New Concept of Controlled Ovarian Stimulation in IVF

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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

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

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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.

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Stimulated ovary

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Ovarian Stimulation for IVF

• Natural Cycles
• Clomiphene, Clomiphene/HMG
• HMG
• FSH stimulation with agonists
• FSH stimulation with antagonists

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Premature LH surge

• Poor quality
• No fertilization or very poor pregnancy rate
• Cancel egg retrieval

5-20
5-20
All cycles treated in early 1980s
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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
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GnRHa Long Protocol vs No Suppressionmeta-analysi
s IVF cases
Odds ratios for IVF clinical pregnancy after
GnRH-a versus clomiphene/FSH/hMG ovulation
induction protocols
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Down Regulation

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Agonist Studies2000 - 2001
Deca Long Luc Long Bus
lt40 lt40 lt40
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
Fertilization Rate 74 76 71
Mean of Embryos Transferred per ET 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

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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.

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Structure of GnRH agonists
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Structure of GnRH antagonists
to achieve antagonistic properties of natural
GnRH more modifications than only in position 6
and 10 are necessary
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Comparison Mode of Actions
Antagonists Agonists
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.
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Cetrotide 0.125 mg vs 0.25 mg, 2004 Sep 2006
0.125 mg/day 0.25 mg/day P
Cycles 121 331
Average age 37.14.0 37.54.2 NS
Days of stimulation 9.31.7 9.41.8 NS
Total dose of FSH used (amp) 31.414.4 36.014.5 0.004
E2 on HCG day (pg/ml) 1943941.8 2028.01376.0 NS
LH on HCG day (IU/L) 3.53.9 2.11.9 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 2.80.8 2.90.8 NS
Pregnancy rate/ET 50/121 (41.3) 106/331 (32.0) NS (P0.066)
Implantation rate 17.3 13.4 NS (P0.081)
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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

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Antagonist vs Agonists
Cet Cet Agonist Agonist
lt40 40 lt40 40 40
Number of OPU Number of OPU 371 184 171 23 23
Number of Eggs Retrieved Number of Eggs Retrieved 3994 1388 2126 199 199
Number of MTII Number of MTII 2984(75) 1055(76) 1575(74) 152(76) 152(76)
Number of MTI Number of MTI 526 (13) 160 (12) 205 (10) 25 (13) 25 (13)
Number of ICSId Number of ICSId 3269 1131 1729 173 173
Number of 2PN Number of 2PN 2472 870 1303 126 126
Fertilization Rate Fertilization Rate 76 77 75 73 73
Total of Embryos Transferred Total of Embryos Transferred 1039 521 532 62 62
Mean of Embryos Transferred per ET Mean of Embryos Transferred per ET 2.8 2.8 3.1 2.7 2.7
Number of Pregnancy Number of Pregnancy 145 25 82 5 5
Pregnancy Rate per ET Pregnancy Rate per ET 39 14 48 22 22
Implantation Rate Implantation Rate 17 5 20 10 10
Average Age Average Age 35.1 41.8 33.7 41.5 41.5
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Problems With Ovarian Stimulation

• Cost
• Physical Suffering
• Immediate side effects
• Future side effects
• OHSS

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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)

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• In 2 surveys on the populations 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

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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

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Problems With Ovarian Stimulation

• OHSS
• Up to 6 of all FSH stimulated IVF cycles
• 1.5 Severe
• Compare NO OHSS with unstimulated cycles

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Problems with Ovarian Stimulation

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

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

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New Mindset

• Dont think STIMULATION
• Think Preparing the Ovary for Egg Collection
• Think Patient Orientated Treatment
• Always Minimise Trauma to Patients

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• 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.

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Patient-friendly treatment approach

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

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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

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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.

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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.
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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.
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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.

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(No Transcript)
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Heijnen E et al. 2007 Lancet 369, 743-749.
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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

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Preparing the Ovary for Egg Collection for IVF

• Group A
• Young age
• No medical problem or history
• Previous Pregnancy
• AFC gt7
• Consider No Stimulation

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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

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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

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Modern Trend in ART

• Minimize multiple pregnancies
• Minimize number of embryos transfer
• Minimize patients load and stress
• Physiological
• Psychological
• Financial

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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

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Answer

• We should look at the clinical aim of Preparing
  Eggs for the treatment of IVF rather than
  Ovarian Stimulation