Why Do Men With COVID-19 Fare Worse Than Women?
Men are at higher risk of poor outcomes with Coronavirus
In the first few months of its existence, much has been learned about the behavior of SARS-CoV-2, the virus that causes COVID-19. The deadly respiratory virus exhibits many unique features including, for example, its incubation period, how it travels through the air, and the age of the people it harms most. Another noteworthy pattern of SARS-CoV-2 is that it appears to affect men more severely and at a higher fatality rate than women. Thus far the mechanism of this phenomenon has not been well described, but a study published on May 7th in the Annals of Oncology by Montopoli, et al. sheds light on the issue and offers hope for a new avenue of treating COVID-19.
The retrospective cohort study was conducted using data from 9280 lab-confirmed SARS-CoV-2 positive patients from 68 hospitals in the Veneto region of Italy. Key findings show that patients receiving anti-androgen medications for prostate cancer had a 4-fold lower risk of developing SARS-CoV-2 infection than those patients with prostate cancer not on such medications. In addition, that same cohort of patients with prostate cancer treated with anti-androgens demonstrated a 5-fold lower risk for SARS-CoV-2 infection compared to patients with any other type of cancer.
To understand the implications of this study let’s dive a little deeper into the cellular mechanisms involved. Before your eyes glaze over, I promise to keep this as simple as possible mainly because I’m not a molecular cell biologist. I’m just a simple country doctor. There’s also a cool diagram below that I found helpful.
You may have heard that SARS-CoV-2 can attach to a cell surface protein called angiotensin-converting enzyme 2 (ACE2) on the cells lining the human respiratory tract. Well, there is another human protein called TMPRSS2 (in purple below) that assists the virus with entering the cell. TMPRSS2 is regulated by androgen hormones in the body. More androgens lead to higher TMPRSS2 expression which, in turn, is thought to allow for easier entry of SARS-CoV-2 into the cells of the lung. Men generally have higher androgen levels than women and are thus predisposed to easer cell-entry and replication of the virus resulting in the higher severity of COVID-19 seen in males.
‘See, Honey, there really is a reason for the man flu!’
Well, sort of. The term ‘man flu’ has certainly taken hold in the modern lexicon such that it has even made its way into medical journals. Dr. Kyle Sue, the author of a 2017 article from The BMJ titled, The science behind “man flu”, sarcastically quipped, “Perhaps now is the time for male-friendly spaces, equipped with enormous televisions and reclining chairs, to be set up where men can recover from the debilitating effects of man flu in safety and comfort.” Yeah, I’ll try explaining that to my wife (who birthed both our children with no more analgesia than a tablet of Tylenol) next time I come down with the flu. Who’s with me? Anyone? (cricket chirps)
Getting back to the issue at hand, I will gladly be the umpteenth person to say that, although there are similarities, COVID-19 is not the same thing as influenza. If there is a mortality difference between men and women with influenza it is debatable and probably minimal. However, as mentioned above, there does appear to be a significant difference in outcomes of COVID-19 based on gender. The work of Montopoli, et al. bears that out with the male to female ratio of hospitalizations, ICU admissions, and deaths in the study being 60/40, 78/22, and 62/38, respectively.
Here’s where it gets even more interesting (at least to us nerds like you and me). Androgen deprivation therapy (ADT) is sometimes used to treat prostate cancer. Examples of drugs used for ADT include leuprolide, goserelin, nilutamide, and flutamide. These drugs affect hormone signaling pathways in the body decreasing the activity of testosterone and other androgens. In addition to their effect on prostate cancer, ADTs are thought to have activity in the lung and can decrease levels of TMPRSS2. So, does that mean ADTs can decrease the risk of COVID-19? That’s the possibility the authors of this study are raising.
Too good to be true?
So, let’s talk about some limitations of the study — of which there are many. Although ethnicity was not mentioned in the study, it would be safe to say it was performed in a geographically homogenous population. In addition, the study was retrospective, rather than prospective, and the most noteworthy outcome occurred among patients with prostate cancer — an important finding but not necessarily translatable to the general population.
I think the most important statistical issue to note is the difference between relative and absolute risk. Among patients with prostate cancer the study suggests a 75% relative reduction in the risk of COVID-19. That sounds really good until it is compared to the absolute risk reduction (ARR). The ARR is calculated by subtracting the percentage of disease in the treatment group (in this case, the treatment was ADT) from the percentage of disease in the control group (i.e. the patients with prostate cancer not on ADT). So, the ARR is 0.307% - 0.076% = 0.23%. Why doesn't that sound as impressive?
The absolute risk reduction is such a small value because of the low measured prevalence of disease. Even though COVID-19 obviously hit Italy extremely hard, this study documents that only 4,532 of the 2.4 million males in the Veneto region tested positive for SARS-CoV-2. The prevalence of COVID-19 was presumably higher than this number would indicate because, in all likelihood, only the sickest patients were being tested during the timeframe in which the study occurred. Regardless, the p-value of 0.0059 suggests that the treatment effect of ADT was not a chance occurrence.
Despite these limitations, the study does generate some excitement for a novel treatment strategy. If ADT’s could be studied in a broader patient population and are found to have a true relative risk reduction of 75%, it would be groundbreaking. For comparison, Remdesivir, the most effective drug against COVID-19 studied so far, has demonstrated the ability to reduce recovery time by a median of 4 days. However, even in its most glowing clinical trial Remdesivir failed to show a statistically significant survival benefit. In contrast, Montopoli, et al. boast zero deaths in their treatment group compared to eighteen in the control group.
Clearly, much remains to be studied on the effects of anti-androgens in patients with COVID-19, but studies like this one continue to foster hope about future treatment. Thank you for reading. Take care, stay positive, and stay safe!