Reproductive Consequences of Steroid Hormone Administration

最近的数据估计，美国有140万变性人成年人和15万变性人青少年 这些州中的许多人正在接受雌激素或睾酮(T)的跨性激素治疗。国家和 国际医学组织建议在开始变性者之前进行生育咨询 荷尔蒙疗法，基于生育能力丧失的假设。然而，长期异性恋的影响 激素治疗对生殖健康的影响在很大程度上是未知的，特别是在变性人男性(女性到 男性或FTM)。现有的人体研究表明，异性T治疗会导致卵巢发生变化，但实际上 观察性研究，结果相互矛盾。此外，缺乏关于T-处理的繁殖力的数据 变性人男性，而且还没有研究表明T诱导的变化在 出于生殖目的停止生育。也没有关于未来生育后果的研究 变性人青少年的治疗模式，其中GnRHa在青春期早期启动，以 在直接过渡到T疗法(GnRHa-T)之前抑制进一步的青春期进展。没有现有的 解决雄激素对雌性生殖功能影响的动物模型直接适用 变性人中跨性别T疗法或变性人中GnRHa-T疗法的临床范例 青少年。为了解决这一知识鸿沟，我们开发了一种模拟T处理的小鼠模型 FTM性别转变。这些小鼠表现出卵巢结构的缺陷，并改变了卵泡的生成。 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。拟议研究的目的是使用FTM小鼠模型来 研究异性T处理对生殖表型和生殖功能的影响，并确定 停止T治疗后这些效应的可逆性我们的中心假设是T治疗将对 影响卵巢结构和生育力，但停止T后生育力可以恢复，而不会产生不良影响 对后代的生殖影响。为了验证这一假设，我们将检验青春期后T细胞的可逆性 雌性小鼠给药，模仿FTM性别转变，对生殖表型(AIM 1)，以及 在停止长期睾酮治疗期间和之后检查生育力，包括生殖表型 在后代中(目标2)。在一个探索性的目标中，我们将研究睾丸激素的生殖后果。 在青春期前给予GnRHa，模拟FTM跨性激素治疗 青少年的生殖表型和生育力(目标3)。这项提议挑战了 建议在异性T治疗之前保留生育能力，并将为进一步 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 跨性别者男性。澄清跨性T疗法对生殖道的影响和可逆性可以 导致跨性别者男性临床生育护理的未来范式转变。

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.