Advances in the molecular genetics of hypogonadotropic hypogonadism

Mutations in several genes have been shown to cause hypogonadotropic hypogo nadism (HHG) in humans, This condition may result from abnormalities in hyp othalamic gonadotropin-releasing hormone (GnRH) secretion, impaired pituita ry gonadotropin release, or both, Here, we consider mutations in KAL in X-l inked Kallmann syndrome; DAX1 in X-linked adrenal hypoplasia congenita; the related orphan nuclear receptor, steroidogenic factor-1; leptin and prohor mone convertase-1, which may influence GnRH release and processing; the GnR H receptor; the pituitary transcription factors, HESX-1, LHX3 and PROP-1; a nd the gonadotropins, follicle stimulating hormone (FSH) and luteinizing ho rmone (LH). Identifying naturally occurring mutations in these genes provid es important information about the role of these factors in the development and function of the hypothalamic-pituitary gonadal axis in humans. Differe nt approaches to treatment and counseling may be needed, depending on the c ondition. Furthermore, the pathophysiological basis of HHG in the majority of individuals remains unclear, despite recent advances. Other candidate ge nes may be involved in these patients.