GnRH Deficient

HYPOTHALAMUS

HYPOTHALAMUS

PITUITARY

GONADS

Fig. 5. Schematic drawing of the hypothalamic-pituitary-gonadal axis in a normal adult male and in congenital hypogonadotropic hypogonadism.

Pathophysiology of CIHH

Biochemical Studies. Despite variation in the clinical phenotype of CIHH men, their biochemical findings are similar. By definition, all patients have T levels in the hypogonadal range. Gonadotropins are low/normal in all subjects, which, in the setting of low T levels, indicate hypogonadotropic hypogonadism (see Figs. 5 and 6). Interestingly, mean LH and FSH levels are significantly higher in those patients with some degree of spontaneous puberty as compared with those men with no prior puberty (31). This may explain partly the spontaneous testicular growth seen in those patients with partial puberty.

The Sertoli cell products inhibin-B and Mullerian inhibitory substance (MIS) can be measured in the serum and provide additional gonadal markers of the onset and extent of GnRH deficiency. In the normal ontogeny of inhibin-B secretion, levels rise during the neonatal activation of the hypothalamic-pituitary-gonadal axis (55) and then decline but remain readily measurable throughout childhood, despite low FSH levels. During the early stages of puberty, inhibin-B levels increase, plateau at stage II of puberty, and remain constant, unless spermatogenesis is disrupted (56). In contrast to normal men, men with CIHH with absent pubertal development display low/unde-tectable inhibin-B levels (11), which are well below those of normal children (55). Therefore, prior gonadotropin exposure is required for normal inhibin-B production during childhood. Thus, inhibin-B levels represent a marker of reproductive axis activity during the fetal/neonatal period in patients with no sexual maturation. In men with IHH with partial puberty, baseline inhibin-B levels reach the normal range, despite low gonadotropins, presumably reflecting adequate Sertoli cell proliferation during the neonatal window and early puberty. MIS, the first detectable secretory product of fetal Sertoli cells (57), is another biochemical marker of pubertal onset (58,59). Indeed, MIS levels are high throughout fetal and postnatal life and decline thereafter with the onset of spermatogenesis and the activation of LH-Leydig cell function (59). Accordingly,

Testosterone Levels Puberty

Fig. 6. Spectrum of gonadotropin-releasing hormone (GnRH) induced luteinizing hormone (LH) secretion abnormalities in men with idiopathic hypogonadotropic hypogonadism (IHH) based on our retrospective study on 78 men with CIHH (np). 75% of men with CIHH exhibit no detectable LH pulses. Seventeen percent had a normal LH frequency but a low LH amplitude. Three percent had a low LH amplitude and low frequency; 2% had a normal LH amplitude but low frequency. Finally, 2% had normal LH amplitude and frequency, deemed pathologic in the setting of hypogonadal testosterone levels.

# LH pulses/12h

Fig. 6. Spectrum of gonadotropin-releasing hormone (GnRH) induced luteinizing hormone (LH) secretion abnormalities in men with idiopathic hypogonadotropic hypogonadism (IHH) based on our retrospective study on 78 men with CIHH (np). 75% of men with CIHH exhibit no detectable LH pulses. Seventeen percent had a normal LH frequency but a low LH amplitude. Three percent had a low LH amplitude and low frequency; 2% had a normal LH amplitude but low frequency. Finally, 2% had normal LH amplitude and frequency, deemed pathologic in the setting of hypogonadal testosterone levels.

MIS levels are high among men with CIHH with no pubertal development and are lower in those men with partial GnRH deficiency (31).

Patterns of GnRH Secretion in Subjects With GnRH Deficiency. Because of low circulating levels and a short half-life (2-4 min), GnRH levels in the peripheral circulation do not accurately reflect its secretion (60,61). Consequently, the study of GnRH secretion is limited to inferential approaches. Traditionally, LH is the most commonly used surrogate marker of the GnRH pulse generator (62,63).

A spectrum of abnormalities in the neuroendocrine pattern of GnRH secretion is observed among men with CIHH. In our retrospective study of 78 men with CIHH, using every-10 min sampling for LH, 75% of patients failed to exhibit any detectable LH pulses, implying a lack of GnRH pulse generator activity (see Figs. 2 and 6) (64,31). The remainder (25%) demonstrated abnormal but detectable LH pulses. Among the latter group, the majority of patients displayed a normal LH pulse frequency with a low LH pulse amplitude (see Fig. 6). Although a higher prevalence of apulsatile LH secretion (80%) is found among those who lack sexual development, detectable LH pulses were identified in up to 20% of subjects in this group (31). Perhaps the initiation of puberty requires higher levels of GnRH stimulation than are required to maintain the neuroendocrine axis after puberty (65). Also, 50% of patients with CIHH with some pubertal development did not exhibit any LH pulses (31). This finding suggests that transient pubertal activation of the hypothalamic-pituitary-gonadal axis occurred, followed by a failure of the GnRH secretory program in these patients. Alternatively, we may have failed to detect a suppressed pulsatile pattern of GnRH, because the LH assay was not sufficiently sensitive. From these data, we conclude that neither mean gonadotropin levels nor the current LH secretion patterns are reliable surrogate markers for complete versus partial CHH.

Genetics of CIHH

Pattern of Inheritance. Considerable genetic heterogeneity underlies CIHH, which may be sporadic or familial (41). Approximately 75% of cases are sporadic (31,66). This may reflect a high rate of spontaneous mutations, or, alternatively, the syndrome may not be uniformly genetic. As more subjects are successfully treated to enhance fertility, the incidence of familial cases may increase. In the familial cases, CIHH can be inherited as an X-linked, autosomal-dominant, or autosomal-recessive trait (41). Interestingly, in our cohort, the familial cases display a more severe phenotype, with 95% of the subjects presenting with absent pubertal development and a higher prevalence of cryptorchidism (71%) and microphallus (55%) (31). To date, the genetic basis of both Kallmann syndrome and nIHH has been established in fewer than 20% of cases (67-69). Interestingly, some subjects with Kallmann syndrome have family members with hypogonadism but normal olfaction, suggesting that the stratification between Kallmann syndrome and nIHH might be oversimplified (54,70,71).

X-Linked Genes. Kallmann Syndrome Gene (KAL). In 1944, Kallmann described the clinical association of familial hypogonadotropic hypogonadism and ansomia (29) that has been classified as Kallmann syndrome. Both X-linked Kallmann syndrome (X-KS) and autosomal Kallmann syndrome pedigrees are well described (72). Although the majority of familial cases of Kallmann syndrome are inherited autosomally (73), much attention has focused on the X-linked form of Kallmann syndrome. Using contiguous gene strategy, X-KS and ichthyosis were found in patients with large Xp22.3 deletions (69,74). In 1992, the first genetic defect in the KAL gene in Xp 22.3 was determined to underlie X-KS (67). Since that report, several different KAL point mutations have been described (73,75,76). Most KAL gene mutations are clustered in the four fibronectin type III repeat domains (77-78). They cause alteration of splicing, frameshift, or stop codons and result in the synthesis of a truncated anosmin protein (79). Missense mutations have rarely been described (66,79). The X-linked form of Kallmann syndrome results from a disruption of the migration of GnRH neurons from the olfactory placode to their final destination in the hypothalamus. A study of a Kallmann syndrome fetus with a deletion from Xp22.31 to Xpter, i.e., including the entire KAL gene, confirmed the causative role of the KAL gene in the pathogenesis of X-KS. Histologic studies of the brain of a subsequent fetus revealed that the migration of GnRH and olfactory neurons was arrested at the cribriform plate (80). This GnRH neuronal migration defect results in the failure to form normal axonal communication with the median eminence and to activate the hypothalamic-pituitary-gonadal axis in patients with X-KS, consistent with their severe phenotype. In our cohort, X-linked men with Kallmann syndrome display a complete absence of pubertal development, an apulsatile pattern of LH secretion, a high frequency of cryptorchidism and microphallus, low inhibin-B levels, and histologically immature testes (31). There is some variability in the phenotypic expression of mutations, both within and between families (75,81). Finally, no correlation has been demonstrated between phenotype and location of the mutation described (79).

DAX-1 Gene. The DAX-1 gene (Xp21) encodes a nuclear hormone receptor with a novel DNA-binding domain (82). Mutations of the DAX-1 gene cause X-linked adrenal hypoplasia congenita (AHC). Although most male subjects with a DAX-1 gene mutation display complete adrenal insufficiency in childhood and subsequent hypogo-nadotropism as teenagers (83), clinical heterogeneity has also been reported, including men with IHH with normal adrenal function (84). The response of patients with AHC to pulsatile GnRH therapy is variable, suggesting a hypothalamic and/or combined pituitary defect (85). Finally, the failure of hCG to induce normal spermatogenesis implies an additional testicular defect (85,86), a finding confirmed in the knockout mouse and our studies (87).

Autosomal Genes. Based on the pattern of inheritance, autosomal genes account for the majority of familial cases of CHH. Of 36 familial cases with CIHH studied at Massachusetts General Hospital, only 21% could be attributed to X-linkage (41). Moreover, when surrogate markers of IHH (isolated congenital anosmia and delayed puberty) were included in the analysis, the X-linked families comprised only 11%, autosomal recessive 25%, and autosomal dominant 64%. These data suggest that in familial cases, the X-linked form of GnRH deficiency is the least common. The genes responsible for most of these autosomal cases remain to be defined.

GnRH Gene. The GnRH gene itself, located at 8p21-8p11.2, is the most obvious autosomal candidate gene in CHH. Indeed, the hypogonadal (hpg) mouse, in which the GnRH gene has been deleted, presents with hypogonadotropic hypogonadism (88). Surprisingly, however, no deletions, rearrangements, or point mutations in the GnRH gene have been described in humans to date (89-91).

GnRH-Receptor Gene. A functional GnRH-R is crucial for both pubertal development and reproductive function. Indeed, hypothalamic GnRH secreted into the hypophysial portal blood interacts with high-affinity GnRH-R expressed in the cell membranes of gonadotrophs. Defects in the GnRH-R have recently emerged as the first autosomal cause of IHH (68,85,92,93). GnRH-R is a G protein-coupled receptor (GPCR), with seven transmembrane segments, that activates phospholipase C, leading to the intracellular increase in inositol phosphate (94,95). Although patients with a GnRH-R mutation were expected to present with complete hypogonadotropic hypogo-nadism and unresponsiveness to GnRH stimulation, milder variants have been described. De Roux et al. described the first family with a partially inactivating mutation in the GnRH-R (68). The affected male had limited testicular growth (8-mL testes), detectable gonadotropins, and a normal response to a single pharmacologic dose of GnRH. Genetic analysis revealed a compound heterozygous mutation (Gln106Arg and Arg 262Gln substitutions). The parents were phenotypically normal, and each was heterozygous for one mutation. In CHO cells expressing Gln106Arg substitution localized in the first extracellular loop of the receptor, the level of GnRH binding and stimulation of IP3 activity was markedly reduced. In contrast, in cells expressing the Arg262Gln substitution localized in the third intracellular loop of the receptor, hormone binding was normal, but IP3 activation was impaired. Thereafter, several additional GnRH-R mutations (either homozygous or compound heterozygous) were found, which significantly impaired GnRH binding and/or signaling to varying degrees (85,96,97). Interestingly, a spectrum of pubertal development has been observed in males with IHH with mutations in the GnRH-R, depending on the genotype, ranging from the fertile eunuch syndrome (53) to partial IHH (68,92,98) to the most severe form of GnRH deficiency characterized by cryptorchidism, microphallus, undetectable gonadotropins, and absent pubertal development (85,96,97).

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