1. The approach to the PCOS patient undergoing IVF
Roy Homburg
Barzili Medical Centre, Ashkelon, Israel
and Homerton University Hospital, London
Antalya, October 2011

2. Problems – IVF for PCOS Excessive ovarian response
Low fertilization rates
High number of immature oocytes
Reduced cleavage rates
Low implantation rates
High miscarriage rates

3. 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

4. Comparison of the long protocol and the antagonist protocols
more
physiologic
no cyst
formation
no hormonal
withdrawal
antagonist administration
gonadotropin administration
multiple dose protocol
Patient-friendly
less gona-
dotropins
early
pregnancy?
Menses
Advantages of the antagonist protocol:
- no cyst formation (since there is no flare up effect)
- no hormonal withdrawal symptoms (since pituitary suppression is achieved after ovarian stimulation has been started and not before)
- the antagonist cannot be given in early pregnancy, since this can be excluded by a pregnancy test
- less gonadotropins necessary
- shorter treatment duration
- more physiologic, since it can be integrated in the spontaneous menstrual cycle
flare up
effect
pituitary
suppression
agonist administration
gonadotropin administration
long protocol
(mid-luteal)
longer
treatment
pre-treatment cycle
treatment cycle

5. O H S S
4.1%
2.6%

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

7. 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

8. 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.

9. F&S 2008
18.1% vs 23.6%

10. Starting with Gn on day 2/3 after the last OC intake
- OC pretreated
Starting with Gn on day 2/3 after the last OC intake
Fixed GnRH antagonist regimen (long-starting SD 1)
Huirne et al, 2007

11. Incidence of OHSS
Objective: to determine OHSS incidence in 2,524 antagonist-based 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 medication”
F&S January 2006

12. Day 5 , 6 or 7 antagonist start FIXED
0.25mg/day antagonist
FSH
Day 5 , 6 or 7 antagonist start FIXED
hcg
0.25mg/day antagonist
FSH
day 8/9
hcg
Follicle size 14mm- start antagonist
Flexible regime
FSH
hcg

13. Flexible regime GnRH agonist GnRH agonist hcg
0.25mg/day antagonist
FSH
Day 5 , 6 or 7 antagonist start FIXED
GnRH agonist
0.25mg/day antagonist
FSH
GnRH agonist
day 8/9
Follicle size 14mm- start antagonist
Flexible regime
FSH
hcg

14. Agonist: 1932 patients, not a single case of OHSS!
hCG: 84 cases in 1760 patients, 4.8%
OHSS % (n) n
Ovulation
trigger
Oocyte source
Trial type
Reference
0 (0/13)
31(4/13) 15 13
GnRHa
hCG
own
RCT, high risk
Babayof et al 2006
0 (0/33)
31 (10/32) 33 32
Engamnn et al 2008
0 (0/30)
17 (5/30) 30
donors
RCT
Acevedo et al 2006
0 (0/1046)
1.3 (13/1031)
1046
1031
Retrospective
Bodri et al 2009
0 (0/20) 20
Observational,
High risk
Griesinger et al 2007
0 (0/152)
2 (3/150)
152
150
Humaidan et al 2009
0 (0/23)
4 (1/23) 23
Retrospective, case-controlled, high risk
Engmann et al 2006
0 (0/42) 42
hCG - cancelled
Retrospective case-control, high risk
Manzanares et al 2009
0 (0/254)
6 (10/175)
254
175
Hernandez et al 2009
0 (0/82)
7 (5/69) 82 69
Retrospective, high risk
Orvieto et al 2006
0 (0/32)
1 (1/42)
Retrospective, high risk: agonist arm only
Shapiro et al 2007
0 (0/44)
7 (3/44) 44
Sismanoglu et al 2009
8 (1/12) 12
GnRH, luteal rescue with hCG 1500IU
Observational, high risk
0 (0/106)
8 (9/106)
106
Galindo et al 2009
0 (0/45)
15 (33) 4 45
Shahrokh et al 2010

15. Agonist versus HCG for oocyte triggering
Youssef et al. Cochrane Review 2010

16. Freeze and thaw cycles Luteal phase support 0.25mg/day antagonist
FSH
Day 5 start FIXED
GnRH agonist
Freeze and thaw cycles
Luteal phase support
FSH
hcg

17. Triggering of final oocyte maturation with GnRH-a or HCG:
Live birth after frozen-thawed embryo replacement cycles
P = 0.02
Griesinger et al., Fertil Steril 2007

18. Frozen-thawed cycles
Manzanares et al, 2009

19. Luteal phase support: 1. Massive doses P +/- E2
0.25mg/day antagonist
FSH
Day 5 start FIXED
GnRH agonist
Luteal phase support:
1. Massive doses P +/- E2
IU hCG on day OPU (Humaidan 2009)
FSH
hcg

20. 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

21. Luteal phase support: 1500 IU hCG on day OPU (Humaidan 2009)
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
FSH
hcg

22. Humaidan et al, 2010 GnRH agonist + 1500 U hCG on day OPU vs hCG
Table 3. Pregnancy outcome in GnRHa vs. hCG-group.
GnRH
agonist +
1500 U hCG
on day OPU
vs hCG
Variable
GnRHa
hCG
OR (95% CI)
P Value
Patients, n
152
150
Clinical pregnancy (%)
50/152 (33)
55/150 (37)
0.8 (0.7–0.9)
.29
Ongoing pregnancy (%)
40/152 (26)
49/150 (33)
0.7 (0.6–0.8)
.69
Delivery rate (%)
36/152 (24)
47/150 (31)
.16
Early pregnancy loss, n (% of positive hCG)
13/63 (21)
11/66 (17)
1.3 (0.7–1.9)
.36
Humaidan et al, 2010

23. 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?

24. 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.

25. Metformin for IVF - metformin (2G/d) - placebo for 16 weeks
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

26. Metformin in IVF Single centre, double-blind RCT
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

27. Metformin in IVF No difference: Total dose FSH No. of oocytes
Fertilisation rates
Tang, Barth & Balen, 2005

28. Metformin for IVF in PCOS
Tang et al., Hum Reprod 2005

29. 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

30. 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 (Orio et al, 2005)
All induced by hyperinsulinemia and improved by metformin.

31. 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

32. 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.