Estradiol increases cortical and trabecular bone accrual and bone strength in an adolescent male-to-female mouse model of gender-affirming hormone therapy

IF 14.3 1区 医学 Q1 CELL & TISSUE ENGINEERING Bone Research Pub Date : 2024-01-11 DOI:10.1038/s41413-023-00308-2
Tian Nie, Varun S. Venkatesh, Suzanne Golub, Kathryn S. Stok, Haniyeh Hemmatian, Reena Desai, David J. Handelsman, Jeffrey D. Zajac, Mathis Grossmann, Rachel A. Davey
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Abstract

The effects of gender-affirming hormone therapy on the skeletal integrity and fracture risk in transitioning adolescent trans girls are unknown. To address this knowledge gap, we developed a mouse model to simulate male-to-female transition in human adolescents in whom puberty is first arrested by using gonadotrophin-releasing hormone analogs with subsequent estradiol treatment. Puberty was suppressed by orchidectomy in male mice at 5 weeks of age. At 3 weeks post-surgery, male-to-female mice were treated with a high dose of estradiol (~0.85 mg) by intraperitoneal silastic implantation for 12 weeks. Controls included intact and orchidectomized males at 3 weeks post-surgery, vehicle-treated intact males, intact females and orchidectomized males at 12 weeks post-treatment. Compared to male controls, orchidectomized males exhibited decreased peak bone mass accrual and a decreased maximal force the bone could withstand prior to fracture. Estradiol treatment in orchidectomized male-to-female mice compared to mice in all control groups was associated with an increased cortical thickness in the mid-diaphysis, while the periosteal circumference increased to a level that was intermediate between intact male and female controls, resulting in increased maximal force and stiffness. In trabecular bone, estradiol treatment increased newly formed trabeculae arising from the growth plate as well as mineralizing surface/bone surface and bone formation rate, consistent with the anabolic action of estradiol on osteoblast proliferation. These data support the concept that skeletal integrity can be preserved and that long-term fractures may be prevented in trans girls treated with GnRHa and a sufficiently high dose of GAHT. Further study is needed to identify an optimal dose of estradiol that protects the bone without adverse side effects.

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雌二醇可增加青少年雄性变雌性小鼠性别确认激素疗法模型的皮质骨和骨小梁增生以及骨强度
性别确认激素疗法对变性少女骨骼完整性和骨折风险的影响尚不清楚。为了填补这一知识空白,我们开发了一种小鼠模型,通过使用促性腺激素释放激素类似物和随后的雌二醇治疗来模拟人类青少年的男变女过程。对 5 周大的雄性小鼠进行睾丸切除术,抑制其青春期。手术后 3 周,雄性变雌性小鼠腹腔植入高剂量雌二醇(约 0.85 毫克),持续 12 周。对照组包括手术后 3 周的完整雄性小鼠和睾丸切除雄性小鼠、接受药物治疗的完整雄性小鼠、治疗后 12 周的完整雌性小鼠和睾丸切除雄性小鼠。与雄性对照组相比,睾丸切除的雄性动物表现出峰值骨量减少,骨折前骨骼可承受的最大力也减少。与所有对照组的小鼠相比,睾丸切除的雄性变雌性小鼠接受雌二醇治疗后,干骺端中部的皮质厚度增加,而骨膜周长增加到介于完整雄性对照组和雌性对照组之间的水平,从而增加了最大力和硬度。在骨小梁中,雌二醇治疗增加了生长板上新形成的骨小梁以及矿化面/骨面和骨形成率,这与雌二醇对成骨细胞增殖的同化作用是一致的。这些数据支持了这样一个概念,即用 GnRHa 和足够高剂量的 GAHT 治疗反式女孩,可以保持骨骼的完整性,并可预防长期骨折。还需要进一步研究,以确定既能保护骨骼又无不良副作用的最佳雌二醇剂量。
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来源期刊
Bone Research
Bone Research CELL & TISSUE ENGINEERING-
CiteScore
20.00
自引率
4.70%
发文量
289
审稿时长
20 weeks
期刊介绍: Established in 2013, Bone Research is a newly-founded English-language periodical that centers on the basic and clinical facets of bone biology, pathophysiology, and regeneration. It is dedicated to championing key findings emerging from both basic investigations and clinical research concerning bone-related topics. The journal's objective is to globally disseminate research in bone-related physiology, pathology, diseases, and treatment, contributing to the advancement of knowledge in this field.
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