Hypothalamic Reproductive Endocrine Pulse Generator Activity Independent of Neurokinin B and Dynorphin Signaling

Abstract

Context Kisspeptin–neurokinin B (NKB)–dynorphin neurons are critical regulators of the hypothalamic–pituitary–gonadal axis. NKB and dynorphin are hypothesized to influence the frequency of GnRH pulses, whereas kisspeptin is hypothesized to be a generator of the GnRH pulse. How these neuropeptides interact remains unclear. Objective To probe the role of NKB in GnRH pulse generation and to determine the interactions between NKB, kisspeptin, and dynorphin in humans and mice with a complete absence of NKB. Design Case/control. Setting Academic medical center. Participants Members of a consanguineous family bearing biallelic loss-of-function mutations in the gene encoding NKB and NKB-deficient mice. Interventions Frequent blood sampling to characterize neuroendocrine profile and administration of kisspeptin, GnRH, and naloxone, a nonspecific opioid receptor antagonist used to block dynorphin. Main Outcome Measures LH pulse characteristics. Results Humans lacking NKB demonstrate slow LH pulse frequency, which can be increased by opioid antagonism. Mice lacking NKB also demonstrate impaired LH secretion, which can be augmented with an identical pharmacologic manipulation. Both mice and humans with NKB deficiency respond to exogenous kisspeptin. Conclusion The preservation of LH pulses in the absence of NKB and dynorphin signaling suggests that both peptides are dispensable for GnRH pulse generation and kisspeptin responsiveness. However, NKB and dynorphin appear to have opposing roles in the modulation of GnRH pulse frequency.

Novel Biology of Tachykinins in Gonadotropin-Releasing Hormone Secretion

“…This is in line with human data from patients bearing inactivating TAC3 mutations who are able to sporadically show rudimentary LH pulses. 89 Interestingly, as mentioned earlier, several of these patients have been reported to spontaneously recover the activity of the HPG axis and reverse their HH phenotype to achieve, in some cases, successful pregnancies. 62 Currently, there is speculation as to whether the other tachykinins (i.e., NKA and SP) are responsible for the "rescuing" of the GnRH pulse activity in mice and humans in the absence of NKB signaling; however, further research is needed to address this question.…”

“…Interestingly, while NKB at the level of KNDy neurons plays an important role in the shaping of kisspeptin-GnRH pulses, as described earlier, this neurokinin appears dispensable for successful reproduction because Tac2KO and Tacr3KO mice are fertile, 60,61 suggesting that LH pulsatility is preserved. Indeed, Tac2KO mice present clearly discernable LH pulses 27,89 ; however, these pulses display decreased amplitude and frequency compared with controls. This indicates that while additional mechanisms take place in the absence of NKB signaling to sustain basal LH pulsatility (enough to maintain reproduction), NKB is necessary for the optimal activation of the HPG axis to attain full reproductive capabilities.…”

Does the KNDy Model for the Control of Gonadotropin-Releasing Hormone Pulses Apply to Monkeys and Humans?

“…The strongest evidence for redundancy among the three major tachykinins comes from reports that some patients with mutations TAC3 or TACR3 show spontaneous recovery of reproductive function, and in some cases fertility, after hormonal treatments to induce development of the reproductive tracks and secondary sexual characteristics. [77][78][79] Similarly, when examined, clear instances of episodic LH secretion have been reported after hormonal treatments, although pulse frequency is slower than in normal individuals. 49,77,79 However, nonepisodic LH patterns after treatment have also been reported 77,80,81 and these have always been observed before treatments.…”

“…[77][78][79] Similarly, when examined, clear instances of episodic LH secretion have been reported after hormonal treatments, although pulse frequency is slower than in normal individuals. 49,77,79 However, nonepisodic LH patterns after treatment have also been reported 77,80,81 and these have always been observed before treatments. 77 Although they have not been directly compared, there is suggestive evidence that the deficits in LH secretion may be more severe with TACR3, than TAC3, mutations.…”

Clinical Translational Studies of Kisspeptin and Neurokinin B

“…10 Patients with either TAC3 or TAC3R mutations were shown to remain responsive to exogenous kisspeptin administration, consistent with NKB exerting its action upstream of kisspeptin. 10,11 Since then, it has been established that kisspeptin acts to stimulate hypothalamic GnRH neurones and thus the remainder of the reproductive axis. In rodent models, kisspeptin was found to co-localize with NKB and dynorphin to form "KNDy" neurones.…”