Clinical Trial Summary
Clinical Role of Testosterone and Dihydrotestosterone and which of them should be inhibited
in COVID-19 patients - A double-edged sword?
COVID-19 attacks and affects Males significantly more than females [1], [2]. Males with
COVID-19 are reported to die at twice the rate of females when they come infected with the
virus [3]. The upregulation of TMPRSS2 by androgens could explain the increased
susceptibility to COVID-19 in men.Contrary to expected, as a study demonstrated that The
expression level of TMPRSS2 increased 6-fold in androgen stimulated LNCaP cells, relative to
androgen-deprived cells[4]. But, surprisingly, low levels of testosterone led to the over
expression and upregulation of ACE2 and TMPRSS2 receptors, facilitating SARS-CoV-1 entry into
the alveolar cells, and deregulating a lung-protective pathway [5].According to literature
Dihydrotestosterone is many times more potent than testosterone, and many of the effects that
testosterone has in the body only happen after it is converted to dihydrotestosterone [6].
Therefore, we hypothesis that testosterone has better effect than dihydrotestosterone in case
of COVID-19, because a study found that DHT significantly induced the expression of TMPRSS2
[7]. And at the same time , decreased testosterone levels in critically diseased males
harmfully affect pulmonary endothelial cell functioning, impair the ability to clear the
virus , promote systemic . Obesity among males, promote defective immune response, , and also
generates more pro-inflammatory cytokines important in cell signaling, emanating in
increased, severe disease, worst outcome and vulnerability. Insufficient serum testosterone
level is a poor prognostic indicator for patients infected with COVID-19 by downregulation
pulmonary protective pathways [5], [8]. On the contrary, high testosterone levels can lead to
complication of thrombosis which is also one of the serious manifestations in COVID-19
patients[9]. Thereby we hypothesize that decreased testosterone levels in men have a direct
relation with the severity of infection and a worse outcome in COVID-19. In this case we
should found an appropriate treatment that induces testosterone level to introduce its
protective effect and up regulate pulmonary protective pathways and at the same time protect
against thrombosis and works to reduce the impact of dihydrotestosterone on lung cells
preventing up regulation of TMPRSS2, Her we shed new light on the appropriate treatment can
overcome the challenges that face testosterone therapy in the era of COVID-19 After searching
MEDLINE , PubMed, , Google Scholar, preprints and Controlled Trials until September , 2020 we
found that the appropriate treatment in this case is aerosolized 13 cis retinoic acid in
combination with testosterone therapy, as more than one study found that 13 cis retinoic acid
reversibly and potentially inhibit the effect of dihydrotestosterone on different targeted
cells. In addition its impact on thrombin.
The study is a randomized interventional comparative Phase IIII trial. 1000 adult male and
female patients with positive COVID-19 diagnosis and fulfilling the below outlined inclusion
criteria will be enrolled into the study.
After searching PubMed, MEDLINE, Google Scholar, preprints and Controlled Trials until
September , 2020 we found that the best and appropriate drug which can be combined with
testosterone replacement therapy is aerosolized 13 cis retinoic acid owing to its impact on
DHT and thrombin in addition it can be given in the form of aerosol for targeting pulmonary
cells with minimal systemic side effects . As previous study found that testosterone therapy
(TTh) administration using both topical and injectable formulations yielded transient and
concomitant rises in both DHT and T, with higher Hct elevations in men with higher DHT and T
levels[38]. As Testosterone is converted to DHT by the action of 5 alpha-reductase enzyme at
these target tissues.[39]. DHT is a potent activator of TMPRSS2[31,4] and this will be
followed by the activation of COVID-2019 spike protein to bind to its ACE2 receptors in lung
which in turn makes it more vulnerable to covid-19. A study demonstrated that 13- cis
-Retinoic acid competitively and reversibly inhibits dihydrotestosterone.[40] on contrary to
other selective inhibitor of serum DHT which led to sexual adverse effects because it usually
given systemically which increases the chance of systemic serious side effects . But 13- cis
-Retinoic acid will be given in the form of aerosol to avoid these systemic side effects.
Therefore, we suggest that 13- cis -Retinoic acid will downregulate TMPRSS2 expression
thorough temporary preventing the effect of dihydrotestosterone (DHT) on the activation of
TMPRSS2 gene expression. Furthermore, 13- cis -Retinoic acid Found to exert potential effect
on thrombin as high testosterone levels can lead to thrombosis which is also one of the fatal
manifestations in COVID-19 patients .A study in vitro found that Retinoic acid showed the
highest inhibition of both the forms of thrombin [41].
Moreover, we hypothesize that any drug which downregulates TMPRSS2 expression through
targeting AR, AR co-regulatory factors, or AR downstream transcription factors might be
potentially effective against COVID-19 and is worth investigating under a clinical trial.
