Adolescent cardiovascular-kidney-metabolic health and estrogen exposure: A cross-sex, gender-inclusive cohort analysis

Abstract While emerging evidence demonstrate the risk of cardiovascular-kidney-metabolic (CKM) syndrome in aging population, these risks remain understudied in adolescents. The physiological demands of puberty and hormonal changes during adolescence may lead to sex-specific susceptibilities to CKM conditions. Additionally, the rising use of exogenous estrogen in this age group, either as hormonal contraceptives in cisgender females (Cis-F) or as gender-affirming therapy in transgender females (Trans-F), may further modulate CKM risk. Therefore, the aim of the current study was to investigate whether biological sex influences CKM risk in adolescents, and whether exogenous estrogen exposure differentially affects these risks in Cis-F and Trans-F individuals. We conducted a retrospective cohort study using the TriNetX de-identified electronic health record network, including data on ~150 million patients from ~106 healthcare organizations worldwide. Adolescents aged 11–21 years were identified in database between June 2015 to June 2025 and categorized into four cohorts: Cis-Female without estrogen exposure [Cis-F(–)E, n=4,282,287], Cis-F with estrogen exposure [Cis-F(+)E, n=1,000,427], Trans-F with estrogen exposure [Trans-F(+)E, n=9,009], and Cis-M without estrogen exposure [Cis-M(–)E, n=4,430,826]. For studying effect of biological sex, the index event was age at healthcare interaction for Cis-F(–)E and Cis-M(–)E. For other analysis, estrogen initiation for Cis-F(+)E and Trans-F(+)E was considered index event and used to match control cohorts, i.e. Cis-F(-)E and Cis-M(-)E respectively. Propensity score matching was applied for every analysis to control for age, baseline comorbidities, and use of antiplatelets/anticoagulants. We performed 3 analysis comparing CKM outcomes between, i) Cis-F(–)E and Cis-M(–)E, ii) Cis-F(+)E and Cis-F(–)E, and Trans-F(+)E and Cis-M. Data were collected for absolute risks and risk ratios with confidence interval (RR, CI) for cardiovascular outcomes [hypertension (HTN), atrial fibrillation (AF), coronary artery disease (CAD), heart failure (HF), deep vein thrombosis (DVT), pulmonary embolism (PE), stroke, and myocardial infarction (MI)], renal outcomes [acute kidney failure (AKF), chronic kidney disease (CKD), and end-stage renal disease (ESRD)], and metabolic outcomes [Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD), hyperlipidemia (HLD), diabetes mellitus (DM), and overweight/obesity]. To examine effect of biological sex, a total of 3,976,434, 3,973,995, 3,975,275 and 3,951,988 Cis-F were matched 1:1 with Cis-M to assess risks for cardiovascular, thrombotic, kidney, and metabolic outcomes, respectively. For comparing risk due to estrogen use in Cis-F, a total of 1,000,427 were matched 1:1 for cardiovascular and thrombotic outcomes, and 1,000,424 and 1,000,422 for renal and metabolic outcomes, respectively. Finally, a total of 9,009 Trans-W was matched 1:1 to Cis-M for all outcomes. Compared to Cis-F(–)E, Cis-M(–)E had significantly higher risk of HTN (RR=1.56), AF (RR=2.06), CAD (RR=1.13), HF (RR=1.40), stroke (RR=1.11), MI (RR=2.24), AKF (RR=1.74), CKD (RR=1.32), ESRD (RR=1.29), MASLD (RR=1.22), HLD (RR=1.44), and DM (RR=1.03), but lower risk for overweight/obesity (RR=0.88) and PE (RR=0.84); DVT showed no significant difference (RR=1.02). Compared to Cis-F(–)E, Cis-F(+)E had significantly increased risk across all outcomes [HTN (RR=1.60), AF (RR=1.67), CAD (RR=1.73), HF (RR=1.16), DVT (RR=1.35), PE (RR=1.58), stroke (RR=1.16), MI (RR=1.52), AKF (RR=1.49), CKD (RR=1.27), MASLD (RR=2.17), HLD (RR=2.01), DM (RR=1.29), and overweight/obesity (RR=1.86)], except for ESRD (RR=0.94). In Trans-F(+)E compared to Cis-M(–)E, a significant increase in the risk was only observed for metabolic outcomes [MASLD (RR=2.19), HLD (RR=1.34), DM (RR=1.29), and overweight/obesity (RR=1.51)]. Our findings highlight increased risk for CKM conditions in male compared to female adolescents even after adjusting for baseline comorbidities. However, the risk for all CKM conditions in female were increased significantly with estrogen use. Furthermore, among Trans-F individuals, estrogen use primarily increased risk of metabolic outcomes when compared to Cis-M. These results underscore the importance of sex- and gender-based risk assessment for CKM conditions specially in the backdrop of estrogen use and support the need for tailored screening and preventive strategies in both cisgender and transgender youth.