Harry J. Karavolas - US grants

Our long-term aim is to investigate and define the biochemistry and mechanisms by which the ovarian steroidal hormones (particularly progesterone) interact and regulate (or "inappropriately" regulate) the aging hypothalamic-pictuitary-ovarian axis (especially gonadotropin regulation.) In this application we wish to examine the hypothesis that the altered responsiveness of the hypothalamus and pituitary to steroid feedbacks during various stages of reproductive senescence is due, at least in part, to altered processing of progesterone at the level of these two neuroendocrine feedback tissues. Toward these ends we propose to pursue during the next 4 years the following lines of integrated research: 1. Determine the characteristics of progesterone metabolism by the anterior pituitary and selected neuroendocrine regions in the medial basal hypothalamic and preoptic areas during the various stages of reproductive senescence in the female rat; i.e. progestin transformations (metabolism), properties and levels of these progestin-metabolizing enzymes, regulation of metabolism andenzymes etc. 2) Determine characteristics of the binding of progesterone and related progestins in these same tissues during the various stages of reproductive decline in the aged female rat; i.e. properties and levels of cytosolic binding; regulation of cytosolic binding, especially by estrogen; levels of cytoplasmic receptors; and possibly, studies on nuclear translocation. 3. Relate any observed differences in progesterone processing (above) to alterations in the effects of progesterone and its metabolites on gonadotropin regulation in aged rats. The information gained is expected to give new insight into the steroidal regulatory mechanisms affecting the aged hypothalamic-pituitary-ovarian axis, which might ultimately improve understanding of age-related changes in the activity of the hypothalamic-pituitary-ovarian axis and reveal new avenues for the control of reproductive senescence.

The continuing aim of our research program is to define the mechanisms by which the ovarian steroids, especially progesterone, regulate the hypothalamic-pituitary-ovarian axis. This renewal is designed to examine especially the biochemistry and molecular basis of the effects of progesterone and some of its metabolites on pituitary and hypothalamic progesterone-sensitive processes such as gonadotropin and LHRH regulation. Specifically, we hope to elucidate: 1) the characteristics of progestin metabolism in hypothalamic and anterior pituitary tissues and its importance as a regulatory mechanism by examining the nature of the metabolites formed, the properties of the enzymes catalyzing these progestin steroid transformations and the regulation of the metabolism and enzymes, 2) the nature of the sequestered and reacting steroidal compounds; target tissue sites of localization and the mechanisms for sequestering and action at cellular and subcellular levels, 3) the biological relevance of metabolism to progesterone's effects on gonadotropin and LHRH regulation. The information gained is expected to give new insights into the steroidal regulatory mechanisms affecting the hypothalamic-ovarian axis, which might ultimately provide important information on the biomedical aspects of contraception and reveal new avenues for the control of fertility.