Transwomen (assigned male at birth and treated with feminizing gender-affirming hormone therapy (f-GAHT) with antiandrogens and estrogens) are reported to develop more cardiovascular disease, especially myocardial infarction with an increased suspicion of atheromatous disease.

Our objective is to understand how f-GAHT may contribute to the development of atherosclerosis. We hypothesize that f-GAHT promotes the development of atherosclerosis by promoting low-grade inflammation and/or modifying lipid metabolism.

We have set up an innovative preclinical transfemale mouse model recapitulating the hormonal status of transwomen. More specifically, C57BL/6 WT male mice are orchidectomized at 3-month end of age, and then exposed to estradiol for 9 weeks through the implantation of estradiol delivering pellets. At 18 weeks of age, mice are sacrificed for histological and gene expression analyses. Transfemale mice were compared with male controls.

In transfemale mice, no relevant effects on circulating inflammation were observed, particularly on leukocyte counts or serum levels of inflammatory cytokines (especially Il-1β, IL-6, IL-17A, Il-18). Hovewer, f-GAHT induced several metabolic changes. First, we found that f-GAHT reduced weight gain and adipocyte size, then we found that f-GAHT altered the lipid profile by lowering HDL levels (P=0.02) and raising LDL levels in transfemale compared to controls. Moreover, f-GAHT causes hepatic steatosis, which also points to a detrimental metabolic context. Notably, these changes were associated with significantly decreased FGF21 serum levels in transfemale mice compared to controls (P=0.03). FGF21 is a hepatokine that plays an important role in the regulation of lipid metabolism notably by downregulating PCSK9 in hepatocytes. Accordingly, we then highlighted a decrease in FGF21 mRNA expression (P=0.022) and an increase in PCSK9 mRNA expression (P=0.0006), known as favourable for the development of atherosclerosis, in the liver of transfemale mice treated with f-GAHT.

F-GAHT in transfemale mice appears to adversely affect lipid metabolism by decreasing FGF21 levels and increasing PCSK9 levels, which could adversely promotes atherosclerosis in tranwomen.