Dr Wambier on What Androgens Might Have to do With COVID-19

Carlos Wambier, MD, with Andy Goren, MD, published “What Does Androgenetic Alopecia Have to do with COVID-19?” in the Dermatologic Therapy journal.¹ In this podcast, Dr Wambier discusses the potential role of androgens in SARS-CoV-2 infection risk and severity, as well as his research in health care prophylaxis.

Since recording this interview, 3 other adolescents have died. On March 30, 2020, the youngest child to die in Europe was a boy, 14 years of age, who had psoriasis.¹ Following his death, 2 other children, one female and one male at ages 12 and 13 years, respectively, died in Belgium and the UK.^2,3 On April 21, 2020, a girl, 5 years of age, was reported to have died from COVID-19 complications in the United States.⁴ In addition, a Morbidity and Mortality Report from the Centers for Disease Control and Prevention in the United States from February 12 through April 2, 2020, reported 3 deaths among pediatric cases, but there is an ongoing review to confirm whether COVID-19 was the likely cause of death.⁵

References:

1. Goren A, McCoy J, Wambier CG, et al. What does androgenetic alopecia have to do with COVID‐19? An insight into a potential new therapy [published online April 1, 2020]. Dermatol Ther. doi:10.1111/dth.13365

2. Grown L. 14-year-old Protuguese boy becomes Europe’s youngest coronavirus victim. New York Post. published March 30, 2020. https://nypost.com/2020/03/30/14-year-old-portuguese-boy-becomes-europes-youngest-coronavirus-victim/. Accessed April 23, 2020.

3. Sandford A. Two COVID-19 infected children, aged 12 and 13, die in Belgium and UK. Updated January 4, 2020. https://www.euronews.com/2020/03/31/coronavirus-doctors-devastated-as-covid-19-claims-life-of-12-year-old-girl-in-belgium. Accessed April 23, 2020.

4. Jane C, Elmer V. ‘The numbers are low until it’s your child’: The coronavirus can be deadly for children, too. Published April 21, 2020. https://www.washingtonpost.com/health/the-numbers-are-low-until-its-your-child-the-coronavirus-can-be-deadly-for-children-too/2020/04/21/0f5ab28a-83e9-11ea-ae26-989cfce1c7c7_story.html. Accessed April 23, 2020.

5. Center for Disease Control and Prevention. Coronavirus Disease 2019 in children — United States, February 12–April 2, 2020. MMWR Morb Mortal Wkly Rep. 2020;69:422–426. doi:10.15585/mmwr.mm6914e4

Transcript

Melissa: Hello, everyone. I’m Melissa, associate editor of The Dermatologist. Today, we will be speaking with Dr Wambier, director of cosmetic dermatology research at Brown University’s Alpert School of Medicine.

You recently published, “What Does Androgenetic Alopecia Have to do with COVID-19?” with Dr Andy Goren, Chief Medical Officer at Applied Biology. What made you decide to start doing research on COVID-19?

Dr Wambier: Well, first of all, the priorities have changed during the pandemic. I had to stop my cosmetic dermatology practice, and I got involved in the COVID-19 research with our team of researchers at Brown. I’m involved in this research about prophylaxis in healthcare workers.

And then, I was researching about COVID-19, and it something caught my attention that this protease that the virus uses to enter the cells, it is a protease that we usually think of when we think of prostate cancer or prostate benign hyperplasia, and it is a protease that is produced by a binding type that connects the androgen receptor.

At first, we were researching about androgenetic alopecia, relating that with polymorphisms of the androgen receptor gene, and I was discussing that with my friend, Andy Goren. And, we started looking at some proteins that the androgen receptor promotes, and it caught our attention that this TMPRSS2, which is the protease that the SARS-CoV-2 uses to enter our cells, it is one of the proteins that is expressed by the androgen receptor. We thought we could contribute to the current pandemic by giving those insights.

Melissa: Could you elaborate further on this mechanism of action between androgenetic receptors and SARS-CoV-2?

Dr Wambier: Yes, I’ll explain. The virus, before it’s able to infect the cell, it needs to have its spikes primed by a protease. The cell surface has this very special protease, which is called the TMPRSS2 which is this protease that primes the spikes of the coronavirus so that the spikes are able to fit into a receptor, which is the ACE2 receptor, the angiotensin-converting enzyme 2, which is another protein in the surface of the cells.

Also, we know that the protease, the TMPRSS2, it also primes the ACE2 receptor. So, it makes the ACE2 receptor more in the right shape, so the primed spikes can bind to the receptor even stronger.

Anyway, it seems that the protease, the TMPRSS2, is the main key to the infection and this protease is only produced through androgen hormones. So, we need androgen hormones to bind to the androgen receptor so the activated androgen receptor can produce or transcribe the gene of the TMPRSS2. This protease is only produced if we have androgen hormones binding to the androgen receptor.

Melissa: What are the different kinds of research that you’re working on now?

Dr Wambier: Now, I’m doing research on healthcare workers’ prophylaxis regarding COVID-19. We are testing some drugs that are not related to androgen inhibition. We are testing probably quercetin and also hydroxychloroquine. We are still working on our project here. The trial will probably start in mid-April now. And, I’m also working on a project to verify the male vulnerability to COVID-19, so we’re checking phenotype. All the subjects, they might present hair loss or acne or other signs of androgen receptor activation, like oily skin, oily hair, acne.

So, I’m engaged in two researches. One in healthcare workers in a prophylaxis trial for COVID-19, and I’m also engaged in research to verify vulnerability to the infection. We’re looking at a lot of variables, not only androgen receptor-related.

Melissa: Could you elaborate further on which therapies for prophylaxis among healthcare workers you’re studying?

Dr Wambier: We’re testing some drugs that might prevent, we still don’t know if they can prevent the infection with COVID-19. We’re testing one substance that is derived from plants, which is called isoquercetin, and another one which will probably be hydroxychloroquine.

But since, it’s been very hard to get hydroxychloroquine because probably a lot of hospitals are using it and also there’s patients that actually need hydroxychloroquine for their rheumatic diseases, so we’ll probably test another medication that has viral action, probably famciclovir.

Melissa: Why did you and Dr Goren decide to examine the role of androgens in SARS-CoV-2?

Dr Wambier: Dr Goren and I, we had these conversations about therapeutic or diagnostic tests for androgenic alopecia, and one of the things that we usually talked was the androgen receptor polymorphism. It seems that the gene that produces the androgen receptor, there are some repeats in the nucleotides, the C-A-G repeats, which are intrinsically related to the trait of the androgen receptor, or how the androgen receptor is able to bind to the DNA to promote the expression of some proteins.

We’ve been talking a lot about that in the past month and having insights about new protein targets to the androgen receptor that we could look for to avoid the genetic disposition to cause baldness. And it was interesting that we came up to the point that we started researching COVID-19 instead of looking for androgenetic alopecia because of the pandemic, we were so focused on COVID-19 now. All the needles are pointed to COVID-19 that we just started to think of how we could contribute and help the healthcare workers and also everyone who has been infected worldwide.

And then, we got this information that was very interesting. It’s a brand-new insight regarding the disease, which we think that SARS-CoV-2 infection is mediated by androgen, and we wanted to bring this to the science and we got this letter out to try to bring this awareness so the new epidemiologic literature, or the new trials that are going on, or the new data that is published, that they at least state if the severe patients were males or females, or if they had another sign or disease that are related to hyper-androgenic expression.

Melissa: Based on those insights, are patients with androgenetic alopecia or other androgenetic disorders at risk for severe COVID-19?

Dr Wambier: Yes, we think that it’s very possible because the androgen receptor activity is intrinsically related to the genetics of the androgen receptor itself. The androgen receptor, it is inside a locus in the X chromosome, so male patients, they only have one gene, while female patients, they have two genes of androgen receptors. The male patients, since they have only one gene of the androgen receptor, the only receptor they have is either very active or not very active, and we know that the very active receptor causes baldness. So, we know that the patients that start to shed hair and lose hair when they’re about 20, sometimes even earlier, they have this very active androgen receptor. This androgen receptor produces a lot of proteins, and one of the proteins is a protease that the virus uses to enter our cells. So, it makes a lot of sense. However, we still need epidemiologic studies to verify this genetic effect.

Sometimes these patients, who knows? Let’s imagine that they have another protein that protects them from the virus. Who knows? But, at least we know that the protease that the virus uses to enter our cells, it is produced by the androgen receptor activation.

Thinking about the androgens mediating the disease, we think that the patients that have more androgens, they are more vulnerable. How would we know that someone has more androgens?

The hormones, they change our body. Usually, people have more oily skin and they also have more acne. Probably they have acne scars because they always had a lot of androgens all their lives. The facial hair has a high density, and they have very thick hair on the face, sometimes on the chest, on the back.

The scalp hair, it is reduced by the androgen hormones. What happens is that people that have a lot of androgens, as they age, they become bald, or at least they have low-density of hair on the scalp, and also, more oily hair.

So, we really think people that have this phenotype, they might be more vulnerable to the virus.

Melissa: Would this also include other conditions like prostate gland enlargement among men, or polycystic ovarian syndrome among women?

Dr Wambier: Yes. Benign prostate enlargement is caused by a very potent androgen hormone, DHT. We know that everyone has some levels of DHT, including women. Women that develop polycystic ovarian syndrome, they can have extremely high levels of androgens, testosterone, and even DHT. They are indeed at risk of having more protease and having more infection with the virus.

Polycystic ovarian syndrome, it’s also related with weight gain and metabolic syndrome. Usually, these females, they have increased blood pressure and they have a higher risk of diabetes.

It seems during the epidemic that these are the kind of patients that the virus likes. I think it would be interesting to try to control the hormones in the subjects, both for their health, because no women that I know would like to have a lot of facial hair or hair loss on the scalp, but also it may even protect from the virus. So, I think that’s a very good question.

The same thing about men. I don’t know any men who would like to have an enlarged prostate so that they cannot urinate. Someone who has any symptoms regarding their prostate should look for a urologist to start medication that reduces DHT levels to prevent further enlargement of the prostate. But it still needs epidemiologic study to confirm that hypothesis.

Melissa: So, if this is confirmed, what are the implications of this for risk stratification and testing and even treatment?

Dr Wambier: If this hypothesis is confirmed that means people that have this expression of more androgen phenotype, they should be regarded as someone with a high risk for infection that means someone who can have severe disease.

So, they should protect themselves even more than usual.  For example, avoiding working in the ICU or in the emergency department, or in the frontline against COVID-19 because if they get infected, they could get this extremely severe disease and die.

Also, if this is true, they can start prophylaxis medications to try to reduce their androgen expressions with medications that we usually use to treat baldness or acne in dermatology, such as spironolactone or finasteride, dutasteride, and there is this other androgen-blocking agent called cyproterone acetate.

So, there are many things that can be done. However, everything needs validation and clinical trials. But it would be very interesting to verify first of all if the patients are more vulnerable. And, we need more reports and literature. Some reports, they don’t even report their data based on male or female percentage of oxygen requirement, or intubation, or ICU admission, and this is extremely important.

Anyway, I think this insight can bring new targets for therapy to try to suppress the androgen expression of the protease along with other treatments that might be implemented with antivirals and the prophylaxis medications and everything.

Melissa: Your article listed several drugs, spironolactone, finasteride, etc. Basically, these would be drugs that could improve disease outcomes for a patient who has higher androgen levels and COVID-19 virus? Is that the theory?

Dr Wambier: The strongest androgen hormone we have in our bodies is called DHT, dihydrotestosterone. It is a testosterone molecule that was modified by this enzyme. This DHT is the molecule that binds to the androgen receptor, and it is the molecule that causes more androgen receptor-mediated proteins to be produced.

We know we can reduce the amount of DHT being produced by many medications such as dutasteride, finasteride. And we can also try to block the androgen receptor itself with another androgen hormone that binds to the androgen receptor with a weak affinity or…that blocks its action. There are many drugs.

And so, we think that by stopping the production of the protease, we might impact two things. First of all, the amount of virus that is spread to the environment because you need the cells to be infected for a virus to come out through the mouth or through the gut, anything. So, we think by blocking this protease, we’ll have less virus in the environment. And also, in the individual, the number of cells that are infected can be reduced if you reduce the expression of this protease. So, it might even protect the patient and might also contribute to less spread of the disease. It’s something that I think needs to be tested.

Melissa: You also mention isotretinoin. How does this therapy relate to androgen, seeing as it’s a retinoid?

Dr Wambier: Isotretinoin is the medication that we use acne. It is a retinoid, so we know it reduces the amount of sebum that is produced in the follicles of the face and also on the body. But also, it is interesting that isotretinoin, it is known to reduce the levels of DHT in the body. So, at very low doses, isotretinoin, by unknown mechanisms, we know reduces DHT levels both in male and female patients.

It is a medication that dermatologists usually use. There are all these risks regarding the possibility of someone become pregnant while they’re on the treatment. But, it is a mild medication, and it seems to have anti-inflammatory effects. Also, it suppresses some of the androgen hormones. That’s why we included it in the list, even though it’s not a hormone, or specifically an androgen-blocking agent.

Melissa: At this time, do you have any recommendations for patients with androgenetic alopecia during the pandemic?

Dr Wambier: Yes. I would say, first of all, if they were prescribed a medication to reduce DHT, they should take it exactly how it was prescribed. We know that some patients, they were prescribed finasteride or even dutasteride off-label and they don’t take it on a regular basis. They take it sometimes, or when they see hair shedding, they go back and take more medication. So, I would say during the epidemics, it is wise to take it regularly like it was prescribed by your physician.

The same thing for spironolactone. These medications are prescribed by the dermatologists because of the androgenic phenotype. So, when we see a patient that has male-pattern hair loss, or a lot of facial hair and they want to reduce the facial hair, we use these medications to reduce the androgen expression.

So that might be interesting during the pandemic, especially if you had the prescription from a dermatologist because that means that he already saw the phenotype, that you expressed a lot of androgens.

Melissa: So, if there is a connection to this, is this going to be for both men and women?

Dr Wambier: I always tell my female patients that it’s very easy to control their hormones, while in men it’s extremely hard. Men produce a lot of hormones by the testes, while in the female patients, we can use these medications that completely inhibit androgen, which is something we usually don’t do in men, otherwise, men would have gynecomastia. They would start to grow breasts. Also, it modifies a lot of the biology of men.

But personally, if that is done, there is this chemical castration, that is done on some patients that have cancer in which the cancer grows with male hormones. There are many men who take these very strong medications. I would say that it’s more important to be alive than to keep the male hormones, but we need more research before we start implementing this therapy on a large scale. We have to be very careful.

Melissa: Right. Are there any other important considerations to keep in mind as more research is coming out?

Dr Wambier: I think during the pandemic, it’s very important for the military and also the police to remain active. We know that many of the military and also the police, they are very well-trained, male, strong people who are trained to fight, trained to have endurance. And we know that some men, they take anabolic hormone, even in the military or some athletes do. I think during this time, it’s very prudent to avoid taking androgen medication and wait for the pandemic to stop, maybe in two or three months, to continue any androgen prescriptions.

So, I think we have to try to keep safe during the pandemic, try to follow all the guidelines, the local guidelines, and also, the federal guidelines regarding everything you can do to avoid being infected by the virus and also to avoid spreading the virus in the community. I think everything we can do that is in our reach to try to, at least for the individual to become less vulnerable to severe disease, we have to try to do everything we can.

Melissa: What is the next step you’re looking at doing in your research, for androgen specifically?

Dr Wambier: Another thing that we’ve been thinking about testing in trials is the genetic profile of the patients to try to verify if there is any genetic variation that causes more vulnerability to the virus. The main candidate for vulnerability that we’re looking for is the androgen receptor. We’re also looking at other proteins to include in the genetic tests, such as the ACE2 protein, which is also produced in the chromosome X. But we’re trying to look at strategies to try to identify subjects that are more vulnerable.

In the same way that now we’re trying to have a test that checks if you were already infected by COVID-19 and if you’re immune by hemoglobulin levels, IGG levels, I think a genetic test would be very appropriate if the test is validated to verify if someone has a chance of having severe COVID-19 infection.

So, we could look for strategies to make the more vulnerable people stay at home or do a job that is not exposed to many people that might be contaminated with the virus.

Melissa: Any final thoughts you’d like to leave our audience with?

Dr Wambier: It’d be very interesting to disseminate this information because you know we’re really thinking that this virus, it is mediated by male hormones. And, we see no kids.

Kids, before they are 10-year-olds, they basically have no male hormones, no androgens. So, they’re very resistant to the disease. One would think that it’s just because kids are very tough, they have a lot of reserve. Then you say, why are kids that are 14-year-olds dying? Puberty. That’s the only thing that changed. They are still healthy. They still have a lot of reserve. But, kids that are 14-year-olds, they are dying while the little kids that are 6, they don’t die. And that has to do with hormones. I think that will completely change the way we think of the disease.

Melissa: That’s very interesting. Thank you for speaking with us today, Dr Wambier. If you’re interested in learning more about Dr Wambier’s research, please leave a comment in the feedback box below, or email us at dermeditor@hmpglobal.com.