THE ROLE OF THE HYPOTHALAMIC-PITUITARY AXIS IN MENOPAUSE

该项目的目标是确定下丘脑机制在多大程度上促进了高等灵长类动物的生殖衰老。更年期标志着生殖功能的停止，并可能导致与卵巢激素分泌不足相关的各种疾病的发作。虽然完整的下丘脑-垂体-卵巢轴是维持正常月经周期所必需的，但大量证据表明，卵巢卵泡丧失是更年期的主要后果。然而，越来越多的数据表明，下丘脑活动受损是老年妇女生殖能力下降的原因之一。对于下丘脑在女性更年期发展过程中的作用到底有多大，目前还没有明确的答案。由于恒河猴的月经周期与女性基本相似，也显示出更年期的发生，这只恒河猴似乎是解决这个问题的绝佳动物模型。因此，我们建议通过将幼龄动物的卵巢移植到老年动物身上来探讨下丘脑-垂体轴在绝经发展中的作用。具体目的是建立一个非人灵长类动物模型，由一个年轻供体移植卵巢的老年雌性猴子组成，以确定更年期期间下丘脑控制卵巢功能的缺陷（如果有的话）。这将通过检查将年轻的卵巢移植给年老的猴子对月经周期的影响，以及移植后受者体内的黄体酮（P4）和促卵泡激素（FSH）水平来实现。卵巢移植将在无菌条件下进行，从年轻捐赠者身上取出卵巢，并将其移植到切除卵巢的老猴子的皮下袋中。通过每日阴道出血观察记录月经周期，通过RIA测定血浆P4和FSH水平。这些研究将进一步加深我们对更年期生物学的理解，因此将与更年期相关疾病的治疗方法的发展有关。

The goal of this project is to determine the extent to which hypothalamic mechanisms contribute to reproductive aging in higher primates. Menopause signals the cessation of reproductive function and may lead to the onset of variety of disorders associated with a deficiency in ovarian hormone secretion. While an intact hypothalamic-pituitary-ovarian axis is required for maintenance of normal menstrual cyclicity, considerable evidence suggests that menopause is the primary consequence of ovarian follicular loss. However, data are accumulating to argue that impaired hypothalamic activity contribute to reproductive decline in aging women. There is still no clear cut answer to the question of the precise degree to which the hypothalamus is involved in the development of the menopause in women. Since the rhesus monkey exhibits a menstrual cycle essentially similar to that of women and also shows the occurrence of menopause, this macaque appears to serve as an excellent animal model to address this question. Thus, we have proposed to ask the question of the involvement of the hypothalamic-pituitary axis in the development of menopause by transplanting ovaries of young to old animals. The Specific Aim is to establish a non-human primate model consisting of the aged female monkey bearing an ovarian transplant from a young donor in order to identify defects, if any, in the hypothalamic control of ovarian function during the menopause.This will be achieved by examining the effects of transplantation of young ovaries to old monkeys on menstrual cycles, and progesterone (P4) and follicle-stimulating hormone (FSH) levels in the recipients during the post-transplantation period. Ovarian transplantation will be conducted under sterile conditions by removing ovaries from young donors and transplanting them in subcutaneous pouches of the ovariectomized old monkeys. Menstrual cycles will be recorded from daily observations of vaginal bleeding, and plasma P4 and FSH levels will be determined by RIA. These studies will further our understanding of the biology of the menopause, and therefore will be relevant to the development of therapeutic approaches to the disorders associated with the menopause.