The studies outlined in this proposal are intended to delineate the mechanisms of action of GnRH in stimulating the synthesis and secretion of LH by the pituitary gonadotrope cells.
We aim to elucidate the role of GnRH given in a physiologic pulsatile manner and to examine the effects of changes in the GnRH secretory pattern whereby alterations in frequency and amplitude of the GnRh stimulus affect gonadotrope responsiveness. In addition, we shall assess the relative importance and intracellular sites of action of polactin and gonadal steroids in modifying gonadotrope responses to GnRH. The mechanisms of GnRH action will be investigated by measurement of plasma membrane GnRH receptors, alpha and LH beta subnit mRNA concentrations, LH storage and acute LH release following GnRH stimulation. Measurements of both steady state mRNA concentrations and transcription assays will be used to assess LH gene expression. The manner of GnRH stimulation of the gonadotrope, both in terms of dose and frequency of GnRH pulses, is crucial in determining gonadotrope responsiveness. We will perform in vivo studies which will define the parameters of the GnRH pulse stimulus which will maintain LH synthesis and secretion and apply these data to assess the physiologic role of GnRH in regulating LH secretion in vivo. Additional experiments will assess whether gonadal steroids directly regulate the intracellular mechanisms involved in GnRH action on the gonadotope and the results will be applied to improve our understanding of normal physiologic regulation of LH secretion. This basic information on the role of GnRH and gonadal steroids will be used to design experiments aimed to determine the relative roles of GnRH and steroid hormones in regulating LH synthesis and secretion during the estrous cycle. The mechanisms of GnRH action have important implications for the regulation of fertility in humans and animals. A pulsatile GnRH stimulus is required to maintain LH secretion and continuous stimulation by GnRH desensitizes LH secretion. Specific syndromes of GnRH deficiency are recognized in humans and fertility can be restored by administration of GnRH in a pulsatile manner. Long acting GnRH agonists which desensitize LH release are being assessed as potential contraceptive agents. The elucidation of the exact mechanisms by which a pulsatile GnRH stimulus maintain LH synthesis and secretion are important for the development of future therapeutic regimens to both enhance or inhibit gonadotope secretion.
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