individualization of cycle control
DESCRIPTION
Individualization of Cycle Control. Dr. Milton Leong MDCM DSc (McGill) Director, IVF Center , HKSH Specialist in Reproductive Medicine Adjunct Professor, OBS-GYN, McGill University. - PowerPoint PPT PresentationTRANSCRIPT
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Individualization of Cycle Control
Dr. Milton Leong MDCM DSc (McGill)
Director, IVF Center, HKSHSpecialist in Reproductive Medicine
Adjunct Professor, OBS-GYN, McGill University
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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
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Preparation for Ovum Collection
• Natural Cycles• Minimal stimulation (clomiphene/FSH)• IVM• FSH stimulation with agonists• FSH stimulation with antagonists
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Ovulation Stimulation
WHAT GOES AROUND COMES AROUND
*American idiom
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Stimulated ovary
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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
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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%
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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
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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
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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
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OVARIAN STIMULATION
• FSH with agonist down regulation• FSH with antagonists• Low dose clomid/FSH stimulation• Delayed stimulation• IVM• Natural cycles
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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
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LH + FSH
post-receptor-cascade
GnRH - receptor
GnRH
GnRH - agonist
Downregulation
Action of GnRH agonists
Pituitary suppressionFlare up effect
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Schematic representation of different protocols using GnRH agonists in combination with gonadotrophi
ns for ovarian stimulation in IVF
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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
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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
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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
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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
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# 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
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Down Regulation
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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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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
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LH + FSH
post-receptor-cascadeGnRH - receptor
GnRH
GnRH - antagonistpituitary suppression
Action of GnRH antagonists
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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
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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
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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
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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
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Cetrorelix 0.125mg Flexible Dose Trial
Selection Criteria:
1. Previous over-suppression with agonist
2. Previous poor response3. Previous LH surge if no agonist
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0123456789
10
<20 20 21 22 >25
Mean = 21.8 (range 19-30)
BMI Distribution
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0123456789
10
1 2 3 4
Mean = 2.2 days (range 1-3)
# Days Cetrorelix Used
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• 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
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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
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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)
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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)
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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
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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
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• 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®
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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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Ovum Preparation for IVF
• FSH/GnRH Down Regulation• FSH/GnRH Antagonists• Clomid, Clomid/FSH • Minimal Stimulation• IVM• Natural Cycles
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Problems with Ovarian Stimulation
• Drug Costs• Side effects: immediate and delayed• Future long term risks• Not “User Friendly”
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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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Individualized stimulation
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Individualized Stimulation
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Individualizing Stimulation
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Individualized Stimulation
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Over responders
• Risk of OHSS• Treatment options
a) Cancel cycleb) Coastingc) No embryo transferd) Convert to IVM
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Individualizing protocols
• For over responders• For low responders
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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
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IVM stimulation
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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)
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Poor responders
• High dose• Microdose flare• Low dose clomid/FSH stimulation• Delayed stimulation• IVM
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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
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Microdose Flare Regimen (2)
• 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
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Microdose Flare Regimen (3)
• 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
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Poor responders
• High dose• Microdose flare• Low dose clomid/FSH stimulation• Delayed stimulation• IVM
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Minimal stimulation
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Poor responders
• High dose• Microdose flare• Low dose clomid/FSH stimulation• Delayed stimulation• IVM
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Delayed Stimulation
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Poor responders
• High dose• Microdose flare• Low dose clomid/FSH stimulation• Delayed stimulation• IVM
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IVM stimulation
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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%
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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
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Preparation for Ovum Collection
• Natural Cycles• Minimal stimulation (clomiphene/FSH)• IVM• FSH stimulation with agonists• FSH stimulation with antagonists
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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.
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Stimulated ovary
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Stimulated ovary