Transcript Agonist vs Antagonist

Is It Time To Replace Ovarian
Stimulation in IVF With
Alternatives
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
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
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
I
• Review “Gold Standard”
• Discuss Alternatives
• Introduce Concept of Preparing Ovary
for Egg Collection in IVF
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
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
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
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%
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
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
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.
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
•
•
•
•
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
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
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
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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
Nulligravid
RR 1.4
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
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
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
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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
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•
•
•
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 options
a)
b)
c)
d)
Cancel cycle
Coasting
No embryo transfer
Convert to IVM
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
Over Responders
• A better choice is to convert overresponders, 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
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•
•
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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 Stimulation
Including 10 cases converted to IUI
25 patients
Age
D2 FSH
FSH 150U/D
(days)
#eggs
% Fert
# Trans/Preg
Impl%
30-45
12.5-34 U/L
3-10
41.5
15.2
4.2
121
93/121
74 (2.9)
4/74
2.2
76.9%
4/25 (16%)
5.4%
Poor responders
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•
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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%)
138 (2.6)
88 (3.7)
23/160 (14.3%)
17.6%
Embryos
transferred
Implantation
rate
IVM/IVF Selection Method
Natural Cycle IVM/IVF
Maria Hospital Korea
Group1: Succeed to collect oocytes from Leading Follicle
Group2: Failed to collect ooyctes from Leading Follicle
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
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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.