ACTION, STRUCTURE AND USE OF GNRH AGONISTS AND ANTAGONIST
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Transcript ACTION, STRUCTURE AND USE OF GNRH AGONISTS AND ANTAGONIST
Recommended Dosage of GnRH
Antagonist is Too High
Presented by
Dr. Milton Leong, MD DSc(McGill)
Director, IVF Centre
When Do I Use GnRH Antagonist
in my IVF Practice?
Presented by
Dr. Milton Leong, MD DSc(McGill)
Director, IVF Centre
ACTION, STRUCTURE AND USE
OF GnRH AGONISTS AND
ANTAGONIST
Action of GnRH agonists
Down
regulation
GnRH
LH + FSH
GnRH - receptor
post-receptor-cascade
flare up effect
pituitary suppression
GnRH - agonist
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
Results of first application of GnRHagonists in the long protocol
• 11 patients eligible for IVF
• GnRH agonist s.c. (Buserelin) started at day
of menstruation or 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
Analysis of protocols using GnRH
agonists for ovarian stimulation
cumulative
live birth rate
p (compared to
long protocol)
long protocol
55%
-
gonadotropins without agonist
29%
p = 0.0001
short or ultrashort protocol
17%
p = 0.005
protocol
• 2893 patients for IVF
• long protocol superior to other protocols in IVF
Tan et al., 1994
Comparison: Mode of Actions
Antagonists
Agonists
•Immediate onset of actions
•long pre-treatment
(shortens treatment durations)
•Prevents hormonal
withdrawal symptoms
•No recovery time of the
pituitary
•Hormonal (estrogen)
withdrawal symptoms through
desensitization of pituitary
•Recovery of the pituitary
gonadotrophin secretion, after
stopping the treatment takes
about 2 weeks.
Meta-analysis of protocols using
GnRH agonists for ovarian
stimulation
• The long protocol is superior to the short
and ultra-short protocol
long versus short
long follicular vs. short
long luteal vs. short
long vs. ultrashort
long luteal vs. long follicular
depot vs. daily (long)
0.1
1
10
Daya, 1997
Action of GnRH antagonists
GnRH
LH + FSH
GnRH - receptor
post-receptor-cascade
pituitary suppression
GnRH - antagonist
Structure of GnRH antagonists
name
GnRH
1st generation
4F Ant
2nd generation
NalArg
Detirelix
3rd generation
NalGlu
Antide
Org30850
Ramorelix
Cetrorelix
Ganirelix
A-75998
Azaline B
Antarelix
amino acid sequence
pGlu – His – Trp – Ser – Tyr – Gly – Leu – Arg – Pro – Gly – NH2
NAc1,1Pro – D4FPhe – DTrp – Ser – Tyr – DTrp – Leu – Arg – Pro – GlyNH2
NACD2Nal – D4lFPhe=pTrp – Ser – Tyr – DArg – Leu – Arg – Pro – GlyNH2
NACD2Nal – D4ClPhe – pTrp – Ser – Tyr – DHarg(Et2) – Leu – Arg – Pro – DAlaNH2
NACD2Nal – D4C7Phe – D3Pal – Ser – Arg – DGlut(AA) – Leu – Arg – Pro – DAlaNH2
NACD2Nal – D4ClPhe – D3Pal – Ser – Lys(Nic) – DDLys(Nic) – Leu – Lys(Isp)Pro – DAlaNH2
NACD4ClPhe – D4ClPhe – DBal – Ser – Tyr – DLys – Leu – Arg – Pro – DAlaNH2
NACD2Nal – D4ClPhe – DTrp – Ser – Tyr – DSet(Rha) – Leu – Arg – Pro – AzaglyNH2
NACD2Nal – D4ClPhe – D3Pal – Ser – Tyr – DCit – Leu – Arg – Pro – DAlaNH2
NACD2Nal – D4ClPhe – D3Pal – Ser – Tyr – DHarg(Et2) – Leu – Harg(Et2) – Pro – DAlaNH2
NACD2Nal – D4ClPhe – D3Pal – Ser – NMeTyr – DLys(Nic) – Leu – Lys(Isp) – Pro – DAlaNH2
NACD2Nal – D4ClPhe – D3Pal – Ser – Aph(atz) – DAph(atz) – Leu – Lys(Isp) – Pro – DAlaNH2
NACD2Nal – D4ClPhe – D3Pal – Ser – Tyr – DHcit – Leu – Lys(Isp) – Pro – DAlaNH2
Two possible antagonist protocols
• multiple dose protocol
- Cetrotide® 0.25mg
• single dose protocol
- Cetrotide® 3mg
The single dose antagonist protocol
compared to the long luteal protocol
• Inclusion criteria
– Age: 18 - 39 years
– Normal menstrual cycle (range: 24 - 35 days) with an
intraindividual variation of max. ± 3 days
– No more than 3 IVF procedures
– Normal uterus and at least one functioning ovary
• Exclusion criteria
– Severe endometriosis (AFS III/IV)
– PCO syndrome
Olivennes et al., 2000
The single dose antagonist protocol
compared to the long luteal protocol
Cetrotide
no of patients undergoing
oocyte pick-up (% of treated
patients)
®
Triptorelin
95% CI
113 (98.3)
36 (92.3)
-0.4
to -12.5
stimulation length (d)
9.4 1.4
10.7 1.7
-1.9
to
-0.7
no of ampoules
24.3 7.4
35.6 15.1
-14.2
to
-7.2
1.786 808
2549 1.194
-1.042 to -368
9.2 5.1
12.6 7.4
estradiol on day of hCG
(pg/ml)
total no. of oocytes retrieved
-5.6
to
-1.3
Olivennes et al., 2000
The single dose antagonist protocol
compared to the long luteal protocol
®
95% CI
Cetrotide
Triptorelin
5.4 3.5
7.5 4.9
- 3.7
to
- 0.6
7.2 4.9
10.3 7.4
- 5.3
to
- 1.2
rate of OHSS (%)
3.5
11.1
- 18.4
to
3.2
OHSS patients
requiring
hospitalisation (%)
1.8
5.6
- 11.7
to
4.1
no. of embryos
obtained
no. of
mature/metaphase
II oocytes
Olivennes et al., 2000
The single dose antagonist protocol
compared to the long luteal protocol
®
Cetrotide
Triptorelin
22.6
28.2
- 23.9 to
12.3
miscarriage rate (%)
15.4 (4/26)
27.3 (3/11)
- 41.6 to
17.9
ectopic pregnancy rate
(%)
7.7 (2/26)
- (0/11)
ongoing pregnancy
rate/oocyte pick up (%)
18.3
23.1
- 20.2 to
- 8.9
ongoing pregnancy
rate/embryo transfer
(%)
21.2
27.3
- 22.9 to
11.0
clinical pregnancy
rate/oocyte pick up (%)
95% CI
-
Olivennes et al., 2000
The multiple dose antagonist
protocol compared to the long luteal
protocol
®
number of patients
age (years)
days of analogue treatment
number of patients who got
hCG (%)
number of gonadotropin
ampoules
days of gonadotropin
treatment
estradiol on day of hCG
(pg/ml)
Cetrotide
188
31.9 3.7
5.7 2.3
Buserelin
85
31.6 3.8
26.6 3.2
p
n.s.
< 0.001
181 (96.3)
77 (90.6)
n.s.
23.6 8.5
25.6 7.6
< 0.01
10.6 2.3
11.4 1.8
< 0.01
1625 836
2082 1049
< 0.01
n.s. not significant
Albano et al., 2000
The multiple dose antagonist
protocol compared to the long luteal
protocol
®
no. of patients
no. of patients with pick-up
no. of cumulus oocyte
complexes per patient
no. of 2 PN oocytes per patient
no. of cleaved embryos (% of 2
PN)
- excellent (n, % of all)
- good (n, % of all)
- fair (n, % of all)
no. of embryos per transfer
Cetrotide
188
178
Buserelin
85
77
p
-
8.0 4.9
10.6 6.6
< 0.01
4.5 3.3
6.0 4.1
= 0.01
671 (89.5)
345 (79.9)
-
235 (35.0)
321 (47.8)
115 (83.5)
2.2 0.6
94 (28.1)
154 (44.6)
67 (78.8)
2.2 0.6
n.s.
n.s. not significant
Albano et al., 2000
The multiple dose antagonist protocol
compared to the long luteal protocol:
significant reduction of OHSS
Cetrotide® group
Agonist group
Phase III
2/181 (1.1%)
Buserelin ® : 5/77 (6.5%)
Phase III
(1.8%)
Triptorelin ® : (5.6%)
Phase III
2/346 (0.6%)
N.A.
Phase IIIb
10/859 (1.2%)
N.A.
Phase IIIb
2/192 (1.1%)
N.A.
Study
Albano et al, 2000
Oliveness et al, 2000
Felberbaum et al, 2000
Diedrich K et al, 2000
Frydman R. et al, 2000
Estradiol drop following
administration of Cetrotide® 3 mg
20
1600
E2 value
Lead Follicle
15
800
10
400
5
0
0
Day 0
Day 1
Day 2
Day 3
Day 4
Days after Cetrotide
® 3mg
Day 5
[mm]
[pg/ml]
1200
Day 6
according to: Olivennes, 2001
Mean number of Cetrotide® 0.25 mg
ampoules in the multiple dose
protocol
25
patients (%)
20
average: 6.3 injections
15
10
5
0
1
2
3
4
5
6
7
8
9
10 11 12 13 14 15
number of injections
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 response
3. Previous LH surge if no agonist
Cetrorelix 0.125mg Flexible Dose
Trial
Methods:
1. FSH LH E2 on day 2
2. U/S on day 3, start Gonal-F 225IU/day
3. Stimulation day 4, check E2 LH U/S
Cetrorelix 0.125mg Flexible Dose
Trial
Treatment Criteria
1. LH > 1.5IU/L
2. Leading follicle = 15mm diameter
• Cetrorelix 0.125mg/day given until day of
HCG injection
• Monitor by E2 LH U/S everyday
Cetrorelix 0.125mg Flexible Dose Trial
RESULTS
Age Distribution
7
6
5
4
3
2
1
0
<32
33-36
37-40
>40
Mean = 36.6 (range 29-44)
BMI Distribution
10
9
8
7
6
5
4
3
2
1
0
<20
20
21
22
Mean = 21.8 (range 19-30)
>25
Cetrorelix Start Cycle Day
8
7
6
5
4
3
2
1
0
5
7
9
11
13
15
17
19
FSH 225 Units/day SC starts on day 3
21
23
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
8
7.8
7
6
6
5
4.9
4
3
2
1
2.4
1.2
2.1
2.5
1.8
0.9
0
pre
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
Clinical Data
•Age
•BMI
36.6 (29-44)
21.8 (19-30)
•Ova # per OPU
•%MT II
•% Fertilization
9
(1-16)
77%
74.4%
•Transfer # embryos
•Pregnancy rate
•Implantation rate
15<40yr
5>40yr
2.6 <40yr
4.8 >40yr
60%<40yr 40% >40yr
25.4% (16/63)
The GnRH Antagonists
Conclusions:
1. Why treat 100% of patients when we are
trying to prevent 5-10% LH surge
2. Avoid over-suppression and poor response
3. Effective in preventing LH surge
4. Reduction of hyper-stimulation
5. Lower costs
Flexible dose GnRH Antagonist
•
•
•
•
1.
2.
3.
4.
To use the lowest effective dosage
0.125mg/day may be adequate
Starting date may be adjusted
Criteria for dose and commencement to
be better defined
• 5. Some may not need suppression
• 6. Future individual FSH GnRH-antagonist
dose
THE FIRST GLOBAL CHINESE CONFERENCE
ON REPRODUCTIVE MEDICINE
14th – 15th December 2002, Hong Kong