Time‐of‐day‐dependent sensitivity of the reproductive axis to RFamide‐related peptide‐3 inhibition in female Syrian hamsters

Abstract

In spontaneously ovulating rodent species, the timing of the luteinising hormone (LH) surge is controlled by the master circadian pacemaker in the suprachiasmatic nucleus (SCN). The SCN initiates the LH surge via the coordinated control of two opposing neuropeptidergic systems that lie upstream of the gonadotrophin‐releasing hormone (GnRH) neuronal system: the stimulatory peptide, kisspeptin, and the inhibitory peptide, RFamide‐related peptide‐3 (RFRP‐3; the mammalian orthologue of avian gonadotrophin‐inhibitory hormone [GnIH]). We have previously shown that the GnRH system exhibits time‐dependent sensitivity to kisspeptin stimulation, further contributing to the precise timing of the LH surge. To examine whether this time‐dependent sensitivity of the GnRH system is unique to kisspeptin or a more common mechanism of regulatory control, we explored daily changes in the response of the GnRH system to RFRP‐3 inhibition. Female Syrian hamsters were ovariectomised to eliminate oestradiol (E2)‐negative‐feedback and RFRP‐3 or saline was centrally administered in the morning or late afternoon. LH concentrations and Lhβ mRNA expression did not differ between morning RFRP‐3‐and saline‐treated groups, although they were markedly suppressed by RFRP‐3 administration in the afternoon. However, RFRP‐3 inhibition of circulating LH at the time of the surge does not appear to act via the GnRH system because no differences in medial preoptic area Gnrh or RFRP‐3 receptor Gpr147 mRNA expression were observed. Rather, RFRP‐3 suppressed arcuate nucleus Kiss1 mRNA expression and potentially impacted pituitary gonadotrophs directly. Taken together, these findings reveal time‐dependent responsiveness of the reproductive axis to RFRP‐3 inhibition, possibly via variation in the sensitivity of arcuate nucleus kisspeptin neurones to this neuropeptide.

Gonadotropin Inhibitory Hormone and Its Receptor: Potential Key to the Integration and Coordination of Metabolic Status and Reproduction

“…In nocturnal species, such as hamsters, studies on the role of GnIH frequently resulted in conflicting results, with both stimulatory and inhibitory effects reported ( 96 , 97 ). This is possibly due to the contrasting role of melatonin in these species, with elevated levels during the dark phase contributing to heightened activity.…”

Mistimed feeding disrupts circadian rhythms of male mating behavior and female preovulatory LH surges in mice

“…Relatedly, it is also possible that TRF enhances or activates upstream inhibitors of the LH surge generator circuitry, though this remains to be tested. This possibility is supported by observations that FOS protein (a marker of heightened neuronal activation) is induced in RFRP3 neurons of the DMH in anticipation of food during TRF (Acosta-Galvan et al, 2011) and that RFRP3, a neuropeptide that inhibits GnRH secretion, released at the wrong circadian time could impede the LH surge (Gotlieb et al, 2019). Moreover, it has been documented that RFRP-3 neuronal activation, as measured by FOS induction, is normally dampened at the time of the LH surge, supporting the possibility that the surge may be modulated by inhibition/disinhibition from RFRP3 signaling (Gibson et al, 2008).…”

“…The SCN transmits a daily signal to AVPV kisspeptin neurons via AVP release (Piet et al, 2015;Jamieson et al, 2021); when E2 is high, as during proestrus, AVPV kisspeptin cells respond robustly during the early evening and activate GnRH neurons that in turn elicit the LH surge (Robertson et al, 2009;Poling et al, 2017). All of these neural populations normally exhibit a circadian rhythm in activity and/or clock gene expression (de la Iglesia et al, 2003;Resuehr et al, 2007;Robertson et al, 2009;Zhao and Kriegsfeld, 2009;Chassard et al, 2015;Gotlieb et al, 2019). Thus, conditions or treatments that cause circadian desynchrony, such as TRF, may impede normal circadian activation of the neural mechanisms generating the LH surge.…”

“…Ovulation and the associated endocrine signals in particular are tightly controlled by the circadian clock (Everett and Sawyer, 1950). Ovulation is preceded by a circadian-timed surge of luteinizing hormone (LH) secretion ('positive feedback') that is triggered via a multisynaptic neural pathway that begins with the SCN (Khan and Kauffman, 2012), and includes hypothalamic and pituitary areas that are also rhythmic and contain circadian clocks (de la Iglesia et al, 2003;Resuehr et al, 2007;Robertson et al, 2009;Zhao and Kriegsfeld, 2009;Chassard et al, 2015;Gotlieb et al, 2019). Rhythms are thus an intimate component of reproduction and disruption of the underlying clocks contribute to infertility.…”

Hypothalamic Astrocyte Development and Physiology for Neuroprogesterone Induction of the Luteinizing Hormone Surge

“…Activation of Kiss1R in GnRH neurons produces robust depolarizing currents and induces GnRH release (43)(44)(45)(46)(47). The timing of the LH surge requires the stimulatory action of kisspeptin and the removal of RFamide-related peptide 3 (RFRP-3; also known as gonadotropin-inhibitory hormone-GnIH) (48)(49)(50)(51)(52)(53). In this model, the daily afternoon increase in GnRH and LH is due to suppression of the RFRP-3 inhibitory input to the GnRH neurons by the suprachiasmatic nucleus (SCN).…”