1. The Women’s Clinic 婦產科中心 New Concept of Controlled Ovarian Stimulation in IVF Dr. Milton Leong MDCM DSc (McGill) Director, IVF Center, HKSH Specialist in Reproductive Medicine Adjunct Professor, OBS-GYN, McGill University

2. The Women’s Clinic 婦產科中心 Review “Gold Standard” Discuss Alternatives Introduce Concept of Preparing Ovary for Egg Collection in IVF

3. The Women’s Clinic 婦產科中心 LEARNING OBJECTIVES At the conclusion of this presentation, participants should be able to: 1.Describe “where we are” with regard to “patient friendly” approaches in current ART treatments. 2.Describe the future prospects for a more patient-friendly fertility treatment.

4. The Women’s Clinic 婦產科中心 Stimulated ovary

5. The Women’s Clinic 婦產科中心 Ovarian Stimulation for IVF Natural Cycles Clomiphene, Clomiphene/HMG HMG FSH stimulation with agonists FSH stimulation with antagonists

6. The Women’s Clinic 婦產科中心 5-20% All cycles treated in early 1980’s Premature LH surge Poor quality No fertilization or very poor pregnancy rate Cancel egg retrieval 5-20%

7. The Women’s Clinic 婦產科中心 Porter et al., 1984 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 Results of first application of GnRH-agonists in the long protocol

8. The Women’s Clinic 婦產科中心 GnRHa Long Protocol vs No Suppression meta-analysis IVF cases Odds ratios for IVF clinical pregnancy after GnRH-a versus clomiphene/FSH/hMG ovulation induction protocols

9. Down Regulation

10. The Women’s Clinic 婦產科中心 DecaLong LucLong Bus <40 Number of OPU697661 Number of Eggs Retrieved881885726 Number of MTII647, 73%642, 73%552, 76% Number of MTI136, 15%44, 5%101, 14% Fertilization Rate74%76%71% Mean # of Embryos Transferred per ET 3.13.22.8 Pregnancy Rate per ET51%49%44% Implantation Rate20%22%18% Average Age34.433.234.9 Agonist Studies 2000 - 2001

11. The Women’s Clinic 婦產科中心 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. The Women’s Clinic 婦產科中心 Modifications of natural GnRH to have GnRH agonistic properties 12436598107 pyro (Glu) – His – Trp – Ser – Tyr – Gly – Leu – Arg – Pro – Gly – NH 2 activation of the GnRH receptor regulation of GnRH receptor affinity regulation of biologic activity Structure of GnRH agonists

13. The Women’s Clinic 婦產科中心 to achieve antagonistic properties of natural GnRH more modifications than only in position 6 and 10 are necessary 12436598107 pyro (Glu) – His – Trp – Ser – Tyr – Gly – Leu – Arg – Pro – Gly – NH 2 activation of the GnRH receptor regulation of GnRH receptor affinity regulation of biologic activity Structure of GnRH antagonists

14. The Women’s Clinic 婦產科中心 AntagonistsAgonists Immediate onset of actions (shortens treatment durations) Prevents hormonal withdrawal symptoms No recovery time of the pituitary long pre-treatment Hormonal (estrogen) withdrawal symptoms through desensitization of pituitary Recovery of the pituitary gonadotrophin secretion, after stopping the treatment takes about 2 weeks. Comparison: Mode of Actions

15. The Women’s Clinic 婦產科中心 0.125 mg/day0.25 mg/dayP Cycles121331 Average age37.1±4.037.5±4.2NS Days of stimulation9.3±1.79.4±1.8NS Total dose of FSH used (amp) 31.4±14.436.0±14.50.004 E2 on HCG day (pg/ml) 1943±941.82028.0±1376.0NS LH on HCG day (IU/L) 3.5±3.92.1±1.90.001 Oocytes collected1160 (9.6)3198 (9.7)NS MTII902 (77.75%)2503 (78.26)NS Fertilized oocytes (fertilization rate) 770 (85.4%)2085 (83.3%)NS Embryos transferred2.8±0.82.9±0.8NS Pregnancy rate/ET50/121 (41.3%)106/331 (32.0%)NS (P=0.066) Implantation rate17.3%13.4%NS (P=0.081) Cetrotide 0.125 mg vs 0.25 mg, 2004 – Sep 2006

16. The Women’s Clinic 婦產科中心 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. The Women’s Clinic 婦產科中心 Antagonist vs Agonists CetAgonist <40≥40<40≥40 Number of OPU37118417123 Number of Eggs Retrieved399413882126199 Number of MTII2984(75%)1055(76%)1575(74%)152(76%) Number of MTI526 (13%)160 (12%)205 (10%)25 (13%) Number of ICSI’d326911311729173 Number of 2PN24728701303126 Fertilization Rate76%77%75%73% Total # of Embryos Transferred103952153262 Mean # of Embryos Transferred per ET 2.8 3.12.7 Number of Pregnancy14525825 Pregnancy Rate per ET39%14%48%22% Implantation Rate17%5%20%10% Average Age35.141.833.741.5

18. The Women’s Clinic 婦產科中心 Problems With Ovarian Stimulation Cost Physical Suffering Immediate side effects Future side effects OHSS

19. The Women’s Clinic 婦產科中心 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. The Women’s Clinic 婦產科中心 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. The Women’s Clinic 婦產科中心 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. The Women’s Clinic 婦產科中心 Problems With Ovarian Stimulation OHSS Up to 6% of all FSH stimulated IVF cycles 1.5% Severe Compare NO OHSS with unstimulated cycles

23. The Women’s Clinic 婦產科中心 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. The Women’s Clinic 婦產科中心 So it is time to Individualise More User Friendly Alternatives

25. The Women’s Clinic 婦產科中心 New Mindset Don’t think STIMULATION Think Preparing the Ovary for Egg Collection Think Patient Orientated Treatment Always Minimise Trauma to Patients

26. The Women’s Clinic 婦產科中心 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. The Women’s Clinic 婦產科中心 Patient-friendly treatment approach Simple follow-up Less side-effects (immediate / long-term) More affordable Favorable treatment outcomes Less complications

28. The Women’s Clinic 婦產科中心 More patient friendly approaches Simplified follow-up No / Minimal stimulation Single embryo transfer Natural cycle IVF Minimal stimulation IVF IVM Natural cycle IVF combined with IVM

29. The Women’s Clinic 婦產科中心 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. The Women’s Clinic 婦產科中心 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. The Women’s Clinic 婦產科中心 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. The Women’s Clinic 婦產科中心 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. The Women’s Clinic 婦產科中心 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. The Women’s Clinic 婦產科中心 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. The Women’s Clinic 婦產科中心 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. The Women’s Clinic 婦產科中心 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. The Women’s Clinic 婦產科中心 Modern Trend in ART Minimize multiple pregnancies Minimize number of embryos transfer Minimize patients’ load and stress Physiological Psychological Financial

40. The Women’s Clinic 婦產科中心 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. The Women’s Clinic 婦產科中心 Answer We should look at the clinical aim of “Preparing Eggs for the treatment of IVF” rather than Ovarian Stimulation