Lara H E, Dissen G A, Leyton V, Paredes A, Fuenzalida H, Fiedler J L, Ojeda S R
Laboratory of Neurobiochemistry, Faculty of Chemistry and Pharmaceutical Sciences, Universidad de Chile, Santiago.
Endocrinology. 2000 Mar;141(3):1059-72. doi: 10.1210/endo.141.3.7395.
A form of polycystic ovary (PCO) resembling some aspects of the human PCO syndrome can be induced in rats by a single injection of estradiol valerate (EV). An increase in sympathetic outflow to the ovary precedes, by several weeks, the appearance of cysts, suggesting the involvement of a neurogenic component in the pathology of this ovarian dysfunction. The present study was carried out to test the hypotheses that this change in sympathetic tone is related to an augmented production of ovarian nerve growth factor (NGF), and that this abnormally elevated production of NGF contributes to the formation of ovarian cysts induced by EV. Injection of the steroid resulted in increased intraovarian synthesis of NGF and its low affinity receptor, p75 NGFR. The increase was maximal 30 days after EV, coinciding with the elevation in sympathetic tone to the ovary and preceding the appearance of follicular cysts. Intraovarian injections of the retrograde tracer fluorogold combined with in situ hybridization to detect tyrosine hydroxylase (TH) messenger RNA-containing neurons in the celiac ganglion revealed that these changes in NGF/p75 NGFR synthesis are accompanied by selective activation of noradrenergic neurons projecting to the ovary. The levels of RBT2 messenger RNA, which encodes a beta-tubulin presumably involved in slow axonal transport, were markedly elevated, indicating that EV-induced formation of ovarian cysts is preceded by functional activation ofceliac ganglion neurons, including those innervating the ovary. Intraovarian administration of a neutralizing antiserum to NGF in conjunction with an antisense oligodeoxynucleotide to p75 NGFR, via Alzet osmotic minipumps, restored estrous cyclicity and ovulatory capacity in a majority of EV-treated rats. These functional changes were accompanied by restoration of the number of antral follicles per ovary that had been depleted by EV and a significant reduction in the number of both precystic follicles and follicular cysts. The results indicate that the hyperactivation of ovarian sympathetic nerves seen in EV-induced PCO is related to an overproduction of NGF and its low affinity receptor in the gland. They also suggest that activation of this neurotrophic-neurogenic regulatory loop is a component of the pathological process by which EV induces cyst formation and anovulation in rodents. The possibility exists that a similar alteration in neurotrophic input to the ovary contributes to the etiology and/or maintenance of the PCO syndrome in humans.
单次注射戊酸雌二醇（EV）可在大鼠中诱导出一种类似于人类多囊卵巢（PCO）综合征某些方面的多囊卵巢形式。卵巢交感神经输出增加在囊肿出现前数周就已发生，这表明神经源性成分参与了这种卵巢功能障碍的病理过程。本研究旨在检验以下假设：交感神经张力的这种变化与卵巢神经生长因子（NGF）产生增加有关，且NGF这种异常升高的产生促成了EV诱导的卵巢囊肿形成。注射该类固醇导致卵巢内NGF及其低亲和力受体p75 NGFR的合成增加。这种增加在EV注射后30天达到最大值，与卵巢交感神经张力升高同时出现且早于卵泡囊肿的出现。卵巢内注射逆行示踪剂荧光金并结合原位杂交以检测腹腔神经节中含酪氨酸羟化酶（TH）信使RNA的神经元，结果显示NGF/p75 NGFR合成的这些变化伴随着投射至卵巢的去甲肾上腺素能神经元的选择性激活。编码可能参与慢速轴突运输的β-微管蛋白的RBT2信使RNA水平显著升高，表明EV诱导的卵巢囊肿形成之前，腹腔神经节神经元包括支配卵巢的神经元发生了功能激活。通过Alzet渗透微型泵在卵巢内给予NGF中和抗血清并结合p75 NGFR反义寡脱氧核苷酸，可使大多数接受EV治疗的大鼠恢复发情周期和排卵能力。这些功能变化伴随着每个卵巢中因EV而减少的窦状卵泡数量的恢复以及囊前卵泡和卵泡囊肿数量的显著减少。结果表明，在EV诱导的PCO中所见的卵巢交感神经的过度激活与腺体中NGF及其低亲和力受体的过度产生有关。它们还表明，这种神经营养 - 神经源性调节回路的激活是EV在啮齿动物中诱导囊肿形成和无排卵的病理过程的一个组成部分。卵巢神经营养输入的类似改变可能导致人类PCO综合征的病因和/或维持。
