Hormone replacement therapy and COVID-19 outcomes in solid organ transplant recipients compared with the general population

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.

Keywords: COVID-19; SARS-CoV-2; androgens; estrogens; exogenous hormones; hormone replacement therapy; immunity; infection; sex; transplantation.

Figure 1

Cohort derivation. COVID-19, coronavirus disease 2019; HIV, human immunodeficiency virus; HRT, hormone replacement therapy; ISC, immunosuppressed/immunocompromised; MS, multiple sclerosis; SARS-CoV, severe acute respiratory syndrome coronavirus; SOT, solid organ transplant.

Figure 2

Event rates in the 90 days post-COVID diagnosis in males and females on exogenous HRT. (A) Males. (B) Females. Numbers above brackets represent P values; ∗P < .001. COVID, coronavirus disease; HRT, hormone replacement therapy; ISC, immunocompromised/immunosuppressed; SOT, solid organ transplant.

Figure 3

Adjusted risk of HRT (testosterone in males; estrogen/progesterone in females) on 90-day outcomes after COVID-19 diagnosis in (A) the nonimmunosuppressed general population and (B) solid organ transplant recipients. AKI, acute kidney injury; COVID-19, coronavirus disease 2019; HR, hazard ratio; HRT, hormone replacement therapy; MACE, major adverse cardiac event; MARCE, major adverse renal or cardiac event; OR, odds ratio; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2. ∗Odds ratio, ∗∗Adjusted for age, sex, race, time since transplant, type of organ transplant (kidney, liver, heart, lung, multiorgan), comorbidities (chronic kidney disease, hypertension, diabetes, chronic obstructive pulmonary disease/asthma, cancer, coronary artery disease, congestive heart failure, peripheral vascular disease, liver disease, and obesity [body mass index >30 kg/m²]), immunosuppression (antithymocyte globulin induction, basiliximab induction, and maintenance therapy with prednisone, tacrolimus, cyclosporine, or mycophenolic acid), prior COVID-19 vaccination status, and SARS-CoV-2 variant dominance period.