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GnRH-a trigger and individualized luteal phase hCG support will avoid OHSS in PCOS patients. Shahar Kol , IVF Unit Rambam Health Care Campus, and Faculty of Medicine, Technion , Israel Institute of Technology, March, 2014. content. OHSS: is it still a problem? - PowerPoint PPT Presentation
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GNRH-A TRIGGER AND INDIVIDUALIZED LUTEAL PHASE HCG SUPPORT WILL AVOID OHSS IN PCOS PATIENTS.
Shahar Kol, IVF Unit Rambam Health Care Campus, and Faculty of Medicine, Technion, Israel Institute of Technology, March, 2014
CONTENT
• OHSS: is it still a problem?• No OHSS post agonist trigger!• Mechanism?• Failures?• The question of pregnancy rate.• Agonist trigger: back to physiology.• Agonist trigger is not the issue, luteal support is. • A revolution in the making.
OHSS: IS IT STILL A PROBLEM?
“We did not have a single case in years.”
SEVERE OHSS: IS IT STILL A PROBLEM?
“In 2003-2005, 4 deaths (of the 12) were due to OHSS”.
~3 OHSS-related deaths per 100,000 ART cycles.
Braat et al, 2010
Three OHSS-related deaths (3:100,000 ART cycles), all had their embryos frozen.
HOW TO PREVENT OHSS?
• Agonist trigger is the most effective approach.
PRE-ANTAGONIST ERA
ANTAGONIST ERA
Use of a single bolus of GnRH agonist triptorelin to trigger ovulation after GnRH antagonist ganirelix treatment in women undergoing ovarian stimulation for assisted reproduction, with special reference to the prevention of ovarian hyperstimulation syndrome: preliminary report: Short communication .
Itskovitz-Eldor et al. 2000
OHSS % (n) n Ovulation trigger
Oocyte source
Trial type Reference
0 (0/13)31(4/13)
1513
GnRHahCG
own RCT, high risk Babayof et al 2006
0 (0/33)31 (10/32)
3332
GnRHahCG
own RCT, high risk Engamnn et al 2008
0 (0/30)17 (5/30)
3030
GnRHahCG
donors RCT Acevedo et al 2006
0 (0/1046)1.3 (13/1031)
10461031
GnRHahCG
donors Retrospective Bodri et al 2009
0 (0/40) 40 GnRHa own Observational,High risk
Griesinger et al 2010
0 (0/152)2 (3/150)
152150
GnRHahCG
own RCT Humaidan et al 2009
0 (0/23)4 (1/23)
2323
GnRHahCG
own Retrospective, case-controlled, high risk
Engmann et al 2006
0 (0/42) 42 GnRHahCG - cancelled
own Retrospective case-control, high risk
Manzanares et al 2009
0 (0/254)6 (10/175)
254175
GnRHahCG
donors Retrospective Hernandez et al 2009
0 (0/82)7 (5/69)
8269
GnRHahCG
own Retrospective, high risk
Orvieto et al 2006
0 (0/32)1 (1/42)
3242
GnRHahCG
donors Retrospective, high risk: agonist arm only
Shapiro et al 2007
0 (0/44)7 (3/44)
4444
GnRHahCG
donors RCT Sismanoglu et al 2009
8 (1/12) 12 GnRH, luteal rescue with hCG 1500IU
own Observational, high risk
Humaidan et al 2009
0 (0/106)8 (9/106)
106106
GnRHahCG
donors RCT Galindo et al 2009
0 (0/50)16(8/50)
5050
GnRHahCG
donors RCT Melo at al 2009
0 (0/45)15 (33)
4545
GnRHahCG
own RCT, high risk Shahrokh et al 2010
16 publications
Agonist: 2,005 patients, not a single case of OHSS!
hCG: 92 cases in 1,810 patients, 5.1%
WHAT REALLY WORKS:
Youssef MA, et al. Human Reprod Update 2010;16:459–466
● GnRH agonist versus hCG for oocyte triggering in GnRH antagonist ART cycles
Total events 0 (GnRH)21 (hCG)
Lower levels of inhibin A and pro-alpha C during the luteal phase after triggering oocyte maturation with GnRH agonist versus hCG
Nevo et al. 2003
Mechanism of OHSS prevention?
Luteal phase
Nevo et al, 2003
Natural cycle day 7-9=75 pg/ml vs. 18
Natural cycle day 7-9=
750 pg/ml vs. 184
A safe and OHSS-free clinical environment
PREGNANCY RATE POST AGONIST TRIGGER
• We showed that agonist trigger causes quick and irreversible luteolysis.
• Therefore, the right luteal support is crucial.• The evolution of post agonist luteal support.
LUTEAL PHASE – NON-SUPPLEMENTED
• Beckers et al (2003) – very low pregnancy rate.
LUTEAL PHASE – CONVENTIONAL SUPPORT
Not good enough!
LUTEAL PHASE – MODIFIED SUPPORT
Study or SubgroupBabayof, 2006Humaidan, 2006Pirard, 2006Engmann, 2008Humaidan, 2010Papanikolaou, 2011
Total (95% CI)Total eventsHeterogeneity: Chi² = 1.35, df = 5 (P = 0.93); I² = 0%Test for overall effect: Z = 1.40 (P = 0.16)
Events152
16364
64
Total15131233
15218
243
Events281
14474
76
Total13156
3215017
233
Weight5.9%5.9%3.4%
13.7%63.8%7.4%
100.0%
M-H, Fixed, 95% CI-0.09 [-0.32, 0.15]-0.15 [-0.51, 0.22]0.00 [-0.37, 0.37]0.05 [-0.19, 0.29]-0.08 [-0.18, 0.02]-0.01 [-0.29, 0.27]
-0.06 [-0.14, 0.02]
Agonist triggering HCG triggering Risk Difference Risk DifferenceM-H, Fixed, 95% CI
-1 -0.5 0 0.5 1Favours HCG trig Favours Agonist trig
We are getting there!
Engmann et al, 2008
LUTEAL PHASE: INTENSIVE E+POHSS high-risk patients
ALL FREEZE ADVANTAGES
• No OHSS• Better endometrium in thaw cycles.• Less ectopic pregnancies in thaw cycles.• Comparable, or even better, clinical outcome in
thaw cycles.• Better obstetric outcome?• Fresh transfer post agonist trigger requires daily
IM injections of progesterone in oil.
“… 42% of those who received hCG reported subjective complaints (mostly abdominal discomfort), whereas this percentage was 0% in those who received GnRH agonist to trigger ovulation.
Cerrillo et al, 2009
…AND WHEN OHSS IS NOT THE MAIN ISSUE?...
HCG DOES NOT IMITATE PHYSIOLOGY!
LH surge goes together with FSH surge. Is FSH surge redundant?
Gonen et al 1990
DUAL ROLE OF HCG TRIGGER
• Final oocyte maturation.• Early luteal phase stimulation.• Same dose for both functions?
hCG
NON OHSS-HIGH-RISK PATIENTS: 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;11:679–6842. Humaidan P, et al. Human Reprod 2009;24:2389–23943. Imoedemhe DA, et al. Fertil Steril 1991;55:328–3324. Oktay K, et al. Reprod Biomed Online 2010;20:783–788 5. Eppig JJ. Nature 1979;281:483–4846. Strickland and Beers. J Biol Chem 1976;251:5694–57027. Yding Andersen C. Reprod Biomed Online 2002;5:232–2398. Yding Andersen C, et al. Mol Hum Reprod 1999;5:726–7319. Zelinski-Wooten MB, et al. Human Reprod 1995;10:1658–1666
WHAT DO PRACTITIONERS SAY?
Among the five most downloaded papers
SURVEY RESULTS:Triggering of ovulation with GnRH-a in ART:
Worldwide feedback on an emerging new option with great potential
TAKE HOME MESSAGE
“The results of this survey indicate that GnRH trigger is widely used worldwide and therefore has become part of the standard of care today. Hence, doctors are entitled to prescribe it just as patients may ask that this option is considered in their case.”
“Agonist triggering is viewed as one of the major advances in ovarian stimulation, with the potential to eliminate OHSS…”
Out In“long agonist” protocols Antagonist-based protocols
hCG trigger Agonist trigger
Progesterone-based luteal support LH activity-based luteal support
~1% severe OHSS Total OHSS elimination
Painful P injections or leaky, messy vaginal P.
Patient friendly luteal phase
Revolution in the making
Thank you