FSHR

Gene Summary

Gene:FSHR; follicle stimulating hormone receptor
Aliases: LGR1, ODG1, FSHRO
Location:2p21-p16
Summary:The protein encoded by this gene belongs to family 1 of G-protein coupled receptors. It is the receptor for follicle stimulating hormone and functions in gonad development. Mutations in this gene cause ovarian dysgenesis type 1, and also ovarian hyperstimulation syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2010]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:follicle-stimulating hormone receptor
HPRD
Source:NCBIAccessed: 25 June, 2015

Ontology:

What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 25 June 2015 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • China
  • Diabetes Mellitus, Type 2
  • Single Nucleotide Polymorphism
  • Gene Expression Regulation
  • Genetic Predisposition
  • Puberty, Precocious
  • Case-Control Studies
  • Genotype
  • Ovarian Cancer
  • Ovary
  • Haplotypes
  • Ovulation Induction
  • Receptors, FSH
  • Cohort Studies
  • Infertility, Female
  • Pregnancy
  • Polymorphism
  • Signal Transduction
  • Follicle Stimulating Hormone
  • Genetic Association Studies
  • Messenger RNA
  • Polymerase Chain Reaction
  • Chromosome 2
  • Base Sequence
  • Alleles
  • Testosterone
  • Childhood Cancer
  • Granulosa Cell Tumor
  • Restriction Fragment Length Polymorphism
  • Asian Continental Ancestry Group
  • Amino Acid Substitution
  • Validation Studies as Topic
  • Polycystic Ovary Syndrome
  • Genetic Loci
  • Risk Factors
  • European Continental Ancestry Group
  • Testicular Cancer
  • Singapore
  • Receptors, LH
  • Sperm Injections, Intracytoplasmic
Tag cloud generated 25 June, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (2)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: FSHR (cancer-related)

Qiu L, Liu J, Hei QM
Association between two polymorphisms of follicle stimulating hormone receptor gene and susceptibility to polycystic ovary syndrome: a meta-analysis.
Chin Med Sci J. 2015; 30(1):44-50 [PubMed] Related Publications
OBJECTIVE: To investigate the association between two polymorphisms of follicle stimulating hormone receptor (FSHR) gene and polycystic ovary syndrome (PCOS) susceptibility.
METHODS: Case-control studies on relationship of Thr307Ala and Asn680Ser polymorphisms in FSHR gene and PCOS susceptibility were searched from PubMed, ISI web of knowledge, EBSCO, and China National Knowledge Infrastructure (CNKI) databases up to March 21, 2013. The pooled odds ratio (OR) and 95% confidence interval (CI) were calculated using fixed- or random-effect model based on heterogeneity test in 5 genotype models analyses.
RESULTS: A total of 11 studies were included in the Meta-analysis. The random-effect analysis showed Asn680Ser was significantly associated with the reduced susceptibility to PCOS with dominant model (Asn/Asn+Asn/Ser vs. Ser/Ser, OR=0.83, 95% CI: 0.69-1.00), recessive model (Asn/Asn vs. Asn/Ser+ Ser/Ser, OR=0.84, 95% CI: 0.72-0.98), homozygote comparison (Asn/Asn vs. Ser/Ser, OR=0.79, 95% CI: 0.63-0.98), and the allele contrast (Asn vs. Ser, OR=0.87, 95% CI: 0.79-0.97) respectively(P=0.02, I(2)=56.0%), being protective factors for PCOS. However, no significant associations were found between Thr307Ala and PCOS.
CONCLUSION: There might be a significant association between Asn680Ser polymorphism and PCOS.

Singhasena W, Pantasri T, Piromlertamorn W, et al.
Follicle-stimulating hormone receptor gene polymorphism in chronic anovulatory women, with or without polycystic ovary syndrome: a cross-sectional study.
Reprod Biol Endocrinol. 2014; 12:86 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Polymorphisms at codons 307 and 680 are the most commonly encountered allelic variants of the follicle-stimulating hormone receptor (FSHR) gene. Studies in Caucasians suggest that certain FSHR variants are more common in women with polycystic ovary syndrome (PCOS) than normal women. The objective of this study was to determine the distribution of FSHR gene polymorphisms at codons 307 and 680 in Thai women with chronic anovulation, without (121 women) and with PCOS (133 women), using 132 known fertile women as controls.
METHODS: DNA samples from peripheral blood lymphocytes were extracted and analyzed by polymerase chain reaction-restriction fragment length polymorphism.
RESULTS: The prevalence of Threonine307Threonine (TT), Threonine307Alanine (TA), and Alanine307Alanine (AA) genotypes at codon 307 was 53.0% (95% CI = 44.2-61.7%), 42.4% (95% CI = 34-51.3%), and 4.5% (95% CI = 1.9-10.1%) in controls; 52.6% (95% CI = 43.8-61.3%), 39.8% (95% CI = 31.6-48.7%), and 7.5% (95% CI = 3.9-13.7%) in PCOS women; and 50.4% (95% CI = 42.8-61.2%), 45.4% (95% CI = 34.9-53.1%), and 4.5% (95% CI = 1.5-9.6%) in anovulatory women without PCOS, respectively. The prevalence of Asparagine680Asparagine (NN), Asparagine680Serine (NS), and Serine680Serine (SS) genotypes at codon 680 was 54.5% (95% CI = 45.7-63.2%), 40.9% (95% CI = 32.5-49.8%), and 4.5% (95% CI = 1.9-10.1%) in controls; 51.9% (95% CI = 43.1-60.6%), 44.4% (95% CI = 35.8-53.2%), and 3.8% (95% CI = 1.4-9.0%) in PCOS women; and 47.9% (95% CI = 40.4-58.8%), 47.1% (95% CI = 36.5-54.7%), and 5.0% (95% CI = 2-10.9%) in anovulatory women without PCOS, respectively. The prevalence of FSHR gene polymorphisms at both codons were not statistically different among the three groups.
CONCLUSIONS: In Thai women, there was no association between the FSHR gene polymorphism at codons 307 and 680 and chronic anovulation.

Welt CK, Duran JM
Genetics of polycystic ovary syndrome.
Semin Reprod Med. 2014; 32(3):177-82 [PubMed] Free Access to Full Article Related Publications
The etiology of polycystic ovary syndrome (PCOS) has been difficult to determine because its features are heterogeneous, and its origin may also be heterogeneous. Twin studies suggest that its etiology is strongly heritable and genetic approaches are rapidly uncovering new regions of the genome that appear to confer risk for PCOS. Recent genome-wide association studies in Han Chinese women with PCOS demonstrate 11 genetic loci that are associated with PCOS. The variants identified are in regions that contain genes important for gonadotropin action, genes that are associated with risk for type 2 diabetes, and other genes in which the relationship to PCOS is not yet clear. Replication studies have demonstrated that variants at several of these loci also confer risk for PCOS in women of European ethnicity. The strongest loci in Europeans contain genes for DENND1A and THADA, with additional associations in loci containing the LHCGR and FSHR, YAP1 and RAB5/SUOX. The next steps in uncovering the pathophysiology borne out by these loci and variants will include mapping to determine the causal variant and gene, phenotype studies to determine whether these regions are associated with particular features of PCOS and functional studies of the causal variant to determine the direct cause of PCOS based on the underlying genetics. The next years will be very exciting times as groups from around the world come together to further elucidate the genetic origins of PCOS.

Qin X, Ma L, Yang S, et al.
The Asn680Ser polymorphism of the follicle stimulating hormone receptor gene and ovarian cancer risk: a meta-analysis.
J Assist Reprod Genet. 2014; 31(6):683-8 [PubMed] Free Access to Full Article Related Publications
PURPOSE: The purpose of this study was to conduct a meta-analysis to assess the association between FSHR Asn680Ser polymorphism and ovarian cancer susceptibility.
METHODS: A literature search was conducted in PubMed, Embase and the China National Knowledge Infrastructure (CNKI) for all relevant studies published up to September 2013. The pooled odds ratios (ORs) with the corresponding 95 % confidence intervals (95 % CIs) were calculated to evaluate the association.
RESULTS: Four case-control studies including 474 ovarian cancer cases and 659 controls met the inclusion criteria. The pooled analyses showed that FSHR Asn680Ser polymorphism was associated with the risk of ovarian cancer (Ser vs Asn: OR=1.295, 95 % CI 1.057-1.498, P=0.01; Ser/Ser + Asn/Ser vs Asn/Asn: OR=1.611, 95 % CI 1.027-2.528, P=0.038). Subgroup analyses by ethnicity (Caucasian and Asian) further revealed significant associations among Asians (Ser vs Asn: OR=1.386, 95 % CI 1.066-1.802, P=0.015; Ser/Ser + Asn/Ser vs Asn/Asn: OR=1.893, 95 % CI 1.329-2.689, P=0.000) but not Caucasians. There was no obvious risk of publication bias.
CONCLUSIONS: The meta-analysis suggests that FSHR Asn680Ser polymorphism may be a risk factor for ovarian cancer in Asians. Due to the limited quantity of the included studies, further studies are needed to validate the above conclusions.

Wu XQ, Xu SM, Liu JF, et al.
Association between FSHR polymorphisms and polycystic ovary syndrome among Chinese women in north China.
J Assist Reprod Genet. 2014; 31(3):371-7 [PubMed] Free Access to Full Article Related Publications
PURPOSE: Polycystic ovary syndrome (PCOS) is a common endocrine disorder disease among women in reproductive-age. Since follicle stimulating hormone (FSH) exerts important biological functions, the association between PCOS and FSH receptor (FSHR) polymorphisms attracts wide attention. The aim of this study was to evaluate whether polymorphisms of FSHR at 307 and 680 codons are associated with PCOS patients in China.
METHODS: Patients with PCOS (n = 215) and controls (n = 205) were recruited from Shanxi Province in north China. They are Han ethnics. Genomic DNA was isolated from the venous blood. The Ala307Thr and Ser680Asn polymorphisms of FSHR were analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and direct DNA sequencing.
RESULTS: The distributions of genotype and allele of Ala307Thr and Ser680Asn polymorphisms of FSHR were not statistically different between the PCOS patients and the controls. Analysis of the frequency of FSHR polymorphisms showed no statistical difference among the PCOS patients with different obesity standards. Although there were no statistical differences in the most of the endocrine parameters including LH, LH/FSH, E2, P and T as well as the clinical pregnancy rate, there were significant differences in the levels of FSH and PRL among PCOS patients carrying different genotypes of Ala307Thr and Ser680Asn polymorphisms.
CONCLUSION: The Ala307Thr and Ser680Asn polymorphisms of FSHR are not associated with PCOS in Han ethnic Chinese women in north China. The FSHR polymorphisms was related to the levels of FSH and PRL but not other PCOS-associated endocrine hormones as well as clinical pregnancy rate in PCOS patients of Han Chinese ethnical population.

Louwers YV, Stolk L, Uitterlinden AG, Laven JS
Cross-ethnic meta-analysis of genetic variants for polycystic ovary syndrome.
J Clin Endocrinol Metab. 2013; 98(12):E2006-12 [PubMed] Related Publications
CONTEXT: Genome-wide association studies (GWAS) have revealed new susceptibility loci for Chinese patients with polycystic ovary syndrome (PCOS). Because ethnic background adds to phenotypic diversities in PCOS, it seems plausible that genetic variants associated with PCOS act differently in various ethnic populations.
OBJECTIVE: We studied cross-ethnic effects of Chinese PCOS loci (ie, LHCGR, THADA, DENND1A, FSHR, c9orf3, YAP1, RAB5B/SUOX, HMGA2, TOX3, INSR, SUMO1P1) in patients of Northern European descent.
DESIGN: This study was a genetic association study conducted at an University Medical Center.
PATIENTS: Association was studied in 703 Dutch PCOS patients and 2164 Dutch controls. To assess the cross-ethnic effect, we performed a meta-analysis of the Dutch data combined with results of previously published studies in PCOS patients from China (n = 2254) and the United States (n = 2618). Adjusted for multiple testing, a P value <3.1 × 10⁻³ was considered statistically significant.
RESULTS: Meta-analysis of the Chinese, US, and Dutch data resulted in 12 significant variants mapping to the YAP1 (P value = 1.0 × 10⁻⁹), RAB5B/SUOX (P value = 3.8 × 10⁻¹¹), LHCGR (P value = 4.1 × 10⁻⁴), THADA (P value = 2.2 × 10⁻⁴ and P value = 1.3 × 10⁻³), DENND1A (P value = 2.3 × 10⁻³ and P value = 2.5 × 10⁻³), FSHR (P value = 3.8 × 10⁻⁵ and P value = 3.6 × 10⁻⁴), c9orf3 (P value = 2.0 × 10⁻⁶ and P value = 9.2 × 10⁻⁶), SUMO1P1 (P value = 2.3 × 10⁻³) loci with odds ratios ranging from 1.19 to 1.45 and 0.79 to 0.87.
CONCLUSIONS: Overall, we observed for 12 of 17 genetic variants mapping to the Chinese PCOS loci similar effect size and identical direction in PCOS patients from Northern European ancestry, indicating a common genetic risk profile for PCOS across populations. Therefore, it is expected that large GWAS in PCOS patients from Northern European ancestry will partly identify similar loci as the GWAS in Chinese PCOS patients.

Uchida S, Uchida H, Maruyama T, et al.
Molecular analysis of a mutated FSH receptor detected in a patient with spontaneous ovarian hyperstimulation syndrome.
PLoS One. 2013; 8(9):e75478 [PubMed] Free Access to Full Article Related Publications
Spontaneous ovarian hyperstimulation syndrome (sOHSS) is a rare event that may result from a FSH-producing pituitary adenoma (FSHoma), activating mutations of the FSH receptor (FSHR), and cross-reactivity of the FSHR to elevated hCG and TSH in the setting of pregnancy or hypothyroidism. The objective of this study was to investigate whether an aberrant FSHR was present in a woman with sOHSS and a non-surgically diagnosed FSHoma whose serum FSH levels and FSH bioactivity were nearly normal. Sequencing of the patient's FSHR gene revealed a heterozygous novel missense mutation c. 1536G>A resulting in an amino acid substitution M512I. We asked whether this mutant FSHR affected FSHR-mediated signaling pathways involving cAMP/protein kinase A (PKA), phosphatidylinositol-3 kinase (PI3K)/protein kinase B (AKT) and v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog kinase (SRC)/ p42/p44 extracellular signal-regulated protein kinases (ERK1/2). Thus, 293T cells expressing wild-type (FSHRwt), the mutant FSHR (FSHRmt), or both (FSHRwt/mt) were treated with FSH and subjected to measurements of intracellular cAMP, cAMP-induced CRE (cAMP response element)-mediated luciferase assays and immunoblot analyses of phosphorylated PI3K and ERK1/2. There were no differences in luciferase activities or phosphorylation levels of ERK1/2 among FSHRwt, FSHRmt cells and FSHwt/mt cells. However, FSHRmt cells showed a significant reduction in both cAMP production and PI3K phosphorylation levels with unchanged phosphorylation of ERK1/2 upon FSH stimulation in comparison to FSHwt cells. Also, FSH treatment did not provoke PI3K phosphorylation in FSHwt/mt cells. These results indicate that the novel missense M512I FSHR mutation identified herein did not participate in hyperactivation of FSHR-mediated signaling pathways but rather in hypoactivation of the FSH-mediated PI3K/AKT pathway. Thus, this study demonstrates a new functional property of this novel mutatnt FSHR, which, however, might not be involved in the pathogenesis of sOHSS in this FSHoma patient.

Heublein S, Mayr D, Vrekoussis T, et al.
The G-protein coupled estrogen receptor (GPER/GPR30) is a gonadotropin receptor dependent positive prognosticator in ovarian carcinoma patients.
PLoS One. 2013; 8(8):e71791 [PubMed] Free Access to Full Article Related Publications
Follicle stimulating hormone receptor (FSHR) and luteinizing hormone receptor (LHCGR) were demonstrated to impact upon survival of patients suffering from epithelial ovarian cancer (EOC). Though structure wise the G-protein coupled estrogen receptor (GPER/GPR30) is related to FSHR/LHCGR, its prognostic impact in EOC remains controversial. We recently found that FSHR negative patients represent a specific EOC subgroup that may behave differently in respect to both treatment response and prognosis. Hence, the current study aimed to analyze how GPER may interact with the FSHR/LHCGR system in EOC and whether the prognostic significance of GPER in EOC cases (n=151) may be dependent on the FSHR/LHCGR immunophenotype of the tumor. Ovarian cancer cell lines were used to study how FSH and LH regulate GPER and whether GPER activation differentially affects in vitro cell proliferation in presence/absence of activated FSHR/LHCGR. In EOC tissue, GPER correlated with FSHR/LHCGR and was related to prolonged overall survival only in FSHR/LHCGR negative patients. Although GPER was found to be specifically induced by LH/FSH, GPER agonists (4-Hydroxy-Tamoxifen, G1) reduced EOC cell proliferation only in case of LH/FSH unstimulated pathways. To the same direction, only patients characterized as LHCGR/FSHR negative seem to gain from GPER in terms of survival. Our combined tissue and in vitro results support thus the hypothesis that GPER activation could be of therapeutic benefit in LHCGR/FSHR negative EOC patients. Further studies are needed to evaluate the impact of GPER activation on a clinical scheme.

Rice S, Elia A, Jawad Z, et al.
Metformin inhibits follicle-stimulating hormone (FSH) action in human granulosa cells: relevance to polycystic ovary syndrome.
J Clin Endocrinol Metab. 2013; 98(9):E1491-500 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Women with anovulatory polycystic ovary syndrome (PCOS) are generally insulin-resistant and as a consequence are often treated with the biguanide metformin. Results with metformin have, however, been variable with some studies demonstrating induction of regular cycles and an increase in ovulation, whereas others do not. Hence more understanding is needed regarding the mechanism of metformin's actions in ovarian granulosa cells especially in light of previous demonstrations of direct actions.
OBJECTIVE: The aim of this study was to investigate metformin's interaction with the FSH/cAMP/protein kinase A pathway, which is the primary signaling pathway controlling CYP19A1 (aromatase) expression in the ovary.
METHODS: The effect of metformin on FSH and forskolin-stimulated aromatase expression in human granulosa cells was measured by quantitative real-time PCR. Activity was assessed after transfection with a promoter II-luciferase construct, and by an RIA measuring conversion of androgen to estrogens. The effect on FSH receptor (FSHR) mRNA was assessed by quantitative PCR. Levels of phosphorylated cAMP response element binding protein (CREB) and CREB-regulated transcription coactivator 2 (CRTC2) were measured by Western blotting and cAMP by a bioluminescent assay.
RESULTS: Metformin markedly reduced FSH but not forskolin-stimulated aromatase expression and activity. This effect was exerted by inhibition of basal and ligand-induced up-regulation of FSHR expression. Metformin also reduced FSH-induced phosphorylation of CREB and hence CRE activity, which could potentially disrupt the CREB-CREB-binding protein-CRTC2 coactivator complex that binds to CRE in promoter II of the aromatase gene. This is mediated in an AMP-activated protein kinase-independent manner, and does not involve alteration of cAMP levels.
CONCLUSION: These finding have implications for the use of metformin in the treatment of anovulation in women with PCOS.

Onori P, Mancinelli R, Franchitto A, et al.
Role of follicle-stimulating hormone on biliary cyst growth in autosomal dominant polycystic kidney disease.
Liver Int. 2013; 33(6):914-25 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is a common genetic disorder characterized by the progressive development of renal and hepatic cysts. Follicle-stimulating hormone (FSH) has been demonstrated to be a trophic factor for biliary cells in normal rats and experimental cholestasis induced by bile duct ligation (BDL).
AIMS: To assess the effect of FSH on cholangiocyte proliferation during ADPKD using both in vivo and in vitro models.
METHODS: Evaluation of FSH receptor (FSHR), FSH, phospho-extracellular-regulated kinase (pERK) and c-myc expression in liver fragments from normal patients and patients with ADPKD. In vitro, we studied proliferating cell nuclear antigen (PCNA) and cAMP levels in a human immortalized, non-malignant cholangiocyte cell line (H69) and in an immortalized cell line obtained from the epithelium lining the hepatic cysts from the patients with ADPKD (LCDE) with or without transient silencing of the FSH gene.
RESULTS: Follicle-stimulating hormone is linked to the active proliferation of the cystic wall and to the localization of p-ERK and c-myc. This hormone sustains the biliary growth by activation of the cAMP/ERK signalling pathway.
CONCLUSION: These results showed that FSH has an important function in cystic growth acting on the cAMP pathway, demonstrating that it provides a target for medical therapy of hepatic cysts during ADPKD.

Anagnostou E, Drakakis P, Marinopoulos S, et al.
The impact of genetics profile (gene polymorphisms) in obese non-PCOS women entering an IVF/ICSI program.
Curr Drug Targets. 2013; 14(8):850-5 [PubMed] Related Publications
Data concerning the effects of increased body mass index (BMI) on ovarian and pregnancy outcome are rich, but the results are rather controversial. Regarding pharmacogenetics, gene polymorphisms of hormonal receptor genes, such as Estrogen Receptor alpha (ESR1), Estrogen Receptor beta (ESR2) and FSH receptor (FSHR) genes, are associated with ovarian stimulation and pregnancy outcome and may constitute a useful tool for ART experts for the prediction of this outcome. The aim of this study is to track differences in the distribution of gene polymorphisms among obese non-PCOS and non-obese patients concerning three distinct genes which are involved in the ovarian stimulation mechanism: PvuII polymorphism of ESR1 gene, RsaI polymorphism of ESR2 gene and Ser680Asn variation of FSHR gene, using restriction fragment length polymorphism analysis and real-time polymerase chain reaction. A total of 151 normally ovulating female patients underwent IVF or ICSI. Interestingly, the pregnancy rate in the BMI≥30 kg/m² group was higher in a statistically significant way (40.9% versus 17.8%, p=0.023). The obese patients of this study were in need of increased total FSH dose in order to achieve a satisfactory oocyte number (p<0.001) and needed more days of stimulation (p=0.002), but also presented lower basal FSH levels (p=0.032), which may explain, to an extend, the better pregnancy outcome. Concerning the polymorphisms of ESR1, ESR2 and FSHR genes, we did not observe differences in the genotype distribution when we compared the obese non-PCOS population with the non-obese population. Thus, obesity does not constitute an additional indication to perform a genetic analysis before entering an IVF/ICSI program.

Fu L, Zhang Z, Zhang A, et al.
Association study between FSHR Ala307Thr and Ser680Asn variants and polycystic ovary syndrome (PCOS) in Northern Chinese Han women.
J Assist Reprod Genet. 2013; 30(5):717-21 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Polycystic ovary syndrome (PCOS) is a common complex genetic endocrinopathy. It has high heritability, and twin studies indicate that it is a complex polygenic disorder. Searching for major genes of PCOS is crucial to clarify its molecular pathogenesis. A previous genome-wide association study in Chinese women with PCOS identified a region on chromosome 2p16.3 that encodes the follicle-stimulating hormone receptor (FSHR) genes as a reproducible PCOS susceptibility locus. In the present study, we performed a replication analysis of the association between two common variants of the FSHR gene and PCOS in Northern Chinese Han women.
RESULTS: We recruited 384 unrelated PCOS patients and 768 healthy individuals from the Shaanxi province in the northern part of China. Two polymorphisms (Ala307Thr and Ser680Asn) of the FSHR gene and the clinical characteristics of the study subjects were analyzed in the case-control sample. The frequency of FSHR Ala307Thr and Ser680Asn variants along with the haplotype was not significantly different between the PCOS patients and the controls; however, the Ser680 variants may be associated with high levels of FSH and low E2 levels.
CONCLUSION: The variant of Ser680 was not associated with PCOS but it may be related to high FSH levels. The present study suggests that the two variants of the FSHR gene are not a causative factor of PCOS in Northern Chinese Han women.

Layman LC
The genetic basis of female reproductive disorders: etiology and clinical testing.
Mol Cell Endocrinol. 2013; 370(1-2):138-48 [PubMed] Free Access to Full Article Related Publications
With the advent of improved molecular biology techniques, the genetic basis of an increasing number of reproductive disorders has been elucidated. Mutations in at least 20 genes cause hypogonadotropic hypogonadism including Kallmann syndrome in about 35-40% of patients. The two most commonly involved genes are FGFR1 and CHD7. When combined pituitary hormone deficiency includes hypogonadotropic hypogonadism as a feature, PROP1 mutations are the most common of the six genes involved. For hypergonadotropic hypogonadism, mutations in 14 genes cause gonadal failure in 15% of affected females, most commonly in FMR1. In eugonadal disorders, activating FSHR mutations have been identified for spontaneous ovarian hyperstimulation syndrome; and WNT4 mutations have been described in mullerian aplasia. For other eugonadal disorders, such as endometriosis, polycystic ovary syndrome, and leiomyomata, specific germline gene mutations have not been identified, but some chromosomal regions are associated with the corresponding phenotype. Practical genetic testing is possible to perform in both hypogonadotropic and hypergonadotropic hypogonadism and spontaneous ovarian hyperstimulation syndrome. However, clinical testing for endometriosis, polycystic ovary syndrome, and leiomyomata is not currently practical for the clinician.

Hersmus R, Stoop H, Turbitt E, et al.
SRY mutation analysis by next generation (deep) sequencing in a cohort of chromosomal Disorders of Sex Development (DSD) patients with a mosaic karyotype.
BMC Med Genet. 2012; 13:108 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The presence of the Y-chromosome or Y chromosome-derived material is seen in 4-60% of Turner syndrome patients (Chromosomal Disorders of Sex Development (DSD)). DSD patients with specific Y-chromosomal material in their karyotype, the GonadoBlastoma on the Y-chromosome (GBY) region, have an increased risk of developing type II germ cell tumors/cancer (GCC), most likely related to TSPY. The Sex determining Region on the Y gene (SRY) is located on the short arm of the Y-chromosome and is the crucial switch that initiates testis determination and subsequent male development. Mutations in this gene are responsible for sex reversal in approximately 10-15% of 46,XY pure gonadal dysgenesis (46,XY DSD) cases. The majority of the mutations described are located in the central HMG domain, which is involved in the binding and bending of the DNA and harbors two nuclear localization signals. SRY mutations have also been found in a small number of patients with a 45,X/46,XY karyotype and might play a role in the maldevelopment of the gonads.
METHODS: To thoroughly investigate the presence of possible SRY gene mutations in mosaic DSD patients, we performed next generation (deep) sequencing on the genomic DNA of fourteen independent patients (twelve 45,X/46,XY, one 45,X/46,XX/46,XY, and one 46,XX/46,XY).
RESULTS AND CONCLUSIONS: The results demonstrate that aberrations in SRY are rare in mosaic DSD patients and therefore do not play a significant role in the etiology of the disease.

Mutharasan P, Galdones E, Peñalver Bernabé B, et al.
Evidence for chromosome 2p16.3 polycystic ovary syndrome susceptibility locus in affected women of European ancestry.
J Clin Endocrinol Metab. 2013; 98(1):E185-90 [PubMed] Free Access to Full Article Related Publications
CONTEXT: A previous genome-wide association study in Chinese women with polycystic ovary syndrome (PCOS) identified a region on chromosome 2p16.3 encoding the LH/choriogonadotropin receptor (LHCGR) and FSH receptor (FSHR) genes as a reproducible PCOS susceptibility locus.
OBJECTIVE: The objective of the study was to determine the role of the LHCGR and/or FSHR gene in the etiology of PCOS in women of European ancestry.
DESIGN: This was a genetic association study in a European ancestry cohort of women with PCOS.
SETTING: The study was conducted at an academic medical center.
PARTICIPANTS: Participants in the study included 905 women with PCOS diagnosed by National Institutes of Health criteria and 956 control women.
INTERVENTION: We genotyped 94 haplotype-tagging single-nucleotide polymorphisms and two coding single-nucleotide polymorphisms mapping to the coding region of LHCGR and FSHR plus 20 kb upstream and downstream of the genes and test for association in the case control cohort and for association with nine quantitative traits in the women with PCOS.
RESULTS: We found strong evidence for an association of PCOS with rs7562215 (P = 0.0037) and rs10495960 (P = 0.0046). Although the marker with the strongest association in the Chinese PCOS genome-wide association study (rs13405728) was not informative in the European populations, we identified and genotyped three markers (rs35960650, rs2956355, and rs7562879) within 5 kb of rs13405728. Of these, rs7562879 was nominally associated with PCOS (P = 0.020). The strongest evidence for association mapping to FSHR was observed with rs1922476 (P = 0.0053). Furthermore, markers with the FSHR gene region were associated with FSH levels in women with PCOS.
CONCLUSIONS: Fine mapping of the chromosome 2p16.3 Chinese PCOS susceptibility locus in a European ancestry cohort provides evidence for association with two independent loci and PCOS. The gene products LHCGR and FSHR therefore are likely to be important in the etiology of PCOS, regardless of ethnicity.

Scholz C, Heublein S, Lenhard M, et al.
Glycodelin A is a prognostic marker to predict poor outcome in advanced stage ovarian cancer patients.
BMC Res Notes. 2012; 5:551 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Glycodelin is a cell surface glycoprotein offering a unique gender specific carbohydrate configuration. Sialylated carbohydrate structures, which are unusual for mammals, characterize Glycodelin isolated from amniotic fluid (Glycodelin A, GdA). Glycodelin in general exerts multiple, partly opposing functions ranging from immunosuppression to cell differentiation. As these markedly influence tumorigenesis, this study aimed to clarify whether expression of different Glycodelin isoforms is related to clinicopathological characteristics and prognosis of ovarian cancer patients. Further the use of Glycodelin as a serum marker in benign and malignant ovarian diseases was evaluated.
METHODS: Ovarian cancer specimens (n = 152) were stained for Glycodelin with carbohydrate and peptide specific antibodies. Associations between Glycodelin expression and histological grading, FIGO stage as well as patient's prognosis were examined. Glycodelin was correlated to expression of gonadotropin receptors and mucin-1, which are discussed as ovarian cancer tissue markers. In addition, Glycodelin serum concentrations were analyzed in patients suffering from benign (n = 73) or malignant (n = 38) ovarian neoplasias.
RESULTS: Glycodelin A was found to be an independent prognostic marker for poor prognosis in advanced ovarian cancer patients. GdA staining correlated with gonadotropin receptor (FSHR and LHCGR) and with hCG expression. Gd expression showed a positive correlation with a tumour-associated epitope of mucin 1 (TA-MUC1). Further, compared to ovarian cancer, serum Gd was increased in patients with benign ovarian tumors.
CONCLUSION: Glycodelin A might be related to tumor aggressiveness and poor clinical outcome in advanced epithelial ovarian cancer. Glycodelin serum levels found in patients suffering from benign ovarian tumors, might contribute to a more global attenuation during progression of these precursor lesions.

Guzman L, Adriaenssens T, Ortega-Hrepich C, et al.
Human antral follicles <6 mm: a comparison between in vivo maturation and in vitro maturation in non-hCG primed cycles using cumulus cell gene expression.
Mol Hum Reprod. 2013; 19(1):7-16 [PubMed] Related Publications
Within the context of an oocyte in vitro maturation (IVM) program for reproductive treatment, oocyte cumulus complexes (COCs) derived from follicles <6 mm in patients with PCOS were matured in vitro. Key transcripts related to meiotic maturation (FSHR, LHCGR, EGFR, PGR) and oocyte competence (AREG, ADAMTS, HAS2, PTGS2) were quantified in cumulus cells (CCs) before and after maturation. Control CC samples were collected from PCOS and normo-ovulatory patients who had undergone conventional gonadotrophin stimulation for IVF/ICSI. Additional control samples from a non-stimulated condition were obtained ex vivo from patients undergoing ovariectomy for fertility preservation. Expression data from CCs from follicles with a diameter of <6 mm before (IVM-CCs) and after in vitro maturation (IVM-CCs) were obtained after pooling CCs into four groups in relation to the percentage of matured (MII) oocytes obtained after 40 h of IVM (0; 40-60; 61-80; 100% MII) and values were compared with in vivo matured controls (IVO-CCs). Genes encoding key receptors mediating meiotic resumption are expressed in human antral follicles of <6 mm before and after IVM. The expression levels of FSHR, EGFR and PGR in CCs were significantly down-regulated in the IVO-CCs groups and in the 100% MII IVM group compared with the BM groups; all the receptors studied in the 100% MII IVM group reached an expression profile similar to that of IVO-CCs. However, after maturation in a conventional IVF/ICSI cycle, IVO-CCs from large follicles contained significantly increased levels of ADAMTS1, AREG, HAS2 and PTGS2 compared with IVM-CCs and IVM-CCs; the expression patterns for these genes in all IVM-CCs were unchanged compared with IVM-CCs. In conclusion, genes encoding receptors involved in oocyte meiotic resumption appeared to be expressed in CCs of small human antral follicles. Expression levels of genes-encoding factors reflecting oocyte competence were significantly altered in IVM-CCs compared with in vivo matured oocytes from large follicles. Observed differences might be explained by the different stimulation protocols, doses of gonadotrophin or by the intrinsic differences between in vivo and in vitro maturation.

Shi Y, Zhao H, Shi Y, et al.
Genome-wide association study identifies eight new risk loci for polycystic ovary syndrome.
Nat Genet. 2012; 44(9):1020-5 [PubMed] Related Publications
Following a previous genome-wide association study (GWAS 1) including 744 cases and 895 controls, we analyzed genome-wide association data from a new cohort of Han Chinese (GWAS 2) with 1,510 polycystic ovary syndrome (PCOS) cases and 2,016 controls. We followed up significantly associated signals identified in the combined results of GWAS 1 and 2 in a total of 8,226 cases and 7,578 controls. In addition to confirming the three loci we previously reported, we identify eight new PCOS association signals at P < 5 × 10(-8): 9q22.32, 11q22.1, 12q13.2, 12q14.3, 16q12.1, 19p13.3, 20q13.2 and a second independent signal at 2p16.3 (the FSHR gene). These PCOS association signals show evidence of enrichment for candidate genes related to insulin signaling, sexual hormone function and type 2 diabetes (T2D). Other candidate genes were related to calcium signaling and endocytosis. Our findings provide new insight and direction for discovering the biological mechanisms of PCOS.

Sardella C, Russo D, Raggi F, et al.
Ectopic expression of FSH receptor isoforms in neoplastic but not in endothelial cells from pancreatic neuroendocrine tumors.
J Endocrinol Invest. 2013; 36(3):174-9 [PubMed] Related Publications
FSH receptor (FSHR) expression is restricted to gonads, where it drives FSH-dependent cell differentiation; in addition, FSHR plays an important role in the regulation of ovarian angiogenesis. Recently, FHSR expression has been shown in blood vessels of various tumors. However, pancreatic neuroendocrine tumors (p-NET), which have high-degree blood supply, were not included in that study. The aim of this study was to evaluate FSHR expression in p-NET. FSHR expression was evaluated in tumor samples from 30 patients with p-NET by immunohistochemistry and Western blot; fluorescence microscopy was used to localize FSHR in specific cells from tissue samples. von Willebrand factor (vWF) and chromograninA (chrA) was used as blood vessel and NET cells marker, respectively, to co-localize FSHR. FSHR expression was detected in all p-NET by immunohistochemistry. Western blot confirmed FSHR expression on p- NET although different FSHR isoforms, ranging from 240 kD to 55 kD were found in the samples studied. Surprisingly, FSHR co-localized with chrA but not with vWF, suggesting that neoplastic cells of neuroendocrine origin rather than blood vessels expressed FSHR. No relationship was found between degree of FSHR expression and histology of p-NET. FSHR may be aberrantly expressed in neoplastic cells from p-NET and not in tumor blood vessels; however, its biological significance as well as its clinical relevance remains to be elucidated.

Mohiyiddeen L, Salim S, Mulugeta B, et al.
PCOS and peripheral AMH levels in relation to FSH receptor gene single nucleotide polymorphisms.
Gynecol Endocrinol. 2012; 28(5):375-7 [PubMed] Related Publications
OBJECTIVES: To determine if an association exists between the follicle-stimulating hormone receptor (FSHR) gene p.Asn680Ser polymorphism and polycystic ovary syndrome (PCOS) or with high anti-mullerian hormone (AMH) levels without PCOS.
PATIENTS: Fifty-eight women with PCOS, 24 women with high AMH (>44.5 pmol/L) without PCOS and 80 healthy ethnically matched female controls.
MAIN OUTCOME MEASURES: Prevalence of the FSHR p.Asn680Ser polymorphism, baseline serum AMH levels and response to ovulation induction with clomiphene citrate.
RESULTS: The frequency of FSHR p.Asn680Ser genotypes were not significantly different between PCOS patients, patients with high AMH without PCOS and controls (p = 0.88). Of the women with PCOS, 34/58 were on clomiphene citrate treatment and 12/34 were resistant. There was no association between sensitivity or resistance to clomiphene and p.Asn680Ser genotypes (p = 0.38).
CONCLUSIONS: There is no evidence that FSHR p.Asn680Ser genotypes are associated with PCOS, high AMH levels or response to clomiphene citrate.

Eggers S, Sinclair A
Mammalian sex determination—insights from humans and mice.
Chromosome Res. 2012; 20(1):215-38 [PubMed] Free Access to Full Article Related Publications
Disorders of sex development (DSD) are congenital conditions in which the development of chromosomal, gonadal, or anatomical sex is atypical. Many of the genes required for gonad development have been identified by analysis of DSD patients. However, the use of knockout and transgenic mouse strains have contributed enormously to the study of gonad gene function and interactions within the development network. Although the genetic basis of mammalian sex determination and differentiation has advanced considerably in recent years, a majority of 46,XY gonadal dysgenesis patients still cannot be provided with an accurate diagnosis. Some of these unexplained DSD cases may be due to mutations in novel DSD genes or genomic rearrangements affecting regulatory regions that lead to atypical gene expression. Here, we review our current knowledge of mammalian sex determination drawing on insights from human DSD patients and mouse models.

Benko S, Gordon CT, Mallet D, et al.
Disruption of a long distance regulatory region upstream of SOX9 in isolated disorders of sex development.
J Med Genet. 2011; 48(12):825-30 [PubMed] Related Publications
BACKGROUND: The early gonad is bipotential and can differentiate into either a testis or an ovary. In XY embryos, the SRY gene triggers testicular differentiation and subsequent male development via its action on a single gene, SOX9. The supporting cell lineage of the bipotential gonad will differentiate as testicular Sertoli cells if SOX9 is expressed and conversely will differentiate as ovarian granulosa cells when SOX9 expression is switched off.
RESULTS: Through copy number variation mapping this study identified duplications upstream of the SOX9 gene in three families with an isolated 46,XX disorder of sex development (DSD) and an overlapping deletion in one family with two probands with an isolated 46,XY DSD. The region of overlap between these genomic alterations, and previously reported deletions and duplications at the SOX9 locus associated with syndromic and isolated cases of 46,XX and 46,XY DSD, reveal a minimal non-coding 78 kb sex determining region located in a gene desert 517-595 kb upstream of the SOX9 promoter.
CONCLUSIONS: These data indicate that a non-coding regulatory region critical for gonadal SOX9 expression and subsequent normal sex development is located far upstream of the SOX9 promoter. Its copy number variations are the genetic basis of isolated 46,XX and 46,XY DSDs of variable severity (ranging from mild to complete sex reversal). It is proposed that this region contains a gonad specific SOX9 transcriptional enhancer(s), the gain or loss of which results in genomic imbalance sufficient to activate or inactivate SOX9 gonadal expression in a tissue specific manner, switch sex determination, and result in isolated DSD.

González-Fernández R, Peña Ó, Hernández J, et al.
Patients with endometriosis and patients with poor ovarian reserve have abnormal follicle-stimulating hormone receptor signaling pathways.
Fertil Steril. 2011; 95(7):2373-8 [PubMed] Related Publications
OBJECTIVE: To study the integrity of the FSH receptor (FSHR) signaling pathway in granulosa-lutein cells at the time of egg retrieval and its relationship with the infertility diagnosis.
DESIGN: In vitro assays.
SETTING: University laboratory and private IVF center.
PATIENT(S): Patients undergoing IVF: 35 controls (no ovarian factor, NOF), 28 poor responders (PR), 32 patients with endometriosis (EM), and 22 patients with polycystic ovary syndrome (PCOS).
INTERVENTION(S): Quantitative reverse transcriptase-polymerase chain reaction (PCR) in granulosa-lutein cells from pooled follicles.
MAIN OUTCOME MEASURE(S): Correlation between expression of FSHR and FSH-regulated genes PAPP/Cyp19A1.
RESULT(S): Positive correlations among FSHR, PAPP, and Cyp19A1 expression levels are observed in NOF and are lost, with different patterns, in poor responder patients and those with endometriosis. Patients with endometriosis are an heterogeneous group including patients with poor ovarian reserve who behave like other poor responders patients (endometriosis-A) and patients with good response to ovarian stimulation (endometriosis-B) who show a specific alteration of the FSHR signaling pathway.
CONCLUSION(S): These preliminary data suggest that the different signaling pathways activated through the FSHR in normal ovaries (NOF) are disrupted in poor responders and in patients with endometriosis. A better knowledge of the molecular origin of these errors may guide clinicians in the choice of personalized ovulation induction protocols for each type of ovarian dysfunction.

Beckmann L, Hüsing A, Setiawan VW, et al.
Comprehensive analysis of hormone and genetic variation in 36 genes related to steroid hormone metabolism in pre- and postmenopausal women from the breast and prostate cancer cohort consortium (BPC3).
J Clin Endocrinol Metab. 2011; 96(2):E360-7 [PubMed] Free Access to Full Article Related Publications
CONTEXT: Sex steroids play a central role in breast cancer development.
OBJECTIVE: This study aimed to relate polymorphic variants in 36 candidate genes in the sex steroid pathway to serum concentrations of sex steroid hormones and SHBG.
DESIGN: Data on 700 genetic polymorphisms were combined with existing hormone assays and data on breast cancer incidence, within the European Prospective Investigation into Cancer and Nutrition (EPIC) and the Nurses' Health Study (NHS) cohorts; significant findings were reanalyzed in the Multiethnic Cohort (MEC).
SETTING AND PARTICIPANTS: We analyzed data from a pooled sample of 3852 pre- and postmenopausal Caucasian women from EPIC and NHS and 454 postmenopausal women from MEC.
MAIN OUTCOME MEASURES: Outcome measures were SHBG, testosterone, dehydroepiandrosterone (DHEAS), androstenedione, estrone (E1), and estradiol (E2) as well as breast cancer risk.
RESULTS: Globally significant associations were found among pre- and postmenopausal women combined between levels of SHBG and the SHBG gene and between DHEAS and the FSHR and AKR1C3 genes. Among postmenopausal women, serum E1 and E2 were significantly associated with the genes CYP19 and FSHR, and E1 was associated with ESR1. None of the variants related to serum hormone levels showed any significant association with breast cancer risk.
CONCLUSIONS: We confirmed associations between serum levels of SHBG and the SHBG gene and of E1 and E2 and the CYP19 and ESR1 genes. Novel associations were observed between FSHR and DHEAS, E1, and E2 and between AKR1C3 and DHEAS.

Kerns SL, Ostrer H, Stock R, et al.
Genome-wide association study to identify single nucleotide polymorphisms (SNPs) associated with the development of erectile dysfunction in African-American men after radiotherapy for prostate cancer.
Int J Radiat Oncol Biol Phys. 2010; 78(5):1292-300 [PubMed] Free Access to Full Article Related Publications
PURPOSE: To identify single nucleotide polymorphisms (SNPs) associated with erectile dysfunction (ED) among African-American prostate cancer patients treated with external beam radiation therapy.
METHODS AND MATERIALS: A cohort of African-American prostate cancer patients treated with external beam radiation therapy was observed for the development of ED by use of the five-item Sexual Health Inventory for Men (SHIM) questionnaire. Final analysis included 27 cases (post-treatment SHIM score ≤7) and 52 control subjects (post-treatment SHIM score ≥16). A genome-wide association study was performed using approximately 909,000 SNPs genotyped on Affymetrix 6.0 arrays (Affymetrix, Santa Clara, CA).
RESULTS: We identified SNP rs2268363, located in the follicle-stimulating hormone receptor (FSHR) gene, as significantly associated with ED after correcting for multiple comparisons (unadjusted p = 5.46 × 10(-8), Bonferroni p = 0.028). We identified four additional SNPs that tended toward a significant association with an unadjusted p value < 10(-6). Inference of population substructure showed that cases had a higher proportion of African ancestry than control subjects (77% vs. 60%, p = 0.005). A multivariate logistic regression model that incorporated estimated ancestry and four of the top-ranked SNPs was a more accurate classifier of ED than a model that included only clinical variables.
CONCLUSIONS: To our knowledge, this is the first genome-wide association study to identify SNPs associated with adverse effects resulting from radiotherapy. It is important to note that the SNP that proved to be significantly associated with ED is located within a gene whose encoded product plays a role in male gonad development and function. Another key finding of this project is that the four SNPs most strongly associated with ED were specific to persons of African ancestry and would therefore not have been identified had a cohort of European ancestry been screened. This study demonstrates the feasibility of a genome-wide approach to investigate genetic predisposition to radiation injury.

Brauner R, Bashamboo A, Rouget S, et al.
Clinical, biological and genetic analysis of prepubertal isolated ovarian cyst in 11 girls.
PLoS One. 2010; 5(6):e11282 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The cause of isolated gonadotropin-independent precocious puberty (PP) with an ovarian cyst is unknown in the majority of cases. Here, we describe 11 new cases of peripheral PP and, based on phenotypes observed in mouse models, we tested the hypothesis that mutations in the GNAS1, NR5A1, LHCGR, FSHR, NR5A1, StAR, DMRT4 and NOBOX may be associated with this phenotype.
METHODOLOGY/PRINCIPAL FINDINGS: 11 girls with gonadotropin-independent PP were included in this study. Three girls were seen for a history of prenatal ovarian cyst, 6 girls for breast development, and 2 girls for vaginal bleeding. With one exception, all girls were seen before 8 years of age. In 8 cases, an ovarian cyst was detected, and in one case, suspected. One other case has polycystic ovaries, and the remaining case was referred for vaginal bleeding. Four patients had a familial history of ovarian anomalies and/or infertility. Mutations in the coding sequences of the candidate genes GNAS1, NR5A1, LHCGR, FSHR, NR5A1, StAR, DMRT4 and NOBOX were not observed.
CONCLUSIONS/SIGNIFICANCE: Ovarian PP shows markedly different clinical features from central PP. Our data suggest that mutations in the GNAS1, NR5A1, LHCGR, FSHR StAR, DMRT4 and NOBOX genes are not responsible for ovarian PP. Further research, including the identification of familial cases, is needed to understand the etiology of ovarian PP.

Gu BH, Park JM, Baek KH
Genetic variations of follicle stimulating hormone receptor are associated with polycystic ovary syndrome.
Int J Mol Med. 2010; 26(1):107-12 [PubMed] Related Publications
Polycystic ovary syndrome (PCOS) is an endocrine disorder and the criteria are specified by hyperandrogenism, oligomenorrhea or amenorrhea and polycystic ovary morphology. Follicle stimulating hormone (FSH) has effects on oogenesis and follicle development. Several polymorphisms of FSH receptor (FSHR) are related to primary amenorrhea, hypoplastic ovary, and high serum levels of FSH. Thus, an increase in FSH level leads to follicle maturation and proliferation of granulosa cells. The aim of this study was to determine whether Ser680Asn and Ala307Thr polymorphisms of FSHR were associated with the clinical features of PCOS in a Korean population. PCOS patients (n=235) and control subjects (n=128) in the reproductive age were recruited from the Fertility Center of CHA General Hospital in Seoul, Korea. For Ser680Asn and Ala307Thr polymorphisms in FSHR, frequency of respective genotypes was measured and statistical analysis was performed. Haplotype analysis between Ser680Asn and Ala307Thr was also performed. We found that the Ser680Asn of FSHR is associated with PCOS (p=0.0195, OR=1.66). However, in case of Ala307Thr, the variant is negligible and is not associated with PCOS (p=0.6963, OR=1.08). In haplotype analysis, Ser680Asn and Ala307Thr polymorphisms are not related with PCOS. Consequently, the Ser680Asn polymorphism of FSHR might significantly affect PCOS patients, separately from the Ala307Thr polymorphism.

Du J, Zhang W, Guo L, et al.
Two FSHR variants, haplotypes and meta-analysis in Chinese women with premature ovarian failure and polycystic ovary syndrome.
Mol Genet Metab. 2010; 100(3):292-5 [PubMed] Related Publications
In this study, two polymorphisms of follicle stimulating hormone receptor (FSHR) gene were analysed in the case-control sample using 40 premature ovarian failure (POF) patients, 60 polycystic ovary syndrome (PCOS) patients and 92 healthy controls. All subjects were unrelated Han Chinese from Shanghai. No difference was observed on the allelic or genotypic distribution of FSHR gene polymorphisms between the groups. However, the two-marker haplotypes covering components Thr307Ala (rs6165) G and Asn680Ser (rs6166) A were observed to be significantly associated with PCOS (p=0.007, corrected p=0.042). Meanwhile, a meta-analysis including our study (altogether six POF and eight PCOS studies) showed significant association between rs6166 marker and PCOS (p<0.05). The results suggest that FSH receptor might play a role in genetic susceptibility to PCOS. However, confirmatory studies in independent samples are needed.

Bas F, Pescovitz OH, Steinmetz R
No activating mutations of FSH receptor in four children with ovarian juvenile granulosa cell tumors and the association of these tumors with central precocious puberty.
J Pediatr Adolesc Gynecol. 2009; 22(3):173-9 [PubMed] Related Publications
STUDY OBJECTIVE: The stimulation of the follicle-stimulating hormone receptor (FSHR) by circulating FSH or some activating mutations of the FSHR may play a causal role in the development of granulosa cell tumors of ovaries.
STUDY DESIGN: We evaluated four patients with ovarian juvenile granulosa cell tumors (age range, 2.4 to 7.2; median, 2.9 years) and five healthy pubertal girls (age range, 16 to 18.5; median, 16.8 years) for activating mutations in exon 10 of the FSHR. The patients were followed and evaluated clinically. Genomic DNA was extracted from the peripheral blood. Exon10 of the FSHR was evaluated for mutations.
RESULTS: All four patients presented with signs of precocious puberty. One patient, who had markedly accelerated growth velocity and advanced bone age, developed central precocious puberty after the removal of her tumor. Another patient was diagnosed to have a left ovarian cyst without tumor recurrence approximately 3.3 years after the removal of the tumor. Activating mutations were not found, but previously reported polymorphisms (Ser680Asn and Ala307Thr) of the FSHR were detected in three of four patients and in three of five controls. The follow-up period of these four patients ranged from 4.5 to 8.8 years, with a median value of 6.7 years.
CONCLUSIONS: We did not find any activating mutation in exon 10 of the FSHR in our patients, and one patient developed precocious puberty after removal of her tumor. The development of ovarian tumors in these patients may have been caused by mutations at other exons of the FSHR and G protein subunits, so the association noted between central precocious puberty and granulosa cell tumors might not be coincidental.

Valkenburg O, Uitterlinden AG, Piersma D, et al.
Genetic polymorphisms of GnRH and gonadotrophic hormone receptors affect the phenotype of polycystic ovary syndrome.
Hum Reprod. 2009; 24(8):2014-22 [PubMed] Related Publications
BACKGROUND: Polycystic ovary syndrome (PCOS) is a complex genetic disorder. Multiple functional polymorphisms have been identified in genes that regulate the hypothalamic-pituitary-gonadal (HPG) axis that regulates ovarian function. The present study aims to examine the influence of genetic variants of the HPG-axis on the severity of clinical features of PCOS and disease susceptibility.
METHODS: We included 518 Caucasian PCOS women and 2996 unselected controls from the general population (the Rotterdam study). Genotype distributions were compared between patients and controls. Subsequently, associations with clinical features of PCOS were studied. Single nucleotide polymorphisms were selected in GnRH (Trp16Ser [rs6185]), the FSH-receptor (FSHR, Ala307Thr [rs6165] and Asn680Ser [rs6166]) and the LH-receptor (18insLQ, Asn291Ser [rs12470652] and Ser312Asn [rs2293275]).
RESULTS: FSHR Ser(680) was associated with higher levels of gonadotrophic hormones (FSH: P < 0.01, LH: P = 0.01), and testosterone (P = 0.05) and a higher frequency of hyperandrogenism (P = 0.04). No differences in risk for PCOS in association with the FSH-receptor variants were observed.
CONCLUSION: Genetic variants of the HPG-axis were associated with a modest but significant effect on the phenotype of PCOS. FSHR variants were strongly associated with the severity of clinical features of PCOS, such as levels of gonadotrophic hormones and the presence of hyperandrogenism, but not disease risk.

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