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The story on COVID-19

June 26, 2021


Since the beginning of the COVID-19 pandemic, in early 2020, Dr. Cadegiani started to notice that several aspects of the infection by SARS-CoV-2, the virus that causes COVID-19, were direct- or indirectly related to endocrine mechanisms, particularly the renin-angiotensin-aldosterone system (RAAS) and the androgen activity, that regulated the angiotensin converting enzyme-2 (ECA-2) and the TMPRSS-2, respectively, the two major proteins involved in the SARS-CoV-2 infectivity. ECA-2 is the protein through which SARS-CoV-2 entries in the cell. TMPRSS-2 ‘prepares’ the virus for its entry in the cell.

Patients with hypertension were amongst the first risk factors detected for severe COVID-19. A hypothesis was that the two most used anti-hypertensive classes, the ECA inhibitors (ECAi) and the angiotensin receptor blocker (ARBs), would be the cause by increasing the ECA-2 attached to the cells. Dr. Cadegiani then proposed that spironolactone, a molecule used as an antihypertensive that has protective effects in the heart, lungs, and kidneys,  could hamper the theoretical risk of these two antihypertensive drug classes. The spironolactone action would be to counterbalance the ECA-2 attached to the cell by leading to an increase of the ECA-2 circulating in the blood. As demonstrated by the use of recombinant ECA-2, the ECA-2 that circulates may neutralize the SARS-CoV-2 virus and prevent its entry and infectivity. In addition, spironolactone may modulate the RAAS by antagonizing the action of the harmful hormone called aldosterone. Other risk factors for severe COVID-19, including obesity and type 2 diabetes, are risk factors likely because of the dysfunctions they cause in the RAAS, which could also be corrected by the use of spironolactone.

The first paper hypothesizing spironolactone as a promising drug against COVID-19 was published in the American Journal of Physiology – Endocrinology and Metabolism (AJP-ENDO) in April of 2020.

Right after this first publication, a great group of researchers from the USA and Spain proposed that androgenetic alopecia (AGA) was an independent risk factor for COVID-19 severity, by the observation that the intensive care units (UCIs) were plenty of males with AGA. This could be explained by the fact that AGA is a clinical sign of enhanced androgen activity, and androgens (which are hormones that act like ‘testosterone’, the ‘masculine’ hormone) are the only molecules known to stimulate the expression of TMPRSS-2. For this reason, it has been hypothesized that males had more severe COVID-19 than females, and that males with AGA had more severe COVID-19 than males without AGA because of the overexpression of TMPRSS-2 induced by the high androgen activity. By April of 2020, the team published a series of papers on the antiandrogen hypothesis for COVID-19.

The fact that androgens could be harmful for COVID-19 allowed the hypothesis that the use of anti-androgens could play a protective role for COVID-19. And spironolactone, when in higher doses, acts as an antiandrogen agent, not only as an antihypertensive drug acting in the RAAS.

For this reason, Dr. Cadegiani got in contact with the research team to talk about the possibility of conducting a clinical trial with spironolactone. From that time on, Dr. Cadegiani joined the team and started to conduct a series of prospective observational studies and randomized clinical trials (RCTs) with different antiandrogens, including spironolactone, dutasteride, and proxalutamide.

Alongside with the RCTs, multiple observations were demonstrating that in fact while hyperandrogenic states were a risk factor for developing severe COVID-19, chronic antiandrogen users seemed to be relatively protected against COVID-19. Together with the research team, Dr. Cadegiani published a few papers showing that women affected by polycystic ovary syndrome and other hyperandrogenic states had more symptoms than women without hyperandrogenism, that men taking dutasteride, a drug that inhibits the conversion of testosterone into dihydrotestosterone (DHT), an androgen approximately five times more potent than testosterone, and that also has a weak effect on the blockage of androgen receptors (ARs), presented fewer and shorter symptoms than both AGA and non-AGA males, that older men hospitalized due to COVID-19 taking dutasteride for prevention and treatment of benign prostate hyperplasia were less likely to progress to the need of ICU compared to non-users, and that the genetic of the androgen receptor was able to predict the severity of COVID-19. Together, this preliminary evidence reinforced the plausibility of the RCTs and other studies that we were starting to conduct.

The preliminary reports of the double-blind, placebo-controlled RCTs with dutasteride and proxalutamide in outpatients infected by the SARS-CoV-2 have been published already, while the main publications are currently under review. The main publication on the double-blind, placebo-controlled RCT conducted in hospitalized patients with proxalutamide is also under review.

Again, bringing the previous knowledge Dr. Cadegiani obtained to COVID-19, it is not testosterone alone that predicts COVID-19 severity. If this was the case, young males would have had the worst outcomes. Instead, it is likely that a combination of: a. The balance between testosterone, DHT, and estradiol, and b. The androgen receptor sensibility to androgens, that more likely predict COVID-19 severity.

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