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Carlo Alviggi

Università degli studi di Napoli “Federico II” Centro di Sterilità ed Infertilità di Coppia Prof. G. De Placido. Ovarian Stimulation in Clinical Practice 2 nd International Meeting “New Perspectives on Ovulation Induction” Istanbul, Turkey – 3-4 June 2010. Carlo Alviggi.

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Carlo Alviggi

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  1. Università degli studi di Napoli “Federico II” Centro di Sterilità ed Infertilità di Coppia Prof. G. De Placido Ovarian Stimulation in Clinical Practice2nd International Meeting“New Perspectives on Ovulation Induction”Istanbul, Turkey – 3-4 June 2010 Carlo Alviggi

  2. “New” trends in COS 3 types of situations Normal responder Poor responder High responder Normal responder Ovarian response Poor responder High responder

  3. Ovarian response to exogenous gonadotrophins in IVF/ICSI • (presumably) normal patients young normogonadotrophic women with normal ovarian reserve (AFC and biomarkers in the normal range) More oocytes or more stimulation cycles?

  4. Ovarian response to exogenous gonadotrophins in IVF/ICSI (presumably) normal responders young normogonadotrophic women with normal ovarian reserve (AFC and biomarkers in the normal range) More oocytes GnRH-a long protocol (most adopted strategy worldwide – more 1a evidence)

  5. (Presumably) normal responders Controlled ovarian stimulation: more oocytes High percentage of mature oocytes presents morphologic anomalies Goal Adeguate number of mature oocytes Good morphology

  6. Ovarian response to exogenous gonadotrophins in IVF/ICSI (presumably) normal responders young normogonadotrophic women with normal ovarian reserve (AFC and biomarkers in the normal range) More oocytes GnRH-a long protocol (most adopted strategy worldwide – more 1a evidence) r-hFSH (75 IU/5.5 mcg FSH) HP-hMG (75 IU FSH + 75 IU LH: 11 IU hCG + <1 IU LH) r-hFSH + r-hLH (75 IU/5.5 mcg FSH + 75 IU/3.5 mcg LH) HP-FSH (75 IU FSH)

  7. Ovarian response to exogenous gonadotrophins in IVF/ICSI (presumably) normal responders young normogonadotrophic women with normal ovarian reserve (AFC and biomarkers in the normal range) More oocytes GnRH-a long protocol (most adopted strategy worldwide – more 1a evidence) r-hFSH (75 IU/5.5 mcg FSH) HP-hMG (75 IU FSH + 75 IU LH: 11 IU hCG + <1 IU LH) r-hFSH + r-hLH (75 IU/5.5 mcg FSH + 75 IU/3.5 mcg LH) HP-FSH (75 IU FSH)

  8. Randomized controlled trial Primary end-point: ongoing pregnancy rates Group A: 363 women undergoing IVF after stimulation with HP-hMG Group B: 368 women unfergoig IVF after stimulation with rFSH Long GnRH agonist protocol

  9. Pituitary down-regulation was done using triptorelin acetate, 0.1 mg/day s.c. started 5–7 days before estimated start of next menses and continued until end of gonadotrophin administration GnRH agonist was administered 10–28 days before start of gonadotrophin treatment The starting dose of HP-hMG or rFSH was 225 IU s.c. for the first 5 days, followed by individual adjustments according to the patient’s follicular response

  10. Non-inferiority with respect to ongoing pregnancy was demonstrated for HP-hMG compared with rFSH.

  11. There was no significant difference in progesterone concentration between treatment groups on day 6, whereas the progesterone concentration was 23% higher with rFSH on the last stimulation day and 31% higher at oocyte retrieval. The increase in progesterone levels negatively influenced endometrial status and pregnancy rates.

  12. Granulosa Theca CHOLESTEROL CHOLESTEROL PREGNENOLONE PREGNENOLONE PROGESTERONE PROGESTERONE 17-hydroxilase (cyp17) 17-hydroxilase (cyp17) Progesterone production in human follicles 17-OH PROGESTERONE 17-OH PROGESTERONE 17,20 desmolase 17,20 desmolase ANDROSTENEDIONE ANDROSTENEDIONE Aromatase P450 Aromatase P450 ESTROGENS ESTROGENS

  13. 2009 Conclusion: Progesterone elevation, on the day of hCG administration for final oocyte maturation, does not appear to be associated with the probability of pregnancy, in women undergoing ovarian stimulation with GnRH analogues and gonadotrophins for IVF.

  14. The CONSORT dosing algorithm individualizes recombinant human FSH (r-hFSH) doses for assisted reproduction technologies, assigning 37.5 IU increments according to patient characteristics Primary end-point was number of oocytes retrieved Dose groups containing > or = 5 patients were analysed: 75 IU (n = 48) 112.5 IU (n = 45) 150 IU (n = 34) 187.5 IU (n = 24) 225 IU (n = 10). Individualizing FSH dose for assisted reproduction using a novel algorithm: the CONSORT study. Reprod Biomed Online. 2009 Feb;18(2):195-204.

  15. Clinical pregnancy rates/cycle started were: 75 IU = 31.3% 112.5 IU = 31.1% 150 IU = 35.3% 187.5 IU = 50.0% 225 IU = 20.0% Use of the CONSORT algorithm achieved an adequate oocyte yield and good pregnancy rates in this preliminary study. Individualizing FSH dose for assisted reproduction using a novel algorithm: the CONSORT study. Olivennes et al., Reprod Biomed Online. 2009 Feb;18(2):195-204.

  16. Ovarian response to exogenous gonadotrophins in IVF/ICSI (presumably) normal patients young normogonadotrophic women with normal ovarian reserve (AFC and biomarkers in the normal range) more stimulation cycles? • Mild stimulation with GnRH-antagonist • Optimize risk/benefit ratio • Reduce OHSS and management strategies • Reduce complexity and patient burden • Shorter treatment cycles • Fewer overall injections • Fewer injections per day Manage the patient dropout rates Maintain cumulative live birth rates

  17. Lancet. 2007 Mar 3;369(9563):743-9. RCT: 404 patients randomised: Hum Reprod. 2006 Feb;21(2):344-51. Epub 2005 Oct 20

  18. Lancet. 2007 Mar 3;369(9563):743-9. Hum Reprod. 2006 Feb;21(2):344-51. Epub 2005 Oct 20

  19. Lancet. 2007 Mar 3;369(9563):743-9. • The 1 year cumulative rate of pregnacy leading to term live bird: • Mild group: 43.4% • Standard group: 44.7%

  20. Lancet. 2007 Mar 3;369(9563):743-9. PREGNANCY OUTCOME

  21. Lancet. 2007 Mar 3;369(9563):743-9.

  22. Lancet. 2007 Mar 3;369(9563):743-9. PATIENTS’ DISCOMFORT: “There were no significant differences between the groups in the anxiety depression, physical discomfort and sleep quality of the mother”

  23. Lancet. 2007 Mar 3;369(9563):743-9. TOTAL COSTS

  24. Lancet. 2007 Mar 3;369(9563):743-9. Conclusion “Interpretation Over 1 year of treatment, cumulative rates of term livebirths and patients’ discomfort are much the same for mild ovarian stimulation with single embryos transferred and for standard stimulation with two embryos transferred. However, a mild IVF treatment protocol can substantially reduce multiple pregnancy rates and overall costs.”

  25. Ovarian response to exogenous gonadotrophins in IVF/ICSI (presumably) normal patients young normogonadotrophic women with normal ovarian reserve (AFC and biomarkers in the normal range) More oocytes or more stimulation cycles? - Standard GnRH-a long protocol still represents the first line treatment worldwide – (more literature) – Relevance of r-FSH starting dose RCTs suggest that mild stimulation could represent a non-inferior strategy in adequately selected patients

  26. Ovarian response to exogenous gonadotrophins in IVF/ICSI (presumably) normal patients young normogonadotrophic women with normal ovarian reserve (AFC and biomarkers in the normal range) More oocytes or more stimulation cycles? - Standard GnRH-a long protocol still represents the first line treatment worldwide – (more literature) – Relevance of r-FSH starting dose RCTs suggest that mild stimulation could represent a non-inferior strategy in adequately selected patients Is it possible apatient-tailored approach?

  27. Ovarian response to exogenous gonadotrophins in IVF/ICSI (presumably) normal patients young normogonadotrophic women with normal ovarian reserve (AFC and biomarkers in the normal range) More oocytes or more stimulation cycles? - Standard GnRH-a long protocol still represents the first line treatment worldwide – (more literature) – Relevance of r-FSH starting dose RCTs suggest that mild stimulation could represent a non-inferior strategy in adequately selected patients Is it possible apatient-tailored approach? Contribute of biomarkers and AFC More adequate identification of specific patients groups Pharmacogenomic approach

  28. Ovarian response to exogenous gonadotrophins in IVF/ICSI (presumably) normal patients young normogonadotrophic women with normal ovarian reserve (AFC and biomarkers in the normal range) More oocytes or more stimulation cycles? - Standard GnRH-a long protocol still represents the first line treatment worldwide – (more literature) – Relevance of r-FSH starting dose RCTs suggest that mild stimulation could represent a non-inferior strategy in adequately selected patients Is it possible apatient-tailored approach? Contribute of biomarkers and AFC More adequate identification of specific patients groups Pharmacogenomic approach

  29. Background:Anti-Müllerian hormone (AMH), a predictor of oocyte yield, may facilitatetreatment strategies for women undergoing COS, to optimize safety and clinical pregnancy rates.

  30. Methods: Prospective cohort study of 538 patients in two centres with differential COS strategies based on a centralized AMH measurement.

  31. Conclusions: The use of circulating AMH to individualize treatment strategies for COS may result in reduced clinical risk, optimized treatment burden and maintained pregnancy rates, and is worthy of prospective randomized examination.

  32. Ovarian response to exogenous gonadotrophins in IVF/ICSI (presumably) normal patients young normogonadotrophic women with normal ovarian reserve (AFC and biomarkers in the normal range) More oocytes or more stimulation cycles? - Standard GnRH-a long protocol still represents the first line treatment worldwide – (more literature) – Relevance of r-FSH starting dose RCTs suggest that mild stimulation could represent a non-inferior strategy in adequately selected patients Is it possible apatient-tailored approach? Contribute of biomarkers and AFC More adequate identification of specific patients groups Pharmacogenomic approach

  33. “New” trends in COS:a patient-tailored approach Normal response: >5 oocytesoestradiol 500–3000 pg/ml Ovarian response High response: ‘necklace’ ultrasonographypattern oestradiol >3000 pg/ml – many eggs Poor response:<5 oocytes oestradiol <500 pg/ml

  34. Hypo-response to rFSH 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 Reprod 2004 Alviggi et al., RBMOnline 2006; Devroey et al., Hum Reprod Update 2009 (Consensus EVIAN 2009)

  35. HYPO RESPONDER “New” trends in COS:a patient-tailored approach Normal response: >5 oocytesoestradiol 500–3000 pg/ml Ovarian response High response: ‘necklace’ ultrasonographypattern oestradiol >3000 pg/ml – many eggs Poor response:<5 oocytes oestradiol <500 pg/ml

  36. Ovarian response to exogenous gonadotrophins in IVF/ICSI (presumably) normal patients young normogonadotrophic women with normal ovarian reserve (AFC and biomarkers in the normal range) More oocytes or more stimulation cycles? - Standard GnRH-a long protocol still represents the first line treatment worldwide – (more literature) – Relevance of r-FSH starting dose RCTs suggest that mild stimulation could represent a non-inferior strategy in adequately selected patients Is it possible apatient-tailored approach? Contribute of biomarkers and AFC More adequate identification of specific patients groups Pharmacogenomic approach

  37. - NH 2 - COOH Hypo-response all’FSHVarianti alleliche Gn e loro recettori approccio farmacogenomico HUMAN FSH RECEPTOR MUTATIONS Ala189Val (Asn191Ile) Ile160Thr Asp224Val * Pro346Arg Thr307Ala The common ‘less active’ FSH Receptor Polymorphism (Ser 680) and LH polymorphism (Trp8Arg/lle15Thr) are associated with ovarian hypo-response to FSH in normo-ovulatory women Pro519Thr Val341Ala Leu 601Val Arg573Cys Ala419Thr * Asp567Gly?? Perez Mayorga et al., JCEM 2000 De Placido et al., Hum Reprod, 2005 Alviggi et al., RBM Online, 2009; Hum Reprod 2009 Ser680Asn

  38. FSH receptor Ser/Ser ovarian response to FSH V-LH ovarian response to FSH 204 normogonadotrophic patients 11.6% v-LH carriers found 10.2 %] heterozygotes 1.4% homozygotes Ser/Ser genotypes are associated with higher AFC! Perez Mayorga et al., 2000 Alviggi et al., 2009

  39. Favours r-hFSH + r-hLH Favours r-hFSH No difference in basal LH levels Mochtar MH, Cochrane Database, 2007, Issue 2 Cochrane review 2007: hypo-respondersr-hFSH alone versus r-hLH + r-hFSHOngoing PR per woman randomized

  40. 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

  41. Ovarian stimulation for IVF/ICSI in good prognosis patientsconclusıon Patient-tailored approach In the clinical practice the stimulation regimen (including standard GnRH-a long protocol, mild stimulation with GnRH-ant, choice of FSH starting dose, use of LH activity) can be personalised on the basis of: Individual characteristics (including biomarkers, AFC, genetics and psychology) Socio-cultural environment Legislative and economical aspects

  42. C. Alviggi R. Clarizia I. Strina A. Mollo M.T. Varricchio A. Ranieri M. D’Uva M. Coppola G. Coppola F. Fabozzi Acknowledgements Centro di Sterilità e Infertilità di Coppia Dipartimento di Scienze Ostetriche Ginecologiche Urologiche e Medicina della Riproduzione Università Federico II, Napoli, Italy

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