Dubois Sharon L, Wolfe Andrew, Radovick Sally, Boehm Ulrich, Levine Jon E
Neuroscience Training Program (S.L.D.) and Department of Neuroscience (S.L.D., J.E.L.), University of Wisconsin-Madison, Madison, Wisconsin 53705; Department of Pediatrics (A.W., S.R.), Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Department of Pharmacology and Toxicology (U.B.), University of Saarland School of Medicine, Homburg D-66421, Germany; and Wisconsin National Primate Research Center (J.E.L.), Madison, Wisconsin 53715.
Endocrinology. 2016 Apr;157(4):1546-54. doi: 10.1210/en.2015-1923. Epub 2016 Jan 29.
Elimination of estrogen receptorα (ERα) from kisspeptin (Kiss1) neurons results in premature LH release and pubertal onset, implicating these receptors in 17β-estradiol (E2)-mediated negative feedback regulation of GnRH release during the prepubertal period. Here, we tested the dependency of prepubertal negative feedback on ERα in Kiss1 neurons. Prepubertal (postnatal d 14) and peripubertal (postnatal d 34) wild-type (WT) and Kiss1 cell-specific ERα knockout (KERαKO) female mice were sham operated or ovariectomized and treated with either vehicle- or E2-containing capsules. Plasma and tissues were collected 2 days after surgery for analysis. Ovariectomy increased LH and FSH levels, and E2 treatments completely prevented these increases in WT mice of both ages. However, in prepubertal KERαKO mice, basal LH levels were elevated vs WT, and both LH and FSH levels were not further increased by ovariectomy or affected by E2 treatment. Similarly, Kiss1 mRNA levels in the medial basal hypothalamus, which includes the arcuate nucleus, were suppressed with E2 treatment in ovariectomized prepubertal WT mice but remained unaffected by any treatment in KERαKO mice. In peripubertal KERαKO mice, basal LH and FSH levels were not elevated vs WT and were unaffected by ovariectomy or E2. In contrast to our previous findings in adult animals, these results demonstrate that suppression of gonadotropins and Kiss1 mRNA by E2 in prepubertal animals depends upon ERα activation in Kiss1 neurons. Our observations are consistent with the hypothesis that these receptors play a critical role in restraining GnRH release before the onset and completion of puberty.
从 kisspeptin（Kiss1）神经元中消除雌激素受体α（ERα）会导致促黄体生成素（LH）过早释放和青春期提前开始，这表明这些受体参与了青春期前阶段 17β-雌二醇（E2）介导的促性腺激素释放激素（GnRH）释放的负反馈调节。在此，我们测试了青春期前负反馈对 Kiss1 神经元中 ERα 的依赖性。对青春期前（出生后第 14 天）和青春期前后（出生后第 34 天）的野生型（WT）和 Kiss1 细胞特异性 ERα 基因敲除（KERαKO）雌性小鼠进行假手术或卵巢切除术，并用含载体或 E2 的胶囊进行处理。术后 2 天收集血浆和组织进行分析。卵巢切除术会增加 LH 和促卵泡生成素（FSH）水平，E2 处理完全阻止了这两种年龄的 WT 小鼠中这些水平的升高。然而，在青春期前的 KERαKO 小鼠中，基础 LH 水平相对于 WT 升高，卵巢切除术并未进一步增加 LH 和 FSH 水平，且不受 E2 处理的影响。同样，在切除卵巢的青春期前 WT 小鼠中，E2 处理会抑制内侧基底下丘脑（包括弓状核）中的 Kiss1 mRNA 水平，但在 KERαKO 小鼠中，任何处理均未对其产生影响。在青春期前后的 KERαKO 小鼠中，基础 LH 和 FSH 水平相对于 WT 并未升高，且不受卵巢切除术或 E2 的影响。与我们之前在成年动物中的发现相反，这些结果表明，青春期前动物中 E2 对促性腺激素和 Kiss1 mRNA 的抑制取决于 Kiss1 神经元中的 ERα 激活。我们观察结果与以下假设一致，即这些受体在青春期开始和结束之前抑制 GnRH 释放中起关键作用。
