FSH pharmacogenetics

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Gertrude Day
6 years ago
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1 5th World Congress on Ovulation Induction Roma, September 2007 FSH pharmacogenetics Hermann M. Behre Center of Reproductive Medicine and Andrology, University Hospital Halle, Germany & Manuela Simoni Institute of Reproductive Medicine, University Hospital Münster, Germany

2 Identification of 2 polymorphisms in exon 10 of the FSH receptor gene with 2 discrete FSH receptor allelic variants, i.e. Thr307-Asn680 and Ala307-Ser680 (Simoni et al. JCEM 1999) gene protein allelic variant 1 Thr Asn allelic variant 2 Ala Ser

3 Effects of FSHR SNP 680 on hormonal dynamics of menstrual cycle (mc) Study design: mc monitoring in volunteers recruited by newspaper adv. Inclusion criteria: age 18-34, regular mc (25-32 days), BMI 19-28, Caucasian Screened: 125 Heterozygous: 64 (excluded) Homoz. Asn: 42 Homoz. Ser: 22 Completed mc monitoring: 13 Asn + 10 Ser Evaluated: 12 Asn + 9 Ser Greb et al. JCEM 2005

4 Ser/Ser Asn/Asn Asn/Asn Ser/Ser Gonadotropins Menstruation Greb et al. JCEM 2005 LH (IU/L) FSH (IU/L) * P < 0.05 ** P < Asn/Asn Day relative to midcycle LH peak * * ** * * * Ser/Ser * ** ** * * * * Day relative to midcycle LH peak * *

5 Conclusions Ser/Ser is associated with: higher FSH levels, lower estradiol recruitment of a larger number of antral follicles longer duration of the menstrual cycle compared to Asn/Asn higher FSH threshold!

6 Can the lower sensitivity of the Ser/Ser genotype of the FSH receptor regarding estradiol be overcome by a higher FSH dose? An interventional, prospective randomised study in homozygous, ovulatory women undergoing COH for ART

7 Relevance of the FSH receptor genotype for controlled ovarian stimulation - a prospective randomized controlled trial - Hypotheses Different sensitivity of the FSH receptor to pharmacological FSH stimulation depending on the single nucleotide polymorphism. In women with the Ser/Ser genotype the same FSH dose results in lower estradiol levels compared to the Asn/Asn genotype. The lower estradiol response in women with the Ser/Ser genotype can be compensated for by an increase of the FSH dose by 50%. Behre et al. Pharmacogenet Genomics 2005

8 Relevance of the FSH receptor genotype for controlled ovarian stimulation - a prospective randomized controlled trial - The study was approved by the local Ethics Committees. The study was sponsored by the German Research Foundation. Inclusion criteria women with indication for IVF or ICSI therapy age 18 to 39 years normal menstrual cycle (24 35 days) no ovarian pathology including ovarian cyst, ovarian endometriosis or polycystic ovary syndrome 3 previous IVF or ICSI cycles serum FSH < 10 U/l on cycle day 3 homozygous FSH receptor allele variant Asn/Asn or Ser/Ser written informed consent

9 FSH receptor genotype and controlled ovarian stimulation a prospective randomized controlled trial Age of the women at study entry Age (years) P = Ser/Ser Ser/Ser Asn/Asn 150 U/d FSH 225 U/d FSH 150 U/d FSH n=24 n=25 n=44 mean ±SEM

10 FSH receptor genotype and controlled ovarian stimulation a prospective randomized controlled trial FSH on cycle day 3 FSH (U/l) P = Ser/Ser Ser/Ser Asn/Asn 150 U/d FSH 225 U/d FSH 150 U/d FSH n=24 n=25 n=44 mean ±SEM

11 FSH receptor genotype and controlled ovarian stimulation a prospective randomized controlled trial FSH stimulation days Stimulation days (n) P = Ser/Ser Ser/Ser Asn/Asn 150 U/d FSH 225 U/d FSH 150 U/d FSH n=24 n=25 n=44 mean ±SEM

12 FSH receptor genotype and controlled ovarian stimulation a prospective randomized controlled trial Total FSH dose (U) Total FSH dose P < Ser/Ser Ser/Ser Asn/Asn 150 U/d FSH 225 U/d FSH 150 U/d FSH n=24 n=25 n=44 mean ±SEM

13 FSH receptor genotype and controlled ovarian stimulation a prospective randomized controlled trial Estradiol before hcg admin. Serum estradiol (pmol/l) n= n.s. Ser/Ser 150 U/d FSH P = sig. Ser/Ser 225 U/d FSH n= Asn/Asn 150 U/d FSH n=44 mean ±SEM

14 Conclusion First randomized controlled trial demonstrating a differential estradiol response to FSH due to single nucleotide polymorphism (SNP) at codon 680 of the FSH receptor gene. In addition to other well-established factors, SNP of the FSH receptor gene could, at least in part, explain the high variability of interindividual ovarian response in IVF/ICSI treatment cycles. The influence of genetic variation on drug response as demonstrated in our RCT points to a possible pharmacogenetic approach to individualized, patienttailored protocols for ovarian stimulation. Behre et al. Pharmacogenet Genomics 2005

15 The Ser 680 genotype of the FSHR is a risk factor for poor response in COH De Castro et al., Pharmacogenetics 14:285, 2004 Retrospective study on 170 women with normal ovarian function undergoing COH

16 FSHR polymorphism and ovarian hyperstimulation syndrome (OHSS) Activating mutations of the FSHR are involved in spontaneous OHSS (Smits et al., NEJM, 2003) The Asn 680 FSHR is associated with severity of iatrogenic OHSS (n=37 patients with OHSS) (Daelemans et al., JCEM, 2004)

17 FSHR SNP polymorphism and ovarian cancer Case-control study: 202 ovarian cancer patients and 266 age-matched controls The Ala 307 /Ser 680 haplotype is significantly associated with a higher ovarian cancer risk compared to Thr 307 /Asn 680 (OR: 1.39, 95% CI ) Yang et al. Carcinogenesis, 2006

18 Overall Conclusions The FSHR genotype influences the ovarian response to FSH Ovarian sensitivity to FSH is a polygenic trait Ovarian stimulation protocols should consider the FSHR genotype Effects of ART outcome are unclear Effects on OHSS and ovarian cancer should be verified

19 Acknowledgement Center of Reproductive Medicine and Andrology, University of Halle, Germany P. Kaltwaßer, E. Seliger, F. Röpke Department of Obstetrics and Gynecology, University of Münster, Germany R.R. Greb, A. Mempel, B. Sonntag, L. Kiesel Institute of Reproductive Medicine, University of Münster, Germany M. Simoni, J. Gromoll, E. Nieschlag

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

Reproductive BioMedicine Online (2010) 20, 588 593 www.sciencedirect.com www.rbmonline.com ARTICLE Frequency distribution of polymorphisms in the FSH receptor gene in infertility patients of different