REGULATION OF GENE EXPRESSION IN THE AGING OVARY

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The decline in fertility with advanced age has emerged as an important issue in reproductive medicine. In this regard, the female rat has provided a relevant and practical modes to study reproductive aging. In the rat and human, reproductive senescence is preceded by neuroendocrine and ovarian impairments which are reflected by altered patterns of gonadotrophin secretion, ovarian follicular development, and ovulation. However, the relationships between circulating gonadotropin levels and changes in ovarian functions preceding reproductive senescence are not well understood. Therefore, the proposed studies are designed to explore the relationships between age-related changes in neuroendocrine function and potential alterations in ovarian gene expression and response to gonadotrophins in regularly cyclic middle-aged female rats. Specifically, the aims of this proposal are: l) To examine whether there is a prolongation of the secondary FSH surge in rats with decreased follicular pools (intact middle-aged rats and hemiox young and middle-aged females, as compared with intact young females), and to determine the relationship between secondary FSH surge profiles and ovarian inhibin gene expression; 2) To assess the relationships between the magnitudes of endogenous LH and FSH surges, ovulation rate, and induced expression of ovarian proteolytic enzymes mediating follicle rupture in regularly cyclic, middle-aged and young female rats; 3) To compare ovarian sensitivity and maximal ovulatory and proteolytic responses to exogenous hCG stimulation in middle-aged and young cyclic rats. Similarly, to assess relative induction of ovarian proteinase expression and ovulation by exogenous recombinant FSH to determine whether age-related changes in ovulatory response are specific to LH stimulation. The findings from these studies will provide new insights regarding the roles of the neuroendocrine system and ovary in the onset of reproductive senescence. Furthermore, age-related changes in neuroendocrine and ovarian function in the aging female rat provide a useful model to study dynamic interactions between hypothalamus, pituitary and ovary. Ultimately, it is hoped that these findings may result in the development of new clinical strategies relevant to age-related declines in human reproductive function.