The role of kisspeptin and RFamide-related peptide-3 neurones in the circadian-timed preovulatory luteinising hormone surge

Abstract

Many aspects of female reproduction often require intricate timing, ranging from the temporal regulation of reproductive hormone secretion to the precise timing of sexual behaviour. In particular, in rodents and other species, ovulation is triggered by a surge in pituitary luteinising hormone (LH) secretion that is governed by a complex interaction between circadian signals arising in the hypothalamus and ovarian-derived oestradiol signals acting on multiple brain circuitries. These circadian and hormonal pathways converge to stimulate a precisely-timed surge in gonadotropin-releasing hormone (GnRH) release (i.e. positive-feedback), thereby triggering the preovulatory LH surge. Reflecting its control by afferent circadian signals, the preovulatory LH surge occurs at a specific time of day, typically late afternoon in nocturnal rodents. Although the specific mechanisms mediating the hormonal and circadian regulation of GnRH/LH release have remained poorly understood, recent findings now suggest that oestradiol and circadian signals govern specific reproductive neuropeptide circuits in the hypothalamus, including the newly-identified kisspeptin and RFamide-related peptide (RFRP)-3 neuronal populations. Neurones producing kisspeptin, the protein product of the Kiss1 gene, and RFRP-3 have been shown to provide excitatory and inhibitory input to GnRH neurones, respectively, and are also influenced by sex steroid and circadian signals. In the present review, we integrate classic and recent findings to form a new working model for the neuroendocrine regulation of the circadian-timed preovulatory LH surge in rodents. This model proposes kisspeptin and RFRP-3 neuronal populations as key nodal points for integrating and transducing circadian and hormonal signals to the reproductive axis, thereby governing the precisely-timed LH surge.

Figure 1

Total Kiss1 mRNA in the AVPV/PeN of OVX mice with (a) and without (b) E₂ treatment that were sacrificed at different circadian times. In the OVX+E₂ mice, an LH surge was detected at CT 11 and CT 12 (see Robertson et al., 2009). (*) indicates a statistical significance of p<0.05 relative to CT 0, CT 4, CT 8, and CT 20.

Figure 2

Schematic summarizing the network of neurons and respective neuropeptides thought to participate in the regulation and timing of the female rodent preovulatory LH surge. This working model suggests that several levels of control are upstream of GnRH neurons: hormonal (ovarian-derived E₂), circadian (SCN-derived AVP and VIP), and intermediate activators/inhibitors (kisspeptin and RFRP-3). VIP neurons in the SCN project to the DMN and GnRH neurons, and AVP neurons in the SCN project to the DMN and AVPV/PeN Kiss1 neurons, potentially providing circadian information relevant to the timing of the LH surge. Kiss1 neurons directly stimulate GnRH neurons, while RFRP-3 neurons directly inhibit them. Some RFRP-3 neurons also project to the AVPV region, but it is not known if these projections target Kiss1 neurons. GnRH neurons integrate input from Kiss1, RFRP-3, and VIP neurons directly and may respond to some of these signals in a temporally-gated manner. In addition, GnRH neurons may possess endogenous circadian oscillators, the function of which is unknown. See text for more detailed description and explanation of abbreviations. Key: Solid lines with boutons represent neuronal connections, dotted lines with arrowhead represent hormonal pathways; Solid sinusoid and dotted sinusoid represents cell-autonomous oscillatory activity and potential cell-autonomous oscillatory activity, respectively.