|Year : 2018 | Volume
| Issue : 2 | Page : 81-87
Association of Thr307Ala and Asn680Ser of Follicle-Stimulating Hormone Receptor Gene Polymorphisms with Gonadotropin Administration during Controlled Ovarian Hyperstimulation
Qing-Xia Meng, Dan Song, Hong Li, Wei Wang, Jian Ou, Yong-Le Xu, Ai-Yan Zheng
Center for Reproduction and Genetics, Suzhou Municipal Hospital, Nanjing Medical University Affiliated Suzhou Hospital, Suzhou, Jiangsu 215002, China
|Date of Submission||06-Apr-2018|
|Date of Web Publication||4-Oct-2018|
Center for Reproduction and Genetics, Suzhou Municipal Hospital, Nanjing Medical University Affiliated Suzhou Hospital, Suzhou, Jiangsu 215002
Source of Support: None, Conflict of Interest: None
Objective: This study is to investigate the effect of different single-nucleotide polymorphisms of follicle-stimulating hormone receptor (FSHR) gene on gonadotropin (Gn) administration dosage during controlled ovarian hyperstimulation (COH) protocol of in vitro fertilization and embryo transfer.
Methods: This retrospective study included 184 Chinese infertile women in Center for Reproduction and Genetics of Suzhou Municipal Hospital from June 2012 to 2014. All of the enrolled patients were homogeneous in some basal characteristics, and they all met the eligibility criteria. Blood tests were conducted on day 3 of menstrual cycle or the day of human chorionic gonadotropin administration for hormonal profile analysis and DNA extraction. DNA sequencing was performed for polymorphism analysis. The participants were classified into threonine (Thr)/Thr, Thr/alanine (Ala), and Ala/Ala groups according to genotype at position 307, and asparagine/asparagine (Asn/Asn), Asn/serine (Ser), and Ser/Ser groups according to genotype at position 680. Logistic regression and correlation analyses were performed to identify the effect of these two polymorphisms on Gn consumption.
Results: The frequency of Thr307Ala and Asn680Ser distribution was consistent with Hardy–Weinberg equilibrium (P > 0.05). No significant difference was found in age, basal hormone levels for different genotype groups. Logistic regression analysis results revealed that patients with Ser680Ser genotype have a higher risk of requiring a high dose of Gn compared with patients with Asn680Asn genotype, while polymorphism of Thr307 Ala has no such effect.
Conclusion: This study suggested that FSHR genotype Asn680Ser would be helpful in determining the dosage of Gn in COH; patients with Ser680Ser genotype may require higher dose of Gn.
Keywords: Controlled Ovarian Hyperstimulation; Follicle-Stimulating Hormone Receptor; Gonadotropin; Single-Nucleotide Polymorphism
|How to cite this article:|
Meng QX, Song D, Li H, Wang W, Ou J, Xu YL, Zheng AY. Association of Thr307Ala and Asn680Ser of Follicle-Stimulating Hormone Receptor Gene Polymorphisms with Gonadotropin Administration during Controlled Ovarian Hyperstimulation. Reprod Dev Med 2018;2:81-7
|How to cite this URL:|
Meng QX, Song D, Li H, Wang W, Ou J, Xu YL, Zheng AY. Association of Thr307Ala and Asn680Ser of Follicle-Stimulating Hormone Receptor Gene Polymorphisms with Gonadotropin Administration during Controlled Ovarian Hyperstimulation. Reprod Dev Med [serial online] 2018 [cited 2020 Jan 29];2:81-7. Available from: http://www.repdevmed.org/text.asp?2018/2/2/81/242750
| Introduction|| |
Follicle-stimulating hormone (FSH) is produced by gonadotrope cells of the anterior pituitary gland, which plays an important role in the normal gonadal function, such as stimulating granulosa cell proliferation and follicular growth and maturation. The effect of FSH is mediated by binding with a FSH receptor (FSHR) that is specifically expressed on the plasma membrane of granulosa cells of the ovary. The FSHR is a G-protein-coupled seven-transmembrane domain receptor, which mediates the activation of adenylate cyclase and elevation of intracellular cyclic adenosine monophosphate, a major transducer of FSHR cascade.
The FSHR gene located at chromosome 2p21, spanning 54 kbp, consists of 10 exons and 9 introns. Exons 1–9 encode the extracellular domain, while exon 10 encodes the transmembrane domain and intracellular domain. More than 900 single-nucleotide polymorphisms (SNPs) have been found in the FSH and FSHR genes, which are mainly caused naturally by mutations. The FSHR function can be influenced by these gene mutations, which may lead to inactivating or activating signal transduction and changed ovarian response. Mechanisms for FSHR gene mutations influence ovarian response based on the changes in molecular phosphorylation and glycosylation, which can modulate receptor sensitivity and intracellular second messenger cascades to exogenous gonadotropin (Gn) since FSHR is its main target.,
Exogenous Gn administration is a critical factor during in vitro fertilization and embryo transfer (IVF-ET) treatment. Although age, body mass index (BMI), and some basal hormone profiles are the common used factors of Gn administration dosage for patients undergoing controlled ovarian hyperstimulation (COH) procedure, more accurate parameters would help to give a more patient-tailored treatment.
The sensitivity of FSHR is associated with the dosage of Gn administration. Mutations on FSHR gene may enhance or reduce the ovarian response to exogenous FSH, resulting in varied ovarian response to the stimulation of Gn. Two common FSHR gene substitutions, 919G>A (rs6165, p.307Thr/Ala) (resulting in Thr change to Ala) and 2039G>A (rs6166, p.680Asn/Ser) (resulting in Asn change to Ser), in exon 10 are considered as main SNPs on the FSHR gene associated with ovarian response. Different from other SNPs, the heterozygosity of these two SNPs (Thr307Ala and Asn680Ser) has a considerably high frequency in the general population.
The clinical benefit of screening of SNPs in predicting COH outcome or pregnancy outcomes during IVF treatment is still unclear. Some studies have proved that polymorphisms of FSHR gene have no significant association with ovarian function or human fertility,, while others proved that it could affect the ovarian response and basal hormone levels., A study by Desai et al. indicated that Asn680Asn combined with AA at position 29 in the 5′-untranslated region of FSHR could be used as a predictive marker for poor ovarian response to Gn stimulation.
Reports about these two SNPs with pregnancy outcome during IVF procedure are still very conflicting. The present study was performed on a group of homogeneous Chinese infertile women with normal ovarian function who underwent IVF-ET. In this retrospective clinical study, data on basal clinical characteristics, FSHR sequencing results, and ovulation outcomes of the selected patients were collected to investigate whether the SNPs of 919G>A and 2039G>A could be used as a predictive parameter for Gn administration during COH.
| Methods|| |
This study was performed on 184 women undergoing the controlled long program ovarian stimulation for IVF treatment in Reproductive Center of Suzhou Municipal Hospital of Nanjing University from June 2012 to 2014.
A total of 184 patients were enrolled in this study according to the following criteria: all had normal menstrual regularity and normal ovarian reserve. All participants met the following admission criteria: first cycle of ovarian stimulation, age <35 years, BMI <24 kg/m2, no history of ovarian surgery, and no other diseases such as two-sided ovarian pathological cyst, severe endometriosis, and polycystic ovary syndrome. This study was approved by Reproductive Medicine Ethics Committee of Suzhou Municipal Hospital. Informed consent was signed by all participants included in this study.
Ovarian stimulation protocol
The standard long protocol was performed in the ovulation induction for all these selected patients. Contraceptive (Marvelon, N.V. Organon, Holland) was administered from day 2 of the cycle for about 2 weeks. On the 15th day of the cycle, the patients were given 0.05 mg/d of a gonadotropin-releasing hormone agonist (Triptorelin Acetate Injection, Ferring Pharmaceuticals, Ltd. Switzerland) for 12–20 days. From the start of the downregulation, the contraceptive administration was continued for about 4–7 days. After pituitary block was confirmed, exogenous Gn was administered at an appropriate starting daily dose. During COH, the dosage of Gn was adjusted. Human chorionic gonadotropin (hCG) (250 μg, Ovidrel, Italy) was administered when the diameter of three dominant follicles exceeded 18 mm or the diameter of four dominant follicles exceeded 17 mm based on transvaginal ultrasounds. The oocytes were retrieved approximately 36 h after hCG administration.
Follicle-stimulating hormone receptor gene polymorphism analysis
Genomic DNA was extracted from the blood samples using the QIAamp DNA Blood Mini Kit (Qiagen, Germany), according to the manufacturer's instruction. The FSHR-919G>A and FSHR-2039G>A polymorphisms were examined by polymerase chain reaction (PCR) using the Taq DNA Polymerase (Thermo Scientific, USA). The primer sequences used for amplification are listed in [Table 1]. The amplified DNA fragments were purified and sequenced in both directions using the ABI 3130 Genetic Analyzer (ABI, USA). The PCR products were further confirmed using gel electrophoresis on a 2% agarose gel.
|Table 1: Sequencing primer of FSHR for SNPs at the position of 307 and 680 of selected patients|
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Basal FSH and luteinizing hormone (LH) levels on day 3 of the menstrual cycle and estradiol levels on the day of hCG administration were measured using the chemiluminescence immunoassay (Beckman Coulter Dxl800, USA). Serum anti-Müllerian hormone (AMH) was measured using the enzyme-linked immunosorbent assay (Beckman Coulter AMH Gen II, USA).
Hardy–Weinberg equilibrium (HWE) was analyzed using the Chi-square test. Differences in basal characteristics (age, BMI, FSH, LH, AMH, and estradiol [E2] on hCG day) in different groups were compared using a nonparametric test. The Kruskal–Wallis test was used to analyze the difference, as data were not normally distributed. Logistic regression analysis was used to analyze the effect of every genotype on the Gn dosage, and the results were adjusted by age, BMI, FSH, LH, and AMH. The SPSS version 16.0 software (SPSS Inc., IL, USA) was used for data analysis. The odds ratios and their respective 95% confidence intervals were calculated to estimate the allele effects.
| Results|| |
Polymorphisms of Thr307Ala (919G>A) and Asn680Ser (2039G>A) in the exon 10 of FSHR gene were identified by sequencing of DNA extracted from the blood sample of the patients [Figure 1]. The participants were classified into Thr/Thr, Thr/Ala, and Ala/Ala groups according to genotype at position 307, and Asn/Asn, Asn/Ser, and Ser/Ser groups according to genotype at position 680.
|Figure 1: Sequencing result of the 919G>A (a-c) on follicle stimulating hormone receptor gene. (a) GG wild-type genotype; (b) AA homozygous mutation; (c) GA heterozygote. 2039 G>A (d-f) (d) GG wild-type genotype; (e) AA homozygous mutation; (f) GA heterozygote.|
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For the polymorphism at position 307, the frequency of Thr/Thr, Thr/Ala, and Ala/Ala variants was 45.11%, 45.11%, and 9.78%, respectively. The frequency distribution for the genotypes at position 307 was found to be consistent with HWE [χ2=0.175, P>0.05, [Table 2]]. No significant difference was found in age, FSH, LH, and AMH for three genotype groups at position 307 (P>0.05), although the serum FSH level in the Ala/Ala group was slightly higher than that in the other two groups. A significant difference was found in the BMI of these three genotype groups [P < 0.05, [Table 3]].
|Table 2: Genotyping distribution of FSHR for SNPs 307 and 680 in 184 patients|
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For the polymorphism at position 680, the distribution of Asn/Asn, Asn/Ser, and Ser/Ser was 45.65%, 44.57%, and 9.78%, respectively. The frequency distribution for these genotypes at position 680 was found to be consistent with HWE [χ2=0.097, P>0.05, [Table 2]]. According to the present study, no significant difference was found between these three genotypes regarding basal hormone profile and characteristics [P > 0.05, [Table 3]]. However, for the Ser/Ser group, the FSH level was slightly higher and the AMH level was slightly lower than those of the other two groups. Seven combinations of genotypes for these two positions were found in this study. The results indicated that Thr307Thr–Asn680Asn, Ala307Ala–Ser680Ser, and Thr307Ala–Asn680Ser were the three major genotype combinations found in about 97.3% of all patients included in the study [Table 4].
|Table 4: Gn dosage in major combinations of alleles at positions 307 and 680 of FSHR for the selected patients|
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Correlation analysis was performed between ovarian reserve testing and Gn administration. The results showed that the dosage of Gn administered had an inverse correlation with the level of AMH on day 3 and number of AFC (r=−0.345, P=0.001, r=−0.545, P=0.001, respectively). Interestingly, for the included patients in this study, the E2 level on the day of hCG administration had an inverse correlation with Gn administration [r=−0.494, P=0.001, [Figure 2]].
|Figure 2: Correlation among Gn administration, the level of E2 on hCG day, level of AMH on day 3 and AFC. (a) Correlation between Gn administration and the level of AMH. (b) Correlation between Gn administration and AFC. (c) Correlation between Gn administration and the level of E2. AFCs: Antral follicle counts; AMH: Anti-Mullerian hormone; hCG: Human chorionic gonadotropin; Gn: Gonadotropin.|
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To get a profile for the effect of these genotypes on Gn administration, a multivariate logistic regression analysis was performed with or without adjusting the clinical characteristics such as age, BMI, FSH, LH, and AMH. According to the dosage of Gn administered, higher than 2000 (IU) (the average dosage of Gn administration in our center (the center of the reproductive and genetic of Suzhou Municipal Hospital)) was defined as the high-dose Gn administration group, and lower than 2,000 (IU) was defined as the low-dose Gn administration group.
In a binary logistic regression model, factors predictive for Gn dosage were analyzed. The results indicated that the Ser680Ser genotype group had a significantly higher risk for higher Gn dosage compared with Asn680Asn genotype group (P < 0.05). The mean of total dose of gonadotropins was 2,168.75 IU and 1,983.04 IU, and total duration stimulation days were 11.36 days and 10.76 days (Ser680Ser genotype group vs. Asn680Asn genotype group). After adjusting age, BMI, FSH, LH, and AMH, the higher risk for Ser680Ser group still existed (P<0.05). Polymorphism at position 307 for increasing the Gn dosage was not obvious [P>0.05, [Table 5]]. Furthermore, the binary logistic regression analysis was performed to determine the effect of the three major genotype combinations at these two positions on the Gn dosage. This study reported no significant effect of different combinations of these two positions on the Gn dosage [Table 4].
|Table 5: The association of genotypes for both these two positions with Gn usage|
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| Discussion|| |
This study reported the frequency distribution of different genotype variants at these two positions. Sudo et al. previously reported that the frequency of Thr/Thr, Thr/Ala, and Ala/Ala in a population of 522 Japanese women was 41.0%, 46.9%, and 12.1%, respectively. A study by Jun et al. reported that the frequency of Asn/Asn, Asn/Ser, and Ser/Ser was 41.8%, 45.6%, and 12.5%, respectively. According to the present study, the frequency of different genotypes at these two positions was highly consistent with those reported in the previous studies. It was reported that polymorphisms at positions 307 and 680 in exon 10 were in strong linkage disequilibrium, resulting in two common variants: Thr307–Asn680 and Ala307–Ser680. The present study also reported that the three major combinations were Thr307Thr–Asn680Asn, Ala307Ala–Ser680Ser, and Thr307Ala–Asn680Ser in the included patients, involving a great portion of all combinations.
A higher basal level of serum FSH level partly reflected a worse ovarian function, while AMH was a comparable precise indicator for the ovarian reserve. A study by Mohiyiddeen and Nardo reported no association between FSHR SNP and these ovarian reserve markers, while other clinical studies reported that FSHR polymorphism Ser680Ser was associated with higher FSH and lower AMH levels.,, A meta-analysis suggested that the population with Ala307Ala genotype had slightly higher basal FSH levels, which were consistent with the present study result. However, the present study found no significant difference among these genotypes regarding basal hormone profile, although a slightly higher level of FSH was observed for Ala307Ala and Ser680Ser groups, and a slightly lower level of AMH for the latter one. These inconsistent results might derive from the various patient selection criteria, different COH protocol administration, and the ethnic populations studied by different studies. Except the difference in BMI for different Thr307Ala groups, most of the clinical characteristics had no significant difference, which suggested that the patients in this study were very homogeneous.
Reserve of small antral follicle size is an important predictor for Gn dosage. The number of AFC (direct) and AMH level (indirect) were often used as parameters for Gn administration. According to the correlation analysis in this study, an inverse association was found between Gn dosage and AMH concentration and the number of AFC, as well as E2 on the day of hCG administration. This phenomenon reflected that the dosage of Gn administration during COH was mainly based on the potential ovarian response. Usually Gn administration was raised for the lower responders and lowered for the high responders during the routine protocol. In addition, the present study found a positive correlation between E2 and oocyte retrieval number (data not shown), which indicated reasonable and effective for the present stimulation protocol.
An effective COH protocol determination is very important to reach an ideal IVF outcome. Precise parameters to help individualize stimulation protocols are needed to get a good COH outcome. The regulation of Gn dosage is critical in optimizing ovarian stimulation protocols. Theoretically, lower or higher FSHR sensitivity caused by inactivating or overactivating FSHR induced by different SNPs could be overcome by modifying FSH dosage during the COH process.
The association of the polymorphism of FSHR at positions 680 and 307 with the requirement of exogenous Gn for ovarian stimulation was one objective of this study. The study reported that the Ser680Ser variant could increase Gn dosage, as FSHR gene polymorphism might act along with other factors, contributing to different ovarian response to Gn. This effect was further adjusted by the basal clinical characteristics such as age, BMI, FSH, LH, and AMH, and its higher risk still existed according to this study. This result implied that the polymorphism of Asn680Ser might be valuable in guiding Gn administration. The previous reports about the relevance of polymorphism of FSHR Thr307Ala with the ovarian response were still conflicting. This study found no significant effect of Thr307 variant on the Gn requirement.
Multifactor and complex network of many factors during ovarian stimulation may contribute to the inconsistent and conflicting reports about the association between polymorphisms of FSHR and ovarian response. Effects from polymorphisms of FSHR on ovarian response may be covered for the patients with normal ovarian reserve. SNPs may not be a decisive factor for the ovarian response outcome in the normal ovarian responders, while it may be a very different situation when it comes to the poor ovarian responder or hyperstimulation patients. These conflicting results for evaluating the influence of these SNPs on the ovarian response to exogenous Gn may be due to the complexity of different modulation function of these SNPs and different population selection criteria. Whether Thr307Ala and Asn680Ser genetic variants could serve as a decisive factor for Gn dosage predictor still needs further study.
Studies on the association of FSHR polymorphisms with Gn dosage during IVF could help give a more precise direction for Gn administration in the COH protocol, such as (i) finding a valuable parameter for clinicians during the COH procedure, (ii) overcoming inactivated FSHR by increasing the Gn dosage, and (iii) avoiding the ovarian hyperstimulation syndrome occurrence by lowering Gn administration.
This study had several shortcomings. First, this was a retrospective clinical study. A case–control study would give a more powerful conclusion. Second, all the patients included in this study underwent their first IVF cycle, whose ovarian response could be predicted only from the basal clinical characteristics. Third, the effect of these two SNPs of FSHR on pregnancy outcome, such as the pregnancy rate and live-birth rate, was not analyzed. And finally, the population studied was small, which should be overcome in the future studies.
This study was financially supported by Province Funds of Zhejiang University Medical School Key Laboratory (2012-RG/GH-0006) and Jiangsu Key talents of maternal and child health (FRC2017250, Clinical research special funds of Wu Jieping Foundation, China (320.6755.15027) and Suzhou Key Medical Center, (SZZX201505).
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]