SUN-145 Effects of Progestogen Supplementation in Feminizing Hormone Therapy: A Mouse Model of Adolescent Gender Transition

Abstract Disclosure: S. Calvo Blanco: None. O. Nobus: None. T. Liekens: None. L. Verlinden: None. I. Stockmans: None. K. Moermans: None. F. Stappers: None. L. Crombez: None. C. Vercruysse: None. K. Van Belleghem: None. S. Lamon: None. E. Gracey: None. D. Elewaut: None. A. De Spiegeleer: None. R.I. Dmitriev: None. G.G. T'sjoen: None. L. Devisscher: None. S. Stegen: None. V. Dubois: None. BACKGROUND: Gender-affirming therapy for transgender adolescents often includes puberty suppression with gonadotropin-releasing hormone analogues (GnRHa), followed by gender-affirming hormones. In those assigned male at birth, the addition of a progestogen – such as natural progesterone (P4) or synthetic medroxyprogesterone acetate (MPA) – to the standard estrogen therapy has gained popularity due to a presumed enhanced feminization. However, the effects of progestogen supplementation on the musculoskeletal system and metabolic tissues remain unclear. To address this gap, we examined the impact of combined estrogen and progestogen therapy on various organ systems using a mouse model that replicates the clinical trajectory of transgender girls. METHODS: Prepubertal 4-week-old male mice received the GnRHa degarelix (DGX) to suppress puberty, followed by estradiol (E2) combined with a progestogen (P4 or MPA) from 8 weeks of age. Their phenotype at 16 weeks of age was compared to puberty-suppressed male mice treated with E2 alone, and to vehicle-treated male and female animals (controls for native sex and gender, respectively). To investigate metabolic changes, body composition was determined by MRI, fasting glucose and insulin levels were measured, and a glucose tolerance test was performed. The impact of the hormonal manipulations on muscle strength and fatigue were assessed by grip strength and treadmill endurance tests, and fiber type composition was determined by immunohistochemistry. Effects on the skeleton were investigated through microcomputed tomography, three-point bending and (dynamic) histomorphometry. RESULTS: DGX strongly decreased the weight of reproductive tissues including testes and seminal vesicles, confirming effective puberty suppression. E2 alone did not further affect reproductive tissue mass in DGX-treated animals, while E2 and progestogen co-administration increased testicular weight, albeit well-below control male levels. Puberty suppression shifted body composition towards increased fat mass and decreased lean mass, and E2 with or without progestogen did not fully reverse these changes. Fasting glucose levels were increased in mice treated with P4 or MPA without differences in glucose tolerance. Muscle strength was slightly higher in P4-treated mice. Resistance to fatigue was decreased upon puberty suppression and restored by E2, and this was accompanied by changes in fiber type composition. Bone strength was diminished by DGX, and restored to control levels by E2 without additional effect of P4 or MPA. CONCLUSION: Addition of a progestogen does not profoundly modulate the effect of estradiol on the body composition and the musculoskeletal system but increases fasting glucose levels in this mouse model of adolescent gender transition. Presentation: Sunday, July 13, 2025