COVID-19 has affected individuals worldwide but how does gender and sex play a role? A recent study by Dr. Amanda Vinson, nephrologist at Nova Scotia Health Authority, explores connections between hormones, gender-specific behaviors, and the severity of COVID-19 outcomes.
Within the general population, men are at a higher risk for poor outcomes after a COVID-19 diagnosis. Both sex (a biological variable) and gender (a sociocultural construct) play a role.
Male Female
**PPE (personal protective equipment)
Biologic sex encompasses a number of factors, including sex hormones; testosterone is a male sex hormone, estrogens and progesterone are female sex hormones. While testosterone is immune suppressing, potentially lowering the effectiveness of a male's immune response, estrogens are immune stimulating, potentially increasing the effectiveness of the immune response in females. Immune response effectiveness is a key player in an individual's ability to recover after a COVID-19 diagnosis.
Beyond biology, gender roles also come into play. At a societal level, men are more likely to be smokers and have been shown to less commonly adhere to behavioral precautions, while women often excel in following guidelines and are more prevalent in frontline healthcare roles. This unique combination of biological and sociocultural variables sets the stage for intriguing exploration of COVID-19 outcomes.
In Dr. Vinson’s earlier research, data from the National COVID Cohort Collaborative (N3C), a secure data enclave that harmonizes millions of patient records across the nation, showed females have a lower risk of major adverse renal or cardiac events (MARCE) compared with males. When considering solid organ transplant (SOT) recipients who are on immunosuppression, these sex and gender factors play less of a role in COVID-19 outcomes. In nearly 11,000 transplant recipients, there was no significant sex difference in risk of MARCE after a COVID-19 diagnosis, unlike the much higher risk in females than males shown in the general population.
The observed COVID-19 outcomes between males and females suggest that sex hormones may be involved. This raised an intriguing question about the effects of sex-specific hormone replacement therapy (HRT) (testosterone in males and estrogens in females) on COVID-19 outcomes, specifically in the general population and the SOT population.
This study compared the outcomes of HRT use in older (>=45 years) males and females both in the general (immunocompetent) and SOT (immunosuppressed) populations using data from the N3C. Of the 2 million general population patients, both males and females using HRT experienced fewer adverse outcomes following a COVID-19 diagnosis than those not using HRT. Of the 29,000 SOT patients, overall, there was very little difference in outcomes for patients using HRT versus not using HRT, regardless of sex. However, in male SOT patients, HRT use was associated with a reduction in both Acute kidney injury (AKI) and mortality after a COVID-19 diagnosis. There was no benefit with HRT use in female SOT patients for any outcome.
These findings persisted in a number of sensitivity analyses including when looking at HRT use in the 6 months before COVID diagnosis (instead of 24 months), restricting the study to patients >=55 years of age, and looking at 30 days outcomes rather than 90 days.
As the largest study by an order of magnitude to examine sex-specific HRT in males and females with COVID-19 and the first to examine HRT use in SOT patients, this study helps develop our understanding of the role sex hormones play in protecting against adverse COVID-19 outcomes. Until now, there was a suggestion of benefit with exogenous estrogen therapy, but the role of exogenous testosterone was unclear. As the first study to demonstrate an attenuation of benefit with HRT in both males and females when immunosuppressed, Dr. Vinson’s study provides further support to the hypothesis that the benefit from HRT in male and female patients with COVID-19 is likely immune mediated. As this was an observational study, future clinical trials examining the use of HRT to mitigate adverse COVID-19 events are warranted, including in the SOT population where patients are at much higher risk than the general population, and there is observational evidence (albeit attenuated from that seen in the general population) of benefit in male patients with COVID-19 who have received testosterone supplementation.
Read the full publication here or view the N3Community Forum YouTube Video here.
