影响后代?Nature子刊:这一女性不孕远比我们想象得复杂
2018/05/18
多囊卵巢综合征(PCOS)影响着全球超10%的育龄女性,是女性不孕的主要原因,容易增加代谢类疾病风险,且有遗传倾向。现在,一篇发表在《Nature Medicine》期刊上的文章揭示:PCOS的发生与胎儿在子宫中的发育环境有关。


多囊卵巢综合征有很多典型的症状,包括无排卵(或者排卵稀少)、多囊卵巢、雄激素高等。但它的致病原因一直是个未解之谜。

之前已有很多研究表明,当孕妇表现有多囊卵巢综合征,那么子宫中的胎儿(女性)也会发生激素的改变,并可能在多年后表现出PCOS症状。特别是,几个基于怀孕动物的研究发现,孕期接触高水平的雄性激素(类似于PCOS),会导致其后代出现不排卵等类似于PCOS的症状。

现在,法国里尔大学的神经内分泌学家Paolo Giacobini带领团队找到了这背后的关键证据:卵巢过度分泌的一种激素antimüllerian(AMH)会与母亲大脑中的一组神经元互作,并引发级联反应,进而破坏胎盘的酶类,最终导致后代表现出类似于PCOS的症状。


doi:10.1038/s41591-018-0035-5

过量的卵巢激素

Antimüllerian激素由卵巢中的小卵泡分泌。因为患有多囊卵巢综合征的女性卵泡异常增加,所以会分泌更多的AMH激素。

Paolo Giacobini团队在之前的研究中发现,AMH激素会影响大脑中的一组神经元,从而刺激脑下垂体分泌促黄体激素(LH)。对于健康女性而言,LH的分泌会促进排卵。但是PCOS患者却会因为高水平的LH,排卵受到抑制,睾酮水平反而上升。

Paolo Giacobini团队招募了4组处于孕中期的女性——体重正常的健康孕妇和PCOS孕妇、肥胖的健康孕妇和PCOS孕妇,分别采集她们的血样样本。正常情况下,AMH激素水平会因为怀孕而下降,因为这期间卵巢不活跃。

但是结果发现,相比于其他3组, 体重正常的PCOS孕妇的AMH激素水平却高出2-3倍。(为什么肥胖的PCOS孕妇AMH激素水平正常?这依然是个谜。)

小鼠试验:雄激素影响胎儿

上调的雄激素如何造成PCOS的遗传倾向?为了找到答案,Paolo Giacobini团队以怀孕的小鼠为模型,在妊娠后期给它们注射AMH激素,用于模拟PCOS女性的特质。结果发现,小鼠生育的雌性后代同样表现出类似于PCOS的症状,例如排卵稀少、高雄激素。

研究发现,在AMH激素的刺激下,母体分泌的过量睾酮会穿过胎盘,影响胎儿。研究人员推测,引起这一现象的原因在于AMH激素会抑制芳香酶(aromatase,一种位于胎盘的酶类,负责将睾酮转换为雌激素)的水平。一旦芳香酶活性降低,多余的睾酮会影响胎儿,使其处于一种类似于PCOS的环境中。

睾酮是PCOS的关键

这一最新研究是在小鼠模型中完成的,人类是否存在同样的机制?加州大学的生殖内分泌学家Jeffrey Chang认为这依然是个未知,因为人类胎盘表达的芳香酶远多于小鼠胎盘,所以AMH激素可能很难抑制芳香酶的作用。

不过值得肯定的是,这一新研究表明,睾酮是胎儿埋下PCOS风险的关键,再一次佐证了之前的研究结论——睾酮(AMH级联反应中的一环)可能是PCOS的“罪魁祸首”。

参考资料:

Scientists may be closer to understanding a mysterious but common cause of female infertility

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  • Elevated prenatal anti-Müllerian hormone reprograms the fetus and induces polycystic ovary syndrome in adulthood

    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.

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