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.
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