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

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Bone Research 2024年第1期12卷 95-106页

作者： 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 department of Medicine Austin HealthUniversity of MelbourneHeidelbergVIC 3084Australia department of Biomedical Engineering University of MelbourneParkvilleVIC 3010Australia ANZAC Research Institute University of Sydney and AndrologyConcord Repatriation General HospitalConcordNSW 2137Australia

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.

关键词： treatment treatment strength

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Hematological changes during androgen deprivation therapy

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Asian Journal of Andrology 2012年第2期14卷 187-192页

作者： mathis grossmann jeffrey d zajac department of Medicine Austin Health/Northern Health University of Melbourne Heidelberg Vic. 3084 Australia

Androgen deprivation therapy （AdT） has been associated with a plethora of adverse effects, consistent with the androgen dependency of multiple reproductive and somatic tissues. One such tissue is the hemopoietic system, and one of the most predictable consequences of AdT is the development of anemia. Although anemia caused by AdT is rarely severe, AdT is often given to frail, elderly men with increased susceptibility to anemia due to multiple other causes. AdT-associated anemia may contribute to fatigue and reduced quality of life （QoL） in such men, although this requires further study. While anemia is an independent risk factor of mortality in men with prostate cancer, it is not known whether treatment of AdT-associated anemia alters clinically important outcomes, or whether treatment affects mortality. Awareness of the phenomenon of AdT-induced anemia should avoid unnecessary work-up in mild cases of normocytic normochromic anemia. However, assessment and treatment of more severe anemia may be required. This should be determined on an individual basis. In contrast to the weli-descrihed actions of AdT on erythropoiesis, its effect on other hemopoietic lineages has been less well elucidated. While preclinical studies have found roles for androgens in maturation and differentiated function of neutrophils, lymphocytes and platelets, the implications of these findings for men with prostate cancer receiving AdT require further studies.

关键词： anemia androgen deprivation therapy （AdT） prostate cancer

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Effects of gender-affirming hormone therapy on insulin resistance and body composition in transgender individuals: A systematic review

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World Journal of diabetes 2020年第3期11卷 66-77页

作者： Cassandra Spanos Ingrid Bretherton jeffrey d zajac Ada S Cheung Trans Medical Research Group Department of Medicine (Austin Health) University of Melbourne

BACKGROUNd Transgender individuals receiving masculinising or feminising gender-affirming hormone therapy with testosterone or estradiol respectively,are at increased risk of adverse cardiovascular outcomes,including myocardial infarction and stroke.This may be related to the effects of testosterone or estradiol therapy on body composition,fat distribution,and insulin resistance but the effect of genderaffirming hormone therapy on these cardiovascular risk factors has not been extensively examined.AIM To evaluate the impact of gender-affirming hormone therapy on body composition and insulin resistance in transgender individuals,to guide clinicians in minimising cardiovascular risk.METHOdS We performed a review of the literature based on PRISMA guidelines.MEdLINE,Embase and PsycINFO databases were searched for studies examining body composition,insulin resistance or body fat distribution in transgender individuals aged over 18 years on established gender-affirming hormone therapy.Studies were selected for full-text analysis if they investigated transgender individuals on any type of gender-affirming hormone therapy and reported effects on lean mass,fat mass or insulin resistance.RESULTS The search strategy identified 221 studies.After exclusion of studies that did not meet inclusion criteria,26 were included(2 cross-sectional,21 prospectiveuncontrolled and 3 prospective-controlled).Evidence in transgender men suggests that testosterone therapy increases lean mass,decreases fat mass and has no impact on insulin resistance.Evidence in transgender women suggests that feminising hormone therapy(estradiol,with or without anti-androgen agents)decreases lean mass,increases fat mass,and may worsen insulin resistance.Changes to body composition were consistent across almost all studies:Transgender men on testosterone gained lean mass and lost fat mass,and transgender women on oestrogen experienced the reverse.No study directly contradicted these trends,though several small studies of short duration reported no changes.Resu

关键词： Transgender persons Insulin resistance Body composition Gender dysphoria Metabolic syndrome

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【特刊综述】利用雄激素受体敲除（ARKO）小鼠模型认识人类雄激素缺乏

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Asian Journal of Andrology 2014年第2期16卷 169-177,I0006页

作者： Kesha Rana Rachel A davey jeffrey d zajac department of Medicine Austin Health University of Melbourne Heidelberg Victoria Australia.

雄激素的作用机理很复杂。最近，使用转基因修饰小鼠模型进行的雄激素受体研究使我们对雄激素作用机理有了更进一步的理解。Cre-loxP系统能够完成组织和／或细胞特异性的敲除。通过使用Cre—loxP系统已经获得了大量整体性或组织特异性... 详细信息

雄激素的作用机理很复杂。最近，使用转基因修饰小鼠模型进行的雄激素受体研究使我们对雄激素作用机理有了更进一步的理解。Cre-loxP系统能够完成组织和／或细胞特异性的敲除。通过使用Cre—loxP系统已经获得了大量整体性或组织特异性雄激素受体（ARK0）敲除模型。这些ARKO模型的多个雄激素作用位点，包括心血管系统、免疫和造血系统、骨骼、肌肉、脂肪组织、前列腺和脑，均已被检测。本篇综述着重阐述了通过针对这些雄激素作用位点的ARKO小鼠模型而取得的人类雄激素缺乏的研究成果，并且指出充分理解Cre-loxPdx鼠模型的优缺点才能正确认识其表型。

关键词：雄激素受体 ARKO小鼠模型雄激素缺乏

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雄激素受体的目标基因在骨骼肌的表达

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Asian Journal of Andrology 2014年第5期16卷 675-683,I0006页

作者： Kesha Rana Nicole KL Lee jeffrey d zajac Helen E MacLean department of Medicine Austin Health University of Melbourne Heidelberg Victoria Australia

本文通过研究体外和体内模型中潜在的雄激素受体调节基因来确定骨骼肌中雄激素的合成代谢作用机制。睾酮治疗组的去势雄性小鼠与对照组去势雄性小鼠比较，其骨骼肌中肌源性调节因子肌细胞生成素的表达显著下降，而缺乏dNA结合活性的雄... 详细信息

本文通过研究体外和体内模型中潜在的雄激素受体调节基因来确定骨骼肌中雄激素的合成代谢作用机制。睾酮治疗组的去势雄性小鼠与对照组去势雄性小鼠比较，其骨骼肌中肌源性调节因子肌细胞生成素的表达显著下降，而缺乏dNA结合活性的雄性雄激素受体敲除小鼠（AR^△ZF2）与野生型小鼠比较，其骨骼肌中肌源性调节因子肌细胞生成素的表达显著升高，证明了肌细胞生成素是通过雄激素／雄激素受体通路被抑制。通过12小时的骨骼肌细胞（SkMC）的成肌细胞联合双氢睾酮治疗，睾酮治疗组的去势雄性小鼠肌肉中的泛素连接酶Fbxo32被抑制，而肌肉中c—Myc表达较对照组去势雄性小鼠降低，在△R^△ZF2组小鼠肌肉中c-Myc表达升高。调节成肌细胞由增殖向分化转变的一组基因如Tceal7,p57^Kip2，Igf2和钙调磷酸酶Aa的表达在AR^△ZF2组小鼠肌肉中升高，除p57^Kip2外的上述所有基因在睾酮治疗组去势雄性小鼠肌肉中的表达均较对照组降低。因此得出结论，雄激素通过雄激素受体在雄性小鼠体内发挥作用，它在肌肉生长和发展过程中可维持成肌细胞处于增殖状态并推迟成肌细胞向分化状态转变，另外还可抑制泛素连接酶介导的导致肌肉萎缩的通路来保持小鼠肌肉质量，从而一定程度上促进肌肉不断生长达到顶峰。

关键词：雄激素受体基因表达骨骼肌合成代谢萎缩

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