In high responders: Antagonist protocol,

triggering with agonist and

freezing all

Aboubakr Elnashar

Benha university Hospital

Elnashar53@hotmail.com

1. High responders

1.1 Definitions

1.2 Hazards

1.3 Management

2. Antagonist protocol

3. Triggering with agonist

4. Freezing all

1. High responders

1.1 Definition:

Prior to an IVF cycle

Young age (22 y), lean (BMI, 19 kg/m2), PCOS

History of:

High response during a previous COS

Cycle cancellation related to high response

Development of moderate or severe OHSS (Golan et al., 1989; Ragni et al, 2005; Griesinger et al, 2007; Imbar et al, 2012)

Basal investigations

Total AFC > 16

AMH>25.0 pmol/l

FSH<4 IU/l (NICE, 2013) -Follicles of 2–10 mm measured by transvaginal ultrasound on day 3 of cycle: high response

was ≥15 oocytes or ≥20 oocytes =3.50ng/ml

During IVF:

One of the following

Peak E2 > 3000-4000 pg/mL,

20 follicles at least 10 mm, in addition to the leading

follicles on the day of hCG

Retrieval of >15 oocytes (Golan et al., 1989; Ragni et al, 2005; Griesinger et al, 2007; Imbar et al, 2012)

For GnRH-antagonist-based stimulation:

18 follicles 11 mm on the day of hCG: 83% specificity

in predicting severe OHSS (Papanikolaou et al.,2006)

1.2 Hazards

Poor pregnancy outcome.

{Elevated E2 level may affect the endometrium at

implantation

high - or excessive- number of oocytes retrieved may

have a higher proportion of immatures}

OHSS.

{acute volume shift from the intravascular to the

extravascular space}: hemoconcentration, ascites,

pleural effusion, renal failure, venothromboembolic,

respiratory failure, and very rarely death

1.3 Reported strategies for the high-responders

Dual suppression with OCP and GnRHa

Minimal stimulation protocols

(CC/gonadotropins/antagonist)

In vitro maturation of human oocytes

GnRH antagonists instead of GnRH-agonists

GnRH-agonists as a substitute for hCG in

antagonist cycles

Coasting

Withholding hCG and cycle cancellation

Reducing the hCG dose

Cryopreservation of all embryos

2. Use of GnRH antagonists in stimulation

protocols

GnRH antagonist protocol is associated

with a lower pregnancy rate compared with GnRHa

long protocol

but with a significant reduction in severe OHSS (Al-Inany et al, Cochrane Database Syst Rev. 2006).

Difference in PR: did not remain significant when a

sub group analysis for ‘low response women’ was

performed. (NICE, 2013)

3. GnRH-agonist as a substitute for hCG in

antagonist cycles in high-responders to

prevent OHSS

Two different methods of ovulatory triggers:

1. Exogenous hCG:

long half life (30 H) with serum hCG detectable up

to 14 days after the injection.

:prolonged luteotrophic effect:

multiple corpora lutea and

supraphysiologic levels of VEGF

(McClure et al., 1994).

development of OHSS via the enhancement of

capillary leak (Lesterhuis et al., 2009).

2. GnRHa in antagonist cycles

: pituitary endogenous LH surge which is enough to

cause a trigger but does not last enough to result in

OHSS.

Itskovitz-Eldor et al., 2000

8 patients: an increased risk for OHSS

(>20 follicles 11 mm and/or E2 3000 pg/ml).

0.2 mg triptorelin (Decapeptyl) to trigger

ovulation

None of the patients developed OHSS.

Four clinical pregnancies have been achieved

from the embryos obtained during these cycles

A new treatment option

reducing

risk of developing OHSS in high responders

cycle cancellation.

Several studies

Confirmed (Gonen et al., 1990; Itskovitz et al., 1991; Itskovitz-Eldor et al., 2000; Kol

and Itskovitz-Eldor, 2000 Fauser et al., 2002; Orvieto et al., 2006; Bodri et al., 2009; Humaidan et al., 2011).

Recently

pregnancy outcome using GnRHa triggering for

final oocyte maturation is superior to that of coasting

in patients at high risk for OHSS (DiLuigi et al., 2010).

GnRHa triggering is a valid alternative to hCG,

resulting in the prevention of OHSS (Humaidan et al., 2011).

Other trials

Beneficial effect of the GnRHa triggering approach

that virtually eliminated OHSS in high-risk patients at

the cost of reduced pregnancy rates (Humaidan et al., 2005; Orvieto et al. 2006)

GnRHa triggering was associated with comparable

numbers of retrieved oocytes but lower ongoing

pregnancy rates, compared with hCG (Griesinger et al., 2006).

Recent Cochrane review

a significant reduction in the OHSS rate when using

the GnRHa to trigger ovulation, the live birth and

ongoing pregnancy rates were lower compared with

protocols using hCG as the ovulation trigger (Youssef et al., 2010).

The cause of lower pregnancy after GnRH-

agonist triggering and fresh embryo transfer

observed in previous RCTs

(Humaidan et al., 2005; Kolibianakis et al., 2005)

1. In general patient population is unknown

{Defective luteal phase} (Fauser et al., 2002; Nevo et al., 2003; Humaidan et al., 2005; Yding Andersen and Humaidan, 2005; Griesinger et al., 2007),

despite luteal phase support with vaginal

progesterone and oral estradiol (E2).

2. In patients at risk of OHSS

A disturbed luteal phase after agonist triggering

and fresh ET will also impair pregnancy, despite a

good prognosis in this patient group (young age,

good ovarian response).

late-onset OHSS in a GnRH-agonist-triggered

cycle as a result of hCG exposure from an

implanting embryo cannot be excluded (Chun, 2005).

Engmann et al., 2005

luteal phase support following GnRHa triggering

should consist of IM progesterone combined with

transdermal E2

An optimal protocol has not been established (Griesinger et al., 2006).

4. Freezing all of the embryos and

refraining from fresh embryo transfer

The unfavorable outcome of f-ET with this

approach had led clinicians to favor

cryopreservation of all the embryos and frozen–

thawed ET (ft-ET) in a future cycle (Griesinger et al., 2007a,b; Griesinger et al., 2011).

ET in an artificial cycle that is unaffected from

ovarian stimulation might be of benefit to patients,

who have a severely altered endocrine situation in

the follicular phase, e.g. excessive steroid

production

N %

Monitored cycles 193

Survival 175 90.67

Pregnant/Started cycles 85 44

Implantaion rate 18.18

Clinical preg./Started

cycles 69 35.8

Clinical preg./ET 69 39.6

Results of blastocyst vitrification and warming in Agial Hospital : from June 2012 till February 2013 (Hisham Saleh)

Kol and Muchtar (2005)

6 patients considered at OHSS risk were triggered

with 0.2 mg triptorelin s.c. and received luteal

phase support with daily 600 mg micronized

vaginal progesterone and 4 mg vaginal E2;

one patient conceived.

Babayof et al. (2006)

15 PCOS patients were agonist triggered and

received luteal phase support with daily 50 mg IM

progesterone and 4 mg oral E2;

one patient conceived.

Imbar et al, 2012

f-ET group (n=70).

intensive luteal phase supplementation

50 mg i.m. progesterone in oil and

6 mg of oral 17ß estradiol initiated on oocyte retrieval

day

ft-ET group (n=40)

embryos were cryopreserved and transferred in the

next cycle.

The live birth rate per f-ET was 27.1 Vs 20% in the

ft-ET group

The implantation, pregnancy and spontaneous

abortion rates were comparable in both groups.

None of the patients developed OHSS.

Acceptable clinical pregnancy and live

birth rates can be achieved by either ft-ET after

cryopreservation of all embryos, or f-ET after

GnRHa trigger, provided that adequate luteal

phase support is administered.

Confirmation of these findings by RCTs is now

required

Conclusion GnRH-agonist triggering of final oocyte maturation

with cryopreservation of all embryos offers patients

at increased risk of OHSS a good chance of

pregnancy while reducing the risk of OHSS.

Although recent study indicated preliminary

promising results on fresh ET with use of intensive

luteal phase support, further RCT are needed to

confirm

Thank you