New Concept of Controlled Ovarian Stimulation in IVF

1. New Concept of ControlledOvarian Stimulation in IVF Dr. Milton Leong MDCM DSc (McGill) Director, IVF Center, HKSH Specialist in Reproductive Medicine Adjunct Professor, OBS-GYN, McGill University

2. Review “Gold Standard” • Discuss Alternatives • Introduce Concept of Preparing Ovary for Egg Collection in IVF

3. LEARNING OBJECTIVES At the conclusion of this presentation, participants should be able to: • Describe “where we are” with regard to “patient friendly” approaches in current ART treatments. • Describe the future prospects for a more patient-friendly fertility treatment.

4. Stimulated ovary

5. Ovarian Stimulation for IVF • Natural Cycles • Clomiphene, Clomiphene/HMG • HMG • FSH stimulation with agonists • FSH stimulation with antagonists

6. Premature LH surge • Poor quality • No fertilization or very poor pregnancy rate • Cancel egg retrieval 5-20% 5-20% All cycles treated in early 1980’s

7. Results of first application of GnRH-agonists in the long protocol • 11 patients eligible for IVF • GnRH agonists s.c. (buserelin) started at day of menstruation • Ovarian stimulation started with HMG or purified FSH when all ovarian follicles and the endometrial lining has disappeared on ultrasound (average 15 days) • One ongoing pregnancy achieved Porter et al., 1984

8. GnRHa Long Protocol vs No Suppressionmeta-analysis IVF cases Odds ratios for IVF clinical pregnancy after GnRH-a versus clomiphene/FSH/hMG ovulation induction protocols

9. Down Regulation

10. Agonist Studies2000 - 2001

11. GnRH agonists Undesirable effects: • Over-suppression: • LH becomes so low that it affects the production of estrogen, and possibly progesterone in the luteal phase • Leads to poor response, poor pregnancy outcome due to early abortion. Also it is: • Too long and too much drug use, cost, cancelled cycles and it is unnatural.

12. Modifications of natural GnRH to have GnRH agonistic properties 1 2 3 4 5 6 7 8 9 10 pyro (Glu) – His – Trp – Ser – Tyr – Gly – Leu – Arg – Pro – Gly – NH2 regulation of GnRH receptor affinity regulation of biologic activity activation of the GnRH receptor Structure of GnRH agonists

13. 1 2 3 4 5 6 7 8 9 10 pyro (Glu) – His – Trp – Ser – Tyr – Gly – Leu – Arg – Pro – Gly – NH2 regulation of GnRH receptor affinity regulation of biologic activity activation of the GnRH receptor Structure of GnRH antagonists to achieve antagonistic properties of natural GnRH more modifications than only in position 6 and 10 are necessary

14. Comparison: Mode of Actions

15. Cetrotide 0.125 mg vs 0.25 mg, 2004 – Sep 2006

16. The GnRH Antagonists • Conclusions: • Why treat 100% of patients when we are trying to prevent 5-10% LH surge • Avoid over-suppression and poor response • Effective in preventing LH surge • Reduction of hyper-stimulation • Lower costs

17. Antagonist vs Agonists

18. Problems With Ovarian Stimulation • Cost • Physical Suffering • Immediate side effects • Future side effects • OHSS

19. Problems with Ovarian Stimulation • Drug Cost • Up to 40% of cost in IVF • 30% of patients who would not choose IVF as fertility treatment cited cost as the deciding factor (fertility survey by YWCA HK 2002)

20. In 2 surveys on the population’s perception of IVF, Europe 1996 and Hong Kong 1998, 50% of infertile couples know about IVF but will not undergo treatment. • The main reasons are: Religion, Cost, Worried about side effects of drugs

21. Problems with Ovarian Stimulation Potential Cancer Risks: Clomiphene use increased risks for Invasive and Borderline epithelial Ovarian tumors Gravid RR 1.4 Nulligravid RR 27.0 Whittemore, Harris et al 1992

22. Problems With Ovarian Stimulation • OHSS • Up to 6% of all FSH stimulated IVF cycles • 1.5% Severe • Compare NO OHSS with unstimulated cycles

23. Problems with Ovarian Stimulation • Waste of Human Resources - Excess eggs ? how to deal with - Excess embryos - even worse • Multiple pregnancies and their associated complications

24. So it is time to • Individualise • More User Friendly Alternatives

25. New Mindset • Don’t think STIMULATION • Think Preparing the Ovary for Egg Collection • Think Patient Orientated Treatment • Always Minimise Trauma to Patients

26. We should stop thinking of Ovarian Stimulation, but start to consider, in all IVF cases, that we have to prepare the ovary for egg collection. Only if we do this, we can set our mind on how best we can serve our patients, NOT based on OUR interest, but primarily in their interest.

27. Patient-friendly treatment approach • Simple follow-up • Less side-effects (immediate / long-term) • More affordable • Favorable treatment outcomes • Less complications

28. Simplified follow-up No / Minimal stimulation Single embryo transfer Natural cycle IVF Minimal stimulation IVF IVM Natural cycle IVF combined with IVM More patient friendly approaches

29. Natural cycle IVF • Natural cycle IVF may offer an effective and potentially cost-effective alternative treatment option for certain groups of infertile couples. • To achieve maximal effectiveness natural cycle IVF can be offered as a series of cycles, over consecutive cycles. • To avoid expensive drugs and reduced intensity of monitoring make it less expensive than conventional treatment.

30. Cumulative probability of pregnancy in natural cycle IVF Nargund G et al. 2001 Cumulative conception and live birth rates in natural (unstimulated) IVF cycles. Human Reprod 16, 259-262.

31. Cumulative probability of live-birth in natural cycle IVF Nargund G et al. 2001 Cumulative conception and live birth rates in natural (unstimulated) IVF cycles. Human Reprod 16, 259-262.

32. Minimal Stimulation IVF • Aim is to use the one dominant follicle that spontaneously develops in a natural cycle. • GnRH antagonist is used to prevent LH surge. • Risk of OHSS is negligible.

34. Heijnen E et al. 2007 Lancet 369, 743-749.

35. Preparation for Egg Collection • Natural Cycle IVF • Minimal Stimulation IVF • In Vitro Maturation of eggs/IVF Ovulation Stimulation FSH FSH with Agonist Down Regulation FSH with Antagonists

36. Preparing the Ovary for Egg Collection for IVF • Group A • Young age • No medical problem or history • Previous Pregnancy • AFC >7 • Consider No Stimulation

37. Preparing the Ovary for Egg Collection in IVF • Group B • PCO • Previous History of Poor Response • Raised Day 2 FSH • Consider IVM/IVF with/without stimulation

38. Preparing the Ovary for Egg Collection • Group C • No Contradiction to stimulation • No previous Adverse History • Normal Day 2 FSH • Normal Antral Follicle Count • Gold Standard: HMG/FSH with Agonist/Antagonist

39. Modern Trend in ART • Minimize multiple pregnancies • Minimize number of embryos transfer • Minimize patients’ load and stress • Physiological • Psychological • Financial

40. Question • Is it time to revisit the aim and clinical practice of so called Controlled Ovarian Hyperstimulation. Should we be heading towards a modified direction

41. Answer • We should look at the clinical aim of “Preparing Eggs for the treatment of IVF” rather than Ovarian Stimulation