OHSS
Should this be treated or be prevented?When to cancel a cycle? All cycles should be triggered with GnRH agonist and not by hCG!
Shahar Kol, IVF Unit Rambam Health Care Campus and Macabbi Health Services, Haifa, Israel
November, 2011
Content
• How do we routinely trigger ovulation?• Is it in agreement with physiology?• Do we have other options?• The physiology of agonist trigger.• Agonist trigger main advantage: OHSS-free
clinic. No need to cancel cycles, ever.• The advantage of agonist trigger for the
“normal responder”.
How do we routinely trigger ovulation?
• We have only one option: hCG.
Is it in agreement with physiology?
• Adequate final oocyte maturation.• Early luteal phase over-stimulation – main
reason for luteal phase defect in IVF.*• No FSH surge.
hCG
*Fauser and Devroey, 2003
Do we have other options?
JCEM 2001
15,000+10,000 IU gave 20% live birth rate but with a 12% OHSS rate.
The physiology of agonist trigger.
Humaidan et al, 2011
LH surge
The physiology of agonist trigger.FSH surge
Gonen et al, 1990
Does it make a difference? (1)
• Agonist trigger: more MII oocytes compared with hCG trigger.
Humaidan et al, 2005, 2009Imoedemhe et al, 1991Octay et al, 2009
Does it make a difference? (2)
F&S 2008
Is it possible that in some patients FSH surge is needed?
The pregnancy rate in completed cycles and the ongoing pregnancy rate per ET weresignificantly higher in the study group (dual trigger) than in the control group (hCG only).
Does it make a difference? (3)
Lamb et al, 2011
The effect of adding 450 IU of FSH to the hCG trigger.
What happens after agonist trigger?Complete luteolysis!
Induction of LH surge and oocyte maturation by GnRH analogue (Buserelin) in women undergoing ovarian stimulation for IVF
Itskovitz et al, Gynecological Endocrinology 1988, 2:Suppl1, 165.
“No signs of OHSS were observed in 2 patients who on previous stimulation developed severe OHSS… GnRHa offers a new means by which OHSS can be prevented.”
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
“agonist trigger provides a safe and OHSS-free clinical environment”
Agonist trigger main advantage: OHSS-free clinic. No need to cancel cycles, ever.
“The utilization of GnRH agonist for triggering ovulation in antagonist cycles hasbeen a breakthrough in the elimination of OHSS.”
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)
445
GnRHahCG
own RCT, high risk Shahrokh et al 2010
16 publications
Agonist: 2005 patients, not a single case of OHSS!
hCG: 92 cases in 1810 patients, 5.1%
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.
Hyper-responder: How to prevent OHSS + good clinical outcome?
• Trigger with agonist.• Intensive luteal support.
Dual suppression OCP’s & luprolideHCG trigger
OCP’s + Ganirelixluprolide trigger
OHSS high risk patients
Randomization
LUTEAL SUPPORT: E2 patches 0.1 mg X 3, qodP4 in oil, 50 mg/day; MONITOR E2+P4 LEVELS!
N=34N=32
Engmann, et al, 2008
Engmann et al, 2008
How high can we go?
FSH/hMG
antagonist
Agonist trigger
36h
OPU
1,500 IU hCG
4 days
1,500 IU hCG
ET
The advantage for the “normal responder”
Kol et al 2011
Engmann et al, 2011
”The granulosa/luteal cells obtained on the day of oocyte retrieval after agonist trigger have the capacity to respond to hCG by increasing the secretion of steroids.”
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
OHSS-related death rate: 3:100,000 Total OHSS elimination
Painful P injections or leaky, messy vaginal P.
Patient friendly luteal phase
Crystal ball: where are we heading?
Thank you
