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The Journal of Clinical Endocrinology & Metabolism Vol. 85, No. 9 3002-3008
Copyright © 2000 by The Endocrine Society

Special Articles

A New Compound Heterozygous Mutation of the Gonadotropin-Releasing Hormone Receptor (L314X, Q106R) in a Woman with Complete Hypogonadotropic Hypogonadism: Chronic Estrogen Administration Amplifies the Gonadotropin Defect1

Marie-Laure Kottler, Stéphanie Chauvin, Najiba Lahlou, Caroline E. Harris, Colin J. Johnston, Jean-Pierre Lagarde, Philippe Bouchard, Nadir R. Farid and Raymond Counis

Endocrinologie Cellulaire et Moléculaire de la Reproduction, Centre National de la Recherche Scientifique, Université Paris VI (M.L.K., S.C., R.C.), 75005 Paris, France; Laboratoire de Biologie Hormonale, Hôpital Saint Vincent de Paul (N.L.), 75014 Paris, France; Department of Endocrinology, Hemel Hempstead General Hospital (C.E.H., C.J.J., N.R.F.), Watford, Hertfordshire HP2 4AD, United Kingdom; Service d’Endocrinologie, Hôpital Saint Antoine (P.B.), 75012 Paris, France; and Unité de Génétique Moléculaire, Service de Biochimie Médicale, Hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris (M.L.K., J.P.L.), 75013 Paris, France

Address all correspondence and requests for reprints to: Dr. Marie-Laure Kottler, Department of Génétique et Reproduction, Hôpital Clémenceau, Centre Hospitalo Universitaire, 14033 CAEN Cedex, France. E-mail: mlkottle{at}snv.jussieu.fr


   Abstract
Top
 Abstract
Introduction
 Subject and Methods
 Results
 Discussion
 References
 
We describe a woman with complete hypogonadotropic hypogonadism and a new compound heterozygous mutation of the GnRH receptor (GnRHR) gene. A null mutation L314X leading to a partial deletion of the seventh transmembrane domain of the GnRHR is associated with a Q106R mutation previously described. L314X mutant receptor shows neither measurable binding nor inositol phosphate production when transfected in CHO-K1 cells compared to the wild-type receptor. The disease is transmitted as an autosomal recessive trait, as shown by pedigree analysis. Heterozygous patients with GnRHR mutations had normal pubertal development and fertility.

The present study shows an absence of LH and FSH response to pulsatile GnRH administration (20 µg/pulse, sc, every 90 min). However, GnRH triggered free {alpha}-subunit (FAS) pulses of small amplitude, demonstrating partial resistance to pharmacological doses of GnRH. FSH, LH, and FAS concentrations were evaluated under chronic estrogen treatment and repeat administration of GnRH. Not only were plasma FSH, LH, and FAS concentrations decreased, but FAS responsiveness was reduced.

This new case emphasizes the implication of the GnRH receptor mutations in the etiology of idiopathic hypogonadotropic hypogonadism. We also have evidence for a direct negative estrogen effect on gonadotropin secretion at the pituitary level, dependent on the GnRHR signaling pathway.


   Introduction
Top
 Abstract
 Introduction
Subject and Methods
 Results
 Discussion
 References
 
ISOLATED HYPOGONADOTROPIC hypogonadism (IHH) is a feature of several genetic conditions, the most common and best defined being X-linked Kallmann’s syndrome. Accumulated evidence suggests that autosomal genes are involved in the majority of cases of familial GnRH deficiency (1). As acute or chronic GnRH administration at pharmacological doses usually results in a normalization of pituitary function, the GnRH receptor (GnRHR) for a long time was not considered to be a good candidate for IHH. Recently, a number of familial cases with GnRHR mutations that impair biological function have been reported. The phenotype of these patients seems to vary from partial (2, 3) to complete (4, 5, 6) hypogonadotropic hypogonadism. In the present study we describe a case of complete hypogonadotropic hypogonadism and a new compound heterozygous mutation of the GnRHR gene. A null mutation L314X leading to a truncated receptor without any biological activity is associated with a previously described Q106R mutation (2). This is a sporadic case.

The mechanisms by which gonadal steroids regulate gonadotropin secretion are only partially understood, showing gender (7, 8) and species variations (9). There is evidence for a pituitary site for estradiol action, but the exact mechanism of this action remain elusive (10). Therefore, we have used this patient with complete hypogonadotropic hypogonadism displaying GnRH resistance to study in vivo the effect of chronic estrogen administration on the gonadotropin and free {alpha}-subunit (FAS) release.


   Subject and Methods
Top
 Abstract
 Introduction
 Subject and Methods
Results
 Discussion
 References
 
Case report

The propositus came to medical attention in 1991 at the age of 16.8 yr with primary amenorrhea and lack of secondary sexual characteristics. Her initial laboratory data revealed low estradiol and gonadotropin concentrations: estradiol was 17 pmol/L (normal range, 37–92), basal serum LH was 0.44 IU/L (normal ranges, 5–12 IU/L), and FSH was 0.50 IU/L (normal range, 2–6 IU/L). Computed tomography scan indicated normal pituitary and infundibulum. Bone age was 13 yr. Transabdominal ultrasound examination and laparoscopy showed an infantile uterus, healthy fallopian tubes, and two small, apparently unstimulated ovaries.

The patient was treated with a combination of estrogen and progestogen. Shortly afterward, she started to have withdrawal bleeding and to develop secondary sexual characteristics. Her subsequent clinical progress was satisfactory.

She was reinvestigated 7 yr later at age 24 yr. The uterus was of normal size ultrasonically, with good endometrial lining. Only the left ovary was identified and measured 11 x 6 mm with few small follicles. GnRH (100 µg, iv) stimulation was repeated 5 weeks after sex steroid replacement therapy was withdrawn (Table 1Go). During this period the patient remained amenorrheic, but did not experience any hot flushes.


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  		Table 1. Plasma basal hormone concentrations of the women and response to GnRH administration (100 µg, iv)

 
The patient’s mother had normal pubertal development and regular menstrual cycles. She has a fertile 26-yr-old sister. The patient’s father was normally virilized, and her 22 yr-old brother was also clinically normal.

Analysis of gonadotropin secretion

Protocol. The patient gave written informed consent for the studies.

Endogenous LH, FSH, and FAS release was evaluated by 20-min sampling over a 6-h period under pulsatile administration of GnRH (20 µg/pulse every 90 min, sc) during two different admissions separated by 3 months. In each case the first sample was taken 10 min after the first GnRH bolus.

During the first admission, the patient had been off sex steroid replacement therapy for 10 weeks. Then the patient received estrogen treatment (Premarin, Wyeth, Taylow, UK; 0.625 mg/day, orally) for 10 weeks and was readmitted under the estrogen treatment, for a repeat pulsatile administration of GnRH at a dose and rate identical to those used in her initial admission.

Assays. Serum FSH and LH concentrations were measured in duplicate by means of sensitive fluoroimmunometric assays (AutoDelphia, Wallac, Inc., Turku, Finland). In brief, 25 µL serum were distributed in wells coated with anti-FSHß or anti-LHß antibody and incubated for 2 h, then europium-labeled antibody was added (anti-FSH{alpha} or anti-LHß, respectively). The detection was based on the time-resolved fluorescent technique. Between- and within-assay coefficients of variation (CVs) were 1.5% and 1.3%, respectively, for FSH at the level of 2 IU/L. The detection limit was 0.05 IU/L. For LH at the level of 0.3 IU/L, between- and within-assay CVs were 6.7% and 1.8%, respectively. The detection limit was 0.05 IU/L. Samples were run in the same assay.

FAS was measured by RIA in duplicate as previously described (11) using the First International Reference Preparation of hCG {alpha}-subunit as a standard. The detection limit was 0.04 IU/L. At the level of 0.3 IU/L, between- and within-assay CVs were 6.2% and 11.5%, respectively, and at the level of 0.9 IU/L, they were 3.2% and 7.0%.

Inhibin B was measured as previously described (12).

Pulse analysis. Hormone secretion was analyzed using Van Cauter’s algorithm (13), which requires a 2 CV threshold above the preceding value to define a pulse.

DNA sequencing and functional analysis of the GnRHR in Chinese hamster ovary (CHO-K1) cells

Genomic DNA was sequenced as previously described (5). Construction of pMSG mammalian expression vector (Pharmacia Biotech, Orsay, France) encoding the wild-type (WT) receptor has been previously described (5). Genomic DNA (exon 3) of the propositus was amplified using primers I3S and E3R located in intron 2 and exon 3, respectively. I3S was previously described (14), and E3R was designed to contain a XhoI restriction site (5'-CAGCTCCAGCATTCCCAGATGGAGAG-ATTC-3'). Mutant DNA fragment was constructed by ex-changing the WT BsiHKA1/XhoI DNA segment with the mutated one.

Transfections and functional studies, binding, and inositol phosphate (IP) production were performed as previously described (5). For radioligand binding studies, CHO-K1 cells were transfected with increasing amounts of L314X GnRHR DNA vector (1.2–9 µg).

WT and mutant GnRHR messenger ribonucleic acids (mRNAs) were extracted from transfected CHO-K1 cells and quantified by dot blot as previously described (5).


   Results
Top
 Abstract
 Introduction
 Subject and Methods
 Results
Discussion
 References
 
DNA sequencing and determination of haplotypes

Two germline mutations were found in the patient’s DNA (Fig. 1Go). In exon 1, a guanine to adenine (G to A) mutation at position 317 resulted in a glutamine to arginine substitution at residue position 106 (Q106R). This amino acid belongs to the first extracellular loop (e1) of the receptor (Fig. 2Go). In exon 3, a thymidine to adenine (T to A) transversion at position 941 resulted in a null mutation at position 314 (L314X), belonging to the seventh transmembrane domain (TM7). We also found at position 151 a previously described Mae polymorphism (15). Segregation analysis provided evidence that the propositus had inherited germline mutations and was compound heterozygote. Her father was heterozygous for the L314X mutation, as was her brother. Her mother carried the Q106R mutation associated with the Mae polymorphism. Her sister was homozygous for the WT receptor.



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  		Figure 1. Automatic DNA sequencing showing the nucleotide mutations of the propositus (II2) and segregation analysis of her family. Half-solid symbols indicate unaffected heterozygous; the open symbol indicates a subject with a normal genotype.

 


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  		Figure 2. List of inactivating mutations identified and schematic representation of their locations within the predicted GnRHR structure. The gray symbols refer to the present study, and the closed circles indicate residues that have been previously described mutated, with references in parentheses.

 
Functional analysis of the GnRHR

The WT receptor exhibited high affinity binding (Kd = 1.61 ± 0.43 nmol/L), and GnRH (107 mol/L) induced a maximum 7-fold increase in total IP production. In contrast, the L314X mutant showed neither measurable binding nor IP production despite transfection with increasing amounts of DNA construct (Table 2Go).


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  		Table 2. Functional analysis of wild-type and L314X GnRHR

 
To examine whether the mutant GnRHR was expressed in CHO-K1 cells, RNA were extracted from cells and quantified. Both WT and mutant mRNA sequences were detected by Northern blot analysis; however, an important reduction of the mutated form was observed compared with the WT (data not shown).

Response to the pulsatile administration of GnRH

During the first 7-h sampling period in the absence of estrogen treatment, only one LH pulse was identified (Fig. 3Go). LH as well as FSH levels remained low. However, pulsatile secretion of FAS was better preserved, and GnRH triggered small FAS pulses with a 40- to 50-min lag time. During treatment, estradiol levels remained low, and no ovarian follicular development occurred, as demonstrated by ultrasonic examination. Inhibin B concentration remain below the normal values (<15 pg/mL).



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  		Figure 3. Plasma FSH, LH, and FAS during pulsatile GnRH administration without (closed circles) or with chronic estrogen treatment (open squares). Each arrow indicates the time of an exogenous GnRH pulse (20 µg, sc). An asterisk denotes a significant pulse.

 
Under chronic estrogen treatment, a significant decrease in mean plasma LH (0.078 ± 0.004 vs. 0.32 ± 0.02 IU/L; P < 0.01) as well as FSH concentration (0.36 ± 0.01 vs. 1.10 ± 0.01 IU/L; P < 0.01) was observed. LH pulse remained erratic. With estrogen treatment, the FAS level decreased (0.35 ± 0.07 vs. 0.42 ± 0.14 IU/L; P < 0.01). In addition, a clear decrease in FAS release in response to GnRH administration was noted in both frequency (1 vs. 3) and amplitude (Fig. 3Go).


   Discussion
Top
 Abstract
 Introduction
 Subject and Methods
 Results
 Discussion
References
 
The present data describe two mutations in a woman with complete hypogonadotropic hypogonadism. The Q106R mutation in e1 of the receptor was previously described by de Roux et al. (2), in combination with a R262Q mutation, in patients with partial hypogonadotropic hypogonadism. In vitro expression studies have shown that the Q106R receptor was able to bind GnRH, but with a low affinity, and a large amount of GnRH agonist (50 times higher than with the WT) was needed to induce half-maximal IP production.

We describe for the first time a nonsense mutation located at position Leu7.44 (314) in TM7 of the GnRHR, generating a mRNA encoding a protein of only 313 amino acids and a partial deletion of the TM7. This deletion includes Tyr7.53 (323), which is a highly conserved residue among the G protein-coupled receptors (GPCRs), and Asp7.49 (319). The latter Asp7.49 (319) has been previously shown to be in spatial relationship with Asn2.50 (87) located in TM2 (16, 17, 18, 19, 20) and contributes to GnRH receptor function (20, 21, 22). Our functional studies, which reveal a complete loss of function of the mutant receptor, are in agreement with a major role of this deleted C-terminal region (22). Other reports have also shown that C-terminal truncated GPCRs frequently tend to be trapped in the endoplasmic reticulum (23) and are not processed to the membrane. In addition, mRNA levels of the L314X mutant receptor were lower than those of the WT. Whether this mutant receptor is really translated in vivo remains uncertain. Nevertheless, whatever the mechanism, disruption of biosynthesis (transcription or translation), trafficking to the membrane, and/or misfolding, it appears evident that the mutant form results in a loss of function.

To date, 8 different mutations of the GnRHR leading to partial or complete loss of function have been reported in patients with IHH (2, 3, 4, 5, 6, 24) as an autosomal recessive trait as shown by pedigree analysis. In all cases, heterozygous patients for the GnRHR mutations have normal pubertal development and fertility. Screening 46 unrelated IHH patients without anosmia, Layman et al. (4) found GnRHR gene mutations in 2.2% (8), although in families with an affected female the incidence of GnRHR mutation was higher (7.1%). Such a low frequency was confirmed in our personal study, emphasizing the implication of a number of important and decisive factors other than GnRH in the modulation of gonadotropin secretion in humans. Mutations are distributed along the coding sequence, as reported for other GPCRs, localized mainly, however, within the transmembrane domain. In previous reports as well as the present study, two hot spots have been noted regardless of the geographic origin of the patients (North or South America and Europe): Q106R (2, 3), which affects the binding, and R262Q, (2, 4, 5), which affects IP production.

The phenotype of the patients appears to vary from partial hypogonadotropic deficiency with significant levels of gonadotropins and gonadal steroids (2, 3) to complete hypogonadism with the absence of pubertal development (4, 5, 6, 24). Our patient displays complete hypogonadism, with low gonadotropin levels and a poor response to GnRH administration, whereas the patient described by De Roux (2) exhibited partial hypogonadism with normal gonadotropin levels. Both share the same Q106R mutation, but the mutation in the second allele is different, L314X instead of R262Q. In vitro studies have shown that either Q106R or R262Q results in a partial loss of receptor function (2, 4). Thus, the difference between the phenotypes could be related to the allelic combination of the mutations, with the biological activity of the L314X receptor being more severely affected than that of the R262Q. However, there is also evidence for heterogeneity in the clinical (3) and biological (5) presentations of family members carrying the same molecular abnormalities, thus supporting the implication of other factors or mechanisms in the expression of the phenotype. In a recent experiment, Grosse et al. (25) found in vitro a possible inhibitory action of a truncated receptor on the functionality of the WT. However, at least two subjects (patient’s father and brother), heterozygous for the L314X GnRHR, have gone through puberty and exhibited normal pubertal development. Thus, a dominant negative effect of the L314X receptor could be excluded in vivo.

Response to pulsatile administration of GnRH

The present study shows an absence of response to pulsatile GnRH administration in term of gonadotropin release. FSH and LH concentrations were low, suggesting that several pathways may converge on gonadotropin to establish a basal level of secretion (26). However, exogenous GnRH stimulation elicits erratic FAS pulses of low amplitude. FAS release is under the dual control of GnRH and TRH; it is, however, a more sensitive index of GnRH administration (27), particularly in patients with IHH (28, 29, 30). This different threshold of sensitivity of gonadotrophs to the GnRH stimulation of LH and FAS was also described in patients with other mutated GnRHR (5). Taken together, these data suggest that FAS may be superior to LH to estimate GnRH sensitivity in patients with GnRHR mutation. As the L314X is nonfunctional, it serves as a null background to interpret results from the Q106R mutant, which was found to have reduced GnRH binding and which requires higher levels of GnRH to elicit responses (2).

Estrogen amplifies the depression of gonadotropin and FAS release

It has long been established that gonadal steroids act on both the hypothalamus and pituitary to regulate the synthesis and release of gonadotropins; however, the specific mechanisms involved are still unclear. Patients with GnRH resistance represent an interesting alternative model to dissect in vivo the effect of estrogen on gonadotropin secretion. We found that estrogen decreases gonadotropin and FAS levels as well as the response of FAS to pharmacological doses of GnRH.

As a clear relationship exists between GnRH secretion and the amplitude of the response to LH, an estradiol-induced decrease in the amount of GnRH released from the hypothalamus could account for the observed decrease in gonadotropin secretion (31). In the hypothalamus, ovariectomy increases, and estradiol replacement restrains both GnRH pulse frequency and amplitude (32). For example, in ovariectomized monkeys, estradiol induces a 4-fold reduction in the concentration of GnRH in cerebral fluid (33). Patients with an altered GnRHR are estrogen-deprived and would therefore, be expected to have a hypothalamic secretion of GnRH similar to that observed in castrates. Thus, the possibility exists that the decrease in the basal level of gonadotropins, due to estrogen, results from a primary effect on endogenous hypothalamic GnRH. Such an indirect action has been demonstrated in vivo to be responsible for the inhibition of the transcription of FAS (34). This mechanism, however, remains difficult to assess in our study, as the altered GnRHR responds poorly to GnRH. Another possibility is a direct action on the pituitary. There are numerous data that suggest that estrogens act at the pituitary level (9). For instance, in GnRH-deficient patients in whom the pattern of the GnRH administration (frequency and doses) can be kept constant without interference with endogenous GnRH, a significant decrease in gonadotropin levels as well as in LH pulse amplitude could be demonstrated under estradiol treatment (35). In addition, a dimorphic effect on the basal activity of the FAS promoter was observed in pituitary cells from rats, with females exhibiting lower basal activity but greater GnRH responses than males (7), reinforcing the hypothesis that estrogens play a role in FAS expression independent of the hypothalamic secretion.

We also document in our study that acute FAS responsiveness to pharmacological doses of GnRH decreased under estrogen administration. A relationship between the dose of bolus GnRH and the pituitary response was found in normal subjects (31) and in patients with GnRH deficiency (35) or GnRH resistance (5). As discussed above, the amount of GnRH-inducing gonadotropin secretion represents, in patients with GnRH resistance, a summation of endogenous vs. exogenous GnRH. Thus, gonadotropin responsiveness may vary according to GnRH input. Data for GnRH levels in pituitary portal blood are unknown in humans, especially in ovariectomized females. Comparatively, in the rhesus monkey (33) or in the ewe (36), levels ranged from 11.6–278 pg/mL and from 15–35 pg/mL, respectively. Pharmacokinetic studies have shown that the concentration of GnRH obtained in response to sc administrations of GnRH pulses (20 µg/pulse or 400 ng/kg) represents a excessive dose compared with that normally present and thus could override the variations in endogenous secretion (37, 38). As in our study bolus GnRH remains at a dose and rate identical to those used in the initial experiment (20 µg/pulse), we suggest that the decrease in FAS response could be due to factors other than variations in GnRH input. Similar results were observed in GnRH-deficient men. LH pulse amplitude was lowered by estradiol, albeit in response to the same GnRH bolus administration (35). Thus, if the variation in gonadotropin secretion does not come from changes in GnRH input, this would suggest an alteration in some mechanism(s) involved in the GnRH signaling pathway at the pituitary level. Due to the complexity of the signaling in gonadotrophs (39), such an alteration could result from changes at a variety of target points within the cascade of reactions, including 1) receptor number, 2) elements of the transduction pathways (postreceptor signaling effect), and/or 3) gonadotropin synthesis and/or release.

Changes in the number of pituitary GnRHR have been implicated as an important mechanism underlying the regulation of gonadotropin secretion (40, 41, 42, 43). Gonadal steroids have been shown to regulate GnRHR expression and to act in concert with GnRH to produce the LH surge in female rats (41, 44) and sheep (45, 46, 47, 48), however with differences between species (9). Whether estrogens can also regulate the expression of GnRHR and alter GnRHR in humans remains unknown. In particular, no canonical estradiol response element has been identified in the human GnRHR promoter (49, 50).

Administration to rhesus monkeys of a potent estrogen receptor antagonist that does not cross the blood-brain barrier blocks the inhibitory action of estradiol on LH secretion (10). In vitro studies have shown that estradiol inhibits the transcription of FAS (51) and suppresses GnRH-stimulated LH release in monkey pituitary cells, whereas it amplifies the action of GnRH in rats (9), blocks LH secretion in ovine pituitary cells (52), and reduces, in the mouse gonadotrope {alpha}T3–1 cell line, GnRH binding and coupling efficiency to second messenger generation (53).

Finally, given the relationship between GnRH dose and gonadotropin response, the fact that estrogen treatment decreases or abolishes the FAS pulse amplitude strongly suggests that estrogen modulates receptor signaling in this patient. We cannot, however, exclude a specific action of the estrogen used in this study (conjugated equine estrogen vs. estradiol).

Taken together, these data support the down-regulation of gonadotropin and FAS by long term estrogen treatment via a direct action in the pituitary that is associated with and possibly also related to a modification of GnRHR expression and/or another postreceptor event involved in the neurohormonal regulation of gonadotropin secretion.

In conclusion, we have described a woman with IHH and compound heterozygote mutations in the GnRHR gene. The new L314X mutation described here totally abolished the biological activity of the receptor. The present study demonstrates the partial resistance of LH and FSH to the GnRH stimulation as a result of expression of the Q106R mutant. We also add arguments suggesting that estrogen has an inhibitory function at the pituitary level, through an alteration of the GnRHR signaling pathway.


   Acknowledgments
 
We are indebted to Dr. A. F. Parlow and the National Hormone and Pituitary Program (Baltimore, MD) and to the WHO International Laboratory for Biological Standards (Potters Bar, Hertfordshire, UK) for the generous gifts of reagents and standards used in the immunoassays for gonadotropins and subunits. We thank Prof. J. C. Thalabard (Hôpital Necker, Paris, France) for performing statistical analysis of LH, FSH, and FAS pulsatile profile. We are grateful to Dr. L. Oliver (INSERM, U-419) for correction of the English text and for editorial assistance.


   Footnotes
 
1 This work was supported in part by the Institut de Recherche Endocrinienne et Métabolique (Hôpital Saint Vincent de Paul, Paris, France). Back

Received December 3, 1999.

Revised April 20, 2000.

Accepted May 13, 2000.


   References
Top
 Abstract
 Introduction
 Subject and Methods
 Results
 Discussion
 References
 

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