Chan Yee-Ming, Lippincott Margaret F, Butler James P, Sidhoum Valerie F, Li Cindy X, Plummer Lacey, Seminara Stephanie B
Harvard Reproductive Sciences Center and Reproductive Endocrine Unit, Department of Medicine (Y-M.C., M.F.L.,V.F.S., C.X.L., L.P., S.B.S.), Massachusetts General Hospital, Boston, Massachusetts 02114; Division of Endocrinology, Department of Medicine (Y-M.C.), Boston Children's Hospital, Boston, Massachusetts 02115; and Division of Sleep Medicine (J.P.B.), Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115.
J Clin Endocrinol Metab. 2014 Dec;99(12):E2762-71. doi: 10.1210/jc.2014-2233.
Idiopathic hypogonadotropic hypogonadism (IHH) results from defective synthesis, secretion, or action of GnRH. Kisspeptin is a potent stimulus for GnRH secretion.
We probed the functional capacity of the GnRH neuronal network in patients with IHH.
Eleven subjects with congenital IHH (9 men and 2 women) and one male subject who underwent reversal of IHH were studied. Six of the twelve subjects had an identified genetic cause of their IHH: KAL1 (n = 1), FGFR1 (n = 3), PROKR2 (n = 1), GNRHR (n = 1).
Subjects underwent q10 min blood sampling to measure GnRH-induced LH secretion at baseline and in response to intravenous boluses of kisspeptin (0.24 nmol/kg) and GnRH (75 ng/kg) both pre- and post-six days of treatment with exogenous GnRH (25 ng/kg sc every 2 h).
All subjects with abiding IHH failed to demonstrate a GnRH-induced LH response to exogenous kisspeptin. In contrast, the subject who achieved reversal of his hypogonadotropism demonstrated a robust response to kisspeptin.
The functional capacity of the GnRH neuronal network in IHH patients is impaired, as evidenced by their inability to respond to the same dose of kisspeptin that effects a robust GnRH-induced LH response in healthy men and luteal-phase women. This impairment is observed across a range of genotypes, suggesting that it reflects a fundamental property of GnRH neuronal networks that have not been properly engaged during pubertal development. In contrast, a patient who had experienced reversal of his hypogonadotropism responded to exogenous kisspeptin.
特发性低促性腺激素性性腺功能减退（IHH）是由促性腺激素释放激素（GnRH）合成、分泌或作用缺陷引起的。 kisspeptin是GnRH分泌的有效刺激物。
我们探究了IHH患者中GnRH神经元网络的功能能力。
研究了11名先天性IHH患者（9名男性和2名女性）以及1名接受IHH逆转治疗的男性患者。12名受试者中有6名已确定其IHH的遗传原因：KAL1（n = 1）、FGFR1（n = 3）、PROKR2（n = 1）、GNRHR（n = 1）。
受试者每10分钟进行一次采血，以测量基线时以及在接受外源性GnRH（每2小时皮下注射25 ng/kg）治疗6天前后静脉注射kisspeptin（0.24 nmol/kg）和GnRH（75 ng/kg）后GnRH诱导的促黄体生成素（LH）分泌情况。
所有持续性IHH患者对外源性kisspeptin均未表现出GnRH诱导的LH反应。相比之下，性腺功能减退症得到逆转的受试者对kisspeptin表现出强烈反应。
IHH患者中GnRH神经元网络的功能能力受损，这表现为他们无法对相同剂量的kisspeptin产生反应，而相同剂量的kisspeptin在健康男性和黄体期女性中能引发强烈的GnRH诱导的LH反应。这种损伤在一系列基因型中均有观察到，表明它反映了GnRH神经元网络在青春期发育过程中未正常激活的基本特性。相比之下，一名性腺功能减退症得到逆转的患者对外源性kisspeptin有反应。
