Association between FSHR polymorphisms and polycystic ovary syndrome among Chinese women in north China

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.     

长三角地区重度少弱精子症与卵泡刺激素受体基因单核苷酸多态性相关性研究

目的:研究卵泡刺激素受体(FSHR)基因Thr307Ala(rs6165)和Asn680Ser(rs6166)单核苷酸多态性(SNP)基因型分布情况及其与中国长三角地区重度少弱精子症的关联性。方法:外周血提纯DNA,PCR扩增后直接测序分析200名已育男性(已生育组)和150名重度少弱精子症不育男性(不育组)FSHR基因Thr307Ala和Asn680Ser位点的SNP,并用χ2检验进行相关性分析。结果:FSHR基因Thr307Ala和Asn680Ser多态性位点的基因型分布在已生育组和不育组间无统计学差异(P>0.05)。Thr-Asn/Ala-Asn和Thr-Ser/Thr-Ser双倍型在已育男性与重度少弱精子症患者间分布差异有统计学意义(P<0.05),组间FSHR的单倍型Thr-Asn和Ala-Asn之间亦有统计学差异(P<0.05)。结论:FSHR基因Thr307Ala和Asn680Ser的2个多态性位点特定的单倍型和双倍型与男性不育有一定的相关性。     

Frequent polymorphisms of FSH receptor do not influence antral follicle responsiveness to follicle-stimulating hormone administration as assessed by the Follicular Output RaTe (FORT)

Purpose

To verify whether carriers of common single-nucleotide polymorphisms (SNPs) of the FSH receptor (FSHR) show reduced responsiveness of antral follicles to FSH administration as assessed by the FORT.

Methods

We performed a prospective study in a university hospital. Study population consisted of 124 Caucasian IVF-ET candidates. FSHR 307Ala and 680Ser variants were analyzed in haplotypes and as separated genes. Serum FSH, estradiol (E₂), and anti-Müllerian hormone (AMH) were measured on cycle-day 3. Antral follicle (3–8 mm) count (AFC) and preovulatory follicle (16–22 mm) count (PFC) were performed, respectively, at the achievement of pituitary suppression (before FSH administration) and on the day of hCG administration. Antral follicle responsiveness to FSH administration assessed by the FORT (PFCx100/AFC).

Results

Data concerning baseline and IVF-ET parameters were similar between SNPs carriers and controls. Moreover, FORT was similar for different haplotypes Thr307-Asn680 (45.9%) and Ala307-Ser680 (39.4%) and 307Thr/Ala-Ala/Ala (41.1%; 5.0–91.6%) versus 307Thr/Thr (44.4%; 17.3–83.3%) and in 680Asn/Ser-Ser/Ser (40.0%; 5.0–91.6%) versus 680Asn/Asn (42.2%; 8.3–90.0%) carriers.

Conclusions

Antral follicle responsiveness to FSH, as far as measured by the FORT, is not influenced by the presence of SNPs of FSHR 307Ala and 680Ser.     

Follicle-stimulating hormone receptor polymorphisms in a population of infertile women

BACKGROUND: There are two known polymorphisms of clinical relevance in the follicle-stimulating hormone (FSH) receptor exon 10, alanine or threonine at position 307, and asparagine or serine at position 680, giving rise to two discrete allelic variants: Thr307/Asn680 and Ala307/Ser680. At position 680, three FSH receptor variants are possible: Asn/Asn, Asn/Ser, and Ser/Ser. We hypothesized an association between FSH receptor polymorphisms and ovarian reserve. METHODS: FSH receptor polymorphisms at position 680 were studied in a population of 68 infertile women. We used serum FSH level at cycle day 3 as a screening for ovarian reserve. DNA was extracted from peripheral leukocytes in whole blood by using PCR and DNA sequencing in order to determine the type of FSH receptor. RESULTS: The distribution of FSH receptor variants was Asn/Asn (AA) 35%, Asn/Ser (AS) 24%, and Ser/Ser (SS) 41%. In women with normal ovarian reserve, FSH levels at cycle day 3 were 5.6 +/- 1.9 (AA group), 6.7 +/- 1.3 (AS group), and 5.7 +/- 1.7 (SS group) (non-significant). Corresponding FSH levels at cycle day 10 were 6.9 +/- 1.9, 6.3 +/- 1.7, and 8.3 +/- 2.8 (P < 0.01, AA and AS vs. SS group). In the SS group, FSH levels at cycle day 10 were significantly higher than they were at cycle day 3 (P < 0.05). CONCLUSIONS: The results show that Ser/Ser-680 predominates in the studied infertile population. Furthermore, women with normal ovarian reserve and the Ser/Ser FSH receptor variant had significantly higher FSH levels, compared to women with Asn/Asn and Asn/Ser variants. FSH receptor genotyping may, thus, be interesting as an adjunct indicator of ovarian reserve for infertile women undergoing assisted reproduction, and may be helpful in the determination of the starting dosage of FSH in in vitro fertilization.     

Follicle-stimulating hormone receptor polymorphisms in women with normogonadotropic anovulatory infertility

OBJECTIVE: To assess the incidence of different FSH receptor genotypes in normogonadotropic anovulatory infertile women (World Health Organization class II) and normo-ovulatory controls and to correlate these genotypes with baseline characteristics and ovarian responsiveness during ovulation induction. DESIGN: Cross-sectional study. SETTING: University hospital. PATIENT(S): Thirty normo-ovulatory controls and 148 normogonadotropic anovulatory infertile women. INTERVENTION(S): All participants underwent a standardized evaluation that included cycle history, body mass index measurement, and transvaginal ultrasonography of ovaries. Fasting blood samples were obtained for endocrine evaluation. Ovarian responsiveness to FSH in normogonadotropic anovulatory infertile women was assessed during ovulation induction, and DNA was analyzed to determine the FSH receptor genotype. MAIN OUTCOME MEASURE(S): Prevalence of FSH receptor polymorphisms, baseline serum FSH levels, amount of FSH administered, duration of stimulation, and ovarian response dose. RESULT(S): The Thr/Thr 307 genotype was significantly less prevalent (52% vs. 23%) and the Ser/Ser 680 polymorphism was significantly more prevalent (40% vs. 16%) in patients compared with controls. Normogonadotropic anovulatory infertile women with the Ser/Ser 680 polymorphism presented with higher median FSH serum levels (5.2 IU/L [range, 2.4-9.7 IU/L]) than did those with the Asn/Asn 680 (4.6 IU/L [range, 1.4-5.8 IU/L) and Asn/Ser 680 (4.5 IU/L [range, 1.8-9.7 IU/L) variants. However, ovarian responsiveness to FSH was similar among anovulatory women with the various polymorphisms. CONCLUSION(S): Normogonadotropic anovulatory infertile patients have a different FSH receptor genotype than do normo-ovulatory controls. Although this characteristic is associated with increased baseline FSH serum levels, altered ovarian sensitivity to exogenous FSH during ovulation induction could not be established.     

Association study between FSHR Ala307Thr and Ser680Asn variants and polycystic ovary syndrome (PCOS) in Northern Chinese Han women

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.     

Follicle-stimulating hormone receptor polymorphism and ovarian function

The FSH receptor presents several polymorphisms. Two of them, located at codon 307 and 680, are the most frequent. Threonine can be substituted by alanine at position 307 and serine can be substituted by asparagine at position 680. The two most frequent allelic combinations are Thr(307) -Asn (680) (60%) and Ala(307) -Ser (680) (40%). As the allelic variants at codon 307 and 680 are almost invariably associated, most of the studies assessed only one codon (680) and classified the women as homozygous (Ser/Ser ou Asn/Asn) or heterozygous (Asn/Ser). Several studies aimed to correlate the follicle-stimulating hormone receptor polymorphism and ovarian function. Women homozygous for the Ser (680) variant have higher follicular FSH levels and longer follicular phase length, which suggest a lower sensitivity to FSH. The FSH receptor genotype would also influence the sensitivity to exogenous FSH: as regards ovarian stimulation, higher recombinant FSH doses are needed for Ser/Ser homozygous women. The analysis of polymorphism in women with premature ovarian failure did not show a link with any particular allelic variant. In women with polycystic ovaries, the distribution of the allelic variants greatly varies from one study to another.     

FSH receptor gene polymorphisms in fertile and infertile Italian men

In women, single nucleotide polymorphisms (SNP) of the FSH receptor (FSHR) gene influence FSH concentrations and the sensitivity of the FSHR to FSH in vivo. In contrast, the significance of FSHR R gene SNP in the male is poorly understood. To this aim, the possible role of three FSHR SNP was evaluated in male infertility. SNP in exon 10 (codon 307 and 680) and in the core promoter region (at position -29) of the FSHR gene were analysed by polymerase chain reaction-restriction fragment length polymorphism technique in 150 men representative of the general population, 107 proven fathers, 92 normozoospermic controls, and 215 infertile patients classified according to sperm parameters (38 azoospermia, 53 severe oligozoospermia, 48 moderate oligozoospermia, and 76 slight oligozoospermia). Reproductive hormones were measured in infertile males and normozoospermic controls. No significant difference was found in allelic variants frequency and genotype distribution between each category of subjects when analysing the FSHR exon 10 SNP alone and in combination with the SNP at position -29. Serum FSH concentrations and other andrological parameters did not differ between subjects with different genotype within each group. The data showed that in the Italian population, FSHR genotypes have no influence on FSH concentrations both in normal and infertile males and do not associate with spermatogenetic impairment.     

A distribution of two SNPs in exon 10 of the FSHR gene among the women with a diminished ovarian reserve in Ukraine

Purpose  To evaluate the association between phenotype and follicle stimulating hormone receptor (FSHR) genotype in women with ovarian dysfunction and patients with “poor response” to gonadotropin stimulation of ovulation. Methods  FSHR gene SNPs were analyzed by PCR and RFLP. “Poor responders” (ovarian dysfunction) group and “good responders” group constituted the study group. Normo-ovulatory women who gave birth to naturally conceived children formed control groups: under 35 years of age (control I) and over 35 years of age (control II). Results  The frequency of Ala307-Ser680/Ala307-Ser680 genotype was significantly more prevalent in the ovarian dysfunction group (26%) compared to the control I (7.7%) (P < 0.001) and a “good responders” group (12.5%) (P < 0.05); and in a “poor responders” group (33.3%) compared to a “good responders” group (P < 0.05), control I (P < 0.001) and control II (17.5%) (P < 0.05). Conclusions  Our data shows the prevalence of the Ala307-Ser680/ Ala307-Ser680 genotype in the both groups of patients. The finding should have impact on the delineation of stimulation protocols. FSHR receptor gene polymorphisms and diminished ovarian reserve. Capsule The association between phenotype and Asn680Ser and Thr307Ala FSHR gene polymorphisms was found in women with ovarian dysfunction and poor response to FSH ovarian stimulation.     

FSH receptor gene polymorphisms have a role for different ovarian response to stimulation in patients entering IVF/ICSI-ET programs

Purpose: To examine the frequency distribution of the Ser680Asn polymorphism of the follicle-stimulating hormone receptor (FSHR) gene in ovarian dysfunction (OD) infertile women, “poor responders” (PR) and “good responders” (GR). Methods: The hormonal profiles and treatment of all patients were analyzed and FSHR polymorphism was examined by PCR and RFLP. Women from all groups were classified as Asn/Asn, Asn/Ser, and Ser/Ser genotypes. Results: The frequency distribution of Ser/Ser, Asn/Ser and Asn/Asn variants in OD patients was 45.5, 22.7, and 31.8%, respectively. Day 3 FSH levels in OD and GR patients were higher in Ser/Ser and Asn/Asn subgroups. Asn/Ser carriers from OD and GR groups provided more follicles and oocytes compared to other allelic variants. Conclusions: GR patients carry more often the Asn/Ser genotype. The latter is correlated with more follicles and oocytes in both OD and GR patients. The Ser/Ser variant might be related to higher serum FSH levels, while the Asn/Ser with lower.     

Alterations of the FSH and LH receptor genes and evaluation of sperm ultrastructure in men with idiopathic hypergonadotropic hypogonadism

Purpose

Gonadotropins, interacting with their gonadal receptors, play a key role in sexual development, reproductive functions and metabolism. In this study we performed the genetic analysis of FSHR and LHR and semen investigation in 14 infertile men with normal level of T and elevated levels of FSH and/or LH in the absence of other causes of infertility.

Methods

Sperm parameters were analysed following WHO (2010) guidelines and sperm morphology by Transmission Electron Microscopy (TEM) analysis mathematically elaborated. FSHR and LHR gene mutations have been searched by PCR technique, followed by DHPLC analysis and direct sequencing.

Results

In FSHR, we found no difference in the frequency between Ala or Thr at position 307, Ser was at codon 680 in all subjects. Three patients had an heterozygous mutation at codon 419. Three intronic polymorphisms (rs2091787, rs6708637, rs1922464) were significantly found compared to controls; the single allele frequency and the odds ratio were calculated. Two new variants: the Cys338Arg and the Gln123Glu were detected in two different patients. Regarding LHR, three patients were heterozygous for the known variant Glu354Lys and two for Ile374Thr. Intronic polymorphisms were not identified. A new variant, the Val144Ile was found. By the routine semen analysis, variable seminal conditions in this group of patients was observed, on the contrary TEM data mathematically elaborated showed a homogeneous decrease in fertility index and increase in sperm pathologies such as apoptosis and immaturity.

Conclusions

The obtained results suggest that a deeper examination of spermatozoa, achieved by the use of more powerful tools such as TEM or molecular analysis, are advisable in patients with hypergonadotropic hypogonadism.     

LH (Trp8Arg/Ile15Thr), LHR (insLQ) and FSHR (Asn680Ser) polymorphisms genotypic prevalence in women with endometriosis and infertility

Purpose

To verify if polymorphisms of LH (Trp8Arg/Ile15Thr), LH receptor (insLQ), and FSH receptor (Asn680Ser) are associated with endometriosis and infertility.

Methods

This is a prospective case–control study. Sixty-seven patients with endometriosis and infertility (study group) and 65 healthy fertile patients (control group) were enrolled in the study between July 2010 and July 2013. All patients had their endometriosis diagnosis made or excluded by laparoscopic surgery; study group was submitted to the surgery for infertility investigation and control group for tubal ligation. Day-3 serum hormones were collected from all patients. Analysis of nucleotide mutations for LH polymorphisms (Trp8Arg and Ile15Thr), LHR polymorphism (insLQ), and FSHR polymorphism (Asn680Ser) were performed by PCR.

Results

Day-3 FSH, estradiol and LH serum levels were not different between the groups, while CA-125 was higher in patients with endometriosis and infertility. All polymorphisms studied were in Hardy-Weinberg equilibrium. The prevalence of insLQ was significantly higher in patients with endometriosis and infertility (P = 0.005). Allele occurrence in control group was 0.10 versus 0.25 in infertile endometriosis group (P = 0.001). There was no difference regarding Trp8Arg/Ile15Thr (P > 0.05) and Asn680Ser (P > 0.05) prevalence between groups.

Conclusion

This is the first time that prevalence of insLQ was shown to be higher in patients with endometriosis and infertility than in healthy fertile patients. There was no difference in LH and FSHR polymorphisms’ prevalence between groups.

Electronic supplementary material

The online version of this article (doi:10.1007/s10815-015-0477-3) contains supplementary material, which is available to authorized users.     

FSH receptor gene p. Thr307Ala and p. Asn680Ser polymorphisms are associated with the risk of polycystic ovary syndrome

Purpose

The purpose of this study was to investigate whether the follicle-stimulating hormone receptor (FSHR) gene p. Thr307Ala (c.919A>G, rs6165) and p. Asn680Ser (c.2039A>G, rs6166) polymorphisms are associated with susceptibility to polycystic ovary syndrome (PCOS).

Methods

Genotyping was performed in 377 women with PCOS and 388 age-matched controls. Difference in the genotype distribution was assessed using a Fisher’s exact or chi-square test, and continuous variables were compared using a Student’s t test. To evaluate the association between the presence of PCOS status and SNP, logistic regression analyses were performed.

Results

Linkage disequilibrium between the two polymorphisms was approximately complete (r ² = 99%). The genotype distributions of the PCOS group significantly differed from those of the control group (Thr/Thr, Thr/Ala, and Ala/Ala frequencies were 38.5, 46.7, and 14.9% for the PCOS group and 46.6, 45.4, and 8.0% for the controls, respectively, P = .005; Asn/Asn, Asn/Ser, and Ser/Ser frequencies were 39.5, 47.2, and 13.3% for the PCOS group and 46.4, 45.4, and 8.2% for the controls, respectively, P = .035). Using the wild-type genotypes as the references, the odds ratios that a woman has PCOS were 2.23 (95% confidence intervals 1.38–3.68) for the Ala/Ala genotype, 1.87 (95% confidence intervals 1.14–3.06) for the Ser/Ser genotype, and 1.96 (95% confidence intervals 1.19–3.24) for the homozygous variant combination (Ser/Ser-Ala/Ala). However, there were no significant differences in serum hormonal, ovarian, and metabolic markers according to each genotype.

Conclusions

Findings of this study suggest a significant association between FSHR gene p. Thr307Ala or p. Asn680Ser coding sequence change and PCOS. The variant homozygote genotype results in a higher risk of PCOS.

     

PCOS and peripheral AMH levels in relation to FSH receptor gene single nucleotide polymorphisms

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.     

Frequency distribution of polymorphisms in the FSH receptor gene in infertility patients of different ethnicity

Studies on the frequency distribution of follicle-stimulating hormone receptor (FSHR) polymorphisms report conflicting results. It has been suggested that ethnicity might influence these outcomes. Therefore, the aim of this study was to determine the frequency distribution of FSHR polymorphisms at position 680 of exon 10 within a large group of women with fertility problems from different ethnic backgrounds. A total of 1771 women of different ethnic origin (Caucasian, Asian, Hindustani, Creole and Mediterranean) were studied. FSHR single-nucleotide polymorphisms at codon 680 of exon 10 were determined by restriction fragment length polymorphism of amplicons generated by polymerase chain reaction. Genotypes were compared with serum FSH concentrations and between different ethnic groups. A significantly lower number of Asians (10.5%) were found to have the Ser680Ser receptor variant compared with Caucasians (21.5%) and Mediterraneans (22.3%) (P = 0.010). FSH concentrations did not differ between the various ethnic groups, or the different FSHR polymorphisms. In conclusion, the Ser680Ser receptor variant is less common in the Asian subgroup compared with Caucasians and Mediterraneans. This indicates that, when comparing allelic frequency distributions of the FSHR polymorphism variants, ethnic background should be accounted for. FSH concentrations did not differ between FSHR polymorphisms or between ethnic groups.     

FSH receptor genotype is associated with pregnancy but not with ovarian response in IVF

Two very common single nucleotide polymorphisms at positions 307 and 680 in exon 10 of the FSH receptor gene have been associated with ovarian response in IVF. This observational study evaluated the role of the FSH receptor genotype in the prediction of poor response and clinical pregnancy in IVF in comparison with other markers, such as age, basal FSH, anti-Müllerian hormone and antral follicle count. In addition, the in-vitro cAMP response towards recombinant FSH in cultured granulosa cells of patients with different FSH receptor genotypes was determined. A total of 105 IVF patients undergoing ovarian stimulation in a long suppression protocol were included in the study. The ovarian response was comparable between patients with different FSH receptor genotypes. Patients with polymorphism Ser/Ser had implantation and pregnancy rates that were three times higher compared with patients with polymorphism Asn/Asn. FSH receptor genotype was not associated with a poor response in IVF, but showed a positive association with pregnancy, independent of age. There was no difference in cAMP production in cultured granulosa cells of patients with different FSH receptor genotypes (n=62). It is concluded that FSH receptor genotype is associated with pregnancy in IVF, but not with ovarian response.     

Are FSHR polymorphisms risk factors to premature ovarian insufficiency?

Abstract

Premature ovarian insufficiency (POI) is an ovarian dysfunction characterized by increased FSH levels and amenorrhea before 40 years old. In recent years, the search for genetic causes of POI intensified and studies have been published relating the presence of mutations and polymorphisms in genes associated with development, recruitment and oocyte atresia. The aim of this study was to evaluate the presence of FSHR polymorphisms in our population and contribute with the elucidation of POI etiology. To achieve it, we have studied 100 patients with POI (G1), 60 patients with border line levels of FSH (G2) and 123 controls with regular menopause onset. Cytogenetic analysis of patients’ samples and genotyping of Asn680Ser and Ala307Thr polymorphisms were performed in cases and controls. Cytogenetic analysis showed that 92% of G1 patients had normal karyotype, 4% presented polymorphic variants, 3% presented mosaic karyotype involving X chromosome. In G2, 91.6% had normal karyotype results, 3.2% displayed polymorphic variants, and 3.3% presented a mosaic karyotype involving X chromosome. Statistical comparison showed that the polymorphic allele of Ala307Thr polymorphism is more frequent in patients than in controls (G1: p?<?0.001 and G2: p?=?0.0259). This association has not been previously reported. We concluded that Ala307Thr polymorphism in FSHR can be potentially associated to POI development and can be considered as a screening marker in patients with ovarian failure signals.     

Role of follicle-stimulating hormone receptor Ser680Asn polymorphism in the efficacy of follicle-stimulating hormone

OBJECTIVE: To evaluate the association between FSH efficacy and FSHR alleles. DESIGN: Retrospective study. SETTING: University-based fertility unit and a private center for biomedical research. PATIENT(S): One hundred two women with ovarian function who were undergoing controlled ovarian stimulation (COS). Women were categorized as poor responders (< or =3 ovarian follicles at the end of the cycle) or normal responders (>3 follicles). INTERVENTION(S): Daily administration of exogenous FSH. MAIN OUTCOME MEASURE(S): Number of good or poor responders. RESULT(S): The allele frequency and genotype distribution of the Ser680Asn marker differed significantly between groups. Cycle cancellations were increased (21%) among women who were homozygous for Ser680 compared with Ser/Asn and Asn/Asn patients, and 36% of poor-responders were homozygous for Ser680. CONCLUSION(S): The results support a role for FSHR gene in COS outcome. However, the weight of this factor is probably low. The Ser680 allele may act in concert with other environmental and genetic factors that contribute to FSH efficacy.     

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

Study ObjectiveThe 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 designWe 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.ResultsAll 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.ConclusionsWe 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.     

A novel mutation in exon8 of the follicle-stimulating hormone receptor in a woman with primary amenorrhea

The FSH receptor (FSHR) gene mutation are rare, but recently have been detected in several cases with primary amenorrhea. We report a 25-year-old female who had primary amenorrhea, moderately developed secondary sex characteristics and normal sized ovaries with small antral follicles. Her ovaries reacted slightly to clomiphene citrate therapy; they did not react to the ordinary dose of human menopausal gonadotropin (hMG) (150 IU/day × 9 days), but did react to high-dose hMG (300 IU/day × 6 days) treatment. These ovarian responses to hMG stimulation suggested an FSHR dysfunction of her ovaries. We extracted genomic DNA and analysed FSHR gene sequence after we obtained the written informed consent from the patient under the approval by the Ethics Committee of Yamaguchi Grand Medical Centre and the Yamaguchi University School of Medicine. Direct sequencing revealed a heterozygous mutation 662T?>G resulting in the substitution of valine for glycine at position 221 in exon8 of the FSHR extracellular domain, which was also confirmed by the PCR-RFLP method. The sequencing results also showed two SNPs, 919G?>A (Ala307Thr) and 2039G?>A (Ser680Asn), in exon10. A novel mutation in exon8 of FSHR was identified in a woman with primary amenorrhea whose ovaries reacted to high-dose hMG treatment.