Although it is recognized that luteinizing hormone (LH) is secreted in a pulsatile manner and that the biological activity of secreted hormone is modulated by the gonadal hormone environment, major questions remain unresolved with respect to the mechanisms through which gonadal products modulate the quantitative and qualitative aspects of LH secretion. Given that certain forms of ovulatory dysfunction and infertility in women may reflect abnormalities in this system, it is imperative that specific mechanisms controlling LH secretion under physiologic circumstances be defined more completely. To this end, we propose a series of focused investigations to define the specific mechanisms of action of estrogen alone, progesterone alone and the combination of estrogen and progesterone (1) on qualitative and quantitative features of LH release both within discrete secretory bursts and between such secretory events using the post- menopausal woman as an in vivo model, and (2) on both the intracellular secretory pathways utilized for exocytosis of LH from gonadotropes and the process through which the LH is post-translationally modified prior to secretion using rat anterior pituitary cells as an in vitro model. The human in vivo studies will couple an intensive blood sampling paradigm and novel deconvolution procedures to appraise the nature both of the discrete GnRH-stimulated secretory events and of secretion occurring separate from such events. The rat in vitro studies will utilize pulse- chase methodologies together with immunoassay and bioassay of fast protein liquid chromatography-resolved isoforms of LH obtained from specific subcellular compartments in which hormone is processed. We believe that these complementary clinical and basic science studies will provide new insights into the mechanisms through which the gonadal hormones estrogen and progesterone influence both the quantitative and qualitative aspects of LH secretion in the human female and elucidate relevant cellular processes ultimately responsible for LH secretion. Such investigations will provide a basic foundation for future studies designed to elucidate the pathophysiologic mechanisms responsible for certain forms of clinical ovulatory dysfunction and infertility.
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