,
DPP4, and
PCSK3 gene variants, the main machinery for orchestrating SARS-CoV-2 cellular host access, may modulate viral infectivity among humans, making some people less or more vulnerable than others.
Taken together, epidemiological data emerging from the COVID-19 pandemic, backed by animal studies and further by preliminary clinical studies in diverse clinical settings, support the notion that high (male) testosterone levels acting
via the AR modulate TMPRSS2 function positively to further prime SARS-CoV-2 S proteins and eventually increase COVID-19 infectivity and severity. Additionally, as in various ethnic backgrounds,
AR mutations or other gene polymorphisms along the pathway of SARS-Co-2 pathogenesis may further lead to COVID-19 expansion and deterioration. This concept ought to be further explored in properly performed targeted studies.
