Kisspeptin Restores Pulsatile LH Secretion in Patients with Neurokinin B Signaling Deficiencies: Physiological, Pathophysiological and Therapeutic Implications

Abstract

Pulsatile gonadotropin-releasing hormone (GnRH) is crucial to normal reproductive function and abnormalities in pulse frequency give rise to reproductive dysfunction. Kisspeptin and neurokinin B (NKB), neuropeptides secreted by the same neuronal population in the ventral hypothalamus, have emerged recently as critical central regulators of GnRH and thus gonadotropin secretion. Patients with mutations resulting in loss of signaling by either of these neuroendocrine peptides fail to advance through puberty but the mechanisms mediating this remain unresolved. We report here that continuous kisspeptin infusion restores gonadotropin pulsatility in patients with loss-of-function mutations in NKB (TAC3) or its receptor (TAC3R), indicating that kisspeptin on its own is sufficient to stimulate pulsatile GnRH secretion. Moreover, our findings suggest that NKB action is proximal to kisspeptin in the reproductive neuroendocrine cascade regulating GnRH secretion, and may act as an autocrine modulator of kisspeptin secretion. The ability of continuous kisspeptin infusion to induce pulsatile gonadotropin secretion further indicates that GnRH neurons are able to set up pulsatile secretion in the absence of pulsatile exogenous kisspeptin.

European Consensus Statement on congenital hypogonadotropic hypogonadism—pathogenesis, diagnosis and treatment

“…However, a male individual with reversible CHH exhibited a robust response to exogenous kisspeptin 145 and continuous kisspeptin infusion was demonstrated to overcome genetic defects in the kisspeptin signalling pathway. 146 In terms of clinical application, kiss peptin has been used with therapeutic effect in women with hypothalamic amenorrhoea, 147 as well as for egg maturation during assisted fertility. 148 Thus, although still investigational, kisspeptin seems to be emerging as useful in several therapeutic areas.…”

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

“…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].…”

Role of Kisspeptine in Regulation of Reproductive Function

“…В то время как триггеры самопроизвольного купирования гипогонадизма остаются мало-изученными, эти клинические наблюдения, очевидно, представляют важные ориентиры и относительно физиологической иерархии, и относительного влияния нейрокинина B и кисспептина на модуляцию выброса ГнРГ. Вероятность того, что действие нейрокинина B содружественно действию кисспептина, под-тверждается наблюдением повышения частоты повторения импульсов ЛГ во время инфузии кисспептина у женщин с недостаточностью В-нейрокининовой сигнализации [96].…”