Aziz Rodan Sarohan M.D.

Why is COVID-19 more severe in men than women?

Although most of the mechanisms described above are true, the main molecules underlying this mysterious mechanism are far from explaining the pathogenesis. Likewise, all the features related to the clinical presentation of COVID-19 can be easily explained through retinol depletion and retinoid signaling disorder, which form the molecular basis of the COVID-19 pathogeny. As an example, I leave a short explanation on this subject below, I present it to your attention.

As it is known, after the SARS-CoV-2 spike protein binds to ACE2, it is processed by TMPRSS2 and taken into the host cell.
As it is known, after the spike protein binds to the host cell membrane, the spike protein is processed by TMPRSS2 and taken into the cell. TMPRSS2, which performs this function, is higher in men. Because testosterone increases the expression of this enzyme.
Dihydrotestosterone (DHT) has previously been shown to be a potent activator of TMPRSS2(1). The presence of DHT and increased expression of TMPRSS2 in COVID-19 also increases the processing and activation of the COVID-19 spike protein to bind to ACE2 receptors in the lung, kidney, and other organs.
The SARS-CoV-2 virus, which adheres to the cell wall in this way, is mostly taken up by the male host cells.

Expression of TMPRSS2 is further increased due to retinol deficiency in COVID-19. Since retinol and retinoic acids inhibit dihydrotestosterone activity, they can also reduce the expression of TMPRSS2, and this must be one of the mechanisms underlying the effectiveness of retinoic acids in COVID-19.
We showed that retinol is depleted in COVID-19 in a clinical study we conducted at the beginning of the pandemic. However, it took a year for the article to be published (2). Retinol depletion in COVID-19 leads to a vicious circle on the spike-ACE2 and TMPRSS2 relationship, resulting in increased TMPRSS2 expression and internalization of the virus into more host cells. Another study showed that 13-cis-retinoic acid competitively and reversibly inhibits dihydrotestosterone (3). Also, in the current study, dihydrotestosterone (DHT) was significantly reduced after treatment in the 13 cis retinoic acid group. Decreased DHT can create a hormonal environment, as in women, reducing the adhesion of Spike protein to the host cell and internalization of the virus.
It has also been found that ACE2 expression is increased in COVID-19 (4,5,6,7). Depletion of retinol appears to be responsible for this as well. Likewise, it has been previously shown that retinoic acids reduce ACE2 expression (8,9). A study last year wrote that retinol inhibits the uptake of the SARS-CoV-2 spike protein, but the researchers explain the mechanism here by placing ATRA in a deep hydrophobic pocket of the receptor-binding domain (RBD) on top of the SARS-CoV-2 spike protein (S) trimer. They attributed this to the direct binding of the spike protein to the ACE2 receptor. They could not see the relationship between retinol depletion in COVID-19 and the pathogenesis of COVID-19, which I explained above (10).
1. Zhou F, Gao S, Han D, et al. TMPRSS2-ERG activates NO-cGMP signaling in prostate cancer cells. Oncogene (2019) 38:4397–411. doi: 10.1038/s41388- 019-0730-9
2. Sarohan AR, Akelma H, Araç E, Aslan Ö, Cen O. Retinol Depletion in COVID-19. Clin Nutr Open Sci. 2022 Jun;43:85-94. doi: 10.1016/j.nutos.2022.05.007. Epub 2022 May 28. PMID: 35664529; PMCID: PMC9142171.
3. Karlsson T, Vahlquist A, Kedishvili N, Törmä H. 13-cis-retinoic acid competitively inhibits 3 alpha-hydroxysteroid oxidation by retinol dehydrogenase RoDH-4: a mechanism for its anti-androgenic effects in sebaceous glands? Biochem Biophys Res Commun (2003) 303(1):273–8. doi: 10.1016/s0006-291x(03)00332-2
4. Patel SK, Juno JA, Lee WS, Wragg KM, Hogarth PM, Kent SJ, et al. Plasma ACE2 activity is persistently elevated following SARS-CoV-2 infection: implications for COVID-19 pathogenesis and consequences. European Respiratory Journal. 2021:2003730. pmid:33479113
5- Lundström A, Ziegler L, Havervall S, Rudberg A-S, von Meijenfeldt F, Lisman T, et al. Soluble angiotensin-converting enzyme 2 is transiently elevated in COVID-19 and correlates with specific inflammatory and endothelial markers. medRxiv.
6. Nagy B Jr., Fejes Z, Szentkereszty Z, Suto R, Varkonyi I, Ajzner E, et al. A dramatic rise in serum ACE2 activity in a critically ill COVID-19 patient. Int J Infect Dis. 2021;103:412–4. pmid:33249290
7. Xu H, Zhong L, Deng J, et al. High expression of ACE2 receptor of 2019- nCoV on the epithelial cells of oral mucosa. Int J Oral Sci (2020) 12(1):8. doi: 10.1038/s41368-020-0074-x
8. Zhong JC, Huang DY, Yang YM, Li YF, Liu GF, Song XH, Du K. Upregulation of angiotensin-converting enzyme 2 by all-trans retinoic acid in spontaneously hypertensive rats. Hypertension. 2004 Dec;44(6):907-12. doi: 10.1161/01.HYP.0000146400.57221.74. Epub 2004 Oct 11. PMID: 15477383.
9. Zhu X, Mou Z, Han W, Chen L. All-trans retinoic acid inhibits oxidative stress via ACE2/Ang (1-7)/MasR pathway in renal tubular epithelial cells stimulated with high glucose. Drug Dev Res. 2023 Apr 28. doi: 10.1002/ddr.22070. Epub ahead of print. PMID: 37114746.
10. Tong L, Wang L, Liao S, Xiao X, Qu J, Wu C, Zhu Y, Tai W, Huang Y, Wang P, Li L, Zhang R, Xiang Y, Cheng G. A Retinol Derivative Inhibits SARS-CoV-2 Infection by Interrupting Spike-Mediated Cellular Entry. mBio. 2022 Aug 30;13(4):e0148522. doi: 10.1128/mbio.01485-22. Epub 2022 Jul 13. PMID: 35862773; PMCID: PMC9426596.