Gonadotrophin‐releasing hormone and kisspeptin: It takes two to tango

Abstract

The neuropeptide kisspeptin (Kp) is expressed by the Kiss1 gene; it was first discovered for its anti-metastasis effect in melanoma tumors. 1 Kiss1 encodes a carboxy-terminally amidated peptide with 54 amino acid residues and is the endogenous ligand of the orphan G-protein-coupled receptor (GPCR) hOT7T175, also named AXOR 12, GPR54 or Kiss-1R. [2][3][4][5] A few years after the discovery of Kp, scientists described a major role of the Kiss1 product/GPR54 on the reproductive axis. By generating knockout (KO) mice GPR54 −/− , Funes et al. 6 demonstrated that the absence of GPR54 results in massive developmental differences in both male and female genitalia that are associated with loss of fertility. In the same year, two groups reported mutations in the Kiss1R in consanguineous family members with hypogonadotrophic hypogonadism. 7,8

Mathematical models in GnRH research

“…However, it should be noted that the one-to-one correspondence between KNDy activation events (proxy for kisspepetin release) and LH pulses (proxy for GnRH release) observed in intact female and gonadectomised male mice, 61,68 suggests that in these contexts the GnRH autocrine feedback is either absent or its timescale is fast relative to the endogenous kisspeptin pulses. 7 Nonetheless, the model raises interesting questions as to whether nonlinear mechanisms operating at the level of the GnRH neuron (rather than the gonadotrope) could also be contributing to the nonlinear relationship observed between pulse generator and pulsatile LH output when the pulse generator frequency is 69 high. 23 As technology will continue to evolve so will our capacity to formulate more accurate models providing further insight into the reproductive neuroendocrine system.…”

“…Analysis of the model predicted that this autocrine signalling could potentially filter out kisspeptin pulses, making the frequency of GnRH release (approximately 7‐fold) slower than the frequency of the kisspeptin input. However, it should be noted that the one‐to‐one correspondence between KNDy activation events (proxy for kisspepetin release) and LH pulses (proxy for GnRH release) observed in intact female and gonadectomised male mice, 61,68 suggests that in these contexts the GnRH autocrine feedback is either absent or its timescale is fast relative to the endogenous kisspeptin pulses 7 . Nonetheless, the model raises interesting questions as to whether nonlinear mechanisms operating at the level of the GnRH neuron (rather than the gonadotrope) could also be contributing to the nonlinear relationship observed between pulse generator and pulsatile LH output when the pulse generator frequency is 69 high 23,69 …”

“…For more technical yet accessible reviews of mathematical modelling in neuroendocrinology we refer the reader to two previous studies. 6,7 The review is based on three key research areas where mathematical modelling has been particularly relevant: the GnRH neuron, GnRH signalling to the pituitary, and GnRH pulsatile secretion.…”

“…Hence, this review focuses on the analysis and interpretation of mathematical models and not on technical details underpinning their development and analysis. For more technical yet accessible reviews of mathematical modelling in neuroendocrinology we refer the reader to two previous studies 6,7 . The review is based on three key research areas where mathematical modelling has been particularly relevant: the GnRH neuron, GnRH signalling to the pituitary, and GnRH pulsatile secretion.…”

Modelling KNDy neurons and gonadotropin-releasing hormone pulse generation

“…Most interestingly, the model predicts that a pulsatile application of kisspeptin to the GnRH neuron can cause the release of GnRH to be locked to this pulsatile input. When pulsatile kisspeptin is applied, GnRH release is locked at a much lower pulse frequency, and this ratio can be decreased by increasing the concentration of kisspeptin used or the timescale of the negative autocrine feedback [ 60 , 63 ]. This prediction could be an interesting avenue of investigation in light of recent experimental observations from rodents showing that the synchronised periods of activity of the KNDy neuronal population have a 1-to-1 relationship with LH pulses [ 18 , 64 ], but this relationship could break down when KNDy pulses are generated at higher frequencies [ 65 ].…”