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Gonadotropins in ART: patterns of use, trends in success rates, and assessing efficacy endpoints

Gonadotropins in ART: patterns of use, trends in success rates, and assessing efficacy endpoints. Jim Toner, MD, PhD Atlanta Center for Reproductive Medicine. IVF’s beginnings. Louise Brown born July 25, 1978 First IVF baby worldwide

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Gonadotropins in ART: patterns of use, trends in success rates, and assessing efficacy endpoints

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  1. Gonadotropins in ART:patterns of use, trends in success rates, and assessing efficacy endpoints Jim Toner, MD, PhD Atlanta Center for Reproductive Medicine

  2. IVF’s beginnings • Louise Brown born July 25, 1978 • First IVF baby worldwide • Pioneering work of Robert Edwards & Patrick Steptoe, England • Elizabeth Carr born December 28, 1981 • First American IVF baby • Drs Howard & Georgeanna Jones, Norfolk

  3. Progress • Improving success rates • Lower rates of multiple pregnancies • New therapies • Simpler therapies • Flexibility of American system • Advantage compared to Europe • Risk of impeded progress with regulation

  4. Simpler treatments • Laparoscopic egg retrieval • Now: transvaginal ultrasound-guided • Laparoscopic replacement of eggs/embryos • Now: transcervical embryo transfer • Daily monitoring of response • Now: every few days during stimulation • Intramuscular injections of hormones • Now: many given subcutaneously

  5. New therapies • Sperm problems: ICSI(Intracytoplasmic sperm injection) • Egg problems: Donor Egg • Uterine problems: Gestational carrier • Surplus embryos: Cryopreservation • Genetic problems: PGD(Preimplantation genetic diagnosis)

  6. Innovations Clinical Pregnancy / Transfer X Nuclear Transfer X Cytoplasmic Transfer PGD Hatching ICSI Subzonal Insertion Partial Zona Dissection X Co-Culture ZIFT GIFT Donor Egg Cryopreservation

  7. Fertility meds in U.S. hMG u-FSH u-HP-FSH r-FSH 1970 1980 1990 2000 Lupron Antagonists

  8. Stimulation trends in U.S. Natural cycle 2 hMG 4-6 hMG/FSH Pure FSH hMG/FSH 1970 1980 1990 2000 OCPs Agonist flare Antagonists Agonist suppression

  9. Clinics Cycles & Deliveries

  10. U.S. success rates

  11. GIFT and ZIFT

  12. ICSI to overcome Male Factor Fertil Steril 78:943-50, 2002.

  13. Multiples

  14. Fewer Multiple Pregnancies Quadruplet delivery rates Triplet delivery rates Fertil Steril 78:943-50, 2002.

  15. Strong effect of woman’s age

  16. Recipient age effects 17,339 cycles; US 1996-1998

  17. US versus EuropeIVF, 1998 +9.1 +10.8 +9.8 Fertil Steril 78:943-50, 2002.

  18. Progress • Improving success rates • Lower rates of multiple pregnancies • New therapies • Simpler therapies • Flexibility of American system • Advantage compared to Europe • Risk of impeded progress with regulation of therapy Fertil Steril 78:943-50, 2002.

  19. Basis for Controlled Ovarian Hyperstimulation (COH) • Potential for multiple eggs / cycle • Individual variation in ability to produce multiple eggs / cycle • Different levels of “Ovarian Reserve” • Management of those with differing Ovarian Reserves • Implications for assessing gonadotropin efficacy

  20. Egg supply dictates Ovarian Reserve Log (# eggs) 0.001% of 100,000 = 100 0.001% of 10,000 = 10 0.001% of 1,000 = 1

  21. Stimulation depends on reserve Ideal for IUI Ideal For IVF Low reserve: --Flare / hi dose Average reserve: --Antag / mid dose High reserve: --Luteal / low dose NOTE: inverse correlation between dose and response across patients

  22. Estimating Ovarian Reserve

  23. Gonadotropin dose effects • Dosage directly affects ovarian response (within a fixed level of Ovarian Reserve) • Among High responders, stronger stimulation yields more eggs • Dosage chosen is inversely correlated with Ovarian Reserve • Low responders: Strong stimulation • High responders: Gentle stimulation

  24. The process of IVF Preparatory Phase Stimulatory Phase Egg Embryo hCG Retrieval Transfer menses + menses + Birth control pills Ovarian stimulation (FSH & LH injections) 1 2 3 ……………………………………………………… ~10 ~12 ~15 -- 17 …plus one of the following… “Luteal phase Lupron” “Microdose Flare” “Antagonist”

  25. The process of IVF Preparatory Phase Stimulatory Phase Egg Embryo hCG Retrieval Transfer menses + menses + Birth control pills Ovarian stimulation (FSH & LH injections) 1 2 3 ……………………………………………………… ~10 ~12 ~15 -- 17 …plus one of the following… “Luteal phase Lupron” “Microdose Flare” “Antagonist”

  26. “Microdose Flare” cycle -low responders BCPs x 14 days (start @ menses) Gonadotropins menses Dilute Lupron

  27. ”Antagonist” cycle-average responders BCPs x 14 days (start @ menses) Gonadotropins menses menses GnRHa once 14mm

  28. “Luteal Suppression” cycle -high responders Gonadotropins menses menses +/- BCPs x 21 days (start @ menses) Lupron 

  29. Typical progression 16 follicles 14 eggs 12 mature eggs & sperm 9 fertilize normally 2 to 5 transferred 5 divide normally Extras frozen if good 4 stop dividing 30-40% of couples

  30. Qualitative effects Eggs 85% 70% 60% 50% 32 y/o 42 y/o Mature Eggs 60%20% 50%10% Fertilized Eggs Pregnancy Good day 3 Embryos Delivery Good day 5 Embryos

  31. Qualitative effects illustratedAge affects pregnancy, but not in vitro development Day 0 Day 1 Day 3 Day 5

  32. Decreasing embryo quality % of embryos that yield pregnancy Age of woman Kooij et al., F&S 66:769-75, 1996

  33. Quantitative and Qualitative Effects Ovarian Quantity reserve (#) Pregnancy Rate Age Quality (Impl.Rate) EGGS

  34. FSH and fertility in IVF FSH level:

  35. General Strategy • Adjust stimulation to the predicted ovarian reserve so as to produce 10 to 20 eggs (no matter the age) • Adjust number of embryos to be transferred according to their predicted quality (as judged by maternal age and morphology)

  36. Assessing Gonadotropin efficacy • Both FSH and LH play critical and complementary roles • FSH necessary for: • Folliculogenesis • Limited steroidogenesis • LH necessary for: • Estrogen production • ‘Healthy’ folliculogenesis

  37. The Goldilocks principle: - for normal folliculogenesis, LH has to be ‘just right’, neither ‘too much’ nor ‘too little’

  38. Factors besides FSH dose that affect egg production (‘confounders’) • LH tone during stimulation • Dose of GnRH analogs • Use of BCPs in prior cycle • Use of hMG vs FSH • Use of metformin • Use of hCG • MD doing retrieval

  39. GnRH analogs pharmacological physiological GnRH agonist FSH & LH Pulsatile GnRH GnRH FSH LH GnRH antagonist FSH & LH FSH & LH

  40. Ganirelix (mg/d) 0.0625 0.125 0.25 0.5 1.0 2.0 LH (IU/L) 3.6 2.5 1.7 1.0 0.6 0.4 E2 (pg/mL) 1475 1130 1160 823 703 430 # Eggs 9.0 9.5 10.0 8.8 9.3 8.6 # Good embr. 3.8 3.3 3.3 2.5 3.3 3.5 Effect of Increasing Ganirelix Doses on Clinical Outcomes n = 333 % Ganirelix Study Grp. Hum Reprod 1998;13:3023

  41. Metformin & IVF in PCO patients Stadtmauer et al., Fertil Steril 2001; 75:505

  42. Retrieval efficiency differs

  43. Endpoint considerations-many factors affect outcomes Influences on quality: * Maternal age * Prior quality Influences on quantity: * Ovarian reserve * Strength of stimulation --LH tone --Metformin use --OC pretreatment --GnRH analog use --Gonadotropin dose --hCG administration Eggs Embryos Pregnancy Delivery Maturity of eggs Sperm supply Fertilization Culture condition Quality of embryo Health of embryo Day of transfer Method of transfer Number transferred Luteal support Quality of embryo Health of embryo Health of sperm Luteal support

  44. Factors besides FSH dose that affect pregnancy outcome (‘confounders’) • Egg / embryo quality • Number transferred • Stage of transfer • Quality of transfer • Normalcy of uterine cavity • Luteal support

  45. Embryo appearance an imperfect predictorAge affects pregnancy, but not in vitro development Day 0 Day 1 Day 3 Day 5

  46. “Day 3” embryos 20-30% implantation rate 8c, gr 1.0 8c, gr 3.0 8c, gr 2.0

  47. Blastocysts 40-50% implantation rate Trophectoderm ICM

  48. Evaluation of cavity

  49. FSH and fertility in IVF FSH level:

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