Gonadotropin Hormones: Disorders


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.



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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.

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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]