New Concept of Controlled Ovarian Stimulation in IVF

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

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

LEARNING OBJECTIVES At the conclusion of this presentation, participants should be able to: The Women’s Clinic 婦產科中心 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.

Stimulated ovary The Women’s Clinic 婦產科中心

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

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

Results of first application of Gn. RHagonists in the long protocol The Women’s Clinic 婦產科中心 • 11 patients eligible for IVF • Gn. RH 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

Gn. RHa Long Protocol vs No Suppression meta-analysis IVF cases The Women’s Clinic 婦產科中心 Odds ratios for IVF clinical pregnancy after Gn. RH-a versus clomiphene/FSH/h. MG ovulation induction protocols

Down Regulation

Agonist Studies 2000 - 2001 The Women’s Clinic 婦產科中心 Deca Long Luc Long Bus <40 <40 Number of OPU 69 76 61 Number of Eggs Retrieved 881 885 726 Number of MTII 647, 73% 642, 73% 552, 76% Number of MTI 136, 15% 44, 5% 101, 14% 76% 71% 3. 1 3. 2 2. 8 Pregnancy Rate per ET 51% 49% 44% Implantation Rate 20% 22% 18% Average Age 34. 4 33. 2 34. 9 Fertilization Rate Mean # of Embryos Transferred per ET

Gn. RH agonists Undesirable effects: • Over-suppression: The Women’s Clinic 婦產科中心 – 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.

Structure of Gn. RH agonists Modifications of natural Gn. RH to have Gn. RH agonistic properties The Women’s Clinic 1 2 3 4 5 6 7 8 9 10 婦產科中心 pyro (Glu) – His – Trp – Ser – Tyr – Gly – Leu – Arg – Pro – Gly – NH 2 activation of the Gn. RH receptor regulation of Gn. RH receptor affinity regulation of biologic activity

Structure of Gn. RH antagonists to achieve antagonistic properties of natural Gn. RH more modifications than only in position 6 and 10 are necessary 1 The Women’s Clinic 婦產科中心 2 3 4 5 6 7 8 9 10 pyro (Glu) – His – Trp – Ser – Tyr – Gly – Leu – Arg – Pro – Gly – NH 2 activation of the Gn. RH receptor regulation of Gn. RH receptor affinity regulation of biologic activity

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

Cetrotide 0. 125 mg vs 0. 25 mg, 2004 – Sep 2006 The Women’s Clinic 婦產科中心 0. 125 mg/day 0. 25 mg/day P Cycles 121 331 Average 37. 1± 4. 0 37. 5± 4. 2 NS Days of stimulation 9. 3± 1. 7 9. 4± 1. 8 NS Total dose of FSH used (amp) 31. 4± 14. 4 36. 0± 14. 5 0. 004 E 2 on HCG day (pg/ml) 1943± 941. 8 2028. 0± 1376. 0 NS LH on HCG day (IU/L) 3. 5± 3. 9 2. 1± 1. 9 0. 001 Oocytes collected 1160 (9. 6) 3198 (9. 7) NS MTII 902 (77. 75%) 2503 (78. 26) NS Fertilized oocytes (fertilization rate) 770 (85. 4%) 2085 (83. 3%) NS Embryos transferred 2. 8± 0. 8 2. 9± 0. 8 NS Pregnancy rate/ET 50/121 (41. 3%) 106/331 (32. 0%) NS (P=0. 066) Implantation rate 17. 3% 13. 4% NS (P=0. 081)

The Gn. RH Antagonists • • The Women’s Clinic 婦產科中心 • • 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

Antagonist vs Agonists Cet The Women’s Clinic 婦產科中心 Agonist <40 ≥ 40 Number of OPU 371 184 171 23 Number of Eggs Retrieved 3994 1388 2126 199 Number of MTII 2984(75%) 1055(76%) 1575(74%) 152(76% ) Number of MTI 526 (13%) 160 (12%) 205 (10%) 25 (13%) Number of ICSI’d 3269 1131 1729 173 Number of 2 PN 2472 870 1303 126 Fertilization Rate 76% 77% 75% 73% Total # of Embryos Transferred 1039 521 532 62 Mean # of Embryos Transferred per ET 2. 8 3. 1 2. 7 Number of Pregnancy 145 25 82 5 Pregnancy Rate per ET 39% 14% 48% 22% Implantation Rate 17% 5% 20% 10% Average Age 35. 1 41. 8 33. 7 41. 5

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

Problems with Ovarian Stimulation The Women’s Clinic 婦產科中心 • 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)

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

Problems with Ovarian Stimulation Potential Cancer Risks: The Women’s Clinic 婦產科中心 Clomiphene use increased risks for Invasive and Borderline epithelial Ovarian tumors Gravid Nulligravid RR 1. 4 RR 27. 0 Whittemore, Harris et al 1992

Problems With Ovarian Stimulation The Women’s Clinic 婦產科中心 • OHSS • Up to 6% of all FSH stimulated IVF cycles • 1. 5% Severe • Compare NO OHSS with unstimulated cycles

Problems with Ovarian Stimulation The Women’s Clinic 婦產科中心 • Waste of Human Resources Excess eggs ? how to deal with Excess embryos - even worse • Multiple pregnancies and their associated complications

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

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

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.

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

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

Natural cycle IVF The Women’s Clinic 婦產科中心 • 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.

Cumulative probability of pregnancy in natural cycle IVF The Women’s Clinic 婦產科中心 Nargund G et al. 2001 Cumulative conception and live birth rates in natural (unstimulated) IVF cycles. Human Reprod 16, 259 -262.

Cumulative probability of livebirth in natural cycle IVF The Women’s Clinic 婦產科中心 Nargund G et al. 2001 Cumulative conception and live birth rates in natural (unstimulated) IVF cycles. Human Reprod 16, 259 -262.

Minimal Stimulation IVF • Aim is to use the one dominant follicle that spontaneously develops in a natural cycle. The Women’s Clinic 婦產科中心 • Gn. RH antagonist is used to prevent LH surge. • Risk of OHSS is negligible.

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

Preparation for Egg Collection The Women’s Clinic • Natural Cycle IVF • Minimal Stimulation IVF • In Vitro Maturation of eggs/IVF 婦產科中心 Ovulation Stimulation FSH with Agonist Down Regulation FSH with Antagonists

Preparing the Ovary for Egg Collection for IVF • Group A The Women’s Clinic 婦產科中心 • • Young age No medical problem or history Previous Pregnancy AFC >7 • Consider No Stimulation

Preparing the Ovary for Egg Collection in IVF • Group B The Women’s Clinic 婦產科中心 • PCO • Previous History of Poor Response • Raised Day 2 FSH • Consider IVM/IVF with/without stimulation

Preparing the Ovary for Egg Collection • Group C The Women’s Clinic 婦產科中心 • • No Contradiction to stimulation No previous Adverse History Normal Day 2 FSH Normal Antral Follicle Count • Gold Standard: HMG/FSH with Agonist/Antagonist

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

Question The Women’s Clinic 婦產科中心 • Is it time to revisit the aim and clinical practice of so called Controlled Ovarian Hyperstimulation. Should we be heading towards a modified direction

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