Reproductive Consequences of Prenatal Androgenization

产前雄激素化的生殖后果

• 批准号: 6902605
• 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 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6902605
• 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.

多囊卵巢综合征(PCOS)是最常见的内分泌疾病，影响10%的育龄妇女。慢性高雄激素无排卵的病因学，如多囊卵巢综合征，可能有遗传基础。尽管其潜在的机制尚不清楚，但现在公认为伴有无排卵的高雄激素血症。多囊卵巢形态与胎儿出生前暴露于高量性类固醇的情况高度相关。例如，患有典型的21-羟基酶缺乏症的女性表现为多囊卵巢综合征，表现为无排卵、卵巢高雄激素血症和黄体生成素高分泌。也许在生命早期过量的性类固醇可能会造成荷尔蒙“侮辱”，导致成年后表现为多囊卵巢综合征。这项建议旨在使用一种新的模型，即产前雄激素化的绵羊(长孕，单卵泡物种)，来研究多囊卵巢综合征的发育起源的原因机制。我们的初步研究表明，这些绵羊在成年后会出现类似于患有多囊卵巢综合征的女性的排卵缺陷：无排卵、黄体生成素水平升高、高雄激素血症、高胰岛素血症和多卵泡卵巢。在这个方案中，我们将检验以下假设：产前暴露于雄激素会扰乱成人的生殖功能，最终导致高雄激素性无排卵，这种干扰是通过降低对雌二醇的正反馈作用、异常的促性腺激素驱动和/或卵巢对FSH的敏感性而介导的。拟议研究的具体目的是确定1)成年后胎儿暴露于雄激素对生殖周期、卵巢功能、排卵能力和生育力的干扰程度，(2)对雌二醇刺激性腺激素分泌反馈的敏感性降低是否有助于产前雄激素对出生后生殖周期的干扰效应，以及(3)性腺激素驱动异常和/或卵巢对FSH敏感性降低是否导致产前雄激素对出生后生殖周期的干扰效应。如果我们的发育不良被证明是正确的，这将为一种重要的成年生殖疾病的独特发育起源奠定基础。具体地说，它将确定离散的、实验诱导的胚胎绵羊雄激素过剩为成年后高雄激素性无排卵提供了第一个明确的病因。

项目成果

Sex differences and effects of prenatal exposure to excess testosterone on ventral tegmental area dopamine neurons in adult sheep.

• DOI: 10.1111/ejn.12871
• 发表时间: 2015-05
• 期刊: The European journal of neuroscience
• 作者: Brown EC;Steadman CJ;Lee TM;Padmanabhan V;Lehman MN;Coolen LM
• 通讯作者: Coolen LM

Prenatal programming by testosterone of hypothalamic metabolic control neurones in the ewe.

• DOI: 10.1111/j.1365-2826.2011.02126.x
• 发表时间: 2011-05
• 期刊: Journal of neuroendocrinology
• 影响因子: 3.2
• 作者: Sheppard KM;Padmanabhan V;Coolen LM;Lehman MN
• 通讯作者: Lehman MN

Postnatal developmental consequences of altered insulin sensitivity in female sheep treated prenatally with testosterone.

• DOI: 10.1152/ajpendo.00107.2005
• 发表时间: 2005-11
• 期刊: American journal of physiology. Endocrinology and metabolism
• 作者: S. Recabarren;V. Padmanabhan;E. Codner;A. Lobos;C. Durán;M. Vidal;D. Foster;T. Sir-Petermann

Fetal programming: testosterone exposure of the female sheep during midgestation disrupts the dynamics of its adult gonadotropin secretion during the periovulatory period.

胎儿编程：雌性绵羊在妊娠中期暴露的睾酮会扰乱其在排卵期期间成年促性腺激素分泌的动态。

• DOI: 10.1095/biolreprod.104.031070
• 发表时间: 2005
• 期刊: Biology of reproduction.
• 作者: Savabieasfahani,Mozhgan;Lee,JamesS;Herkimer,Carol;Sharma,TejinderP;Foster,DouglasL;Padmanabhan,Vasantha
• 通讯作者: Padmanabhan,Vasantha

Developmental programming in sheep: administration of testosterone during 60-90 days of pregnancy reduces breeding success and pregnancy outcome.

• DOI: 10.1016/j.theriogenology.2006.08.010
• 发表时间: 2007-02
• 期刊: Theriogenology
• 影响因子: 2.8
• 作者: T. Steckler;E. K. Roberts;D. D. Doop-D.;Theresa M. Lee;V. Padmanabhan