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The approach to the PCOS
patient undergoing IVF
Roy Homburg
Barzili Medical Centre, Ashkelon, Israel
and Homerton University Hospital, London
Antalya, October 2011
Problems – IVF for PCOS
• Excessive ovarian response
•
•
•
•
•
Low fertilization rates
High number of immature oocytes
Reduced cleavage rates
Low implantation rates
High miscarriage rates
Overcoming the problems for
PCOS in IVF
Diagnosis and mild stimulation
Agonist vs antagonist
Oral contraceptive pre-treatment
GnRH agonist to trigger ovulation
Metformin
Freeze embryos
IVM
Comparison of the long protocol
and the antagonist protocols
multiple dose protocol
no cyst
formation
no hormonal
withdrawal
more
physiologic
antagonist administration
Patient-friendly
gonadotropin administration
less gonadotropins
early
Menses
pregnancy?
flare up pituitary
gonadotropin administration
effect
suppression
long protocol
agonist administration
(mid-luteal)
longer
treatment
pre-treatment cycle
treatment cycle
4.1
%
2.6
%
Hospital admission due to OHSS
RR: 0.47
~50% less risk for hospital admission due to OHSS
with GnRH antagonists
Kolibianakis et al. Hum Reprod Update. 2006
GnRH antagonists are safer
than agonists: an update of a
Cochrane review.
Al-Inany HG, Youssef MA, Aboulghar M,
Broekmans F, Sterrenburg M, Smit J,
Abou-Setta AM.
Hum Reprod Update, May 2011
Finally…..no difference in live birth rate 2011
May 11, 2011
With new information available, authors of a Cochrane Systematic Review have revised their conclusions about the
relative effectiveness of two different treatments used to help women become pregnant. They now conclude that
giving women GnRH-antagonists leads to similar live-birth rates compared with GnRH agonists. Previously they
had concluded that women who used antagonists tended to have lower birth-rates than those using agonists.
[........]
In 2006, when the researchers reached their earlier conclusion, they were only able to draw data from 27 trials. Since
then more research has been published, allowing them to consider the findings of 45 randomised controlled studies
that involved a total of 7,511 women. “This increased amount of data lets us get a much better idea of how well the
two approaches compare,” says Dr Hesham Al-Inany, who was lead author of the research and works at Cairo
University, Egypt. Dr Al-Inany led a multi-centre team, with researchers also based in the Netherlands and Canada.
“The reduction in ovarian hyperstimulation combined with a comparable live-birth rate mean justifies a move
away from the standard GnRH agonist to using GnRH antagonists,” says Dr Al-Inany.
http://eu.wiley.com/WileyCDA/PressRelease/pressReleaseId-9635
F&S 2008
18.1% vs 23.6%
- OC pretreated
Starting with Gn on day 2/3 after the last OC intakeFixed GnRH antagonist regimen (long-starting SD 1)-
Huirne et al, 2007
Incidence of OHSS
Objective: to determine OHSS incidence in 2,524 antagonistbased cycles (1801 patients).
Results: fifty three patients (2%) were hospitalized because of
OHSS.
Conclusions: clinically significant OHSS is a limitation even in
antagonist cycles.
“There is more than ever an urgent need for
alternative final oocyte maturation – triggering
F&S January 2006
medication”
0.25mg/day antagonist
FSH
Day 5 , 6 or 7 antagonist start
FIXED
hcg
0.25mg/day antagonist
FSH
hcg
day 8/9
Follicle size 14mm- start antagonist
Flexible regime
0.25mg/day antagonist
FSH
Day 5 , 6 or 7 antagonist start
FIXED
GnRH agonist
0.25mg/day antagonist
FSH
day 8/9
GnRH agonist
Follicle size 14mm- start antagonist
Flexible regime
Agonist: 1932 patients, not a single case of OHSS!
hCG: 84 cases in 1760 patients, 4.8%
Ovulation
trigger
n
OHSS % (n)
RCT, high risk
Oocyte
source
own
GnRHa
hCG
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 2007
Observational,
High risk
RCT
own
GnRHa
15
13
33
32
30
30
1046
1031
20
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)
0 (0/20)
own
GnRHa
hCG
Engmann et al 2006
Retrospective, casecontrolled, high risk
own
GnRHa
hCG
152
150
23
23
0 (0/152)
2 (3/150)
0 (0/23)
4 (1/23)
Manzanares et al 2009
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
own
risk
Retrospective, high
donors
risk: agonist arm only
GnRHa
hCG
254
175
82
69
32
42
0 (0/254)
6 (10/175)
0 (0/82)
7 (5/69)
0 (0/32)
1 (1/42)
Sismanoglu et al 2009
RCT
donors
GnRHa
hCG
Humaidan et al 2009
Observational, high
risk
own
GnRH, luteal rescue
with hCG 1500IU
44
44
12
0 (0/44)
7 (3/44)
8 (1/12)
Galindo et al 2009
RCT
donors
GnRHa
hCG
Shahrokh et al 2010
RCT, high risk
own
GnRHa
hCG
106
106
4
45
0 (0/106)
8 (9/106)
0 (0/45)
15 (33)
Reference
Trial type
Babayof et al 2006
Humaidan et al 2009
Shapiro et al 2007
GnRHa
hCG
Agonist versus HCG for oocyte triggering
Youssef et al. Cochrane Review 2010
0.25mg/day antagonist
FSH
Day 5 start
FIXED
Freeze and thaw cycles
Luteal phase support
GnRH agonist
Triggering of final oocyte maturation with GnRH-a or
HCG:
Live birth after frozen-thawed embryo replacement cycles
30
25
20
hCG
GnRH-a
15
10
5
0
LBR/ET
Cum LBR
P = 0.02
Griesinger et al., Fertil Steril 2007
Frozen-thawed cycles
Manzanares et al, 2009
0.25mg/day antagonist
FSH
Day 5 start
FIXED
Luteal phase support:
1. Massive doses P +/- E2
2. 1500 IU hCG on day OPU
(Humaidan 2009)
GnRH agonist
GnRH agonist vs hCG in high risk IVF patients
RCT, n=66 with PCO’s
Antag + GnRH trigger
vs
Agonist + hCG trigger
OHSS – 0% vs 31%
Ongoing pregnancy rates – 53% vs 48%
Adequate E2 , P supplementation in luteal phase
Engmann et al, 2008
0.25mg/day antagonist
FSH
Day 5 start
FIXED
GnRH agonist
Luteal phase support:
1500 IU hCG on day OPU
(Humaidan 2009)
No significant difference in outcome compared with hCG trigger
GnRH agonist +
1500 U hCG on day OPU vs hCG
Variable
GnRHa
hCG
Patients, n
152
150
OR (95% CI) P Value
Clinical
)33( 50/152
pregnancy (%)
)37( 55/150
)0.9–0.7( 0.8 29.
Ongoing
)26( 40/152
pregnancy (%)
)33( 49/150
)0.8–0.6( 0.7 69.
Delivery rate
(%)
)31( 47/150
)0.8–0.6( 0.7 16.
)17( 11/66
)1.9–0.7( 1.3 36.
)24( 36/152
Early
pregnancy loss,
)21( 13/63
n (% of positive
hCG)
Humaidan et al, 2010
Beyond the context of OHSS: Patient-friendly luteal phase
• Abdominal pain and discomfort due to enlarged ovaries.
• How to minimize ovarian volume post oocyte retrieval?
Clinical use of agonist trigger
opinion
• Primarily in the context of OHSS
prevention.
• Prevention is total.
• A major reason to use GnRH antagonists
in ovarian stimulation of high-risk
patients: to keep the option of agonist
trigger if needed.
Metformin for IVF
• n=73 PCOS for IVF/ICSI
- metformin (2G/d)
- placebo
for 16 weeks
• No difference in any stimulation, IVF or
clinical criteria.
• BUT in group with BMI < 28, pregnancy
rates double on metformin.
Kjotrod et al, 2004
Metformin in IVF
Tang, Bart & Balen, 2005
• Single centre, double-blind RCT
• 94 patients, PCOS,
BMI 27.8
101 IVF/ICSI cycles, long agonist protocol
• Metformin (850mg bd)
or placebo from start of agonist to OPU
Metformin in IVF
• No difference:
Total dose FSH
No. of oocytes
Fertilisation rates
Tang, Barth & Balen, 2005
Metformin for IVF in PCOS
45
40
35
30
25
placebo
metformin
20
15
10
5
0
CPR/Cycle
CPR/Transfer
P = 0.02
Tang et al., Hum Reprod 2005
Metformin in IVF
• Short term co-treatment with metformin
for PCOS in IVF/ICSI :
• Does not improve response to stimulation
• Improves pregnancy rates
• Reduces the risk of OHSS
Tang, Bart & Balen, 2005
Endometrial dysfunction
• Low luteal phase serum glycodelin and
IGFBP-1 (Jacubowicz et al, 2001)
• Plasma endothelin-1 levels high in PCOS
(Diamantis-Kandarakis et al, 2005)
• Inadequate endometrial blood flow
et al, 2005)
All induced by hyperinsulinemia and
improved by metformin.
(Orio
IVM from unstimulated PCO
N=118 women, PCOS. 152 cycles
OPU day 9-14
ET – 140 cycles
Clinical pregnancy rate – 40% / transfer
56 livebirths and another 10 ongoing.
Zhao et al, F&S, 2008
Summary –High responders
IVF
•The GnRH antagonist protocol appears to be an
attractive option for PCOS patients undergoing IVF.
•Ovulation triggering with GnRH-a may be a better
option than cycle cancellation or prolonged coasting.
•The addition of metformin to the treatment protocol
may be beneficial for PCOS.
•Pretreatment with an OCP may be beneficial.