Individualization of Cycle Control

Individualization of Cycle Control

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

Preparation for Ovum Collection

• Natural Cycles• Minimal stimulation (clomiphene/FSH)• IVM• 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%

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

GnRHa Long Protocol vs No Suppressionmeta-analysis GIFT cases

Odds ratios for GIFT 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

LH + FSH

post-receptor-cascade

GnRH - receptor

GnRH

GnRH - agonist

Downregulation

Action of GnRH agonists

Pituitary suppressionFlare up effect

Schematic representation of different protocols using GnRH agonists in combination with gonadotrophi

ns for ovarian stimulation in IVF

22nd dayof previous

cycle

14 days

1st dayof gonado-

tropins

gonadotropin administrationin an individualized dosage

ovulationinduction

oocytepick up

embryotransfer

luteal phase support

start ofGnRH agonist

The long luteal protocol

Individualizing protocols

• Our contribution to1. low dose short term agonist down

regulation using decapeptyl2. flexible low dose antagonist

• Aims: - to simplify treatment - to minimize drug usage

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

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

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

LH + FSH

post-receptor-cascadeGnRH - receptor

GnRH

GnRH - antagonistpituitary suppression

Action of GnRH antagonists

Ganirelix• Fully effective

within 4 hours, with a half-life of about 13 hours

Cetrorelix• Fully effective

within 8 hours, with a half-life of about 36 hours

R.E. Felberbaum and K. Diedrich, 1999.

Characteristics of GnRH antag

1st dayof gonado-

tropins

gonadotropin administrationin an individualized dosage

ovulationinduction

oocytepick up

embryotransfer

luteal phase support

1st dayof menstruation

Cetrotide® 0.25 mg administrationdaily s.c. starting on day 6 of stimulation

The Cetrotide® 0.25 mg multiple dose protocol

Possibilities to individualize the multiple dose protocol

• To avoid a premature LH rise the administration of cetrotide® 0.25 mg on day 6 of stimulation should be the standard procedure

• Using the standard procedure, a mean of 6.3 injections are necessary

• This is in accordance with the package size of 7 ampoules cetrotide® 0.25 mg per patient

Possibilities to individualize the multiple dose protocol

• Individualized administration of Cetrotide® 0.25 mg can be done– According to follicle size:

only if leading follicle is 14 mm• Thereby, the multiple dose protocol can

also be adapted to patients with a lower response

Cetrorelix 0.125mg Flexible Dose Trial

Selection Criteria:

1. Previous over-suppression with agonist

2. Previous poor response3. Previous LH surge if no agonist

0123456789

10

<20 20 21 22 >25

Mean = 21.8 (range 19-30)

BMI Distribution

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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

1.2 0.9

1.82.4 2.1

2.5

7.8

4.9

6

0

1

2

3

4

5

6

7

8

9

Pre-CET Day 1 Post Day HCG

LowAverageHigh

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


Cycles 86 215

Average age 35.1±3.1 35.2±2.9 NS



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


MTII 732 (77.78%) 1742 (77.76) NS


623 (85.1%) 1448 (83.1%) 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)


Cycles 35 116

Average age 41.6±1.7 42.0±2.3 NS



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


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


147 (86.5%) 637 (83.7%) 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)

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

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

• 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®

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

Ovum Preparation for IVF

• FSH/GnRH Down Regulation• FSH/GnRH Antagonists• Clomid, Clomid/FSH • Minimal Stimulation• IVM• Natural Cycles

Problems with Ovarian Stimulation

• Drug Costs• Side effects: immediate and delayed• Future long term risks• Not “User Friendly”

Problems with Ovarian Stimulation

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

associated complications

Individualized stimulation

Individualized Stimulation

Individualizing Stimulation

Individualized Stimulation

Over responders

• Risk of OHSS• Treatment options

a) Cancel cycleb) Coastingc) No embryo transferd) Convert to IVM

Individualizing protocols

• For over responders• For low responders

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

IVM stimulation

Poor responders

• Age (average age of ML patient 38.7 yrs)• Decrease ovarian reserve (↑D2 FSH)• Decrease preantral follicles• Previous ovarian surgery

(Laparoscopic ovarian cystectomy)

Poor responders

• High dose• Microdose flare• Low dose clomid/FSH stimulation• Delayed stimulation• IVM

Microdose Flare Regimen (1)

• Oral Contraceptive• 20 mcg leuprolide cs bd x 2 d• uFSH for ovarian stimulation• Results:

↑oocytesLess ampoules FSH

Source: Scott et al, 1994


• Oral Contraceptive• 40 mcg leuprolide sc bd• 4 IU/d growth hormone IM• Followed by uFSH 2 days later• Results:

↓Cancellation rate↑E2 levels, number of oocytes

Source: Schoolcraft et al, 1997


• Oral Contraceptive• 40 mcg leuprolide sc bd• uFSH starting 2 days later• Results

↓Cancellation rate↑E2 levels, number of oocytes

Source: Surrey et al, 1998

Poor responders


Minimal stimulation

Poor responders


Delayed Stimulation

Poor responders


IVM stimulation

IVM results 2004 Aug to 2007 Jun

<38 ≥38

Patients (n) 33 16

Average age 32.6 40.0

Total eggs 420 (12.7 ) 160 (10.0)

MTII stage 314 (74.8%) 123( 76.9%)

Fertilization rate 254 (80.9%) 107 (87.0%)

Pregnancy rate 33.3% 37.5%

Embryos transferred

84 34

Implantation rate

14.3% 17.6%

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 history

2. 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.

Stimulated ovary

Stimulated ovary

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Individualization of Cycle Control