Steroidogenic versus Metabolic Programming of Reproductive Neuroendocrine, Ovarian and Metabolic Dysfunctions.
Steroidogenic versus Metabolic Programming of Reproductive Neuroendocrine, Ovarian and Metabolic Dysfunctions.
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DOI：
10.1159/000381830
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发表时间：
2015
影响因子：
4.1
通讯作者：
Padmanabhan V
中科院分区：
文献类型：
--
作者：
Cardoso RC;Puttabyatappa M;Padmanabhan V
生殖系统对早期接触类固醇激素的敏感性已经成为我们现代社会的一个主要问题。人类胎儿由于暴露于干扰内分泌的化学物质、在怀孕期间无意中使用避孕药以及在疾病状态下过量暴露于类固醇而面临异常编程的风险。动物模型为了解疾病的发育起源提供了无与伦比的资源。在雌性绵羊中，产前暴露于睾酮(T)过量会导致一系列与多囊卵巢综合征（PCOS）女性相似的成年生殖疾病，包括神经内分泌反馈机制中断，垂体对促性腺激素释放激素（GnRH）的敏感性增加，黄体生成素（LH）过量，功能性高雄激素症和多卵泡卵巢形态，最终导致早期生殖功能衰竭。产前t治疗也会导致胎儿生长迟缓、胰岛素抵抗和高血压。越来越多的证据表明，发育中暴露于不适当的类固醇和代谢环境可能会介导产前t治疗的雌性成年障碍的编程，而这些缺陷在产后的性类固醇和代谢环境中得以维持或放大。本文综述了甾体激素和代谢对产前t治疗绵羊PCOS表型的发展和维持的贡献，特别关注产前和产后雄激素拮抗剂或胰岛素增敏剂治疗作为预防/改善这些功能障碍的潜在策略的影响。从这些干预策略中获得的关于这些缺陷背后机制的见解可能与人类多囊卵巢综合征具有翻译相关性。
The susceptibility of the reproductive system to early exposure to steroid hormones has become a major concern in our modern societies. Human fetuses are at risk of abnormal programming via exposure to endocrine disrupting chemicals, inadvertent use of contraceptive pills during pregnancy, as well as from excess exposure to steroids through disease states. Animal models provide an unparalleled resource to understand the developmental origin of diseases. In female sheep, prenatal exposure to testosterone (T) excess results in an array of adult reproductive disorders that recapitulate those seen in women with polycystic ovary syndrome (PCOS), including disrupted neuroendocrine feedback mechanisms, increased pituitary sensitivity to gonadotropin-releasing hormone (GnRH), luteinizing hormone (LH) excess, functional hyperandrogenism, and multifollicular ovarian morphology culminating in early reproductive failure. Prenatal T-treatment also leads to fetal growth retardation, insulin resistance, and hypertension. Mounting evidence suggests that developmental exposure to improper steroidal as well as metabolic environment may mediate the programming of adult disorders in prenatal T-treated females and these defects are maintained or amplified by postnatal sex steroid and metabolic milieu. This review addresses the steroidal and metabolic contributions to the development and maintenance of PCOS phenotype in the prenatal T-treated sheep model, centering specifically on the effects of prenatal and postnatal treatment with androgen antagonist or insulin sensitizer as potential strategies to prevent/ameliorate these dysfunctions. Insights obtained from these intervention strategies on the mechanisms underlying these defects are likely to have translational relevance to human PCOS.