Gonadotropin-Releasing Hormone Deficiency in Adults Clinical Presentation

Updated: Jan 09, 2017
  • Author: Vaishali Popat, MD, MPH; Chief Editor: Richard Scott Lucidi, MD, FACOG  more...
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Presentation

History

The age of onset, whether congenital or acquired, and the severity, whether complete or partial, determines the phenotypic expression.

During the neonatal period, boys present with micropenis. The incomplete descent of the testes and immaturity of the external genitalia are due to failure of the hypothalamic-pituitary-gonadal axis to activate in the late fetal and neonatal periods. In the embryonic and early fetal periods, fetal testosterone is required for full sexual and external genital development, which is stimulated by maternal human chorionic gonadotropin (hCG) and does not require the stimulation of fetal pituitary gonadotropins. Newborn girls have no obvious abnormalities. Cryptorchidism has been reported in as many as 50% of males with idiopathic hypogonadotropic hypogonadism (IHH) or Kallmann syndrome (KS), and microphallus is present in as many as 30% of affected individuals.

During childhood, anosmia is the only manifestation in patients with KS.

In most cases, diagnosis is made much later, with absence of pubertal development. Histologically, the ovaries of affected women rarely possess follicles matured past the primordial stages. Hence, most of these women present with primary amenorrhea.

Some patients undergo early pubertal development but subsequently develop hypogonadism, leading to infertility and sexual dysfunction. [12]

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Physical

Most physical findings are related to failure of sexual maturation. These patients have eunuchoidal body habitus, with arm-span greater than height by 5 cm or more. Secondary sexual characteristics are often absent. Women have little or no breast development, and men have little or no facial hair. In both genders, pubic hair may be present, as adrenarche may not be affected. Gynecomastia is not a typical feature. Gonadotropin-releasing hormone (GnRH) deficiency results in decreased testosterone as well as estrogen production.

Many affected individuals are unaware of their loss of olfaction, especially those with partial defects. Testing with graded dilutions of pure scents is often necessary to identify the impaired olfaction. The magnitude of GnRH deficiency appears to correlate to the severity of anosmia. In cases where KS or IHH is suspected but cryptorchidism and microphallus are absent, an MRI may reveal olfactory bulbs, although normal olfactory bulbs have been demonstrated in only 25% of males with KS.

Along with the anosmia, another interesting neurological finding is that of mirror movements related to cerebellar defects. Present in as many as 85% of patients with KS, mirroring is the involuntary movements in a limb that mirror the voluntary movements of the contralateral limb.

Many associated defects have been reported in patients with KS. These can be defined as sporadic and include uterine malformation, congenital heart defects, and dental agenesis. X-linked KS can be associated with another X-linked disorder known as ichthyosis (steroid sulfatase disorder). The finding of renal agenesis/hypoplasia has been noted in some individuals with X-linked KS. Colquhoun-Kerr et al (1999) described an Australian family with a high frequency of renal agenesis in the presence or absence of the KAL1 mutation, suggesting an autosomal dominant or X-linked gene, which may independently or codependently contribute to renal agenesis. [13]

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Causes

GnRH deficiency is inherited through autosomal dominant, autosomal recessive, and X-linked transmissions. However, more than two thirds of cases are sporadic. In fact, only 30% of cases of GnRH deficiency are due to mutations in known genes.

Evidence suggests that most familial cases of GnRH deficiency are controlled by autosomal inheritance. In a study of 106 patients with GnRH deficiency at Massachusetts General Hospital, only 21% of familial cases were X-linked. [11] Using isolated congenital anosmia as a marker for KS, X-linked and autosomal recessive transmission was 18% and 32%, respectively. Autosomal dominance accounted for 50% of cases. When delayed puberty was included in the phenotypic analysis, X-linked cases accounted for 11% of cases, whereas autosomal recessive and autosomal dominant cases were 25% and 64%, respectively.

KAL1 gene

The KAL1 gene, described in 1991, is an example of an X-linked gene that encodes anosmin 1, an extracellular glycoprotein that is similar in amino acid structure to molecules involved in neural development, such as protease inhibitors, neurophysins, and neural cell adhesion molecules. [14] Anosmin 1 appears to be important to the migration of the GnRH neurons to their resting place in the hypothalamus. The KAL1 gene is located on the short arm of the X chromosome at Xp22.3. Approximately 10-20% of males with KS have KAL1 gene mutations, and the phenotypes associated with this mutation tends to be more severe and less variable compared to other KS mutations. KAL1 mutations are inherited in an X-linked recessive pattern and produce a syndrome of short stature, mental retardation, ichthyosis, chondroplasia punctata, and KS.

Most of the data on the KAL1 gene come from studies in chickens. The timing of KAL1 expression in the chicken has aided in understanding the migration defects of GnRH neurons in human KS. KAL1 is expressed in 2 distinctly different periods of embryonic development. KAL1 expression is found in limb buds, facial mesenchyme, and the neurons innervating the extrinsic eye muscles during embryonic development. By embryonic day 5 (of a 21 day incubation period of a chicken), GnRH neurons migrate along the olfactory nerve and penetrate the olfactory bulb by embryonic day 7-8. KAL1 expression is increased in the olfactory bulb by embryonic day 7-8. At embryonic day 9-10, KAL1 expression is up-regulated as synapses are formed between the olfactory nerve and the mitral cell layer.

Studies have demonstrated that neural migration is controlled by factors intrinsic to the olfactory epithelium. When the olfactory placode is destroyed in the chick, KAL1 expression continues in the olfactory bulb, suggesting that KAL1 expression and olfactory nerve innervation are independent of one another. In humans, KAL1 transcripts are not identified at the time of olfactory nerve migration, again suggesting independence between KAL1 expression and olfactory nerve migration. In KS, a defect in neuronal interaction, rather than neural migration, has been suggested. In a study of a 19-week fetus with X-linked KS, the olfactory nerves were shown to have arrested within the meninges, whereas the GnRH neurons were arrested in the forebrain, never reaching the hypothalamus. Both groups of neurons passed through the cribriform plate but arrested prematurely. The KAL1 gene may play a later role, such as controlling the penetration of GnRH neurons into the olfactory bulb.

Without KAL1 and without functioning synaptic connections, the olfactory nerve might atrophy and degenerate, causing the defective GnRH migration.

The KAL1 gene may also play a role in the development of other tissues, such as facial mesenchyme, fibrous and perichondral cells, blood vessels, renal glomeruli, and developing limb buds. In humans, defective KAL1 expression in the cerebellum may be linked to nystagmus and ataxia observed in some patients with KS.

Fibroblast growth factor receptor 1 and fibroblast growth factor 8

There are 2 KS-related loci, KAL1 and KAL2. The former encodes anosmin and is described above. KAL–2 encodes the fibroblast growth factor receptor 1 (FGFR1). Approximately 10% of patients with KS have loss-of-function mutations in FGFR1. [15] The KAL2- associated disorder is inherited in an autosomal dominant manner. The clinical phenotype ranges from severe KS to delayed puberty. [16] Associated features include cleft palate, hearing loss, agenesis of the corpus callosum, and fusion of metacarpal bones. In affected individuals, the lack of smell has a variable penetrance. [17] Anosmin, a product of KAL1 gene, interacts and enhances the signaling of FGFR1. [18] Thus, in FGFR1 heterozygous affected women, the KAL gene, by escaping X-inactivation, may rescue FGFR1 signaling. [19] This effect of X-inactivation likely explains why this condition is more prevalent in males.

In addition to FGFR1, fibroblast growth factor 8 (FGF8) gene mutations have also been associated with KS and IHH, with varying degrees of olfactory and reproductive function. [20] Interestingly, a mouse model of FGF8 deficiency lacks both hypothalamic GnRH neurons and olfactory bulbs, suggesting a role for FGF8 in olfactory and GnRH neuron migration. [21]

Prokineticin 2 and prokineticin 2 receptor genes

Prokineticin 2 (PROK2) and its receptor (PROKR2) are a ligand-receptor pair involved in the development of the olfactory bulbs and GnRH neuron migration. Neurogenesis persists in the olfactory bulb of the adult mammalian brain due to the chemoattractant effect of prokineticin 2 (PROK2). In PROK2 -deficient and PROKR2 -deficient mice, there is a significant reduction in olfactory bulb size and impaired neuronal migration. [22, 23] Mutations in PROK2 and in the receptor (PROKR2) gene have been associated with the development of KS and normosmic IHH, with variable phenotypic severities. [24, 25] In one series, 9% of patients with KS had mutations in either PROK2 or PROKR2. [26] Accompanying phenotypic features include fibrous dysplasia, synkinesia, and epilepsy.

G protein-coupled receptor 54

G protein-coupled receptor 54 (GPR54) binds to kisspeptin and its derivatives. This receptor is widely expressed throughout the brain. It has been shown that in a large consanguineous Saudi family with 6 individuals with IHH, a homozygous single nucleotide change in exon 3 of GPR54 was found in all 6 affected individuals, resulting in substitution of a serine for the normal leucine in the second intracellular loop of the receptor (L148S). See the image below.

Human GPR54 receptor model. Mutations identified i Human GPR54 receptor model. Mutations identified in patients with idiopathic hypogonadotropic hypogonadism are indicated.

This change did not occur in the homozygous state in any unaffected family members and was not identified in any controls. This 7-transmembrane domain receptor shares highest homology, about 45%, with the galanin subfamily of receptors. The amino acid sequence is highly conserved across species, with 95% homology between the rat and mouse and 82% between mouse and human (98% in the transmembrane domains). [27]

A GPR54-deficient mouse model resulted in a phenotype similar to that seen in humans with KS. These mice have normal hypothalamic GnRH content, but develop IHH that is responsive to GnRH therapy, suggesting that. GnRH neurons continue to synthesize GnRH, but that GPR54 is necessary for GnRH processing and/or secretion. The ligand for GPR54 has been identified as the 54 amino acid protein metastatin. Kisspeptin, a 145-amino acid precursor, gives rise to metastin after cleavage. GPR54 activation advances puberty in rodents and overcomes amenorrhea that is due to starvation or leptin deficiency. Thus, the kisspeptin/metastin/GPR54 system is clearly a major gatekeeper of the pubertal process. [28] Furthermore, the kisspeptin/metastin/GPR54 system plays a major role in the sexual differentiation of the brain and sexual behavior. [29]

Of note, no mutations responsible for KS/IHH have been reported in the KISS1 gene, the gene encoding kisspeptin itself.

Gonadotropin-releasing hormone receptor and gonadotropin-releasing hormone 1

The GnRH receptor is a G protein–coupled receptor, which activates phospholipase C, ultimately mobilizing intracellular calcium. Mutations in the GnRH receptor (GnRHR) have been described in families with hypogonadotropic hypogonadism. One case reports phenotypically normal parents heterozygous for a GnRHR mutation who had a son with normal puberty and normal olfaction but with small (8-mL) testes and an abnormal semen analysis. Their daughter had primary amenorrhea and was infertile. LH pulse frequency was normal but with low amplitude pulsation.

Other reports describe GnRHR mutations causing hypogonadotropic hypogonadism that presents with complete gonadotropin deficiency. An example is a male patient seeking treatment for delayed puberty who presented with no secondary sexual characteristics, cryptorchid testes, low gonadotropins, and low testosterone. The patient did not respond to exogenous GnRH, but treatment with gonadotropins corrected testicular growth and descent, confirming a defect at the level of the GnRHR.

Recently, homozygous mutations in GNRH1, the genetic precursor to GnRH, have been shown to be a rare cause of normosmic IHH. The GNRH1 mutation is inherited in an autosomal recessive pattern. Administration of exogenous pulsatile GnRH restores the hypothalamic-pituitary-gonadal axis in these patients. [30]

DAX1 gene

Adrenal hypoplasia congenita arises from X-linked or autosomal recessive syndromes and presents in infancy with primary adrenal insufficiency. Treatable with steroids, it has resulted in affected adults developing hypogonadotropic hypogonadism. A pituitary origin for one group with hypogonadotropic hypogonadism has been suggested by the failed attempts in those patients to stimulate LH and FSH with pulsatile GnRH. A smaller group has had gonadotropin responses to GnRH therapy, characterizing a hypothalamic-versus-pituitary defect.

The DAX1 gene has been identified at Xp21 as the gene responsible for adrenal hypoplasia congenita. As with the KAL gene, there is a growing body of evidence that DAX mutations result in a wide phenotypic range. These data suggest that DAX1 mutations impair gonadotropin production via defects at the levels of both the pituitary and the hypothalamus. One suggested role for DAX1 is as a "brake" for normal male maturation, while also being necessary for normal adrenal and hypothalamic/pituitary development. DAX1 has been shown to block steroidogenesis in adrenal cells by transcriptional repression. Indeed, loss of function of this repressor may lead to a host of adrenal, hypothalamic, and pituitary abnormalities.

Additionally, steroidogenic factor 1 (SF-1), a nuclear hormone receptor for DAX1 (dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1), plays a regulatory role in adrenal development and development of the hypothalamic-pituitary-gonadal axis. [31] Specifically, SF-1 regulates expression of the p450 steroid hydroxylase genes in the gonads and the adrenal cortex, Mullerian Inhibitory Substance (MIS), the alpha subunit of the gonadotropins, and the beta subunit of LH.

Leptin and leptin receptor

Mutations in either leptin, a cytokine secreted from adipocytes that serves as a central satiety signal and a permissive signal to the reproductive system, or the leptin receptor lead to normosmic hypogonadotropic hypogonadism. Patients with this rare disorder fail to progress through puberty without exogenous leptin administration. The major associated phenotypic feature is obesity due to hyperphagia, which is also attenuated by leptin treatment. [32]

TAC3 and TACR3

Recently, analysis of single nucleotide polymorphisms (SNPs) among families with multiple members affected by IHH have identified autosomal recessive mutations in TAC3 and its receptor, TACR3, as another cause of IHH. [33] TAC3 encodes for neurokinin B, which is the ligand for the neurokinin-3 receptor (TACR3), Patients with mutations in TAC3 or TACR3 have isolated IHH without other phenotypic features, suggesting TAC3 and TACR3 function specifically to promote GnRH release. In fact, neurokinin B is found co-localized with kisspeptin and dynorphin in neurons of the arcuate nucleus of the hypothalamus. These neurons project to the median eminence and are closely opposed to GnRH neurons. Further, GnRH neurons have been shown to express TACR3. Communication between GnRH neurons and neurons co-expressing kisspeptin, dynorphin, and neurokinin B has been proposed to represent the "GnRH pulse generator." [15]

NELF

Nasal epithelial LHRH factor (NELF) is involved in GnRH and olfactory neuronal development and has been implicated in rare cases of IHH. NELF co-localizes with GnRH in stem cells of the olfactory system. Heterozygous mutations have been identified in only 2 reported cases of IHH; thus, the role of NELF as a genetic cause of IHH has not been fully elucidated. [34]

Others

Advances in molecular genetics have lead to the discovery of several additional candidate genes for KS and IHH, and the future holds much more to be discovered in this area. These include SEMA3A, a semaphorin protein family member that is necessary for GnRH neuron development due to its role as a guidance cue for GnRH neuron migration. Lack of SEMA3A signaling in mice causes hypogonadal hypogonadism, and this mutation has been described in one case of human KS. [35] Missense mutations in WDR11, a gene involved in olfactory neuron development and human puberty, have also recently been described in patients with KS and IHH. [36]

Although most cases of IHH have been attributed to single gene defects, Pitteloud et al reported 2 families with this condition but with 2 different gene mutations. [25] With oligogenic mutations resulting in compound heterozygotes, synergistic effects of the mutated genes are hypothesized to result in hypothalamic hypogonadism. Since this initial finding by Pitteloud, several additional cases of oligogenic mutations have been identified in patients with KS and normosmic IHH. Mutations of PROKR2 + GPR54, PROKR2 + GnRHR, PROKR2 + KAL1, PROKR2 + FGFR1, PROKR2 + PROK2, FGFR1 + NELF, FGFR1 + GnRHR, and FGFR1 + FGF8 have been identified.

Interestingly, in addition, one patient normosmic IHH and 3 different mutations has been identified to date (PROKR2, GnRHR, and FGFR1). [37, 24] Furthermore, a study of a large cohort of patients suggests that oligogenicity is the norm in KS and IHH, rather than monogenicity. [38] With the advanced technology available for genetic analysis and with the identification of the human genome, scientists are constantly shedding new light on the complex genetic transmission of KS and IHH. This oligogenic model may explain the phenotypic variability observed within and across families with single gene defects.

Furthermore, cases of adult-onset and reversible IHH suggest that not only are genetic abnormalities involved in the pathogenesis of this disorder but that nongenetic factors may also contribute, such as hormonal and/or environmental factors. These have yet to be elucidated but research is ongoing.

An analysis of a cohort of 81 Greek isolated GnRH Deficiency patients found the prevalence of normosmic idiopathic hypogonadotropic hypogonadism higher than Kallmann Syndrome (67% to 33%) and putative causal genetic change was discovered in approximately 21% of the cohort. [39]

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