eMedicine Specialties > Obstetrics and Gynecology > Reproductive Endocrinology and Infertility
Gonadotropin-Releasing Hormone Deficiency in Adults
Updated: Sep 7, 2008
Introduction
Background
Gonadotropin-releasing hormone (GnRH) is a neurohormone central to initiation of the reproductive hormone cascade. Pulsatile secretion of gonadotropin-releasing hormone from the hypothalamus is key in establishing normal gonadal function. Failure of this release results in isolated gonadotropin-releasing hormone deficiency that can be distinguished by partial or complete lack of gonadotropin-releasing hormone–induced luteinizing hormone (LH) pulse, normalization with gonadotropin-releasing hormone replacement, and otherwise normal hypothalamic-pituitary neuroanatomy and neurophysiology.
Clinicians and scientists long have been intrigued by the findings of olfactory disturbances and concomitant reproductive dysfunction. Spanish pathologist Maestre de San Juan noted in 1856 the association between the failure of testicular development and the absence of the olfactory bulbs. However, the syndrome is named Kallmann syndrome (KS) after the American geneticist Kallmann. Kallmann, Schoenfeld, and Barrera in 1944 were the first to identify a genetic basis to this disorder.1 In 1954, de Morsier connected the syndrome of hypogonadism and anosmia with the abnormal development of the anterior portion of the brain.2 Kallmann syndrome is a rare disorder that occurs in both sexes.
Pathophysiology
Gonadotropin-releasing hormone neurons
A fundamental understanding of the anatomy, biochemistry, ontogeny, and physiology of gonadotropin-releasing hormone neurons aids in understanding the pathophysiology, diagnosis, and treatment of KS and idiopathic hypogonadotropic hypogonadism (IHH).
Gonadotropin-releasing hormone and gonadotropin-releasing hormone receptors
The decapeptide gonadotropin-releasing hormone is derived from posttranslation processing of a tripartite 92–amino acid (AA) pre-pro-gonadotropin-releasing hormone. The first 23 AA is a signal peptide and the last 56 AA is known as gonadotropin-releasing hormone–associated protein (GAP). Gonadotropin-releasing hormone is encoded from a single gene located on the short arm of chromosome 8. Serum levels of gonadotropin-releasing hormone are difficult to obtain due to its short half-life (2-4 min) and complete confinement to the hypophyseal-portal blood supply. Due to the small structure and ease of mutation of gonadotropin-releasing hormone, chemists have created several clinically useful gonadotropin-releasing hormone analogs. Gonadotropin-releasing hormone binds with high affinity to cell surface receptors located on the pituitary gonadotrophs. These 7 transmembrane cell surface G protein; coupled receptors activate phospholipase C.
This enzyme leads to the activation of several second messenger molecules, the most important being diacylglycerol (DG) and inositol 1,4,5-trisphosphate (IP3). In turn, DG activates protein kinase C and causes IP3 -stimulated release of calcium ions from intracellular pools. The result is the synthesis and release of follicle-stimulating hormone (FSH) and LH from the pituitary gonadotrophs. The released gonadotropins stimulate the gonads to produce steroid hormones and sperm or to release oocytes. Mutated gonadotropin-releasing hormone receptors, as predicted by the biochemistry, could result in clinical manifestation of isolated gonadotropin deficiency. The control of gonadotropin-releasing hormone and its receptor are regulated by many factors; the review of this regulation is beyond the scope of this article.
Ontogeny and function
The migration of gonadotropin-releasing hormone neurons follows a precise path from the nose to the forebrain in humans. The olfactory placode is composed of thickened ectoderm that is lateral to the head of the developing embryo and invaginates to form simple olfactory pits on either side of the nasal septum. The lateral epithelium of the olfactory pits gives rise to olfactory nerves. The medial portion develops into the site of initial gonadotropin-releasing hormone appearance and the terminal nerve. This ganglionated cranial nerve, the exact function of which is unknown, enters the forebrain and serves as a highway for the gonadotropin-releasing hormone neuronal migration.
These migrating neurons do not contain neurosecretory vesicles until they reach the area of the arcuate nucleus in the hypothalamus. For this reason, neurons that do not reach the forebrain are unable to secrete gonadotropin-releasing hormone. The gonadotropin-releasing hormone neurons have been identified in the fetal hypothalamus at 9 weeks' gestation and are connected to the portal system by 16 weeks' gestation. At 10 weeks' gestation, gonadotropins are detectable in the pituitary, and by the 12th week, they are measurable in the bloodstream. Peripheral blood levels peak during the second trimester and decrease by term as the negative feedback mechanism develops.
Gonadotropin-releasing hormone is secreted during the neonatal period, resulting in pulsatile LH and FSH secretion, which decreases by age 6 months in boys and by age 1-2 years in girls until puberty. During childhood, gonadotropin-releasing hormone is still secreted in pulsatile fashion but at reduced amplitude. The hypothalamic pulse generator is likely suppressed by a mechanism that inhibits gonadotropin-releasing hormone release but not its synthesis.
This theory has been demonstrated in primates because gonadotropin-releasing hormone messenger RNA (mRNA) and proteins are abundant in the hypothalamus during an equivalent developmental stage. The mechanism that awakens the pubertal onset of gonadotropin-releasing hormone secretion still is unknown. Metabolic enzymes have been implicated, as have norepinephrine, neuropeptide gamma, aspartate, gamma-aminobutyric acid, transforming growth factor-alpha, and leptin. The pubertal period is characterized by an increase in the amplitude of gonadotropin-releasing hormone–induced LH as well as a small increase in the frequency of amplitude increases. Sex steroids are secreted from the gonads in response to this nocturnal increase in gonadotropins. Gonadotropins continue to be secreted in pulsatile fashion during adulthood.
Most studies in males have shown LH pulses to occur every 2 hours, while, in females, gonadotropin-releasing hormone pulse frequency changes throughout the menstrual cycle. In the early follicular phase, gonadotropin-releasing hormone pulse frequency is every 90 minutes and increases to 60 minutes by the late follicular phase. Gonadotropin-releasing hormone pulse frequency during the luteal phase varies from 4-8 hours.
Studying gonadotropin-releasing hormone secretion
Studying gonadotropin-releasing hormone physiology in humans has been challenging. gonadotropin-releasing hormone itself is almost entirely confined to the portal blood supply of the pituitary, and direct sampling in humans is not feasible. Samples of gonadotropin-releasing hormone in the periphery are inaccurate because of the rapid 2-minute to 4-minute half-life. Much of the information known about gonadotropin-releasing hormone has come from animal studies.
Belchetz and coworkers in the 1970s demonstrated in rhesus monkeys that pulsatile gonadotropin-releasing hormone is responsible for maintaining gonadotrope function.3 The researchers were able to differentiate between episodic and continuous stimulation causing maintenance and desensitization, respectively, of the gonadotrope response.
Another animal example in unscrambling the gonadotropin-releasing hormone puzzle is the use of transgenic mice in developing immortalized gonadotropin-releasing hormone cell lines. Interestingly, implantation of these cells into the hypothalamus of gonadotropin-releasing hormone–deficient mice restores their estrus cycle. This has provided an important in vitro tool for studying neuroendocrine function.
Human studies have been limited to frequent sampling studies in healthy and diseased models, the use of pharmacological probes, and genetic studies. LH has long been used as a marker of gonadotropin-releasing hormone pulse activity in humans. Most recently, the glycoprotein free alpha subunit (FAS) has been used as a marker due to its correlation with LH. FAS is useful in tracking gonadotropin-releasing hormone because of its 12- to 15-minute half-life. An estimate of endogenous gonadotropin-releasing hormone can be obtained using gonadotropin-releasing hormone antagonists as probes. Administering a gonadotropin-releasing hormone antagonist induces a gonadotropin-releasing hormone receptor blockade so that the amount of gonadotropin-releasing hormone present is inversely proportional to the amount of LH inhibitor.
Frequency
United States
The incidence in the United States is 1 case per 10,000 men and 1 case per 50,000 women.
International
By examining military records, the incidence of KS has been estimated to be between 1 case per 86,000 in Sardinia and 1 case in 10,000 in France.4
Mortality/Morbidity
These patients do not have an increased mortality rate.
Race
Race is not a factor in incidence.
Sex
In the referral population at Massachusetts General Hospital over a 20-year period, the male-to-female ratio was 3.9 to 1.5
A spectrum of gonadotropin-releasing hormone deficiency with various secretory patterns ranging from complete lack of LH pulse to diminished amplitude similar to early puberty occurs in both men and women, contributing to the clinical heterogeneity of the disorder. This suggests that multiple genetic determinants may control the expression of gonadotropin-releasing hormone secretion.
Age
The disease comes to attention when the patient fails to begin puberty and develops secondary sexual characteristics.
Clinical
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 the 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.
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 beard development. 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. The testing with graded dilutions of pure scents is necessary to identify the impaired olfaction. The magnitude of gonadotropin-releasing hormone 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.6
Causes
Gonadotropin-releasing hormone 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 gonadotropin-releasing hormone deficiency are due to mutations in known genes.
KAL1 gene
The KAL1 gene, described in 1991, is an example of an X-linked gene controlling gonadotropin-releasing hormone secretion.7 The gene is located on the short arm of the X chromosome at Xp22.3. Deletions produce a syndrome of short stature, mental retardation, ichthyosis, chondroplasia punctata, and KS. Anosmin, the protein encoded by KAL, is similar in amino acid structure to molecules involved in neural development, such as protease inhibitors, neurophysins, and neural cell adhesion molecules. Anosmin appears to be important to the migration of the gonadotropin-releasing hormone neurons to their resting place in the hypothalamus.
Most of the data on the KAL gene come from studies in chickens. The timing of KAL expression in the chicken has aided in understanding the migration defects of gonadotropin-releasing hormone neurons in human KS. KAL is expressed in 2 distinctly different periods of embryonic development. KAL expression is found in limb buds, facial mesenchyme, and the neurons innervating the extrinsic eye muscles during embryonic days. By embryonic day 5, gonadotropin-releasing hormone neurons migrate along the olfactory nerve and penetrate the olfactory bulb by embryonic day 7-8. KAL expression is increased in the olfactory bulb by embryonic day 7-8. At embryonic day 9-10, KAL expression up-regulates as synapses are formed between the olfactory nerve and the mitral cell layer.
Studies have demonstrated that the migration of the nerves is controlled by the olfactory epithelium. When the olfactory placode is destroyed in the chick, KAL expression continues in the olfactory bulb. This suggests that KAL expression and olfactory nerve innervation are independent of one another. In humans, KAL transcripts are not identified at the time of olfactory nerve migration, again suggesting independence between KAL expression and olfactory nerve migration. In KS, a defect in neuron interaction rather than neuron 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 gonadotropin-releasing hormone neurons were arrested in the forebrain, never reaching the hypothalamus. Both groups of neurons passed through the cribriform plate but arrested prematurely. The KAL gene may play a later role, such as controlling the penetration of gonadotropin-releasing hormone neurons into the olfactory bulb.
Without KAL and without functioning synaptic connections, the olfactory nerve might atrophy and degenerate, causing the gonadotropin-releasing hormone defective migration.
The KAL gene also may 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. Again, this has been studied in the chicken. In humans, defective KAL expression in the cerebellum may be linked to nystagmus and ataxia observed in some patients with KS.
Fibroblast growth factor receptor 1
There are 2 KS-related loci, KAL1 and KAL2. The former encodes anosmin and has been described earlier. KAL–2 encodes the fibroblast growth factor receptor 1 (FGFR1). The KAL2 associated disorder is inherited in an autosomal dominant manner. 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.8 Anosmin, a product of KAL1 gene, interacts and enhance the signaling of FGFR1.9 Thus in FGFR1 heterozygous affected women, the KAL gene, by escaping X-inactivation, may rescue the FGFR1 signaling.10 This may also explain why this condition is more prevalent in males.
G protein-coupled receptor 54
G protein-coupled receptor 54 (GPR54) binds to kisspeptins 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 Media file 1). 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).11
A GPR54-deficient mouse model resulted in a phenotype similar to that in humans The mice had normal hypothalamic gonadotropin-releasing hormone content, but developed IHH that was responsive to gonadotropin-releasing hormone therapy. This finding suggests that gonadotropin-releasing hormone neurons are present in the hypothalamus and can synthesize the peptide but that GPR54 is necessary for processing or secretion of gonadotropin-releasing hormone. The ligand for GPR54 is identified as metastatin. Kisspeptin, a 145-amino acid precursor, gives rise to a 54 amino acid product termed metastin after cleavage. Together, this ligand/receptor combination (metastin/GPR54) can advance puberty in rodents and can overcome the amenorrhea of congenital leptin and leptin receptor deficiency, and starvation. Thus, this system is clearly a major gatekeeper of the pubertal process.12 Furthermore, this kisspeptin receptor is required for sexual differentiation of the brain and behavior.13
Gonadotropin-releasing hormone receptor
The gonadotropin-releasing hormone receptor is a G protein–coupled receptor, which activates phospholipase C, mobilizing intracellular calcium. Mutations in this receptor have been described in families with hypogonadotropic hypogonadism. One case reports phenotypically normal parents heterozygous for a gonadotropin-releasing hormone receptor mutation who had a son with normal puberty and normal olfaction but with 8-mL testes and an abnormal semen analysis. Their daughter had primary amenorrhea and was infertile. LH probe frequency was normal but with low amplitude pulsation.
Other reports describe gonadotropin-releasing hormone receptor mutations causing hypogonadotropic hypogonadism that presents with complete gonadotropin deficiency. An example is a male patient seeking treatment for delayed puberty presenting with no secondary sexual characteristics, cryptorchid testes, low gonadotropins, and low testosterone. The patient did not respond to gonadotropin-releasing hormone, but treatment with gonadotropins corrected testicular growth and descent.
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 gonadotropin-releasing hormone. A smaller group has had gonadotropin responses to gonadotropin-releasing hormone 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, growing evidence for DAX mutation suggests a wide phenotypic range. Data has suggested that DAX1 mutations impair gonadotropin production at the levels of both the pituitary and the hypothalamus. Steroidogenic factor 1 (SF-1), a nuclear hormone receptor, plays a regulatory role in adrenal development and development of the hypothalamic-pituitary-gonadal axis.
Specifically, SF-1 regulates the expression of the p450 steroid hydroxylase genes in the gonads and the adrenal cortex, regulates the MIS gene, regulates the alpha subunit of the gonadotropins, and regulates the beta subunit of LH. Another suggested role for DAX1 is as a "brake" for normal male maturation while being necessary for normal adrenal and hypothalamic/pituitary development. DAX1 has been shown to block steroidogenesis in adrenal cells by transcriptional repression. Loss of function of this repressor may lead to a host of adrenal, hypothalamic, and pituitary abnormalities.
Evidence suggests that most familial cases of gonadotropin-releasing hormone deficiency are controlled by autosomal inheritance. In a study of 106 patients with gonadotropin-releasing hormone deficiency at Massachusetts GeneralHospital, only 21% of familial cases were X-linked.5 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.
Prokineticin 2 gene
Neurogenesis persists in the olfactory bulb of the adult mammalian brain due to the chemoattractant effect of prokineticin 2 (PROK2). In PROK2-deficient mice, there is a significant reduction in olfactory bulb size and impaired neuronal migration.14,15 Mutations in this gene and in the receptor (PROKR2) gene has been associated with the development of KS and normosmic IHH.16,17
Digenic mutations
Although most cases of IHH have been attributed to several single gene defects, Pitteloud et al reported 2 families with this condition but with 2 different gene mutations.17 As a compound heterozygote, the mutated genes may have a synergistic effect that result in hypothalamic hypogonadism. This model may explain the phenotypic variability observed within and across families with single gene defects. Furthermore, Dode at al showed another case where a patient had a mutation in both KAL1 and PROKR2 genes.16 With the advanced technology available, and the identification of the human genome, scientists are constantly shedding new light on the complex genetic transmission of KS.
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References
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Further Reading
Keywords
gonadotropin-releasing hormone deficiency, GnRH deficiency, luteinizing hormone, LH, isolated GnRH deficiency with or without associated anosmia, Kallmann syndrome, KS, idiopathic hypogonadotropic hypergonadism, IHH, gonadotropins, fertile eunuch, micropenis, fetal testosterone, cryptorchidism, microphallus, amenorrhea, hypogonadism, sexual dysfunction, gynecomastia, decreased testosterone production, anosmia, uterine malformation, congenital heart defects, dental agenesis, short stature, mental retardation, ichthyosis, chondroplasia punctata, cleft palate, hearing loss, adrenal hypoplasia congenita
