Increasing LH Pulsatility in Women With Hypothalamic Amenorrhoea Using Intravenous Infusion of Kisspeptin-54

Abstract

Background:Hypothalamic amenorrhea (HA) is the one of the most common causes of period loss in women of reproductive age and is associated with deficient LH pulsatility. High-dose kisspeptin-54 acutely stimulates LH secretion in women with HA, but chronic administration causes desensitization. GnRH has paradoxical effects on reproductive activity; we therefore hypothesized that a dose-dependent therapeutic window exists within which kisspeptin treatment restores the GnRH/LH pulsatility in women with HA.Aim:The aim of the study was to determine whether constant iv infusion of kisspeptin-54 temporarily increases pulsatile LH secretion in women with HA.Methods:Five patients with HA each underwent six assessments of LH pulsatility. Single-blinded continuous iv infusion of vehicle or kisspeptin-54 (0.01, 0.03, 0.10, 0.30, or 1.00 nmol/kg/h) was administered. The LH pulses were detected using blinded deconvolution.Results:Kisspeptin increased LH pulsatility in all patients with HA, with peak responses observed at different doses in each patient. The mean peak number of pulses during infusion of kisspeptin-54 was 3-fold higher when compared with vehicle (number of LH pulses per 8 h: 1.6 ± 0.4, vehicle; 5.0 ± 0.5, kisspeptin-54, P < .01 vs vehicle). The mean peak LH pulse secretory mass during kisspeptin-54 was 6-fold higher when compared with vehicle (LH pulse secretory mass in international units per liter: 3.92 ± 2.31, vehicle; 23.44 ± 12.59, kisspeptin-54; P < .05 vs vehicle).Conclusions:Kisspeptin-54 infusion temporarily increases LH pulsatility in women with HA. Furthermore, we have determined the dose range within which kisspeptin-54 treatment increases basal and pulsatile LH secretion in women with HA. This work provides a basis for studying the potential of kisspeptin-based therapies to treat women with HA.

The effects of kisspeptin on β‐cell function, serum metabolites and appetite in humans

“…Our findings have pharmacological and potential therapeutic relevance as the plasma kisspeptin levels achieved in this study, which enhanced GSIS, are similar to those required to restore LH pulsatility in women with hypothalamic amenorrhea3 and trigger oocyte maturation in in vitro fertilisation protocols 2. During IVGTTs, pharmacological kisspeptin administration increased insulin secretion and increased disposition index (IVGTT‐DI).…”

Rola sygnalizacji kisspeptyny w osi podwzgórze–przysadka–nadnercza — aktualna perspektywa

“…Similarly, in women with HA, desensitisation was observed after continuous SC administration of Kp-54 for two weeks [106], but the evidence is not consistent in other studies [1]. Recently in a study in women having HA, eight hours infusion of low dose Kp-54 restored pulsatile release of LH in addition to continuous LH secretion [59], and in another study in healthy women, their menstrual cycle was advanced by continuous administration of Kp-54 [94]. The studies done in healthy men showed varied results with no evidence of desensitisation to continuous infusion of Kp-10 at lower dose while LH response was reduced when continuous infusion of high dose Kp-10 was given for 24 hours [1,57].…”

“…There was sustained gonadotrophins secretion over the eight weeks period although the response was reduced in the later period compared to day 1 and it again did not result in significant oestradiol release and ovulation was not achieved [107]. Furthermore, it has been shown recently that LH pulsatility could be achieved after Kp-54 infusion for eight hours with a three-fold rise in LH pulse frequency and mass per pulse [59], which supports the hypothesis that in order to restore reproductive endocrine activity in females with HA, pulsatile delivery of kisspeptins should be given because kisspeptin release is pulsatile [54,108]. This is similar to the fact that in order to stimulate the reproductive axis GnRH must be delivered in a pulsatile mode [109].…”

“…Pharmacological evidence revealed that injection of kisspeptin-10 and kisspeptin-54 in humans increased gonadotrophin pulsatile release, especially LH [57,58]. The increase in pulsatile secretion of LH by kisspeptins has also been shown in human disease models [59][60][61] has been suggested that kisspeptins also help in adjusting the hypothalamic clock of GnRH pulsatile release in addition to its stimulation in men [62], but the evidence does not support this effect in women [63]. The reason suggested for this was differential sex steroid feedback in females due to changes in hormonal levels across the menstrual cycle and sexual dimorphism in functional neuroanatomy of kisspeptins [1].…”

Serum kisspeptin concentrations are negatively correlated with body mass index in adolescents with anorexia nervosa and amenorrhea

“…4 In women with functional hypothalamic amenorrhea, the reactivation of GnRH/LH pulsatility by kisspeptin administration suggests that exogenous kisspeptin enters the central nervous system somehow crossing the blood-brain barrier. 5 Studies in energy-depleted animals with hypogonadotropic hypogonadism have reported a reduction in hypothalamic kisspeptin mRNA as well as in circulating LH levels. 2 To what extent hypothalamic mRNA changes due to undernutrition translate into alterations of kisspeptin release in the circulation remains as yet unknown.…”