AGING EFFECTS ON GONADOTROPIN STRUCTURE/FUNCTION

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This pilot project examines potential effects of reproductive aging on the structure and biological activity of the gonadotropin hormones; luteinizing hormone (LH) and follicle-stimulating hormone (FSH). The maintenance of reproductive competence in female mammals requires highly integrated feedback interactions between the hypothalamus, the pituitary gland, and the ovary. The regulation of normal levels and activities of FSH and LH is critical in maintaining ovarian functions. Reproductive aging is characterized by gradually declining fertility and the onset of irregular ovulatory cycles. In both rat and human species, these age-related changes are associated with altered patterns of plasma gonadotropins, and related changes in ovarian steroidogenesis and ovulation. However, while many studies have focused upon age-related alterations in the immunoreactive levels of FSH and LH in the circulation, increasing evidence indicates that changes in gonadotropin protein structure may occur as well, significantly influencing the biological potency of these hormones. FSH and LH are glycosylated hormones, with N-linked oligosaccharide chains attached in a specific manner to their primary amino acid structure. The oligosaccharide composition of LH and FSH is regulated by a number of factors, and changes in the glycosylation of gonadotropins can have dramatic effects on their biological activity. However, despite profound effects of altered gonadotropin structure on their biological potencies, sparse attention has been paid to potential changes in glycosylation and biological activity of gonadotropins during aging in females. This project will therefore test the hypothesis that alterations in the structure and biological activity of LH and FSH occur during reproductive aging, contributing to altered ovarian function and age- related infertility. Specifically, this pilot project will examine potential age-related changes in structure and biological activity of stored and secreted forms of LH and FSH during the ovulatory cycle in middle-aged rats. These findings will provide the basis of future in-depth studies on the mechanisms regulating hormone glycosylation during aging, and may provide new insights into the potential role of altered protein structure in age-related infertility in women.