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.
Subject(s)
Dynorphins/genetics , Hypogonadism/genetics , Kisspeptins/genetics , Luteinizing Hormone/administration & dosage , Neurokinin B/genetics , Signal Transduction/drug effects , Academic Medical Centers , Adolescent , Adult , Animals , Case-Control Studies , Child , Disease Models, Animal , Female , Gonadotropin-Releasing Hormone/administration & dosage , Humans , Hypogonadism/blood , Hypogonadism/drug therapy , Mice , Mice, Knockout , Narcotic Antagonists/administration & dosage , Neurons/drug effects , Substance P/metabolism , Treatment Outcome , Young AdultABSTRACT
CONTEXT: Individuals with idiopathic hypogonadotropic hypogonadism (IHH), even those with evidence of some hypothalamic reproductive endocrine activity, fail to complete puberty and fail to respond to physiologic doses of kisspeptin. OBJECTIVE: This case series examined whether treatment with sex steroids could stimulate kisspeptin responsiveness in patients with IHH. DESIGN: This was a case series. SETTING: This study was conducted at an academic medical center. PARTICIPANTS: Seven patients with IHH were studied. INTERVENTIONS: Participants, both on and off sex steroid therapy, underwent frequent blood sampling to measure LH at baseline, in response to kisspeptin and GnRH. MAIN OUTCOME MEASURES: The main outcome measure was LH responses to kisspeptin on and off sex steroids. RESULTS: All participants responded to exogenous GnRH, but no participant responded to exogenous kisspeptin. Sex steroid treatment did not modify responsiveness to kisspeptin. CONCLUSIONS: The functional impairment of the GnRH neuronal network in patients with IHH, as evidenced by their inability to respond to a physiologic dose of kisspeptin, is observed in both sex steroid- deficient and sex steroid-replete states. In this case series, a normalized sex steroid milieu does not appear capable of overcoming the kisspeptin resistance of these patients.
ABSTRACT
The hypothalamic hormone GnRH has traditionally been viewed as a central driver of the hypothalamic-pituitary-gonadal axis. Pulsatile GnRH release is required for pulsatile gonadotropin secretion, which then modulates gonadal steroid feedback and brings about full fertility in the adult. Pathways governing GnRH ontogeny and physiology have been discovered by studying humans with disorders of GnRH secretion. In this chapter, the human genetics of the kisspeptin signaling pathway in patients with diverse reproductive phenotypes will be explored. The discovery of defects in the kisspeptin system in several reproductive disorders has shed light on the mechanisms involved in regulating GnRH secretion, revealing the critical role played by the kisspeptin signaling pathway in pubertal initiation and reproductive function.
