Sotomayor-Zárate Ramón, Dorfman Mauricio, Paredes Alfonso, Lara Hernán E
Laboratory of Neurobiochemistry, Department of Biochemistry and Molecular Biology, Faculty of Chemistry and Pharmaceutical Sciences, University of Chile, Santiago 838-0492, Chile.
Biol Reprod. 2008 Apr;78(4):673-80. doi: 10.1095/biolreprod.107.063974. Epub 2007 Dec 12.
A single injection of estradiol valerate (EV) to 14-day-old rats (when the ovarian follicle population has been already established) disrupts cyclicity, increases the activity of key enzymes of androgen biosynthesis, and develops polycystic ovary by a causally related increase in ovarian noradrenaline (NA). The current study examined an early window of ovarian development to look for a specific stage of development at which estradiol can induce such changes in sympathetic activity and follicular development. A single dose of EV applied to rats before the first 12 h of life rapidly increases (after 24 h) the ovarian expression of nerve growth factor (Ngfb) and p75 low-affinity neurotrophic receptor (Ngfr) mRNAs. When adults, rats presented early vaginal opening, disrupted cyclicity, appearance of follicular cyst, absence of corpus luteum, and infertility. Total follicles decreased, mainly due to a reduced number of primordial follicles, suggesting that estradiol acts in the first stages of folliculogenesis, when primordial follicles are organizing. These changes paralleled a 6-fold increase in NA concentration. No changes in NA content were found in the celiac ganglia, suggesting a local, non-centrally mediated effect of estradiol. Surgical section of the superior ovarian nerve (the main source of sympathetic nerves to the ovary) to rats neonatally treated with EV decreased intraovarian NA, delayed vaginal opening, and blocked the development of follicular cyst and that of preovulatory follicles. Therefore, we can conclude that early exposure to estradiol permanently modifies ovarian sympathetic activity and causes profound changes in follicular development, leading to the polycystic ovary condition.
对14日龄大鼠（此时卵巢卵泡群体已经形成）单次注射戊酸雌二醇（EV）会破坏其月经周期，增加雄激素生物合成关键酶的活性，并通过卵巢去甲肾上腺素（NA）的因果性增加而导致多囊卵巢的形成。本研究检查了卵巢发育的早期窗口，以寻找一个特定的发育阶段，在此阶段雌二醇可诱导交感神经活动和卵泡发育发生此类变化。在出生后前12小时内给大鼠单次注射EV，会迅速（24小时后）增加神经生长因子（Ngfb）和p75低亲和力神经营养受体（Ngfr）mRNA的卵巢表达。成年后，大鼠出现阴道早熟开放、月经周期紊乱、卵泡囊肿出现、黄体缺失和不孕。卵泡总数减少，主要是由于原始卵泡数量减少，这表明雌二醇在卵泡发生的早期阶段起作用，即原始卵泡正在形成之时。这些变化与NA浓度增加6倍平行。在腹腔神经节中未发现NA含量有变化，这表明雌二醇的作用是局部的，而非由中枢介导。对新生期接受EV治疗的大鼠进行卵巢上神经（卵巢交感神经的主要来源）手术切断，可降低卵巢内NA水平，延迟阴道开放，并阻止卵泡囊肿和排卵前卵泡的发育。因此，我们可以得出结论，早期暴露于雌二醇会永久性改变卵巢交感神经活动，并导致卵泡发育发生深刻变化，从而导致多囊卵巢状况。
