Normosmic idiopathic hypogonadotropic hypogonadism: update on the genetic background and future challenges

Purpose of review: What controls puberty remains largely unknown, and current gene mutations account for only about one-third of the apparently genetic cases of idiopathic hypogonadotropic hypogonadism. Lately, important developments have occurred in this field. Recent findings: The neuroendocrine control of reproduction in all mammals is governed by a hypothalamic neural network of approximately 1500 gonadotropin-releasing hormone (GnRH) secreting neurons that control the activity of the reproductive axis across life. Recently, the syndrome of human GnRH deficiency, either with anosmia, termed Kallmann syndrome, or with a normal sense of smell, termed normosmic idiopathic hypogonadotropic hypogonadism, has proven to be important disease models that have revealed much about the abnormalities that can befall the GnRH neurons as they differentiate, migrate, form networks, mature and senesce. Mutations in several genes responsible for these highly coordinated developmental processes have thus been unearthed by the study of this prismatic disease model. These genetic studies have opened up a new chapter in the physiology and the pharmacology of the gonadotropic axis.