Expert Interview

Endocrine-related targets may drive treatments for COVID-19

Alice C. Levine
Alice C. Levine

Available data assessing the COVID-19 pandemic indicate that case fatality rates are higher among men compared with women, and this distinction becomes more pronounced with advancing age. Little evidence supports theories that a higher prevalence of smoking among men or immune factors can explain the higher death rate among men.

As research on COVID-19 continues, endocrinologists are focusing on the mechanism of entry of the virus into cells — angiotensin-converting enzyme 2, or ACE2, which has been established as the COVID-19 receptor; however, data are conflicting regarding its translational relevance. Research also suggests that the downstream transmembrane protease serine 2, or TMPRSS2, an enzyme encoded by the TMPRSS2 gene, is required for COVID-19 viral spike protein priming and onward transmission.

Healio spoke with Alice C. Levine, MD, professor of medicine, endocrinology, diabetes and bone disease at the Icahn School of Medicine at Mount Sinai, New York, about the connection between TMPRSS2 and COVID-19 in the context of the greater fatality among men, the role of androgens in the disease, and how antiandrogen treatments could potentially improve — or worsen — disease outcomes.

What is the connection between the TMPRSS2 gene and COVID-19?

Levine: The TMPRSS2 gene, located on human chromosome 21, has several androgen receptor elements, or AREs, located upstream of the transcription start site and the first intron. The gene encodes a protein of 492 amino acids that is highly expressed in both normal prostate epithelial cells and in prostate cancer cells. There is also low-level expression of TMPRSS2 in the lungs, colon, liver, kidneys and pancreas. Notably, in both prostate and lung cancer cells, TMPRSS2 is expressed in an androgen-dependent manner. Androgen-regulated TMPRSS2 in prostate cells plays a role in both normal male reproduction and in prostate cancer progression and metastases. The highly related SARS-CoV1, often called SARS, also utilizes TMPRSS2 for spike protein priming and also exhibits a male predominance in terms of morbidity and mortality. Given the seminal role of TMPRSS2 in SARS-CoV2 viral uptake and priming, and the data indicating that men with the disease exhibit higher case fatality rates, it is plausible that androgen-driven TMPRSS2 expression among men may explain the sex discrepancy in this disease.

Available data assessing the COVID-19 pandemic indicate that case fatality rates are higher among men compared with women, and this distinction becomes more pronounced with advancing age.
Source: Adobe Stock

How does COVID-19 use the ACE2 receptor and TMPRSS2 gene to infect people?

Levine: COVID-19 cell entry depends on ACE2 and TMPRSS2. The “spike” protein of the coronavirus — what makes the “corona” on the outside of the virus — facilitates viral entry into cells. That spike protein itself has two key portions: S1, for attachment, and S2, for fusion. The virus engages ACE2 as an entry receptor and employs the cellular serine protease TMPRSS2 for spike protein priming — this is when the spike protein gets cleaved in the middle — in human lung epithelial cells. After S protein cleavage by TMPRSS2, , the cells are primed, allowing a large viral load to enter the cell. Since TMPRSS2 is androgen-regulated, it is possible that one of the explanations for the higher case fatality rates in men worldwide might be due to androgenic upregulation of TMPRSS2 protein in alveolar epithelial cells.

What could this connection potentially mean for people who are prescribed the antiandrogen spironolactone?

Levine: Spironolactone is a complicated drug. It is both an androgen receptor blocker and an aldosterone receptor blocker. There are two ways that COVID-19 gets into the cell. One is the ACE2 receptor, which has to do with the mineralocorticoid pathway, and the other is this androgen-regulated TMPRSS2. With spironolactone, it is hard to know how that might shake out. In terms of its anti-androgen receptor, one would expect that it might be helpful. If the lung cells are expressing TMPRSS2, and you add an androgen receptor blocker, that should be beneficial in terms of downregulation of TMPRSS2 expression. However, via its mineralocorticoid receptor blockade, it is possible — although not proven — that spironolactone might increase ACE2 receptor expression. Again, possible benefits vs. risks of spironolactone therapy at this point are purely theoretical.

There has been controversy recently over claims that treatment with renin-angiotensin-aldosterone system antagonists could increase risk for COVID-19 and increase severity of the disease. Given these connections, what should clinicians know?

Levine: With ACE2, things get complicated. ACE2 is not the angiotensin-converting enzyme (ACE) we all know and love. ACE inhibitors do not inhibit ACE2. The ACE that we know is a soluble enzyme that catalyzes the conversion of angiotensin 1 to angiotensin 2. ACE2 is expressed on the surface of alveolar epithelial cells, and what it does as an enzyme is the opposite of ACE. It inhibits angiotensin 2, almost like an angiotensin receptor blocker, because it catalyzes the conversion of angiotensin 2 to a vasodilatory protein. In general, yes, the virus gets in via ACE2, and then via TMPRSS2; however, once the virus gets in, it downregulates ACE2 surface expression in lung cells (the virus and the ACE2 get incorporated together into cells). Most cardiologists feel that the people who get really sick don’t have enough ACE2, because they present with all of this edema and heart problems. Therefore, the recommendation of cardiologists has been that if someone might have COVID-19, you do not discontinue ACE inhibitors and angiotensin receptor blockers. As a matter of fact, one of the therapeutics being tried is an ACE inhibitor, and some have even tried giving ACE2.
What do we still need to learn?

Levine: There are no data on spironolactone, at least none that I can find. However, if we can extract from what we know about ACE inhibitors and angiotensin receptor blockers, it is not at all clear that they even upregulate ACE2 expression or whether increasing ACE2 is beneficial or harmful in patients currently ill with the virus. Therefore, there is no evidence-based rationale for discontinuing spironolactone to prevent or treat COVID-19. Theoretically though, in terms of androgenic regulation of TMPRSS2, the anti-androgen effect of spironolactone could be beneficial. So, it’s a “dirty” drug, especially in this particular case, because of its dual receptor antagonism (anti-mineralocorticoid and antiandrogen receptor activities). The study of the effects of pure antiandrogens, such as the androgen synthesis inhibitor abiraterone acetate, or antiandrogen receptor compounds such as hydroxyflutamide or enzalutamide, both used in prostate cancer, would likely yield some interesting data regarding the role of androgen-driven TMPRSS2 expression in COVID-a19 infection and outcomes. – by Regina Schaffer

Disclosure: Levine reports no relevant financial disclosures.

 

Alice C. Levine
Alice C. Levine

Available data assessing the COVID-19 pandemic indicate that case fatality rates are higher among men compared with women, and this distinction becomes more pronounced with advancing age. Little evidence supports theories that a higher prevalence of smoking among men or immune factors can explain the higher death rate among men.

As research on COVID-19 continues, endocrinologists are focusing on the mechanism of entry of the virus into cells — angiotensin-converting enzyme 2, or ACE2, which has been established as the COVID-19 receptor; however, data are conflicting regarding its translational relevance. Research also suggests that the downstream transmembrane protease serine 2, or TMPRSS2, an enzyme encoded by the TMPRSS2 gene, is required for COVID-19 viral spike protein priming and onward transmission.

Healio spoke with Alice C. Levine, MD, professor of medicine, endocrinology, diabetes and bone disease at the Icahn School of Medicine at Mount Sinai, New York, about the connection between TMPRSS2 and COVID-19 in the context of the greater fatality among men, the role of androgens in the disease, and how antiandrogen treatments could potentially improve — or worsen — disease outcomes.

What is the connection between the TMPRSS2 gene and COVID-19?

Levine: The TMPRSS2 gene, located on human chromosome 21, has several androgen receptor elements, or AREs, located upstream of the transcription start site and the first intron. The gene encodes a protein of 492 amino acids that is highly expressed in both normal prostate epithelial cells and in prostate cancer cells. There is also low-level expression of TMPRSS2 in the lungs, colon, liver, kidneys and pancreas. Notably, in both prostate and lung cancer cells, TMPRSS2 is expressed in an androgen-dependent manner. Androgen-regulated TMPRSS2 in prostate cells plays a role in both normal male reproduction and in prostate cancer progression and metastases. The highly related SARS-CoV1, often called SARS, also utilizes TMPRSS2 for spike protein priming and also exhibits a male predominance in terms of morbidity and mortality. Given the seminal role of TMPRSS2 in SARS-CoV2 viral uptake and priming, and the data indicating that men with the disease exhibit higher case fatality rates, it is plausible that androgen-driven TMPRSS2 expression among men may explain the sex discrepancy in this disease.

Available data assessing the COVID-19 pandemic indicate that case fatality rates are higher among men compared with women, and this distinction becomes more pronounced with advancing age.
Source: Adobe Stock

How does COVID-19 use the ACE2 receptor and TMPRSS2 gene to infect people?

Levine: COVID-19 cell entry depends on ACE2 and TMPRSS2. The “spike” protein of the coronavirus — what makes the “corona” on the outside of the virus — facilitates viral entry into cells. That spike protein itself has two key portions: S1, for attachment, and S2, for fusion. The virus engages ACE2 as an entry receptor and employs the cellular serine protease TMPRSS2 for spike protein priming — this is when the spike protein gets cleaved in the middle — in human lung epithelial cells. After S protein cleavage by TMPRSS2, , the cells are primed, allowing a large viral load to enter the cell. Since TMPRSS2 is androgen-regulated, it is possible that one of the explanations for the higher case fatality rates in men worldwide might be due to androgenic upregulation of TMPRSS2 protein in alveolar epithelial cells.

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What could this connection potentially mean for people who are prescribed the antiandrogen spironolactone?

Levine: Spironolactone is a complicated drug. It is both an androgen receptor blocker and an aldosterone receptor blocker. There are two ways that COVID-19 gets into the cell. One is the ACE2 receptor, which has to do with the mineralocorticoid pathway, and the other is this androgen-regulated TMPRSS2. With spironolactone, it is hard to know how that might shake out. In terms of its anti-androgen receptor, one would expect that it might be helpful. If the lung cells are expressing TMPRSS2, and you add an androgen receptor blocker, that should be beneficial in terms of downregulation of TMPRSS2 expression. However, via its mineralocorticoid receptor blockade, it is possible — although not proven — that spironolactone might increase ACE2 receptor expression. Again, possible benefits vs. risks of spironolactone therapy at this point are purely theoretical.

There has been controversy recently over claims that treatment with renin-angiotensin-aldosterone system antagonists could increase risk for COVID-19 and increase severity of the disease. Given these connections, what should clinicians know?

Levine: With ACE2, things get complicated. ACE2 is not the angiotensin-converting enzyme (ACE) we all know and love. ACE inhibitors do not inhibit ACE2. The ACE that we know is a soluble enzyme that catalyzes the conversion of angiotensin 1 to angiotensin 2. ACE2 is expressed on the surface of alveolar epithelial cells, and what it does as an enzyme is the opposite of ACE. It inhibits angiotensin 2, almost like an angiotensin receptor blocker, because it catalyzes the conversion of angiotensin 2 to a vasodilatory protein. In general, yes, the virus gets in via ACE2, and then via TMPRSS2; however, once the virus gets in, it downregulates ACE2 surface expression in lung cells (the virus and the ACE2 get incorporated together into cells). Most cardiologists feel that the people who get really sick don’t have enough ACE2, because they present with all of this edema and heart problems. Therefore, the recommendation of cardiologists has been that if someone might have COVID-19, you do not discontinue ACE inhibitors and angiotensin receptor blockers. As a matter of fact, one of the therapeutics being tried is an ACE inhibitor, and some have even tried giving ACE2.
What do we still need to learn?

Levine: There are no data on spironolactone, at least none that I can find. However, if we can extract from what we know about ACE inhibitors and angiotensin receptor blockers, it is not at all clear that they even upregulate ACE2 expression or whether increasing ACE2 is beneficial or harmful in patients currently ill with the virus. Therefore, there is no evidence-based rationale for discontinuing spironolactone to prevent or treat COVID-19. Theoretically though, in terms of androgenic regulation of TMPRSS2, the anti-androgen effect of spironolactone could be beneficial. So, it’s a “dirty” drug, especially in this particular case, because of its dual receptor antagonism (anti-mineralocorticoid and antiandrogen receptor activities). The study of the effects of pure antiandrogens, such as the androgen synthesis inhibitor abiraterone acetate, or antiandrogen receptor compounds such as hydroxyflutamide or enzalutamide, both used in prostate cancer, would likely yield some interesting data regarding the role of androgen-driven TMPRSS2 expression in COVID-a19 infection and outcomes. – by Regina Schaffer

Disclosure: Levine reports no relevant financial disclosures.

 

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