Idiopathic hypogonadotropic hypogonadism (IHH) is a condition where the brain doesn't release enough GnRH, leading to delayed puberty and infertility. Over 60 genes can cause it, and many people have mutations in more than one gene. Recent research uncovered that a group of brain cells called KNDy neurons act as the GnRH pulse generator, and a new drug that blocks neurokinin B receptors (fezolinetant) has been approved for menopause symptoms.

Idiopathic hypogonadotropic hypogonadism (IHH) comprises a group of disorders characterized by deficient secretion or action of gonadotropin-releasing hormone (GnRH), leading to impaired pubertal development and infertility. Traditionally, IHH is classified into Kallmann syndrome (KS), associated with anosmia, and normosmic IHH (nIHH), in which olfactory function is preserved. The condition exhibits marked genetic heterogeneity. Advances in next generation sequencing have significantly expanded the genetic landscape of IHH, with pathogenic variants identified in over 60 genes, accounting for up to 50% of cases. Oligogenic inheritance is increasingly recognized, occurring in 10-20% of individuals. The potential for spontaneous or treatment-induced clinical recovery in a subset of patients, along with phenotypic overlap with constitutional delay of growth and puberty (CDGP), presents additional diagnostic challenges. Despite these complexities, genetic studies of IHH have provided critical insights into fundamental neuroendocrine processes, most notably the recent elucidation of the KNDy (Kisspeptin, Neurokinin B, Dynorphin) neurons as the GnRH pulse generator. These discoveries have also informed the development of targeted therapies, exemplified by the recent FDA approval of fezolinetant, a neurokinin B receptor antagonist, for the treatment of menopausal vasomotor symptoms.