The genetic and molecular basis of idiopathic hypogonadotropic hypogonadism

Abstract

Idiopathic hypogonadotropic hypogonadism (IHH) has an incidence of 1–10 cases per 100,000 births. About 60% of patients with IHH present with associated anosmia, also known as Kallmann syndrome, characterized by total or partial loss of olfaction. Many of the gene mutations associated with Kallmann syndrome have been mapped to KAL1 or FGFR1. However, together, these mutations account for only about 15% of Kallmann syndrome cases. More recently, mutations in PROK2 and PROKR2 have been linked to the syndrome and may account for an additional 5–10% of cases. The remaining 40% of patients with IHH have a normal sense of smell. Prior to 2003, the only gene linked to normosmic IHH was the gonadotropin-releasing hormone receptor gene. However, mutations in this receptor are believed to account for only 10% of cases. Subsequently, mutations in KISS1R, TAC3 and TACR3 were identified as causes of normosmic IHH. Certain genes, including PROK2 and FGFR1, are associated with both anosmic and normosmic IHH. Despite recent advances in the field, the genetic causes of the majority of cases of IHH remain unknown. This Review discusses genes associated with hypogonadotropic disorders and the molecular mechanisms by which mutations in these genes may result in IHH.

European Consensus Statement on congenital hypogonadotropic hypogonadism—pathogenesis, diagnosis and treatment

“…At birth, GnRH neurons have reached their final destination in the brain and many of them project into the median eminence, where they release the GnRH decapeptide from their axon terminals into the hypophyseal portal vasculature. 1 GnRH acts via the GnRH receptor, which is expressed on gonadotropic cells in the anterior pituitary gland. This action regulates both synthesis and release of gonadotropins such as luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which control gonadal maturation and adult reproductive physiology via the hypothalamic-pituitary-gonadal (HPG) axis.…”

“…Some key molecules have been discovered through the study of the genetics of CHH. 1 Inactivating mutations in genes encoding kisspeptin-1 (KISS1) 40 and its receptor (KISS1R) 41,42 halt pubertal development in humans. Extensive experimental studies in various species have demonstrated that kisspeptin-producing neurons are major afferents to GnRH neurons and are essential for different aspects of GnRH function, ranging from the tonic feedback control of GnRH and/or gonadotropin secretion to generation of the pre-ovulatory surge responsible for ovulation.…”

“…1 CHH is characterized by incomplete or absent puberty and infertility in the setting of isolated hypogonadotropic hypogonadism (that is, otherwise normal anterior pitui tary function). CHH can present solely as congenital GnRH deficiency or be associated with other develop mental anomalies such as cleft lip or palate, dental agenesis, ear anomalies, congenital hearing impairment, renal agenesis, bimanual synkinesis or skeletal anomalies.…”

Male infertility: Pathogenesis and clinical diagnosis

“…3,4 A detailed description of the congenital forms of HH is already provided in this issue by Dr Rey and Dr Grinspon. The list of candidate genes (Table 2) both for normosmic HH and Kallmann syndrome is constantly growing and genetic testing should be based on the patient's gender, family history (if any), mode of disease inheritance, and the presence of additional clinical anomalies.…”

“…In about 30-40% of patients mutation in one (or more than one) candidate gene(s) can be now identified. 4 The diagnosis of acquired HH, is of importance not only with respect to infertility but also for its potential implications to general health (in some cases it may represent a life-threatening condition). In fact, acquired HH can be related to tumours (both benign or malignant), and may affect the secretion of more than one pituitary hormone leading to their deficit or excess.…”