The Additive Effect of Combinations of FSH Receptor Gene Variants in Ovarian Response to Stimulation

Overview

Journal Reprod Sci

Publisher Springer

Specialty Reproductive Medicine

Date 2024 Sep 25

PMID 39322797

Authors

Ana Raquel Neves

Sandra Garcia

Lan N Vuong

Christophe Blockeel

Claudia Spits

Nikolaos P Polyzos

Affiliations

Soon will be listed here.

Abstract

To analyze whether combinations of polymorphisms within FSHR gene influence ovarian response (OR) to stimulation. A multicenter prospective cohort study was conducted from 11/2016-06/2019 in Europe and Asia including predicted normo-responders under 38y. Patients underwent ovarian stimulation using fixed-dose 150 IU rFSH in a GnRH antagonist protocol. FSHR variants rs6165, rs6166 and rs1394205 were genotyped and combined in diplotypes. OR was compared following multivariable regression. rs6165/rs6166 genotype AG/AG exhibited more hypo-response (33.1% vs. 24%,adjOR 1.77 [95%CI 1.08-2.90]) and lower Follicle to Oocyte Index (FOI) compared with other diplotypes (EMD -11.72 [95%CI -20.89;-2.55]). Genotype GG/AA showed less hypo-response (19.1% vs. 31%, adjOR 0.48 [95%CI 0.24-0.96]), while AA/AA had higher FOI (EMD 20.04 [95%CI 4.51;35.56]). Concerning rs6165/rs1394205, less oocytes (EMD -1.99 [95%CI -3.57;-0.42]) and lower FOI (EMD -12.07 [95%CI -23.09;-1.05]) were retrieved with genotype AG/AG and higher FORT with genotype AA/AG (EMD 17.88 [95%CI 3.77;31.98]). Regarding rs6166/rs1394205, less hypo-response (16.3% vs. 29.5%,adjOR 0.42 [95%CI 0.19-0.97]), more oocytes (EMD 3.45 [95%CI 1.57;5.34]) and higher FOI (EMD 17.57 [95%CI 4.41;30.73) were found with genotype AA/GG. Genotype AA/AG presented higher FORT (EMD 13.47 [95%CI 2.51,24.42]), while more hypo-response (56.3% vs. 26.4%,adjOR 6.30 [95%CI 1.88;21.08]) and lower FOI (EMD -23.51 [95%CI -45.04;-1.97]) was reported with AG/AA. In accordance with our previous studies, FSHR polymorphisms have a statistically significant impact on OR, both individually and in association. However, only rs6166/rs1394205 genotype AA/GG seems to have a clinically significant effect, with a decrease in the prevalence of hypo-response, higher oocyte yield and increase in FOI.

References

Neves A, Montoya-Botero P, Sachs-Guedj N, Polyzos N . Association between the number of oocytes and cumulative live birth rate: A systematic review. Best Pract Res Clin Obstet Gynaecol. 2023; 87:102307. DOI: 10.1016/j.bpobgyn.2022.102307. View

Polyzos N, Drakopoulos P, Parra J, Pellicer A, Santos-Ribeiro S, Tournaye H . Cumulative live birth rates according to the number of oocytes retrieved after the first ovarian stimulation for in vitro fertilization/intracytoplasmic sperm injection: a multicenter multinational analysis including ∼15,000 women. Fertil Steril. 2018; 110(4):661-670.e1. DOI: 10.1016/j.fertnstert.2018.04.039. View

Devesa M, Tur R, Rodriguez I, Coroleu B, Martinez F, Polyzos N . Cumulative live birth rates and number of oocytes retrieved in women of advanced age. A single centre analysis including 4500 women ≥38 years old. Hum Reprod. 2018; 33(11):2010-2017. DOI: 10.1093/humrep/dey295. View

Drakopoulos P, Blockeel C, Stoop D, Camus M, De Vos M, Tournaye H . Conventional ovarian stimulation and single embryo transfer for IVF/ICSI. How many oocytes do we need to maximize cumulative live birth rates after utilization of all fresh and frozen embryos?. Hum Reprod. 2016; 31(2):370-6. DOI: 10.1093/humrep/dev316. View

Broer S, van Disseldorp J, Broeze K, Dolleman M, Opmeer B, Bossuyt P . Added value of ovarian reserve testing on patient characteristics in the prediction of ovarian response and ongoing pregnancy: an individual patient data approach. Hum Reprod Update. 2012; 19(1):26-36. DOI: 10.1093/humupd/dms041. View

Polyzos N, Stoop D, Blockeel C, Adriaensen P, Platteau P, Anckaert E . Anti-Müllerian hormone for the assessment of ovarian response in GnRH-antagonist-treated oocyte donors. Reprod Biomed Online. 2012; 24(5):532-9. DOI: 10.1016/j.rbmo.2012.01.024. View

Vaiarelli A, Drakopoulos P, Blockeel C, De Vos M, van de Vijver A, Camus M . Limited ability of circulating anti-Müllerian hormone to predict dominant follicular recruitment in PCOS women treated with clomiphene citrate: a comparison of two different assays. Gynecol Endocrinol. 2015; 32(3):227-30. DOI: 10.3109/09513590.2015.1110138. View

Polyzos N, Tournaye H, Guzman L, Camus M, Nelson S . Predictors of ovarian response in women treated with corifollitropin alfa for in vitro fertilization/intracytoplasmic sperm injection. Fertil Steril. 2013; 100(2):430-7. DOI: 10.1016/j.fertnstert.2013.04.029. View

Neves A, Blockeel C, Griesinger G, Garcia-Velasco J, La Marca A, Rodriguez I . The performance of the Elecsys® anti-Müllerian hormone assay in predicting extremes of ovarian response to corifollitropin alfa. Reprod Biomed Online. 2020; 41(1):29-36. DOI: 10.1016/j.rbmo.2020.03.023. View

10.

Riccetti L, De Pascali F, Gilioli L, Santi D, Brigante G, Simoni M . Genetics of gonadotropins and their receptors as markers of ovarian reserve and response in controlled ovarian stimulation. Best Pract Res Clin Obstet Gynaecol. 2017; 44:15-25. DOI: 10.1016/j.bpobgyn.2017.04.002. View

11.

Nakayama T, Kuroi N, Sano M, Tabara Y, Katsuya T, Ogihara T . Mutation of the follicle-stimulating hormone receptor gene 5'-untranslated region associated with female hypertension. Hypertension. 2006; 48(3):512-8. DOI: 10.1161/01.HYP.0000233877.84343.d7. View

12.

Simoni M, Casarini L . Mechanisms in endocrinology: Genetics of FSH action: a 2014-and-beyond view. Eur J Endocrinol. 2013; 170(3):R91-107. DOI: 10.1530/EJE-13-0624. View

13.

Casarini L, Moriondo V, Marino M, Adversi F, Capodanno F, Grisolia C . FSHR polymorphism p.N680S mediates different responses to FSH in vitro. Mol Cell Endocrinol. 2014; 393(1-2):83-91. DOI: 10.1016/j.mce.2014.06.013. View

14.

Santi D, Poti F, Simoni M, Casarini L . Pharmacogenetics of G-protein-coupled receptors variants: FSH receptor and infertility treatment. Best Pract Res Clin Endocrinol Metab. 2018; 32(2):189-200. DOI: 10.1016/j.beem.2018.01.001. View

15.

Perez Mayorga M, Gromoll J, Behre H, Gassner C, Nieschlag E, Simoni M . Ovarian response to follicle-stimulating hormone (FSH) stimulation depends on the FSH receptor genotype. J Clin Endocrinol Metab. 2000; 85(9):3365-9. DOI: 10.1210/jcem.85.9.6789. View

16.

Behre H, Greb R, Mempel A, Sonntag B, Kiesel L, Kaltwasser P . Significance of a common single nucleotide polymorphism in exon 10 of the follicle-stimulating hormone (FSH) receptor gene for the ovarian response to FSH: a pharmacogenetic approach to controlled ovarian hyperstimulation. Pharmacogenet Genomics. 2005; 15(7):451-6. DOI: 10.1097/01.fpc.0000167330.92786.5e. View

17.

Alviggi C, Conforti A, Caprio F, Gizzo S, Noventa M, Strina I . In Estimated Good Prognosis Patients Could Unexpected "Hyporesponse" to Controlled Ovarian Stimulation be Related to Genetic Polymorphisms of FSH Receptor?. Reprod Sci. 2016; 23(8):1103-8. DOI: 10.1177/1933719116630419. View

18.

Huang X, Li L, Hong L, Zhou W, Shi H, Zhang H . The Ser680Asn polymorphism in the follicle-stimulating hormone receptor gene is associated with the ovarian response in controlled ovarian hyperstimulation. Clin Endocrinol (Oxf). 2014; 82(4):577-83. DOI: 10.1111/cen.12573. View

19.

Klinkert E, Te Velde E, Weima S, van Zandvoort P, Hanssen R, Nilsson P . FSH receptor genotype is associated with pregnancy but not with ovarian response in IVF. Reprod Biomed Online. 2006; 13(5):687-95. DOI: 10.1016/s1472-6483(10)60660-8. View

20.

Laven J, Mulders A, Suryandari D, Gromoll J, Nieschlag E, Fauser B . Follicle-stimulating hormone receptor polymorphisms in women with normogonadotropic anovulatory infertility. Fertil Steril. 2003; 80(4):986-92. DOI: 10.1016/s0015-0282(03)01115-4. View