ESPE Abstracts

Background: The increasing number of transgender adolescents presenting in early puberty requires to investigate the effects of long-term puberty suppression and gender-affirming hormones (GAH) on body composition and metabolism. Clinical studies have ethical and practical limitations. A preclinical mouse model may be helpful to gain mechanistic insights.

Methods: Prepubertal (4week-old) female mice were treated with the gonadotropin-releasing hormone analogue (GnRHa) Degarelix (DGX), followed by testosterone administration started in early (6week-old) or late (8week-old) puberty. At adult age (16week-old), body composition (echoMRI), grip strength, glucose tolerance and hepatic lipids were assessed. The translational potential of our preclinical findings was verified in a cohort of 16 transboys who received GnRHa starting at Tanner stage 2-3, followed by testosterone around 16years [mean GnRHa duration 40 (±7.6) months]. Body composition (DXA), grip strength and fasting blood sampling were assessed at start of GnRHa and at start of testosterone. Z-scores were calculated using reference values for cis-girls (Z-scoreAFAB) and cis-boys (Z-scoreAMAB).

Results: In the mouse model, DGX decreased lean mass% (-6.98%, P<0.001) and increased fat mass% (+7.51%, P<0.001) compared to female controls. The decreased lean mass was accompanied by diminished grip strength (-8.84% P=0.062). The increased body fat was paralleled by accumulation of subcutaneous (+106.52% P<0.001), gonadal (+121.88% P<0.001) and perirenal (+100.51% P<0.001) fat, and hepatic triglycerides (+66.09% P<0.001). DGX increased fasting glucose and HOMA-index, and decreased glucose tolerance. Testosterone reversed all DGX effects, irrespective of being started in early or late puberty. Effects on lean and fat mass% were most pronounced, both parameters reaching male control levels. Similar effects were observed in transboys on GnRHa: fat mass% increased significantly (+5%, P<0.001) while lean mass% decreased significantly (-3.46%, P<0.001). Grip strength Z-scoreAFAB increased non-significantly, Z-scoreAMAB decreased significantly [-1.36 (±0.64) to -2.28 (±0.44), P<0.001]. HOMA-index, tot-C, HDL-C, LDL-C and triglycerides did not change. Seven transboys were re-evaluated 31 (±2.6) months after start of testosterone. Fat mass% showed a decreasing trend, lean mass% an increasing trend. Muscle strength increased significantly [Z-scoreAFAB -0.87 (±0.28) to 1.36 (±0.15), P=0.002; Z-scoreAMAB -2.64 (±0.19) to -1.72 (±0.13), P=0.003]. HDL-C decreased significantly [68 (±22.01) to 45.2 (±11.65) mg/dl, P=0.025].

Conclusions: Prolonged puberty suppression in female mice decreases lean mass%, increases fat mass%, and causes metabolic alterations. Testosterone reverses these changes, earlier testosterone administration has no additional beneficial effect. Our clinical observations support the effects on body composition and muscle strength, however changes in metabolic profile were not observed.