GnRH-a to trigger ovulation should be used in all
PCOS patients to prevent OHSS
Dr. Shahar Kol
Disclaimer
• The following presentation reflects my own
experience and opinion.
• The presentation does not necessarily reflect
drug companies’ policies.
• I mention off-label use of medications, this
use is not endorsed by drug companies.
IVM
• This option is thoroughly discussed in this
meeting.
• If you adopt IVM you need not worry about
OHSS.
• If you choose to stimulate your PCOS patient,
please use the GnRH antagonist option.
• Mild stimulation is a great idea, not easy to
implement.
AUGUST 2009
If you choose a long GnRH agonist protocol,
this what might happen
Basic clinical details
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25-year-old, 2 years of primary infertility
Irregular cycles, facial hair
BMI=24, LH=14.9, Testo=2.5, FSH-normal
US: PCOS
Impaired glucose tolerance – started
Metformin 850 twice daily
• Sperm-normal
• FSH-normal
Pre-IVF treatment
• CC up to 100 mg daily – no ovulation
• 5 cycles with recFSH 50 U daily. Four cycles
mono-ovulation, 1 cycle cancelled for
multifollicular development. No pregnancy.
• Referral to IVF.
IVF – cycle I
• Long agonist protocol, continue metformin,
daily gonadotropin dose of 112.5 U – no
response, increase to 150 U – good response
• Trigger with hCG 10,000 U
• OPU: 16 eggs from 20 follicles.
• ET: 2 embryos, no pregnancy.
IVF-cycle II
• Same long protocol, continue metformin, starting
dose 150 U.
• After 7 days: “unfortunately” 25 follicles<12 mm,
9 follicles 13-16 mm, dose reduced to 125 U,
trigger with hCG 5,000 U.
• OPU: 41 eggs, 21 embryos frozen.
• 2 days later: abdominal pain, vomiting.
• US: large ovaries.
• Hemoglobin -16.3, WBC-31,700.
• Decision to hospitalize.
In hospital
•
•
•
•
IV fluid (crystaloid), enoxaparin 40mg
Poor urinary output, albumin i.v
Fluid balance +1,500 in 24 h.
Chest X-ray: pleural effusion
Getting worse
• Chest and abdominal drains.
• During 24h 2 L of ascitic fluid and 1 L pleuritic
fluid was drained.
• Further deterioration: O2 sat <95%, X-ray:
bilateral pleural effusion and pulmonary
edema.
ICU
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•
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•
•
Risk of adult RDS – transferred to ICU
2nd chest tube inserted
Central i.v. line
Continue albumin
Gradual improvement and discharge after a
few days.
Severe OHSS: is it still a problem?
Maternal deaths and rates per 100,000 ART procedures,
including IVF: United Kingdom: 1997–2005
Year
Number
Rate
95% CI
Number of
treatment
cycles
1997– 1999
20
19.17
12.41–29.61
104,320
2000–2002
8
7.32
3.71–14.44
109,308
2003–2005
12
10.08
5.76–17.61
119,080
Deaths
* Source Human Fertilisation and Embryology Authority
•
“In 2003–2005, 4 deaths (of the 12) were due to OHSS”
•
~3 OHSS-related deaths per 100,000 ART cycles
Three OHSS-related deaths (3:100,000), all had their embryos frozen
Braat DDM, et al. Hum Reprod
2010;25:1782–1786
What really works:
● GnRH agonist versus hCG for oocyte triggering in GnRH antagonist ART cycles
Youssef MA, et al. Human Reprod Update
2010;16:459–466
•
16 publications
•
Agonist: 2005
patients, not a single
case of OHSS!
•
hCG: 92 cases in 1810
patients, 5.1%
Ovulation
trigger
RCT, high risk
Oocyte
source
Own
Engamnn, et al 2008
RCT, high risk
Own
GnRHa
hCG
Acevedo, et al 2006
RCT
Donors
GnRHa
hCG
Bodri, et al 2009
Retrospective
Donors
GnRHa
hCG
Griesinger, et al 2010
Observational,
High risk
RCT
Own
GnRHa
Own
Engmann, et al 2006
Retrospective, casecontrolled, high risk
Manzanares, et al 2009
Reference
Trial type
Babayof, et al 2006
n
OHSS % (n)
15
13
33
32
30
30
1046
1031
0 (0/13)
31(4/13)
0 (0/33)
31 (10/32)
0 (0/30)
17 (5/30)
0 (0/1046)
1.3 (13/1031)
40
0 (0/40)
GnRHa
hCG
152
150
0 (0/152)
2 (3/150)
Own
GnRHa
hCG
23
23
0 (0/23)
4 (1/23)
Retrospective casecontrol, high risk
Own
GnRHa
hCG - cancelled
42
0 (0/42)
Hernandez, et al 2009
Retrospective
Donors
GnRHa
hCG
Orvieto, et al 2006
Retrospective, high
risk
Retrospective, high
risk: agonist arm only
Own
GnRHa
hCG
254
175
82
69
0 (0/254)
6 (10/175)
0 (0/82)
7 (5/69)
Donors
GnRHa
hCG
32
42
0 (0/32)
1 (1/42)
Sismanoglu, et al 2009
RCT
Donors
GnRHa
hCG
44
44
0 (0/44)
7 (3/44)
Humaidan, et al 2009
Observational, high
risk
Own
GnRH, luteal rescue
with hCG 1500IU
12
8 (1/12)
Galindo, et al 2009
RCT
Donors
GnRHa
hCG
Melo, et al 2009
RCT
Donors
GnRHa
hCG
Shahrokh, et al 2010
RCT, high risk
Own
GnRHa
hCG
106
106
50
50
4
45
0 (0/106)
8 (9/106)
0 (0/50)
16(8/50)
0 (0/45)
15 (33)
Humaidan, et al 2009
Shapiro, et al 2007
GnRHa
hCG
The physiology of agonist trigger
LH surge1
1. Humaidan P, et al. Reprod Biomed Online 2011; (Epub ahead of print);
2. Gonen Y, et al. J Clin Endocrinol Metab 1990;71:918–922
FSH surge2
What happens after agonist trigger?
Complete luteolysis!
Luteal phase
Natural cycle
Day 7–9 = 75 pg/mL vs 18
Natural cycle
Day 7–9 = 750 pg/mL vs 84
Nevo O, et al. Fertil Steril 2003;79:1123–1128
“The concept of an OHSS-Free Clinic has become a reality. This
approach should include pituitary down-regulation using a
GnRH antagonist, ovulation triggering with a GnRH agonist
and vitrification of oocytes or embryos”
“…luteal phase supplementation with low-dose hCG has to be
fine tuned.”
Devroey P, et al. Human Reprod 2011; 26:
2593–2597
Failures?
OHSS prevention by GnRH agonist triggering of final oocyte maturation
in a GnRH antagonist protocol in combination with freeze-all strategy:
a prospective multicenter study
• Conclusions: “…a single case of a severe early onset OHSS occurred”
– E2 trigger day=47,877 pmol/L
– 13 oocytes
– The patient was hospitalized on day of OPU, with abdominal
distension, drastically enlarged ovaries (right and left ovarian volume
363 cm2 and 261 cm2, respectively), and lower abdominal pain.
– She received low molecular weight heparin, cabergoline (0.5 mg/d),
and IV infusion therapy, including albumin.
Griesinger G, et al. Fertil Steril
2011;95:2029–2033
Failures? (cnt’d)
– “drastic decrease of hemoglobin levels to 4.9
mmol/L” (8 grams/dL) patient received blood
transfusion 2 days post OPU.
– Hematocrit: 41 trigger day, 37 OPU day, ‘,<35’ post
blood transfusion.
– 3–4 days post trigger 3.9 litres of “blood-stained
ascites which was indicative of a subacute
intraperitoneal hemorrhage”.
How to secure good clinical outcome post agonist
trigger?
• High risk fresh transfer: intensive E2+P luteal
support
• High risk: ‘freeze-all’
• Low risk: luteal rescue based on LH activity
Luteal phase: intensive E+P
OHSS high-risk patients
Study group
Control group
Odds ratio (95%CI)
p value
0/33 (0)
10/32 (31.3)
0 (0–0.26)a
<0.01
0/33 (0)
5/32 (15.6)
0 (0–0.74)a
0.02
Total, n (%)
0/30 (0)
10/2 (34.5)
0 (0–0.26)a
<0.01
Moderate/severe, n (%)
0/30 (0)
5/29 (17.2)
0 (0–0.73)a
0.02
22/61 (36)
20/64 (31)
1.18 (0.52–2.65)
0.69
Positive pregnancy, n (%)
19/30 (63.3)
18/29 (62.1)
1.06 (0.37–3.0)
0.92
Clinical pregnancy rate, n (%)
17/30 (56.7)
15/29 (51.7)
1.22 (0.4–3.4)
0.45
Ongoing pregnancy rate, n (%)
16/30 (53.3)
14/29 (48.3)
1.22 (0.4–3.4)
0.45
Primary end points
OHSS (ITT)
Total, n (%)
Moderate/severe, n (%)
OHSS (PP)
Secondary end point (PP)
Implantation rate, n (%)
Other end points (PP)
aThe
estimates of these odds ratios are zero, because no patient developed OHSS in the study group; ITT=intention to treat; PP=per
protocol
Engmann L, et al. Fertil Steril 2008;89:84–91
GnRHa Trigger and Total Freeze in High Risk Patients
Griesinger et al., 2007, observational, 20 high- risk
patients (≥ 20 follicles ≥ 11mm)
- cumulative ongoing pregnancy rate 37 %
Griesinger at al., 2011, observational, 51 high-risk
patients (≥ 20 follicles ≥ 11mm)
- cumulative live bith rate 37 %
The advantage for the ‘normal responder’
Agonist
Antagonist trigger
FSH/hMG
OPU
36 hours
1500 IU hCG
Kol S, et al. Human Reprod
2011;26:2874–2877
ET
4 days
1500 IU hCG
Stimulation characteristics and embryology data
Stimulation (days)
9.3 ± 2.0
GnRH antagonist (days)
3.8 ± 0.9
FSH (units)
2443 ± 925
E2 day of trigger (pmol/L)
3764 ± 1227
P day of trigger (nmol/L)
2.4 ± 1.65
LH day of trigger (IU/L)
1.9 ± 1.3
Oocytes retrieved
6.7 ± 2.5
Embryos obtained
3.6 ± 1.7
Embryos transferred
2.9 ± 0.9
Embryos frozen
0.8 ± 1.5
Beta hCG (IU/L)
152 ± 86
E2 (day of pregnancy test, pmol/L)
6607 ± 3789
P (day of pregnancy test, nmol/L)
182 ± 50
Values are mean ± SD
Reproductive outcomes
Positive hCG/cycle, n (%)
11/15 (73)
Clinical ongoing pregnancy, n (%)
7/15 (47)
Early pregnancy loss, n (%)
4/11 (36)
Kol S, et al. Human Reprod 2011;26:2874–2877
Side benefits
• Agonist trigger: more MII oocytes compared
with hCG trigger1-4
• Potential benefit of FSH surge:5-9
– Promotes LH receptor formation in luteinizing
granulosa cells
– Promotes nuclear maturation (i.e. resumption of
meiosis)
– Promotes cumulus expansion
1.
Humaidan P, et al. Reprod Biomed Online 2005;11:679–684
2.
3.
4.
5.
6.
7.
8.
9.
Humaidan P, et al. Human Reprod 2009;24:2389–2394
Imoedemhe DA, et al. Fertil Steril 1991;55:328–332
Oktay K, et al. Reprod Biomed Online 2010;20:783–788
Eppig JJ. Nature 1979;281:483–484
Strickland and Beers. J Biol Chem 1976;251:5694–5702
Yding Andersen C. Reprod Biomed Online 2002;5:232–239
Yding Andersen C, et al. Mol Hum Reprod 1999;5:726–731
Zelinski-Wooten MB, et al. Human Reprod 1995;10:1658–1666
Anecdotal cases
• You may consider GnRH agonist trigger in the
following cases:
– Repeated IVF failure
– “empty follicles” syndrome
– Immature oocytes despite adequate follicular
diameter
Crystal ball: where are we heading?
In
Out
Antagonist-based protocols
‘Long agonist’ protocols
Agonist trigger
hCG trigger
Total OHSS elimination
1–2% severe OHSS
Total OHSS elimination
OHSS-related death rate: 3:100,000