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The Journal of Clinical Endocrinology & Metabolism Vol. 84, No. 2 567-572
Copyright © 1999 by The Endocrine Society

Original Studies

The Same Molecular Defects of the Gonadotropin-Releasing Hormone Receptor Determine a Variable Degree of Hypogonadism in Affected Kindred1

Nicolas de Roux, Jacques Young, Sylvie Brailly-Tabard, Micheline Misrahi, Edwin Milgrom and Gilbert Schaison

INSERM U-135 et Laboratoire d’Hormonologie et Biologie Moléculaire (N.d.R., S.B.T., M.M., E.M.), and Service d’Endocrinologie et des Maladies de la Reproduction (J.Y., G.S.), Hôpital de Bicêtre, 94275 Le Kremlin Bicetre, France

Address all correspondence and requests for reprints to: Dr. E. Milgrom, Hôpital de Bicêtre, 78 rue du Général Leclerc, 94275 Le Kremlin Bicetre, France. E-mail: u135{at}infobiogen.fr


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Detailed endocrinological studies were performed in the three affected kindred of a family carrying mutations of the GnRH receptor gene. All three were compound heterozygotes carrying on one allele the Arg262Gln mutation and on the other allele two mutations (Gln106Arg and Ser217Arg). When expressed in heterologous cells, both Gln106Arg and Ser217Arg mutations altered hormone binding, whereas the Arg262Gln mutation altered activation of phospholipase C.

The propositus, a 30-yr-old man, displayed complete idiopathic hypogonadotropic hypogonadism with extremely low plasma levels of gonadotropins, absence of pulsatility of endogenous LH and {alpha}-subunit, absence of response to GnRH and GnRH agonist (triptorelin), and absence of effect of pulsatile administration of GnRH.

The two sisters, 24 and 18 yr old, of the propositus displayed, on the contrary, only partial idiopathic hypogonadotropic hypogonadism. They both had primary amenorrhea, and the younger sister displayed retarded bone maturation and uterus development, but both sisters had normal breast development. Gonadotropin concentrations were normal or low, but in both cases were restored to normal levels by a single injection of GnRH. In the two sisters, there were no spontaneous pulses of LH, but pulsatile administration of GnRH provoked a pulsatile secretion of LH in the younger sister.

The same mutations of the GnRH receptor gene may thus determine different degrees of alteration of gonadotropin function in affected kindred of the same family.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
HYPOTHALAMIC GnRH plays a key role in the regulation of gonadotropin secretion and the reproductive cascade in humans. This action of GnRH is mediated through a receptor present in the cell membrane of gonadotropes. The complementary DNA and the gene for the human GnRH receptor were recently cloned (1, 2), showing that it belongs to the G protein-coupled receptor family with seven transmembrane domains. Activation of this receptor mainly results in increased activity of phospholipase C and mobilization of intracellular calcium (3).

We have previously described a familial case of idiopathic hypogonadotropic hypogonadism (IHH) associated with compound heterozygous inactivating mutations of the GnRH receptor gene (4). One mutation in the first extracellular loop (Gln106Arg) of the receptor decreased GnRH binding to its receptor. The other mutation in the third extracellular loop (Arg262Gln) did not modify the ligand binding, but decreased the activation of phospholipase C. The male propositus and his sister presented with a typical case of incomplete IHH. The incomplete phenotype was associated with partial impairment of the hormonal response of the mutant receptors in transfection experiments (4). This initial description was followed by the report of another family carrying the same Arg262Gln mutation as well as a new Tyr284Cys mutation (5).

However, in all of these cases only limited clinical information was available, and in our initial report we had only been able to study the propositus in detail. We have now observed another family carrying mutations of the GnRH receptor and presenting three affected siblings. It has been possible to undertake endocrinological studies in all members of this family, including analysis of gonadotropin pulsatility and response to pulsatile administration of GnRH. These studies have shown variable degrees of hypogonadism in the three subjects carrying the same molecular defects.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Patients

The propositus (subject II-1) was a 30-yr-old man referred for hypogonadism. His height was 188 cm, his weight was 76 kg, and his arm span was 187 cm. Physical examination revealed sparse pubic hair (Tanner stage III) short penis of 5.5 cm, and small scrotal testes (the volume of each was 3 mL; normal, 15–25 mL). Scrotal pigmentation and rugae were absent. Olfactometry revealed a normal sense of smell. There was no bimanual synkinesia, no abnormal eye movements, no color blindness, and no renal or craniofacial abnormalities. Audiometry was normal. The plasma ferritin concentration was normal. Magnetic resonance imaging excluded a lesion of the hypothalamic pituitary area and showed normal olfactory bulbs and corpus callosum. The karyotype was 46,XY. The plasma testosterone (1.9 nmol/L; normal range, 11–34 nmol/L) and inhibin B (13 pg/mL; normal range, 105–160 pg/mL) levels were low, as were baseline plasma LH (0.5 IU/L) and FSH (0.5 IU/L) levels (normal range, 2.0–5.0 IU/L and 1.9–5.7 IU/L, respectively). After 3 months of hCG treatment (1500 U twice a week, im), plasma testosterone levels were in the normal range (15 nmol/L), but semen analysis showed azoospermia. To induce spermatogenesis, hCG (1500 U) and purified urinary FSH (150 U) were administered twice a week by im injection. After 6 months of this combined therapy, testicular volume had increased from 3 to 6 mL, and sperm analysis showed a sperm density of 0.13 x 106/mL, with a semen volume of 2.25 mL. GH and PRL plasma levels and pituitary-thyroid and pituitary adrenal functions were normal.

The patient’s older affected sister (subject II-2) was a 24-yr-old woman who presented primary amenorrhea. Spontaneous thelarche had occurred at the age of 14 yr. From the age of 18 yr she received combined oral contraceptive treatment, which induced cyclical withdrawal bleeding. At examination, pubic hair, breasts, and external genitalia were those of a normal woman. Evaluation of the hypothalamo-pituitary gonadal axis was performed 1 month after the withdrawal of estrogen and progestin treatment. The plasma estradiol (85 pmol/L; normal range during the early follicular phase, 90–320 pmol/L) and basal plasma LH (2.3 IU/L) levels were low, whereas the plasma FSH (2.7 IU/L) level was in the normal range (normal ranges during the early follicular phase, 2.5–5.4 and 2.3–6.5 IU/L, respectively). Pelvic ultrasonography showed a normal uterus and two small ovaries (right ovary, 1.7 mL; left ovary, 1.8 mL), with no follicle larger than 10 mm.

The proband’s younger affected sister (subject II-4) was an 18-yr-old woman with a history of primary amenorrhea. Spontaneous thelarche had occurred at the age of 15 yr. At physical examination, her height was 178 cm, and her weight was 70 kg. Pubic hair and breast development were at Tanner stages V and IV, respectively. The plasma estradiol level was low (30 pmol/L). The plasma LH concentration (1.2 IU/L) was low, but the plasma FSH concentration (3.5 IU/L) was normal. The plasma androstenedione level was 3.2 nmol/L (normal range, 2.4–12 nmol/L). Pelvic ultrasonography showed a hypoplasic uterus and two small ovaries (right ovary, 1.9 mL; left ovary, 1.6 mL) with no follicle larger than 7 mm. Bone age was delayed (15 yr). The plasma PRL level was normal.

The patients’ 50-yr-old mother (subject I-2) had had a normal pubertal development and regular menstrual cycles. The patients’ 52-yr-old father (subject I-1) and 20-yr-old brother (subject II-3) were normally virilized men with normal plasma LH, FSH, and testosterone levels. Subject II-5 was a normal 11-yr-old prepubertal girl. There was no indication of parental consanguinity. All subjects gave written informed consent for the studies.

Analysis of gonadotropin secretion

The GnRH test (100 µg, iv) was performed in the three affected subjects, and plasma LH and FSH levels were measured at -15, 0, 15, 30, 60, and 120 min. In the propositus, plasma LH and FSH levels were measured every 4 h for 24 h after a single injection of the GnRH agonist DTrp6 (Triptorelin; 100 µg, sc).

Endogenous LH secretion was evaluated by 10-min sampling over an 8-h period in the propositus and over a 4-h period in his sisters, II-2 and II-4. In addition, LH secretion was evaluated by 10-min sampling over an 8-h period in the proband and over a 4-h period in subject II-4 on day 10 of pulsatile administration of GnRH (20 µg/pulse every 120 min and every 90 min, respectively; both sc). Free {alpha}-subunit secretion was also evaluated in the proband before and on day 10 of pulsatile GnRH administration. Pulses were analyzed according to the method of Thomas et al. (6).

Plasma LH and free {alpha}-subunit concentrations were measured as previously described (7). For the latter, results were expressed as international units per L (activity per µg pure {alpha}-subunit) Medical Research Council 75/569, and the normal range was 0.12–0.4 IU/L in men.

DNA sequencing and expression vectors

Genomic DNA were sequenced as previously described (4). Construction of expression vectors encoding wild-type and mutant Gln106Arg has previously been described (4). The mutation Ser217Arg was introduced into the vector encoding the wild-type receptor or into the vector encoding the mutant Gln106Arg. PCR amplification of the propositus genomic DNA (second exon) was followed by the replacement of the wild-type PstI/PshA1 fragment of the expression vector (4) with the corresponding fragment containing the mutated DNA.

Transfections and functional studies

These studies were performed as previously described (4).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Sequencing of the GnRH receptor

Sequencing of the three exons of the GnRH receptor gene in the propositus revealed three heterozygous mutations (Fig. 1AGo). In the first exon, mutation of an adenine into a guanine changed glutamine 106 into an arginine. In the third exon, the substitution of an adenine for a guanine yielded an Arg262Gln substitution. Both of these mutations, located, respectively, in the first extracellular loop and the third intracellular loop, have previously been described (4). A new mutation was observed in the second exon, changing a cytosine into an adenine and thus substituting serine 217 by an arginine in the fifth transmembrane span (Fig. 1BGo).



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  		Figure 1. Automatic DNA sequencing of the GnRH receptor gene. A, Heterozygotic mutations are indicated by arrows. Exons are shown in rectangles, and their coding regions are represented in dark shading. B, Localization of the mutations.

 
These mutations introduced a new cleavage site for PvuII in exon 3 and suppressed an XcmI site in exon 1 and a PvuII site in exon 2 (Fig. 2AGo). Study of the family (Fig. 2BGo) showed that the father of the propositus was heterozygous for both the Gln106Arg and Ser217Arg mutations, whereas his mother carried a heterozygous Arg262Gln mutation. The two affected sisters with primary amenorrhea had the same genotype as the propositus. The third sister (11 yr old) was homozygous for the wild-type receptor. The unaffected brother was heterozygous for the Arg262Gln mutation.



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  		Figure 2. Pedigree of the propositus and his family. A, The propositus is indicated by an arrow. Solid symbols indicate affected family members; half-solid symbols indicate unaffected heterozygous; open symbols indicate subjects with a normal genotype. Circles indicate females, and squares indicate males. Representative patterns of digestion by PvuII and XcmI are shown. B, The haplotype of each family member is represented: + indicates the presence, and - the absence of each mutation.

 
Functional studies of the mutated receptors

The Gln106Arg and Arg262Gln mutated receptors have been expressed and characterized previously (4). The former mutation impairs hormone binding, whereas the latter only decreases signal transduction. With both mutated receptors, activation of phospholipase C was markedly diminished, although it was not completely suppressed.

The Ser217Arg mutation is located on the same allele as the Gln106Arg mutation. It was thus studied either alone or in combination with the latter mutation. The Ser217Arg mutant did not bind the hormone (Fig. 3AGo). This deficiency was also observed with the double mutant Gln106Arg and Ser217Arg. Stimulation of phospholipase C by GnRH was in accordance with these results. Both the Ser217Arg mutated receptor and the double mutant (Gln106Arg and Ser217Arg) failed to increase inositol phosphate synthesis under the effect of GnRH (Fig. 3BGo).



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  		Figure 3. Functional studies of the wild-type and mutated GnRH receptors. A, Ligand binding. Transfected COS-7 cells were incubated with [125I]GnRH-A and increasing concentrations of unlabeled GnRH. B, Phospholipase C activation. Transfected cells were incubated with increasing concentrations of GnRH, and inositol phosphate accumulation was measured. Cell surface expression of the Arg262Gln mutant is similar to that of the wild-type receptor (4 ).

 
Gonadotropin secretion

In the propositus, LH and FSH plasma levels were very low and did not increase either after a single GnRH injection (Fig. 4AGo) or after the triptorelin challenge (Fig. 4BGo). After 6 months of treatment with hCG and FSH, his plasma testosterone level was 14.2 nmol/L. Ten days after the treatment was stopped, plasma LH and FSH levels remained very low and did not increase after the administration of GnRH. In the proband’s affected sisters, basal LH levels were low, but increased to 10 and 21 IU/L in patients II-2 and II-4, respectively, after GnRH administration, whereas plasma FSH increased to 5.5 and 6.0 IU/L, respectively (Fig. 4AGo).



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  		Figure 4. A, Plasma LH and FSH responses to GnRH (100 µg, iv) in the propositus (subject II-1) and the two affected sisters (subjects II-2 and II-4) of this family. B, Plasma gonadotropin levels in subject II-1 and in six normal men (21–27 yr) before and after the administration of a single triptorelin dose (100 µg, sc) at time zero (0800–0900 h).

 
Evaluation of spontaneous LH secretion in the propositus showed very low plasma LH levels and a complete absence of LH pulses (Fig. 5AGo). In addition, a complete absence of LH pulses was observed on day 10 of pulsatile GnRH administration (Fig. 5AGo). Furthermore, a complete absence of free {alpha}-subunit was observed before and on day 10 of pulsatile GnRH administration in this patient (Fig. 5BGo). Mean plasma LH levels were higher in both affected sisters than in the propositus, but no detectable pulses were observed (Fig. 6Go). LH pulses, synchronous with GnRH bolus and with a mean amplitude of 0.6 ± 0.2 IU/L, were detected in patient II-4 on day 10 of pulsatile GnRH administration (Fig. 6Go).



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  		Figure 5. A, Secretory patterns of LH in the propositus (subject II-1) before and on day 10 of pulsatile administration of GnRH. B, Free {alpha}-subunit secretion before and on day 10 of pulsatile administration of GnRH in subject II-1 (see Materials and Methods).

 


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  		Figure 6. Baseline secretory patterns of LH in the two affected sisters of this family. In patient II-4, LH secretion was also evaluated on day 10 of pulsatile administration of GnRH (see Materials and Methods. Arrows indicate an exogenous GnRH bolus (20 µg), and asterisks denote LH detectable pulses in subject II-4.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
We report here a novel family with IHH and loss of function mutations in the GnRH receptor. The previously described Arg262Gln mutation was present in one allele. This mutation affects a residue located in the third intracellular loop and partially decreased signal transduction, but did not impair hormone binding (4). The double mutation, Gln106Arg and Ser217Arg, located in the other allele completely abolished both hormone binding and activation of phospholipase C. The mutation Gln106Arg has previously been described and shown to markedly alter hormone binding (4). The mutation Ser217Arg, located in the fifth transmembrane span, displayed a similar defect when it was expressed alone. Analogous results indicating the functional importance of the latter domain have been obtained for several other G protein-coupled receptors (8). Ser217 is conserved in all mammalian GnRH receptors that have been cloned, except in the mouse, where it is replaced by a glycine (3). X-Ray studies of rhodopsin crystals have shown a close relationship between helixes 3 and 5 (9). Indeed, mutation of Lys121 (located in the third transmembrane span) into a neutral or acidic amino acid completely abolished GnRH binding (10). It is thus possible that alterations of the ionic environment in the third and fifth transmembrane domains inactivate the protein. Similar observations have been made for the angiotensin II receptor (11).

The propositus of the family described here displayed a complete IHH. The severity of gonadotropin deficiency was indicated by the very low levels of plasma gonadotropins, the apulsatile profile of endogenous LH and {alpha}-subunit secretion, and the absence of response of gonadotropins to GnRH or even to the potent GnRH agonist triptorelin. The complete resistance of pituitary gonadotropes to GnRH in this patient was confirmed by the failure of exogenous GnRH pulsatile administration to induce a pulsatile secretion of LH and free {alpha}-subunit (12). This phenotype was more severe than that previously described in a patient carrying the heterozygotic mutation Gln106Arg and Arg262Gln. This may be due to the additional mutation Ser217Arg, which completely abolishes phospholipase C activation by GnRH. A limited activation persisted in the Gln106Arg and Arg262Gln mutated receptors previously described (4).

The proband’s affected sisters had both a history of spontaneous thelarche and primary amenorrhea. Estradiol production was sufficient to promote breast pubertal changes in these patients, indicating a partial activation of ovarian steroidogenesis. However, estradiol secretion was not sufficient to achieve bone maturation and uterus development in patient II-4. The partial IHH, suggested by the clinical presentation, was confirmed by the evaluation of endogenous LH secretion, which showed higher LH levels in the affected sisters than in the propositus and normal GnRH-stimulated gonadotropin levels. The failure to detect LH pulses could be related to the decrease in LH pulse amplitude previously reported in patients with GnRH receptor dysfunction (4). Finally, in subject II-4 the partial pituitary defect was confirmed by the LH response to pulsatile GnRH administration. Marked clinical differences were thus observed in the affected kindred, although all three carried the same molecular abnormalities.

Such phenotypic differences may be due to a variety of factors. Several genes are probably involved in gonadotrope cell development, and functional allelic variation in such genes may affect GnRH action. Alternatively, there may be a sexual difference in the tolerance of alterations in GnRH function. Indeed, the most affected individual was a male; his sisters were more mildly affected. Sex differences in gonadotrope function have previously been described (13).

Clinically, these observations add more complexity to the task of detecting patients carrying GnRH receptor defects, as very different clinical expressions may be observed from complete to incomplete hypogonadism. It is also possible that mutations provoking minor functional receptor defects may result either in subjects having partial hypogonadism or presenting a normal phenotype.


   Acknowledgments
 
We thank Dr. J. C. Thalabard for performing statistical analysis of LH pulsatile profile.


   Footnotes
 
1 This work was supported by INSERM, the Faculté de Médecine Paris-Sud, and the Assistance Publique-Hôpitaux de Paris. Back

Received July 9, 1998.

Revised October 26, 1998.

Accepted October 27, 1998.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Kakar SS, Musgrove LC, Devor DC, Sellers JC, Neill JD. 1992 Cloning, sequencing, and expression of human gonadotropin releasing hormone (GnRH) receptor. Biochem Biophys Res Commun. 189:289–295.[CrossRef][Medline]
  2. Fan NC, Jeung EB, Peng C, Olofsson JI, Krisinger J, Leung PC. 1994 The human gonadotropin-releasing hormone (GnRH) receptor gene: cloning, genomic organization and chromosomal assignment. Mol Cell Endocrinol. 103:R1–R6.
  3. Stojilkovic SS, Reinhart J, Catt KJ. 1994 Gonadotropin-releasing hormone receptors: structure and signal transduction pathways. Endocr Rev. 15:462–499.[CrossRef][Medline]
  4. de Roux N, Young J, Misrahi M, et al. 1997 A family with hypogonadotropic hypogonadism and mutations in the gonadotropin-releasing hormone receptor. N Engl J Med. 337:1597–1602.[Free Full Text]
  5. Layman LC, Cohen DP, Jin M, et al. 1998 Mutations in gonadotropin-releasing hormone receptor gene cause hypogonadotropic hypogonadism. Nat Genet. 18:14–15.[CrossRef][Medline]
  6. Thomas G, Plu G, Thalabard JC. 1992 Identification of pulses in hormone time series using outlier detection methods. Stat Med. 11:2133–2145.[Medline]
  7. Chanson P, Pantel J, Young J, Couzinet B, Bidart JM, Schaison G. 1997 Free luteinizing-hormone beta-subunit in normal subjects and patients with pituitary adenomas. J Clin Endocrinol Metab. 82:1397–1402.[Abstract/Free Full Text]
  8. Baldwin JM. 1994 Structure and function of receptors coupled to G proteins. Curr Opin Cell Biol. 6:180–190.[CrossRef][Medline]
  9. Unger VM, Hargrave PA, Baldwin JM, Schertler GF. 1997 Arrangement of rhodopsin transmembrane alpha-helices. Nature. 389:203–206.[CrossRef][Medline]
  10. Zhou W, Rodic V, Kitanovic S, et al. 1995 A locus of the gonadotropin-releasing hormone receptor that differentiates agonist and antagonist binding sites. J Biol Chem. 270:18853–18857.[Abstract/Free Full Text]
  11. Conchon S, Barrault MB, Miserey S, Corvol P, Clauser E. 1997 The C-terminal third intracellular loop of the rat AT1A angiotensin receptor plays a key role in G protein coupling specificity and transduction of the mitogenic signal. J Biol Chem. 272:25566–25572.[Abstract/Free Full Text]
  12. Habiby RL, Boepple P, Nachtigall L, Sluss PM, Crowley Jr WF, Jameson JL. 1996 Adrenal hypoplasia congenita with hypogonadotropic hypogonadism: evidence that DAX-1 mutations lead to combined hypothalmic and pituitary defects in gonadotropin production. J Clin Invest. 98:1055–1062.[Medline]
  13. Tougard C, Tixier-Vidal A. 1994 Lactotropes and gonadotropes. In: Knobil E, Neill JD, eds. The physiology of reproduction. New York: Raven Press; 1711–1747.



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B. Karges, W. Karges, M. Mine, L. Ludwig, R. Kuhne, E. Milgrom, and N. de Roux
Mutation Ala171Thr Stabilizes the Gonadotropin-Releasing Hormone Receptor in Its Inactive Conformation, Causing Familial Hypogonadotropic Hypogonadism
J. Clin. Endocrinol. Metab., April 1, 2003; 88(4): 1873 - 1879.
[Abstract] [Full Text] [PDF]

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 J. Clin. Endocrinol. Metab.Home page
G. Y. Bedecarrats, K. D. Linher, and U. B. Kaiser
Two Common Naturally Occurring Mutations in the Human Gonadotropin-Releasing Hormone (GnRH) Receptor Have Differential Effects on Gonadotropin Gene Expression and on GnRH-Mediated Signal Transduction
J. Clin. Endocrinol. Metab., February 1, 2003; 88(2): 834 - 843.
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 Mol. Interv.Home page
P. M. Conn, A. Leanos-Miranda, and J. A. Janovick
Protein Origami: Therapeutic Rescue of Misfolded Gene Products
Mol. Interv., September 1, 2002; 2(5): 308 - 316.
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 J. Clin. Endocrinol. Metab.Home page
J. A. Janovick, G. Maya-Nunez, and P. M. Conn
Rescue of Hypogonadotropic Hypogonadism-Causing and Manufactured GnRH Receptor Mutants by a Specific Protein-Folding Template: Misrouted Proteins as a Novel Disease Etiology and Therapeutic Target
J. Clin. Endocrinol. Metab., July 1, 2002; 87(7): 3255 - 3262.
[Abstract] [Full Text] [PDF]

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S. N. Kalantaridou and G. P. Chrousos
Monogenic Disorders of Puberty
J. Clin. Endocrinol. Metab., June 1, 2002; 87(6): 2481 - 2494.
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L. F. G. Silveira, P. M. Stewart, M. Thomas, D. A. Clark, P. M. G. Bouloux, and G. S. MacColl
Novel Homozygous Splice Acceptor Site GnRH Receptor (GnRHR) Mutation: Human GnRHR "Knockout"
J. Clin. Endocrinol. Metab., June 1, 2002; 87(6): 2973 - 2977.
[Abstract] [Full Text] [PDF]

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 J. Clin. Endocrinol. Metab.Home page
G. Maya-Nunez, J. A. Janovick, A. Ulloa-Aguirre, D. Soderlund, P. M. Conn, and J. P. Mendez
Molecular Basis of Hypogonadotropic Hypogonadism: Restoration of Mutant (E90K) GnRH Receptor Function by a Deletion at a Distant Site
J. Clin. Endocrinol. Metab., May 1, 2002; 87(5): 2144 - 2149.
[Abstract] [Full Text] [PDF]

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L C Layman
Human gene mutations causing infertility
J. Med. Genet., March 1, 2002; 39(3): 153 - 161.
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 J. Clin. Endocrinol. Metab.Home page
N. Pitteloud, F. J. Hayes, P. A. Boepple, S. DeCruz, S. B. Seminara, D. T. MacLaughlin, and W. F. Crowley Jr.
The Role of Prior Pubertal Development, Biochemical Markers of Testicular Maturation, and Genetics in Elucidating the Phenotypic Heterogeneity of Idiopathic Hypogonadotropic Hypogonadism
J. Clin. Endocrinol. Metab., January 1, 2002; 87(1): 152 - 160.
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 J. Clin. Endocrinol. Metab.Home page
N. Pitteloud, P. A. Boepple, S. DeCruz, S. B. Valkenburgh, W. F. Crowley Jr., and F. J. Hayes
The Fertile Eunuch Variant of Idiopathic Hypogonadotropic Hypogonadism: Spontaneous Reversal Associated with a Homozygous Mutation in the Gonadotropin-Releasing Hormone Receptor
J. Clin. Endocrinol. Metab., June 1, 2001; 86(6): 2470 - 2475.
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 J. Clin. Endocrinol. Metab.Home page
E. M. F. Costa, G. Y. Bedecarrats, B. B. Mendonca, I. J. P. Arnhold, U. B. Kaiser, and A. C. Latronico
Two Novel Mutations in the Gonadotropin-Releasing Hormone Receptor Gene in Brazilian Patients with Hypogonadotropic Hypogonadism and Normal Olfaction
J. Clin. Endocrinol. Metab., June 1, 2001; 86(6): 2680 - 2686.
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M. Beranova, L. M. B. Oliveira, G. Y. BÉdÉcarrats, E. Schipani, M. Vallejo, A. C. Ammini, J. B. Quintos, J. E. Hall, K. A. Martin, F. J. Hayes, et al.
Prevalence, Phenotypic Spectrum, and Modes of Inheritance of Gonadotropin-Releasing Hormone Receptor Mutations in Idiopathic Hypogonadotropic Hypogonadism
J. Clin. Endocrinol. Metab., April 1, 2001; 86(4): 1580 - 1588.
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 J. Clin. Endocrinol. Metab.Home page
M.-L. Kottler, S. Chauvin, N. Lahlou, C. E. Harris, C. J. Johnston, J.-P. Lagarde, P. Bouchard, N. R. Farid, and R. Counis
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 Defect
J. Clin. Endocrinol. Metab., September 1, 2000; 85(9): 3002 - 3008.
[Abstract] [Full Text]

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 Mol. Endocrinol.Home page
S. H. Hoffmann, T. t. Laak, R. Kühne, H. Reiländer, and T. Beckers
Residues within Transmembrane Helices 2 and 5 of the Human Gonadotropin-Releasing Hormone Receptor Contribute to Agonist and Antagonist Binding
Mol. Endocrinol., July 1, 2000; 14(7): 1099 - 1115.
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 J. Clin. Endocrinol. Metab.Home page
S. B. Seminara, M. Beranova, L. M. B. Oliveira, K. A. Martin, W. F. Crowley Jr., and J. E. Hall
Successful Use of Pulsatile Gonadotropin-Releasing Hormone (GnRH) for Ovulation Induction and Pregnancy in a Patient with GnRH Receptor Mutations
J. Clin. Endocrinol. Metab., February 1, 2000; 85(2): 556 - 562.
[Abstract] [Full Text]

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