In Estimated Good Prognosis Patients Could Unexpected “Hyporesponse” to Controlled Ovarian Stimulation be Related to Genetic Polymorphisms of FSH Receptor?

Abstract

It has been reported that 10% to 15% of young normogonadotrophic women show suboptimal response to standard gonadotropin-releasing hormone—a long protocol. These patients require higher doses of exogenous follicle-stimulating hormone (FSH). This phenomenon could be associated with genetic characteristics. In this study, FSH receptor polymorphism was retrospectively evaluated in 42 normoresponder young women undergoing an in vitro fertilization/intracytoplasmic sperm injection cycle; patients were stratified according to recombinant human FSH (r-hFSH) consumption. We selected 17 normoresponder young patients who required a cumulative dose of recombinant FSH (rFSH) >2500 UI (group A). A control group was randomly selected among patients who required a cumulative dose of rFSH <2500 UI (group B). Follicle-stimulating hormone receptor (FSH-R) 307Ala and 680Ser variants were analyzed in all our patients. Our results show that the mean number of rFSH vials (36.3 ± 7.5 vs 28.6 ± 4.5, P = .0001) and days of stimulation (12.7 ± 2.4 vs 10.8 ± 2.8, P = .03) were significantly lower in group B, whereas the number of oocytes retrieved (7.1 ± 1.5 vs 9.6 ± 2.4; P = .0005) and the average number of embryos transferred (2.1 ± 0.7 vs 2.7 ± 0.4; P = .001) were significantly lower in group A. Estradiol serum levels on the human chorionic gonadotrophin day were significantly lower in group A (997.8 ± 384.9 pg/mL vs 1749.1 ± 644.4; P = .0001). The incidence of the Ser/Ser genotype was higher in patients with higher r-hFSH consumption (group A; P = .02). Based on our results, we hypothesize an association between the FSH-R polymorphisms and a “hyporesponse” to exogenous FSH.

Keywords

controlled ovarian stimulation FSH receptor genetic mutation receptor polymorphism recombinant FSH in vitro fertilization ovarian response

Get full access to this article

View all access options for this article.

References

Ferraretti

La Marca

Fauser

Tarlatzis

Nargund

Gianaroli

; ESHRE working group on Poor Ovarian Response Definition. ESHRE consensus on the definition of ‘poor response’ to ovarian stimulation for in vitro fertilization: the Bologna criteria. Hum Reprod. 2011;26(7):1616–1624.

Gizzo

Andrisani

Esposito

. Ovarian reserve test: an impartial means to resolve the mismatch between chronological and biological age in the assessment of female reproductive chances. Reprod Sci. 2014;21(5):632–639.

Ferraretti

Gianaroli

Magli

D’angelo

Farfalli

Montanaro

. Exogenous luteinizing hormone in controlled ovarian hyperstimulation for assisted reproduction techniques. Fertil Steril. 2004;82(6):1521–1526.

De Placido

Alviggi

Perino

.; Italian Collaborative Group on Recombinant Human Luteinizing Hormon. Recombinant human LH supplementation versus recombinant human FSH (rFSH) step-up protocol during controlled ovarian stimulation in normogonadotrophic women with initial inadequate ovarian response to rFSH. A multicentre, prospective, randomized controlled trial. Hum. Reprod. 2005;20(2):390–396.

De Placido

Mollo

Alviggi

. Rescue of in vitro fertilisation cycles by human menopausal gonadotrophinin pituitary down-regulated normogonadotrophic young women characterised by a poor initial response to recombinant follicle stimulating hormone. Hum Reprod. 2001;16(9):1875–1879.

Devroey

Fauser

Diedrich

; Evian Annual Reproduction (EVAR) Workshop Group 2008. Approaches to improve the diagnosis and management of infertility. Hum Reprod Update. 2009;15(4):391–408.

Alviggi

Clarizia

Mollo

Ranieri

De Placido

. Who needs LH in ovarian stimulation? Reprod Biomed Online. 2011;12(Suppl 1):599–607.

Alviggi

Pettersson

Longobardi

. A common polymorphic allele of the LH beta-subunit gene is associated with higher exogenous FSH consumption during controlled ovarian stimulation for assisted reproductive technology. Reprod Biol Endocrinol. 2013;11:51.

Huhtaniemi

Jiang

Nilsson

Pettersson

. Mutations and polymorphisms in gonadotropin genes. Mol Cell Endocrinol. 1999;151(1-2):89–94.

10.

Haavisto

Pettersson

Bergendahl

Virkamäki

Huhtaniemi

. Occurrence and biological properties of a common genetic variant of luteinizing hormone. J Clin Endocrinol Metab 1995;80(4):1257–1263.

11.

Alviggi

Clarizia

Pettersson

. A common LH polymorphism (LH-beta variant) is associated with suboptimal response to GnRH-a long protocol in normogonadotrophin women undergoing ovarian stimulation with r-hFSH. Reprod Biomed Online. 2009;18(1):9–14.

12.

Alviggi

Clarizia

Pettersson

. Suboptimal response to GnRHa long protocol is associated with a common LH polymorphism. Reprod Biomed Online. 2011;22 Suppl 1:S67–S72. doi: 10.1016/S1472-6483(11)60011-4.

13.

De Placido

Alviggi

Mollo

. Effects of recombinant LH (rLH) supplementation during controlled ovarian hyperstimulation (COH) in normogonadotrophic women with an initial inadequate response to recombinant FSH (rFSH) after pituitary down regulation. Clin Endocrinol. 2004;60(5):637–643.

14.

Alviggi

Mollo

Clarizia

De Placido

. Exploiting LH in ovarian stimulation. Reprod Biomed Online. 2006;12(2):221–233.

15.

Gizzo

Andrisani

Noventa

. Recombinant LH supplementation during IVF cycles with a GnRH-antagonist in estimated poor responders: A cross-matched pilot investigation of the optimal daily dose and timing. Mol Med Rep. 2015;12(3):4219–4229.

16.

Perez Mayorga

Gromoll

Behre

Gassner

Nieschlag

Simoni

. Ovarian response to follicle-stimulating hormone (FSH) stimulation depends on the FSH receptore genotype. J Clin Endocrinol Metab. 2000;85(9):3365–3369.

17.

Mohiyiddeen

Nardo

. Single-nucleotide polymorphisms in the FSH receptor gene and ovarian performance: future role in IVF. Hum Fertil (Camb). 2010;13(2):72–78.

18.

Yao

Tang

. Influence of follicle-stimulating hormone receptor (FSHR) Ser680Asn polymorphism on ovarian function and in-vitro fertilization outcome: a meta-analysis. Mol Genet Metab. 2011;103(4):388–393.

19.

Simoni

Gromoll

Nieschlag

. The follicle-stimulating hormone receptor: biochemistry, molecular biology, physiology, and pathophysiology. Endocr Rev. 1997;18(6):739–773.

20.

Greb

Grieshaber

Gromoll

. A common single nucleotide polymorphism in exon 10 of the human follicle stimulating hormone receptor is a major determinant of length and hormonal dynamic of the mestrual cycle. J Clin Endocrinol Metab. 2005;90(8):4866–4872.

21.

Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril. 2004;81(1):19–25.

22.

Revised American Society for Reproductive Medicine classification of endometriosis: 1996. Fertil Steril. 1997;67(5):817–821.

23.

Patrelli

Berretta

Gizzo

. CA 125 serum values in surgically treated endometriosis patients and its relationships with anatomic sites of endometriosis and pregnancy rate. Fertil Steril. 2011;95(1):393–396.

24.

De Castro

Ruiz

Monitoro

. Role of follicle-stimulating hormone receptor Ser680Asn polymorphism in the efficacy of follicle-stimulating hormone. Fertil Steril. 2003;80(3):571–576.

25.

Behre

Greb

Mempel

. 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):451–456.

26.

Loutradis

Patsoula

Minas

. FSH receptor gene polymorphisms have a role for different ovarian response to stimulation in patients entering IVF/ICSI-ET programs. J Assist Reprod Genet. 2006;23(4):177–184.

27.

Genro

Matte

De Conto

Cunha-Filho

Fanchin

. Frequent polymorphism of FSH receptor do not influence antral follicle responsiveness to follicle-stimulating hormone administration as assessed by the Follicular Output RaTe (FORT). J Assist. Reprod. Genet. 2012;29(7):657–663.

28.

Jun

Yoon

. Follicle stimulating hormone receptor gene polymorphism and ovarian responses to controlled ovarian hyperstimulation for IVF-ET. J Hum Genet. 2006;51(8):665–670.

29.

Gizzo

Quaranta

Andrisani

. Serum stem cell factor assay in elderly poor responder patients undergoing IVF: a new biomarker to customize follicle aspiration cycle by cycle. Reprod Sci. 2016;23(1):61–68.