By taking a lesson from prostate cancer, researchers now have a promising lead on a treatment for COVID-19.
Two proteins, ACE2 and TMPRSS2, help the coronavirus gain entry and replicate within cells. TMPRSS2 is well-known to Arul Chinnaiyan, M.D., Ph.D. His lab discovered that TMPRSS2 fuses with the ETS gene to drive more than half of all prostate cancers. They also knew that TMPRSS2 was regulated by the androgen receptor.
So when cancer research shut down in the spring, Chinnaiyan’s lab turned its attention to the coronavirus. With a grant from the National Cancer Institute, the team used its existing knowledge and resources to determine how TMPRSS2 was regulated in the lungs.
They found that, just like in prostate cancer, TMPRSS2 is regulated by the androgen receptor in the lungs. And notably, blocking the androgen receptor led to lower expression of TMPRSS2 as well as ACE2, which led to decreased coronavirus infection in mice and cellular models. Results are published in PNAS.
“What’s especially appealing about this is that anti-androgen treatments are already FDA-approved. This opens the door to look at these drugs, which we know work in prostate cancer, as potential COVID-19 treatments,” says Chinnaiyan, director of the Michigan Center for Translational Pathology.
Using cell lines infected with SARS-CoV-2, the virus that causes COVID-19, researchers found that inhibitors of androgen receptor, including enzalutamide, apalutamide and darolutamide, inhibited the coronavirus infection.
They also tested a class of drugs designed to inhibit or degrade BET proteins. BET protein activity is essential for androgen signaling and these drugs are being looked at for prostate cancer. In cell lines infected with coronavirus, the BET inhibitors decreased androgen signaling and inhibited viral infection.
The findings also provide some explanation for observations that COVID-19 affects men more than women.
Researchers looked at human lung tissue and found higher androgen receptor signaling in men than women. They also found androgen signaling was highest in men over 70 and in smokers.
“This explains why elderly men who are smokers are more vulnerable to COVID-19 infection. High androgen receptor signaling allows the virus to gain entry and replicate more easily. This may explain why the disease is often particularly severe in older men,” Chinnaiyan says.
Several clinical trials are underway testing androgen receptor inhibitors as a treatment for COVID-19, and additional trials are being developed to look at BET inhibitors.
Sex hormones and the immune system
Sex hormones have a considerable effect on both regulation and immune response , as androgen receptors are effective in adaptive and innate immunity by using macrophages and neutrophils which are firmly related to coronavirus in the lungs .
Androgens can also cause severe infection in men by affecting the immune response. It seems that the mechanism is through increasing blood neutrophils count and function, increasing the interleukin production (IL-1b, IL-10, IL-2), transforming growth factor-b (TGF-b) by immune cells, and reducing the antibody response to the infectious conditions .
This issue becomes more important as the cytokine storm syndrome is seen in patients with severe COVID-19 and neutrophils are responsible for this event .
In addition, a German retrospective study reported elevated testosterone levels in most females (60%) with the COVID-19 disease, and also mentioned a positive correlation between testosterone levels and pro-inflammatory cytokines in female COVID-19 patients .
In counterpoint to the androgens, estrogen as a feminine hormone enhances immunological markers and response. This hormone links to T-cell proliferation. Moreover, X chromosome-linked genes are known to increase the female’s immune response .
Thus, during an infection, women show a stronger response. So, this response can cause faster removal of the infectious agent and assists immunopathological issues. These sex-related differences in the immune response could affect viral infections in terms of the prevalence, severity, and outcome . Therefore, the severity of the COVID-19 disease reported in males can be justified.
Biology of androgens and COVID-19
There are several androgen pathways in COVID-19 infection. One of them is the transmembrane protease, serine 2 (TMPRSS2) gene that is expressed principally in the adult prostate , and localized and metastatic prostate cancers [25,26]. This gene is also expressed in other tissues such as the colon, small intestine, pancreas, kidney, lung, and liver . The target organs of TMPRSS2 expression for COVID-19 are the lungs, liver, and kidneys .
The transcription of the TMPRSS2 gene is regulated by the androgen receptor . This feature revealed how oncogene is under the control of the androgen receptor . In addition to androgens, TMPRSS2 expression could be increased by other steroid hormones such as estrogen and glucocorticoids and this occurs by attaching relevant nuclear receptors to responsive elements (such as ERE and GRE) in the gene promoter, so the observation of severe disease in some female patients can be comprehended .
The other is angiotensin-converting enzyme 2 (ACE-2) which is a protein enzyme that adheres to the viral spike and acts as a functional receptor for the coronavirus . In fact, male sex hormones affect ACE-2 passageway and facilitate SARS-CoV-2 entry into host cells . It has been shown that lowering androgen hormones, reduced the ACE-2 activity (probably by decreased expression of ACE-2) .
The ACE-2 expression is very similar to TMPRSS2 and is expressed in different tissues such as the lungs, liver, kidneys, and prostate . The high ACE-2 expression is shown widely in the female reproductive system . In addition, ACE-2, like TMPRSS2, is regulated by the androgen receptor. Thus, sex-related differences in the severity and mortality of COVID-19 disease could be explained through the androgen-mediated expression of ACE-2 and TMPRSS2 .
Genetic factors are another item that influences the geographical spread of COVID-19. The hydroxy-delta-5-steroid dehydrogenase, 3 beta- and steroid delta-isomerase 1)HSD3B1 ( gene is an example of this factor, which is involved in the androgen metabolism.
The most frequent of HSD3B1 allele is found in the general population of Italy and Spain . This may explain why androgenic alopecia was reported in Spain for the first time during the outbreak of COVID-19 .
The other important factor in the severe form of the disease in men is androgen sensitivity as the location of the androgen receptor gene is on the X chromosome. Androgen sensitivity is related to the CAG repeat length polymorphisms in the androgen receptor gene, thus shorter CAG repeat length makes men more prone to symptoms such as androgenic hair loss, acne, and oily skin.
In the same way, increased severity and mortality from COVID-19 disease in male patients could be correlated with shorter CAG replications in the androgen receptor gene. The imbalances of mortality rate, which has been seen in African-American patients with COVID-19 can support this theory .
COVID-19 drugs and hair loss
Multiple medications have been used in the management of the COVID-19 infection, which includes antivirals, antimalarial, ACE-2 inhibitor, immunosuppressive agents, TMPRSS2 inhibitors, and anti-parasitic drugs . As we all know, medications can have side effects that hair loss is one of these side effects .
According to the results of a review study on cutaneous side-effects of anti-COVID-19 medicines, alopecia is the side-effect of medicines such as colchicine, ribavirin, interferons, antiretroviral drugs, anti-malarial drugs (including chloroquine and hydroxychloroquine) and, checkpoints inhibitors. IVIG (intravenous immunoglobulin) treatments are also accompanied alopecia. Moreover, hair loss is one of the side-effects of nitazoxanide , azithromycin, lopinavir, and ritonavir .
Furthermore, the results of a case report study of a 35-year-old woman in Baghdad reported sudden excessive hair loss ten days after hospitalization due to COVID-19 disease. This hair loss was related to the COVID-19 anagen effluvium, probably due to the excessive inflammatory response associated with the infection .
The other type of hair loss that may be seen in COVID-19 condition is telogen effluvium, which is recognized by sporadic hair loss, and the hair quickly enters the telogen stage due to conditions such as systemic disorders, stressful situations, medications, nutrient deficiencies, and surgeries .
The results of an observational/cross-sectional study on 563 participants during the COVID-19 pandemic, telogen effluvium were observed in 27.9% of the participants .
reference link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7557269/
More information: Yuanyuan Qiao et al, Targeting transcriptional regulation of SARS-CoV-2 entry factors ACE2 and TMPRSS2, Proceedings of the National Academy of Sciences (2020). DOI: 10.1073/pnas.2021450118