Improving Success by Tailoring Infertility Treatments - We are all individuals

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Aula ministrada pelo Dr. Sandro Esteves no 5th. Dubai International Obs-Gyne & Fertility Conference & eXHIBITION DIOFCE 2010, em 05 de novembro de 2010.

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Improving Success by Tailoring Infertility Treatments - We are all individuals

  1. 1. Improving Success by Tailoring Ovarian Stimulation - We are all individuals -
  2. 2. Lecture Outline
  3. 3. UN Census Estimates, 2008
  4. 4. Ovarian Stimulation Pharmaceutical industry One size fits all protocol for OS suppress LH surge: GnRHa ovarian stimulation with HMG/FSH high doses of gonadotropin high number oocytes high number of embryos Results not the same for all poor response and OHSS side effects patient satisfaction neglected
  5. 5. Psychological burden 49%-26% Prognosis 40%-23% Cost of treatment 23%-0% Relationship/divorce 15%-9% Physical burden 7-6% Up to 65% of couples dropout from IVF without achieving pregnancy before they complete 3 cycles1-5 Oocyte retrieval 52% Embryo transfer 29% Injections 29% Physical pain 20% Blood tests 14% 1. Olivius K t al, Fertil Steril 2004;81:258; 2. Land JA et al, Fertil Steril 1997; 68:278; 3. Schroder AK, et al, RBM Online 2004; 5:600; 4. Osmanangaoglu K et al, Hum Reprod 2002; 17:2655; 5. Rajkhowa M et al, Hum Reprod 2006; 21:358; 6. Brandes M et al, Hum Reprod 2009; 24:3127; 7. Hammarberg K et al, Hum Reprod 2001; 16:374. Reasons1,5,6 IVF events women find stressful7 Pregnancy loss 94% Unsuccessful cycle 87% Waiting after ET 81% Waiting to find out how many eggs fertilized 68% Result of pregnancy scan 47% Patient Satisfaction Why should I care?
  6. 6. Ovarian Stimulation One size fits all? Patient is the main variable of OS response  Demographics and anthropometrics (Age, BMI, Race)  Genetics profile  Cause of Infertility  Years of Infertility  Health status  Nutritional status
  7. 7. How to define the right individual treatment for the right patient: ● Prevent poor response and OHSS (reduce cancellation) ● Reduce side effects ● Increase pregnancy rates ● Reduce physical, psychological and financial burden Understanding the Problem What we really want to know is... Esteves, 10
  8. 8. Lecture Outline Gonadotropins: better now
  9. 9. Age Biomarkers ● Hormonal Biomarkers, FSH, Inhibin-B, AMH ● Functional Biomarkers: Antral Follicle Count (AFC) ● Genetic Biomarkers: Single Nucleotide Polymorphisms for FSH-R/LH/LH-R/E2-R/AMH-R Markers of Ovarian Response Can we predict ovarian response? Esteves, 12
  10. 10. 1. Akande et al. Hum Reprod 2002;17:2003–2008 (n = 1019) 20–24 25–29 30–34 35–39 40–44 45–49 5 0 10 15 20Livebirths(%) Age (years) 6–8.9 3–5.9 <3 FSH IU/L ≥12 9–11.9 Age and FSH chronological vs biological in IVF MariaHana Esteves, 13
  11. 11. La Marca, et al. Hum Reprod 2009. AMH levels are correlated with the number of follicles at gonadotropin independent stage Markers of Ovarian Response Biomarkers and follicular development Esteves, 14
  12. 12. AMH: a cut-off 1.26 ng/ml was able to predict poor response (<4 oocytes) with 97% sensitivity Gnoth, et al. Hum Reprod 2008. Retrospective analysis, 316 patients (1st IVF cycle) in GnRH-a long protocol Variables: age, basal FSH, AMH, Inhibin-B Endpoint: number of oocytes Cut-off of poor response: 4 oocytes Markers of Ovarian Response anti-Mullerian hormone (AMH) Esteves, 15
  13. 13. Verhagenet al. 2008; Broer et al., 2010 Markers of Ovarian Response Prediction of response by AMH AMH category (ng/mL) 0.14 to <0.7 (N=74) 0.7 to <2.1 (N=128) >2.1 (N=148) Agonist protocol + rFSH 375 225 150 Oocytes (n) 5 (3-7) 10 (7-15) 14 (10-19) Severe OHSS 0 (0%) 3 (2%) 20 (13.9%) Cancellation 19 (25.7%) 3 (2.3%) 4 (2.7%) CPR per transfer 11.1% 34.6% 40.1% Adapted from Nelson SM et al . Anti-Müllerian hormone-based approach to controlled ovarian stimulation for assisted conception. Hum Reprod. 2009 ;24(4):867-75. Esteves, 16
  14. 14. Markers of Ovarian Response Antral Follicle Count (AFC) No. of antral follicles < 3 4-10 > 10 No. of cycles 16 76 57 Mean age (years) 36.8 2.9 36.3 4.0 32.8 3.8 Day 3 FSH (IU/l) 12.7 8.5 7.1 4.1 5.6 1.7 Cx rate 68.8% 5.3% 0% Peak E2 (pg/ml) 432 157 1.001 627 1.912 1.355 Mean No. of eggs 2.0 0.9 6.3 4.4 14.1 8.5 OG pregnancy rate 0% 13.2% 26.3% Chang, et al. Fertil Steril. 1998;69:505. Hansen KR, et al. Fertil Steril 2003;80:577–83 Number of antral follicles Meannumberofoocytesretreived r=0.64 p<0.001 0 5 10 15 20 25 25 20 15 10 5 0 Esteves, 17
  15. 15. Markers of Ovarian Response Antral Follicle Count (AFC) Broekmans et al., Fertil Steril, 2009 Clinical considerations ● Cycle day 2-4 ● Count all AF 2-10mm Technical considerations ● Real-time 2 dimension image adequate ● Transvaginal probe 7Mhz minimum Esteves, 18
  16. 16. Broer et al. , 2010 AMH = AFC >Inhibin B >FSH >Age Markers of Ovarian Response Prediction of response Esteves, 19
  17. 17. Lecture Outline
  18. 18. Gonadotropins: better today Urinary-derived products
  19. 19. Culture media HarvestBioreactor Production Cell attachment and proliferation r-hFSH production and secretion Collection of cell culture supernatant medium containing r-hFSH In-process QC Purification Concentration of supernatant Chromatographic purification steps Ultrasterile filtration Characterization and full QC of bulk r-hFSH Esteves, 22 Gonadotropins: better today Recombinants
  20. 20. Gonadotropins: better today From urinaries to recombinants Bassett et al. Reprod Biomed Online 2005;10:169–177 Purity (FSH content) Mean specific FSH activity (IU/mg protein) Injected protein per 75 IU (mcg) hMG < 5% ~100 ~750* hMG-HP < 70% 2000–2500 ~33* r-hFSH Follitropin beta – 7000–10,000 8.1* Follitropin alfa > 99% 13,645 6.1 Esteves, 23
  21. 21. 1. Bassett et al. Reprod Biomed Online 2005;10:169–177 2. Driebergen et al. Curr Med Res Opin 2003;19:41–46 Conventional Bioassay High variability (~20%) in vivo (rat) Novel analitycal method Physiochemical technique Minimal batch-to- batch variability (1.6%)1,2 Gonadotropins: an overview Product Quality: Filled by Mass (FbM) Esteves, 24
  22. 22. Concept of Dose Precision Clinical implications Batch variability +20%, -25% 225 270 170 IU Bioassay Urinary and Follitropin beta 16.5 mcg (225 IU) Filled by Mass Folitropin alfa (Gonal-f FbM) Batch variability  2% Risk of OHSS Poor response
  23. 23. Esteves, 26 18.7 20.3 53.4* % Cycles with “Step-down” during ovarian stimulation HMG HP-HMG rec-hFSH (fbm) *P<0.01 TotalDoseperLiveBirth(IU)* 0 3.000 7.000 10.000 21.6% r-hFSH HP-hMG 6,324* 7,739 hMG 9,690 52.2% * Mean total dose per cycle/Live birth rate (≤35 years)
  24. 24. LH surge prevention GnRH antagonists pyro (Glu) – His – Trp – Ser – Tyr – Gly – Leu – Arg – Pro – Gly – NH2 Activation of the GnRH receptor Regulation of receptor affinity Regulation of receptor biological activity Antagonistic effect 1 32
  25. 25. Agonist administration Gonadotropin administration Long GnRH agonist protocol Antagonist administration Gonadotropin administration Single or multiple dose GnRH antagonist protocol Flare up effect Pituitary suppression Longer treatment Can exclude early pregnancy Can be integrated in spontaneous and OI cycles Pre-treatment cycle Treatment cycle No hormonal withdrawal No flare effect with possible cyst formation Less gona- dotropins Prevent OHSS by GnRH-a LH surge prevention GnRH antagonists vs agonists
  26. 26. Kolibianakis et al (2006)2 N studies 22 Included non peer-reviewed data No Included IUI cycles No N patients 3176 Odds ratio 0.86 (0.72-1.02; p=.08)* Duration of stimulation -1.54 days (OR: -2.42; -0.66; p=.0006) Oocytes retrieved -1.19 (OR: -1.82; -0.56) Risk of severe OHSS OR=0.61 (0.42; 0.89; p=.01)* GnRH antagonists vs agonists Meta-analysis *For every 59 women treated with a GnRH agonist vs GnRH antagonist, one additional case of severe OHSS will occur. Esteves, 29
  27. 27. Lecture Outline
  28. 28. AMH category (ng/mL) >2.1 GnRH analogue + r-hFSH 150UI Agonist Antagonist Oocytes (n) 14 (10-19) 10 (8.5-13.5) Severe OHSS 20 (13.9%) 0 (0%)* Cancellation 4 (2.7%) 1 (2.9%) CPR per transfer 40.1% 63.6%* Adapted from Nelson SM et al . Anti-Müllerian hormone-based approach to controlled ovarian stimulation for assisted conception. Hum Reprod. 2009 ;24(4):867-75. *P<0.01 Individualized Treatment with AMH AMH + antagonists in hyper-responders Esteves, 31
  29. 29. 31.3% 31.1% 35.3% 50.0% 20.0% 0% 10% 20% 30% 40% 50% 60% 75 IU 112.5 IU 150 IU 187.5 IU 225 IU Clinical pregnancy rates/cycle started Olivennes F, et al. The CONSORT study. Reprod Biomed Online. 2009;18:195–204. Individualized dosing in increments of 37.5 IU of Gonal-f possible by FbM technology Use of algorithm of patients characteristics ● basal FSH ● body mass index (BMI) ● age ● antral follicle count Age (28-32) Oocytes retrieved (8-12) CONSORT = CONsistency in r-hFSH Starting dOses for Individualized tReatmenT Esteves, 32
  30. 30. 1. Alviggi et al. Reprod Biomed Online 2006;12:221–233; 2. Tarlatzis et al. Hum Reprod 2006;21:90–94 3. Esteves et al. Reprod Biol Endocrinol 2009;7:111; 4. Marrs et al. Reprod Biomed Online 2004;8:175–182 5. Mochtar MH, Cochrane Database, 2007; 6. De Placido et al. Clin Endocrinol (Oxf) 2004;60:637–643 7. Alviggi, et al. RBMOnline 2009. LH supplementation in ART What do we know today  The majority of patients do not need LH supplementation as endogenous LH levels are sufficient1–3  15-20% of women have less sensitive ovaries Older patients (> 35 years)4 Low responders5 Deeply suppressed endogenous LH6 Hypo-responders7 FSH and AFC considered adequate Genetic characteristics Single nucleotide polymorphisms of FSH-R and LH-R Esteves, 33
  31. 31. Mochtar MH, Cochrane Database, 2007 No difference in basal LH levels. Less bioactive LH/LH receptor polymorphism ? LH supplementation in ART Cochrane review 2007: hypo-responders r-hFSH vs r-hLH + r-hFSH (Ongoing PR)
  32. 32. Tailoring Ovarian Stimulation Treatment individualization strategies • Antagonist + r-FSH FbM 112.5-150 UI • Normal oocyte yield • Very low cancellation/OHSS • Adequate LBR High Responders AFC >10 AMH >2.1 • Antagonist or Agonist + r-hFSH 187.5-262.5 UI • Low cancellation & OHSS • Adequate LBR Normal Responders AFC 4-10 AMH 0.7-2.1 • Antagonist + r-hFSH (+r-hLH) 300-375 UI • Short stimulation Moderate cancellation Low LBR Poor Responders AFC <4 AMH <0.7
  33. 33. Thank you...

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