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Endocr Rev. 2019 Jan 29. doi: 10.1210/er.2018-00116. [Epub ahead of print]

Clinical management of congenital hypogonadotropic hypogonadism.

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University of Paris-Sud, Paris-Sud Medical School, Le Kremlin-Bicêtre, France.
Department of Reproductive Endocrinology, Assistance Publique-Hôpitaux de Paris, Bicêtre Hôpital, Le Kremlin-Bicêtre, France.
INSERM Unité 1185, Le Kremlin-Bicêtre, France.
Service of Endocrinology, Diabetology and Metabolism, Lausanne University Hospital, Lausanne, Switzerland.
Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland.
Children's Hospital, Pediatric Research Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
Faculty of Medicine, Department of Physiology, University of Helsinki, Helsinki, Finland.


The initiation and maintenance of reproductive capacity in humans is dependent upon pulsatile secretion of the hypothalamic hormone gonadtropin-releasing hormone, GnRH. Congenital hypogonadotropic hypogonadism (CHH) is a rare disorder that results from the failure of the normal episodic GnRH secretion, leading to delayed puberty and infertility. CHH can be associated with an absent sense of smell, also termed Kallmann syndrome, or with other anomalies. CHH is characterized by rich genetic heterogeneity, with mutations in more than 30 genes identified to date acting either alone or in combination. CHH can be challenging to diagnose, particularly in early adolescence where the clinical picture mirrors that of constitutional delay of growth and puberty. Timely diagnosis and treatment will induce puberty, leading to improved sexual, bone, metabolic and psychological health. In most cases, patients require lifelong treatment yet a significant portion of male patients (around 10-20%) exhibit a spontaneous recovery of their reproductive function. Finally, fertility can be induced with pulsatile GnRH treatment or gonadotropin regimens in a majority of patients. In summary, this review is a comprehensive synthesis of the current literature available regarding the diagnosis, patient management and genetic foundations of congenital hypogonadotropic hypogonadism relative to normal reproductive development.


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