Neuroendocrinology. 2018;106(2):101-115. doi: 10.1159/000471878. Epub 2017 Apr 7.
Positive feedback on gonadotropin release requires not only estrogen but also progesterone to activate neural circuits. In rodents, ovarian estradiol (E2) stimulates progesterone synthesis in hypothalamic astrocytes (neuroP), needed for the luteinizing hormone (LH) surge. Kisspeptin (kiss) neurons are the principal stimulators of gonadotropin-releasing hormone neurons, and disruption of kiss signaling abrogates the LH surge. Similarly, blocking steroid synthesis in the hypothalamus or deleting classical progesterone receptor (PGR) selectively in kiss neurons prevents the LH surge. These results suggest a synergistic action of E2 and progesterone in kiss neurons to affect gonadotropin release. The mHypoA51, immortalized kiss-expressing neuronal cell line derived from adult female mice, is a tractable model for examining integration of steroid signaling underlying estrogen positive feedback. Here, we report that kiss neurons in vitro integrate E2 and progesterone signaling to increase levels of kiss translation and release. mHypoA51 neurons expressed nonclassical membrane progesterone receptors (mPRα and mPRβ) and E2-inducible PGR, required for progesterone-augmentation of E2-induced kiss expression. With astrocyte-conditioned media or in mHypoA51-astrocyte co-culture, neuroP augmented stimulatory effects of E2 on kiss protein. Progesterone activation of classical, membrane-localized PGR led to activation of MAPK and Src kinases. Importantly, progesterone or Src activation induced release of kiss from E2-primed mHypoA51 neurons. Consistent with previous studies, the present results provide compelling evidence that the interaction of E2 and progesterone stimulates kiss expression and release. Further, these results demonstrate a mechanism though which peripheral E2 may prime kiss neurons to respond to neuroP, mediating estrogen positive feedback.
促性腺激素释放的正反馈不仅需要雌激素，还需要孕激素来激活神经回路。在啮齿动物中，卵巢雌激素（E2）刺激下丘脑星形胶质细胞（neuroP）合成孕激素，这对于促黄体生成激素（LH）激增是必要的。Kisspeptin（Kiss）神经元是促性腺激素释放激素神经元的主要刺激物，而 Kiss 信号的中断会消除 LH 激增。同样，阻断下丘脑的类固醇合成或选择性地在 Kiss 神经元中删除经典孕激素受体（PGR）可防止 LH 激增。这些结果表明 E2 和孕激素在 Kiss 神经元中具有协同作用，以影响促性腺激素的释放。源自成年雌性小鼠的永生性 Kiss 表达神经元细胞系 mHypoA51 是研究雌激素正反馈下类固醇信号整合的可行模型。在这里，我们报告体外 Kiss 神经元整合 E2 和孕激素信号以增加 Kiss 翻译和释放水平。mHypoA51 神经元表达非经典膜孕激素受体（mPRα 和 mPRβ）和 E2 诱导型 PGR，这是孕激素增强 E2 诱导的 Kiss 表达所必需的。用星形胶质细胞条件培养基或在 mHypoA51-星形胶质细胞共培养物中，神经 P 增强了 E2 对 Kiss 蛋白的刺激作用。孕激素激活经典的、膜定位的 PGR 导致 MAPK 和 Src 激酶的激活。重要的是，孕激素或 Src 激活诱导来自 E2 预刺激的 mHypoA51 神经元的 Kiss 释放。与先前的研究一致，本研究结果提供了令人信服的证据，表明 E2 和孕激素的相互作用刺激了 Kiss 的表达和释放。此外，这些结果表明了一种机制，即外周 E2 可以使 Kiss 神经元对神经 P 作出反应，从而介导雌激素正反馈。
