Plasma Proteomics and Insulin Sensitivity Changes with Sex Hormone Therapy

Overview

This study investigated the effects of feminizing and masculinizing hormone therapy on insulin sensitivity and plasma proteome in transgender individuals. Feminizing therapy increased insulin sensitivity significantly, while masculinizing therapy showed no change. Proteomic analysis identified proteins linked to inflammation, iron homeostasis, and oxidative stress correlating with insulin sensitivity changes.

Background

Insulin resistance is a central defect in type 2 diabetes and related diseases, with biological sex influencing insulin sensitivity. Estradiol generally protects women against insulin resistance, while testosterone's effects vary by sex and context. Prior studies on sex hormones and insulin sensitivity often used less precise measures and included confounding medications. Transgender individuals undergoing hormone therapy provide a unique model to study these effects using gold-standard methods and proteomics to elucidate underlying molecular mechanisms.

Data Highlights

Key Findings

• Feminizing hormone therapy (estradiol + GnRH analogue) significantly increased insulin sensitivity by approximately 20-23% after 3 months.
• Masculinizing hormone therapy (testosterone) did not produce significant changes in insulin sensitivity over the same period.
• Proteomic analysis revealed 49 and 356 differentially expressed plasma proteins during feminizing and masculinizing therapies, respectively.
• Sixteen plasma proteins correlated with changes in insulin sensitivity, involving pathways of immunoregulation, inflammation, iron homeostasis, erythropoiesis, and oxidative stress.
• Key proteins included vascular endothelial growth factor D, 5′-nucleotidase, hepcidin, transferrin receptor protein 1, and superoxide dismutase 3.
• Findings suggest estradiol's role in enhancing insulin sensitivity and provide molecular targets for sex-specific metabolic interventions.

Clinical Implications

Clinicians should recognize that feminizing hormone therapy can improve insulin sensitivity, potentially reducing metabolic risk in transgender women. The lack of insulin sensitivity change with masculinizing therapy suggests different metabolic monitoring strategies may be needed. Understanding proteomic changes may guide personalized approaches to managing insulin resistance based on sex hormone status.

Conclusion

Feminizing sex hormone therapy enhances insulin sensitivity in transgender individuals, accompanied by specific plasma proteomic alterations. These results underscore the significant impact of sex hormones on metabolic health and support the development of sex-specific precision medicine strategies.

References

1. Knorr et al. 2024 -- Plasma Proteomics and Insulin Sensitivity in Relation to Sex Hormone Treatment