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Carlo Alviggi

Pharmacogenomic approach to OS International Symposium on Reproductive Medicine -1 June 4 - 6, 2010 Istanbul, Turkey. Carlo Alviggi. Università degli studi di Napoli “Federico II” Centro di Sterilità ed Infertilità di Coppia Prof. G. De Placido.

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Carlo Alviggi

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  1. Pharmacogenomic approach to OSInternational Symposium onReproductive Medicine -1June 4 - 6, 2010Istanbul, Turkey Carlo Alviggi Università degli studi di Napoli “Federico II” Centro di Sterilità ed Infertilità di Coppia Prof. G. De Placido

  2. In the survival of favoured individuals, during the constantly-recurring struggle for existence, we see a powerful and ever-acting form of selection Charles Darwin

  3. LH-R 4-A E2 Production and release of 4-androgens Aromatase activity LH Leading follicle FSH Theca interna Paracrine network (EGF, IGF-1, Inhibin) GRANULOSA LH levels IU/L

  4. LH Leading follicle FSH Adaptation mechanisms to “abnormal” LH exogenous (supra-physiological) FSH activity LH-R Theca interna 4-A E2 Enhancement of paracrine network (Inhibin and GFs) Paracrine network (EGF, IGF-1, Inhibin) GRANULOSA Theca cells (all follicles) Granulosa cells Compensation in the reduction of LH Increase in sensitivity to LH activity: optimal androgen production with <1% LH receptors occupied (spare receptor hypothesis) Production and release of 4-androgens Aromatase activity LH levels IU/L

  5. Kolibianakis EM et al., 2007 7 RCT’s (701 patients), among which 5 reported agonist and 2 antagonist cycles.

  6. Ovarian response to exogenous gonadotrophins in IVF/ICSI • Good prognosis patients young normogonadotrophic women with normal ovarian reserve (AFC and biomarkers in the normal range) GnRH-a long protocol with FSH monotherapy - normal responders (80-85%) - abnormal (hypo-slow) responders (15-25%) - (unexpected) poor responders (<5%)

  7. Hypo-response to r-hFSH GnRH–a long protocol: different categories of ovarian response to FSH Normal response: >5 oocytesoestradiol 500–3000 pg/ml Poor response: <5 oocytes oestradiol <500 pg/ml High response: ‘necklace’ ultrasonography (USG) pattern oestradiol >3000 pg/ml – many eggs

  8. 85% of normogonadotrophic women rFSH 150–225 IU/day Hypo-response to r-hFSH GnRH–a long protocol hCG DAYS 21 1 2 3 4 5 6 7 8 9 10 11 12 13 GnRH – a daily-depot hCG, human chorionic gonadotrophin; rFSH, recombinant follicle-stimulating hormone

  9. 15% of normogonadotrophic women rFSH 150–225 IU/day Hypo-response to r-hFSH GnRH–a long protocol hCG DAYS 21 1 2 3 4 5 6 7 8 9 10 11 12 13 GnRH – a daily-depot Apparently ‘normal’ response (i.e. at least 5 oocytes retrieved) but… De Placido et. al, Hum Reprod 2001, Clin Endocrinol 2004, Hum Reprod 2005; Drugs 2008 Ferraretti et. al, Fertil Steril 2004; Kailasam et. al, Hum Reprod2004 Alviggi et al., RBMOnline 2006; RBMOnline 2009; Devroey et al., Hum Reprod Update 2009

  10. rFSH 150–225 IU/day Hypo-response to r-hFSH 15% of normogonadotrophic women GnRH–a long protocol hCG DAYS 21 1 2 3 4 5 6 7 8 9 10 11 12 13 GnRH – a daily-depot Increase in the cumulative rFSH dose (>3000 IU) and in the stimulation length De Placido et. al, Hum Reprod 2001, Clin Endocrinol 2004, Hum Reprod 2005; Drugs 2008 Ferraretti et. al, Fertil Steril 2004; Kailasam et. al, Hum Reprod2004 Alviggi et al., RBMOnline 2006; RBMOnline 2009; Devroey et al., Hum Reprod Update 2009

  11. rFSH 150–225 IU/day GnRH–a long protocol 15% of normogonadotrophic women hCG DAYS 21 1 2 3 4 5 6 7 8 9 10 11 12 13 GnRH – a daily-depot Significant reduction of the oocytes retrieved, implantation and pregnancy rates (PRs) (versus ‘normal responders’) De Placido et. al, Hum Reprod 2001, Clin Endocrinol 2004, Hum Reprod 2005; Drugs 2008 Ferraretti et. al, Fertil Steril 2004; Kailasam et. al, Hum Reprod2004 Alviggi et al., RBMOnline 2006; RBMOnline 2009; Devroey et al., Hum Reprod Update 2009

  12. Hypo-response to r-hFSH • Hypo-responders can achieve ‘adequate’ number of oocytes retrieved and oestradiol production BUT… There is an increase in the cumulative rFSH dose (i.e. >3000 IU) and in the stimulation length • Reduction of the implantation and PRs De Placido et. al, Hum Reprod 2001, Clin Endocrinol 2004, Hum Reprod 2005; Drugs 2008 Ferraretti et. al, Fertil Steril 2004; Kailasam et. al, Hum Reprod2004 Alviggi et al., RBMOnline 2006; RBMOnline 2009; Devroey et al., Hum Reprod Update 2009

  13. FSH hypo-response Deep circulating LH suppression Less performing LH FSH dependent mechanisms

  14. R-hLH in women who received >3000 IU of r-hFSH during a previous IVF cycle (self-control study) Lisi et al., RBMOnline, 2001 Lisi et al., RBMOnline, 2001

  15. Hypo-respondersClinical evidence and pathogenesis rFSH 150–225 IU/day RCTs evaluated the efficacy of r-hLH vs increasing r-hFSH dose in women displaying initial slow-response to r-hFSH mono-therapy (De Placido et al., 2004; Ferraretti et al., 2004; De Placido et al., 2005) Is hypo-response related to a less bioactive LH? R-hLH vs r-hFSH step up Slow follicular growth DAYS 21 1 2 3 4 5 6 7 8 9 10 11 12 13 GnRH – a daily-depot

  16. Cochrane review 2007: hypo-respondersr-hFSH alone versus r-hLH + r-hFSHOngoing PR per woman randomized Favours r-hFSH + r-hLH Favours r-hFSH The efficacy of r-hLH was independent of LH endogenous levels during OS Mochtar MH, Cochrane Database, 2007, Issue 2

  17. FSH hypo-response Deep circulating LH suppression Less performing LH FSH dependent mechanisms

  18. LH variant to the native molecule The common Trp8Arg/Ile15Thr Y LH 30 b 121 1 Trp8Arg Ile15Thr additional sulphated sugar at asn-13 K. Pettersson and I. Huhtaniemi, 1998

  19. The common LH variant Structure - Function • Two amino acid changes in b-chain • Additional sulphation in b-chain • Increased in vitro bioactivity • Decreased circulatory half-life • Increased promoter activity Net effect…? • Association with ovulatory disorders and infertility Takahashi et al., Hum Reprod,1998

  20. Western India (Kota) Mexico (Mayan) Spain (Vasco) United States (Hispanic) Japan Jordan Thailand Italy Sweden (Göteborg) China The Netherlands United States (black) United Kingdom South Africa (black) Sweden (Stockholm) Poland Estonia Greenland Iceland Faroe Islands Finland Finland (Lapp) Australia/Aboriginals Worldwide occurrence of variant LH Percent V/V + V/WT 0 13.6% 0 10 20 30 40 50 60

  21. LH gene polymorphism in women with ovarian resistance to FSH • 60 patients screened for V-bLH • Group A: 22 women requiring a cumulative dose of rFSH >3500 IU • Group B: 15 patients requiring 2000–3500 IU • Group C: 23 women requiring <2000 IU In collaboration with K. Petterson, Turku, Finland and P. Humaidan, Skive, Denmark

  22. V-LH and ovarian responseto FSH: retrospective analysis • Cycles of in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) have been studied • Only normogonadotrophic women in whom at least 5 oocytes had been retrieved, were retrospectively included • Inclusion criteria • menstrual cycles ranged 24–35 days (intra-individual variability ± 3 days) • hysteroscopic evidence of a normal uterine cavity • Exclusion criteria • bFSH >10 mIU/mL • age 37 years • Body mass index (BMI) >29 Kg/m2 • biochemical and/or (USG) evidence of polycystic ovary syndrome (PCOS) • stage III–IV endometriosis rAFS classification • autoimmune, thyroid, and chromosomal abnormalities • presence of only one ovary rAFS, revised American Fertility Society (1985 classification criteria)

  23. LH gene polymorphism in women with ovarian resistance to FSH • 60 patients screened for V-bLH • Group A: 22 women requiring a cumulative dose of rFSH >3500 IU • Group B: 15 patients requiring 2000–3500 IU • Group C: 23 women requiring <2000 IU • 8 variants found • 7 carriers of V-LH (2 homozygosis and 5 heterozygosis) were found in group A, whereas only 1 variant (heterozygosis) was found in group B; no variant was found in group C Alviggi et al., RBMOnline 2009

  24. LH gene polymorphism in women with ovarian resistance to FSH • Overall incidence: 8/60 (13.3%) • ‘Normal responders’: 0/22 (0%) • ‘Ovarian resistance’: 7/22 (31.8%) Alviggi et al., RBMOnline 2009

  25. Association between a point mutation of native LH and different profiles of ovarian response to rFSH Alviggi et al., Hum Reprod - Supp.1 2009 204normogonadotrophic patients undergoing a GnRH-a long protocol with rFSH prospectively collected and retrospectively analysed. IFMA assays were performed in each patient to find out the presence of v-LH Statistic model: one-way ANOVA with v-LH as independent variant

  26. Group 0= wild tipe carriers Group 1= heterozygotes Group 2= homozygotes RESULTS 24 [11.6 %] v-LH carriers found 21 [10.2 %] heterozygotes 3 [1.4%] homozygotes

  27. FSH hypo-response Deep circulating LH suppression Less performing LH FSH dependent mechanisms 25-30%

  28. - NH 2 Gonadotropin receptor - COOH FSH-R: Ser680 genotype Locus FSHR (680) polymorphic variability Three genotypes: Asn/Asn (45%) Ser/Ser (26%) Asn/Ser (29%) HUMAN FSH RECEPTOR MUTATIONS Ala189Val (Asn191Ile) Ile160Thr Asp224Val * Pro346Arg Thr307Ala Pro519Thr Val341Ala Leu 601Val Perez-Mayorga et al., 2000 Arg573Cys Ala419Thr * Asp567Gly?? • FSH basal level are increased in Ser/Ser carriers • Perez Mayorga et al., 2000; Sudo et al., 2002; Choi et al., 2004; Falconer et al., 2005 Ser680Asn

  29. FSHR Ser680 and menstrual cycle • 21 giovani donne: 12 con genotipo Asn680/Asn680 e 9 con genotipo Ser680/Ser680 Ser/Ser less active variant Greb et al., JCEM, 2005

  30. FSH receptor genotype and ovarian response to FSH Perez Mayorga et al., JCEM 2000

  31. 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 • Behre et al., Pharmacogenet Genomics, 2005 • Patients with the Ser680/Ser680 genotype randomized into two groups with daily rFSH administration of 150 IU (group I) or 225 IU (group II). Patients with Asn680/Asn680 served as a control (group III) • No differences in the total duration of FSH stimulation nor in the number of follicles or retrieved oocytes • Significantly higher peak estradiol concentrations in group II than in group I, comparable to those of group III • Conclusions: FSH appears to be less ‘efficient’ in women with the Ser680/Ser680 receptor genotype, at least in terms of oestradiol production

  32. FSH hypo-response Deep circulating LH suppression Less performing LH FSH dependent mechanisms 25-30% 25-30% 40-50 ?

  33. Pharmacogenomic approach to OSCONCLUSIONS About 15-20% of normogonadotrophic patients show hypo-sensitivity to exogenous FSH during standard GnRH-a long protocol Common LH and FSH-R polymorphisms are associated with hypo-response Pharmacogenetic bases for personalizing controlled OS protocols (higher FSH doses - LH supplementation) Genetic characteristics can affect biomarkers and AFC and should be taken into account in the elaboration of algorithms aimed at defining gonadotrophins doses

  34. Without speculation there is no good and original observation Charles Darwin

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