A three‑month study found that women‑type hormone therapy (high estradiol plus a GnRH analogue to keep testosterone low) boosted insulin sensitivity by about 20%, while testosterone‑only therapy didn’t change it. Changes in blood proteins tied to inflammation, iron handling, and oxidative stress were linked to the insulin improvements.

Women are generally protected against insulin resistance and related comorbidities when compared with men, potentially due to the role of sex hormones. While epidemiological and animal studies suggest that sex hormones may impact insulin sensitivity, studies in humans on the effects of estradiol and testosterone treatment on insulin sensitivity assessed by gold-standard measures remain limited. The molecular mechanisms involved are also not well understood. Therefore, we aimed to investigate changes in insulin sensitivity and associated change in plasma proteome following three months of sex hormone therapy. This prospective, observational study included 29 individuals initiating feminizing (estradiol with gonadotropin-releasing hormone analogue; n=16) or masculinizing (testosterone; n=13) therapy. Measurements at baseline and after three months included insulin sensitivity, assessed via hyperinsulinemic-euglycemic clamp (M-value; adjusted for lean body mass and M/I ratio; M-value adjusted for plasma insulin concentrations), along with plasma proteomics. During feminizing hormone therapy, insulin sensitivity increased (M-value: +23.3%, M/I ratio: +20.2%; p<0.05), whereas during masculinizing hormone therapy, no changes were observed. Of the differentially expressed plasma proteins (49 during feminizing, and 356 during masculinizing hormone therapy), 16 correlated with changes in insulin sensitivity. Several were involved in immunoregulation and inflammation (vascular endothelial growth factor D, 5'-nucleotidase), iron homeostasis and erythropoiesis (hepcidin, transferrin receptor protein 1:cytoplasmic domain), and oxidative stress (superoxide dismutase 3). Feminizing hormone therapy, characterized by high serum estradiol and low serum testosterone concentrations, enhanced insulin sensitivity. These findings highlight the impact of sex hormones on insulin sensitivity and may inform sex-specific precision medicine.