Is It Time To Replace Ovarian Stimulation in IVF With Alternatives

Dr. Milton Leong MDCM DSc (McGill)

Director, IVF Center, HKSHSpecialist in Reproductive Medicine

Adjunct Professor, OBS-GYN, McGill University

The first IVF Baby

Drs. Steptoe and Edwards decided to abandon the use of fertility medications and try aspirating a single egg in a natural menstrual cycle. On their second attempt, Louise Brown was conceived

Ovarian Stimulation for IVF

• Natural Cycles

• Clomiphene, Clomiphene/HMG

• HMG

• FSH stimulation with agonists

• FSH stimulation with antagonists

Ovulation Stimulation

WHAT GOES AROUND COMES AROUND

*American idiom

Stimulated ovary

Adapted from: Lunenfeld. Reprod Biomed Online 2002;4:11

1930 1940 1950 1960 1980 1990 1995 2003

Horse PMSG

Pig FSH

PituitaryFSH

u-hMG u-FSH u-FSH r-hFSH (HP)

r-hFSH FbM

Local reactions

Potential side-effects

Consistency

Quality

Antibodies Local, systemic reactions

Creutzfeldt–Jacob disease

Technology and product development timeline: gonadotrophins

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%

I

• Review “Gold Standard”

• Discuss Alternatives

• Introduce Concept of Preparing Ovary for Egg Collection in IVF

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

Porter et al., 1984

• 11 patients eligible for IVF• GnRH agonists s.c. (busereline) started at day of

menstruation of one day before• 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

OVARIAN STIMULATION

• FSH with agonist down regulation

• FSH with antagonists

• Low dose clomid/FSH stimulation

• Delayed stimulation

• IVM

• Natural cycles

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

Individualizing protocols

• Our contribution to

1. low dose short term agonist down regulation using decapeptyl

2. flexible low dose antagonist

• Aims: - to simplify treatment

- to minimize drug usage

Total < 40 ≥ 40

# of patients 90 76 (32.9) 14(40.8)

# of pregnancy 42 40 2

Pregnancy % 46.7 52.6 14

# of twins+ 10 10 0

# of babies 43 42 1

Miscarriage rate 16% 50%

Decapeptyl Down Regulation2000-2002

# of eggs 831 MTII 539 (67%)

MTI 139 (16.7%)

# of eggs ICSI 551

# of fertilized 427 Fert. % 76.4

# of E.T. 244 Mean transferred 2.7

# of preg. (F.H.) 46 Implantation rate 21%

Decapeptyl Down Regulation 2000-2003Laboratory Data

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

Down Regulation

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.

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

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

Cetrorelix 0.125mg Flexible Dose Trial

Selection Criteria:

1. Previous over-suppression with agonist

2. Previous poor response

3. Previous LH surge if no agonist

01

23

45

67

89

10

<20 20 21 22 >25

Mean = 21.8 (range 19-30)

BMI Distribution

01234567

89

10

1 2 3 4

Mean = 2.2 days (range 1-3)

# Days Cetrorelix Used

• Range mIU/ml• Pre 1.2 - 7.8• Day 1 post 0.9 - 4.9• Day HCG 1.8 - 6

LH and Cetrorelix 0.125mg/day

1.20.9

1.8

2.42.1

2.5

7.8

4.9

6

0

1

2

3

4

5

6

7

8

9

Pre-CET Day 1 Post Day HCG

Low

Average

High

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

0.125 mg/day 0.25 mg/day P

Cycles 86 215

Average age 35.1±3.1 35.2±2.9 NS

Days of stimulation 9.4±1.7 9.3±1.8 NS

Total dose of FSH used (amp)

29.6±11.9 33.2±11.6 0.016

E2 on HCG day (pg/ml) 2081.5±977.6 2040.6±1300.2 NS

LH on HCG day (IU/L) 3.7±4.4 2.1±1.8 0.002

Oocytes collected 941 (10.9) 2240 (10.4) NS

MTII 732 (77.78%) 1742 (77.76) NS

Fertilized oocytes (fertilization rate)

623 (85.1%) 1448 (83.1%) NS

Embryos transferred 2.8±0.6 2.8±0.7 NS

Pregnancy rate/ET 43/86 (50.0%) 84/215 (39.1%) NS (P=0.083)

Implantation rate 21.8% 17.4% NS (P=0.144)

Cetrotide 0.125 mg vs 0.25 mg, 2004 – Sep 2006(age <40)

0.125 mg/day 0.25 mg/day P

Cycles 35 116

Average age 41.6±1.7 42.0±2.3 NS

Days of stimulation 9.1±1.8 9.4±1.9 NS

Total dose of FSH used (amp)

36.0±18.6 41.1±17.7 NS

E2 on HCG day (pg/ml) 1602.2±756.1 2003.9±1517.8 NS

LH on HCG day (IU/L) 3.0±2.4 2.2±2.1 NS

Oocytes collected 219 (6.26) 958 (8.25) NS

MTII 170 (77.6%) 761 (79.4%) NS

Fertilized oocytes (fertilization rate)

147 (86.5%) 637 (83.7%) NS

Embryos transferred 2.9±1.1 3.0±1.0 NS

Pregnancy rate/ET 7/35 (20.0%) 22/116 (19.0%) NS

Implantation rate 6.9% 6.6% NS

Cetrotide 0.125 mg vs 0.25 mg, 2004 – Sep 2006 (age ≥40)

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

Antagonist vs Agonists

Cet 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

Problems With Ovarian Stimulation

• Cost

• Physical Suffering

• Immediate side effects

• Future side effects

• OHSS

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)

• 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:

Clomiphene use increased risks for Invasive and Borderline epithelial Ovarian tumors

Gravid RR 1.4 Nulligravid RR 27.0

Whittemore, Harris et al 1992

Problems With Ovarian Stimulation

• OHSS

• Up to 6% of all FSH stimulated IVF cycles

• 1.5% Severe

• Compare NO OHSS with unstimulated cycles

• Multiple dose protocol– rate of OHSS: 6.5% vs. 1.1% (agonist vs. antagonist protocol)– RR 6.2, 95% CI: 1.4 - 27.1, p = 0.03

• Single dose protocol– rate of OHSS: 11.1% vs. 3.5% (agonist vs. antagonist protocol)

95% CI: - 18.4 to 3.2– patients requiring hospitalisation: 5.6% vs. 1.8% – (agonist vs. antagonist protocol)

95% CI: - 11.7 to 4.1

• With both Cetrotide protocols a clear reduction of OHSS was achieved

Reduction of OHSS using Cetrotide

Problems with Ovarian Stimulation

• 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

• Individualise

• More User Friendly Alternatives

New Mindset

• Don’t think STIMULATION

• Think Preparing the Ovary for Egg Collection

• Think Patient Orientated Treatment

• Always Minimise Trauma to Patients

Ovum Preparation for IVF

• FSH/GnRH Down Regulation

• FSH/GnRH Antagonists

• Clomid, Clomid/FSH

• Minimal Stimulation

• IVM

• Natural Cycles

Preparation for Egg Collection

Routine IVF

Ovulation Stimulation

FSH

FSH with Agonist Down Regulation

FSH with Antagonists

Preparation for Egg Collection

• Natural Cycle IVF

• Minimal Stimulation IVF

• In Vitro Maturation of eggs/IVF

• 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, in their interest and primarily in their interest.

Preparing the Ovary for Egg Collection for IVF

• Group A

• Young age• No medical problem or history• Previous Pregnancy• ANC >5

• Consider No Stimulation

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

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

Over responders

• Risk of OHSS

• Treatment optionsa) Cancel cycle

b) Coasting

c) No embryo transfer

d) Convert to IVM

Over responders

Prolonged Coasting• Aim: To prevent hyperstimulation• Practice: Coast till E2 ≤ 3000 pg/mL• Sher, 1995 Start when 30% follices > 15

mm• Nilsson, 1999 When 3 follicles > 17mm

Over Responders

• A better choice is to convert over-responders, once recognised, to IVM. IN this case, OHSS can be avoided, and pregnancy maintained, as coasting cannot guarantee relief of OHSS, and sometimes oocyte quality is compromised

Over Responders

Poor responders

• Age (average age of ML patient 38.7 yrs)

• Decrease ovarian reserve (↑D2 FSH)

• Decrease antral follicles count

• Previous ovarian surgery(Laparoscopic ovarian cystectomy)

Poor responders

• High dose

• Microdose flare

• Low dose clomid/FSH stimulation

• Delayed stimulation

• IVM

Poor Responders

• Review of randomised control trials and retrospective studies showed that increasing the FSH dosage over 300U/day has no clinical benefit. The cost of treatment and side-effects were higher

• Hamilton et al 2007

Minimal stimulation

Delayed Stimulation

Delayed StimulationIncluding 10 cases converted to IUI

25 patients

Age 30-45 41.5

D2 FSH 12.5-34 U/L 15.2FSH 150U/D

(days)3-10 4.2

#eggs 121 2.2

% Fert 93/121 76.9%

# Trans/Preg 74 (2.9) 4/25 (16%)

Impl% 4/74 5.4%

Poor responders

• High dose

• Microdose flare

• Low dose clomid/FSH stimulation

• Delayed stimulation

• IVM

Stimulation in IVM

• No difference in laboratory data• No difference in clinical data• Makes ovum collection easier• In non-PCO patients who needs IVM

• medical, psychological reasons• slow responding IVM patients

• Makes IVM User Friendly

IVM stimulation

IVM results 2004 Aug to 2006 Dec

<38 ≥38

Patients (n) 53 24

Average age 32.6 40.0

Total eggs 674 (12.7 ) 166 (8.3)

MTII stage 504 (74.8%) 146 ( 76.9%)

Fertilization rate 408 (80.9%) 113 (87.0%)

Pregnancy rate 19/53 (35.8%) 8/24 (33.3%)

Embryos transferred

138 (2.6) 88 (3.7)

Implantation rate

23/160 (14.3%) 17.6%

IVM/IVF Selection Method

Group1: Succeed to collect oocytes from Leading FollicleGroup2: Failed to collect ooyctes from Leading Follicle

Natural Cycle IVM/IVF Maria Hospital Korea

Comparison of Outcomes in IVF/M, IVM and COH

Modern Trend in ART

• Minimize multiple pregnancies

• Minimize number of embryos transfer

• Minimize patients’ load and stress

• Physiological

• Psychological

• Financial

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

Answer

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

Preparation for Ovum Collection

• Natural Cycles

• Minimal stimulation (clomiphene/FSH)

• IVM

• FSH stimulation with agonists

• FSH stimulation with antagonists

Conclusions:

1. It is possible to choose stimulation procotol according to: age

Ovarian statusPrevious

history2. We should aim for minimal stress (in all

senses) for the patients provided similar result can be obtained.

3. Individualization of stimulation should be considered for every case.