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