the women’s clinic 婦產科中心 new concept of controlled ovarian stimulation in ivf dr. milton...

The Women’s Clinic

婦產科中心

New Concept of ControlledOvarian Stimulation in IVF

Dr. Milton Leong MDCM DSc (McGill)

Director, IVF Center, HKSHSpecialist in Reproductive Medicine

Adjunct Professor, OBS-GYN, McGill University


婦產科中心

• Review “Gold Standard”

• Discuss Alternatives

• Introduce Concept of Preparing Ovary for Egg Collection in IVF


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.


婦產科中心

Stimulated ovary


婦產科中心

Ovarian Stimulation for IVF

• Natural Cycles

• Clomiphene, Clomiphene/HMG

• HMG

• FSH stimulation with agonists

• FSH stimulation with antagonists


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%


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


婦產科中心

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

Down Regulation


婦產科中心

Deca Long Luc Long Bus

<40 <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%

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

Agonist Studies2000 - 2001


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.


婦產科中心

Modifications of natural GnRHto have GnRH agonistic properties

1 2 43 65 98 107

pyro (Glu) – His – Trp – Ser – Tyr – Gly – Leu – Arg – Pro – Gly – NH2

activation of the GnRH receptor

regulation of GnRHreceptoraffinity

regulation ofbiologic activity

Structure of GnRH agonists


婦產科中心

to achieve antagonistic properties of natural GnRH moremodifications than only in position 6 and 10 are necessary

1 2 43 65 98 107

pyro (Glu) – His – Trp – Ser – Tyr – Gly – Leu – Arg – Pro – Gly – NH2

activation of the GnRH receptor

regulation of GnRHreceptoraffinity

regulation ofbiologic activity

Structure of GnRH antagonists


婦產科中心

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.

Comparison: Mode of Actions


婦產科中心

0.125 mg/day 0.25 mg/day P

Cycles 121 331

Average age 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

E2 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)

Cetrotide 0.125 mg vs 0.25 mg, 2004 – Sep 2006


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


婦產科中心

Antagonist vs AgonistsCet Agonist

<40 ≥40 <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 2PN 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 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


婦產科中心

Problems With Ovarian Stimulation

• Cost

• Physical Suffering

• Immediate side effects

• Future side effects

• OHSS


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)


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


婦產科中心


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


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


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


婦產科中心

So it is time to

• Individualise

• More User Friendly Alternatives


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


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.


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


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


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.


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. HumanReprod 16, 259-262.


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. HumanReprod 16, 259-262.


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.

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


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


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


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


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


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


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


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

the women’s clinic 婦產科中心 new concept of controlled ovarian stimulation in ivf dr. milton...

Documents