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Significance: Over 1.3 million adults in the U.S. identify as transgender. Transgender women (TW) are individuals born biologically male but identify as a woman. Studies report elevated cardiovascular (CV) risk in TW, yet, whether this is due to gender affirming hormone therapy (GAHT), is unknown. GAHT includes 17β-estradiol (E2) and the anti-androgen (AA), spironolactone, which is also an inhibitor of the renin angiotensin system (RAS). In women, estrogen is associated with protection and downregulation of vasoconstrictor arm of the RAS. However, whether estrogen supplementation in TW plays a similar role is unknown. Further, the average age of participants in TW studies is around 30, limiting insights into GAHT effects on CV risk in older patients. Methods: Data was collected from UMMC’s Research Data Warehouse (RDW), a UMMC-specific clinical database of electronic health records that includes over 1 million de-identified patients spanning from 2013 to 2024 that is exempt from IRB approval. Inclusion criteria included male individuals with a gender dysphoria or transgender diagnosis. TW were stratified across three age groups for further comparisons (<30, 30-50, and >50 years old). Age-matched male hypertensives prescribed spironolactone were used as a control group. Longitudinal data from 1 year prior and 1 year after E2 prescription was used to investigate BP control, changes in lipids, and eGFR. We investigated the role of baseline characteristics on long-term CV risk including body mass index (BMI), presence of comorbidities for chronic kidney disease (CKD), acute kidney injury (AKI), heart failure (HF), type 2 diabetes (T2D), myocardial infarction (MI), hypertension (HTN), and coronary artery disease (CAD). Cox proportional hazards regression models were constructed for incident CKD, AKI, end stage renal disease (ESRD), and HF. Results: A total of 202 males with a diagnosis of transgender or gender dysphoria, of which 97 were taking E2 with 83 taking both E2 and AA were included. BMI and weight significantly increased in TW with E2 therapy (p<0.05). There were no significant changes seen in cholesterol, HDL, LDL, triglycerides, or eGFR after E2. TW less than 30 years of age had a significant fall in BP after E2, however, this was not seen in those >50 years of age following E2 therapy (-9 mmHg vs -1 mmHg, respectively). As expected, TW >50 years of age also had higher prevalence of CKD, AKI, HTN, T2D, MI, and CAD compared to those in the <30 age group. Black race and Medicaid were consistently associated with increased risk of CV risk, while E2 was associated with significantly lower incident CKD, AKI, and HF (0.3, 0.27, 0.07 HR, respectively) when controlling for confounders. However, in TW >50 there was no significant effect of E2 to lower AKI or CKD incidence and actually increased incident ESRD. Conclusion: Our data suggests that E2 therapy in men increases CV protection but may not persist with aging. Funding: T32-HL105324, HL143459, P30GM149404, P20GM104357, P20GM121334, R00MD014738 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.