Transcript Agonist vs Antagonist

Individualization of Cycle Control
Dr. Milton Leong
MDCM DSc (McGill)
Director, IVF Center, HKSH
Specialist 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
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•
•
•
•
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
Technology and product development
timeline: gonadotrophins
Horse
PMSG
Pig
FSH
Pituitary
FSH
u-hMG
1930
1940
1950
1960
u-FSH
1980
FbM
1995
2003
Quality
Potential side-effects
Creutzfeldt–
Jacob disease
1990
r-hFSH r-hFSH
Consistency
Local reactions
Antibodies
u-FSH
(HP)
Local, systemic
reactions
Adapted from: Lunenfeld. Reprod Biomed Online 2002;4:11
Premature LH surge
• Poor quality
• No fertilization or very poor pregnancy rate
• Cancel egg retrieval
5-20%
5-20%
All cycles treated in early 1980’s
GnRHa Long Protocol vs No Suppression
meta-analysis IVF cases
Odds ratios for IVF clinical pregnancy after GnRH-a versus
clomiphene/FSH/hMG ovulation induction protocols
GnRHa Long Protocol vs No Suppression
meta-analysis GIFT cases
Odds ratios for GIFT clinical pregnancy after GnRH-a versus
clomiphene/FSH/hMG ovulation induction protocols
Results of first application of GnRH-agonists
in the long protocol
• 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
Porter et al., 1984
OVARIAN STIMULATION
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•
•
•
•
•
FSH with agonist down regulation
FSH with antagonists
Low dose clomid/FSH stimulation
Delayed stimulation
IVM
Natural cycles
Structure of GnRH agonists
Modifications of natural GnRH
to have GnRH agonistic properties
1
2
3
4
5
6
7
8
9
10
pyro (Glu) – His – Trp – Ser – Tyr – Gly – Leu – Arg – Pro – Gly – NH2
activation of the
GnRH receptor
regulation
of GnRH
receptor
affinity
regulation of
biologic activity
Action of GnRH agonists
Down
regulation
GnRH
LH + FSH
GnRH - receptor
post-receptor-cascade
Flare up effect
Pituitary suppression
GnRH - agonist
Schematic representation of different protocols
using GnRH agonists in combination with
gonadotrophins for ovarian stimulation in IVF
The long luteal protocol
ovulation
induction
gonadotropin administration
in an individualized dosage
oocyte
pick up
embryo
transfer
start of
GnRH agonist
22nd day
of previous
cycle
1st day
of gonadotropins
14 days
luteal phase support
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
Agonist Studies
2000 - 2001
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%
74%
76%
71%
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
Fertilization Rate
Mean # of Embryos Transferred
per ET
Decapeptyl Down Regulation
2000-2002
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
16%
50%
Miscarriage rate
Decapeptyl Down Regulation 2000-2003
Laboratory Data
# 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%
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.
Structure of GnRH antagonists
to achieve antagonistic properties of natural GnRH more
modifications than only in position 6 and 10 are necessary
1
2
3
4
5
6
7
8
9 10
pyro (Glu) – His – Trp – Ser – Tyr – Gly – Leu – Arg – Pro – Gly – NH2
activation of the
GnRH receptor
regulation
of GnRH
receptor
affinity
regulation of
biologic activity
Action of GnRH antagonists
GnRH
LH + FSH
GnRH - receptor
post-receptor-cascade
pituitary suppression
GnRH - antagonist
Characteristics of GnRH antag
Ganirelix
Cetrorelix
• Fully effective
• Fully effective
within 4 hours, with
within 8 hours, with
a half-life of about
a half-life of about
13 hours
36 hours
R.E. Felberbaum and K. Diedrich, 1999.
The Cetrotide® 0.25 mg
multiple dose protocol
ovulation
induction
gonadotropin administration
in an individualized dosage
oocyte
pick up
embryo
transfer
1st day
of menstruation
1st day
of gonadotropins
luteal phase support
Cetrotide® 0.25 mg administration
daily s.c. starting on day 6 of stimulation
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.
2.
3.
Previous over-suppression with
agonist
Previous poor response
Previous LH surge if no agonist
BMI Distribution
10
9
8
7
6
5
4
3
2
1
0
<20
20
21
22
Mean = 21.8 (range 19-30)
>25
# Days Cetrorelix Used
10
9
8
7
6
5
4
3
2
1
0
1
2
3
Mean = 2.2 days (range 1-3)
4
LH and Cetrorelix 0.125mg/day
9
7.8
8
7
6
6
4.9
5
Low
Average
4
High
3
2
2.4
1.2
1
2.1
2.5
1.8
0.9
0
Pre-CET
Day 1 Post
Day HCG
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Range
Pre
Day 1 post
Day HCG
mIU/ml
1.2 - 7.8
0.9 - 4.9
1.8 - 6
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
37.1±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
(age <40)
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
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
Comparison: Mode of Actions
Antagonists
•Immediate onset of
actions (shortens
treatment durations)
•Prevents hormonal
withdrawal symptoms
Agonists
•long pre-treatment
•Hormonal (estrogen)
withdrawal symptoms
through desensitization
of pituitary
•Recovery of the
•No recovery time of the pituitary gonadotrophin
pituitary
secretion, after
stopping the treatment
takes about 2 weeks.
Reduction of OHSS using Cetrotide®
• 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
The GnRH Antagonists
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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
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FSH/GnRH Down Regulation
FSH/GnRH Antagonists
Clomid, Clomid/FSH
Minimal Stimulation
IVM
Natural Cycles
Problems with Ovarian Stimulation
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•
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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
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•
Risk of OHSS
Treatment options
a)
b)
c)
d)
Cancel cycle
Coasting
No embryo transfer
Convert to IVM
Individualizing protocols
• For over responders
• For low responders
Over responders
Prolonged Coasting
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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
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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
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•
High dose
Microdose flare
Low dose clomid/FSH stimulation
Delayed stimulation
IVM
Microdose Flare Regimen (1)
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•
•
•
Oral Contraceptive
20 mcg leuprolide cs bd x 2 d
uFSH for ovarian stimulation
Results:
↑oocytes
Less ampoules FSH
Source: Scott et al, 1994
Microdose Flare Regimen (2)
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•
•
•
•
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
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
Poor responders
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High dose
Microdose flare
Low dose clomid/FSH stimulation
Delayed stimulation
IVM
Minimal stimulation
Poor responders
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High dose
Microdose flare
Low dose clomid/FSH stimulation
Delayed stimulation
IVM
Delayed Stimulation
Poor responders
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High dose
Microdose flare
Low dose clomid/FSH stimulation
Delayed stimulation
IVM
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%
84
34
14.3%
17.6%
Embryos
transferred
Implantation
rate
Modern Trend in ART
• Minimize multiple pregnancies
• Minimize number of embryos transfer
• Minimize patients’ load and stress
•
Physiological
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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
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•
•
•
•
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 status
Previous 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