Polycystic ovary syndrome (PCOS) is the main cause of female infertility worldwide and corresponds with a high degree of comorbidities and economic burden. How PCOS is passed on from one generation to the next is not clear, but it may be a developmental condition. Most women with PCOS exhibit higher levels of circulating luteinizing hormone, suggestive of heightened gonadotropin-releasing hormone (GnRH) release, and anti-Müllerian hormone (AMH) as compared to healthy women. Excess AMH in utero may affect the development of the female fetus. However, as AMH levels drop during pregnancy in women with normal fertility, it was unclear whether their levels were also elevated in pregnant women with PCOS. Here we measured AMH in a cohort of pregnant women with PCOS and control pregnant women and found that AMH is significantly more elevated in the former group versus the latter. To determine whether the elevation of AMH during pregnancy in women with PCOS is a bystander effect or a driver of the condition in the offspring, we modeled our clinical findings by treating pregnant mice with AMH and followed the neuroendocrine phenotype of their female progeny postnatally. This treatment resulted in maternal neuroendocrine-driven testosterone excess and diminished placental metabolism of testosterone to estradiol, resulting in a masculinization of the exposed female fetus and a PCOS-like reproductive and neuroendocrine phenotype in adulthood. We found that the affected females had persistently hyperactivated GnRH neurons and that GnRH antagonist treatment in the adult female offspring restored their neuroendocrine phenotype to a normal state. These findings highlight a critical role for excess prenatal AMH exposure and subsequent aberrant GnRH receptor signaling in the neuroendocrine dysfunctions of PCOS, while offering a new potential therapeutic avenue to treat the condition during adulthood.

中文翻译：

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产前抗苗勒管激素升高会重新编程胎儿并在成年期诱发多囊卵巢综合征。

多囊卵巢综合征 (PCOS) 是全球女性不孕症的主要原因，伴随着高度的合并症和经济负担。PCOS如何从一代传给下一代尚不清楚，但它可能是一种发育状况。与健康女性相比，大多数 PCOS 女性的循环黄体生成素水平较高，这表明促性腺激素释放激素 (GnRH) 和抗苗勒管激素 (AMH) 释放增加。子宫内过多的 AMH 可能会影响女性胎儿的发育。然而，由于生育能力正常的女性在怀孕期间 AMH 水平下降，因此尚不清楚 PCOS 孕妇的 AMH 水平是否也升高。在这里，我们在一组患有 PCOS 的孕妇和对照孕妇中测量了 AMH，发现前者的 AMH 明显高于后者。为了确定患有 PCOS 的女性在怀孕期间 AMH 的升高是旁观者效应还是后代状况的驱动因素，我们通过用 AMH 治疗怀孕小鼠并在出生后跟踪其雌性后代的神经内分泌表型来模拟我们的临床发现。这种治疗导致母体神经内分泌驱动的睾酮过量和睾酮向雌二醇的胎盘代谢减少，导致暴露的女性胎儿男性化，成年期出现 PCOS 样生殖和神经内分泌表型。我们发现受影响的雌性具有持续过度活化的 GnRH 神经元，并且成年雌性后代的 GnRH 拮抗剂治疗将其神经内分泌表型恢复到正常状态。这些发现强调了产前 AMH 过度暴露和随后异常 GnRH 受体信号传导在 PCOS 神经内分泌功能障碍中的关键作用，同时为成年期治疗该病提供了新的潜在治疗途径。