LH IN GNRH NEURONS DURING REPRODUCTIVE SENESCENCE

在女性和一些实验动物的生殖衰老过程中观察到GnRH下降，但FSH和LH水平升高。这些矛盾的变化不能简单地用卵巢功能障碍来解释，其机制仍有待确定。GnRH神经元含有LH受体，而LH抑制GnRH的合成和分泌，这一事实使我们假设LH可能在生殖衰老过程中发挥作用。在生殖衰老过程中，LH对GnRH合成影响的潜在机制可能是由于LH水平不断升高，并反馈到下丘脑，在下丘脑，LH与GnRH神经元中的受体结合，抑制GnRH合成。另外，LH受体水平可能随着年龄的增长而变化，因此GnRH神经元对LH抑制作用的敏感性可能会增加。以下两个特定的目的是为了测试我们的假设，使用几种完善的细胞和分子生物学技术。(1)测定生殖衰老过程中GnRH神经元中LH受体水平。(2)探讨生殖衰老过程中LH对GnRH基因表达的调控作用。由于GnRH在调节哺乳动物生殖的内分泌系统中处于顶端，并且还具有许多其他生理功能，因此确定导致GnRH神经元功能与年龄相关改变的因素将极大地推进我们目前对生殖衰老的认识。

Decreased GnRH, but increased FSH and LH levels, have been observed during reproductive aging in women and some species of laboratory animals. These paradoxical changes can not simply be explained by the dysfunctions developing in the ovary, and the mechanism remains to be determined. The facts that GnRH neurons contain LH receptors and LH inhibits GnRH synthesis and secretion lead us to postulate that LH may play a role during reproductive senescence. The underlying mechanism on the effect of LH on GnRH synthesis during reproductive aging may result from the constantly elevated LH levels that feedback on the hypothalamus where LH binds to its receptors in GnRH neurons to inhibit GnRH synthesis. Alternatively, LH receptor levels may change with age and thus the sensitivity of GnRH neurons in response to the inhibitory effect of LH may be increased. The following two specific aims are designed to test our hypothesis using several well-established cellular and molecular biology techniques. (1) To determine LH receptor levels in GnRH neurons during reproductive aging. (2) To investigate the regulation of GnRH gene expression by LH during reproductive aging. Since GnRH is at the top of the endocrine hierarchy regulating mammalian reproduction and also has a number of other physiological functions, determining the factors that contribute to age-related alteration of GnRH neuronal functions will greatly advance our current knowledge of reproductive senescence.