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Reproductive Consequences of Steroid Hormone Administration

类固醇激素管理的生殖后果

基本信息

批准号：
10619517
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
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-05-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10619517
关键词：
Address Adolescent Adult Affect Agonist Androgens Animal Model Animals Architecture Assisted Reproductive Technology Breeding Caring Clinical Clinical Research 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 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 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

项目摘要

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，140万变性成年人和15万变性青少年生活在美国。其中许多人正在接受雌二醇或睾酮（T）的跨性别激素治疗。国家和国际医学组织建议，在开始跨性别生育之前，激素疗法，基于生育能力丧失的假设。但是，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，特别是在变性男性（女性对男性）中。男性或FTM）。现有的人类研究表明，卵巢的变化，从跨性别的T治疗，但观察性研究，结果相互矛盾。此外，缺乏关于T处理的生殖力的数据。跨性别男性，并且还没有研究解决T诱导的变化的可逆性，停止T用于生殖目的。也没有关于未来生殖后果的研究，跨性别青少年的治疗模式，其中GnRHa在青春期早期开始，在直接过渡到T治疗（GnRHa-T）之前抑制进一步的青春期进展。并没有任何一名现任研究雄激素对雌性生殖功能影响的动物模型可直接应用跨性别男性的跨性别T治疗或跨性别男性的GnRHa-T治疗的临床范例青少年。为了解决这一知识缺口，我们开发了一种小鼠模型来模拟T治疗， FTM性别转换。这些小鼠表现出卵巢结构缺陷，并改变了卵泡发生。该模型为阐明T治疗对生殖表型和功能的影响提供了有力的工具，这在人类身上是不可能的拟定研究的目的是使用FTM小鼠模型，研究跨性别T处理对生殖表型和功能的影响，并确定这些影响的可逆性后停止T。我们的中心假设是T疗法会对影响卵巢结构和生育能力，但生育能力可以随着T的停止而恢复，对后代的生殖影响。为了验证这一假设，我们将研究青春期后T细胞的可逆性。在雌性小鼠中给药，模拟FTM性别转换，对生殖表型（AIM 1）的影响，以及在长期睾酮治疗期间和停止后检查生育能力，包括生殖表型在后代中（AIM 2）。在一个探索性的目标，我们将研究睾丸激素的生殖后果用青春期周围GnRHa预处理后给药，模拟FTM交叉性激素治疗，青少年，生殖表型和生育力（AIM 3）。这一提议挑战了建议在跨性别T治疗之前保持生育能力，并将为进一步的研究奠定基础。翻译研究我们的长期目标是为循证生育咨询提供必要的数据跨性别男性阐明跨性别T治疗对生殖道的影响和可逆性，导致跨性别男性临床生育护理的未来范式转变。