Original Article
The GPR54 Gene as a Regulator of Puberty
N Engl J Med 2003; 349:1614-1627October 23, 2003
- Abstract
Background
Puberty, a complex biologic process involving sexual development, accelerated linear growth, and adrenal maturation, is initiated when gonadotropin-releasing hormone begins to be secreted by the hypothalamus. We conducted studies in humans and mice to identify the genetic factors that determine the onset of puberty.
Methods
We used complementary genetic approaches in humans and in mice. A consanguineous family with members who lacked pubertal development (idiopathic hypogonadotropic hypogonadism) was examined for mutations in a candidate gene, GPR54, which encodes a G protein–coupled receptor. Functional differences between wild-type and mutant GPR54 were examined in vitro. In parallel, a Gpr54-deficient mouse model was created and phenotyped. Responsiveness to exogenous gonadotropin-releasing hormone was assessed in both the humans and the mice.
Results
Affected patients in the index pedigree were homozygous for an L148S mutation in GPR54, and an unrelated proband with idiopathic hypogonadotropic hypogonadism was determined to have two separate mutations, R331X and X399R. The in vitro transfection of COS-7 cells with mutant constructs demonstrated a significantly decreased accumulation of inositol phosphate. The patient carrying the compound heterozygous mutations (R331X and X399R) had attenuated secretion of endogenous gonadotropin-releasing hormone and a left-shifted dose–response curve for gonadotropin-releasing hormone as compared with six patients who had idiopathic hypogonadotropic hypogonadism without GPR54 mutations. The Gpr54–deficient mice had isolated hypogonadotropic hypogonadism (small testes in male mice and a delay in vaginal opening and an absence of follicular maturation in female mice), but they showed responsiveness to both exogenous gonadotropins and gonadotropin-releasing hormone and had normal levels of gonadotropin-releasing hormone in the hypothalamus.
Conclusions
Mutations in GPR54, a G protein–coupled receptor gene, cause autosomal recessive idiopathic hypogonadotropic hypogonadism in humans and mice, suggesting that this receptor is essential for normal gonadotropin-releasing hormone physiology and for puberty.
Media in This Article
Figure 1
Pedigree of a Family with Idiopathic Hypogonadotropic Hypogonadism.Figure 2
Targeted Deletion in the Gpr54 Locus in Mice.Article Activity
- Article
The neuroendocrine and genetic control of sexual maturation at puberty remains one of the great mysteries of human biology. The secretion of gonadotropin-releasing hormone by the hypothalamus represents the first known step in the reproductive cascade — initiating pulsatile release of gonadotropins, gonadal secretion of sex steroids, pubertal development, and gametogenesis. Although the central role of gonadotropin-releasing hormone in the reproductive hierarchy of all mammals is undisputed, little is understood of the genetic factors that modulate its secretion. The identification of such factors is critical for advancing the understanding of normal reproduction and for providing insight into disorders of the pubertal process.
We used complementary genetic approaches in humans and mice to study a gene involved in the onset of puberty. Idiopathic hypogonadotropic hypogonadism in humans is characterized by the absence of spontaneous sexual maturation in the face of concentrations of gonadotropins in the low-normal range. Affected patients have a complete or partial absence of luteinizing hormone pulsations induced by endogenous gonadotropin-releasing hormone1 and have normal responsiveness to physiological replacement with exogenous gonadotropin-releasing hormone. These observations localize the defect to an abnormality of gonadotropin-releasing hormone synthesis, secretion, or activity.2-4
Using linkage analysis and candidate-gene screening, we identified mutations in a G protein–coupled receptor gene, GPR54, in a large, consanguineous Saudi Arabian family with idiopathic hypogonadotropic hypogonadism and in one unrelated black male proband in the United States. Through a complementary approach, we generated Gpr54-deficient mice with a phenotype that demonstrated a lack of adult sexual development and low circulating gonadotropin concentrations — features that closely resemble their human counterparts.
Methods
Family History
A large Saudi Arabian family in which there had been three marriages between first cousins sought medical attention for infertility (Figure 1Figure 1
Pedigree of a Family with Idiopathic Hypogonadotropic Hypogonadism.). Six of the 19 offspring (4 men and 2 women) met the standard diagnostic criteria for idiopathic hypogonadotropic hypogonadism (inappropriately low gonadotropin concentrations in the presence of prepubertal concentrations of sex steroids, normal anterior pituitary function, and normal findings on imaging of the brain) and had responsiveness to exogenous, pulsatile gonadotropin-releasing hormone, as previously reported.5 The collection of blood samples for genetic studies and the clinical protocols were approved by the Subcommittee on Human Studies of the Massachusetts General Hospital, and all participants provided written informed consent.Mutation Analysis
Linkage to a 1.06-Mb interval on chromosome 19p13.3 was previously demonstrated.6 Mutation analysis of candidate genes, beginning with GPR54, was initiated with the use of DNA extracted from whole blood. The sequence of GPR54 complementary DNA (cDNA) (GenBank accession number AY253981) was aligned with the published genomic sequence7 to identify the genomic structure. Details of polymerase-chain-reaction (PCR) amplifications, sequencing, control populations, transient transfections, the targeting construct, and biochemical assays are provided in Supplementary Appendix 1 (available with the full text of this article at http://www.nejm.org).
Additional Populations
To determine whether the observed base-pair changes in GPR54 were normal variants, control populations of 80 North American persons (primarily anonymous blood donors), 50 Middle Eastern persons, and 50 black persons from North America were also screened. An additional 63 patients with normosmic idiopathic hypogonadotropic hypogonadism and 20 patients with anosmic idiopathic hypogonadotropic hypogonadism (Kallmann's syndrome) were also screened for coding-sequence mutations in GPR54. Six patients with normosmic idiopathic hypogonadotropic hypogonadism who had participated in dose–response studies of exogenous, pulsatile gonadotropin-releasing hormone and who were negative for GPR54 mutations on genomic screening were selected for comparisons of genotypes and phenotypes.
Allele-Specific Cloning
To demonstrate that there were base-pair changes on separate alleles, specific PCR products were cloned into a pCRII-TOPO plasmid vector (Invitrogen). Colonies were grown, and their DNA sequenced.
Reverse-Transcriptase PCR
Subjects in whom coding sequence changes were identified in GPR54 were further screened by means of reverse-transcriptase (RT)–PCR to rule out cryptic splicing events. Total RNA was extracted from lymphoblastoid cell lines, and GPR54 cDNA was amplified and sequenced.
Generation of Mutant Constructs
The sequence of the mammalian expression vector pCMVsport 6 containing full-length wild-type GPR54 (clone CS0DE005YC17, Invitrogen) was confirmed by direct sequencing and found to contain a polyA tail. Site-directed mutagenesis was performed to introduce the three mutations (L148S, R331X, and X399R) into this vector. In addition, a stop codon was introduced immediately after the polyA tail (the construct was called “X399R polyA stop”).
Studies of GPR54 Signaling
A natural ligand for GPR54, kisspeptin-1 (encoded by the gene KISS1), has been identified by three separate groups.8-10 Its C-terminal decapeptide kisspeptin-1 112–1219 was demonstrated to be the minimal-length peptide required for the full stimulation of GPR54 (the Gq class of G proteins, coupled to phospholipase C). Stimulation of GPR54 by kisspeptin-1 112–121 has been shown to increase phosphatidylinositol turnover.10
Kidney (COS-7) cells from African green monkeys were transiently transfected with 1.5 μg of each GPR54 construct or empty vector (pCMVsport6) per well, were stimulated with varying doses of kisspeptin-1 112–121 for 45 minutes, and were subsequently extracted with 20 mM of formic acid. Supernatants were loaded onto anion-exchange columns, and inositol phosphates were extracted.11 Assays were performed in triplicate.
Quantitative RT-PCR
Quantitative RT-PCR was performed on RNA isolated from immortalized lymphoblasts obtained from patients (TaqMan One-Step RT-PCR Master Mix, Applied Biosystems). Different primers and probes capable of specifically amplifying the R331X and X399R alleles were used. Samples were run in quadruplicate in a minimum of two independent experiments. The β-actin gene was used as an endogenous control to standardize the assays in terms of expression levels.
Genotype–Phenotype Correlations
The patient carrying mutations R331X and X399R was admitted to the General Clinical Research Center of the Massachusetts General Hospital. Blood sampling was performed every 10 minutes for 12 hours. The patient then received gonadotropin-releasing hormone subcutaneously every two hours, and his dose was titrated while he was an outpatient until his pituitary–gonadal axis had normalized. After 11 months of treatment, the patient underwent a dose–response study in which four doses of gonadotropin-releasing hormone spanning 1.5 logarithmic orders (7.5 to 250 ng per kilogram of body weight per bolus) were administered intravenously in random order, and luteinizing hormone was sampled frequently.12 Pulsatile hormone secretion was assessed with the use of the modified version of the method of Santen and Bardin.13,14
Studies in Mice
The transgenic mice (Gpr54tm1PTL ) were maintained as an inbred stock on a 129S6/SvEv genetic background. The gene-targeting strategy engineered a germ-line deletion of transmembrane loops 1 and 2 and the encompassing domains (Figure 2AFigure 2
Targeted Deletion in the Gpr54 Locus in Mice.). Correct targeting was verified for the 3' and 5' arms by Southern blotting and PCR (Figure 2B). The generation of a null Gpr54 allele was confirmed by RT-PCR (Figure 2C). Genotyping was performed by PCR (see Supplementary Appendix 2, available with the full text of this article at http://www.nejm.org). All experiments were performed under the authority of a U.K. Home Office Project License and were approved by a local ethics panel.Gonadotropin-Releasing Hormone Injection
Wild-type female mice were staged with the use of vaginal smears. Wild-type female mice at diestrus and Gpr54 –/– female mice received four intraperitoneal injections of 25 ng of gonadotropin-releasing hormone (Sigma) at 30-minute intervals.15 The mice were killed 30 minutes after the last injection. Blood samples and pituitary specimens were treated as previously described,15 except that the pituitary specimens were homogenized in 0.3 ml of phosphate-buffered saline.
Hormone Assays
The sensitivity of the immunoradiometric assay for luteinizing hormone was 0.07 ng per milliliter (intraassay variation, 6.0 percent; interassay variation, 12.5 percent), and the sensitivity of the radioimmunoassay for follicle-stimulating hormone was 2 ng per milliliter (intraassay variation, 10 percent; interassay variation, 18 percent). Gonadotropin-releasing hormone was measured by radioimmunoassay,16 with a detection limit of 0.2 pg per tube (0.83 pg per milliliter) and an intraassay variation of 13 percent. Testosterone was measured by radioimmunoassay, with a sensitivity of 0.2 nmol per liter (intraassay variation, 6.0 percent; interassay variation, 18 percent). 17β-estradiol was measured by enzyme-linked immunosorbent assay (ELISA), with a sensitivity of 10 pg per milliliter (intraassay variation, 3.9 percent; interassay variation, 10 percent).
Histologic Studies
Mouse tissues were dissected and fixed for four hours in 4 percent formaldehyde and were then washed three times in 0.01 percent phosphate-buffered saline. Ovaries, testes, and adrenal glands were wax-embedded and sectioned at 3 to 4 μm. Tissue sections were stained with hematoxylin and eosin. Mammary glands were dissected and fixed for 2 to 4 hours at 23°C in fixative (six parts absolute ethanol to three parts chloroform to one part glacial acetic acid), washed in 70 percent ethanol for 15 minutes, rehydrated, and stained overnight in carmine alum stain that has been boiled for 20 minutes in 500 ml of distilled water. Slides were washed in increasing concentrations of ethanol (70 percent, 95 percent, and 100 percent) for 15 minutes each, cleared in xylene for 30 minutes, and mounted.
Results
Mutation Analysis
Linkage in a consanguineous Saudi Arabian family was previously demonstrated on chromosome 19p13.3 with a maximal two-point lod score of 5.17.6 The candidate region on chromosome 19 contained 23 known genes,7 including GPR54, which is expressed in the human brain, pituitary gland, and placenta, as assessed with the use of RT-PCR.9,10 GPR54 has five exons and contains an open reading frame of 1197 bp that encodes a 398-amino-acid protein.
A homozygous single-nucleotide variant (443T>C) in exon 3, which substitutes a serine for the normal leucine at position 148 (L148S) in the second intracellular loop, was found in all six affected persons in the Saudi pedigree and did not occur in a homozygous state in any unaffected family members (all references to base-pair positions are reported according to standard numbering and nomenclature17) (see Supplementary Appendix 3, available with the full text of this article at http://www.nejm.org). This variant does not appear to be a polymorphism, since it occurs only in affected family members; is absent in 160 chromosomes from unrelated, unaffected controls from the United States and 100 chromosomes from controls from the Middle East; is present in an amino acid residue that is conserved among species including mouse, rat, amphioxus, and pufferfish (GenBank accession numbers AF343726, BAB55447, and AAM18884, and Fugu Genome Server18 accession number SINFRUP00000071513,19 respectively); and changes the polarity of the encoded amino acid from hydrophobic to neutral.
Of the 63 unrelated patients with normosmic idiopathic hypogonadotropic hypogonadism and the 20 patients with Kallmann's syndrome, one black man with idiopathic hypogonadotropic hypogonadism was discovered to have a heterozygous C-to-T transition at nucleotide 991 in exon 5, in which an arginine at residue 331 was replaced with a premature stop codon (991C>T [R331X]). In addition, a heterozygous T-to-A transversion was identified at nucleotide 1195 in exon 5, which replaced the stop codon at residue 399 with an arginine (1195T>A [X399R]) (Supplementary Appendix 3). This nonstop mutation results in the continuation of the open reading frame to the polyA signal, with no intervening stop codon. Neither change was identified in the 160 chromosomes from North American controls or the 100 chromosomes from black controls.
To confirm that the nonsense and nonstop mutations are found on separate chromosomes, allele-specific cloning was performed. Seventeen clones contained either R331X or X399R, and no clones contained both, confirming that the two variants occur on separate alleles (making the patient a compound heterozygote) (data not shown).
RT-PCR
RT-PCR products generated from the Saudi Arabian proband and the compound heterozygote were of the expected size for all segments. Sequence analysis of these products revealed that the newly identified mutations did not result in cryptic splicing (data not shown).
Functional Assays
To determine whether the identified changes in GPR54 affect the function of the receptor, inositol phosphate production was measured in COS-7 cells in response to kisspeptin-1 112–121. The maximal inositol phosphate response of the cells that were transfected with the mutant L148S and R331X constructs was decreased by 65 percent and 67 percent, respectively, as compared with the cells that were transfected with the wild-type gene (Figure 3AFigure 3
Dose–Response Curves for the Ligand-Stimulated Production of Inositol Phosphate in Mutant Constructs, Corrected for Protein Content. and Figure 3B). RT-PCR of COS-7 cells transfected with the X399R construct revealed a transcript that contained 3' untranslated region, polyA tail, and expression-vector sequence (data not shown). In the absence of the physiologic stop codon at position 399 (but with a stop codon in the vector sequence), the in vitro transcript resulted in an elongated receptor protein. Because this in vitro construct did not accurately mimic in vivo physiology, it was not used in the functional studies. The X399R polyA stop construct, which makes a protein identical to that encoded by the nonstop transcript, stimulates inositol phosphate production that is 61 percent of that of wild-type GPR54 (Figure 3C). No inositol phosphate stimulation was observed with pCMVsport 6.Quantitative RT-PCR
Expression analysis of the GPR54 alleles was performed by means of real-time PCR, with the use of lymphoblastic messenger RNA (mRNA) as a template. The mutant alleles were expressed at concentrations correlated with concentrations of control lymphoblasts. When compared with the standardized control mRNA, the mean (±SE) total concentration of GPR54 mRNA in the compound-heterozygous patient was 17.6±1.6 percent of the normal concentration (P<0.001 by Student's t-test); the expression concentration of the R331X allele was 17.9±1.9 percent of the normal concentration, and the expression concentration of the X399R allele was 2.5±0.3 percent of the normal concentration (Figure 3D).
Endocrinologic Phenotyping
A base-line profile of luteinizing hormone in the proband carrying the heterozygous mutations R331X and X399R is shown in Figure 4AFigure 4
Biochemical Phenotyping in a Patient Carrying the GPR54 Mutations R331X and X399R.. The patient had low concentrations of luteinizing hormone and low testosterone concentrations, particularly as compared with the mean (±2 SD) luteinizing hormone level measured in 20 normal men.20,21 Nonetheless, nine low-amplitude pulses of luteinizing hormone are present, as determined by formal pulse analysis. The responses to four doses of intravenous gonadotropin-releasing hormone are compared with the mean amplitude of luteinizing hormone pulses in six other patients with idiopathic hypogonadotropic hypogonadism who were treated with the same regimen (Figure 4B and Figure 4C). The dose–response curve for the proband is shifted leftward as compared with the 95 percent confidence intervals around the mean responses in men with idiopathic hypogonadotropic hypogonadism who did not have any GPR54 mutations.Pathophysiology, Anatomy, and Behavior of Homozygous Gpr54-Deficient Mice
Homozygous mutant mice (Gpr54 –/–) (Figure 2A and Figure 2B) were viable and obtained at the expected mendelian frequency from heterozygous breeding pairs (Figure 2B and Supplementary Appendix 2). RT-PCR analysis of transcripts showed no detectable transcription in the 3' end of the homozygous Gpr54tm1PTL allele (Figure 2C). Gpr54 +/– mice were phenotypically normal and were fertile. Gpr54 –/– mice did not display any of the physiologic changes associated with sexual maturation. The testes of male Gpr54 –/– mice were significantly smaller than those of age-matched controls (Figure 5AFigure 5
Gonadal Anatomy and Secondary Sexual Characteristics of Gpr54 –/– Mice.) (mean weight in nine Gpr54 –/– mice, 0.05±0.00 g; mean weight in eight age-matched controls, 0.18±0.01 g; P<0.001 by the unpaired Mann–Whitney U test) and did not contain spermatozoa in the lumen of the seminiferous tubules or the epididymis (Figure 5C, Figure 5D, Figure 5E, and Figure 5F). Primary spermatocytes were present, but there were very few haploid spermatids, which suggests that spermatogenesis had been initiated but had stopped before the meiotic-division stage.Male mice also lacked development of secondary sex glands, including the preputial gland (Figure 5G and Figure 5H), the seminal vesicles, and the prostate (not shown). In the adrenal glands of the mutant animals, the innermost region of the cortex, which normally regresses at puberty, was still present (Figure 5I and Figure 5J). Sexual mounting behavior was also not observed among the male mice. No gross morphologic abnormalities were found in the central nervous system of Gpr54 –/– mice, and the mutant mice thrived, apart from the reproductive defect.
Female mutant mice also had defective sexual development; they had small vaginal openings and did not become pregnant after appropriate mating exposure. Vaginal smears consisted of nonkeratinized epithelia and mucus strands similar to those observed in immature female mice, indicating the lack of an estrus cycle. The uterine horns in female Gpr54 –/– mice were threadlike, and the ovaries were significantly smaller than normal (mean weight in nine wild-type mice, 5.7±0.7 mg; mean weight in eight mutant mice, 1.0±0.1 mg; P<0.001 by the unpaired Mann–Whitney U test) (Figure 5B). Mammary tissue showed no postpubertal maturation of branched epithelial ducts (Figure 5K and Figure 5L). The ovaries contained primary and secondary follicles and occasionally an early antral follicle but no large graafian follicles or corpora lutea (Figure 5M and Figure 5N).
Endocrinologic Phenotypes in Gpr54-Deficient Mice
Male Gpr54 –/– mice had significantly lower blood testosterone concentrations than age-matched +/+ controls (mean among 12 mutant mice, 0.1±0.02 pg per milliliter; mean among 11 wild-type mice, 4.6±1.6 pg per milliliter; P<0.001 by the unpaired Mann–Whitney U test). The testosterone concentrations in male Gpr54 –/– mice were similar to those observed in female Gpr54 +/+ mice (mean among eight female mice, 0.2±0.02 pg per milliliter) (Figure 6AFigure 6
Hormone Levels in Gpr54 –/– Mice.). The 17β-estradiol concentrations in female Gpr54 –/– mice were similar to those in Gpr54 +/+ females at nonestrus stages of the reproductive cycle (Figure 6B) and to the base-line serum estradiol concentrations in male Gpr54 +/+ mice (data not shown). No Gpr54 –/– females were identified that had a 17β-estradiol concentration similar to that found at estrus (mean concentration among five wild-type females, 96.5±16.3 pg per milliliter) (Figure 6B).The lack of an estrus cycle in female mice was not caused by an inability of gonadal tissue to respond to gonadotropins. Female Gpr54 –/– mice could be induced to ovulate after sequential injection of the gonadotropins pregnant mares serum and human chorionic gonadotropin (data not shown). The lack of an estrus cycle and the failure to produce sperm in Gpr54 –/– mice were caused by a significant reduction in the serum follicle-stimulating hormone concentration (P=0.009) and a more moderate decrease in the luteinizing hormone concentration (Figure 6C and Figure 6D). Possible explanations of the reduced concentrations of circulating gonadotropins include an absence of pituitary gonadotropes, an inability of existing gonadotropes to respond to stimulation by gonadotropin-releasing hormone, and a lack of gonadotropin-releasing hormone production. This last possibility was ruled out because there was no significant difference between normal and mutant mice in the concentration of gonadotropin-releasing hormone in hypothalamic extracts (Figure 6E).
In addition, measurements of pituitary luteinizing hormone and follicle-stimulating hormone showed that although the total amount of each hormone was lower in Gpr54 –/– mice than in wild-type mice, significant quantities of each hormone were found, indicating that the pituitary gonadotropes are present in Gpr54 –/– mice and are capable of synthesizing luteinizing hormone and follicle-stimulating hormone. Furthermore, in adult female Gpr54 –/– mice, luteinizing hormone was secreted into the bloodstream in response to the injection of gonadotropin-releasing hormone (Figure 6F), and there was a corresponding depletion in pituitary luteinizing hormone (Figure 6G). Studies of the secretion of follicle-stimulating hormone in response to the injection of gonadotropin-releasing hormone had similar results (data not shown). Although the absolute concentration of serum luteinizing hormone after the injection of gonadotropin-releasing hormone was lower in Gpr54 –/– mice than in +/+ mice, the proportional increase in the luteinizing hormone concentration was similar (an increase by a factor of five from base line). These responses are consistent with a first exposure to gonadotropin-releasing hormone.22,23
Discussion
In primates, the hypothalamic–pituitary–gonadal axis is fully active during neonatal life, followed by a mysterious period of dormancy during childhood. The triggers of the onset of gonadotropin-releasing hormone secretion at puberty are as unclear as those that halt its secretion at the end of the neonatal period. Insight into this process has been gained through the study of various diseases in humans and animal models in which genetic defects cause abnormalities of sexual maturation. Mutations in both GPR54 in humans and Gpr54 in mice cause hypogonadotropic hypogonadism, pubertal delay, and sexual infantilism that can be corrected by the administration of exogenous gonadotropin-releasing hormone. Taken together, these observations establish that the effect of GPR54 on gonadotropin-releasing hormone secretion is conserved in multiple mammalian species and is a genetic determinant of sexual maturation.
GPR54 is a member of the rhodopsin family of G protein–coupled receptors whose sequences are most similar to those of members of the galanin-receptor family (35 to 40 percent identity).9 Although galanin and galanin-like peptide appear not to bind to GPR54,9,24 endogenous peptides derived from a precursor protein, kisspeptin-1, have recently been identified that do display agonist activity.8-10 The longest of these peptides is kisspeptin-1 68–121, or metastin, so called because of its ability to suppress metastatic potential in melanoma and breast-cancer cell lines.25-27 Metastin is secreted into the circulation by the placenta in relatively large quantities throughout gestation, although its physiologic role in pregnancy remains unknown.28
In this study, a variety of mutations in GPR54 were identified in patients with idiopathic hypogonadotropic hypogonadism. The index family was found to carry a homozygous L148S substitution. When expressed in cell lines, the L148S mutant construct markedly reduced inositol phosphate production as compared with the wild-type construct. A male patient with sporadic idiopathic hypogonadotropic hypogonadism was also found to be a compound heterozygote for the mutations R331X and X399R, which gave rise to nonsense and nonstop transcripts. It has been shown that mRNAs with premature termination codons can be targeted to nonsense-mediated decay,29 whereas mRNAs without an in-frame termination codon can be subject to nonstop decay, a recently identified degradation pathway that is initiated when the ribosome reaches the 3' terminal of the mRNA.30,31
We hypothesized that this combination of nonstop and nonsense mutations in GPR54 in the patient with sporadic idiopathic hypogonadotropic hypogonadism would result in the absence of a functional receptor. Quantitative RT-PCR confirmed the presence of dramatically reduced concentrations of GPR54 mRNA in the patient with the R331X and X399R alleles. Moreover, this total concentration appeared to be composed almost exclusively of the nonsense transcript. These results indicate that the contribution of the nonstop transcript was almost negligible, supporting the hypothesis of nonstop decay. In the unlikely event that a protein were produced by the X399R transcript, our findings regarding the X399R polyA stop construct suggest that it would function poorly.
The clinical phenotype of the patient carrying the R331X and X399R mutations was associated with a neuroendocrine profile involving low-amplitude pulses of luteinizing hormone, suggesting reduced secretion of gonadotropin-releasing hormone. This notion is supported by the leftward-shifted dose–response curve as compared with those for other patients with idiopathic hypogonadotropic hypogonadism who were undergoing the same therapy, suggesting that this patient was more sensitive to exogenous gonadotropin-releasing hormone. Since these studies were performed, deletions in GPR54 have been described in a separate family with idiopathic hypogonadotropic hypogonadism, although the phenotypic features of this family were not detailed.32 Although the investigators in that case agree with our conclusion that the frequency of GPR54 mutations as a cause of idiopathic hypogonadotropic hypogonadism is low (4 of 113 total cases), GPR54 reveals a new direction for the exploration of other genes that are essential for the secretion of gonadotropin-releasing hormone.
The Gpr54-deficient mice had striking physiological similarities to the patients with idiopathic hypogonadotropic hypogonadism, including a lack of sexual maturation associated with low concentrations of gonadotropins. In addition, their gonads remained sensitive to exogenous gonadotropins, and their pituitary gonadotropes remained responsive to stimulation by gonadotropin-releasing hormone. This strong similarity between the findings in the patients and those in the mouse model establishes a central role for GPR54 in gonadotropin-releasing hormone secretion and the onset of sexual maturation among mammalian species. Moreover, the use of Gpr54-deficient mice permitted the quantitation of their hypothalamic gonadotropin-releasing hormone concentrations, which were normal in the face of their hypogonadotropism. The presence of normal concentrations of gonadotropin-releasing hormone in the hypothalamus of Gpr54-deficient, sexually immature mice is reminiscent of prepubertal rats and monkeys who have normal numbers of gonadotropin-releasing hormone–containing neurons, normal mRNA concentrations, and normal concentrations of gonadotropin-releasing hormone in the hypothalamus.33,34 Extrapolation from the Gpr54-deficient mice to nonhuman primates and humans suggests that GPR54 may have a substantial effect on the processing or secretion of gonadotropin-releasing hormone.
There are three possible mechanisms that may allow abnormalities in GPR54 to cause pubertal delay. The first possibility is that defects in the metastin–GPR54 system perturb gonadotropin-releasing hormone neuronal migration that is analogous to the abnormal axonal targeting that occurs in the X-linked form of Kallmann's syndrome (idiopathic hypogonadotropic hypogonadism with anosmia).35-37 In vitro, the metastin–GPR54 system induces an “adhesive phenotype” with inhibition of chemotaxis, focal adhesions and stress fibers, and phosphorylation of focal adhesion kinase and paxillin.8 However, the normal content of gonadotropin-releasing hormone in the hypothalamus of Gpr54-deficient mice argues that there has been an appropriate migration of the neurons containing gonadotropin-releasing hormone from their origin in the olfactory placode to their destination in the hypothalamus. The possibility remains, however, that there is a subtle defect in the terminal migration or differentiation of these neurons within the hypothalamus.
The second possibility is that GPR54 modulates the activity of gonadotropin-releasing hormone at the level of the pituitary. The presence of small but detectable pulses of luteinizing hormone induced by gonadotropin-releasing hormone in the patient with the R331X and X399R mutations and his leftward-shifted dose–response curve suggest that pituitary responsiveness in the GPR54-deficient patient is, if anything, enhanced, suggesting that loss-of-function mutations in GPR54 do not diminish the sensitivity of gonadotropes to gonadotropin-releasing hormone.
The third possibility is that GPR54 regulates the release of gonadotropin-releasing hormone at the level of the hypothalamus. This hypothesis is supported by three observations: the low-amplitude pulses of luteinizing hormone in the patient carrying the R331X and X399R mutations, his leftward-shifted dose–response curve, and the normal content of gonadotropin-releasing hormone in the hypothalamus of Gpr54-deficient mice. Further studies will be required to determine the precise mechanisms of action within the hypothalamus as well as the physiological functions of the peptide ligands for GPR54.
Currently, it appears that the frequency of GPR54 mutations as a cause of idiopathic hypogonadotropic hypogonadism is not high. However, the elucidation of the role of GPR54 as a regulator of gonadotropin-releasing hormone–related physiology and puberty may well provide a seminal clue, offering a new perspective on other candidate genes that may control sexual maturation and puberty. These include the genes affecting the biosynthesis, processing, and secretion of the putative ligands, kisspeptin–metastin; the transcriptional regulation of GPR54 itself; and the signaling pathways downstream of the gene. Our data from patients with idiopathic hypogonadotropic hypogonadism and a mouse model provide strong evidence that GPR54 is a key regulator of the biology of puberty.
Supported by grants (U54 HD28138-13, 5R01 HD15788-17, 3M01 RR01066-22S2, GM61354, and T32 HD40135) from the National Institutes of Health.
Drs. Seminara, Messager, Chatzidaki, and Thresher contributed equally to the article. Drs. Crowley, Aparicio, and Colledge were the senior authors.
We are indebted to the staff of the General Clinical Research Center and the Reproductive Endocrine Unit of the Massachusetts General Hospital for their clinical care and investigation of patients with hypogonadotropic hypogonadism; to Alan Schneyer, Israel Sidis, Gregoy Bedecarrats, and Sandra Ryeom for their insights and expertise in molecular biology; to Cricket and Jon Seidman, David Altshuler, and Eric Lander for their advice regarding genetic analysis; to the Genomics and Peptide Core Facilities of Massachusetts General Hospital; to Victoria Petkova of the TaqMan Real-Time PCR Core Laboratory of the Beth Israel Deaconess Medical Center; to Astrid Meysing for assistance with sequencing; to Dr. A. Caraty from the Unité Mixte de Recherche Physiologie de la Reproduction et des Comportements, Institut National de la Recherche Agronomique, Nouzilly, France, for assistance with the gonadotropin-releasing hormone radioimmunoassay; to the Ligand Core Laboratory, supported by grant U54 HD28934; and to all the patients with hypogonadotropic hypogonadism who have donated their time, energy, and blood samples and have been our coinvestigators.
Source Information
From the Reproductive Endocrine Unit (S.B.S., J.S.A., J.K.S., K.M.S., W.F.C.) and the Molecular Neurogenetics Unit, Center for Human Genetic Research (S.A.S., J.F.G.), Massachusetts General Hospital; the Division of Endocrinology, Diabetes, and Hypertension, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School (W.K., U.B.K.); and the Harvard Institute of Human Genetics, Harvard Medical School (S.A.S., J.F.G.) — all in Boston; Paradigm Therapeutics (S.M., R.R.T., A.G.H., D.Z., J.D., M.B.L.C., S.A.J.R.A, W.H.C.); the Departments of Physiology (E.E.C., W.H.C.), Oncology (S.A.J.R.A.), and Clinical Biochemistry (S.O.) and the Cambridge Institute for Medical Research, Addenbrooke's Hospital (S.O.), University of Cambridge, Cambridge, United Kingdom; and the Faculty of Medicine, Kuwait University, Al-Jabriyah (Y.B.-A.).
Address reprint requests to Dr. Colledge at whc23@cam.ac.uk; to Dr. Aparicio at Paradigm Therapeutics, 214 Cambridge Science Park, Milton Rd., Cambridge CB4 0WA, United Kingdom, or at saparicio@paradigm-therapeutics.com; or to Dr. Crowley at the Reproductive Endocrine Unit, BHX 505, Massachusetts General Hospital, 55 Fruit St., Boston, MA 02114, or at crowley.william@mgh.harvard.edu.
- References
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- Citing Articles (346)
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C. True, M. A. Kirigiti, P. Kievit, K. L. Grove, M. S. Smith. (2011) Leptin is not the Critical Signal for Kisspeptin or Luteinising Hormone Restoration During Exit from Negative Energy Balance. Journal of Neuroendocrinology 23:11, 1099-1112
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J.C. BARNES, KEVIN M. BEAVER, BRIAN B. BOUTWELL. (2011) EXAMINING THE GENETIC UNDERPINNINGS TO MOFFITT'S DEVELOPMENTAL TAXONOMY: A BEHAVIORAL GENETIC ANALYSIS*. Criminology 49:4, 923-954
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J.T. Smith. (2011) The role of kisspeptin and gonadotropin inhibitory hormone in the seasonal regulation of reproduction in sheep. Domestic Animal Endocrinology
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Manuel Tena-Sempere, Alicia Felip, Ana Gómez, Silvia Zanuy, Manuel Carrillo. (2011) Comparative insights of the kisspeptin/kisspeptin receptor system: Lessons from non-mammalian vertebrates. General and Comparative Endocrinology
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William F. Crowley. (2011) The developmental biology of the GnRH neurons. Molecular and Cellular Endocrinology 346:1-2, 1-3
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Julie A. Chowen, Jesús Argente. (2011) Leptin and the brain. Hormone Molecular Biology and Clinical Investigation 7:2, 351-360
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G. Pacheco-Cuellar, L. M. González-Huerta, J. M. Valdés-Miranda, H. Peláez-González, S. Zenteno-Bacheron, J. Cazarin-Barrientos, S. A. Cuevas-Covarrubias. (2011) Hereditary sensory and autonomic neuropathy II due to novel mutation in the HSN2 gene in Mexican families. Journal of Neurology 258:10, 1890-1892
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Margaret G. Au, William F. Crowley, Cassandra L. Buck. (2011) Genetic counseling for isolated GnRH deficiency. Molecular and Cellular Endocrinology 346:1-2, 102-109
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Y. Uenoyama, N. Inoue, V. Pheng, T. Homma, K. Takase, S. Yamada, K. Ajiki, M. Ichikawa, H. Okamura, K.-I. Maeda, H. Tsukamura. (2011) Ultrastructural Evidence of Kisspeptin-Gonadotrophin-Releasing Hormone (GnRH) Interaction in the Median Eminence of Female Rats: Implication of Axo-Axonal Regulation of GnRH Release. Journal of Neuroendocrinology 23:10, 863-870
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Ravikumar Balasubramanian, William F. Crowley. (2011) Isolated GnRH deficiency: A disease model serving as a unique prism into the systems biology of the GnRH neuronal network. Molecular and Cellular Endocrinology 346:1-2, 4-12
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Fazal Wahab, Richard Quinton, Stephanie B. Seminara. (2011) The kisspeptin signaling pathway and its role in human isolated GnRH deficiency. Molecular and Cellular Endocrinology 346:1-2, 29-36
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Milena Gurgel Teles, Leticia Ferreira Gontijo Silveira, Cintia Tusset, Ana Claudia Latronico. (2011) New genetic factors implicated in human GnRH-dependent precocious puberty: The role of kisspeptin system. Molecular and Cellular Endocrinology 346:1-2, 84-90
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Q.Q. Tang, M.X. Chu, G.L. Cao, L. Fang, R. Di, T. Feng, D.W. Huang, N. Li. (2011) Association between polymorphism of GPR54 gene and litter size in Small Tail Han sheep. Livestock Science
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Carol F. Elias. (2011) Leptin action in pubertal development: recent advances and unanswered questions. Trends in Endocrinology & Metabolism
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Nicolas Chartrel, Jessy Alonzeau, David Alexandre, Lydie Jeandel, Rodrigo Alvear-Perez, Jérôme Leprince, Jean Boutin, Hubert Vaudry, Youssef Anouar, Catherine Llorens-Cortes. (2011) The RFamide neuropeptide 26RFa and its role in the control of neuroendocrine functions. Frontiers in Neuroendocrinology 32:4, 387-397
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Victor M. Navarro, Manuel Tena-Sempere. (2011) Neuroendocrine control by kisspeptins: role in metabolic regulation of fertility. Nature Reviews Endocrinology
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J. S. Redmond, G. M. Baez-Sandoval, K. M. Spell, T. E. Spencer, C. A. Lents, G. L. Williams, M. Amstalden. (2011) Developmental Changes in Hypothalamic Kiss1 Expression during Activation of the Pulsatile Release of Luteinising Hormone in Maturing Ewe Lambs. Journal of Neuroendocrinology 23:9, 815-822
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L. Ansel, A. H. Bentsen, C. Ancel, M. Bolborea, P. Klosen, J. D. Mikkelsen, V. Simonneaux. (2011) Peripheral kisspeptin reverses short photoperiod-induced gonadal regression in Syrian hamsters by promoting GNRH release. Reproduction 142:3, 417-425
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David García-Galiano, Leonor Pinilla, Manuel Tena-Sempere. (2011) Sex Steroids and the Control of the Kiss1 System: Developmental Roles and Major Regulatory Actions. Journal of Neuroendocrinologyno-no
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Johanna K. Mueller, Anja Dietzel, Alejandro Lomniczi, Alberto Loche, Katrin Tefs, Wieland Kiess, Thomas Danne, Sergio R. Ojeda, Sabine Heger. (2011) Transcriptional regulation of the human KiSS1 gene. Molecular and Cellular Endocrinology 342:1-2, 8-19
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Byung Jun Ryu, Han Rae Kim, Jin Kwon Jeong, Byung Ju Lee. (2011) Regulation of the female rat estrous cycle by a neural cell-specific epidermal growth factor-like repeat domain containing protein, NELL2. Molecules and Cells 32:2, 203-207
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Iain J. Clarke. (2011) Control of GnRH secretion: One step back. Frontiers in Neuroendocrinology 32:3, 367-375
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J. Pasquier, A.-G. Lafont, J. Leprince, H. Vaudry, K. Rousseau, S. Dufour. (2011) First evidence for a direct inhibitory effect of kisspeptins on LH expression in the eel, Anguilla anguilla. General and Comparative Endocrinology 173:1, 216-225
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G. L. Cao, M. X. Chu, L. Fang, T. Feng, R. Di, N. Li. (2011) Analysis on DNA sequence of GPR54 gene and its association with litter size in goats. Molecular Biology Reports 38:6, 3839-3848
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Jimena Pita, Vicente Barrios, Teresa Gavela-Pérez, Gabriel Á. Martos-Moreno, María T. Muñoz-Calvo, Jesús Pozo, Adela Rovira, Jesús Argente, Leandro Soriano-Guillén. (2011) Circulating kisspeptin levels exhibit sexual dimorphism in adults, are increased in obese prepubertal girls and do not suffer modifications in girls with idiopathic central precocious puberty. Peptides
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Yann Le Page, Mélanie Vosges, Arianna Servili, François Brion, Olivier Kah. (2011) Neuroendocrine Effects of Endocrine Disruptors in Teleost Fish. Journal of Toxicology and Environmental Health, Part B 14:5-7, 370-386
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Dávid Csercsik, Imre Farkas, Erik Hrabovszky, Zsolt Liposits. (2011) A simple integrative electrophysiological model of bursting GnRH neurons. Journal of Computational Neuroscience
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Daniel Alexander Beyer, Feriel Amari, Marc Thill, Askan Schultze-Mosgau, Safaa Al-Hasani, Klaus Diedrich, Georg Griesinger. (2011) Emerging gonadotropin-releasing hormone agonists. Expert Opinion on Emerging Drugs 16:2, 323-340
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Zhifang Xu, Shigehito Kaga, Jun Tsubomizu, Jun Fujisaki, Akikazu Mochiduki, Takafumi Sakai, Hiroko Tsukamura, Kei-ichiro Maeda, Kinji Inoue, Akihito A. Adachi. (2011) Circadian transcriptional factor DBP regulates expression of Kiss1 in the anteroventral periventricular nucleus. Molecular and Cellular Endocrinology 339:1-2, 90-97
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Yathindar S. Rao, Natasha N. Mott, Toni R. Pak. (2011) Effects of kisspeptin on parameters of the HPA axis. Endocrine 39:3, 220-228
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Carmen Capito, Alexis Arnaud, Frederic Hameury, Benjamin Fremond, Hubert Lardy, Marc David Leclair, Yves Heloury. (2011) Dysgerminoma and gonadal dysgenesis: The need for a new diagnosis tree for suspected ovarian tumours. Journal of Pediatric Urology 7:3, 367-372
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S. Constantin. (2011) Physiology of the Gonadotrophin-Releasing Hormone (GnRH) Neurone: Studies from Embryonic GnRH Neurones. Journal of Neuroendocrinology 23:6, 542-553
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Suzanne M Moenter. (2011) No holy grail for puberty. Nature Neuroscience 14:6, 670-672
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Christian Mayer, Ulrich Boehm. (2011) Female reproductive maturation in the absence of kisspeptin/GPR54 signaling. Nature Neuroscience 14:6, 704-710
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Stefanie Klenke, Winfried Siffert. (2011) SNPs in genes encoding G proteins in pharmacogenetics. Pharmacogenomics 12:5, 633-654
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Jimena Pita, Sandra Rado-Peralta, Teresa Gavela-Pérez, Isabel Aragón, Vicente Barrios, Adela Rovira, Jesús Argente, Leandro Soriano-Guillén. (2011) Plasma kisspeptin levels are elevated in cord blood and present sexual dimorphism in the adult population: Relation with leptin, gonadotropins and anthropometrical data. Peptides 32:5, 983-988
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Azim R. Khan, Alexander S. Kauffman. (2011) The Role of Kisspeptin and RFRP-3 Neurons in the Circadian-Timed Preovulatory Luteinizing Hormone Surge. Journal of Neuroendocrinologyno-no
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F. M. Pinto, A. Cejudo-Román, C. G. Ravina, M. Fernández-Sánchez, D. Martín-Lozano, M. Illanes, M. Tena-Sempere, M. L. Candenas. (2011) Characterization of the kisspeptin system in human spermatozoa. International Journal of Andrologyno-no
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Sandra M. Losa, Karina L. Todd, Alana W. Sullivan, Jinyan Cao, Jillian A. Mickens, Heather B. Patisaul. (2011) Neonatal exposure to genistein adversely impacts the ontogeny of hypothalamic kisspeptin signaling pathways and ovarian development in the peripubertal female rat. Reproductive Toxicology 31:3, 280-289
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Takeshi Iwasa, Toshiya Matsuzaki, Masahiro Murakami, Riyo Kinouchi, Ganbat Gereltsetseg, Satoshi Yamamoto, Akira Kuwahara, Toshiyuki Yasui, Minoru Irahara. (2011) Delayed puberty in prenatally glucocorticoid administered female rats occurs independently of the hypothalamic Kiss1–Kiss1r–GnRH system. International Journal of Developmental Neuroscience 29:2, 183-188
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Ning Xu, Hyung-Goo Kim, Balasubramanian Bhagavath, Sung-Gyu Cho, Jae Ho Lee, Kyungsoo Ha, Irene Meliciani, Wolfgang Wenzel, Robert H. Podolsky, Lynn P. Chorich, Kathryn A. Stackhouse, Anna M.H. Grove, Lawrence N. Odom, Metin Ozata, David P. Bick, Richard J. Sherins, Soo-Hyun Kim, Richard S. Cameron, Lawrence C. Layman. (2011) Nasal embryonic LHRH factor (NELF) mutations in patients with normosmic hypogonadotropic hypogonadism and Kallmann syndrome. Fertility and Sterility 95:5, 1613-1620.e7
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Anna L. Mitchell, Andrew Dwyer, Nelly Pitteloud, Richard Quinton. (2011) Genetic basis and variable phenotypic expression of Kallmann syndrome: towards a unifying theory. Trends in Endocrinology & Metabolism
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J. Clarkson, A. E. Herbison. (2011) Dual Phenotype Kisspeptin-Dopamine Neurones of the Rostral Periventricular Area of the Third Ventricle Project to Gonadotrophin-Releasing Hormone Neurones. Journal of Neuroendocrinology 23:4, 293-301
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Mete Ozcan, Ergul Alcin, Ahmet Ayar, Bayram Yılmaz, Suleyman Sandal, Haluk Kelestimur. (2011) Kisspeptin-10 elicits triphasic cytosolic calcium responses in immortalized GT1-7 GnRH neurones. Neuroscience Letters 492:1, 55-58
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K. Krabchi, I. Berthaut, S. Chantot-Bastaraud, C. Ravel, N. Chabbert-Buffet, V. de Larouzière, P. Bouchard, J. Mandelbaum, J.-P. Siffroi, S. Christin-Maitre. (2011) Quality assessment of induced spermatogenesis in hypogonadotrophic hypogonadic men treated with gonadotrophins. Reproductive BioMedicine Online 22:3, 277-283
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Lorah D. Dorn, Frank M. Biro. (2011) Puberty and Its Measurement: A Decade in Review. Journal of Research on Adolescence 21:1, 180-195
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Alejandro Martinez-Aguayo, Mehul T Dattani, John C Achermann. 2011. Gonadotropin Hormones: Disorders. .
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W. Les Dees, Jill K. Hiney, Vinod K. Srivastava. 2011. Actions of Manganese on Pubertal Development. , 195-209.
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Jose Donato, Roberta M. Cravo, Renata Frazão, Laurent Gautron, Michael M. Scott, Jennifer Lachey, Inar A. Castro, Lisandra O. Margatho, Syann Lee, Charlotte Lee, James A. Richardson, Jeffrey Friedman, Streamson Chua, Roberto Coppari, Jeffrey M. Zigman, Joel K. Elmquist, Carol F. Elias. (2011) Leptin’s effect on puberty in mice is relayed by the ventral premammillary nucleus and does not require signaling in Kiss1 neurons. Journal of Clinical Investigation 121:1, 355-368
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Wendy Saltzman, Suzette D. Tardif, Julienne N. Rutherford. 2011. Hormones and Reproductive Cycles in Primates. , 291-327.
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Pei-San Tsai. 2011. Neuroendocrine Control of Reproduction in Amphibians. , 21-37.
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Leah M Prentice, Xavier d'Anglemont de Tassigny, Steven McKinney, Teresa Ruiz de Algara, Damian Yap, Gulisa Turashvili, Steven Poon, Margaret Sutcliffe, Pat Allard, Angela Burleigh, John Fee, David G Huntsman, William H Colledge, Samuel AJ Aparicio. (2011) The testosterone-dependent and independent transcriptional networks in the hypothalamus of Gpr54 and Kiss1 knockout male mice are not fully equivalent. BMC Genomics 12:1, 209
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Faiqah Ramzan, Irfan Zia Qureshi. (2011) Intraperitoneal kisspeptin-10 administration induces dose-dependent degenerative changes in maturing rat testes. Life Sciences 88:5-6, 246-256
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Olivier Kah, Sylvie Dufour. 2011. Conserved and Divergent Features of Reproductive Neuroendocrinology in Teleost Fishes. , 15-42.
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Young Jun Rhie, Kee Hyoung Lee, So Hee Eun, Byung Min Choi, Hyun Wook Chae, Ah Reum Kwon, Woo Jung Lee, Jung Hyun Kim, Ho-Seong Kim. (2011) Serum Kisspeptin Levels in Korean Girls with Central Precocious Puberty. Journal of Korean Medical Science 26:7, 927
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