Gonadotropin Hormones: Disorders

Abstract

Abnormalities in gonadotropin hormone release and function can arise from changes in a variety of genes expressed throughout the hypothalamic–pituitary (gonadotrope)–gonadal (HPG) axis. Alterations in these genes can disrupt proteins that are involved in many different biological processes such as neuronal migration, gonadotropin‐releasing hormone (GnRH) release and action, and pituitary development, as well as affecting synthesis and function of the gonadotropin hormones (follicle‐stimulating hormone and luteinising hormone) themselves. The identification and characterisation of these factors is providing important insight into the reproductive axis in humans and may result in improved treatment and counselling for patients with infertility problems. However, the underlying cause of GnRH deficiency or altered gonadotropin action is not currently known in most cases, and it is emerging that digenic or oligogenic inheritance patterns are important in some situations. Therefore, the molecular basis of disorders of gonadotropin hormones may be more complex than originally thought.

Key Concepts:

  • The gonadotropins, FSH and LH, are heterodimeric glycoprotein hormones released in pulses from the pituitary gonadotrope cells.

  • FSH and LH secretion is regulated by hypothalamic GnRH, which itself is pulsatile.

  • GnRH‐secreting neurons originate in the olfactory placode and migrate to the hypothalamus during development; defects affecting neuronal migration can be associated with a lack of smell (anosmia).

  • Gonadotropes develop within the anterior pituitary gland, which originates from the oral ectoderm; defects affecting gonadotrope function can be associated with other pituitary hormone deficiencies.

  • FSH and LH act through peripheral G protein‐coupled receptors to stimulate gonad development and function.

  • Some factors can influence the hypothalamic–pituitary–gonadal axis at multiple levels.

  • More than 30 single gene disorders affecting gonadotropin function have now been described, often affecting receptor‐ligand pairs.

  • Phenotypic penetrance can be variable, even within families and may reflect the influence of modifier genes, epigenetic factors or environmental stimuli.

  • In some situations, changes in two genes can result in a clinical phenotype (digenic inheritance).

  • In many cases the underlying molecular basis of hypogonadism is still unknown.

Keywords: gonadotropin‐hormone releasing‐hormone (GnRH); luteinising hormone (LH); follicle‐stimulating hormone (FSH); pituitary; hypothalamus; reproduction; puberty; infertility; Kallmann syndrome; hypogonadotropic hypogonadism (HH)

Figure 1.

Overview of the hypothalamic–pituitary (gonadotrope)–gonadal (HPG) axis.

Figure 2.

Overview of hypothalamic–gonadotrope development. (a) Migration of gonadotropin‐releasing hormone (GnRH) neurons from the olfactory placode to the fetal hypothalamus. (b) Differentiation of the specific cell lineages in the developing anterior pituitary gland.

Figure 3.

Overview of HPG axis development and function. Mutations in the genes listed in italics have been shown to cause hypogonadotropic hypogonadism (HH) in humans. (a) Migration of gonadotropin‐releasing hormone (GnRH) neurons from the olfactory placode to the fetal hypothalamus is facilitated by: anosmin‐1 (encoded by KAL1); the fibroblast growth factor receptor 1 (FGFR1) and fibroblast growth factor 8 (FGF8); the prokineticin‐2 receptor (PROKR2) and prokineticin‐2 (PROK2); chromatin organisation modifier (CHD7); nasal embryonic LHRH factor (NELF) and WD repeat‐containing protein 11 (WDR11). Defects in this process result in Kallmann syndrome. SRY‐related high mobility group (HMG) box gene 2 (SOX2) has also been implicated in GnRH neuronal migration and differentiation. (b) GnRH release and signalling are modulated by: the kisspeptin receptor (KISS1R, also known as GPR54); tachykinin 3 (TAC3) and the tachykinin receptor 3 (TAC3R); leptin (LEP) and the leptin receptor (LEPR) and proprotein convertase, subtilisin/kexin‐type 1 (PCSK1). (c) Anterior pituitary development and function. Mutations in the genes shown cause distinct phenotypes in humans: Homeobox (expressed in ES cells) 1 (HESX1); Orthodenticle homeobox 2 (OTX2); SRY‐box 3 (SOX3); GLI‐Kruppel family member 2 (GLI2); LIM homeobox protein 3 (LHX3); LIM homeobox protein 4 (LHX4) and Prophet of Pit1, paired‐like homeodomain transcription factor (PROP1). (d) Gonadotropin synthesis and function: gonadotropin‐releasing hormone receptor (GnRHR); steroidogenic factor‐1 (NR5A1) and DSS‐AHC critical region on the X‐chromosome 1, gene1 (DAX‐1) (NR0B1); follicle‐stimulating hormone, beta polypeptide (FSHB) and FSH receptor (FSHR); luteinising hormone, beta polypeptide (LHB) and the luteinising hormone/choriogonadotropin receptor (LHCGR). (*), Variable gonadotropin pituitary phenotype.

Figure 4.

Overview of human FSH and LH β subunit and receptor mutations. (a) Representation of the FSH/LH β subunit. Missense or frameshift mutations in FSHB affect the ‘cysteine knot’. This ‘seatbelt’ region of the molecule is involved in heterodimer stability. In contrast, a missense mutation in LHB affects the long loop of the molecule, a region involved in receptor binding. (b) Representation showing a selection of inactivating (circles) and activating (stars) mutations in the FSH and LH receptors. LH receptor mutations associated with a milder phenotype (e.g. micropenis) are located in the seventh transmembrane domain. Part (a) is modified with permission from Achermann JC, Weiss J, Lee EJ and Jameson JL (2001) Inherited disorders of the gonadotropin hormones. Molecular and Cellular Endocrinology179(1–2): 89–96. Copyright 2001, Elsevier.

close

References

Abreu AP, Trarbach EB, de Castro M et al. (2008) Loss‐of‐function mutations in the genes encoding prokineticin‐2 or prokineticin receptor‐2 cause autosomal recessive Kallmann syndrome. Journal of Clinical Endocrinology Metabolism 93(10): 4113–4118.

Achermann JC, Ito M, Ito M et al. (1999) A mutation in the gene encoding steroidogenic factor‐1 causes XY sex reversal and adrenal failure in humans. Nature Genetics 22(2): 125–126.

Aittomaki K, Lucena JL, Pakarinen P et al. (1995) Mutation in the follicle‐stimulating hormone receptor gene causes hereditary hypergonadotropic ovarian failure. Cell 82(6): 959–968.

Beau I, Touraine P, Meduri G et al. (1998) A novel phenotype related to partial loss of function mutations of the follicle stimulating hormone receptor. Journal of Clinical Investigation 102(7): 1352–1359.

Bouligand J, Ghervan C, Tello JA et al. (2009) Isolated familial hypogonadotropic hypogonadism and a GNRH1 mutation. New England Journal of Medicine 360(26): 2742–2748.

Brioude F, Bouligand J, Trabado S et al. (2010) Non‐syndromic congenital hypogonadotropic hypogonadism: clinical presentation and genotype‐phenotype relationships. European Journal of Endocrinology 162(5): 835–851.

Chan YM, de Guillebon A, Lang‐Muritano M et al. (2009) GNRH1 mutations in patients with idiopathic hypogonadotropic hypogonadism. Proceedings of the National Academy of Sciences of the USA 106(28): 11703–11708.

Colledge WH (2009) Transgenic mouse models to study Gpr54/kisspeptin physiology. Peptides 30(1): 34–41.

Dateki S, Kosaka K, Hasegawa K et al. (2010) Heterozygous orthodenticle homeobox 2 mutations are associated with variable pituitary phenotype. Journal of Clinical Endocrinology Metabolism 95(2): 756–764.

Dattani MT, Martinez‐Barbera JP, Thomas PQ et al. (1998) Mutations in the homeobox gene HESX1/Hesx1 associated with septo‐optic dysplasia in human and mouse. Nature Genetics 19(2): 125–133.

Dode C, Levilliers J, Dupont JM et al. (2003) Loss‐of‐function mutations in FGFR1 cause autosomal dominant Kallmann syndrome. Nature Genetics 33(4): 463–465.

Dode C, Teixeira L, Levilliers J et al. (2006) Kallmann syndrome: mutations in the genes encoding prokineticin‐2 and prokineticin receptor‐2. PLoS Genetics 2(10): e175.

El‐Khairi R, Martinez‐Aguayo A, Ferraz‐de‐Souza B et al. (2011) Role of DAX‐ 1 (NR0B1) and steroidogenic factor‐1 (NR5A1) in human adrenal function. Endocrine Development. In press.

Falardeau J, Chung WC, Beenken A et al. (2008) Decreased FGF8 signaling causes deficiency of gonadotropin‐releasing hormone in humans and mice. Journal of Clinical Investigation 118(8): 2822–2831.

Farooqi IS, Jebb SA, Langmack G et al. (1999) Effects of recombinant leptin therapy in a child with congenital leptin deficiency. New England Journal of Medicine 341(12): 879–884.

Farooqi IS, Wangensteen T, Collins S et al. (2007) Clinical and molecular genetic spectrum of congenital deficiency of the leptin receptor. New England Journal of Medicine 356(3): 237–247.

Franco B, Guioli S, Pragliola A et al. (1991) A gene deleted in Kallmann's syndrome shares homology with neural cell adhesion and axonal path‐finding molecules. Nature 353(6344): 529–536.

Gianetti E, Tusset C, Noel SD et al. (2010) TAC3/TACR3 mutations reveal preferential activation of gonadotropin‐releasing hormone release by neurokinin B in neonatal life followed by reversal in adulthood. Journal of Clinical Endocrinology Metabolism 95(6): 2857–2867.

Guran T, Tolhurst G, Bereket A et al. (2009) Hypogonadotropic hypogonadism due to a novel missense mutation in the first extracellular loop of the neurokinin B receptor. Journal of Clinical Endocrinology Metabolism 94(10): 3633–3639.

Hochberg Z, Feil R, Constancia M et al. (in press) Child health, developmental plasticity, and epigenetic programming. Endocrine Reviews.

Jackson RS, Creemers JW, Farooqi IS et al. (2003) Small‐intestinal dysfunction accompanies the complex endocrinopathy of human proprotein convertase 1 deficiency. Journal of Clinical Investigation 112(10): 1550–1560.

Jongmans MC, van Ravenswaaij‐Arts CM, Pitteloud N et al. (2009) CHD7 mutations in patients initially diagnosed with Kallmann syndrome – the clinical overlap with CHARGE syndrome. Clinical Genetics 75(1): 65–71.

Kelberman D, Rizzoti K, Avilion A et al. (2006) Mutations within Sox2/SOX2 are associated with abnormalities in the hypothalamo‐pituitary‐gonadal axis in mice and humans. Journal of Clinical Investigation 116(9): 2442–2455.

Kelley CG, Lavorgna G, Clark ME et al. (2000) The Otx2 homeoprotein regulates expression from the gonadotropin‐releasing hormone proximal promoter. Molecular Endocrinology 14(8): 1246–1256.

Kim HG, Kurth I, Lan F et al. (2008) Mutations in CHD7, encoding a chromatin‐remodeling protein, cause idiopathic hypogonadotropic hypogonadism and Kallmann syndrome. American Journal of Human Genetics 83(4): 511–519.

Kim HG, Pedersen‐White J, Bhagavath B et al. (2010) Genotype and phenotype of patients with gonadotropin‐releasing hormone receptor mutations. Frontiers in Hormone Research 39: 94–110.

Latronico AC, Anasti J, Arnhold IJ et al. (1996) Brief report: testicular and ovarian resistance to luteinizing hormone caused by inactivating mutations of the luteinizing hormone‐receptor gene. New England Journal of Medicine 334(8): 507–512.

Layman LC, Lee EJ, Peak DB et al. (1997) Delayed puberty and hypogonadism caused by mutations in the follicle‐stimulating hormone beta‐subunit gene. New England Journal of Medicine 337(9): 607–611.

Layman LC, Porto ALA, Xie J et al. (2002) FSHbeta gene mutations in a female with partial breast development and a male sibling with normal puberty and azoospermia. Journal of Clinical Endocrinology Metabolism 87(8): 3702–3707.

Lourenco D, Brauner R, Lin L et al. (2009) Mutations in NR5A1 associated with ovarian insufficiency. New England Journal of Medicine 360(12): 1200–1210.

Martos‐Moreno GA, Chowen JA and Argente J (2010) Metabolic signals in human puberty: effects of over and undernutrition. Molecular and Cellular Endocrinology 324(1–2): 70–81.

Matthews C and Chatterjee VK (1997) Isolated deficiency of follicle‐stimulating hormone re‐revisited. New England Journal of Medicine 337(9): 642.

Matthews CH, Borgato S, Beck‐Peccoz P et al. (1993) Primary amenorrhoea and infertility due to a mutation in the beta‐subunit of follicle‐stimulating hormone. Nature Genetics 5(1): 83–86.

Miura K, Acierno JS Jr and Seminara SB (2004) Characterization of the human nasal embryonic LHRH factor gene, NELF, and a mutation screening among 65 patients with idiopathic hypogonadotropic hypogonadism (IHH). Journal of Human Genetics 49(5): 265–268.

Montague CT, Farooqi IS, Whitehead JP et al. (1997) Congenital leptin deficiency is associated with severe early onset obesity in humans. Nature 387(6636): 903–908.

Netchine I, Sobrier ML, Krude H et al. (2000) Mutations in LHX3 result in a new syndrome revealed by combined pituitary hormone deficiency. Nature Genetics 25(2): 182–186.

Ojeda SR, Dubay C, Lomniczi A et al. (2010) Gene networks and the neuroendocrine regulation of puberty. Molecular and Cellular Endocrinology 324(1–2): 3–11.

Pfaeffle RW, Hunter CS, Savage JJ et al. (2008) Three novel missense mutations within the LHX4 gene are associated with variable pituitary hormone deficiencies. Journal of Clinical Endocrinology Metabolism 93(3): 1062–1071.

Phillip M, Arbelle JE, Segev Y et al. (1998) Male hypogonadism due to a mutation in the gene for the beta‐subunit of follicle‐stimulating hormone. New England Journal of Medicine 338(24): 1729–1732.

Pitteloud N, Quinton R, Pearce S et al. (2007a) Digenic mutations account for variable phenotypes in idiopathic hypogonadotropic hypogonadism. Journal of Clinical Investigation 117(2): 457–463.

Pitteloud N, Zhang C, Pignatelli D et al. (2007b) Loss‐of‐function mutation in the prokineticin 2 gene causes Kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadism. Proceedings of the National Academy of Sciences of the USA 104(44): 17447–17452.

de Roux N, Young J, Misrahi M et al. (1997) A family with hypogonadotropic hypogonadism and mutations in the gonadotropin‐releasing hormone receptor. New England Journal of Medicine 337(22): 1597–1602.

Seminara SB, Messager S, Chatzidaki EE et al. (2003) The GPR54 gene as a regulator of puberty. New England Journal of Medicine 349(17): 1614–1627.

Sykiotis GP, Plummer L, Hughes VA et al. (2010) Oligogenic basis of isolated gonadotropin‐releasing hormone deficiency. Proceedings of the National Academy of Sciences of the USA 107(34): 15140–15144.

Teles MG, Bianco SD, Brito VN et al. (2008) A GPR54‐activating mutation in a patient with central precocious puberty. New England Journal of Medicine 358(7): 709–715.

Topaloglu AK, Reimann F, Guclu M et al. (2009) TAC3 and TACR3 mutations in familial hypogonadotropic hypogonadism reveal a key role for neurokinin B in the central control of reproduction. Nature Genetics 41(3): 354–358.

Valdes‐Socin H, Salvi R, Daly AF et al. (2004) Hypogonadism in a patient with a mutation in the luteinizing hormone beta‐subunit gene. New England Journal of Medicine 351(25): 2619–2625.

Weiss J, Axelrod L, Whitcomb RW et al. (1992) Hypogonadism caused by a single amino acid substitution in the beta subunit of luteinizing hormone. New England Journal of Medicine 326(3): 179–183.

Woods KS, Cundall M, Turton J et al. (2005) Over‐ and underdosage of SOX3 is associated with infundibular hypoplasia and hypopituitarism. American Journal of Human Genetics 76(5): 833–849.

Wu W, Cogan JD, Pfaffle RW et al. (1998) Mutations in PROP1 cause familial combined pituitary hormone deficiency. Nature Genetics 18(2): 147–149.

Young J, Bouligand J, Francou B et al. (2010) TAC3 and TACR3 defects cause hypothalamic congenital hypogonadotropic hypogonadism in humans. Journal of Clinical Endocrinology Metabolism 95(5): 2287–2295.

Further Reading

Abreu AP, Kaiser UB and Latronico AC (2010) The role of prokineticins in the pathogenesis of hypogonadotropic hypogonadism. Neuroendocrinology 91(4): 283–290.

Balasubramanian R, Dwyer A, Seminara SB et al. (2010) Human GnRH deficiency: a unique disease model to unravel the ontogeny of GnRH neuron. Neuroendocrinology 92(2): 81–99.

Kelberman D, Rizzoti K, Lovell‐Badge R et al. (2009) Genetic regulation of pituitary gland development in human and mouse. Endocrine Reviews 30(7): 790–829.

Nagirnaja L, Rull K, Uusknla L et al. (2010) Genomics and genetics of gonadotropin beta‐subunit genes: unique FSHB and duplicated LHB/CGB loci. Molecular and Cellular Endocrinology 329(1–2): 4–16.

Roa J, Garcia‐Galiano D, Castellano JM et al. (2010) Metabolic control of puberty onset: new players, new mechanisms. Molecular and Cellular Endocrinology 324(1–2): 87–94.

Semple RK and Topaloglu AK (2010) The recent genetics of hypogonadotrophic hypogonadism: novel insights and new questions. Clinical Endocrinology (Oxford) 72(4): 427–435.

Sykiotis GP, Pitteloud N, Seminara SB et al. (2010) Deciphering genetic disease in the genomic era: the model of GnRH deficiency. Science Translational Medicine 2(32): 32rv2.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Martinez‐Aguayo, Alejandro, Dattani, Mehul T, and Achermann, John C(Feb 2011) Gonadotropin Hormones: Disorders. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0006089.pub2]