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.

Figure 1

The pattern of a selected subset of circulating hormone levels changes during the transition to reproductive senescence (acyclicity) for (A) the menstrual cycle of primates (human and nonhuman) and (B) the estrous cycle of rodents. A. Regularly cycling primates have approximately 28-day cycles. Positive feedback of the preovulatory estradiol (E₂) peak leads to the gonadotropin-releasing hormone/luteinizing hormone (GnRH/LH) surge. The GnRH/LH surge then causes ovulation (OV), followed by the postovulatory progesterone (P₄) peak and smaller E₂ increase. In perimenopausal primates, the menstrual cycle becomes longer and anovulatory, and the GnRH/LH surge is attenuated. Eventually the preovulatory E₂ peak no longer elicits a GnRH/LH response. During the menopausal transition, females become acyclic, and E₂ and P₄ levels decrease while GnRH/LH levels rise. B. Regularly cycling rodents have 4–5 day cycles. Similar to primates, there is a preovulatory E₂ peak, leading to the GnRH/LH surge, which causes ovulation. Ovulation is followed by an increase in P₄. At middle age the GnRH/LH surge is delayed and attenuated, the cycle length increases, and eventually the cycles become anovulatory. Next, the female transitions to persistent estrus (PE), an acyclic state characterized by elevated E₂ and decreased GnRH/LH. Later, acyclic rodents move into persistent diestrus (PD), in which the circulating E₂ decreases. Hash marks indicate the passing of time (years in primates, months in rodents). Dashed lines show the temporal relationship of the hormone peaks relative to ovulation. The postovulatory period is denoted by a black bar.

Figure 2

Regulatory inputs to the gonadotropin-releasing hormone (GnRH) neuron, as well as the surrounding glial micro-environment, undergo modulation with reproductive aging. This model depicts the situation in aging rodents. Regulation of GnRH release can take place at the GnRH perikarya in the preoptic area or at the GnRH neuroterminals in the median eminence. The stimulatory influence of glutamate (GLU) and kisspeptin (KISS) on GnRH neurons decreases in middle-aged rats, particularly during the preovulatory GnRH surge. The smaller size of neurons indicates diminished influence compared to larger-sized neurons. In addition, there is an increase in inhibitory tone by GABA signaling. Glial cells may also play a role in the regulation of GnRH release during reproductive aging. In the median eminence, tanycytes (green) become larger and lose their linear organization in middle-aged rats compared to young. In addition, the pericapillary boundary (red line) becomes more convoluted. Although not shown, other neural and glial changes occur during aging, including release of transforming growth factor (TGF)α, and its effects on erb-B receptors on glial cells. Red lines (bottom) represent the portal capillary vasculature. Green features at the GnRH neuroterminals are tanycytes.