Reproductive Consequences of Prenatal Androgenization

产前雄激素化的生殖后果

• 批准号: 6536420
• 负责人: VASANTHA PADMANABHAN
• 金额: $ 37.75万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-08-08 至 2006-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6536420
• 关键词: androgens; disease /disorder etiology; embryo /fetus; embryo /fetus drug adverse effect; estradiol; female; fertility; follicle stimulating hormone; glucose tolerance test; gonadotropins; histology; hormone regulation /control mechanism; in situ hybridization; longitudinal animal study; mature animal; ovulation; pathologic process; polycystic ovary syndrome; radioimmunoassay; reproductive development; reproductive system disorder; sex cycle; sheep; ultrasonography

Polycystic ovarian syndrome (PCOS) is the most common endocrinopathy and it affects 10 percent of reproductive-aged women. The etiology of chronic hyperandrogenic anovulations, such as PCOS, may have genetic underpinnings. Although the underlying mechanisms are unknown, PCOS is now recognized as hyperandrogenism accompanied by anovulation. Polycystic ovarian morphology is highly correlated with conditions in which the fetus has been exposed to high amounts of sex steroids before birth. For example, women with classical 21-hydroxylase deficiency mimic PCOS, exhibit anovulation, ovarian hyperandrogenism, and LH hypersecretion. Perhaps excess sex steroids early in life may provide a hormonal "insult" that results in manifestation of PCOS later in adulthood. This proposal aims to use a new model, the prenatally-androgenized sheep (long gestation, mono-ovular species), to investigate causal mechanisms for the developmental origins of PCOS. Our preliminary studies indicate that these sheep develop ovulatory defects during adulthood similar to those of women with PCOS: anovulation, elevated LH levels, hyperandrogenemia, hyperinsulinemia, and multifollicular ovaries. In this proposal, we will test the following hypothesis: prenatal exposure to androgens disrupts adult reproductive function culminating in hyperandrogenic anovulation and that this disruption is mediated via reduced sensitivity to the positive feedback actions of estradiol, abnormal gonadotropic drive and/or altered ovarian sensitivity to FSH. The specific Aims of the proposed research are to determine 1) the extent to which fetal exposure to androgens disrupts reproductive cyclicity, ovarian function, ovulatory capacity and fertility in adulthood, (2) if reduced sensitivity to estradiol stimulatory feedback of gonadotropin secretion contributes to the disruptive effects of prenatal- androgenization on postnatal reproductive cyclicity, and (3) if abnormal gonadotropic drive and/or reduced ovarian sensitivity to FSH contributes to the disruptive effects of prenatal- androgenization on postnatal reproductive cyclicity. If our hyposthesis proves to be correct, this would form the basis for a distinct developmental origin of an important reproductive disease in adulthood. Specifically it will establish that discrete, experimentally induced androgen excess of fetal sheep provides the first clear etiology for hyperandrogenic anovulation in adulthood.

多囊卵巢综合症 (PCOS) 是最常见的内分泌疾病，影响 10% 的育龄女性。 慢性高雄激素性无排卵（例如多囊卵巢综合症）的病因可能有遗传基础。 尽管根本机制尚不清楚，但多囊卵巢综合症现在被认为是伴有无排卵的高雄激素血症。 多囊卵巢形态与胎儿出生前接触大量性类固醇的情况高度相关。 例如，患有典型 21-羟化酶缺乏症的女性会表现出类似 PCOS 的症状，表现为无排卵、卵巢雄激素过多症和 LH 分泌过多。 也许生命早期过量的性类固醇可能会造成荷尔蒙“侮辱”，导致成年后出现多囊卵巢综合症。 该提案旨在使用一种新模型，即产前雄激素化绵羊（妊娠期长、单卵泡物种）来研究多囊卵巢综合症发育起源的因果机制。 我们的初步研究表明，这些绵羊在成年期会出现与 PCOS 女性相似的排卵缺陷：不排卵、LH 水平升高、高雄激素血症、高胰岛素血症和多卵泡卵巢。 在本提案中，我们将检验以下假设：产前暴露于雄激素会扰乱成年生殖功能，最终导致高雄激素性无排卵，并且这种扰乱是通过对雌二醇正反馈作用的敏感性降低、促性腺激素异常和/或卵巢对 FSH 敏感性改变来介导的。 拟议研究的具体目的是确定：1​​）胎儿暴露于雄激素对成年期生殖周期、卵巢功能、排卵能力和生育能力的干扰程度，（2）对促性腺激素分泌的雌二醇刺激反馈的敏感性降低是否会导致产前雄激素化对产后生殖的破坏性影响 (3) 促性腺激素异常驱动和/或卵巢对 FSH 敏感性降低是否会导致产前雄激素化对产后生殖周期的破坏性影响。 如果我们的假设被证明是正确的，这将为成年期一种重要生殖疾病的独特发育起源奠定基础。 具体来说，它将确定离散的、实验诱导的胎羊雄激素过多，为成年期高雄激素无排卵提供了第一个明确的病因。