Lamiya Mohiyiddeen

Single-nucleotide polymorphisms in the FSH receptor gene and ovarian performance: Future role in IVF

The ovarian response to follicle stimulating hormone (FSH) stimulation in assisted conception cycles is variable. Although it would be beneficial to predict accurately the response of patients to FSH, to date no absolute predictors of ovarian performance have been identified. Recently, there have been a number of studies on the effect of single-nucleotide polymorphisms (SNPs) in the FSH receptor gene and its predictability in ovarian response to FSH stimulation. Several reports have shown that two very common SNPs at positions 307 and 680 in exon 10 of the FSH receptor gene are associated with ovarian response in IVF. The SNPs in exon 10 result in four discrete allelic variants characterised by the amino acid combinations Thr307-Asn680, Ala307-Ser680, Ala307-Asn680 and Thr307-Ser680. Because Thr307 is almost always in linkage disequilibrium with Asn680, and Ala307 almost always with Ser680, most studies are focussed solely on position 680. Some authors have shown predictability of ovarian response to FSH stimulation in patients with different alleles, while others have refuted this finding. In vitro models have not shown any difference in response among various alleles. Most of the available studies are retrospective, observational. Until now, there is no clear clinical benefit in the screening for SNP before IVF treatment. However, there is the prospect of devising mathematical models using a group of polymorphisms to provide an important tool for improving ovulation induction, especially in poor responders.

A common Asn680Ser polymorphism in the follicle-stimulating hormone receptor gene is not associated with ovarian response to gonadotropin stimulation in patients undergoing in vitro fertilization

OBJECTIVE To assess the role of the variant p.Asn680Ser in the follicle-stimulating hormone receptor (FSHR) gene in determining ovarian response in patients undergoing in vitro fertilization (IVF) treatment. DESIGN Prospective observational study. SETTING Tertiary referral center for reproductive medicine. PATIENT(S) Women (n = 421) undergoing their first cycle of controlled ovarian stimulation for IVF and 83 healthy, ethnically matched controls. INTERVENTION(S) Baseline pelvic ultrasound and blood tests taken on days 2 to 3 of the cycle for assessment of baseline hormones and for DNA extraction. MAIN OUTCOME MEASURE(S) Genotypes for FSHR p.Asn680Ser determined using TaqMan allelic discrimination assay, and ovarian response to gonadotropin treatment classified as normal, poor, or overresponse based on the number of oocytes retrieved. RESULT(S) The FSHR p.Asn680Ser genotype frequencies were similar in IVF patients and controls. The number of oocytes retrieved was comparable between patients with different FSHR receptor genotypes. The total amount of gonadotropin used was also similar in all the genotype groups. A logistic regression analysis showed nonstatistically significant twofold difference in the distribution of genotypes between the groups with poor and normal ovarian response. CONCLUSION(S) The variant FSHR p.Asn680Ser was not shown to be predictive of ovarian response, but clinically relevant differences cannot be ruled out.

Follicle-stimulating hormone receptor gene polymorphisms are not associated with ovarian reserve markers

OBJECTIVE To evaluate the association between variants in the FSHR receptor (FSHR) gene and current markers of ovarian reserve (antimüllerian hormone, antral follicle count, FSH). DESIGN Prospective observational study. SETTING Tertiary referral center for reproductive medicine. PATIENT(S) Women (n = 421) undergoing their first cycle of controlled ovarian stimulation for IVF. INTERVENTION(S) Baseline pelvic ultrasound and blood tests were taken on day 2-3 of the cycle for assessment of baseline hormones and for DNA extraction. Genotypes for FSHR p.Asn680Ser and p.Thr307Ala variants were determined using TaqMan allelic discrimination assays. MAIN OUTCOME MEASURE(S) Association of FSHR single nucleotide polymorphisms with markers of ovarian reserve. RESULT(S) There was no evidence of any difference in basal FSH, antimüllerian hormone, or antral follicle count between the patients with different genotypes, with or without an adjustment for age or body mass index. CONCLUSION(S) No associations of FSHR genotypes with markers of ovarian reserve were detected in our cohort.

Transvaginal biopsy in the diagnosis of ovarian cancer

Laparotomy and debulking surgery followed by chemotherapy have been the treatment of choice in late stage ovarian carcinoma. Developments in the chemotherapeutic management of ovarian cancer have resulted in a change in opinion as to the optimal management of this disease. Many patients are now receiving initial chemotherapy and trials are in place to compare up front and adjuvant surgery. Tissue diagnosis is required prior to commencing chemotherapy. This article describes one method for accurately obtaining a tumour biopsy. A retrospective case note review of 14 women with a provisional diagnosis of ovarian carcinoma who underwent transvaginal biopsy of their pelvic disease is described. Only 7/12 cases with a positive biopsy had a definite diagnosis of ovarian cancer. The procedure was found to be safe and well tolerated.

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.

Association of a promoter polymorphism in FSHR with ovarian reserve and response to ovarian stimulation in women undergoing assisted reproductive treatment

Previous studies have suggested an association between a variant in the promoter region of the FSHR gene and diminished response to controlled ovarian hyperstimulation (COH) in women undergoing assisted reproduction. FSHR -29G>A was genotyped in 559 women undergoing their first cycle of COH for IVF/intracytoplasmic sperm injection (ICSI) using TaqMan allelic discrimination assay. Correlation and regression analysis was performed to assess the relationship between FSHR promoter genotypes and markers of ovarian reserve and measures of response to COH, including the number of oocytes retrieved, gonadotrophin dose used and the live-birth rate. There were no statistically significant differences between the genotype frequencies and the markers of ovarian reserve or the early measures of response to COH. However, the live-birth rate was higher for women carrying the variant A allele (odds ratio [OR] 1.37; 95% confidence interval [CI] 1.02-1.84 per allele). This relationship did not reach statistical significance after adjustment for the number of embryos transferred (OR 1.33; 95% CI 0.98-1.83 per allele). Results from this study do not provide evidence that the FSHR -29G>A variant can be used in the individualization of the treatment protocol for women undergoing IVF/ICSI.

FSH receptor genotype does not predict metaphase-II oocyte output or fertilization rates in ICSI patients

The objective of this study was to assess the role of the variant p.Asn680Ser in the FSH receptor gene (FSHR) in determining oocyte maturity. It also assessed the relationship between this FSHR variant with metaphase-II oocyte output rate (MOR) and the fertilization rate. This was a prospective observational study based at a tertiary referral centre for reproductive medicine. Women (n=212) undergoing their first cycle of ovarian stimulation for IVF with intracytoplasmic sperm injection (ICSI) were included in the study. Baseline pelvic ultrasound and blood tests were taken on day 2 or 3 of the cycle for assessment of baseline hormones and for DNA extraction. Genotypes for FSHR p.Asn680Ser was determined using TaqMan allelic discrimination assay. The outcome measures were the total dose of exogenous gonadotrophins used, antral follicle count (AFC), number of mature (metaphase-II) oocytes retrieved, MOR and fertilization rate. No statistically significant differences were found between the number of mature oocytes retrieved, MOR or fertilization rates among the patients with different p.Asn680Ser FSHR genotypes. No significant difference was noted in the clinical pregnancy rates per transfer. There is no evidence that the p.Asn680Ser FSHR genotype predicts oocyte maturity.

AMH type II receptor and AMH gene polymorphisms are not associated with ovarian reserve, response, or outcomes in ovarian stimulation.

PurposeGenetic variation may influence women’s response to ovarian stimulation therapy. The purpose of this study was to investigate any effects of genetic variants in the anti-Müllerian hormone (AMH) and AMH type II receptor genes on ovarian response/treatment outcomes and on current markers of ovarian reserve in individuals undergoing in vitro fertilisation (IVF) treatment.MethodsIn this prospective observational study, we genotyped the AMH c.146G>T, p.(Ile49Ser) and AMHR2 -482A>G variants in 603 unrelated women undergoing their first cycle of controlled ovarian stimulation for IVF and ICSI (intracytoplasmic sperm injection) using gonadotrophins at a tertiary referral centre for reproductive medicine. Pelvic ultrasound and blood hormone levels were taken on days 2–3 of the cycle. Genotypes were determined using TaqMan allelic discrimination assay. Regression analysis was performed to assess the relationship between the genotypes and the ovarian reserve markers (FSH, AMH, antral follicle count) and the early outcomes of response (number of oocytes retrieved and gonadotropin dose) as well as the treatment outcome (live birth).ResultsThere were no significant associations between the variants AMH c.146G>T and AMHR2 -482A>G with ovarian response in terms of number of oocytes retrieved (p = 0.08 and p = 0.64, respectively), live births (p = 0.28 and p = 0.52) and/or markers of ovarian reserve.ConclusionsGenotyping of the AMH c.146G>T and AMHR2 -482A>G polymorphisms does not provide additional useful information as a predictor of ovarian reserve or ovarian response and treatment outcomes.