Section of Endocrinology and Investigative Medicine, Imperial College London, Hammersmith Hospital, London, United Kingdom.
Institute of Reproductive and Developmental Biology, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, United Kingdom.
J Clin Invest. 2020 Dec 1;130(12):6739-6753. doi: 10.1172/JCI139681.
BACKGROUNDKisspeptin is a key regulator of hypothalamic gonadotropin-releasing hormone (GnRH) neurons and is essential for reproductive health. A specific kisspeptin receptor (KISS1R) agonist could significantly expand the potential clinical utility of therapeutics targeting the kisspeptin pathway. Herein, we investigate the effects of a KISS1R agonist, MVT-602, in healthy women and in women with reproductive disorders.METHODSWe conducted in vivo and in vitro studies to characterize the action of MVT-602 in comparison with native kisspeptin-54 (KP54). We determined the pharmacokinetic and pharmacodynamic properties of MVT-602 (doses 0.01 and 0.03 nmol/kg) versus KP54 (9.6 nmol/kg) in the follicular phase of healthy women (n = 9), and in women with polycystic ovary syndrome (PCOS; n = 6) or hypothalamic amenorrhea (HA; n = 6). Further, we investigated their effects on KISS1R-mediated inositol monophosphate (IP1) and Ca2+ signaling in cell lines and on action potential firing of GnRH neurons in brain slices.RESULTSIn healthy women, the amplitude of luteinizing hormone (LH) rise was similar to that after KP54, but peaked later (21.4 vs. 4.7 hours; P = 0.0002), with correspondingly increased AUC of LH exposure (169.0 vs. 38.5 IU∙h/L; P = 0.0058). LH increases following MVT-602 were similar in PCOS and healthy women, but advanced in HA (P = 0.004). In keeping with the clinical data, MVT-602 induced more potent signaling of KISS1R-mediated IP1 accumulation and a longer duration of GnRH neuron firing than KP54 (115 vs. 55 minutes; P = 0.0012).CONCLUSIONTaken together, these clinical and mechanistic data identify MVT-602 as having considerable therapeutic potential for the treatment of female reproductive disorders.TRIAL REGISTRATIONInternational Standard Randomised Controlled Trial Number (ISRCTN) Registry, ISRCTN21681316.FUNDINGNational Institute for Health Research and NIH.
kisspeptin 是下丘脑促性腺激素释放激素（GnRH）神经元的关键调节剂，对生殖健康至关重要。 kisspeptin 途径的特定 kisspeptin 受体（KISS1R）激动剂可以显著扩大治疗方法的潜在临床应用。在此，我们研究了 KISS1R 激动剂 MVT-602 在健康女性和生殖障碍女性中的作用。
我们进行了体内和体外研究，以比较 MVT-602 与天然 kisspeptin-54（KP54）的作用。我们确定了 MVT-602（剂量为 0.01 和 0.03 nmol/kg）与 KP54（9.6 nmol/kg）在健康女性（n=9）和多囊卵巢综合征（PCOS；n=6）或下丘脑闭经（HA；n=6）的卵泡期的药代动力学和药效学特性。此外，我们研究了它们对 KISS1R 介导的肌醇单磷酸（IP1）和 Ca2+信号转导以及 GnRH 神经元在脑片中动作电位放电的影响。
在健康女性中，LH 升高的幅度与 KP54 相似，但峰值较晚（21.4 与 4.7 小时；P=0.0002），相应地增加了 LH 暴露的 AUC（169.0 与 38.5 IU∙h/L；P=0.0058）。MVT-602 引起的 LH 增加在 PCOS 和健康女性中相似，但在 HA 中提前（P=0.004）。与临床数据一致，MVT-602 诱导的 KISS1R 介导的 IP1 积累信号更强，并且 GnRH 神经元放电时间更长，比 KP54 长 115 分钟（P=0.0012）。
综上所述，这些临床和机制数据表明，MVT-602 具有治疗女性生殖障碍的巨大治疗潜力。
国际标准随机对照试验编号（ISRCTN）登记处，ISRCTN21681316。
英国国家健康研究所和美国国立卫生研究院。
