Gonadotropin-Releasing Hormone Deficiency in Adults

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Background

Gonadotropin-releasing hormone (GnRH) is a neurohormone central to initiation of the reproductive hormone cascade. Pulsatile secretion of GnRH from the hypothalamus is key in establishing and maintaining normal gonadal function. Failure of this release results in isolated GnRH deficiency that can be distinguished by partial or complete lack of GnRH–induced luteinizing hormone (LH) pulses, normalization with pulsatile GnRH replacement therapy, and otherwise normal hypothalamic-pituitary neuroanatomy and neurophysiology.

Clinicians and scientists have long been intrigued by the findings of olfactory disturbances and concomitant reproductive dysfunction. In 1856, Spanish pathologist Maestre de San Juan noted the association between the failure of testicular development and the absence of the olfactory bulbs. However, the syndrome comprising complete GnRH deficiency and lack of olfactory senses is named Kallmann syndrome (KS) after the American geneticist Kallmann.

In 1944, Kallmann, Schoenfeld, and Barrera were the first to identify a genetic basis to this disorder.[1, 2] In 1954, de Morsier connected the syndrome of hypogonadism and anosmia with the abnormal development of the anterior portion of the brain.[3] KS is a rare disorder that occurs in both sexes. In contrast to KS, GnRH deficiency leading to hypogonadotropic hypogonadism with an intact sense of smell is termed idiopathic hypogonadotropic hypogonadism (IHH). IHH results from dysfunction of GnRH neurons that have developed and migrated properly, whereas KS is caused by defective migration of GnRH neurons to their proper position in the hypothalamus during fetal development.[4]

Pathophysiology

Gonadotropin-releasing hormone neurons

A fundamental understanding of the anatomy, biochemistry, ontogeny, and physiology of GnRH 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 GnRH is derived from posttranslation processing of a tripartite 92–amino acid (AA) pre-pro-GnRH. The first 23 AA is a signal peptide and the last 56 AA is known as GnRH–associated protein (GAP). GnRH is encoded from a single gene located on the short arm of chromosome 8. Serum levels of GnRH 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 GnRH, chemists have created several clinically useful GnRH analogs. GnRH binds with high affinity to cell surface LH and follicle stimulating hormone (FSH) receptors located on the pituitary gonadotrophs. These 7-transmembrane, cell surface G protein-coupled receptors activate phospholipase C (PLC).

PLC 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 FSH and LH from the pituitary gonadotrophs. The released gonadotropins stimulate the gonads to produce steroid hormones, and in the testes, to produce sperm or in the ovaries, to release oocytes. Mutated GnRH receptors (GnRH-R), as predicted by the biochemistry, could result in the clinical manifestations of isolated gonadotropin deficiency. Many factors interact to regulate the synthesis and secretion of GnRH, and to regulate the translation of GnRH receptors; the review of this regulation is beyond the scope of this article.

Ontogeny and function

During fetal development, the migration of GnRH neurons follows a precise path from the olfactory placode to the preoptic area of the hypothalamus in mammals. 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 the olfactory nerves. The medial portion develops into the site of initial GnRH appearance and the terminal nerves. The terminal nerves, ganglionated cranial nerves for which the exact function is unknown, enter the forebrain and serve as a highway for the GnRH neuronal migration. In humans, GnRH neuron migration begins in the 6th week of embryonic development.

Migrating GnRH 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 GnRH. GnRH neurons have been identified in the fetal hypothalamus at 9 weeks' gestation and are connected to the pituitary portal system by 16 weeks' gestation. At 10 weeks' gestation, gonadotropes are detectable in the pituitary, and by the 12th week, FSH and LH are measurable in the bloodstream. Fetal peripheral blood levels of gonadotropins peak during the second trimester of pregnancy and decrease by term as the negative feedback mechanism develops.

LH pulsatility, which can be measured in the bloodstream, is determined by the precise frequency and amplitude of pulsatile GnRH release; thus, serum LH is used as a marker of GnRH pulsatility.[5]

GnRH 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. Before the initiation of puberty, GnRH is still secreted in a pulsatile fashion but at reduced amplitude and frequency. The hypothalamic pulse generator, the master regulator of GnRH secretion, is likely suppressed by a mechanism that inhibits GnRH release but not its synthesis.

This theory has been demonstrated in primates, in which GnRH messenger RNA (mRNA) and proteins are abundant in the hypothalamus during an equivalent developmental stage.

The pubertal period is characterized by a predominantly nocturnal increase in both the amplitude and frequency of GnRH–induced LH pulses. Sex steroids are secreted from the gonads in response to this nocturnal increase in gonadotropins. Gonadotropins continue to be secreted in a pulsatile fashion, under the control of pulsatile GnRH release, during adulthood. The mechanism that awakens the pubertal surge of more robust GnRH secretion is not completely understood. Metabolic cues, steroid hormones, neurosteroids, growth factors, and neurotransmitter systems have been implicated, including glutamate, gamma-aminobutyric acid, neuropeptide Y (NPY), opioids, leptin, kisspeptin, and estradiol.[6]

Most studies in males have shown LH pulses to occur every 2 hours; in females, LH (and thus GnRH) pulse frequency varies throughout the menstrual cycle. In the early follicular phase, LH pulse frequency is every 90 minutes and increases to every 60 minutes by the late follicular phase. The LH "surge" that triggers ovulation occurs due to a "switch" from negative to positive feedback of estrogen at the pituitary, leading to a brief burst of pulsatile LH release, which stimulates ovulation.[7] Following ovulation, LH pulse frequency decreases, with frequency ranging from every 4-8 hours during the luteal phase.

Studying gonadotropin-releasing hormone secretion

Studying GnRH physiology in humans and animal models has been challenging. GnRH itself is almost entirely confined to the portal blood supply of the pituitary, thus direct sampling in humans is not feasible, and difficult if not impossible in animal models. Measurements of GnRH in the periphery are inaccurate because of its rapid 2-minute to 4-minute half-life. Much of the information known about GnRH has come from animal studies.

Belchetz and coworkers in the 1970s demonstrated in rhesus monkeys that pulsatile release of GnRH is required for maintaining gonadotrope function.[8] The researchers were able to differentiate between episodic and continuous stimulation by GnRH causing maintenance and desensitization, respectively, of the gonadotrope response.

Another model developed to study GnRH neuron function is immortalized GnRH cell lines. Interestingly, implantation of these cells into the hypothalami of female GnRH–deficient mice restores normal estrus (equivalent of menstrual) cycles. Immortalized GnRH cell lines in culture have provided an important in vitro tool for studying reproductive neuroendocrine function. In vivo studies of GnRH neuron function have also been possible since development of transgenic mouse models in which GnRH neurons are labeled with green fluorescent protein (GnRH-GFP mouse).[9] This model allows GnRH neurons to be visualized in vivo in hypothalamic sections. Studies from this model are elucidating the complex physiology of GnRH neurons, including neuronal firing patterns, neuronal inputs, migratory patterns, and intracellular signaling systems.

Human studies have been limited to frequent sampling studies in healthy and diseased models, the use of pharmacological probes, and genetic studies. As in animals, LH has long been used as a marker of GnRH 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 GnRH because of its 12-minute to 15-minute half-life. In addition to LH and FAS, an estimate of endogenous GnRH can be obtained using GnRH antagonists as probes. Administering a GnRH antagonist induces a GnRH receptor blockade so that the amount of GnRH present is inversely proportional to the amount of LH inhibitor.

Epidemiology

Frequency

United States

The incidence of KS in the United States is 1 case per 10,000 men and 1 case per 50,000 women. The incidence of normosmic IHH is also rare and is estimated to be around 1 case in 70,000 to 1 case in 100,000 individuals.

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.[10]

Mortality/Morbidity

These patients are not known to have an increased mortality rate; however, prolonged deficiency in gonadal hormones contributes to increased morbidity and may contribute to the aging process.

Race

Race is not a factor in incidence.

Sex

In a referral population at Massachusetts General Hospital over a 20-year period, the male-to-female ratio was 3.9 to 1.[11]

A spectrum of GnRH deficiency, with various secretory patterns ranging from complete lack of LH pulsatility to diminished pulse 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 GnRH secretion.

Age

The disease comes to attention when the patient fails to begin puberty and does not develop secondary sexual characteristics.

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]

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]

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.



View Image

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]

Laboratory Studies

Along with the above-described clinical manifestations, most patients have low serum levels of basal gonadotropins, estrogen/testosterone, and poor response to gonadotropin-releasing hormone (GnRH) stimulation. The difficulty arises when trying to differentiate between healthy prepubertal males and those with idiopathic hypogonadotropic hypogonadism (IHH) or Kallmann syndrome (KS).

Patients with KS can be distinguished from prepubertal males aged 12.5 years or older by determining the level of luteinizing hormone (LH) in pooled serum samples collected every 20 minutes for 6 hours commencing 1 hour after sleep onset.

The GnRH stimulation test using a synthetic GnRH analog, such as buserelin, has been used to differentiate males with gonadotropin deficiency from those with delayed puberty. In a study by Wilson et al, a total 31 prepubertal males were given 100 µcg of buserelin subcutaneously, and blood samples for LH and follicle-stimulating hormone (FSH) were obtained at 0 and 4 hours after treatment.[46, 47] Participants were then followed for a mean duration of 4.2 years to determine if they progressed through puberty. Twenty-six percent of individuals failed to undergo puberty and were diagnosed with gonadotropin deficiency. None of these men had had a buserelin-stimulated serum LH level higher than 5 U/L. In fact, the LH response was significantly lower when compared with those males who ultimately developed puberty. The stimulated FSH levels were comparable in both groups, and thus are not useful when distinguishing delayed puberty from IHH or KS.

Imaging Studies

MRI appears to be the single best study for the diagnosis of KS and exclusion of other CNS disorders associated with hypogonadotropic hypogonadism.

T1-weighted MRI of the inferior frontal region in the coronal plane appears most helpful in examining the olfactory sulci, bulbs, and rhinencephalon.

Because of the lack of production of sex steroids, men and women with KS and IHH can experience abnormal bone development. The prudent use of a dual-energy x-ray absorptiometry (DEXA) scan to monitor bone mineral density in these individuals is appropriate.

Other Tests

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 with the severity of anosmia.

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

Medical Care

The choice of therapy depends on the patient's desire to achieve one or more of the following: secondary sex characteristics, fertility, and bone and muscle mass.

Treatment in males

In deciding when and how to provide androgen replacement in males, the patient's age, the potential adverse effects of therapy, and the patient's desire for fertility should be considered. In the prepubertal male who has congenital hypogonadism, androgens stimulate penile growth, body and facial hair growth, bone and muscle development, and voice changes. In addition, androgens stimulate growth hormone production, thus contributing to the adolescent growth spurt.

Because males with androgen deficiency can experience significant social ridicule, starting androgen therapy around age 14-15 years is prudent.

Oral, injectable, transdermal, and implantable (pellets) androgen formulations currently are available for the treatment of males with Kallmann syndrome (KS) and idiopathic hypogonadotropic hypergonadism (IHH). Oral androgen preparations should not be used due to their toxic effects on the liver and adverse effects on lipids.

The injectable long-acting testosterone esters (eg, testosterone enanthate/cypionate) are low-cost, relatively safe, and effective, with a proven 50-year record. The disadvantages include intramuscular injection and a nonphysiologic pattern of testosterone over the dosing interval that in some men can cause wide swings in libido and mood. Research currently is being conducted on longer-acting and sustained-release formulation of testosterone injectables.

Transdermal application avoids first-pass liver metabolism, provides a noninvasive method of replacement, and results in more physiologic serum concentration of testosterone over a daily dosing period. Transdermal patches (scrotal and nonscrotal) and a gel preparation of testosterone are currently available. The most common adverse effect with these formulations is skin reactions at the application site. The gel preparation may be preferred by some patients because it is not visibly apparent and has fewer dermal reactions. However, the gel formulation may result in cross contamination to those in close contact with the patient.

In prepubertal patients, a usual starting dose of 50-75 mg of testosterone injection is used monthly with the expectation of increasing the dose by 50 mg every 4-6 months until sexual maturation has been reached. The troublesome adverse effects of acne and gynecomastia should be monitored closely and the dose adjusted accordingly.

In place of testosterone replacement, injections (200-500 IU alternate d) of human chorionic gonadotropin (hCG) can also be used in the prepubertal male. Although doses should ultimately be based on clinical response and testosterone levels, a twice-weekly dosing regimen of 100-1500 IU or 200-500 IU on alternate days is typical. The advantages of hCG are the normalization of testosterone levels and stimulation of testicular growth. The cost and numerous injections have primarily resulted in reserving hCG for men attempting fertility.

In adult males desiring fertility, a different approach to replacement therapy is employed. Spermatogenesis can be restored with a combination of hCG and human menopausal gonadotropin (hMG, follicle-stimulating hormone [FSH], and luteinizing hormone [LH]), hCG and FSH alone, or gonadotropin-releasing hormone (GnRH) injections. Occasionally, patients may respond to hCG alone. Testicular volumes greater than 3-4 mL can be used to predict those individuals who will respond to hCG. Careful monitoring of testicular size is helpful in gauging the effect of treatment. Those individuals who reach testicular sizes of 12-15 mL usually produce sperm after 12 months of treatment initiation. These hCG-only responsive individuals usually represent the fertile eunuch or patients with late-onset adult IHH.

Most patients with IHH and KS require a combination of hCG and FSH to stimulate sperm production. The starting dose for hCG is 1000 IU, and FSH is 75-150 IU on alternate days with dosage adjusted based on trough testosterone level, testicular growth, sperm production, and avoidance of adverse effects. The most common adverse effect is gynecomastia, which occurs in as many as 30% of patients. This is related to increased estrogen production from several factors, such as hCG induction of testicular aromatase and increase in the peripheral aromatization of testosterone. These monitoring periods should occur every 3 months until an adequate level of replacement is documented. Pregnancy has occurred with counts as low as 2.5 X 106, but 20-40 X 106/mL produces higher pregnancy rates. The median time to induction of spermatogenesis is 6-8 months.

The pulsatile administration of GnRH is an effective alternative to gonadotropin administration. The dose of GnRH ranges from 25-600 ng/kg every 2 hours delivered subcutaneously using a programmable portable infusion pump. As with gonadotropins, the dose and pulse are alternated based on testicular size, testosterone levels, spermatogenesis, and adverse effects. Once the testis has reached 8 mL, regular semen analysis can be obtained. Most patients require as long as 2 years of therapy before they reach maximal gonadal size and sperm production.

GnRh therapy in prepubertal boys to evoke puberty may represent a more physiologic approach because the pulse of GnRH can be altered to mimic the natural process of puberty. Again, the response time appears to be influenced by the initial testicular size; larger testes at the start of therapy result in less time on gonadotropins or GnRH.

Determination of which therapy to use (ie, gonadotropins or GnRH pulses) is related more to preference than science. Therapies appear to be equally effective. The time to full testicular growth and spermatogenesis may be somewhat shorter when using GnRH, although this appears controversial. Some anecdotal evidence suggests that GnRH therapy has proven successful in individuals refractory to gonadotropin treatments. The disadvantage of GnRH, beyond the need to use a pump, is that it is available only at specialized centers pending approval by the Food and Drug Administration (FDA) for this indication.

Treatment in females

In females, as in males, treatment is dictated by the age and fertility desires of the patient. For the woman not currently desiring fertility, estrogen replacement is required to prevent osteoporosis.

The principal estrogen produced by the functioning premenopausal ovary is 17beta-estradiol. Daily serum measurements of estradiol in regularly menstruating women indicate that the mean estradiol levels throughout the menstrual cycle are approximately 104 pg/mL (382 pmol/L).[48] Oral and parenteral preparations (ie, subcutaneous pellets and implants, transdermal patches, vaginal creams and rings) are available for standard hormone replacement therapy in normal postmenopausal women.

Oral estrogens have the disadvantage of the first hepatic passage. Parenteral administration bypasses the intestine, avoids the first pass effect of liver metabolism, and thus prevents the abnormal E2/E1 ratio observed following oral administration.[49, 50] Transdermally administered 17-beta estradiol has been shown to be an effective regimen for preventing bone loss in normal postmenopausal women.[50] The goal is to replace sex hormones in young women by trying to mimic the normal ovarian function.

All women with an intact uterus should receive a cyclical progestin to accompany estradiol replacement. The 12-day administration of medroxyprogesterone acetate (10 mg by mouth daily) per month has been shown to adequately protect the endometrium in continuous hormone replacement therapy. Alternatively, oral micronized progesterone (100 mg by mouth daily for 12-14 days per month) can be used.

Optimal hormone therapy depends on whether the patient has primary or secondary amenorrhea. Young women with primary amenorrhea in whom secondary sex characteristics have failed to develop should initially be exposed to very low doses of estrogen in an attempt to mimic the gradual pubertal maturation process. A typical regimen is as follows: 0.3 mg of conjugated equine estrogens or 25-μg estradiol patch unopposed (ie, no progestogen) daily for 6 months with incremental dose increases at 6-month intervals until the required maintenance dose is achieved. Gradual dose escalation often results in optimal breast development and allows time for the young woman to adjust psychologically to her physical maturation. Cyclical progestogen therapy, given 12-14 days per month, should be instituted toward the end of the second year of treatment.

Barrier methods of contraception should also be provided in the rare event that one of these patients spontaneously ovulates. For the same reason, barrier contraception should also be recommended to women with adult-onset IHH who do not wish to become pregnant.

Women who desire fertility, similar to males, are faced with a much more complicated process. Reports of women with KS achieving a spontaneous pregnancy are rare, with only about 20 described in the literature. The medical treatment strategy is to increase gonadotropin stimulation of the ovaries; 2 pathways (exogenous or endogeneous) are recognized. Exogenous stimulation of the ovaries is accomplished with various preparations of human menopausal gonadotropin composed of FSH with different concentrations of LH. Endogeneous stimulation is accomplished with pulsatile GnRH. Intravenous pulsatile GnRH appears to have advantages over gonadotropins because it can be pulsed to mimic the normal menstrual dynamics. When applied to other IHH conditions, the pregnancy rate, cancellation of cycles, and multiple births rate are improved when compared to gonadotropin therapy.

Reversal of idiopathic hypogonadotropic hypogonadism

Recent reports have shown possible reversal of KS after therapy with hormone replacement.[51, 52] As many as 10% of males with KS have resumption of endogenous androgen production. Men who receive exogenous testosterone rarely have an increase in testicular volume. However, an increase in size reflects the impact of endogenous androgen action. Therefore, assessing reversibility of the condition after a brief discontinuation of hormonal therapy in men who demonstrate an increase in testicular volume is recommended.

In one report, adult-onset IHH was postulated to be a consequence of an altered central set point for estradiol-mediated negative feedback.[53] A 31-year-old man with this condition was treated with low-dose clomiphene citrate (25-50 mg/d) for 4 months with complete reversal of the condition. This method of treatment normalized the endogenous pulsatility of the gonadotropins, testosterone production, and sexual function and, thus, may result in improved fertility in patients with IHH.

Medication Summary

The goals of pharmacotherapy are to correct gonadal hormone deficiency and thereby reduce morbidity and prevent complications of hypogonadism.

Testosterone (Depo-Testosterone, Delatestryl, Androderm, AndroGel, Testim)

Clinical Context:  Mainstay of treatment that is low-cost, safe, and effective. Dosage adjustments are made by monitoring trough levels prior to next injection. The goal is to maintain trough level in the low-normal range.

Class Summary

These agents are used for replacement therapy in hypogonadism associated with a deficiency or absence of endogenous testosterone.

Human chorionic gonadotropin (Pregnyl, Novarel)

Clinical Context:  Spermatogenesis may be restored. In children, although doses should be based ultimately on clinical response and testosterone levels, a twice-weekly dosing regimen of 100-1500 U or 200-500 U on alternate days is typical. Advantages of hCG are normalization of testosterone levels and stimulation of testicular growth. Cost and numerous injections have led hCG to be reserved for those males attempting fertility.

Follicle-stimulating hormone (Follistim, Gonal-f)

Clinical Context:  Stimulates gonadal steroid production

Class Summary

These agents stimulate production of gonadal steroid hormones.

Gonadorelin acetate (GnRH)

Clinical Context:  Stimulates pituitary release of luteinizing hormone. Two years of therapy may be required to reach maximal gonadal size and sperm production. Response time is influenced by initial testicular size; larger initial size yields less time on therapy. Once testis has reached 8 mL, regular semen analysis can be obtained. As with gonadotropins, dose and pulse are alternated based on testicular size, testosterone levels, spermatogenesis, and adverse effects.

Therapy in prepubertal boys may represent a more physiologic approach because the pulse of GnRH may be altered to mimic the natural process of puberty. The disadvantage of treatment, other than the need to use a pump, is that it is available at specialized centers only due to pending approval by FDA for this indication.

In females, this appears to be an effective method of stimulation of the ovary.

Class Summary

The determination of which therapy to use gonadotropins or gonadotropin releasing hormone pulses is related more to preference than to science. Therapies appear to be equally effective. Time to full testicular growth and spermatogenesis may be somewhat shorter when using gonadotropin releasing hormone, although this appears controversial. Some anecdotal evidence suggests that gonadotropin releasing hormone therapy has proven successful in individuals refractory to gonadotropin treatments

Ethinyl estradiol and norethindrone (Ovcon 35, Ovcon 50, Modicon)

Clinical Context:  In young females, low-dose PO contraception generally is an excellent method of hormone replacement. Any low-dose combination pill with 35 μg of ethinyl estradiol or less and any progestin is appropriate. Also useful because, on occasion, these women may spontaneously ovulate and become pregnant.

Conjugated equine estrogen and medroxyprogesterone (Prempro, Premphase)

Clinical Context:  Hormone replacement therapy that induces the synthesis of DNA, RNA, and various proteins in target tissues. Promotes development of secondary sex characteristics. Inhibits secretion of pituitary gonadotropins.

Class Summary

These agents may be used as hormone replacement therapy in women with IHH or KS; however, OCPs less closely mimic the physiologic menstrual cycle and thus are inferior to true hormone replacement therapy (eg, transdermal estradiol plus cyclic progesterone, see below). On the other hand, OCPs have the added advantage of contraception, if pregnancy is not desired, and they are more convenient to use. Importantly, OCPs should not be used in preadolescent girls with IHH and KS because a gradual exposure to estradiol is needed to induce secondary sexual characteristics, and early exposure to progestins results in abnormal breast development.

Conjugated estrogens (Premarin)

Clinical Context:  Induces the synthesis of DNA, RNA, and various proteins in target tissues. Promotes development of secondary sex characteristics. Titrate dose depending on the hypoestrogenic symptoms

Estradiol (Climara, Estraderm, Estrace, Menostar)

Clinical Context:  Restores estrogen levels to concentrations that induce negative feedback at gonadotropic regulatory centers. Used for the purpose of hormone replacement and induction of puberty. Acts by regulating transcription of a limited number of genes. Estrogens diffuse through cell membranes, distribute themselves throughout the cell, and bind to and activate the nuclear estrogen receptor, a DNA-binding protein found in estrogen-responsive tissues. The activated estrogen receptor binds to specific DNA sequences or hormone-response elements, which enhances transcription of adjacent genes and, in turn, leads to the observed effects.

Continue treatment until breakthrough menstrual bleeding occurs and then initiate cyclical therapy. This can be achieved with any of a variety of PO contraceptives or the addition of medroxyprogesterone 10 mg to an estradiol regimen for 12 d every month.

Progesterone (Prometrium, Endometrin, Crinone)

Clinical Context:  Can be administered PO, vaginally, or IM. All routes of administration are equally effective. For inducing withdrawal bleeding in a woman in estrogen replacement, give daily for 12-14 d of each month. If pregnancy occurs, continue treatment for the first 10 wk of pregnancy.

Medroxyprogesterone acetate (Provera, Depo-Provera)

Clinical Context:  For inducing withdrawal bleeding in a woman in estrogen replacement, give daily for 12-14 d of each month.

Class Summary

Physiologic hormone replacement therapy (HRT) most closely mimics the natural menstrual cycle by replacing (1) adequate levels of estradiol to maintain bone health and prevent symptoms of hypoestrogenemia (hot flashes, vaginal dryness, decreased libido) and (2) cyclic progesterone to induce withdrawal bleeding and thereby protect the endometrium in uterus-intact women. HRT can also be used in lower doses and without the progesterone component to induce secondary sexual characteristics in preadolescents with IHH and KS and primary amenorrhea.

Further Outpatient Care

The care of the patient depends on the goals of treatment, such as induction of puberty in preadolescents or increase in sperm production or ovulation induction in adults. In all cases, monitor the patient for problems associated with hypogonadism. One of the primary health concerns is osteoporosis.

Patient Education

For excellent patient education resources, visit eMedicineHealth's Thyroid and Metabolism Center, Women's Health Center, and Pregnancy Center. Also, see eMedicineHealth's patient education articles Hypopituitary, Anatomy of the Endocrine System, Menopause, Amenorrhea, Birth Control Overview, and Birth Control Methods.

Author

Vaishali Popat, MD, MPH, Clinical Investigator, Intramural Research Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health

Disclosure: Nothing to disclose.

Coauthor(s)

Karim Anton Calis, PharmD, MPH, FASHP, FCCP, Clinical Professor, Medical College of Virginia, Virginia Commonwealth University School of Pharmacy; Clinical Professor, University of Maryland School of Pharmacy; Director of Clinical Research and Compliance, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health

Disclosure: Nothing to disclose.

Ziad Rafic Hubayter, MD, MPH, Fellow, The Howard and Georgeanna Jones Division of Reproductive Endocrinology and Infertility, Department of Gynecology and Obstetrics, Johns Hopkins University, National Institute of Health, National Institute of Child Health and Human Development

Disclosure: Nothing to disclose.

Specialty Editors

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Chief Editor

Richard Scott Lucidi, MD, FACOG, Associate Professor of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Virginia Commonwealth University School of Medicine

Disclosure: Nothing to disclose.

Additional Contributors

Bruce A Meyer, MD, MBA, Executive Vice President for Health System Affairs, Executive Director, Faculty Practice Plan, Professor, Department of Obstetrics and Gynecology, University of Texas Southwestern Medical School

Disclosure: Nothing to disclose.

Acknowledgements

The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous authors James N Anasti, MD and Michael Cackovic, MD to the development and writing of this article.

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

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

KiSS-1 protein product model. Amino acids 1-19 are predicted to form a signal peptide. Proteolytic processing is predicted to produce kisspeptin-54, corresponding to amino acids 68-121. Shown is the C-terminal amidated decapeptide sequence, wherein biologic actively resides.