Background: Hypogonadotropic hypogonadism is hypogonadism due to either hypothalamic or pituitary dysfunction. Whilst gonadotropin releasing hormone (GnRH) can directly test pituitary function, no specific test of hypothalamic function exists. Kisspeptin-54 (KP54) is a neuropeptide that directly stimulates hypothalamic GnRH-release and thus could be used to specifically interrogate hypothalamic function. Congenital Hypogonadotropic Hypogonadism (CHH) is typically due to variants in genes that control hypothalamic GnRH neuronal migration of function. Thus, we investigated whether KP54 could accurately identify hypothalamic dysfunction in men with CHH. Methods: Men with CHH (n=21) and healthy eugonadal men (n=21) received an intravenous bolus of either GnRH (100mcg), or KP54 (6.4nmol/kg), on two occasions, and were monitored for 6hrs after administration of each neuropeptide. Results: Maximal LH-rise after KP54 was significantly greater in healthy men (12.5 iU/L) than in men with CHH (0.4 iU/L; P<0.0001). KP54 more accurately differentiated CHH men from healthy men than GnRH (auROC curve KP54: 1.0, 95%CI 1.0-1.0; GnRH: 0.88, 95%CI 0.76-0.99). Indeed, all CHH men had an LH-rise <2.0 iU/L following KP54, whereas all healthy men had an LH-rise >4.0 iU/L. Anosmic men with CHH (i.e. Kallmann syndrome) had even lower LH-rises after KP54 than did normosmic men with CHH (P=0.017). Likewise, men identified to have pathogenic/likely pathogenic variants in CHH genes had even lower LH-rises after KP54 than other men with CHH (P=0.035). Conclusion: KP54 fully discriminated men with CHH from healthy men. Thus, KP54 could be used to specifically interrogate hypothalamic GnRH neuronal function in patients with congenital hypogonadotropic hypogonadism.


中文翻译：

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Kisspeptin-54 准确识别先天性促性腺激素性性腺功能减退症男性的下丘脑 GnRH 神经元功能障碍

背景：低促性腺激素性腺功能减退症是由于下丘脑或垂体功能障碍引起的性腺功能减退。虽然促性腺激素释放激素 (GnRH) 可以直接测试垂体功能，但不存在对下丘脑功能的特异性测试。Kisspeptin-54 (KP54) 是一种直接刺激下丘脑 GnRH 释放的神经肽，因此可用于特异性询问下丘脑功能。先天性低促性腺激素性功能减退症 (CHH) 通常是由于控制下丘脑 GnRH 神经元功能迁移的基因变异所致。因此，我们调查了 KP54 是否可以准确识别 CHH 男性的下丘脑功能障碍。方法：患有 CHH 的男性 (n=21) 和健康的性腺功能正常的男性 (n=21) 两次接受 GnRH (100mcg) 或 KP54 (6.4nmol/kg) 的静脉推注，并在每种神经肽给药后监测 6 小时。结果：健康男性（12.5 iU/L）在 KP54 后的最大 LH 升高显着高于 CHH 男性（0.4 iU/L；P<0.0001）。KP54 比 GnRH 更准确地将 CHH 男性与健康男性区分开来（auROC 曲线 KP54：1.0，95%CI 1.0-1.0；GnRH：0.88，95%CI 0.76-0.99）。事实上，在 KP54 后，所有 CHH 男性的 LH 升高 <2.0 iU/L，而所有健康男性的 LH 升高 >4.0 iU/L。患有 CHH（即 Kallmann 综合征）的无嗅觉男性在 KP54 后的 LH 升高甚至低于患有 CHH 的正常嗅觉男性（P=0.017）。同样，被鉴定为 CHH 基因致病/可能致病变异的男性在 KP54 后的 LH 升高甚至低于其他 CHH 男性（P=0.035）。结论：KP54 完全区分 CHH 男性和健康男性。因此，