Neuroendocrine Control of the Transition to Reproductive Senescence: Lessons Learned from the Female Rodent Model

Abstract

The natural transition to reproductive senescence is an important physiological process that occurs with aging, resulting in menopause in women and diminished or lost fertility in most mammalian species. This review focuses on how rodent models have informed our knowledge of age-related changes in gonadotropin-releasing hormone (GnRH) neurosecretory function and the subsequent loss of reproductive capacity. Studies in rats and mice have shown molecular, morphological and functional changes in GnRH cells. Furthermore, during reproductive aging altered sex steroid feedback to the hypothalamus contributes to a decrease of stimulatory signaling and increase in inhibitory tone onto GnRH neurons. At the site of the GnRH terminals where the peptide is released into the portal vasculature, the cytoarchitecture of the median eminence becomes disorganized with aging, and mechanisms of glial-GnRH neuronal communication may be disrupted. These changes can result in the dysregulation of GnRH secretion with reproductive decline. Interestingly, reproductive aging effects on the GnRH circuitry are observed in middle age even prior to any obvious physiological changes in cyclicity. We speculate that the hypothalamus may play a critical role in this mid-life transition. Because there are substantial species differences in these aging processes, we also compare and contrast rodent aging to that in primates. Work discussed herein shows that in order to understand neuroendocrine mechanisms of reproductive senescence, further research needs to be conducted in ovarian-intact models.