Department of Obstetrics and Gynaecology, IWK Health Centre, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada B3K 6R8.
Brain Res. 2012 Jul 27;1467:1-9. doi: 10.1016/j.brainres.2012.05.049. Epub 2012 Jun 2.
An intact hypothalamic kiss1/kisspeptin/kiss1r complex is a prerequisite for reproductive competence, and kisspeptin treatment could be a practical therapeutic approach to some problems of infertility. One such disorder is polycystic ovarian syndrome (PCOS), a common cause of infertility affecting more than 100 million women. A rodent model of PCOS is the prepubertal female rat treated for a prolonged period with dihydrotestosterone (DHT), which induces many of the metabolic characteristics of the syndrome. We hypothesized that hypothalamic kiss1 mRNA levels, and kisspeptin immunoreactivity (ir), would be abnormal in these rats. Prepubertal female rats were exposed to DHT for 60 days. Rats were killed in two groups: at 26 and 60 days of DHT exposure. Kiss1 mRNA was quantified in hypothalamus, pituitary, ovary and visceral adipose tissue. Separate groups of rats provided brain tissue for immunohistochemical analysis of kisspeptin-ir. At 26 days of DHT exposure, hypothalamic kiss1 mRNA was severely depleted. In contrast DHT had no effect on pituitary kiss1 expression but it significantly increased levels of kiss1 mRNA in fat (+9-fold; p<0.01) and in ovary (+3-fold; p<0.05). At 60days, kiss1 expression had reverted to normal in hypothalamus and ovary but remained elevated in fat (+4-fold; p<0.05). Immunohistochemical analysis revealed that after 26 days of exposure to DHT, kisspeptin-ir was almost completely absent in the arcuate nucleus and a large depletion in kisspeptin +ve fibers was also seen in the paraventricular nucleus, supraoptic nucleus and in the anteroventral periventricular area. At 60 days, despite restored normal levels of kiss1 mRNA, hypothalamic kisspeptin-ir remained depleted in the treated rats. In summary Kiss1 gene expression is differentially affected in various tissues by chronic exposure to dihydrotestosterone in a rat model of polycystic ovary syndrome. In hypothalamus, specifically, kiss1 mRNA, and levels of kisspeptin immunoreactivity, are significantly reduced. Since these rats exhibit many of the characteristics of polycystic ovary syndrome, we suggest that atypical kiss1 expression may contribute to the multiple tissue abnormalities observed in women with this disorder. However, and of some importance, our data do not appear to be consistent with the elevated levels of LH seen in women with PCOS; i.e. reduced levels of hypothalamic kiss1 mRNA and kisspeptin immunoreactivity observed in DHT-treated rats are unlikely to produce elevated LH secretion.
一个完整的下丘脑 kiss1/kisspeptin/kiss1r 复合体是生殖能力的先决条件，而 kisspeptin 治疗可能是治疗某些不孕问题的一种实用方法。多囊卵巢综合征（PCOS）就是这样一种疾病，它是一种常见的导致不孕的疾病，影响着超过 1 亿名女性。PCOS 的啮齿动物模型是接受长期二氢睾酮（DHT）治疗的青春期前雌性大鼠，这种治疗会引起该综合征的许多代谢特征。我们假设这些大鼠的下丘脑 kiss1 mRNA 水平和 kisspeptin 免疫反应（ir）会异常。青春期前的雌性大鼠接受 DHT 治疗 60 天。将大鼠分为两组：DHT 暴露 26 天和 60 天。在下丘脑、垂体、卵巢和内脏脂肪组织中定量 kiss1 mRNA。另一组大鼠提供脑组织进行 kisspeptin-ir 的免疫组织化学分析。在 DHT 暴露 26 天时，下丘脑 kiss1 mRNA 严重耗竭。相比之下，DHT 对垂体 kiss1 的表达没有影响，但它显著增加了脂肪组织中的 kiss1 mRNA 水平（增加 9 倍；p<0.01）和卵巢中的 kiss1 mRNA 水平（增加 3 倍；p<0.05）。60 天时，下丘脑和卵巢中的 kiss1 表达已恢复正常，但脂肪组织中的 kiss1 mRNA 仍升高（增加 4 倍；p<0.05）。免疫组织化学分析显示，在接受 DHT 治疗 26 天后，弓状核中的 kisspeptin-ir 几乎完全缺失，室旁核、视上核和前腹侧脑室周围区中的 kisspeptin +ve 纤维也大量缺失。60 天时，尽管 kiss1 mRNA 恢复正常水平，但接受治疗的大鼠下丘脑 kisspeptin-ir 仍耗竭。总之，在多囊卵巢综合征大鼠模型中，慢性暴露于二氢睾酮会对各种组织中的 Kiss1 基因表达产生不同的影响。特别是在下丘脑，kiss1 mRNA 和 kisspeptin 免疫反应性显著降低。由于这些大鼠表现出多囊卵巢综合征的许多特征，我们认为异常的 kiss1 表达可能导致该疾病女性的多种组织异常。然而，重要的是，我们的数据似乎与多囊卵巢综合征女性中升高的 LH 水平不一致；即 DHT 处理大鼠中观察到的下丘脑 kiss1 mRNA 和 kisspeptin 免疫反应性降低不太可能导致 LH 分泌升高。
