雄激素过多对女性生殖的胎儿编程:多囊卵巢综合征的一种发育病因?

Androgen excess fetal programming of female reproduction: a developmental aetiology for polycystic ovary syndrome?

作者信息

Abbott D H, Barnett D K, Bruns C M, Dumesic D A

机构信息

National Primate Research Center.

出版信息

Hum Reprod Update. 2005 Jul-Aug;11(4):357-74. doi: 10.1093/humupd/dmi013.

Abstract

The aetiology of polycystic ovary syndrome (PCOS) remains unknown. This familial syndrome is prevalent among reproductive-aged women and its inheritance indicates a dominant regulatory gene with incomplete penetrance. However, promising candidate genes have proven unreliable as markers for the PCOS phenotype. This lack of genetic linkage may represent both extreme heterogeneity of PCOS and difficulty in establishing a universally accepted PCOS diagnosis. Nevertheless, hyperandrogenism is one of the most consistently expressed PCOS traits. Animal models that mimic fetal androgen excess may thus provide unique insight into the origins of the PCOS syndrome. Many female mammals exposed to androgen excess in utero or during early post-natal life typically show masculinized and defeminized behaviour, ovulatory dysfunction and virilized genitalia, although behavioural and ovulatory dysfunction can coexist without virilized genitalia based upon the timing of androgen excess. One animal model shows particular relevance to PCOS: the prenatally androgenized female rhesus monkey. Females exposed to androgen excess early in gestation exhibit hyperandrogenism, oligomenorrhoea and enlarged, polyfollicular ovaries, in addition to LH hypersecretion, impaired embryo development, insulin resistance accompanying abdominal obesity, impaired insulin response to glucose and hyperlipidaemia. Female monkeys exposed to androgen excess late in gestation mimic these programmed changes, except for LH and insulin secretion defects. In utero androgen excess may thus variably perturb multiple organ system programming and thereby provide a single, fetal origin for a heterogeneous adult syndrome.

摘要

多囊卵巢综合征(PCOS)的病因仍不清楚。这种家族性综合征在育龄妇女中很常见,其遗传表明存在一个具有不完全外显率的显性调节基因。然而,有前景的候选基因已被证明作为PCOS表型的标志物并不可靠。这种基因连锁的缺乏可能既代表了PCOS的极端异质性,也代表了难以建立一个普遍接受的PCOS诊断标准。尽管如此,高雄激素血症是PCOS最一致表现的特征之一。因此,模拟胎儿雄激素过多的动物模型可能会为PCOS综合征的起源提供独特的见解。许多在子宫内或出生后早期暴露于雄激素过多的雌性哺乳动物通常会表现出男性化和去女性化行为、排卵功能障碍和生殖器男性化,尽管根据雄激素过多的时间,行为和排卵功能障碍可以在没有生殖器男性化的情况下同时存在。一种动物模型与PCOS特别相关:产前雄激素化的雌性恒河猴。在妊娠早期暴露于雄激素过多的雌性除了会出现高雄激素血症、月经过少和卵巢增大、多囊外,还会出现促黄体生成素(LH)分泌过多(高分泌)、胚胎发育受损、伴有腹部肥胖的胰岛素抵抗、胰岛素对葡萄糖反应受损和高脂血症。在妊娠后期暴露于雄激素过多的雌性猴子会模拟这些程序化的变化,但LH和胰岛素分泌缺陷除外。因此,子宫内雄激素过多可能会不同程度地扰乱多个器官系统的程序化,从而为一种异质性成人综合征提供单一的胎儿起源。

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