Oral Estrogen, Thromboembolic Events and Cardiometabolic Risk in Older vs. Younger Transgender Women Veterans
Authors: Iwamoto Sean J , Janson Marnie T , Grau Laura K , Roberts Samantha C , Moore Troy A , Wierman Margaret E 
Published: May 2021

Abstract
Data support increases in absolute thromboembolic event (TE) risk and worsening of cardiometabolic (CM) risk factors associated with estrogen (E)-based feminizing gender-affirming hormone therapy (GAHT). Few data exist comparing age, E type and CM risk in transgender women (TW) veterans. We conducted a retrospective analysis in TW prescribed E through our local Veterans Health Administration (VHA) between 2014-2019. Rates of TE (venous and arterial) and CM risk factors (hypertension [HTN], hyperlipidemia [HLD], type 2 diabetes mellitus [T2DM], obesity and smoking) were stratified by age (&lt;45 vs. ≥45 years) and oral vs. never-oral E therapy and compared using Fisher’s Exact Tests. We also compared TW rates with those of local men (N=77,514) and women (N=11,918) veterans using Chi-Square and Fisher’s Exact tests. Of 226 veterans with gender dysphoria, 130 identified as TW and 100 used VHA-prescribed E (&lt;45 years: N=54, ≥45 years: N=46). Only 9 TW (9%) had a history of TE (55.6% venous: 4 deep venous thrombosis +/- pulmonary embolism, 1 superficial thrombophlebitis; 44.4% arterial: 2 myocardial infarction, 2 ischemic stroke). Of the 7 TW with documented age at TE (median: 67 years, range: 33-80) and duration of E prior to TE (median: 5 years, range: 0-22), 4 were on E at the time of TE (2 oral estradiol, 1 conjugated Es, 1 injectable), 2 discontinued E 1-2 years prior to TE, and 1 unknown. Age and HTN were predictors of TE (P&lt;0.01) in univariate logistic regressions. Smoking history, body mass index (BMI) and oral E were not. Odds of TE were 10% higher (95% CI: 2-19%; P&lt;0.05) for every 1-year of any E therapy and 9% higher (95% CI: 3-16%; P&lt;0.01) for every 1-year increase in age at E initiation. TW ≥45 years had higher rates of CM risk including T2DM, 23.9%, HTN, 52.2%, and HLD, 54.3%, than TW &lt;45 years (5.6%, 16.7% and 20.4%, respectively). Obesity rates were similar between age groups (&lt;45 years: 53.7%; ≥45 years: 52.2%). Among TW with oral E, obesity rates were also similar between age groups (&lt;45 years: 54.5%; ≥45 years: 51.4%). Increased levels of LDL-cholesterol, triglycerides, systolic blood pressure (BP), diastolic BP and BMI were observed after any E initiation (P&lt;0.001). These increases remained significant after adjusting for time elapsed between pre-hormone and highest post-hormone values, age at initiation and oral E therapy. In addition, rates of HTN, HLD, obesity and smoking were significantly higher for TW compared to men and women in age-stratified analyses. TW &lt;45 years had a higher rate of T2DM than women (P=0.04) of the same age. TW ≥45 years had higher rates of arterial TE compared to men (p&lt;0.001) and women (P&lt;0.001), and higher rates of venous TE (P=0.02) and T2DM (P=0.01) compared women of the same age. In TW, absolute TE risk was low, but GAHT increased CM risk factors regardless of age and oral E use. Clinicians should consider these findings when discussing risks and benefits of E-based GAHT with TW veterans.