Cardiovascular risk of gender-affirming estrogen therapy in a transgender rat model

Abstract

The purpose of this study was to investigate the poorly understood cardiovascular effects of estrogen therapy (ET) in a transgender female (TGF) rat model of hypertension. This study provides novel insights into the potential risks and benefits of gender-affirming hormone therapy (GAHT). Three-month-old male spontaneously hypertensive rats were gonadectomized, and 2 months later were randomly assigned to two different groups: GDX (3-month gonadectomy) and TGF (subcutaneous 10 μg/0.2 ml estradiol cypionate treatment every 4 days for 1 month). An age-matched control group received surgical anesthesia and vehicle (filtered corn oil) injections for the same time period (SHAM). Testosterone deprivation promoted a reduction in cardiac hypertrophy that was canceled by ET without changes in blood pressure. Echocardiographic analysis revealed different types of cardiac remodeling among groups. Isolated left ventricle papillary muscles of GDX exhibited greater stiffness than SHAM or TGF. Contractility of these muscles was reduced in TGF, showing higher response to extracellular calcium increase. An alteration in calcium handling protein expressions was observed. Oxidative stress was higher in GDX myocardium, and ET reversed this effect. Nitric oxide production increased in TGF hearts. White adipose tissue index increased in TGF without affecting body weight, and plasma cholesterol levels followed the same pattern. ET in TGF comprises a complex scenario characterized by high cardiovascular risk, reduced contractility presumably linked to changes in calcium handling proteins, and similar redox status probably due to compensatory mechanisms. Altogether, these findings have implications for long-term cardiovascular health prognosis of transgender patients and emphasize the need for further research to optimize GAHT. KEY MESSAGES: Clinical evidence suggests an increase in cardiovascular risk with GAHT, but evidence is limited. We developed a transgender female animal model that fosters unbiased research. Cardiovascular remodeling in hypertension is strongly related with circulating testosterone even in transgender females. Estrogen therapy in transgender female rats compensates ROS and myocardial distensibility. Estrogen therapy in transgender female rats worsens lipid management and cardiac contractility.