Reproductive Consequences of Prenatal Androgenization

多囊卵巢综合征（PCOS）是最常见的内分泌疾病，影响了10%的育龄妇女。慢性高雄激素无排卵的病因，如多囊卵巢综合征，可能有遗传基础。虽然潜在的机制尚不清楚，多囊卵巢综合征现在被认为是高雄激素症伴随无排卵。多囊卵巢形态与胎儿出生前暴露于大量性类固醇的情况高度相关。例如，典型的21-羟化酶缺乏症女性与多囊卵巢综合征相似，表现为无排卵、卵巢雄激素过多和黄体生成素分泌过多。也许在生命早期过量的性类固醇可能提供荷尔蒙“侮辱”，导致成年后多囊卵巢综合征的表现。本研究旨在利用一种新的模型，即产前雄激素化的绵羊（长妊娠期，单卵种），探讨多囊卵巢综合征的发育起源的因果机制。我们的初步研究表明，这些羊在成年期出现与多囊卵巢综合征女性相似的排卵缺陷：无排卵、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，我们将验证以下假设：产前暴露于雄激素会破坏成人生殖功能，最终导致高雄激素无排卵，这种破坏是通过对雌二醇正反馈作用的敏感性降低、促性腺激素驱动异常和/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生殖周期、卵巢功能、排卵能力和成年后生育能力的破坏程度，(2)对促性腺激素分泌的雌二醇刺激反馈敏感性的降低是否有助于产前雄激素化对产后生殖周期的破坏作用。(3)促性腺激素驱动异常和/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，它将建立离散的，实验诱导的胚胎羊雄激素过量，为成年期高雄激素无排卵提供了第一个明确的病因。

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.