Anterior Pituitary Gland in Female Reproductive Aging

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Reproductive aging in the female is identified by a progressive decline in ovarian gametogenesis and steroidogenesis. Investigations in animal models and in humans suggest that, in addition to ovarian failure, this decline may be attributable to age-related dysfunction at the hypothalamic-pituitary level of the reproductive axis. In order to understand the mechanisms which lead to the loss of reproductive function, investigators have increasingly focused on the period just preceding the establishment of permanent acyclicity (ie., events that occur during the fifth decade of life in women or the equivalent stage in laboratory animals). These studies have clearly documented age-related perturbations in pituitary gonadotropin gene expression; however, it is not known currently whether these changes reflect known alterations in hypothalamic gonadotropin-releasing hormone (GnRH) stimulation or are due additionally to primary dysfunction of the pituitary gonadotropes. The proposed studies are aimed at elucidation of the role of the anterior pituitary gland in the development of reproductive senescense in the female, utilizing an ovariectomized, steroid-replaced female rat model. This model eliminates confounding effects due to age-specific differences in circulating gonadal steroid levels. The Specific Aims are: 1) to identify age-related changes in pituitary expression of genes with known relevance for normal gonadotrope function, and 2) to compare GnRH-stimulated expression of gonadotropin and GnRH-receptor gene expression in perifused anterior pituitaries from young and middle-aged female rats. Preliminary experiments have demonstrated blunted expression of the gonadotropin and GnRH-receptor genes on the day of the LH surge in middle-aged animals. In SA#I, these observations will be extended to the analysis of additional gonadotrope-relevant genes, including: a) gonadal steroid receptors, b) activin, inhibin, and follistatin, and c) pituitary adenylate-cyclase activating peptide (PACAP). In SA#2, age-related alterations in gonadotrope-specific gene expression will be characterized in response to identical pulsatile GnRH treatment, enabling the detection of intrinsic pituitary defects distinct from hypothalamic dysfunction. These studies will provide additional insight into the molecular and cellular mechanisms which contribute to female reproductive aging and will, thereby, improve our understanding of the repercussions of this stage of life.