GNRH AND HOT FLASHES

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。在美国，超过2500万女性受到潮热的影响，其严重程度从刺激到严重虚弱不等。以前用激素替代疗法治疗，这种疗法不再可取，显然必须开发非甾体替代品。我们对潮热的原因了解甚少。该建议寻求进一步了解负责潮热产生的神经元机制，这可能导致非类固醇治疗的发展。近30年前，有证据表明潮热与黄体生成素（LH）的间歇性释放有关。虽然很明显，黄体生成素与潮热没有因果关系，但几乎没有关于产生黄体生成素脉冲的神经激素，促性腺激素释放激素（GnRH）的研究。我们的实验室在绵羊身上提供了令人信服的证据，表明GnRH以高浓度释放到CSF中，这表明这种肽可能通过非神经内分泌途径与大脑交流。确定GnRH在脑脊液中的生理功能是我们的长期目标。初步数据表明，低雌激素环境导致释放到CSF的GnRH显著增加。还有令人信服的证据表明，GnRH可能影响热敏神经元。综合这些研究，我们的中心假设是明确的：类固醇控制GnRH分泌到脑脊液（CSF），从而影响体温调节。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Hot flashes affect over 25 million women in the US and range in severity from irritating to severely debilitating. Previously treated with hormone replacement therapy, this therapy is no longer advisable and clearly non-steroidal alternatives must be developed. Our understanding of the causes of hot flashes is poor. This proposal seeks further understanding of the neuronal mechanisms responsible for the generation of hot flashes, which may lead to the development of non-steroid treatments. Nearly 30 years ago, evidence was provided that linked hot flashes to the episodic release of luteinizing hormone (LH). Although it is clear that LH is not involved causally in hot flashes, there are almost no studies on the neurohormone responsible for the generation of LH pulses, Gonadotropin-Releasing Hormone (GnRH). Our laboratory has provided compelling evidence in the sheep that GnRH is released into the CSF in high concentrations, suggesting a non-neuroendocrine route that this peptide may communicate with the brain. It is our long-term objective to determine the physiological functions of GnRH in CSF. Preliminary data suggest that a hypo-estrogen environment causes a significant increase in GnRH released into CSF. There is also compelling evidence that GnRH may affect thermosensitive neurons. Taking these studies together, our central hypothesis is clear: steroids control the secretion of GnRH into the cerebrospinal fluid (CSF) and, thereby, influence thermoregulation.