LH IN GNRH NEURONS DURING REPRODUCTIVE SENESCENCE

在女性和某些实验动物的生殖老化过程中，观察到促性腺激素释放激素(GnRH)水平下降，但卵泡刺激素(FSH)和黄体生成素(LH)水平升高。这些矛盾的变化不能简单地用卵巢发育的功能障碍来解释，其机制仍有待确定。促性腺激素释放激素神经元含有促黄体生成素受体，而促黄体生成素抑制促性腺激素释放激素的合成和分泌，这一事实使我们推测促黄体生成素可能在生殖衰老过程中发挥作用。在生殖老化过程中，黄体生成素对促性腺激素释放激素合成的影响可能是由于下丘脑持续升高的促黄体生成素水平所致，在下丘脑，黄体生成素与促性腺激素释放激素神经元中的受体结合，从而抑制促性腺激素释放激素的合成。另外，促黄体生成素受体水平可能随着年龄的增长而改变，因此促性腺激素释放激素神经元对促黄体生成素抑制效应的敏感性可能增加。以下两个具体目标旨在使用几种成熟的细胞和分子生物学技术来验证我们的假设。(1)测定生殖衰老过程中促性腺激素释放激素(GnRH)神经元的黄体生成素受体水平。(2)探讨黄体生成素对生殖衰老过程中促性腺激素释放激素基因表达的调节作用。由于GnRH处于调节哺乳动物生殖的内分泌系统的顶端，还具有许多其他生理功能，因此确定与年龄相关的GnRH神经元功能改变的因素将极大地促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.