Genetics of hypogonadotropic hypogonadism

Abstract

Determining the physiologic influences that modulate GnRH secretion, the prime initiator of reproductive function in the human, is fundamental not only to our understanding of the rare condition of congenital idiopathic hypogonadotropic hypogonadism (IHH), but also common disorders such as constitutional delay of puberty and hypothalamic amenorrhea. IHH is characterized by low levels of sex steroids and gonadotropins, normal findings on radiographic imaging of the hypothalamic-pituitary regions, and normal baseline and reserve testing of the remainder of the hypothalamic-pituitary axes. Failure of the normal pattern of episodic GnRH secretion results in delay of puberty and infertility. IHH is characterized by rich clinical and genetic heterogeneity, variable modes of inheritance, and association with other anomalies. To date, 4 genes have been identified as causes of IHH in the human; KAL [the gene for X-linked Kallmann syndrome (IHH and anosmia)], DAX1 [the gene for X-linked adrenal hypoplasia congenita (IHH and adrenal insufficiency)], GNRHR (the GnRH receptor), and PC1 (the gene for prohormone convertase 1, causing a syndrome of IHH and defects in prohormone processing). As these mutations account for less than 20% of all IHH cases, discovery of additional gene mutations will continue to advance our understanding of this intriguing syndrome.

Expression and Function of Gonadotropin-releasing Hormone (GnRH) Receptor in Human Olfactory GnRH-secreting Neurons

“…Kallmann's syndrome is considered a congenital form of hypogonadotropic hypogonadism. It is characterized by the association of an inability to smell (anosmia) with a defect in gonadal development due to GnRH deficiency (13)(14)(15)(16)(17)(18)(19). However, in humans, Kallmann's syndrome is characterized by considerable clinical and genetic heterogeneity.…”

“…For the congenital forms of hypogonadotropic hypogonadism, the genes currently recognized are KAL and FGFR1, associated with Kallmann's syndrome; DAX 1, associated with adrenohypoplasia congenita; GnRH receptor, associated with resistance to GnRH therapy; and three loci also associated with obesity, leptin (OB), leptin receptor (DB), and prohormone convertase (PC1) (17,19,20). A less well characterized group of acquired hypogonadotropic hypogonadism encompasses a wide range of disorders such as infiltrative processes and space-occupying lesions, i.e.…”

“Been hit twice”: a novel bi-allelic heterozygous mutation in LHCGR

“…Second, cases of sex reversal resulting in Leydig cell defects that could have been misdiagnosed as androgen-insensitivity could be revisited and genetic screening of these patients for any potential mutations in LHCGR could be undertaken [33]. Third, digenic and oligo-genic mutations in several genes that act in concert are known to cause a variety of human reproductive disorders [33][34][35][36][37]. It is likely that some forms of idiopathic infertility cases could result from heterozygous mutations in one allele of LHCGR and another yet unidentified gene (s).…”

“…It is likely that some forms of idiopathic infertility cases could result from heterozygous mutations in one allele of LHCGR and another yet unidentified gene (s). One could begin to analyze DNA samples from such patients using the emerging high-throughput sequencing approaches [33][34][35][36][37]. Finally, if indeed the 27 bp mutation in LHCGR exon I results in mis-routing and ER trapping of the mutant LHCGRs, attempts to rescue these misfolded/ ER-trapped receptors in vitro [38] and eventually in patients using a pharmacoperone-based therapeutic approach should be feasible [25,39,40].…”

Aspectos clínicos e moleculares do hipogonadismo hipogonadotrófico isolado congênito

“…CARACTeRíSTICAS ClíNICAS e hORMONAIS DO hIpOgONADISMO hIpOgONADOTRófICO ISOlADO NORMóSMICO e DA SíNDROMe De KAllMANN O HHI congênito é definido pela ausência parcial ou completa de desenvolvimento puberal, secundário a um defeito na produção ou na secreção hipotalâmica de GnRH ou pela resistência hipofisária à ação do GnRH (12). O diagnóstico de hipogonadismo é suspeitado diante da ausência ou parada de desenvolvimento puberal após os 18 anos em meninos e 16 anos em meninas.…”