Progestogens Modulate the Metabolic but Not the Musculoskeletal Response to Estradiol in a Mouse Model of Adolescent Gender Transition

Gender‐affirming hormone therapy in transgender girls typically consists of gonadotropin‐releasing hormone analog (GnRHa)‐mediated puberty suppression followed by estradiol (E2) treatment. While the skeletal effects of this approach have been investigated, its impact on skeletal muscle and metabolism remains unclear. Moreover, the addition of a progestogen such as natural progesterone (P4) or synthetic medroxyprogesterone acetate (MPA) to the standard E2 regimen has gained popularity due to presumed enhanced feminization, despite limited evidence regarding its effects on musculoskeletal and metabolic tissues. Here, we used a mouse model of adolescent male‐to‐female transition to address these questions. Peripubertal male mice were treated with a GnRHa to suppress endogenous sex hormone production, followed by E2 alone or in combination with P4 or MPA. Puberty suppression reduced the acquisition of bone mass and strength, impaired endurance capacity, decreased lean mass, altered muscle fiber type composition, and increased adiposity. E2 treatment increased bone outcomes to female control levels, and partially normalized endurance capacity, body composition, and metabolic parameters. Addition of a progestogen did not further affect bone or muscle outcomes beyond E2 alone. In contrast, progestogen co‐administration worsened metabolic parameters, resulting in increased adiposity, impaired glucose tolerance, elevated fasting glucose and insulin, and hepatic lipid accumulation. These effects were more pronounced with MPA than with P4. In conclusion, E2 drives musculoskeletal recovery following puberty suppression, whereas progestogens do not provide additional benefits in these tissues. However, they adversely affect metabolic outcomes, highlighting the need for careful evaluation when these compounds are included in gender‐affirming therapy.