ESPE Abstracts

Background: Transgender individuals increasingly present at gender services in childhood. Consequently, to suppress pubertal development, more adolescents are long-term exposed to gonadotropin-releasing hormone analogues (GnRHa), from onset of puberty until start of gender-affirming hormones (GAH), around 16 years. Prolonged GnRHa may compromise bone health more than shorter-term treatment. If earlier start of GAH, when psychologically indicated, may partially restore bone health, is currently unknown. As clinical studies have ethical and practical limitations, a preclinical mouse model may provide mechanistic insight.

Methods: DXA [lumbar spine (LS), femoral neck (FN)] and pQCT (tibia 4%, 38%) were performed at start of GnRHa (Tanner stage 2-3), and at start of GAH in 16 transboys. Z-scores were calculated using references for cis-girls (Z-scoreAFAB) and cis-boys (Z-scoreAMAB). Similarly, we assessed the impact of long-term GnRHa on bone development in a mouse model and explored the effect of earlier start of GAH. Prepubertal (4week-old) female mice were treated with either the GnRHa Degarelix (DGX) alone, DGX at 4 weeks supplemented with testosterone at 6 weeks (early puberty), or DGX at 4 weeks supplemented with testosterone at 8 weeks (late puberty). Mice were sacrificed at adult age (16weeks) for bone phenotyping.

Results: In transboys, mean age was 12.4 (±0.93) years at start of GnRHa and 15.8 (±0.60) years at start of GAH; mean duration of GnRHa monotherapy was 40 (±7.6) months. All bone mineral apparent density (BMAD) Z-scores decreased significantly.

In line, pQCT trabecular density at tibia 4% significantly decreased. Seven transboys were re-evaluated at gonadectomy, 31 (±2.6) months after addition of testosterone, showing partial restoration of trabecular bone. In mice, DGX treatment significantly reduced femoral trabecular bone volume fraction (BV/TV) assessed by microCT from 4.03 ± 0.74% in female controls to 1.19 ± 0.34% in DGX-treated mice, P<0.001. Late testosterone restored BV/TV to 7.47 ± 2.07%, P<0.001. Early testosterone further increased BV/TV to 12.33 ± 1.46%, P<0.001, similar to male controls (11.81 ± 2.38%). Cortical bone loss in DGX-treated mice was less pronounced and completely reversed by testosterone in both early and late groups.

Conclusions: Prolonged GnRHa induce significant bone loss, mainly at the trabecular compartment. Early GAH start in a mouse model can restore bone volume up to male references.