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.

最近的数据估计有140万跨性别成年人和150,000名跨性别青少年居住在曼联州，其中许多人正在接受雌二醇或睾丸激素（T）的跨性激素治疗。国家和国际医学组织在启动跨性别之前建议生育保存咨询基于生育能力丧失的假设，激素治疗。但是，长期跨性别的影响生殖健康的激素疗法在很大程度上是未知的，尤其是在变性男性中（女性到女性男性或ftm）。可用的人类研究表明，跨性别疗法的卵巢变化，但观察性研究，结果矛盾。此外，缺乏有关T处理的繁殖力的数据变性人，并且没有研究能够解决T诱导的变化后的可逆性停止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范式，其中gnrha在peripubertal时期开始在直接过渡到T治疗（GNRHA-T）之前，抑制了进一步的青春期进展。没有现有的解决雄激素对女性生殖功能影响的动物模型直接适用在跨性别男性或跨性别者GNRHA-T治疗中跨性别治疗的临床范式青少年。为了解决这一知识差距，我们开发了一种鼠标模型来模仿t处理 FTM性别转变。这些小鼠在卵巢结构中表现出缺陷，并改变了卵泡发生。该模型提供了一种强大的工具来阐明T疗法对生殖表型和功能的影响，人类不可能的一种方式。拟议研究的目的是使用FTM小鼠模型研究跨性别处理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疗法将对影响卵巢的建筑和生育能力，但是可以通过停止T来恢复生育能力，而不会不利后代生殖效应。为了检验这一假设，我们将检查后假设的可逆性在雌性小鼠中给药，模仿FTM性别转变，生殖表型（AIM 1）和在停止长期睾丸激素治疗期间和之后的生育能力，包括生殖表型在后代（AIM 2）。在探索性目的中，我们将研究睾丸激素的生殖后果用腹膜GNRHA进行预处理后的管理，模仿FTM跨性激素治疗青少年，关于生殖表型和生育能力（AIM 3）。该提议挑战了现状建议在跨性别治疗之前保存生育能力，并将为进一步的基础奠定基础翻译研究。我们的长期目标是为基于证据的生育咨询提供必要的数据跨性别男人。阐明跨性别治疗对生殖道的影响和可逆性可能导致未来的跨性别男性临床生育护理范式转变。