Abstract
Exogenous estrogen is associated with reduced coronavirus disease (COVID) mortality in nonimmunosuppressed/immunocompromised (non-ISC) postmenopausal females. Here, we examined the association of estrogen or testosterone hormone replacement therapy (HRT) with COVID outcomes in solid organ transplant recipients (SOTRs) compared to non-ISC individuals, given known differences in sex-based risk in these populations. SOTRs ≥45 years old with COVID-19 between April 1, 2020 and July 31, 2022 were identified using the National COVID Cohort Collaborative. The association of HRT use in the last 24 months (exogenous systemic estrogens for females; testosterone for males) with major adverse renal or cardiac events in the 90 days post-COVID diagnosis and other secondary outcomes were examined using multivariable Cox proportional hazards models and logistic regression. We repeated these analyses in a non-ISC control group for comparison. Our study included 1135 SOTRs and 43 383 immunocompetent patients on HRT with COVID-19. In non-ISC, HRT use was associated with lower risk of major adverse renal or cardiac events (adjusted hazard ratio [aHR], 0.61; 95% confidence interval [CI], 0.57-0.65 for females; aHR, 0.70; 95% CI, 0.65-0.77 for males) and all secondary outcomes. In SOTR, HRT reduced the risk of acute kidney injury (aHR, 0.79; 95% CI, 0.63-0.98) and mortality (aHR, 0.49; 95% CI, 0.28-0.85) in males with COVID but not in females. The potentially modifying effects of immunosuppression on the benefits of HRT requires further investigation.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1035-1047 |
| Number of pages | 13 |
| Journal | American Journal of Transplantation |
| Volume | 23 |
| Issue number | 7 |
| DOIs | |
| State | Published - Jul 2023 |
Funding
Our study is the largest by several orders of magnitude to examine sex-specific HRT in the general population with COVID-19, with nearly 8000 males on testosterone and over 35 000 females on sex hormone supplementation. It is also the first to examine sex-specific HRT in immunosuppressed SOTRs. Like earlier studies, we show that HRT use is associated with benefit in immunocompetent females with COVID-19. In our primary analysis, we defined HRT use in females as including estrogen and/or progesterone, but the results were nearly identical in a sensitivity analysis excluding women on progesterone monotherapy, suggesting estrogen was likely driving this effect. In addition, we show quite decisively that testosterone supplementation also associates with significant benefit in immunocompetent males with COVID-19. The benefit of HRT in transplanted females was abrogated, although in male SOTRs, HRT remained associated with a lower adjusted risk of AKI and death. Although there are many potential and as yet unknown explanations for this, this finding supports the hypothesis that the benefit of HRT in both males and females is via an immune-mediated pathway that is inhibited in immunosuppressed transplant recipients. This is an important mechanistic discovery that requires further investigation.In conclusion, sex-specific HRT was associated with fewer adverse COVID-19 outcomes in older non-ISC males and females (exogenous testosterone supplementation in males; exogenous estrogen and/or progesterone supplementation in females). The benefit of HRT in SOTRs with COVID was limited to reduced AKI and mortality risk in SOT males in adjusted analyses. This is the largest study to examine sex-specific HRT in males and females with COVID-19 and the first to examine HRT use in SOTRs. We show for the first time that the beneficial effect of HRT in males and females with COVID-19 in the general population is not preserved in immunosuppressed transplant recipients. This provides further support to the hypothesis that the mechanism of benefit from HRT in both male and female patients with SARS-CoV-2 may be immune mediated. This, however, requires further investigation.The project described was supported by the National Institute of General Medical Sciences, U54GM104942-05S2 and U54GM115458. R.B.M. is supported in part by the Dr Dennis Ross fund for Nephrology Research, the Nebraska Foundation. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or the N3C program. The funders had no role in the design or conduct of the study. NCATS and N3C had a role in the review and approval of all results reported in the manuscript for public review. The authors of this manuscript have conflicts of interest to disclose as described by theAmerican Journal of Transplantation. A. Vinson has done consultancy work and received funding for a fellowship project grant through Paladin Labs Inc. R. Mannon reports grant funding from VericiDX, honoraria from Olaris Inc and Chinook Therapeutics and personal fees from Vitaerris as member of the IMAGINE Trial Steering committee, and personal fees from American Journal of Transplantation as Deputy Editor of the journal, outside the submitted work. The project described was supported by the National Institute of General Medical Sciences , U54GM104942-05S2 and U54GM115458 . R.B.M. is supported in part by the Dr Dennis Ross fund for Nephrology Research, the Nebraska Foundation. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or the N3C program. The funders had no role in the design or conduct of the study. NCATS and N3C had a role in the review and approval of all results reported in the manuscript for public review.
Keywords
- COVID-19
- SARS-CoV-2
- androgens
- estrogens
- exogenous hormones
- hormone replacement therapy
- immunity
- infection
- sex
- transplantation
ASJC Scopus subject areas
- Immunology and Allergy
- Transplantation
- Pharmacology (medical)
