Open AccessKisspeptin-54 Accurately Identifies Hypothalamic Gonadotropin-Releasing Hormone Neuronal Dysfunction in Men with Congenital Hypogonadotropic Hypogonadism
Author(s) -
Ali Abbara,
Pei Chia Eng,
Maria Phylactou,
Sophie Clarke,
Edouard Mills,
Germaine Chia,
Lisa Yang,
Chioma IzziEngbeaya,
Neil Smith,
Channa Jayasena,
Alexander N Comninos,
Ravinder AnandIvell,
Jesse Rademaker,
Chao Xu,
Richard Quinton,
Nelly Pitteloud,
Waljit S. Dhillo
Publication year - 2020
Publication title -
neuroendocrinology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.493
H-Index - 101
eISSN - 1423-0194
pISSN - 0028-3835
DOI - 10.1159/000513248
Subject(s) - hypogonadotropic hypogonadism , endocrinology , medicine , kisspeptin , kallmann syndrome , luteinizing hormone , gonadotropin releasing hormone , hypothalamic disease , hypothalamus , gonadotropin , neuropeptide , hormone , receptor , disease , covid-19 , infectious disease (medical specialty)
Background: Hypogonadotropic hypogonadism (HH) is hypogonadism due to either hypothalamic or pituitary dysfunction. While 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 HH (CHH) is typically due to variants in genes that control hypothalamic GnRH neuronal migration or 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 (100 μg) or KP54 (6.4 nmol/kg), on 2 occasions, and were monitored for 6 h after administration of each neuropeptide. Results: Maximal luteinizing hormone (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 (area under receiver operating characteristic 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 CHH.