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Original Articles: Hormones and Reproductive Health |
Reproductive Endocrine Unit of the Department of Medicine and National Center for Infertility Research, Massachusetts General Hospital, Boston, Massachusetts 02114
Address all correspondence and requests for reprints to: Nelly Pitteloud, M.D., Reproductive Endocrine Unit and National Center for Infertility Research, Bartlett Hall Extension 5, Massachusetts General Hospital, Boston, Massachusetts 02114. E-mail: npitteloud{at}partners.org
Abstract
Mutations in the GnRH receptor (GnRH-R) gene have been reported to cause idiopathic hypogonadotropic hypogonadism (IHH). Herein, we describe a 26-yr-old male with a mild phenotypic form of IHH, the fertile eunuch syndrome (IHH in the presence of normal testicular size and some degree of spermatogenesis), associated with a homozygous mutation (Gln106Arg) in the GnRH-R. This mutation, located in the first extracellular loop of the GnRH-R, has been previously shown to decrease but not eliminate GnRH binding. The proband had hypogonadal testosterone levels, detectable but apulsatile gonadotropin secretion, and a normal adult male testicular size of 17 mL at baseline. After only 4 months of treatment with hCG alone, he developed sperm in his ejaculate and his wife conceived. Following cessation of hCG therapy, the patient demonstrated reversal of his hypogonadotropism as evidenced by normal adult male testosterone levels and the appearance of pulsatile luteinizing hormone secretion.
This case thus expands the emerging clinical spectrum of GnRH-R mutations, provides the first genetic basis for the fertile eunuch variant of IHH and documents the occurrence of reversible IHH in a patient with a GnRH-R mutation.
IDIOPATHIC HYPOGONADOTROPIC HYPOGONADISM (IHH) is a clinical disorder defined as the selective failure of the neuroendocrine components of the reproductive system in the absence of an anatomic or functional cause. The classical clinical and biochemical features of IHH include the absence of pubertal development by age 18 yr in males, prepubertal sex steroids, and low or inappropriately normal gonadotropin levels. In males, the presence of microphallus and/or cryptorchidism in IHH subjects attests to an in utero deficiency of androgens. However, there is a wide clinical spectrum in both the time of onset and the completeness of this syndrome (1). At the mildest end lie the rare IHH patients with the so-called fertile eunuch syndrome who present with decreased virilization, eunuchoidal proportions, and hypogonadal testosterone levels despite normal testicular size and preserved spermatogenesis.
Considerable genetic heterogeneity also underlies IHH, which may be sporadic or familial in occurrence, with the latter inherited in either X-linked or autosomal modes (2). To date, the genetic basis of IHH has been established in fewer than 20% of cases. Mutations in the KAL-1 gene (Xp22.3) cause an X-linked form of Kallmann syndrome (KS) in which IHH is accompanied by anosmia (3, 4). In addition, cases of X-linked adrenal hypoplasia congenita accompanied by IHH stem from defects in the DAX-1 gene (Xp21), which encodes a nuclear hormone receptor with a novel DNA-binding domain (5). The adrenal hypoplasia congenita phenotype is also marked by clinical heterogeneity. At one end of the spectrum lie patients with IHH and normal adrenal function (6) while others have the complete syndrome of adrenal insufficiency in childhood and subsequent hypogonadotropism at puberty (7).
As defects in the GnRH receptor (GnRH-R) have recently emerged as the first autosomal cause of IHH (8, 9, 10, 11, 12, 13), a similarly broad phenotypic spectrum has begun to unfold in these patients. For example, although patients with a GnRH-R mutation might a priori be anticipated to manifest complete hypogonadism and unresponsiveness to GnRH stimulation, milder variants of GnRH-R mutations exist in which GnRH responsiveness is partially maintained. Functional analyses of these GnRH-R mutants have revealed defects with varying degrees of decreased GnRH binding and/or activation of the mutant receptor (8, 9, 10, 11, 12). Similarly, the phenotype of these patients varies from partial (8, 12) to complete (10, 11) forms of IHH. Based on these clinical and in vitro data, we hypothesized that patients with the fertile eunuch syndrome might harbor partially inactivating defects in the GnRH-R.
In this report, we describe molecular, genetic, and physiological studies in such a fertile eunuch variant of IHH displaying a novel homozygous mutation (Gln106Arg) in the first extracellular loop of the GnRH-R. This unique case extends the emerging clinical spectrum of GnRH-R mutations and provides a novel genetic basis for one of the variants occupying the mild end of the IHH spectrum. It also documents the occurrence of an apparent spontaneous reversal of this disorder following therapy with hCG alone.
Case Report
The proband (Subject II-1 in Fig. 1
), a 26-yr-old Caucasian male from
Brazil, presented at age 18 yr with incomplete puberty manifested by
decreased virilization, a high pitched voice, eunuchoidal body
proportions but normal testicular size. He reported normal libido and
erections but was unable to ejaculate and to complete intercourse. He
had a normal sense of smell and no history of cryptorchidism and denied
use of anabolic steroids or nutritional supplements. He had a normal
diet and no history of excessive exercise. His testosterone level was
reported to be extremely low at that time, and he was prescribed
testosterone replacement. Because of financial difficulties, therapy
was not instituted, and he was subsequently lost to follow-up for 8 yr
during which he reported continued linear growth.
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Hormonal evaluation demonstrated a testosterone level of 3.1 nmol/L (reference range 10–35), an estradiol of less than 73 pmol/L (normal <180), a luteinizing hormone (LH) of 3.5 IU/L (3.3 to 25), an FSH of 2.4 IU/L (1.6 to 16.8), and a normal inhibin B level of 352 pg/mL (150 to 400). Baseline and stimulated thyroid, adrenal, and GH axes were normal as assessed by TRH and insulin tolerance tests, as were his serum PRL and ferritin concentrations. Semen analysis could not be performed because the proband was unable to produce an ejaculate. Magnetic resonance imaging of the hypothalamic-pituitary region demonstrated no anatomic abnormality.
A clinical diagnosis of the fertile eunuch syndrome was made and because the patient’s major concern was fertility, human chorionic gonadotropin (hCG) therapy (1000 IU sc every other day) was initiated. Testosterone levels increased promptly to 13 nmol/L, reaching a plateau after 2 months of therapy at which time he had a sperm count of 89 million/mL. Inhibin B levels were unchanged. After 4 months of hCG therapy, his wife conceived and subsequently delivered a healthy boy.
The patient’s 49-yr-old mother (Subject I-2) had a normal puberty and regular menstrual cycles; she is not yet menopausal. The 52-yr-old father (Subject I-1) and his 24-yr-old and 26-yr-old brothers (Subjects II-2 and II-3, respectively) are normally virilized. There was no family history of delayed puberty or infertility. There was no indication of parental consanguinity.
Materials and Methods
Preparation of genomic DNA and DNA sequencing
After obtaining written informed consent, whole blood samples were donated by all members of the proband’s nuclear family, and DNA was extracted. Exons of the GnRH-R were amplified by PCR using sets of primers reported previously (8). Amplified products were sequenced using the AmpliTaq dye terminator cycle sequencing kit and an ABI PRISM 377 DNA sequencer (Perkin-Elmer Corp., Foster City, CA).
In vivo studies
Written informed consent was obtained from the subject before commencing physiologic studies. Assessment of baseline gonadotropin secretion was performed as part of the phenotypic evaluation before starting therapy. After a mutation in the GnRH-R was identified in the proband, further studies were performed to characterize the phenotype more completely by assessing the responsiveness of the mutant receptor to stimulation by exogenous GnRH.
1) Characterization of baseline gonadotropin secretion
Before any therapy, blood samples were drawn every 10 min for
12 h overnight; each sample was assayed for LH and free
-subunit (FAS). Pulsatile hormone secretion was analyzed using a
modification of the Santen and Bardin method (14). FSH and
testosterone were measured in serum pools comprising equal aliquots of
each individual sample.
2) Gonadotropin response to exogenous GnRH administration
To assess the in vivo responsiveness of the mutant GnRH-R, a standard GnRH test was performed followed by administration of a physiologic regimen of pulsatile GnRH for 7 days, which our group has shown to be a more sensitive method of evaluating the response of IHH patients to GnRH (7).
a) A standard GnRH test was performed 2 weeks after discontinuing hCG therapy. Blood samples were drawn at times 0, +30, +60 min after a bolus injection of GnRH, 100 µg iv.
b) A 7-day GnRH responsiveness study was performed 10 days after the GnRH test. The patient initiated pulsatile GnRH therapy administered sc by a mini-infusion pump (Zyklomat, Ferring Pharmaceuticals Ltd., Kiel, Germany) at a dose of 25 ng/kg every 2 h for 7 days (15). Each day, a 2-h window of gonadotropin responsiveness to a single dose of iv GnRH (25 ng/kg) was monitored with measurement of LH, FSH, and FAS levels at 15 min-intervals post bolus dose. Testosterone was measured at time 0 each day. The response of the proband was compared with that of a cohort of 10 patients with KS and one normal adult male.
3) Repeat characterization of gonadotropin secretion after hCG therapy
a) Six weeks after discontinuing hCG. As testosterone levels were noted to be increased, compared with baseline following discontinuation of hCG, the patient consented to a repeat neuroendocrine assessment (blood sampling every 10 min for 12 h) to assess any change in his endogenous GnRH-induced LH secretion pattern 6 weeks after hCG had been discontinued.
b) Six months after discontinuing hCG. Although he had normal libido, potency, and energy levels, the patient consented to another neuroendocrine assessment 6 months after discontinuing hCG. On this occasion, blood was sampled every 20 min for 2 h for measurement of LH, FSH, and testosterone and a repeat semen analysis was obtained.
Hormone assays
Serum LH and FSH concentrations were determined by microparticle
enzyme immunoassay using the automated Abbott AxSYM system
(Abbott Laboratories, Chicago, IL). The Second
International Reference Preparation was used as the reference standard.
The assay sensitivity for both LH and FSH was 1.6 IU/L. The intraassay
coefficient of variation (CV) values for LH and FSH were less than 7%
and less than 6%, respectively, with interassay CVs for both hormones
of less than 7.4%. Serum FAS concentrations were determined by a
monoclonal antibody RIA using highly purified -subunit of hCG as the
assay calibrator (16). Serum testosterone concentrations
were measured using the DPC Coat-A-Count RIA kit (Diagnostic Products, Los Angeles, CA), which had an intra- and interassay
CV of less than 10%. Inhibin B was measured using a commercially
available (Serotec, Oxford, UK) double-antibody
enzyme-linked immunosorbent assay as previously described
(17). In our use, the clinical detection limit of this
assay is 50 pg/mL, with a CV of 4–6% within plate and 15–18%
between plates.
Results
Characterization of the GnRH-R
Direct sequencing of the PCR products amplified from the DNA of
the proband revealed a single homozygous mutation in the GnRH-R gene
(Fig. 1
). A substitution of guanine for adenine at nucleotide 317
converts glutamine to arginine at codon 106 (Gln106Arg) in the first
extracellular loop of the GnRH-R. The proband’s mother, father, and
brothers were all confirmed to be heterozygotes for this mutation.
Restriction enzyme Xcm I analysis confirmed the homozygosity of the
mutation in the proband (-/-).
In vivo studies
1) Characterization of baseline gonadotropin secretion. Mean
LH, FSH, and FAS levels from pooled samples were within the normal
range (Table 1). However, only a single
LH pulse was detected and the FAS secretory pattern was apulsatile,
even though all individual samples were well within the working range
of the gonadotropin assays (Fig. 2). The
pooled testosterone level was in the hypogonadal range at 3.1 nmol/L,
and inhibin B was normal (18) (Table 1).
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a) Standard GnRH test (100 µg). Despite the fact that hCG had been discontinued 2 weeks previously, a blood sample drawn before injection of GnRH demonstrated a testosterone level that was elevated, compared with baseline (7.6 vs. 3.1 nmol/L). In response to a single pharmacologic dose of GnRH, gonadotropins increased differentially with a greater change in LH (from 6.2 to 14.5 IU/L) than FSH (3.4 to 4.6 IU/L).
b) Seven days of physiologic GnRH (25 ng/kg/bolus every 2
h). Administration of low-dose pulsatile GnRH resulted in
differential gonadotropin secretion (Fig. 3). Each GnRH dose triggered an LH pulse
with a mean amplitude of 3.8 IU/L, confirming that the mutant receptor
was capable of signaling adequately to the LH-ß subunit gene in
vivo. The LH response was consistent over the 7 days of GnRH
administration. The FAS response to a GnRH bolus was barely detectable,
suggesting that the mutant receptor interferes predominantly with FAS
secretion. Unlike LH, the FSH response during the 7-day protocol was
completely flat. This blunted FSH response could be secondary to the
robust inhibin B level given that the latter is known to be an
important negative regulator of FSH in the adult male (19)
and/or reflect the inability of the mutant receptor to signal
adequately to the FSH-ß subunit gene. In response to GnRH-induced LH
pulses, testosterone levels ranged from 11 to 15 nmol/L during the
7-day period of study.
Qualitatively, the proband’s responses resembled those of a normal
adult male except for the dissociation of FAS responsiveness from that
of LH (Fig. 3) (20, 21). In contrast to the proband,
patients with KS who lack endogenous GnRH and have low levels of
gonadotropins and inhibin B at baseline exhibit a progressive increase
in LH, FSH, and FAS during the same protocol because of priming of the
pituitary with ongoing exposure to GnRH (Fig. 3) (7).
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a) Six weeks after discontinuing hCG. Repeat evaluation of
endogenous gonadotropin secretion 6 weeks after discontinuing hCG
therapy demonstrated an increase in mean LH, FSH, and FAS levels (Table 1). Pulsatile LH secretion was now normal with a frequency of 5
pulses/12 h and a mean LH amplitude of 2 IU/L (Fig. 2)
(22). Similar to the 7-day study of GnRH responsiveness,
the close concordance between LH and FAS secretion seen in physiologic
conditions (20, 21) was not observed in that only one
discrete FAS pulse was evident in 12 h. The pooled testosterone
level had now increased to the lower end of the normal range, and
inhibin B levels were stable (Table 1). The patient’s sperm count was
91.4 million/mL.
b) Six months after discontinuing hCG. Mean hormone levels were 6.1 IU/L for LH, 3.9 IU/L for FSH, and 7 nmol/L for testosterone. Semen analysis revealed a sperm count of 42 million/mL.
Discussion
In this report, we describe an adult male with the fertile eunuch syndrome because of a partially inactivating, homozygous mutation (Gln106Arg) in the first extracellular loop of the GnRH-R. This case expands the clinical spectrum of GnRH-R mutations and is unique in documenting reversible IHH in an affected patient.
Since 1997, rare missense mutations of the GnRH-R gene distributed along the coding sequence have been reported in hypogonadotropic patients (8, 9, 10, 11, 12). De Roux et al. (8) described the first kindred with a compound heterozygous mutation in the GnRH-R including the same locus involved in the current report. Their functional analyses demonstrated that the Gln106Arg mutation in the first extracellular loop markedly reduced GnRH binding. The second Arg262Gln mutation in the third intracellular loop did not affect GnRH binding but decreased inositol triphosphate production. The affected male had some testicular growth (8-mL testes), detectable gonadotropins, and a normal response to a single pharmacologic dose of GnRH.
Following this initial report, several additional GnRH-R mutations have been described including mutations in the transmembrane domains, which significantly impair GnRH binding and/or signaling (9, 10, 11, 12, 13). These variable genotypes result in a similar phenotypic spectrum ranging from partial IHH (8, 12) to the most complete form of GnRH deficiency characterized by cryptorchidism, microphallus, undetectable gonadotropins, and absence of pubertal development (9, 10, 11).
This report provides the first genetic basis for the fertile eunuch variant of IHH in demonstrating a partially inactivating defect of the GnRH-R. A similar clinical picture has been described because of an activating mutation of the FSH receptor; however, that patient exhibited an acquired hypogonadism following therapy for a pituitary adenoma (23). The present case is also the first report of a patient homozygous for the Gln106Arg mutation in the first extracellular loop; as such, its in vivo activity is not obscured by the occurrence of a second defect.
In patients with the fertile eunuch variant of IHH, gonadotropin activity appears sufficient to stimulate the local intratesticular testosterone concentrations required to support testicular growth and spermatogenesis yet insufficient to achieve the normal circulating testosterone levels required for full virilization. Typically, these patients achieve normal virilization and fertility with testosterone or hCG therapy alone (24, 25, 26, 27). A "pubertal arrest" pattern of GnRH secretion characterized by nocturnal LH and testosterone secretion has been documented in a few patients with the fertile eunuch syndrome (27, 28). These cases may well stem from defects in GnRH regulation and thus along with the current report underscore the considerable clinical, genetic, and pathophysiologic heterogeneity that exists within the syndrome of IHH. Although our patient fulfills the clinical criteria for fertile eunuch syndrome (27, 28), he displays several unique features. He presented with an apulsatile pattern of nocturnal LH secretion. Moreover, an intriguing reversal of his hypogonadism occurred following several months of hCG therapy.
It is likely that hCG administration contributed to the reversal of IHH in our patient by inducing maturation of Leydig cells. In the human, several lines of evidence support an LH-dependent process of Leydig cell differentiation (29, 30). Therefore, it is likely that our patient’s abnormal endogenous LH secretion at baseline resulted in incomplete Leydig cell differentiation, as previously demonstrated by testicular biopsy in men with the fertile eunuch syndrome (24, 25, 26). Administration of hCG would have induced further maturation of Leydig cells, increased Leydig cell number, and stimulated normal testosterone production. It is possible that restoration of normal testosterone levels in turn led to reversal of the patient’s hypogonadotropism in one or both of the following ways.
First, testosterone is known to be an important negative regulator of GnRH pulse frequency (31). Because there is no reason for hypothalamic secretion of GnRH to be impaired in the current case, the patient’s baseline GnRH pulse frequency would be expected to be increased to that of a castrate given the absence of sex steroid feedback (32, 33). It is possible, therefore, that such a fast GnRH frequency led to a partial, reversible desensitization of the mutant receptor and a resulting apulsatile pattern of LH secretion (34, 35, 36). Therefore, the production of physiologic testosterone levels with hCG could potentially have reversed desensitization by restoring a normal pulse frequency, thereby permitting more effective signaling through the mutant receptor.
An alternative explanation is that the initiation of puberty requires a prolonged period of gonadotrope priming with GnRH doses that are higher than those required to maintain the neuroendocrine axis in the adult, as demonstrated previously in both the ram (37) and human (38, 39). Thus, in the presence of an impaired GnRH-R, this "threshold effect" on the gonadotrope might have proved insurmountable for initiating puberty. However, production of normal testosterone levels with hCG therapy may have activated testosterone-dependent genes within the pituitary and thereby facilitated normal gonadotrope function with lower levels of endogenous GnRH secretion.
Other potential reasons for reversal of HH in this patient were also considered. The patient’s normal testicular size despite the absence of nocturnal LH secretion is not compatible with delayed puberty. In addition, no risk factors for functional HH were elicited in the patient’s history. It is also possible that GnRH-independent factors may have played a role in triggering the reversal of IHH. Among them, there is evidence from studies in the rat that testosterone can positively regulate FSH-ß mRNA directly at the pituitary (40). However, the same studies demonstrate that testosterone has no positive effect on LH-ß or FAS mRNA levels (40). In addition, nonsteroidal peptides including activin, follistatin, and inhibin B also affect the synthesis of FSH directly at the level of the pituitary but are without effect on LH synthesis (41).
In conclusion, this case is unique for several reasons. It provides a novel molecular defect in the GnRH-R that is associated with the fertile eunuch syndrome. Moreover, the patient underwent a remarkable, spontaneous reversal of his IHH, likely triggered by the trophic effect of hCG on Leydig cells, emphasizing the delicate interplay between the gonad and the neuroendocrine axis. Although his testosterone level had fallen below the normal range at his 6-month assessment, he continued to have normal libido and potency and spermatogenesis was maintained. In addition, our group has previously documented that as many as 15% of normal healthy men have T levels in this range at some point during a 24-h period of blood sampling (22). It will be very interesting to perform serial assessments in this patient to see whether he can maintain this hormonal balance over time and a range of physiologic circumstances.
Acknowledgments
We acknowledge the participation of Luciana Mattos-Barros-Oliveira, M.D., in assisting us in communications with the proband and his family.
Footnotes
1 This work was supported by NIH Grants R01-HD-15788-15, DK-07028-24,
M01-RR-01066, and 2U54H028138-10. 
Received September 18, 2000.
Revised December 18, 2000.
Accepted February 8, 2001.
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normal and GnRH-deficient men. J Clin Endocrinol Metab. 70:1654–1661.
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