Receptor Biology Group, Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, USA.
Pregnancy and Female Reproduction Group, Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, USA; and.
FASEB J. 2019 Jun;33(6):7375-7386. doi: 10.1096/fj.201802653RR. Epub 2019 Mar 13.
Polycystic ovary syndrome (PCOS) is a hypothalamic-pituitary-gonadal (HPG) axis disorder. PCOS symptoms most likely result from a disturbance in the complex feedback regulation system of the HPG axis, which involves gonadotrophic hormones and ovarian steroid hormones. However, the nature of this complex and interconnecting feedback regulation makes it difficult to dissect the molecular mechanisms responsible for PCOS phenotypes. Global estrogen receptor α (ERα) knockout (KO) mice exhibit a disruption of the HPG axis, resulting in hormonal dysregulation in which female ERα KO mice have elevated levels of serum estradiol (E2), testosterone, and LH. The ERα KO females are anovulatory and develop cystic hemorrhagic ovaries that are thought to be due to persistently high circulating levels of LH from the pituitary. However, the role of ERα in the pituitary is still controversial because of the varied phenotypes reported in pituitary-specific ERα KO mouse models. Therefore, we developed a mouse model where ERα is reintroduced to be exclusively expressed in the pituitary on the background of a global ERα-null (PitERtgKO) mouse. Serum E2 and LH levels were normalized in PitERtgKO females and were comparable to wild-type serum levels. However, the ovaries of PitERtgKO adult mice displayed a more overt cystic and hemorrhagic phenotype when compared with ERα KO littermates. We determined that anomalous sporadic LH secretion caused the severe ovarian phenotype of PitERtgKO females. Our observations suggest that pituitary ERα is involved in the estrogen negative feedback regulation, whereas hypothalamic ERα is necessary for the precise control of LH secretion. Uncontrolled, irregular LH secretion may be the root cause of the cystic ovarian phenotype with similarities to PCOS.-Arao, Y., Hamilton, K. J., Wu, S.-P., Tsai, M.-J., DeMayo, F. J., Korach, K. S. Dysregulation of hypothalamic-pituitary estrogen receptor α-mediated signaling causes episodic LH secretion and cystic ovary.
多囊卵巢综合征（PCOS）是一种下丘脑-垂体-性腺（HPG）轴紊乱。PCOS 症状很可能是由于 HPG 轴复杂的反馈调节系统紊乱引起的，该系统涉及促性腺激素和卵巢甾体激素。然而，这种复杂的相互关联的反馈调节的性质使得难以剖析导致 PCOS 表型的分子机制。全球雌激素受体α（ERα）敲除（KO）小鼠表现出 HPG 轴的破坏，导致激素失调，其中雌性 ERα KO 小鼠的血清雌二醇（E2）、睾丸酮和 LH 水平升高。ERα KO 雌性动物无排卵，并发展为囊性出血性卵巢，这被认为是由于来自垂体的持续高循环 LH 水平。然而，由于在垂体特异性 ERα KO 小鼠模型中报告了不同的表型，因此 ERα 在垂体中的作用仍然存在争议。因此，我们开发了一种小鼠模型，其中 ERα 仅在全球 ERα 缺失（PitERtgKO）小鼠的背景下在垂体中重新表达。PitERtgKO 雌性小鼠的血清 E2 和 LH 水平正常化，与野生型血清水平相当。然而，与 ERα KO 同窝仔鼠相比，PitERtgKO 成年小鼠的卵巢表现出更明显的囊性和出血性表型。我们确定异常散发性 LH 分泌导致 PitERtgKO 雌性小鼠严重的卵巢表型。我们的观察表明，垂体 ERα 参与雌激素的负反馈调节，而下丘脑 ERα 是精确控制 LH 分泌所必需的。不受控制的、不规则的 LH 分泌可能是与 PCOS 相似的囊性卵巢表型的根本原因。-Arao，Y.，Hamilton，K. J.，Wu，S.-P.，Tsai，M.-J.，DeMayo，F. J.，Korach，K. S. 下丘脑-垂体雌激素受体α介导的信号转导失调导致 LH 间歇性分泌和囊性卵巢。
