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In high responders: Antagonist protocol,
triggering with agonist and
freezing all
Aboubakr Elnashar
Benha university Hospital
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