Abstract
Reproductive senescence, the point in time when females cease to show estrous cyclicity, is associated with endocrine changes in the hypothalamus, pituitary, and gonads. However, the mechanisms triggering this transition are not well understood. To gain a better understanding of the top-down control of the transition from reproductive competence to a state of reproductive senescence, we investigated middle-aged female rats exhibiting varying degrees of reproductive decline, including individuals with normal cycles, irregular cycles, and complete cessation of cycles. We identified hormonal changes in the brain that manifest before ovarian cycles exhibit any deterioration. We found that females exhibit an increase in RFamide-related peptide-3 (RFRP3) mRNA expression in the hypothalamus in middle age prior to changes in estrous cycle length. This increase is transient and followed by subsequent decreases in kisspeptin (KiSS1) and gonadotropin-releasing hormone (GnRH) mRNA expression. Expression of RFRP3 and its receptor also increased locally in the ovaries with advancing age. While it is well known that aging is associated with decreased GnRH release and downstream disruption of the hypothalamic–pituitary–gonadal (HPG) axis, herein, we provide evidence that reproductive senescence is likely triggered by alterations in a network of regulatory neuropeptides upstream of the GnRH system.
Highlights
Female reproduction is a complex process that requires precise neurochemical timing
The present findings suggest that the inhibitory neuropeptide, RFamide-related peptide-3 (RFRP3), may play a role in the initiation of reproductive decline in female rats, prior to change in cyclicity
We found that hypothalamic RFRP3 expression increases significantly in middle age, concomitant with an increase in the RFRP3 receptor, GPR147, in the hypothalamus and gonads
Summary
Female reproduction is a complex process that requires precise neurochemical timing. From puberty through senescence, a complex interplay among central neuroendocrine circuits, peripheral hormonal systems, and internal and external cues is required for successful procreation. Middle-aged rats transition from regular 4- to 5-day estrous cycles to irregular cycle lengths of over 6 days, followed by a complete cessation of cyclicity, characterized as either a state of persistent estrus or diestrus. This final transition occurs in female rats between 12 and 15 months of age [5], appropriately corresponding to about 45–50 years old in women [4]. The hypothalamic–pituitary–gonadal (HPG) axis is highly conserved across mammals, and the hypothalamic and ovarian changes in the rodent resemble menopausal changes in humans [6]
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