Dubois Vanessa, Ciancia Silvia, Doms Stefanie, El Kharraz Sarah, Sommers Vera, Kim Na Ri, David Karel, Van Dijck Jolien, Valle-Tenney Roger, Maes Christa, Antonio Leen, Decallonne Brigitte, Carmeliet Geert, Claessens Frank, Cools Martine, Vanderschueren Dirk
Clinical and Experimental Endocrinology, Department of Chronic Diseases and Metabolism (Chrometa), KU Leuven, Leuven, Belgium.
Basic and Translational Endocrinology (BaTE), Department of Basic and Applied Medical Sciences, Ghent University, Ghent, Belgium.
J Bone Miner Res. 2023 Oct;38(10):1497-1508. doi: 10.1002/jbmr.4832. Epub 2023 Jun 8.
Transgender youth increasingly present at pediatric gender services. Some of them receive long-term puberty suppression with gonadotropin-releasing hormone analogues (GnRHa) before starting gender-affirming hormones (GAH). The impact of GnRHa use started in early puberty on bone composition and bone mass accrual is unexplored. It is furthermore unclear whether subsequent GAH fully restore GnRHa effects and whether the timing of GAH introduction matters. To answer these questions, we developed a mouse model mimicking the clinical strategy applied in trans boys. Prepubertal 4-week-old female mice were treated with GnRHa alone or with GnRHa supplemented with testosterone (T) from 6 weeks (early puberty) or 8 weeks (late puberty) onward. Outcomes were analyzed at 16 weeks and compared with untreated mice of both sexes. GnRHa markedly increased total body fat mass, decreased lean body mass, and had a modest negative impact on grip strength. Both early and late T administration shaped body composition to adult male levels, whereas grip strength was restored to female values. GnRHa-treated animals showed lower trabecular bone volume and reduced cortical bone mass and strength. These changes were reversed by T to female levels (cortical bone mass and strength) irrespective of the time of administration or even fully up to adult male control values (trabecular parameters) in case of earlier T start. The lower bone mass in GnRHa-treated mice was associated with increased bone marrow adiposity, also reversed by T. In conclusion, prolonged GnRHa use started in prepubertal female mice modifies body composition toward more fat and less lean mass and impairs bone mass acquisition and strength. Subsequent T administration counteracts GnRHa impact on these parameters, shaping body composition and trabecular parameters to male values while restoring cortical bone architecture and strength up to female but not male control levels. These findings could help guide clinical strategies in transgender care. © 2023 American Society for Bone and Mineral Research (ASBMR).
越来越多的跨性别青少年前往儿科性别服务机构就诊。他们中的一些人在开始使用性别确认激素（GAH）之前，会长期使用促性腺激素释放激素类似物（GnRHa）抑制青春期发育。青春期早期开始使用GnRHa对骨成分和骨量积累的影响尚未得到研究。此外，尚不清楚后续的GAH是否能完全恢复GnRHa的作用，以及GAH开始使用的时间是否重要。为了回答这些问题，我们建立了一个模拟应用于跨性别男性临床策略的小鼠模型。对4周龄青春期前的雌性小鼠单独使用GnRHa，或从6周龄（青春期早期）或8周龄（青春期晚期）开始使用GnRHa并补充睾酮（T）。在16周时分析结果，并与未治疗的雌雄小鼠进行比较。GnRHa显著增加了全身脂肪量，减少了瘦体重，并对握力有适度的负面影响。早期和晚期给予T均可使身体成分达到成年男性水平，而握力恢复到女性水平。接受GnRHa治疗的动物小梁骨体积较低，皮质骨量和强度降低。无论给药时间如何，T均可将这些变化逆转至女性水平（皮质骨量和强度），如果早期开始给予T，甚至可将小梁参数完全恢复至成年男性对照值。接受GnRHa治疗的小鼠骨量较低与骨髓脂肪增多有关，T也可将其逆转。总之，青春期前雌性小鼠长期使用GnRHa会使身体成分向脂肪增多、瘦体重减少的方向改变，并损害骨量获取和强度。随后给予T可抵消GnRHa对这些参数的影响，使身体成分和小梁参数达到男性水平，同时将皮质骨结构和强度恢复至女性但非男性对照水平。这些发现有助于指导跨性别护理的临床策略。© 2023美国骨与矿物质研究学会（ASBMR）
