Isolated gonadotropin-releasing hormone deficiency (idiopathic hypogonadotropic hypogonadism)

INTRODUCTION — Isolated gonadotropin-releasing hormone (GnRH) deficiency (IGD), also referred to as idiopathic hypogonadotropic hypogonadism (IHH), is a family of genetic disorders that are associated with defects in the production and/or action of hypothalamic peptide that controls human reproduction, GnRH. IHH can occur either with normal olfaction (normosmic IHH) or with anosmia. This latter clinical presentation of IHH with anosmia is referred to as Kallmann syndrome (KS) [1]. The pathogenesis, genetics, clinical presentation, and management of isolated GnRH deficiency (IGD or IHH) will be discussed here [2,3]. Other causes of hypogonadotropic hypogonadism (HH) are reviewed separately. (See "Causes of secondary hypogonadism in males" and "Evaluation and management of secondary amenorrhea".)

TERMINOLOGY — Patients with IHH often have clinical features that are present at birth (cryptorchidism, microphallus, and/or biochemical evidence of low gonadotropins and sex steroids during the three to six months after birth referred to as "mini-puberty"). Some experts consider this to be a congenital disorder and refer to it in the literature as "congenital hypogonadotropic hypogonadism."

However, more often, these neonatal features are absent and the age of onset or its precise etiology cannot be determined, and thus, the term "idiopathic" is used. Regardless of the terminology, this disorder is characterized by hypogonadotropic hypogonadism (HH), eg inappropriately low or normal serum concentrations of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) in the setting of prepubertal levels of gonadal steroids. IHH is difficult to distinguish from the more common constitutional delay of puberty or functional hypogonadotropic hypogonadism (FHH) prior to age 18 years. (See 'Diagnosis' below.)

PATHOGENESIS — The lack of endogenous hypothalamic gonadotropin-releasing hormone (GnRH) secretion/action in patients with IHH cannot be proven by direct assay of GnRH in the portal circulation but can be reasonably inferred by two findings:

●The lack of any endogenous GnRH-induced luteinizing hormone (LH) pulses during frequent blood sampling (figure 1) [4].

●Typically, most IHH patients respond to exogenous GnRH when administered in a pulsatile regimen designed to mimic endogenous GnRH secretion (GnRH dose and frequency based upon a previous study of LH secretion in normal men) with robust gonadotropin secretion [5]. This responsiveness demonstrates the intact anatomic and functional integrity of the gonadotrophs and the gonads in these patients.

However, some IHH patients display atypical responses to pulsatile GnRH administration with evidence of some additional pituitary and/or testicular defects. These include patients with IHH caused by inactivating mutations of the GnRH receptor, hypogonadotropic hypogonadism (HH) seen in syndromic cases due to genetic defects that impair anterior pituitary gonadotroph function (eg, mutations in NROB1 that cause IHH and Gordon Holmes syndrome with mutations in the ubiquitination pathway genes), and some patients with ANOS1 mutations. These patients can have a poor response to pulsatile GnRH administration [6,7].

GENETICS — IHH (with or without anosmia) can be inherited in an autosomal dominant, autosomal recessive, or X-linked recessive manner. Increasingly, however, oligogenic inheritance (mutations in more than one IHH gene) is being recognized as contributing to incomplete penetrance and variable expressivity that occurs within and across IHH families [8,9]. The role of genetic testing is reviewed below. (See 'Approach to genetic testing' below.)

At first examination, more than two-thirds of IHH patients appear to be sporadic, ie, their IHH occurs in the absence of other family members being affected. However, the true familial nature of many cases becomes apparent only upon extensive questioning of the proband and other family members. Critical clues (such as a family history of anosmia; the absence of menstrual periods; delayed puberty; or the presence of skeletal, renal, or cardiac abnormalities associated with various genetic forms of gonadotropin-releasing hormone [GnRH] deficiency) are often not appreciated by close family members [10,11]. Thus, these apparently "sporadic" appearing cases can really represent familial pedigrees that display variable penetrance and/or variable expressivity when questioned in more detail. To date, several genes have been implicated in the etiology of IHH. What follows are some of the most common genetic causes and their associated phenotypes.

Anosmic form of IHH (Kallmann syndrome [KS]) — Genes that typically cause the anosmic form of IHH (Kallmann syndrome [KS]) include the following:

●ANOS1 (formerly KAL1), X-linked recessive KS – ANOS1, located in the Xp22.3 region of the X chromosome was the first gene found to be mutated in KS [12-14]. This discovery, coupled with neuroanatomic observations in mice, demonstrated that GnRH deficiency in these patients result from impaired migration of GnRH neurons to the mediobasal hypothalamus during embryogenesis [15-17]. Unlike other hypothalamic neurosecretory neurons, GnRH neurons originate from the olfactory epithelium, which lies outside the developing brain, and then migrate into the developing hypothalamus during fetal life [16,17]. Proper migration of these neurons is dependent upon the correct expression of anosmin-1, a 680-amino acid neural cell adhesion molecule-like protein, which is encoded by the ANOS1 gene. In the rat, anosmin-1 promotes formation of collateral branches and enhances axonal branching of olfactory bulb neurons [18].

Mutations in ANOS1 are either gene deletions or point mutations. The initial discovery of ANOS1 as a causal gene for KS came from studies in patients with contiguous gene deletions in the Xp22.3 region. These patients, in addition to KS, also displayed X-linked ichthyosis and chondrodysplasia punctata, linked to disruption of adjacent genes (STS and ARSE, respectively). While such large deletions are rare, overall, ANOS1 genomic changes/mutations together account for 10 to 14 percent of familial KS cases but are seen less often in sporadic cases. An X-linked mode of inheritance within the family is a clue to this gene as the cause of KS [19,20]. Obligate female carriers of ANOS1 mutations typically have no discernible abnormal phenotype [20].

In general, the clinical phenotypes of KS subjects with ANOS1 mutations lie in the more severe end of the phenotypic spectrum of IHH, demonstrating a high incidence of microphallus, cryptorchidism, and small testes [21,22]. This subset of KS patients also has the poorest response to therapy in terms of spermatogenesis [23], largely relating to the duration and severity of their cryptorchidism. Generally, ANOS1 mutations appear to be the most penetrant of the genes causing congenital GnRH deficiency. KS subjects with ANOS1 mutations also display several nonreproductive features, including unilateral renal agenesis and synkinesia (or mirror movements) that signal renal and cerebellar abnormalities in these cases [24,25]. In keeping with these distinguishing clinical signatures, anosmin-1 is expressed in nonreproductive tissues, such as mesonephric tubules, ureteric bud, digestive tract, large blood vessels, and inner ear [26].

●SOX10 (SRY-box 10 gene), autosomal dominant KS with variable penetrance – The SOX10 gene (SRY-box 10) had previously been associated with Waardenburg syndrome (WS), a heterogeneous human "neurocristopathy" (ie, disorders in cells from the neural crest origin) characterized by variable sensorineural deafness, abnormal skin and iris pigmentation, and Hirschsprung's disease. An involvement of SOX10 in KS was hypothesized due to the fact that some WS patients also have olfactory bulb agenesis. In one report, 30 percent of patients with KS and hearing loss had mutations in SOX10 [27]. Thus, this gene should be screened early in KS patients with hearing defects.

●SEMA3A, autosomal dominant KS with variable penetrance – Loss-of-function mutations in SEMA3A, a gene encoding semaphorin 3A, have been identified in patients with KS [28,29]. Semaphorin 3A, a secreted guidance cue of the class 3 semaphorin family, is critical for GnRH neuronal migration [30].

●IL17RD, autosomal dominant KS with variable penetrance – Mutations in IL17RD encoding the interleukin-17 receptor D protein, have been found exclusively in KS patients and showed a strong association with hearing loss as well [31]. IL17RD, a single transmembrane glycoprotein, is one of the major antagonists of fibroblast growth factor (FGF) downstream signaling, and as part of the "FGF8 synexpression group," IL17RD can contribute in a di- or oligogenic inheritance of IHH.

●FEZF1, autosomal recessive KS – A consanguineous family with two affected KS subjects, homozygous loss-of-function mutations in the gene FEZF1, encoding FEZ family zinc finger 1, has been reported [32]. The FEZ family zinc finger 1 is a transcriptional repressor selectively present during embryogenesis in the olfactory epithelium, and deficiency of FEZF1 results in impaired GnRH migration.

Normosmic form of IHH — Genes that typically cause the normosmic forms of IHH include the following:

●KISS1R, autosomal recessive normosmic IHH – IHH due to mutations in KISS1R (kisspeptin 1 receptor gene, formerly GPR54, located on chromosome 19p13.3 and encodes the G-protein coupled receptor-54) has been reported in individuals from a large, consanguineous family and from an unrelated patient with sporadic IHH [33]. Another group reported similar KISS1R mutations [34].

How these mutations might lead to IHH was assessed in a GPR54-deficient mouse model that resulted in a phenotype similar to that in humans (ie, IHH that was responsive to exogenous GnRH) [33]. The mice had normal hypothalamic GnRH content, thus demonstrating that GnRH neurons are present in the hypothalamus and can synthesize their peptide but KISS1R is necessary for processing or secretion of GnRH. These observations suggest that the KISS1R gene may be an important gatekeeper gene for puberty. (See "Normal puberty", section on 'Physiology of pubertal onset'.)

The ligand for KISS1R was identified by both experimental and bioinformatic approaches [34]. Kisspeptin is a 145-amino acid precursor that upon cleavage gives rise to a 54-amino acid product termed metastin, so-called because of its ability to suppress metastases in vitro in various solid tumor cell lines [35-37]. In animal models, this ligand/receptor combination (metastin/GPR54) can advance puberty [38] and overcome the amenorrhea of congenital leptin and leptin receptor deficiencies as well as starvation [39]. Gain-of-function mutations in the kisspeptin 1 gene (KISS1) [40] and KISS1R [41] have been implicated in the pathogenesis of some cases of GnRH-dependent precocious puberty. Thus, it is becoming clear that this system is a major gatekeeper of the pubertal process.

●KISS1, autosomal recessive normosmic IHH – As noted above, inactivating mutations in the KISS1R gene may result in IHH. In addition, homozygous loss-of-function mutations in KISS1, encoding kisspeptin 1 (the ligand for KISS1R), have now been identified in four sisters from a large, consanguineous family [42].

●GNRHR, autosomal recessive normosmic IHH – Some cases of IHH are caused by homozygous loss-of-function mutations in the GnRH receptor gene (GNRHR) [43,44]. In a series of 48 probands with IHH, two of five patients with normosmic, autosomal recessive IHH had GNRHR mutations, while 3 of 18 patients with normosmic, sporadic IHH had such mutations [45]. Thus, in autosomal recessive families with affected siblings, especially if both sexes are affected with the normosmic form of IHH, GNRHR should be the first gene screened (unless the family is of Turkish origin, in which case TAC3/TAC3R should be screened first, because the Turkish population has a higher incidence of TAC3/TAC3R mutations causing autosomal recessive IHH) [3].

Patients with hypogonadism caused by inactivating mutations of the GnRH receptor tend to have a poor response to pulsatile GnRH administration [6]. However, somewhat surprisingly, successful ovulation and conception can be achieved in patients with inactivating GnRH receptor mutations receiving high doses of pulsatile GnRH. These findings indicate that many GnRH receptor mutations create a relative, rather than an absolute, resistance to pulsatile GnRH administration [46], thus opening another alternative for their treatment.

●GNRH1, autosomal recessive normosmic IHH – Mutations of GNRH1 (GnRH 1 gene), the gene encoding preproGnRH, can also cause an autosomal recessive form of normosmic IHH [47,48]. In one report, a teenage brother and sister who both had normosmic IHH with severe GnRH deficiency (microphallus and cryptorchidism in the brother and absent puberty in both siblings) were found to have a frameshift mutation in GNRH1 that resulted in a protein precursor that lacked the GnRH sequence [47]. In a second study of 310 patients with normosmic IHH, one male with severe GnRH deficiency had a frameshift mutation that predicted the presence of a stop codon. Four patients also had heterozygous GNHR1 mutations not seen in controls but may have contributed to the IHH in digenic/oligogenic manner [48].

●TAC3 and TAC3R, autosomal recessive normosmic IHH – Mutations in TAC3 and TACR3 (tachykinin 3 and tachykinin 3 receptor genes, encoding neurokinin B and its receptor, respectively) have been reported as autosomal recessive causes of normosmic IHH. The tachykinins are a family of neurosecretory peptides and a distinct subset of hypothalamic neurons that co-express Kisspeptin, Neurokinin B, and Dynorphin that are collectively referred to as KNDy neurons. In one study of a consanguineous Turkish population, mutations in both its receptor and ligand were identified that caused an autosomal recessive form of normosmic IHH (similar to KISS1R mutations) [49]. In subsequent studies, however, while it seems that the Turkish population has a higher incidence of this mutated gene as a cause of autosomal recessive IHH in endogamous populations, this gene causes IHH in several other populations and can be found in the heterozygous state rather than in the homozygous state, suggesting a complex inheritance pattern [50,51].

In addition, male patients with TAC3/TACR3 mutations typically display microphallus and cryptorchidism, as well as reversibility during adulthood in both males and females, as a unique clinical feature of the GnRH deficiency due to mutations in this signaling pathway [51,52]. Taken together, this clinical feature implies that the neurokinin B pathway may be more critical during the neonatal period and adolescence but perhaps less critical for functioning of the GnRH neurons in adulthood.

Both KS and normosmic forms of IHH — Genes that cause both KS and normosmic forms of IHH include:

●FGFR1, autosomal dominant IHH with variable penetrance – The molecular origin of an autosomal dominant form of KS was identified by loss-of-function mutations of the FGF-1 receptor (FGFR1) in patients with chromosomal breaks in the 8p gene associated with ankyrin deficiency and hereditary spherocytosis [53]. In that series, heterozygous FGFR1 mutations were found in four familial cases and eight sporadic KS cases. In addition to cleft palate, the only patient in the series who harbored a homozygous mutation exhibited the most severe phenotype combining agenesis of the corpus callosum, unilateral hearing loss, and fusion of the fourth and fifth metacarpal bones. In these cases, there was considerable variability in the lack of sense of smell both within and across different families and a broad range of both testicular sizes and endogenous luteinizing hormone (LH) pulses prior to therapy [53].

The protein products of ANOS1 and FGFR1 seem to interact functionally; anosmin-1 (the product of ANOS1) may facilitate the signaling of FGF through its receptor, FGFR1, where anosmin-1 appears to act as a co-receptor for FGFR1 [54]. As the ANOS1 gene can partially escape X-inactivation, it has been proposed that a higher production of anosmin-1 in females may rescue FGFR1 signaling in certain cases of haploinsufficiency, thus explaining the higher prevalence of the disease in males.

In addition to KS, mutations in FGFR1 can also cause normosmic IHH, and in some cases, both normosmic IHH and KS may be present even within a single family [55,56].

●FGF8, autosomal dominant IHH with variable penetrance – In 2008, FGF8 (FGF-8 gene) was discovered as the critical ligand for FGFR1 in GnRH ontogeny [57]. Most patients harboring heterozygous FGF8 mutations exhibit KS, although normosmic IHH can also be associated, and patients with FGF8 mutations display a broad spectrum of pubertal development ranging from absent to partial to complete puberty (in a male with adult-onset hypogonadotropic hypogonadism [HH]). Their associated nonreproductive phenotypes include hearing loss and a range of skeletal features (high arched palate, cleft lip/palate, severe osteoporosis, camptodactyly, and hyperlaxity of the digits). Variable expressivity is evident in family members harboring the identical mutation [57,58].

●PROK2 and PROKR2, autosomal recessive IHH and heterozygous mutations with putative dominant inheritance with variable penetrance – Mutations in PROK2 and PROKR2 (encoding the ligand, prokineticin 2, and its cognate receptor, prokineticin 2 receptor, respectively) have been associated with both KS and normosmic IHH.

Mutations in these two genes can be inherited in a recessive manner (homozygous or compound heterozygous), as well as in a seemingly dominant manner (heterozygous), with the latter accounting for nearly 90 percent of mutations in this ligand or receptor [59,60]. Given the increasing evidence of oligogenic inheritance in this condition, patients with the heterozygous PROK2/PROKR2 mutations may harbor additional mutations in novel, yet-to-be-described genes. PROK2 is known to function as a chemoattractant for the types of neural progenitor cells that ultimately populate the olfactory bulb and assist in its dynamic function during life. It has been hypothesized that this olfactory developmental role of PROK2 is the major determinant of its role in GnRH neuronal ontogeny [59,60].

●CHD7, autosomal dominant IHH with variable penetrance – The clinical features of KS (IHH and anosmia/hyposmia) are often present in patients with CHARGE syndrome (a syndrome caused by mutations in CHD7, chromodomain helicase DNA-binding protein 7 gene). CHARGE syndrome is a nonrandom clustering of congenital anomalies including Coloboma of the eye, Heart defects, choanal Atresia, retarded growth and development, Genital hypoplasia, dysmorphic Ears, and/or hypoplasia or aplasia of the semicircular canals and deafness [61].

While truncating loss-of-function mutations in CHD7 typically cause the full CHARGE phenotype, missense mutations in CHD7 occur in both isolated KS and normosmic IHH patients, accounting for 5 to 6 percent of cases. Some of these IHH patients also had additional features of CHARGE syndrome [62-64].

We therefore recommend that patients with KS and normosmic IHH be screened for clinical features suggestive of CHARGE syndrome [61-63]. If any of these additional features of CHARGE syndrome are present, we suggest CHD7 sequencing.

●NSMF, indeterminate/oligogenic inheritance of IHH – Mutations in NSMF (NMDA [N-methyl-D-aspartate] receptor synaptonuclear signaling and neuronal migration factor gene, formerly known as the NELF gene) have been reported in mostly KS patients but also in normosmic IHH patients. Most patients harboring mutations in NSMF typically carry mutations in other KS-related genes such as FGFR1 [8] or HS6ST1 [65], suggesting that NSMF mutations may act as modifiers that synergize with other pathogenic genes to result in the observed human phenotype, supporting NSMF's role in oligogenicity.

●HS6ST1, indeterminate/oligogenic inheritance of IHH – In 2011, heterozygous mutations in the HS6ST1 (the heparin sulfate 6-o-sulfotransferase 1 gene) were found in seven patients diagnosed with IHH with or without anosmia [65]. Probands in two families were also found to have mutations in the FGFR1 and NSMF genes, suggesting that missense mutations in HS6ST1 alone may not be sufficient to result in IHH and that HS6ST1 may be an important component of a more complex genetic network of genes responsible for the GnRH ontogeny. It appears that mutations in several of these genes would be required to express the HH phenotype (ie, digenic or oligogenic inheritance).

●FGF17, indeterminate/oligogenic inheritance of IHH – A network of genes involved in the FGFR1 signaling pathway known as the "FGF8 synexpression group" have been identified [31]. Subsequent screening of the genes in this putative pathway identified HH patients harboring mutations in the FGF17 (FGF-17 gene), IL17RD, DUSP6, SPRY4, and FLRT3 in a complex, oligogenic pattern of inheritance. Mutations in FGF17 were found in both KS and normosmic IHH patients.

●DUSP6, indeterminate/oligogenic inheritance of IHH – Mutations in DUSP6 (dual-specificity phosphatase 6 gene) have similarly been identified in both normosmic IHH and KS patients, as part of the "FGF8 synexpression group" [31].

●SPRY4, indeterminate/oligogenic inheritance of IHH – Mutations in SPRY4 have been identified in both normosmic IHH and KS patients, also as part of the "FGF8 synexpression group" [31]. Although found in digenic concert with mutations of both DUSP6 and FGFR1, the majority of HH patients with mutations in SPRY4 did not carry mutations in other members of the FGFR1 or "FGF8 synexpression group." It is unclear whether this is due to a stronger impact of SPRY4 mutations or interactions with a yet-to-be-discovered gene.

●FLRT3, indeterminate/oligogenic inheritance of IHH – Mutations in FLRT3 (fibronectin-like domain-containing leucine rich transmembrane protein 3 gene) have been identified in both normosmic IHH and KS patients, as part of the "FGF8 synexpression group" [31]. Only a single patient with a mutation in FLRT3 was described. In this KS patient, an oligogenic mode of inheritance was supported by the presence of mutations in FGF17, HS6ST1, and FGFR1.

●WDR11, indeterminate/oligogenic inheritance of IHH – Six unrelated IHH probands, including five who were normosmic and one anosmic, were found to have mutations in WDR11 (WD repeat-containing protein 11 gene) [66]. WDR11 encodes the WD repeat domain 11 and interacts with EMX1, a homeobox transcription factor involved in specifying cell fates in the developing central nervous system and in the development of olfactory neurons [66].

●AXL, indeterminate/oligogenic inheritance of IHH – Based on the observation of a reproductive phenotype in AXL-null mice, 104 patients with KS or normosmic IHH were screened for AXL mutations; four heterozygous mutations in AXL (AXL receptor tyrosine kinase gene) were found [67]. Functional studies supported the involvement of AXL mutations in the development of the GnRH deficient phenotype.

Mutations in CCDC141 [68], POLR3B [69], SEMA3E [70], and SRA1 [71] have also been recently reported in IHH; these require additional functional and phenotypic characterization.

Digenic and oligogenic mutations — Although IHH has been considered to be a monogenic disorder, the phenotypic variability within and across families with single-gene defects suggests that in some cases there may be additional gene defects. This clinical feature was illustrated in a report of two families with IHH (one anosmic and one normosmic pedigree) in whom mutations in two IHH genes were found [8]:

●A heterozygous FGFR1 mutation and heterozygous deletion in the NSMF gene in the anosmic pedigree

●A compound heterozygous GNRHR mutation and heterozygous FGFR1 mutation in the normosmic pedigree

In a subsequent study of nearly 400 patients with IHH who had their full exonic sequences determined for the eight then-known genes causing this syndrome, the following observations were reported [9]:

●A heterozygosity of 10 percent of coding sequence mutations in many of the genes causing IHH in the normal control populations in the absence of any phenotype.

●Of the 88 patients with a demonstrable defect in a single gene known to cause this disease, 10 (11 percent) harbored a previously unsuspected second mutation (ie, "second hit" genetically).

●Multiple gene involvement accounts for much of the variable phenotypic expressivity, as evidenced by the observation that the identical mutation in patients both within and across families can result in variable phenotypes.

Some studies have demonstrated a complex, oligogenic mode of inheritance in some instances [27,31,65,72]; however, larger studies are needed to clearly elucidate the mutational pattern and genetic load required to differentiate between a normal developmental and reproductive state, a modified phenotypic presentation, and complete IHH.

CLINICAL PRESENTATION — IHH affects both sexes but has a significant male preponderance. A population-based, epidemiological study from Finland showed a minimal prevalence estimate of the Kallmann syndrome (KS) form of IHH to be 1:48,000 with a clear difference between males (1:30,000) and females (1:125,000) [73].

Spectrum of clinical expression — There is a relatively broad spectrum of clinical expression that can occur in IHH, ranging from complete absence of sexual development to partial completion of puberty that does not subsequently progress. Of note, the X-linked form of KS form of IHH relating to mutations in the ANOS1 gene has the most consistent severe phenotypic presentation (ie, prepubertal testes size and complete absence of gonadotropin-releasing hormone [GnRH]-induced luteinizing hormone [LH] pulsations during frequent sampling studies) of all of the genes associated with this condition [21,24].

IHH can present at any age, but the presenting signs and symptoms are a function of the age-related period of reproductive activity.

●During the neonatal period, boys with the more severe cases of IHH can present with microphallus and/or cryptorchidism, presumably due to in utero and/or neonatal GnRH deficiency; approximately one-half of boys with microphallus have IHH as the underlying diagnosis. In comparison, newborn girls with IHH have no obvious abnormal reproductive tract findings that might provide clues to the diagnosis. However, in both sexes, other congenital nonreproductive features may be present (eg, midline facial defects, skeletal abnormalities).

●During childhood, since the hypothalamic GnRH-pituitary-gonadal axis is quiescent, a diagnosis of IHH can generally be heralded only in the presence of nonreproductive phenotypes (eg, the lack of sense of smell in some patients [anosmia] or skeletal abnormalities, such as cleft lip/cleft palate, hearing deficits, or syndactyly).

●At puberty, patients of both sexes can present with a complete form of IHH that is characterized by a failure to initiate sexual maturation (eg, lack of secondary sexual characteristics, primary amenorrhea in girls, lack of virilization in boys) and failure to establish a pubertal growth spurt. (See "Approach to the patient with delayed puberty" and "Evaluation and management of primary amenorrhea".)

●Some patients present with partial forms of IHH and undergo some degree of pubertal development that subsequently ceases. For example, some males with IHH exhibit some testicular growth, while some females can have thelarche and menarche, but hypogonadotropic hypogonadism (HH) is demonstrable soon thereafter. Extremely rarely, a few have completely normal pubertal development and adulthood gonadal function, only to develop HH with prepubertal levels of testosterone but sometimes with normal testicular size as a clue to its acquired status, ie, developing only after adult testicular development has been complete subsequently in adulthood, leading to infertility and sexual dysfunction [74]. These patients are referred to as having the adult-onset or acquired form of IHH. (See "Clinical features and diagnosis of male hypogonadism".)

Physical findings

General appearance

●The body habitus of adolescent patients failing to undergo puberty often is eunuchoidal, with arm span exceeding height by 5 cm or more. This finding reflects the delayed closure of the epiphyses of long bones caused by hypogonadism and lack of sex steroid production during puberty.

●In women, secondary sexual characteristics are often completely absent, with little or no breast development or axillary hair.

●Men have little or no beard and body hair development, no increase in bulk of the muscles, and failure of the voice to deepen.

●In both sexes, some pubic hair can be present because adrenarche, with its concomitant small amounts of adrenal androgen and estrogen secretion, is characteristically normal (dehydroepiandrosterone sulfate [DHEAS] being the best single test of adrenal maturation). In comparison, both adrenarche and the normal growth spurt are attenuated in constitutional delay of puberty, which is otherwise difficult to distinguish from GnRH deficiency (see "Approach to the patient with delayed puberty"). If there is evidence of overt adrenal failure, the clinician should consider and investigate for rare genetic forms of HH that is associated with congenital adrenal failure (NROB1 deficiency) [75].

●While testicular volume is typically prepubertal (ie, <4 mL) in males with IHH, a discrete subset of men with congenital GnRH deficiency can have normal, adult-size testes (>12 to 15 mL) and even demonstrate sperm in the presence of a small ejaculate volume (a typically androgen-dependent component of the semen analysis). This combination of relatively well-preserved seminiferous tubular development, normal size of testes, and spermatogenesis in the presence of deficient Leydig cell secretion of testosterone is referred to as the "fertile eunuch variant" of IHH [76]. These subjects with partial puberty can undergo spontaneous recovery, as has been described in a fertile eunuch IHH patient who harbored a GNRHR mutation [77] and in another fertile eunuch IHH patient with a loss-of-function mutation in the fibroblast growth factor (FGF) receptor-1 (FGFR1) gene. (See 'Both KS and normosmic forms of IHH' above.)

For most male patients with this partial puberty phenotype, the mechanisms responsible for complete Leydig cell failure, with its attendant eunuchoidism and relative preservation of seminiferous tubular function, are poorly understood. This variant does, however, illustrate the relatively broad spectrum of clinical expression that can occur in GnRH deficiency, ranging from complete absence of sexual development to near-normal completion of puberty [4].

●Gynecomastia is not typically a feature of men with GnRH deficiency. The total absence of gonadotropins results in low testicular aromatase activity and, therefore, little estrogen production.

Congenital abnormalities — Several congenital abnormalities can be found in patients with IHH, particularly those with the KS form of IHH, due to its developmental etiology. These congenital features include:

●Midline defects (ie, cleft lip/palate)

●Anosmia/hyposmia

●Unilateral renal agenesis

●Uni- or bilateral cryptorchidism

●Bimanual synkinesia (or mirror movements)

●Syndactyly or other skeletal abnormalities [78]

●Hearing loss

●Dental agenesis

Studies have examined specific genotype-phenotype relationships, and in one large series of patients with IHH, unilateral renal agenesis and synkinesia (mirror movements) appeared to be phenotypic markers for the X-linked form of KS. However, synkinesia has also been reported in autosomal dominant forms of IHH as well [53]. Recent studies have now established the following additional phenotype-genotype correlations: dental agenesis (FGF8/FGFR1 [25,79]), digital bony abnormalities (FGF8/FGFR1 [25,80]), and hearing loss (CHD7, SOX10, IL17RD [25,79]).

In contrast to the KS form of IHH, the normosmic form of IHH is not typically associated with congenital nonreproductive anomalies, and in the absence of clinical information about their response to exogenous GnRH, patients with normosmic IHH due to defects in GnRH secretion cannot be distinguished clinically from patients with inactivating mutations of the GNRH receptor or those with mutations of the gonadotroph cells resulting in production of gonadotropins with decreased biological activity.

DIAGNOSIS — When suspected on the basis of the clinical presentation or physical findings, the diagnosis of IHH should be confirmed biochemically. The diagnosis requires the following findings:

●The demonstration of prepubertal serum concentrations of sex steroid hormones (serum testosterone less than 100 ng/dL [3.5 nmol/L] in males or serum estradiol less than 20 pg/mL [73 pmol/L] in females).

●Inappropriately low or normal serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) concentrations (usually less than 4 to 5 international units/L) rather than the high concentrations expected with primary gonadal failure.

●Otherwise normal anterior pituitary function.

●Normal appearance of the hypothalamus and pituitary region on magnetic resonance imaging (MRI); when seeking this diagnosis, it is useful to request fine (1 mm) cuts through the olfactory bulb region of the MRI to define subtle abnormalities of the olfactory system that may signal which genetic tests to request first.

●Serum inhibin B can be used as a biochemical index of gonadal function in boys. For individuals with secondary (hypogonadotropic) hypogonadism with no clear cause, a very low level of inhibin B is more likely to be associated with isolated GnRH deficiency with absent puberty, rather than constitutional delay of growth and puberty (CDGP) [81]. However, inhibin B levels are not useful to distinguish between CDGP and milder forms of isolated GnRH deficiency. For boys, serial measurements of inhibin B can help to monitor pubertal progression, as a supplement to measurements of testicular volume, because inhibin B and testicular size are well correlated.

Differential diagnosis — For patients fulfilling the above laboratory criteria, the main (and most difficult) differential diagnosis is with CDGP.

●IHH versus CDGP – A definitive diagnosis of IHH in the absence of a family history or prior genetic testing is difficult to make until the patient reaches at least 18 years of age, unless other suggestive features are present (ie, prior microphallus and/or cryptorchism, anosmia, renal agenesis, skeletal defects, etc). CDGP is far more common than IHH, affecting approximately 3 percent of adolescents while the incidence of the Kallmann syndrome (KS) form of IHH is 1:48,000 with a clear difference between males (1:30,000) and females (1:125,000) [73]. (See "Approach to the patient with delayed puberty".)

●No single test can reliably distinguish between IHH and CDGP until more widespread genetic testing becomes available, and therefore, one has to rely on an array of clinical clues as well as on the natural evolution over time. However, certain features may indicate a higher likelihood of IHH rather than CDGP:

•A family history of gonadotropin-releasing hormone (GnRH) deficiency, anosmia, and/or the presence of one or several associated congenital abnormalities suggests congenital nonreproductive abnormalities (eg, cleft lip/palate, syndactyly) suggest KS form of GnRH deficiency.

•A history of "stalled" puberty rather than total absence of development, a family history of delayed puberty, or early evidence of breast or testicular development are useful indicators that puberty is likely to occur spontaneously (ie, CDGP).

•The presence of pubic hair suggests IHH because normal adrenarche still occurs; in comparison, both adrenarche and gonadarche are delayed in CDGP, and therefore, pubic hair is usually absent.

•Stimulation testing with kisspeptin is a promising approach to help distinguish between patients with CDGP and isolated GnRH deficiency/Kallmann syndrome. (See "Approach to the patient with delayed puberty", section on 'Endocrine tests'.)

●Functional hypothalamic amenorrhea (FHA) – In females, FHA or functional hypogonadotropic hypogonadism (FHH) is part of the differential diagnosis for IHH. The presence of predisposing factors like excessive exercise, weight loss, or psychological stress point towards the diagnosis of FHH rather than IHH.

●Other causes of secondary hypogonadism – When GnRH deficiency presents after puberty [74], other causes of secondary hypogonadism (particularly tumors of the hypothalamic-pituitary axis) must be eliminated, as IHH is really a diagnosis of exclusion (table 1). These include:

•Tumors of the hypothalamic-pituitary region that occasionally can be suspected by the presence of other neurologic symptoms (headaches, visual disturbances) or the demonstration of other defects or excess in anterior pituitary hormone secretion on initial biochemical screening. However, enlarging mass lesions in either the pituitary or the central nervous system decrease the secretion of corticotropin (ACTH) or thyroid-stimulating hormone (TSH) less than that of gonadotropins or growth hormone.

•Similarly, hemochromatosis should be eliminated by appropriate testing of serum iron, total iron binding capacity, and ferritin levels.

Approach to genetic testing — When the diagnosis of IHH is suspected, we suggest referral to a clinical geneticist for further evaluation and possible genetic testing. As many of the genes causing IHH have pleotropic physiologic functions, genetic testing can aid assessment of both reproductive and nonreproductive clinical features. In addition, ascertaining the specific inheritance modes can aid genetic screening within the family to predict future recurrence risk in siblings, family members or offspring of IHH patients. However, genetic testing in IHH is challenging, given the genetic and allelic heterogeneity, as well as complex oligogenic inheritance patterns. However, in the presence of either clear Mendelian inheritance patterns or specific phenotypic cues, targeted genetic testing or multigene panel testing may be performed. However, if such testing is done, variant interpretation and genetic counseling should be performed in conjunction with a clinical genetics service. Alternatively, several research units have special interests in the genetics of IHH, and clinicians can consider referring these patients to such specialized centers. Genetic testing is now commercially available through several Clinical Laboratory Improvement Amendments (CLIA) laboratories in the United States (GeneDx, Athena Diagnostics, Fulgent Diagnostics).

MANAGEMENT — The choice of therapy for IHH depends upon the patient's age and desire to achieve one or more of the following goals:

●Induction of puberty and/or maintenance of sexual maturation

●Induction or restoration of fertility

Puberty induction and sexual maturation

Girls and women — Exogenous estrogens are used to start secondary sexual development in prepubertal girls and to build and sustain normal bone and muscle mass. Initiation of treatment should be based upon the patient's bone age, current height percentiles, psychosexual needs, and predicted adult height. The shorter the predicted adult height, the later puberty should be induced. Inappropriate use of estrogens may result in rapid osseous maturation with resulting short stature and irregular menstrual bleeding. (See "Approach to the patient with delayed puberty", section on 'Estradiol therapy'.)

Initiation of puberty can begin with any type or route of exogenous estrogen, oral or transdermal. Initiation of puberty with transdermal 17-beta estradiol, starting with low doses of approximately 0.08 to 0.12 mcg estradiol per kg/day body weight, is successful and commonly prescribed by pediatricians [82]. The dose is then gradually increased over several years. Initial therapy should consist of unopposed estrogen alone to maximize breast growth, achieve appropriate skeletal maturation, and to induce uterine and endometrial proliferation. A progestin eventually needs to be added to prevent endometrial hyperplasia, but adding it prematurely or administering combinations of estrogens and progestins (eg, birth control pills) before completion of breast development should be avoided because it is likely to reduce ultimate breast size. (See "Approach to the patient with delayed puberty", section on 'Estradiol therapy'.)

Once pubertal induction is completed, estrogen and progestin therapy are continued indefinitely. Doses and principles of therapy are similar to those for women with primary ovarian insufficiency. Additional details on progestin therapy and maintenance hormone therapy are found separately. (See "Management of primary ovarian insufficiency (premature ovarian failure)", section on 'Importance of estrogen therapy'.)

Boys and men — In boys, puberty can be induced with testosterone, exogenous gonadotropins, or pulsatile gonadotropin-releasing hormone (GnRH) therapy. The latter two options also induce spermatogenesis, which is not necessary for this age group. We therefore suggest testosterone therapy for pubertal induction in boys. The goals of therapy are to:

●Induce virilization

●Promote optimal skeletal maturation (with bone age monitoring)

●Maximize adult height

●Promote psychosexual development

●Build and sustain normal bone and muscle mass

Oral testosterone preparations should not be used, because of hepatic toxicity. The choices for testosterone replacement include intramuscular injections of long-acting testosterone preparations or topical gels/solutions/patches. Serum testosterone levels should be monitored and dose adjusted.

Whichever form of testosterone replacement is chosen, providing psychological support is important because the patient will have a variety of new and often confusing symptoms, much like an adolescent undergoing puberty but more difficult because it will likely be at a later age. Testosterone therapy should be initiated at a low dose and gradually increased to an adult dose over a few years. Additional details on the use of testosterone therapy for pubertal induction can be found separately. (See "Approach to the patient with delayed puberty", section on 'Testosterone therapy'.)

Once pubertal induction is completed, testosterone therapy is continued indefinitely. Testosterone therapy for male hypogonadism is reviewed in detail elsewhere. (See "Testosterone treatment of male hypogonadism".)

Fertility

Ovulation induction in women — When fertility is desired, administration of either gonadotropins or pulsatile GnRH results in ovulation in 95 percent of women. A full evaluation of tubal patency and a semen analysis in the male partner should be performed before undertaking gonadotropin therapy with its attendant risks and costs. Gonadotropin therapy for ovulation induction remains the principal form of therapy. This topic is discussed in detail elsewhere. (See "Overview of ovulation induction".)

Pulsatile administration of exogenous GnRH is also an equally effective therapy for the stimulation of endogenous gonadotropin secretion, follicular development, and ovulation in women with GnRH deficiency. A distinct feature of pulsatile GnRH therapy is that given the physiologic stimulation, the resulting serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH) concentrations remain within the normal range and the chances of multifollicular development and ovarian hyperstimulation are therefore low [83]. Pulsatile GnRH is available in some countries but not the United States. However, it is available in some United States centers as a research-based therapy.

Induction of spermatogenesis in men — Testosterone replacement, while effective for achieving eugonadal serum testosterone concentrations, does not restore normal spermatogenesis in men with GnRH deficiency. The traditional approach to inducing spermatogenesis in men with IHH is the administration of human chorionic gonadotropin (hCG) to induce full steroidogenesis from Leydig cells along with either menopausal gonadotropins (the less expensive option) or recombinant FSH (rFSH) to induce spermatogenesis. This is reviewed in detail separately. (See "Induction of fertility in males with secondary hypogonadism".)

Pulsatile GnRH therapy is an effective therapy, but it is not currently approved for use in the United States or in Europe for GnRH-deficient men seeking fertility [5,74,84]. The importance of pulsatile secretion is reviewed separately (see "Physiology of gonadotropin-releasing hormone"). GnRH is administered subcutaneously at two-hour intervals via a portable mini-pump that infuses GnRH over 60 seconds. This frequency is set to replicate that of endogenous GnRH-induced LH pulses in normal men (every 120 minutes). Treatment is begun at a dose of 25 ng/kg per bolus and adjusted upward on the basis of the serum testosterone concentration. When normal values have been achieved, the dose is held constant, and measurement of testicular size and seminal fluid analysis are performed at serial intervals (every two to three months).

Maturation of spermatogenesis can take one to two years during normal puberty. Thus, both gonadotropin therapy as well as pulsatile GnRH therapy must be given for an equivalent period depending upon the pretreatment testicular volume. Men with infantile testes (eg, 1 to 3 mL) or a past history of cryptorchidism require the longest durations of therapy, whereas those with larger testicular size respond sooner [5,84].

Since FSH induces Sertoli cell and germ cell proliferation in immature testes and androgen production from the Leydig cells terminates proliferation and promotes differentiation, a randomized, open-label trial tested the hypothesis that FSH priming for four months prior to LH and FSH (using pulsatile GnRH) could enhance fertility outcomes in IHH men with infantile testes and no cryptorchidism. FSH priming nearly doubled the testicular volume with histologic evidence of Sertoli cell proliferation, and all men receiving FSH priming developed sperm in their ejaculate [85]. Thus, men with infantile testes may benefit from pretreatment with rFSH alone prior to hCG and FSH to maximize sperm output [85].

Pulsatile GnRH and gonadotropin therapy have been compared directly. Pulsatile GnRH results in more testicular growth than do gonadotropins. However, they do not seem to have any difference in the outcome of induction of spermatogenesis, which occurs in approximately 75 to 90 percent of men with either approach [86-89]. Likewise, sperm concentration upon induction of spermatogenesis is comparable between the two therapies [89]. There are sparse comparative data on pregnancy rates between the two therapies as the number of patients who have been studied after pulsatile GnRH therapy is quite limited [23,90].

It is important to recognize that conception can occur in IHH patients even with relatively low sperm counts since sperm function is usually normal in those without a history of cryptorchidism. Previous treatment with gonadotropins may reduce the period of subsequent gonadotropin treatment required for initiation of spermatogenesis. If natural conception does not occur despite spermatogenesis, assisted reproductive techniques (intracytoplasmic sperm insemination or in vitro fertilization) should be considered.

Therapeutic failure with gonadotropin therapy can occur in IHH men with severe pubertal delay with prepubertal testicular volume at baseline. Therapeutic failure with pulsatile GnRH therapy can occur in IHH men with unresponsive pituitaries to GnRH (eg, due to hemochromatosis) or secondary failures coincident with the development of antibodies to GnRH. The latter is a rare occurrence and generally occurs in the setting of intermittent or discontinuous therapy. Additionally, rare instances of failure to respond to GnRH therapy have uncovered additional defects in the hypothalamic-pituitary-gonadal axis [7].

Reversal of IHH — IHH was previously thought to be a permanent disorder requiring lifelong therapy. However, reversal of the disorder has been reported in approximately 10 percent of male patients after discontinuation of hormonal therapy [91,92]. This was illustrated in a report of 15 male patients (mean age 21 years), 10 of whom were identified retrospectively [92]. The other five patients were identified prospectively among 50 men with IHH (10 percent) at a mean of 6±3 weeks after discontinuation of therapy. Sustained reversal of IHH was defined as the presence of normal adult testosterone levels after hormonal therapy was discontinued. The rate of reversal was similar for men who had absent or partial puberty at initial presentation. Mean testicular volume and serum total testosterone concentrations increased into the normal adult male range, and both pulsatile LH secretion and spermatogenesis were documented.

Paradoxical increase in testicular volume in a male IHH patient while on testosterone therapy should alert the clinician that potential endogenous GnRH secretory activity has occurred. Normalization of serum testosterone levels off therapy is diagnostic of reversal of IHH. The precise mechanisms behind this reversal process remain unknown and can occur even in those with severe hypogonadotropic hypogonadism including those with anosmic form of IHH, ie, Kallmann syndrome (KS). In a study, nearly 45 percent of reversal subjects had demonstrable IHH-related gene mutations, but a significant number of reversal subjects harbored mutations that disrupt neurokinin B signalling (TAC3/TACR3), suggesting that the neurokinin B pathway, although critical for puberty, may be dispensable later in life [52]. However, reversal of hypogonadism in other genetic forms of IHH has also been reported, suggesting that this is not unique to a single genetic group of patients.

Longitudinal review of subjects undergoing reversal has also demonstrated a fragility of this reversal phenomenon as some patients manifest relapse into an IHH state, requiring reintroduction of therapy [80,93]. Hence, it is important for clinicians to periodically reassess IHH subjects for evidence of reversal but also assess the persistence of this reversal state and reintroduce therapy if required.

Stopping treatment — Based upon these above observations, we use the following approach in men with IHH. For men who have achieved normal testicular volume while being treated with testosterone alone (which is often the initial treatment when fertility is not yet desired), we suggest that testosterone treatment be discontinued and serum testosterone be determined after two to three months. The rationale is that testosterone treatment will not directly increase testicular size, and therefore, the increase is probably the result of endogenous gonadotropin secretion. For men who have achieved adult reproductive parameters (testicular volume, serum testosterone concentrations, and sperm in the ejaculate) during treatment with gonadotropins or GnRH, hormonal therapy could be discontinued for two to three months if the patient wishes to evaluate for possible reversibility.

SUMMARY AND RECOMMENDATIONS

●Isolated gonadotropin-releasing hormone (GnRH) deficiency (IGD), or idiopathic hypogonadotropic hypogonadism (IHH), refers to the functional absence of GnRH secretion from hypothalamic hypophysiotropic neurons or a defect in its action at the level of the gonadotrope in the case of mutations in the GnRH receptor. (See 'Terminology' above.)

●IHH (with or without anosmia) can be inherited as an autosomal dominant, autosomal recessive, or X-linked condition. While mutations in several genes cause monogenic forms of IHH, increasingly, oligogenic inheritance is also being appreciated wherein mutations in more than one gene may be present in an IHH individual, especially in families that display incomplete penetrance and variable expressivity. (See 'Genetics' above.)

●IHH is primarily a disease of males, with the male-to-female ratio of approximately 4:1. (See 'Clinical presentation' above.)

●The diagnosis of IHH is based upon the demonstration of prepubertal serum concentrations of sex steroid hormones, low/normal serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) concentrations, otherwise normal anterior pituitary function, and normal magnetic resonance imaging (MRI) of the hypothalamic-pituitary region. (See 'Diagnosis' above.)

●The main differential diagnosis is constitutional delay of growth and puberty (CDGP), which is far more common than IHH. A definitive diagnosis of IHH in the absence of a family history or prior genetic testing is difficult to make until the patient reaches at least 18 years of age, unless other suggestive features are present (ie, prior microphallus and/or cryptorchism, anosmia, renal agenesis, skeletal defects, etc). (See 'Differential diagnosis' above.)

●When the diagnosis of IHH is suspected, we suggest referral to a clinical geneticist for further evaluation and possible genetic testing. Clinicians may also refer patients to specialized research centers that focus on the genetics of IHH. (See 'Approach to genetic testing' above.)

●The management of GnRH deficiency includes replacing sex steroids to develop secondary sex characteristics and to build and sustain normal bone and muscle mass. Exogenous gonadotropin or pulsatile GnRH therapy are used for ovulation induction in women and for induction of spermatogenesis in men. (See 'Management' above.)