Corticosterone Blocks Ovarian Cyclicity and the LH Surge via Decreased Kisspeptin Neuron Activation in Female Mice
Corticosterone Blocks Ovarian Cyclicity and the LH Surge via Decreased Kisspeptin Neuron Activation in Female Mice
复制标题
DOI：
10.1210/en.2015-1711
复制
发表时间：
2016-03-01
期刊：
影响因子：
4.8
通讯作者：
Breen, Kellie M.
中科院分区：
文献类型：
--
作者：
Luo, Elena;Stephens, Shannon B. Z.;Breen, Kellie M.
应激刺激下丘脑-垂体-肾上腺轴的激活，导致循环糖皮质激素增加，促性腺激素分泌和卵巢周期性受损。在这里，我们检验了一个假设，即应激状态下糖皮质激素水平的升高通过干扰LH峰所必需的排卵前内分泌事件序列而破坏卵巢周期性。在植入胆固醇或皮质酮（Cort）颗粒的雌性小鼠中监测卵巢周期。Cort，而不是胆固醇，在间情期阻止了周期性。随后的研究集中在Cort通过评估对正反馈雌二醇信号的反应性来阻止排卵前序列的机制上。卵巢切除小鼠接受LH激增诱导雌二醇植入物以及Cort或胆固醇治疗，并在几天后评估预期激增当晚的LH水平。所有胆固醇雌性动物均显示出明显的LH激增。在预期激增时，皮质醇给药雌性动物中未检测到LH水平。原位杂交分析的前腹侧脑室周围核显示，Cort鲁棒地抑制Kiss 1细胞共表达c-fos的百分比，以及减少Kiss 1细胞的数量和每个细胞的Kiss 1 mRNA的量，与对照组的表达相比。此外，Cort减弱了编码GnRH受体和LH β的基因的垂体表达，表明在LH峰阻断期间对促性腺激素的抑制。总的来说，我们的研究结果支持这一假设，即生理应激水平的Cort破坏卵巢周期性，部分是通过破坏下丘脑和垂体水平的正反馈机制，这是产生排卵前LH峰所必需的。
Stress elicits activation of the hypothalamic-pituitary-adrenal axis, which leads to enhanced circulating glucocorticoids, as well as impaired gonadotropin secretion and ovarian cyclicity. Here, we tested the hypothesis that elevated, stress-levels of glucocorticoids disrupt ovarian cyclicity by interfering with the preovulatory sequence of endocrine events necessary for the LH surge. Ovarian cyclicity was monitored in female mice implanted with a cholesterol or corticosterone (Cort) pellet. Cort, but not cholesterol, arrested cyclicity in diestrus. Subsequent studies focused on the mechanism whereby Cort stalled the preovulatory sequence by assessing responsiveness to the positive feedback estradiol signal. Ovariectomized mice were treated with an LH surge-inducing estradiol implant, as well as Cort or cholesterol, and assessed several days later for LH levels on the evening of the anticipated surge. All cholesterol females showed a clear LH surge. At the time of the anticipated surge, LH levels were undetectable in Cort-treated females. In situ hybridization analyses the anteroventral periventricular nucleus revealed that Cort robustly suppressed the percentage of Kiss1 cells coexpressing cfos, as well as reduced the number of Kiss1 cells and amount of Kiss1 mRNA per cell, compared with expression in control brains. In addition, Cort blunted pituitary expression of the genes encoding the GnRH receptor and LH beta, indicating inhibition of gonadotropes during the blockage of the LH surge. Collectively, our findings support the hypothesis that physiological stress-levels of Cort disrupts ovarian cyclicity, in part, through disruption of positive feedback mechanisms at both the hypothalamic and pituitary levels which are necessary for generation of the preovulatory LH surge.