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Gonadotropin-Releasing Hormone Deficiency in the Human (Idiopathic Hypogonadotropic Hypogonadism and Kallmann’s Syndrome): Pathophysiological and Genetic Considerations

Reproductive Endocrine Unit of the Department of Medicine and the National Center for Infertility Research, Massachusetts General Hospital, Boston, Massachusetts 02114

	Abstract

Top Abstract I. Introduction II. Ontogeny of Normal... III. Historical Perspective IV. Clinical Presentation of... V. Approaches to Studying... VI. Patterns of GnRH... VII. Patterns of GnRH... VIII. Genetic Studies IX. X-Linked Genes Controlling... X. Autosomal Genes Controlling... XI. Conclusion References

 

I. Introduction

II. Ontogeny of Normal GnRH Secretion

A. Fetal life

B. Neonatal and childhood periods

C. Puberty

D. Adulthood

III. Historical Perspective

IV. Clinical Presentation of GnRH Deficiency

A. Congenital GnRH deficiency

B. Adult-onset GnRH deficiency

C. Variant or partial forms of GnRH deficiency

D. Associated anomalies in KS

E. Differential diagnosis

V. Approaches to Studying GnRH Secretion

A. Animal and in vitro studies

B. Human studies

VI. Patterns of GnRH Secretion in Men with GnRH Deficiency

VII. Patterns of GnRH Secretion in Women with GnRH Deficiency

VIII. Genetic Studies

IX. X-Linked Genes Controlling GnRH Secretion

A. Kallmann’s syndrome gene

B. Adrenal hypoplasia congenita (AHC) gene product

X. Autosomal Genes Controlling GnRH Secretion

A. The genetics of autosomal inheritance

B. GnRH gene

C. GnRH receptor gene

D. Other autosomal genes

XI. Conclusion

	I. Introduction

Top Abstract I. Introduction II. Ontogeny of Normal... III. Historical Perspective IV. Clinical Presentation of... V. Approaches to Studying... VI. Patterns of GnRH... VII. Patterns of GnRH... VIII. Genetic Studies IX. X-Linked Genes Controlling... X. Autosomal Genes Controlling... XI. Conclusion References

 
INITIATION and maintenance of the reproductive axis in the human are contingent upon the pulsatile secretion of GnRH from the hypothalamus. Isolated GnRH deficiency is the clinical syndrome that results from failure of this normal pattern of episodic GnRH secretion to occur. It is characterized by 1) complete or partial absence of any endogenous GnRH-induced LH pulsations (1, 2, 3, 4, 5); 2) normalization of pituitary and gonadal function in response to physiological regimens of exogenous GnRH replacement (3, 4, 6, 7, 8, 9); 3) normal findings on radiographic imaging of the hypothalamic-pituitary region, and; 4) normal baseline and reserve testing of the remainder of the hypothalamic-pituitary axes. Typically, patients with hypogonadotropic hypogonadism and anosmia have been given the diagnosis of Kallmann’s syndrome (KS), and those with normal olfaction have been diagnosed as idiopathic hypogonadotropic hypogonadism (IHH). However, both of these presentations (i.e., with and without anosmia) can occur in the same family with this disorder, thus demonstrating the variability of expression of this trait. Isolated GnRH deficiency is remarkable for its heterogeneity of clinical presentation (1, 3, 4, 5, 10, 11), variable modes of inheritance (11, 12, 13, 14, 15, 16, 17), and inconsistent association with other anomalies (11, 12, 16, 18, 19, 20).

	II. Ontogeny of Normal GnRH Secretion

Top Abstract I. Introduction II. Ontogeny of Normal... III. Historical Perspective IV. Clinical Presentation of... V. Approaches to Studying... VI. Patterns of GnRH... VII. Patterns of GnRH... VIII. Genetic Studies IX. X-Linked Genes Controlling... X. Autosomal Genes Controlling... XI. Conclusion References

 
In the human, the pattern of GnRH-induced gonadotropin secretion is constantly changing across sexual development. Hence, making the diagnosis of isolated GnRH deficiency on the basis of serum gonadotropins and sex steroids is critically dependent upon a clear understanding of the normal developmental timing and sequence of GnRH-induced activation of the reproductive axis, which provides an ever changing backdrop of normative data.

A. Fetal life
GnRH has been detected in human embryonic brain extracts as early as 4.5 weeks (21). By 9 weeks gestation, GnRH neurons have been demonstrated in the fetal hypothalamus, although functional connections between these neurons and the portal system are not established until 16 weeks (21). LH and FSH are first detectable in the pituitary at 10 weeks, are measurable in peripheral blood by 12 weeks, reach a peak in midgestation, and then decrease toward term with the development of functioning gonadal negative feedback mechanisms (for review see Ref. 22). The fact that gonadotropins are undetectable in the serum and pituitaries of anencephalic infants (22), as well as the ability of GnRH to induce LHß mRNA synthesis in pituitary cells from normal second trimester fetuses (23), suggests a role for GnRH in gonadotropin regulation during early fetal life. Further evidence for an operative hypothalamic GnRH "pulse generator" activity at this time is provided by studies in the ovine fetus, which demonstrate a pulsatile mode of LH secretion as early as midgestation that can be blocked by chronic administration of a GnRH agonist (24).

B. Neonatal and childhood periods
During the neonatal period there is clear evidence of GnRH secretion as evidenced by the persistence of pulsatile secretion of gonadotropins (25), which then decrease by approximately 6 months in boys and 1–2 yr in girls to the low levels that are present until the onset of puberty (26, 27). For many years, the childhood period was considered a time of complete hypothalamic-pituitary quiescence. However, newer ultrasensitive LH assays have revealed that pulsatile GnRH secretion continues throughout this period, albeit at a markedly reduced amplitude (28). The precise mechanism responsible for reversibly restraining the hypothalamic GnRH pulse generator at this time has not yet been elucidated. However, it is likely to involve a process that inhibits GnRH release rather than its synthesis, based on the demonstration in primates that abundant GnRH mRNA and protein are present within the appropriate hypothalamic neurons at an equivalent developmental stage (29). While the mechanism that subsequently triggers the onset of augmented GnRH secretion at puberty is still unclear, potential candidates include metabolizing enzymes responsible for GnRH secretion (30, 31), neurotransmitters such as norepinephrine (32), neuropeptide Y (33), aspartate (34), or -aminobutyric acid (35), glial growth factors such as transforming growth factor- (36, 37), and/or metabolic signals such as leptin (38, 39, 40).

C. Puberty
Commensurate with the onset of puberty, there is a sleep-entrained reactivation of the reproductive axis characterized by a marked increase in the amplitude of GnRH-induced LH pulses with much more modest changes in frequency (41, 42, 43, 44, 45, 46, 47). This nocturnal augmentation of LH secretion stimulates secretion of sex steroids and inhibin from the gonads at night with a subsequent decrease to prepubertal levels during the day (41). As puberty progresses, secretion of gonadotropins occurs during both day and night, thus completing sexual development.

D. Adulthood
Both sexes secrete gonadotropins in a pulsatile fashion during adulthood but in very different patterns. In the adult male, wide variations in LH interpulse interval have been reported with parallel changes in sex steroids (48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62). However, in the majority of studies in which intensive frequent sampling has been employed, LH pulses have been shown to occur at an approximately 2-h frequency (49, 50, 51, 52, 53, 54, 56, 58, 59, 61, 62) (Fig. 1A). In the female, the reproductive axis is under more dynamic regulation, with a complex series of changes in GnRH pulse frequency occurring throughout the menstrual cycle (3, 63, 64, 65, 66, 67, 68). In the early follicular phase, the GnRH pulse frequency starts at approximately 90 min, increases to 60 min in the mid- and late-follicular phases and, with the appearance of progesterone secretion in the luteal phase, slows to approximately every 4–6 h. By the late luteal phase, the GnRH pulse generator is active only at intervals of 6–8 h, but accelerates once again during the luteal-follicular transition to approximately hourly intervals during the day, acquiring the sleep-induced slowing typical of the early follicular phase (69).

View larger version (24K): [in this window] [in a new window]   Figure 1. Spectrum of GnRH-induced LH secretion in men with GnRH deficiency. LH pulsations are indicated by asterisks. Black bars indicate periods of sleep. A, Normal adult male pattern of GnRH secretion with high-amplitude regular LH pulsations and normal serum T and testicular volume (TV). B, Apulsatile pattern of GnRH secretion in an IHH male with complete absence of endogenous LH pulsations. C, Sleep-entrained or developmental arrest pattern of LH secretion in an IHH male characterized by relatively low amplitude LH pulsations clustered during the nighttime hours analogous to the pattern that normally occurs at puberty. D, Disordered amplitude pattern of LH secretion in an IHH male. [Adapted with permission from N. Santoro et al.: Endocr Rev 7:11–23, 1986 (3 ). © The Endocrine Society.]

	III. Historical Perspective

Top Abstract I. Introduction II. Ontogeny of Normal... III. Historical Perspective IV. Clinical Presentation of... V. Approaches to Studying... VI. Patterns of GnRH... VII. Patterns of GnRH... VIII. Genetic Studies IX. X-Linked Genes Controlling... X. Autosomal Genes Controlling... XI. Conclusion References

It has been difficult to ascertain the true incidence and mode of transmission of GnRH deficiency with certitude. Since examination for military service is required in some countries, reviewing military records is a potential method (however limited) of ascertainment for large male populations. Examining the medical records of 600,000 Sardinian conscripts over 37 yr identified 344 individuals rejected for military service due to bilateral testicular atrophy. From 265 men available for follow-up, 7 had a normal karyotype and were anosmic, giving an incidence of KS of approximately 1 in 86,000 in this somewhat isolated geographic population (72). In a separate review of 45,000 French men presenting for military service in 1 yr, 4 cases of hypogonadotropic hypogonadism were identified, giving an incidence of about 1 in 10,000 (73). The variations in these two studies portray the difficulties of using military screening as a method of accurately ascertaining the true incidence and prevalence of these conditions. Moreover, given these crude estimates, it has also been challenging to determine the true male to female ratio of reported cases, a ratio that may shed light on the different modes of inheritance of this condition. Our referral population at Massachusetts General Hospital of 250 consecutive cases over 20 yr demonstrates a ratio of male to female subjects of 3.9:1. When familial cases are analyzed separately, the ratio drops to 2.3:1. Thus, understanding the incidence of GnRH deficiency remains a challenge; there may be differences in incidence in different populations.

	IV. Clinical Presentation of GnRH Deficiency

Top Abstract I. Introduction II. Ontogeny of Normal... III. Historical Perspective IV. Clinical Presentation of... V. Approaches to Studying... VI. Patterns of GnRH... VII. Patterns of GnRH... VIII. Genetic Studies IX. X-Linked Genes Controlling... X. Autosomal Genes Controlling... XI. Conclusion References

 
The clinical manifestation of isolated GnRH deficiency represents a failure of GnRH secretion at puberty and possibly during the neonatal period. Its phenotypic expression varies with its age of onset (congenital vs. acquired) and its severity (complete vs. partial).

A. Congenital GnRH deficiency
The diagnosis of isolated GnRH deficiency is occasionally made in the neonatal period when male infants are found to have cryptorchidism and microphallus in association with inappropriately low gonadotropin and sex steroid levels, given the normal activation of the hypothalamic-pituitary-gonadal axis that occurs in this window of development. In utero, the early fetal testosterone (T) production required for full sexual and external genital differentiation is thought to have been stimulated by maternal hCG alone. The resulting incomplete descent of the testes and growth of the external genitalia occasionally observed in GnRH-deficient subjects at this time implies failure of activation of the hypothalamic-pituitary axis during the late fetal and early neonatal periods. While cryptorchidism has been reported in up to 50% of patients with IHH or KS in some small series (16, 74, 75), our experience at the Massachusetts General Hospital suggests that this clinical presentation occurs in only a minority of cases. Similarly, in our patient population microphallus is rarely seen in association with GnRH deficiency; however, approximately 30% of cases of microphallus in the neonatal period may be attributed to hypogonadotropic hypogonadism (76).

Even when cryptorchidism and microphallus are not present, some studies have suggested that absence or anomalous morphology of the olfactory bulbs on magnetic resonance imaging permits a presumptive diagnosis of KS and is particularly useful for patients too young to undergo meaningful testing of olfaction or of the hypothalamic-pituitary-gonadal axis (77, 78). However, a more recent study demonstrated normal olfactory bulbs in 25% of male KS patients (79), suggesting either that this technique is not sufficiently sensitive to differentiate KS from IHH in all cases or that the phenotypic expression is wider than appreciated.

More typically, the diagnosis of GnRH deficiency is delayed until adolescence when there is failure of pubertal development and absence of appearance of secondary sex characteristics. Gynecomastia is rarely seen in untreated IHH or KS patients. However, the clinical setting in which it may occur is when patients are treated with either hCG or suboptimal doses of T, in which case peripheral aromatization of T may lead to a decrease in the T to estradiol ratio (75, 80, 81). Given that adrenarche is independent of pubarche and therefore occurs normally in patients with GnRH deficiency, it is theoretically possible that peripheral aromatization of adrenal androgens may also play a role in the origin of this gynecomastia.

Patients with isolated GnRH deficiency may be distinguished from adolescents with constitutional delay by virtue of their growth pattern, which indicates that they are of normal height for age (75), while the latter tend to be short for chronological age (82). In addition to the absence of sexual maturation, hypogonadism is also associated with marked decreases in both cortical and trabecular bone density compared with age-matched controls (83), which can be normalized by long-term sex steroid replacement therapy (84, 85).

B. Adult-onset GnRH deficiency
We recently described an acquired form of GnRH deficiency in men termed adult-onset IHH, which appears to be irreversible (86). In these patients, there is a history of an age-appropriate normal puberty followed by a postpubertal decrease in libido and fertility with near-normal testicular size. Their biochemical profile is indistinguishable from men with congenital GnRH deficiency in that they have an apulsatile pattern of LH secretion on frequent blood sampling, low serum T concentrations, and normal restoration of the pituitary-gonadal axis in response to a physiological regimen of exogenous GnRH replacement in the majority of cases (90%). The acquired nature of the defect is supported by the historical and physical evidence of normal spontaneous sexual maturation, documented fertility in several cases, and the results of serial neuroendocrine studies in one individual that clearly document the progression from normal to apulsatile LH secretion over a 4-yr period (Fig. 2). Unlike patients with functional GnRH deficiency, such as hypothalamic amenorrhea, we were unable to identify any factors typically known to impair GnRH secretion transiently in these men, e.g., stress, exercise, or weight loss. The neuroendocrine abnormality in adult-onset hypogonadotropic hypogonadism appears to be permanent based upon serial observation in these cases without any evidence of spontaneous waxing and waning of the hypothalamic-pituitary-gonadal axis, as is typically seen in women with hypothalamic amenorrhea.

View larger version (55K): [in this window] [in a new window]   Figure 2. Serial studies of GnRH-induced LH secretion in a man with adult-onset hypogonadotropic hypogonadism. The patient initially presented with oligospermia, but at the time of the second evaluation 4 yr later had symptoms of hypogonadism. The shaded areas represent the mean LH levels ± 2 SD in 29 normal men sampled at 10-min intervals. [Adapted with permission from L. B. Nachtigall et al.: N Engl J Med 336:410–415, 1997 (86 ). © 1997 Massachusetts Medical Society. All rights reserved.]

2. Delayed puberty. Patients with isolated GnRH deficiency often relate a history of partial progression through puberty followed by a permanent arrest of sexual maturation and an apulsatile pattern of GnRH activity (4, 86). However, what is less well appreciated is that frequently there is a history of delayed, but otherwise normal, puberty in the families of patients with IHH (11, 19). In the general population the incidence of delayed puberty is less than 1% (96). However, in our series of 106 patients with isolated GnRH deficiency, 12% had relatives with a history of delayed puberty in the absence of any other phenotypic features of IHH (11). A similar estimate was provided by Schwankhaus et al. (19) who reported that approximately one-third of their series of 41 men with IHH related a history of delayed puberty in at least 1 family member. Only half these cases were subsequently confirmed to have hypogonadotropic hypogonadism. Taken together, these data suggest that delay in initiating puberty, but subsequent normal progression of sexual development, may represent the mildest end of the phenotypic spectrum of GnRH deficiency.

D. Associated anomalies in KS
In addition to GnRH deficiency and anosmia, KS may be variably associated with a variety of anomalies, including midline facial defects such as cleft lip and/or palate, short metacarpals, and renal agenesis (11, 16, 20). Neurological manifestations of this disorder include sensorineural hearing loss (11, 12, 14, 16, 19, 81), mirror movements (synkinesia) (12, 18, 19, 97), oculomotor abnormalities (11, 19), and cerebellar ataxia (19, 98). To date, the occurrence of renal agenesis and synkinesia has been limited to the X-linked forms of KS (99). The relationship between these somatic abnormalities and expression of the KAL gene will be elaborated in Section IX.A.3.

E. Differential diagnosis
1. Functional GnRH deficiency. Classic isolated GnRH deficiency must be distinguished from functional forms of GnRH deficiency where the defect in GnRH secretion is clearly transient rather than permanent. This latter presentation is most commonly seen in women in the setting of hypothalamic amenorrhea (HA). In susceptible individuals, HA may be precipitated by factors such as significant weight loss, exercise, or stress (100, 101, 102, 103, 104). In this situation, the defect in GnRH secretion is reversible such that menstruation resumes when the underlying abnormality is corrected. While in females the presence or absence of menses serves as an obvious clinical marker of the functioning of the hypothalamic-pituitary-gonadal axis, there is no comparable clinical marker in the male. Moderate to severe dietary restriction in otherwise healthy males has also been shown to decrease T levels due to compromised GnRH secretion (105, 106). However, the existence of a syndrome of functional GnRH deficiency in men analogous to HA in females has yet to be definitively confirmed.

2. Structural lesions. Structural lesions of the hypothalamus can interfere with the normal pattern of GnRH synthesis, secretion, or stimulation of gonadotropes. These patients can be distinguished from those with IHH or KS by the presence of multiple pituitary hormone deficiencies and by the demonstration of a neuroanatomic lesion on magnetic resonance imaging of the hypothalamic-pituitary region (107).

	V. Approaches to Studying GnRH Secretion

Top Abstract I. Introduction II. Ontogeny of Normal... III. Historical Perspective IV. Clinical Presentation of... V. Approaches to Studying... VI. Patterns of GnRH... VII. Patterns of GnRH... VIII. Genetic Studies IX. X-Linked Genes Controlling... X. Autosomal Genes Controlling... XI. Conclusion References

 
Defining the physiology of GnRH in the human to understand the clinical heterogeneity of IHH has proven a clinical investigational challenge. One of the main obstacles to studying GnRH secretion is its relatively complete confinement within the hypophyseal-portal blood supply. As direct sampling of GnRH in the hypophyseal portal blood is not feasible in the human and measurements of GnRH in the peripheral circulation do not accurately reflect its secretion due to its rapid half-life of 2–4 min (108, 109, 110), studies of GnRH secretion have had to rely on inferential approaches.

A. Animal and in vitro studies
Using the ablation-replacement model, pioneering studies by Knobil and co-workers (111) in the 1970s were the first to demonstrate that pulsatile GnRH secretion is a prerequisite for the maintenance of physiological gonadotrope function. In rhesus monkeys rendered GnRH deficient by radiofrequency lesions in the hypothalamus, episodic stimulation of the gonadotrope by GnRH restores appropriate gonadotropin levels, whereas continuous stimulation results in a paradoxical desensitization of the gonadotrope response. Alternative approaches to studying GnRH secretion include the "push-pull" technique developed in sheep in which a direct readout of GnRH release can be obtained by inserting a perfusion cannula into the brain (112, 113, 114, 115). This technique confirmed the pulsatile mode of GnRH secretion and also validated the concept that each LH pulse represents a secondary secretory derivative of an antecedent GnRH pulse from the hypothalamus (112, 113).

An important recent advance has been the development of immortalized GnRH cell lines by genetically targeted tumorigenesis in transgenic mice (116, 117). These cell lines maintain many differentiated functions in vitro and thus provide an important experimental model for the study of neuroendocrine regulation. While all these models have made valuable contributions to the study of GnRH physiology, they suffer from inherent limitations when applied to the human in that the animal studies are limited by species specificity while the GnRH cell lines are additionally "developmentally frozen."

B. Human studies
The current armamentarium available to the clinical investigator interested in studying GnRH secretion in the human includes frequent sampling studies in both normal and disease models, use of pharmacological probes (e.g., a GnRH antagonist), and genetic studies, all of which provide complementary information. Traditionally, LH has been used as a surrogate marker of GnRH pulse generator activity in the human (62, 66, 118), based on its validation in several animal models as a faithful mirror of GnRH secretion (112, 113). More recently, the pulsatile component of glycoprotein-free -subunit (FAS) secretion has been shown to be closely correlated with that of LH (119) and to be driven by GnRH, based on its eradication by blockade of the GnRH receptor (120). Given its half-life of 12–15 min, FAS is particularly useful in tracking GnRH when it is being secreted at fast frequencies and at low amplitudes (121). In addition, much information has been gained from the study of disease models such as IHH, in which examining the baseline characteristics as well as the ability of exogenously administered GnRH to restore normal function allows one to determine the normal requirements for endogenous GnRH secretion. GnRH antagonists also act as useful physiological probes in that they can provide a semiquantitative estimate of endogenous GnRH secretion (122), analogous to the previous use of naloxone to quantitate endorphin tone (123). The principle employed is that at submaximal levels of GnRH receptor blockade induced by the administration of a pure GnRH antagonist, the amount of GnRH present will be inversely proportional to the degree of LH inhibition. This review will focus on the contribution made by both frequent sampling and genetic studies to our understanding of the pathophysiology of isolated GnRH deficiency in the human.

	VI. Patterns of GnRH Secretion in Men with GnRH Deficiency

Top Abstract I. Introduction II. Ontogeny of Normal... III. Historical Perspective IV. Clinical Presentation of... V. Approaches to Studying... VI. Patterns of GnRH... VII. Patterns of GnRH... VIII. Genetic Studies IX. X-Linked Genes Controlling... X. Autosomal Genes Controlling... XI. Conclusion References

 
In isolated GnRH deficiency, a variety of aberrant gonadotropin-secretory patterns have been observed, indicating a spectrum of defects in GnRH secretion in keeping with the diverse clinical presentation (1, 3, 4, 86) (Fig. 1).

In a well defined population of 50 men with isolated GnRH deficiency, we examined pulsatile gonadotropin secretion during frequent blood sampling at 10- to 20-min intervals for 12–24 h (3, 4). The largest subset (84%) of patients exhibited no detectable LH pulses (apulsatile pattern, Fig. 1B). In the majority, there was neither historical nor physical evidence of sexual maturation, an indication of the most severe form of GnRH deficiency. A second group demonstrated LH pulsations that were evident predominantly during sleep (developmental arrest pattern, Fig. 1C) similar to the pattern described by Boyar et al. both in early puberty (41) and in the fertile eunuch syndrome (1). When correlated with the clinical presentation, subjects with this sleep-entrained pattern of GnRH secretion exhibited some evidence of testicular growth and gave a history consistent with an arrest of pubertal development. Therefore, it appears that there is an abnormality in the program for maturation of the hypothalamic-pituitary axis in these subjects resulting from a "developmental arrest" in GnRH secretion. Repeat studies in these subjects using both a second gonadotropin assay system as well as a second period of frequent sampling confirmed the reproducibility of this pattern.

A third pattern of GnRH secretion was discernible in a family of four brothers with IHH, three of whom had frequent sampling studies. In these individuals, pulsatile GnRH secretion was evident, but individual LH pulses were noted to be of diminished amplitude compared with normal men, as well as their three unaffected siblings (decreased amplitude pattern, Fig. 1D). This pattern of a normal pulse frequency but decreased pulse amplitude is suggestive of either an enfeebled pattern of endogenous GnRH secretion or a state of GnRH resistance as can occur with a partial defect at the level of the GnRH receptor. Recently, there have been a number of reports of IHH due to mutations of the GnRH receptor gene (Refs. 124, 125, 126 ; see Section X). Finally, in a single patient, pulsatile LH activity appeared normal by RIA; however, LH bioactivity was absent when tested in the dispersed rat Leydig cell assay (127).

In an interesting subset of GnRH-deficient men, an apulsatile pattern of LH secretion was observed when measured by RIA, whereas distinct pulses were observed for FAS (128). Whether this finding implies a different threshold of sensitivity of the gonadotrope for stimulation of LH and FAS by GnRH, or whether this finding is merely a reflection of greater sensitivity of the FAS assay is unclear.

	VII. Patterns of GnRH Secretion in Women with GnRH Deficiency

Top Abstract I. Introduction II. Ontogeny of Normal... III. Historical Perspective IV. Clinical Presentation of... V. Approaches to Studying... VI. Patterns of GnRH... VII. Patterns of GnRH... VIII. Genetic Studies IX. X-Linked Genes Controlling... X. Autosomal Genes Controlling... XI. Conclusion References

 
Unlike men in whom secretion of GnRH is maintained at a relatively stable frequency of 2 h, the ovulatory menstrual cycle in the female involves the above mentioned dynamic sequence of changes in the hypothalamic-pituitary-ovarian axis (3, 63, 64, 65, 66, 67, 68, 118). Frequent sampling studies of women with hypothalamic hypogonadism demonstrate a spectrum of defects in pulsatile LH secretion analogous to those just described in the male (3, 118, 129, 130). In 52 studies performed in 40 women with hypogonadotropic amenorrhea, the early follicular phase of the menstrual cycle was chosen as the most appropriate reference point for comparison with normal women based upon its analogous sex steroid milieu (3). Nineteen of the women had primary amenorrhea secondary to either IHH (n = 12) or KS (n = 7). The remaining 21 women had experienced a secondary loss of menstrual function of at least 6 months duration and were classified as having hypothalamic amenorrhea. Frequent sampling of gonadotropins was performed at 10- to 20-min intervals for a period of 12–24 h.

As described for the male, the LH secretory pattern varied from an apulsatile pattern, to defects in pulse frequency and amplitude, to sleep augmentation of LH secretion (Fig. 3). In the group with primary amenorrhea, all but one subject had no endogenous LH pulsations (Fig. 3A); the single exception exhibited only one LH pulse during a 24-h study. However, in the subjects with HA, the most common abnormality was a decrease in LH pulse frequency, which occurs in approximately 40% of subjects (Fig. 3B). In almost a quarter of the HA patients studied, the LH secretory pattern was indistinguishable from that of the early follicular phase controls. Interestingly, several of the women in this category resumed spontaneous menstrual activity within a 2-yr period of follow-up, unlike women in any other category. Therefore, it would appear that these women were sampled during a period of almost complete recovery from more severely deranged patterns of GnRH secretory activity.

View larger version (18K): [in this window] [in a new window]   Figure 3. Patterns of GnRH secretion in women with amenorrhea associated with hypogonadotropic hypogonadism. Detected LH pulsations are indicated by asterisks. Black bars indicate periods of sleep. A, Apulsatile pattern with no endogenous LH pulsations. B, Disordered frequency pattern of LH secretion. C, Decreased amplitude pattern of LH secretion. D, Developmental arrest or sleep-entrained pattern of LH secretion with augmentation of pulsatile LH activity during sleep. [Reproduced with permission from J. E. Hall et al.: In: Nutrition & Reproduction. Louisiana State University Press, Baton Rouge, LA, in press (214 )].

Thus, an identical spectrum of abnormalities in GnRH secretion, which is likely to contribute to the clinical and biochemical heterogeneity of this disorder, occurs in both men and women with isolated GnRH deficiency. The variety of patterns observed, as well as the consistency of the abnormal pulse pattern within families, suggests that differing genetic determinants may govern the expression of GnRH secretion.

	VIII. Genetic Studies

Top Abstract I. Introduction II. Ontogeny of Normal... III. Historical Perspective IV. Clinical Presentation of... V. Approaches to Studying... VI. Patterns of GnRH... VII. Patterns of GnRH... VIII. Genetic Studies IX. X-Linked Genes Controlling... X. Autosomal Genes Controlling... XI. Conclusion References

 
GnRH deficiency may be inherited via autosomal dominant, autosomal recessive, and X-linked modes of inheritance, underscoring considerable genetic heterogeneity in this syndrome (11, 12, 14, 15, 16, 81, 131, 132, 133) (Figs. 4 and 5). Unique genetic mechanisms for both KS and IHH have been described (124, 126, 134, 135). However, some probands with KS have family members with congenital hypogonadotropic hypogonadism but normal olfaction (11, 12, 14, 81) (Fig. 4). This variable expressivity suggests that some individuals with isolated GnRH deficiency may line a single diagnostic spectrum of hypogonadism rather than represent discrete diagnostic subsets.

View larger version (19K): [in this window] [in a new window]   Figure 4. Autosomal recessive inheritance of GnRH deficiency in a family with evidence of consanguinity, multiple affected members of the same generation, and an equal sex distribution. Note the presence of GnRH deficiency both with and without anosmia in the same family. [Adapted with permission from J. Waldstreicher et al.: J Clin Endocrinol Metab 81:4388–4395, 1996 (11 ). © The Endocrine Society.]

View larger version (13K): [in this window] [in a new window]   Figure 5. Father-to-son transmission of KS, which is incompatible with X-linked inheritance. Autosomal dominant transmission is most likely. [Adapted with permission from J. Waldstreicher et al.: J Clin Endocrinol Metab81:4388–4395, 1996 (11 ). © The Endocrine Society.]

	IX. X-Linked Genes Controlling GnRH Secretion

Top Abstract I. Introduction II. Ontogeny of Normal... III. Historical Perspective IV. Clinical Presentation of... V. Approaches to Studying... VI. Patterns of GnRH... VII. Patterns of GnRH... VIII. Genetic Studies IX. X-Linked Genes Controlling... X. Autosomal Genes Controlling... XI. Conclusion References

Multiple lines of investigation have provided evidence confirming the causative role of KAL in KS. A cDNA probe covering the KAL gene was used to search for Xp22.3 deletions in 20 unrelated X-linked cases (138). Two deletions, including the entire KAL gene, were identified. Similar molecular analyses revealed a 3.3-kb intragenic deletion in another series of patients (139). These deletions upheld the role of KAL, but suggested that large deletions are uncommon in individuals with the X-linked form of the disease.

Final validation of the KAL gene was established with the discovery of point mutations in additional X-linked patients. A sequencing approach was used to identify such mutations in the 14 coding exons and splice junctions in 19 unrelated men with KS (140). Nine unique point mutations were identified, eight occurring within 4 exons and one at a splice site junction. The mutations consisted of five nonsense mutations, a single-base deletion, a single-base insertion, a missense mutation, and the mutation at the splice site (Fig. 6).

View larger version (15K): [in this window] [in a new window]   Figure 6. The locations of the reported KAL mutations are depicted relative to its domain structure by the arrows. The distribution of exons encoding different domains of the protein is indicated on top. The relative positions of the fibronectin type III repeats (R1–R4) are indicated. [Adapted with permission from N. A. Georgopoulos et al.: J Clin Endocrinol Metab 82:213–217, 1997 (195 ). © The Endocrine Society.]

2. KAL protein. The protein encoded by the KAL gene, termed anosmin, has 680 amino acids and shares homologies with molecules involved in neural development. The N terminus contains a domain with similarities to a consensus sequence of the whey acidic protein family and a 4-disulfide core motif (141, 142) found in protease inhibitors (143) and neurophysins (144). The C terminus contains four contiguous fibronectin type III repeats (145) found in neural cell adhesion molecules such as N-CAM, N-CAM L1, TAG1, and contactin (146, 147), receptor-linked protein kinases, and phosphatases (148). Although the protein has a leader peptide, the absence of a transmembrane domain or phosphoinositol linkage site suggests that KAL is an extracellular matrix protein.

Both the human and chick KAL cDNAs have been expressed in transfected Chinese hamster ovary (CHO) cells to characterize the KAL gene product. The protein is N-glycosylated and bound to the plasma membrane (149). Heparan-sulfate chains of heparan-sulfate proteoglycans are involved in the binding of the protein to the cell membrane (149). In addition to being localized on the cell surface, KAL is cleaved at a major proteolytic site and secreted in culture medium (150).

3. Histopathology and spatiotemporal pattern of expression. As a prerequisite to understanding the spatiotemporal expression of KAL, it is first necessary to understand the migratory pathways of GnRH-containing neurons. Studies in several species have demonstrated that GnRH neurons originate outside the central nervous system (CNS) from the olfactory placode (151, 152, 153). The placode is a discrete thickening of ectoderm that subsequently develops into an epithelium from which the GnRH and olfactory neurons differentiate. In the chick, GnRH neurons can first be detected within the olfactory placode on embryonic day (ED) 3.5 (152) and ED4 (153). By ED5, olfactory axons have exited the olfactory placode, and GnRH neurons can be detected after the extracranial course of the olfactory nerve to the developing forebrain (154). As embryogenesis continues through ED7–9, the majority of GnRH neurons can be detected in close apposition throughout the length of the olfactory nerve (154). Once in the CNS, the GnRH neurons disperse, reaching the olfactory bulb, nucleus accumbens, preoptic area, and medial septal area by ED10–12 (154).

In mammalian systems, additional nerves also derive from the olfactory epithelium, but the migration pathway of GnRH neurons is similar to the chick. Immunohistochemistry and in situ hybridization in mouse embryos have demonstrated that both GnRH and olfactory neurons originate in the olfactory placode (151). In addition, the terminalis and vomeronasal nerves also originate from the olfactory epithelium and migrate to the developing forebrain to reach their final destinations in the preoptic area and accessory olfactory bulbs, respectively (155, 156). GnRH neurons migrate along these "cranial" nerves to their final destinations in the hypothalamus and preoptic areas (151).

"Zoo blot" analysis using a human cDNA clone has revealed sequence homologies for KAL among many species, including monkey, cow, rabbit, sheep, and chicken (157). Homology between the human and chicken KAL genes is greater than 90% within the putative functional domains. Curiously, despite this evidence for evolutionary conservation of the gene, no mouse homolog has yet been identified, a feature apparently common to genes from the Xp22.3 region (158).

The time course of KAL expression in the chicken has yielded valuable insights into the migration defect of GnRH neurons in human KS and possibly into the associated somatic anomalies seen in this condition (i.e., renal agenesis). In situ hybridization studies in chick embryos have revealed a wide range of ectodermal, mesodermal, and endodermal derivatives that express KAL during two distinctly different periods of embryonic development. During ED3–6, KAL transcripts are found in developing limb buds, facial mesenchyme, and selected neuronal populations such as the oculomotor nucleus primordium, which contains neurons for innervation of the extrinsic eye muscles (156, 157). Expression of KAL within the brain varies temporally through development with an interesting discordance between KAL expression and GnRH neuronal migration. By ED5, only background levels of KAL mRNA are detected in the olfactory epithelium and mesenchymal tissue, although the GnRH neurons have already embarked upon their migration pathway along the olfactory nerve. KAL then appears to be up-regulated in the olfactory bulb by ED7–8 (156, 157) at a time when most GnRH neurons are penetrating the bulb region (152). By ED9–10, KAL expression can be found in the mitral cells, coinciding with the formation of synapses between the incoming olfactory nerves and the mitral cell layer (156). Notably, studies of isolated olfactory epithelium have shown preserved olfactory axon outgrowth, demonstrating that early migration of these nerves is an intrinsic property of the olfactory epithelium (159). Moreover, if the olfactory placode is ablated in the chick, KAL expression is still maintained in the olfactory bulb (160), suggesting that expression of this gene is independent of incoming innervation by the olfactory nerve.

In the human, by 45 days of embryogenesis (approximately equal to ED8 in the chick), KAL transcripts cannot be detected in the brain (161), but olfactory nerves have already begun their migration from the nasal epithelium. These observations again strongly suggest that KAL expression in the human is not necessary for early migration of nerves from the olfactory epithelium. However, by 11 weeks gestation, KAL expression can be found in the olfactory bulbs with greatest expression over the outer olfactory nerve layer (161). By 19 weeks of development, the highest levels of KAL are found in the granule cell and olfactory nerve layers (160), distinctly different from the chick olfactory bulb in which the mitral cells demonstrate the highest KAL expression.

In a 19-week human fetus with X-linked KS, the olfactory nerves were shown to have passed through the cribiform plate but arrested prematurely in a tangle of nerve fibers within the meninges (162). Use of anti-GnRH antibodies revealed that the GnRH neurons also had migrated from their origins in the olfactory placode and crossed the perforations in the cribiform plate but were similarly arrested on the dorsal surface of the plate below the forebrain, never reaching their normal location in the hypothalamus (162). Thus, although GnRH and olfactory neurons share a common migration route, a defect in neuronal interaction, rather than migration, appears to be the primary defect in KS. As KAL expression occurs both before and during the 19-week stage of development, the fetus study demonstrates that KAL expression is required neither for nerve outgrowth from the placode nor navigation toward the meninges. Collectively, therefore, it appears that KAL may play a role in the later events of neuronal migration including 1) the entrance of GnRH neurons into the olfactory bulb (157) and/or 2) the establishment of contact between the incoming olfactory axons and the central neurons of the bulb (156, 161). In the absence of KAL and, by extension, the absence of normal synaptic connections, it has been hypothesized that the olfactory nerve might undergo retrograde degeneration (156), with the GnRH migration defect secondary to this defective scaffold.

In situ hybridization data in other nonolfactory tissues suggest that KAL may have a more generalized role in development. In the chick, strong expression of KAL occurs in the striatum by ED8, in the Purkinje cells of the cerebellum by ED9–10, and in the optic tectum by the last days of incubation (156). Expression of KAL in these structures appears to persist into adult life (156, 157). Outside the CNS, expression of KAL has also been detected in mesenchymal derivatives, including facial mesenchyme, fibrous and perichondral cells, small blood vessel walls, glomeruli of mesonephros and metanephros, and developing limb buds (156, 157). In the human, abnormal KAL expression in the cerebellum may be related to symptoms such as nystagmus and ataxia seen in some patients with KS (19). Likewise, correlations may also exist between expression in the facial mesenchyme and cleft palate, and expression in the mesonephros/metanephros and renal agenesis. Because not all KS patients display the same constellation of symptoms, these correlations are crude and suggest that different mechanisms may be at play between the chick and human KAL expression or that alternative mechanisms affect phenotypic expression (157). Moreover, since the frequency of these anomalies has been best described in X-linked cases (140), it is not clear whether the frequency and/or phenotypic expression of these associated findings in autosomally transmitted forms is comparable.

An immunofluorescent double immunostaining technique with antisera raised against human GnRH and the ubiquitin-processing enzyme Protein Gene Product-9.5 (PGP-9.5) has been used to evaluate GnRH immunoreactivity in the nasal epithelia of patients with both KS and IHH (163). Colocalization of GnRH+ and PGP+ immunoreactivity has indicated the presence of GnRH-synthesizing cells in the upper nasal epithelia in two adult KS males, one KS female, one IHH male, and one control eugonadal male. This finding of GnRH-synthesizing cells in the nasal mucosa in human adult life in affected patients raises a number of possibilities regarding the distribution of this cell population: the GnRH neurons may represent remnant cells that simply failed to migrate normally during embryogenesis or they may have been generated postnatally de novo. In either case, the presence of cells with GnRH-synthesizing capability in the nasal mucosa of an IHH normosmic subject demonstrates that a GnRH synthetic defect is not responsible for this subtype of GnRH deficiency.

Because the histopathology of KAL suggests involvement in early morphogenetic events as well as neuronal differentiation, its transcriptional control may also involve both developmental and cell-specific mechanisms. Characterization of the human KAL promoter (1.9-kb fragment upstream from the first exon) has revealed two sites of gene transcription initiation in a quail embryonic neuroretina QNR/D cell line (164). Although neural cell adhesion molecule is controlled by homeobox transcription factors, no homology between the KAL promoter and any homeodomain binding site has yet been found. The KAL promoter does contain a typical CCAAT box that binds nuclear factor Y, two GC boxes that bind SP1 transcription factor, and two AP2-binding sites, but no TATA box (164). A deletion mutant containing nucleotides +2 to -437 demonstrated weak but tissue-specific transcriptional activity in quail neuroretina cell lines. No activity was detected using longer segments, suggesting that upstream sequences in the KAL promoter may contain negative regulatory elements.

4. Clinical paradoxes. By using increasingly sophisticated tools to phenotype patients, investigators have expanded the list of occasional symptoms and signs found in GnRH-deficient patients in addition to hypogonadotropic hypogonadism and anosmia. Within this ever-expanding roster, unilateral renal agenesis appears to have the most important clinical implications for patients and may be quite prevalent in X-linked individuals. Six of 11 men with an identified mutation in the KAL gene were found to have unsuspected unilateral renal aplasia (140), a finding of sufficient frequency and importance to warrant screening with renal ultrasound in all such cases. Thus, although the KAL gene defect is the best characterized of the familial genes for GnRH deficiency to date, numerous questions regarding its biology remain unanswered. Despite the wide range of KAL expression during early mesenchymal development in the chicken (arterial walls, limb buds, etc.), there is not a parallel range of clinical signs in most human patients. Although the role of the KAL gene in axonal migration may explain some of the neurological defects in X-linked KS (e.g., synkinesia), the role of KAL in renal development remains unknown.

Numerous clinical reports have demonstrated a puzzling lack of genotype/phenotype correlation in KS. For example, despite having an identical deletion spanning the STS and KAL genes, two brothers were reported as demonstrating a marked discordance in phenotype (165). One brother had hypogonadotropic hypogonadism and severe hyposmia while the other had normal pubertal development and only a mild olfactory defect. In another set of two brothers bearing the same point mutation within KAL (G₉₂₄ to A base substitution creating a premature stop codon), different phenotypes were again observed (79). One had KS with bilateral synkinesia, left renal agenesis, and cryptorchidism while his brother also had KS but none of the associated findings. These observations suggest that 1) other proteins with redundant function to those of KAL can possibly compensate when the KAL gene is defective and/or that 2) other epigenetic phenomena may be involved in the phenotypic manifestations of KS. Compensatory mechanisms may also exist in IHH as identical twins discordant only for GnRH deficiency have been identified (Fig. 7).

View larger version (19K): [in this window] [in a new window]   Figure 7. Example of identical twins discordant for IHH. The fertile twin took diethylstilbestrol during her pregnancies and bore two affected children. The pedigree is compatible with autosomal dominant transmission with incomplete penetrance. [Adapted with permission from J. Waldstreicher et al.: J Clin Endocrinol Metab 81:4388–4395, 1996 (11 ). © The Endocrine Society.]

As with KAL, molecular studies of patients with contiguous gene syndromes including AHC, Duchenne muscular dystrophy, and glycerol kinase deficiency led to the localization and isolation of the gene responsible for AHC at Xp21, referred to as DAX-1 [dosage-sensitive sex-reversal (DSS) AHC critical region on human X chromosome, gene 1] (171). DAX-1 is located within the DSS locus, which, when duplicated in 46XY males, causes development into phenotypic females (172). In AHC, missense mutations in DAX-1 have been identified in the C-terminal presumptive ligand-binding domain, whereas frameshift or nonsense mutations have been described in the N-terminal domain, suggesting that the C-terminal half of the protein may be more important for protein function (172, 173, 174, 175, 176, 177, 178, 179) (Fig. 8). De novo deletions of the DAX gene have also been reported in patients, suggesting that molecular analysis of the DAX-1 gene may be helpful in the genetic counseling of families (179, 180). Similar to KAL, the regulation of DAX expression appears to be complex. Not every suspected case of X-linked AHC has yielded DAX-1 mutations, suggesting considerable genetic heterogeneity or differential expression of the gene (173). In an X-linked pedigree of AHC and GnRH deficiency with a proven DAX mutation, an affected 3-month-old demonstrated normal T and LH levels, consistent with an intact hypothalamic-pituitary axis (178). Therefore, the growing body of literature on DAX-1 suggests that a wide range of phenotypes may be associated with the same DAX mutation.

View larger version (30K): [in this window] [in a new window]   Figure 8. The locations of representative examples of DAX-1 mutations are depicted relative to its domain structure. The nuclear receptor-like domain is blackened, and the amino-terminal repeats are depicted by arrows. The junction of exons 1 and 2 is denoted by an arrowhead. Frameshift and nonsense mutations leading to premature truncation of the protein are shown in the upper two panels. Missense mutations and the single codon deletion (dV269) are shown in the bottom panel. The black bars below the figure indicate protein domains that are involved in transcriptional silencing. Nucleotides are numbered such that the A of the ATG initiation codon is +1, as per the recommendation of the Nomenclature Working Group. [Reprinted from R. N. Yu et al.: The role of DAX-1 in reproduction. In: Trends in Endocrinology and Metabolism, vol 9 (5 ):169–175, 1998 with permission from Elsevier Science (215 ).]

View larger version (65K): [in this window] [in a new window]   Figure 9. Baseline secretory patterns of LH and free -subunit in two patients with DAX mutations. Gonadotropin secretion was determined by 10-min blood sampling. Shaded areasrepresent the mean ± 2 SD for each hormone determined in 20 normal adult males studied using the same protocol (62 119 ). Mean FSH and T levels determined from pools of samples are indicated. Pulses were detected by a modified version of the Santen and Bardin (54 ) procedure and are denoted by arrowheads. Panel A shows the secretory patterns for the patient with a thr418asp mutation. Panel B shows the secretory patterns for the patient with a gly329glu mutation. [Adapted with permission from R. L. Habibyet al.: J Clin Invest 98:1055–1062, 1996 (177 ) by copyright permission of The American Society for Clinical Investigation.]

As observed with other members of the nuclear hormone receptor superfamily, the C terminus of the DAX gene contains transcriptional silencing activity (192). DAX-1 has been shown to bind to DNA hairpin secondary structures and to block steroidogenesis in adrenal cells via transcriptional repression of the steroidogenic acute regulatory protein (StaR) promoter (193). DAX-1 is also able to repress the transcriptional activity of SF-1 (194). Since the missense mutations described for DAX-1 in AHC appear to be clustered in its C terminus (ligand-binding domain), it is possible that such mutations impair the potent transcriptional silencing properties of this protein. Taken together, DAX-1 appears to be a transcriptional repressor whose loss of function may be associated with a spectrum of adrenal, hypothalamic, and pituitary abnormalities.

	X. Autosomal Genes Controlling GnRH Secretion

Top Abstract I. Introduction II. Ontogeny of Normal... III. Historical Perspective IV. Clinical Presentation of... V. Approaches to Studying... VI. Patterns of GnRH... VII. Patterns of GnRH... VIII. Genetic Studies IX. X-Linked Genes Controlling... X. Autosomal Genes Controlling... XI. Conclusion References

 
A. The genetics of autosomal inheritance
Despite the biology revealed by the X-linked genes, considerable evidence has accumulated to suggest that not only are there autosomal genes responsible for GnRH deficiency, but that these genes may well account for the majority of familial cases (11) (Fig. 10). One hundred six patients with GnRH deficiency studied at Massachusetts General Hospital were reviewed. Genetic criteria were used to estimate the likely mode of transmission in probands with a positive family history of GnRH deficiency (n = 36). The proportion of those familial cases that could be attributable to X linkage was only 21%. When the analysis was extended to include a surrogate marker of KS (isolated congenital anosmia), the frequencies of X linkage and autosomal recessive transmission dropped to 18% and 32%, respectively, while the proportion of dominant cases increased to 50%. When the phenotypic analysis was extended further to include delayed puberty, the X-linked pedigrees decreased further to 11%, autosomal recessive decreased to 25% and autosomal dominance rose to 64%.

View larger version (27K): [in this window] [in a new window]   Figure 10. Evaluation of Massachusetts General Hospital series of 106 cases of GnRH deficiency seen in a referral population. Upon careful review, 34% indicated a positive family history. Within that subgroup, only 11% of the pedigrees were consistent with an X-linked mode of inheritance. Of the 66% of patients who were sporadic, less than 5% demonstrated a mutation in the coding sequence of the KAL gene (195 ). Taken together, these parallel analyses point to the fact that the majority of cases appear to be due to autosomal mutations in as yet to be described genes.

Although the identities of the autosomal genes for GnRH deficiency remain a mystery in the vast majority of cases, new evidence for their existence is emerging in syndromes of gonadotropin deficiency. For example, mutations in leptin and the leptin receptor have recently been described in familial cases of morbid obesity and hypogonadotropic hypogonadism (125, 196). Such cases reinforce the important role of neuroendocrine modulators of GnRH secretion in human reproductive function. Within the hypothalamic-pituitary axis, however, anticipated defects in the GnRH gene in patients with GnRH deficiency have not been observed.

B. GnRH gene
Despite the complexities of multiple modes of autosomal inheritance, the most obvious autosomal candidate gene for GnRH deficiency is the GnRH gene itself, located at 8p21–8p11.2. The hypogonadal (hpg) mouse is an animal model in which hypogonadotropic hypogonadism is linked to an autosomal recessive mutation at the GnRH gene (197). Comparisons of the gene between normal and mutant mice revealed a deletional mutation of 33.5 kb consisting of two exons encoding most of the GAP (GnRH-associated peptide) peptide. Although this partially deleted gene appeared to be transcriptionally active, immunocytochemistry failed to detect any hypothalamic GnRH. Gene therapy completely reversed the hypogonadal phenotype in hpg mice and restored GnRH expression (198). Interestingly, in humans, no deletions, arrangements, or point mutations in the GnRH gene have yet been described (199, 200, 201, 202). Yet, while no documentation of a mutation has occurred, there are descriptions of patients with hypogonadotropic hypogonadism and other associated anomalies who have been found to have deletions on the short arm of chromosome 8, consistent with a contiguous gene syndrome (203, 204).

C. GnRH receptor gene
Although the GnRH receptor might be considered the next "candidate" gene for hypogonadotropic hypogonadism, the nearly universal response of patients to pulsatile GnRH initially made this notion seem a remote possibility. The GnRH receptor is a G protein-coupled receptor with seven transmembrane segments and an extracellular amino terminus but no intracellular carboxy terminus (205, 206) (Fig. 11). The receptor activates phospholipase C and mobilizes intracellular calcium via G proteins (207). Two different compound heterozygote mutations of the GnRH receptor have recently been described in families with hypogonadotropic hypogonadism. In the first, a 22-yr-old male presented with normal puberty and normal olfaction but testes of only 8 ml and an abnormal semen analysis (124). Frequent blood sampling studies revealed a normal LH pulse frequency but low-amplitude pulsations. The proband’s sister had primary amenorrhea and infertility. Direct DNA sequencing of the GnRH receptor revealed a gln106arg mutation in the first extracellular loop, decreasing the binding of GnRH to its receptor. An arg262 gln mutation in the third intracellular loop impaired signal transduction by decreasing the activation of phospholipase C (Fig. 11). Both mutations occurred in amino acids that are conserved in a variety of species (207). Interestingly, the parents who were heterozygous for these defects had no phenotypic expression.

View larger version (21K): [in this window] [in a new window]   Figure 11. Structure of the GnRH receptor with compound heterozygote mutations. Solid symbols indicate the mutated amino acids arginine (R) and glutamine (Q). [Reprinted from N. de Roux et al.: N Engl J Med337:1597–1602, 1997 (124 ). © 1997 Massachusetts Medical Society. All rights reserved.]

Denaturing gradient gel electrophoresis has been used to screen 32 males and 14 females with IHH (126). In a sibship with 3 affected females and 1 affected male, DNA sequencing again revealed two compound heterozygote mutations, the same arg262 gln mutation described earlier, and a tyr284cys mutation in the sixth transmembrane domain, also impairing signal transduction (126). The discovery of this compound heterozygote GnRH receptor mutation occurred in 1 of 14 families studied with an affected female; further studies will need to be done to determine the overall prevalence of GnRH receptor mutations in humans.

D. Other autosomal genes
Numerous chromosomal rearrangements in patients with hypogonadotropic hypogonadism have suggested other autosomal loci that may be implicated in GnRH deficiency. In patients with KS, these include a balanced translocation (7q22;12q24) (209); a balanced translocation involving chromosomes 1 and 10 (210); a balanced complex chromosome rearrangement (3q13.2; 9q21.2,p13; 12q15) (211); a metacentric chromosome (212); and a balanced translocation (13 q14.11;16 q24) in a man with IHH (213). The finding of such translocations may give a clue to autosomal loci for KS or may simply be coincidentally associated with the disorder in these patients. In our own patient cohort, we found a centromeric inversion of chromosome 10 in one of our female IHH probands. However, the same inversion was shared by her phenotypically normal mother. Thus, the autosomal genes responsible for what appears to be the majority of familial cases (Fig. 11) remain elusive.

	XI. Conclusion

Top Abstract I. Introduction II. Ontogeny of Normal... III. Historical Perspective IV. Clinical Presentation of... V. Approaches to Studying... VI. Patterns of GnRH... VII. Patterns of GnRH... VIII. Genetic Studies IX. X-Linked Genes Controlling... X. Autosomal Genes Controlling... XI. Conclusion References

 
In summary, isolated GnRH deficiency presenting as hypogonadotropic hypogonadism ± anosmia encompasses a broad spectrum of phenotypes in both men and women. Isolation of the gene responsible for X-linked KS has led to a pathogenic model that explains the developmental association of GnRH deficiency and anosmia. The migration defect of GnRH neurons appears to be a secondary effect caused by the lack of communication between the olfactory nerves and the forebrain. Moreover, KAL appears to have a generalized role in development, affecting both neuronal and nonneuronal populations. Many questions remain regarding the fascinating neurobiological model presented by this syndrome. What are the autosomal dominant and recessive genes responsible for GnRH deficiency and are they homologous to KAL? Do the gene defects that cause KS also cause isolated hypogonadotropic hypogonadism without anosmia? Much work remains to be done to completely characterize this intriguing syndrome.

	Footnotes

 
Address reprint requests to: Stephanie Seminara, M.D., Reproductive Endocrine Unit, BHX-5, Massachusetts General Hospital, Fruit Street, Boston, MA 02114 USA.

¹ These authors contributed equally to this work and should both be considered first authors.

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Top Abstract I. Introduction II. Ontogeny of Normal... III. Historical Perspective IV. Clinical Presentation of... V. Approaches to Studying... VI. Patterns of GnRH... VII. Patterns of GnRH... VIII. Genetic Studies IX. X-Linked Genes Controlling... X. Autosomal Genes Controlling... XI. Conclusion References

 

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