Hypothalamic molecular changes underlying natural reproductive senescence in the female rat.

The role of the hypothalamus in female reproductive senescence is unclear. Here we identified novel molecular neuroendocrine changes during the natural progression from regular reproductive cycles to acyclicity in middle-aged female rats, comparable with the perimenopausal progression in women. Expression of 48 neuroendocrine genes was quantified within three hypothalamic regions: the anteroventral periventricular nucleus, the site of steroid positive feedback onto GnRH neurons; the arcuate nucleus (ARC), the site of negative feedback and pulsatile GnRH release; and the median eminence (ME), the site of GnRH secretion. Surprisingly, the majority of changes occurred in the ARC and ME, with few effects in anteroventral periventricular nucleus. The overall pattern was increased mRNA levels with chronological age and decreases with reproductive cycle status in middle-aged rats. Affected genes included transcription factors (Stat5b, Arnt, Ahr), sex steroid hormone receptors (Esr1, Esr2, Pgr, Ar), steroidogenic enzymes (Sts, Hsd17b8), growth factors (Igf1, Tgfa), and neuropeptides (Kiss1, Tac2, Gnrh1). Bionetwork analysis revealed region-specific correlations between genes and hormones. Immunohistochemical analyses of kisspeptin and estrogen receptor-α in the ARC demonstrated age-related decreases in kisspeptin cell numbers as well as kisspeptin-estrogen receptor-α dual-labeled cells. Taken together, these results identify unexpectedly strong roles for the ME and ARC during reproductive decline and highlight fundamental differences between middle-aged rats with regular cycles and all other groups. Our data provide evidence of decreased excitatory stimulation and altered hormone feedback with aging and suggest novel neuroendocrine pathways that warrant future study. Furthermore, these changes may impact other neuroendocrine systems that undergo functional declines with age.

Disruption of reproductive aging in female and male rats by gestational exposure to estrogenic endocrine disruptors.

Polychlorinated biphenyls (PCBs) are industrial contaminants and known endocrine-disrupting chemicals. Previous work has shown that gestational exposure to PCBs cause changes in reproductive neuroendocrine processes. Here we extended work farther down the life spectrum and tested the hypothesis that early life exposure to Aroclor 1221 (A1221), a mixture of primarily estrogenic PCBs, results in sexually dimorphic aging-associated alterations to reproductive parameters in rats, and gene expression changes in hypothalamic nuclei that regulate reproductive function. Pregnant Sprague Dawley rats were injected on gestational days 16 and 18 with vehicle (dimethylsulfoxide), A1221 (1 mg/kg), or estradiol benzoate (50 µg/kg). Developmental parameters, estrous cyclicity (females), and timing of reproductive senescence were monitored in the offspring through 9 months of age. Expression of 48 genes was measured in 3 hypothalamic nuclei: the anteroventral periventricular nucleus (AVPV), arcuate nucleus (ARC), and median eminence (females only) by real-time RT-PCR. Serum LH, testosterone, and estradiol were assayed in the same animals. In males, A1221 had no effects; however, prenatal estradiol benzoate increased serum estradiol, gene expression in the AVPV (1 gene), and ARC (2 genes) compared with controls. In females, estrous cycles were longer in the A1221-exposed females throughout the life cycle. Gene expression was not affected in the AVPV, but significant changes were caused by A1221 in the ARC and median eminence as a function of cycling status. Bionetwork analysis demonstrated fundamental differences in physiology and gene expression between cycling and acyclic females independent of treatment. Thus, gestational exposure to biologically relevant levels of estrogenic endocrine-disrupting chemicals has sexually dimorphic effects, with an altered transition to reproductive aging in female rats but relatively little effect in males.

Neuroendocrine control of the transition to reproductive senescence: lessons learned from the female rodent model.

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.