Reproductive Consequences of Steroid Hormone Administration

类固醇激素管理的生殖后果

• 批准号: 10393053
• 负责人: Molly Bennette Moravek
• 金额: $ 53.22万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10393053
• 关键词: Address; Adolescent; Adult; Affect; Agonist; Androgens; Animal Model; Animals; Architecture; Assisted Reproductive Technology; Breeding; Caring; Clinical; Clinical Research; Conflict (Psychology); Counseling; Data; Defect; Development; Estradiol; Estrous Cycle; Female; Fertility; Fertilization; Fertilization in Vitro; Foundations; Future; Gender Identity; Goals; Gonadal Steroid Hormones; Gonadotropin Hormone Releasing Hormone; Histologic; Histology; Hormones; Human; Infertility; International; Knowledge; Lead; Medical; Modeling; Mus; Neurosecretory Systems; Observational Study; Oocytes; Operative Surgical Procedures; Outcome; Ovarian; Ovarian Stimulations; Ovary; Patients; Phenotype; Polycystic Ovary Syndrome; Prevalence; Puberty; Recommendation; Regimen; Reproduction; Reproductive Health; Research; Research Personnel; Role; Serum; Sex Characteristics; Superovulation; Testing; Testosterone; Time; Translational Research; United States; base; body system; clinical practice; clinically relevant; evidence base; experimental study; fertility preservation; folliculogenesis; gender transition; hormone therapy; implantation; improved; insight; male; mouse model; offspring; oocyte cryopreservation; ovary transplantation; peripubertal period; prenatal; prepuberty; reproductive; reproductive function; reproductive outcome; reproductive tract; response; sex; steroid hormone; tool; transgender; transgender men; translational study

Recent data estimates 1.4 million transgender adults and 150,000 transgender adolescents live in the United States, many of whom are on cross-sex hormone therapy with estradiol or testosterone (T). National and international medical organizations recommend fertility preservation counseling prior to initiation of cross-sex hormone therapy, based on an assumption of fertility loss. However, the impact of long-term cross-sex hormone therapy on reproductive health is largely unknown, particularly in transgender men (female-to- male or FTM). The available human studies suggest ovarian changes from cross-sex T therapy, but are observational studies, with conflicting results. Moreover, there is a lack of data on the fecundity of T-treated transgender men, and there have been no studies that address the reversibility of T-induced changes after cessation of T for reproductive purposes. There are also no studies on future reproductive consequences of the treatment paradigm for transgender adolescents, in which GnRHa is initiated in the early peripubertal period to suppress further pubertal progression prior to transitioning directly to T therapy (GnRHa-T). None of the existing animal models that address the effect of androgens on reproductive function in females are directly applicable to the clinical paradigm of cross-sex T therapy in transgender men or GnRHa-T therapy in transgender adolescents. To address this knowledge gap, we have developed a mouse model to mimic T treatment for FTM gender transition. These mice manifest defects in ovarian architecture and have altered folliculogenesis. This model provides a powerful tool to clarify the effects of T therapy on reproductive phenotype and function, in a manner not possible in humans. The objective of the proposed studies is to use the FTM mouse model to investigate the effects of cross-sex T treatment on reproductive phenotype and function, and determine the reversibility of these effects following cessation of T. Our central hypothesis is that T therapy will adversely affect ovarian architecture and fertility, but that fertility can be recovered with cessation of T, without adverse reproductive effects in offspring. To test this hypothesis, we will examine the reversibility of postpubertal T administration in female mice, mimicking FTM gender transition, on reproductive phenotype (AIM 1), and examine fertility during and after cessation of long-term testosterone therapy, including reproductive phenotype in offspring (AIM 2). In an exploratory aim, we will examine the reproductive consequences of testosterone administration after pretreatment with peripubertal GnRHa, mimicking FTM cross-sex hormone therapy in adolescents, on reproductive phenotype and fertility (AIM 3). This proposal challenges the status quo of recommending fertility preservation prior to cross-sex T therapy, and will lay the foundation for further translational studies. Our long-term goal is to provide the necessary data for evidence-based fertility counseling of transgender men. Clarifying the effects and reversibility of cross-sex T therapy on the reproductive tract could lead to future paradigm shifts in clinical fertility care of transgender men.

最近的数据估计，美国有 140 万跨性别成年人和 15 万跨性别青少年 其中许多人正在接受雌二醇或睾酮 (T) 的跨性别激素治疗。国家和 国际医疗组织建议在开始异性交之前进行生育力保存咨询 激素疗法，基于生育能力丧失的假设。但长期跨性别的影响 激素治疗对生殖健康的影响在很大程度上是未知的，特别是对于跨性别男性（女性到女性） 男性或 FTM）。现有的人体研究表明跨性别 T 疗法会导致卵巢变化，但 观察性研究，结果相互矛盾。此外，缺乏有关 T 处理的繁殖力的数据。 跨性别男性，并且还没有研究解决 T 诱导的变化的可逆性 出于生殖目的而停止 T。也没有关于未来生殖后果的研究 跨性别青少年的治疗范例，其中 GnRHa 在青春期早期开始，以 在直接过渡到 T 疗法 (GnRHa-T) 之前抑制青春期的进一步进展。现有的都没有 解决雄激素对女性生殖功能影响的动物模型可直接应用 跨性别男性跨性别 T 治疗或跨性别 GnRHa-T 治疗的临床范例 青少年。为了解决这一知识差距，我们开发了一种小鼠模型来模拟 T 治疗 FTM 性别转变。这些小鼠表现出卵巢结构缺陷并改变了卵泡发生。 该模型提供了一个强大的工具来阐明 T 疗法对生殖表型和功能的影响，例如 这是人类不可能实现的方式。拟议研究的目的是使用 FTM 小鼠模型 研究跨性别 T 治疗对生殖表型和功能的影响，并确定 停止 T 后这些影响的可逆性。我们的中心假设是 T 治疗会产生不利影响 影响卵巢结构和生育能力，但生育能力可以通过停止 T 来恢复，不会产生不利影响 对后代的生殖影响。为了检验这一假设，我们将检查青春期后 T 的可逆性 模拟 FTM 性别转变的雌性小鼠给药对生殖表型 (AIM 1) 的影响，以及 检查长期睾酮治疗期间和停止后的生育能力，包括生殖表型 后代（AIM 2）。为了探索性的目的，我们将检查睾酮对生殖的影响 青春期前后 GnRHa 预处理后给药，模仿 FTM 跨性别激素疗法 青少年的生殖表型和生育能力（AIM 3）。该提案挑战了现状 建议在跨性别 T 治疗之前保留生育能力，并将为进一步的治疗奠定基础 转化研究。我们的长期目标是为循证生育咨询提供必要的数据 的跨性别男性。阐明跨性别 T 疗法对生殖道的影响和可逆性可以 导致跨性别男性临床生育护理的未来范式转变。