what is new in controlled ovarian stimulation?
TRANSCRIPT
What is new in COS?
Prof. Aboubakr Elnashar
Benha university Hospital, EgyptABOUBAKR ELNASHAR
I. NEW FORMS OF DRUGS
1.Long acting FSH
2.FSH Biosimilars
3.SC ProgestagenII. NEW PROTOCOLS
1.Minimal number of injections
2.No routine antagonist
3.Progestagen to block LH surge
4.Flexibility in starting COS
5.Double ovarian stimulation
6.Double triggering
7. Individualization of starting FSH
dose for prevention of OHSS
Reviewing literature
ABOUBAKR ELNASHAR
I. NEW FORMS OF DRUGS1. Long acting FSH- corifollitropin alfa (Elonva)
Rec DNA technology
Single dose:
keep FSH level above the threshold necessary to
support multi-follicular growth for 7 days.
Reduce the injection frequency:
more patient friendly.
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Dose:
150 to 180 μg:
Safe
equally effective compared to daily recFSH
60 to 120 μg
reduced LBR compared to daily FSH.(Pouwer et al, 2015 Cochrane SR)
Pregnancy
similar to daily recFSH
Risk of OHSS
Slightly higher compared with daily rec FSH.(Loutradis et al, 2010)
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2. FSH BiosimilarsFollow-on biologics=Subsequent entry biologics
Officially approved versions of original “innovator”
products
Manufactured when original product’s patent expires.
Cheaper
Biologically and clinically “non inferior” to the originator
product.
2 FSH biosimilars approvedOvaleap for Gonal F
Gonapure
حق الملكيهABOUBAKR ELNASHAR
3. SC Progestagen(Prolutex)
Suitable:
Prefer not to use a vaginal preparation
Avoid the side effects of vaginal or IM
Dose:
25 mg daily
SC Progestagen Vs. either
vaginal gel 90mg/d or
vaginal caps 100mg twice a day
No statistical significant differences(Doblinger et al, MA 2016)
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II. NEW PROTOCOLS1. Minimal number of injections protocol
Based on:
Depot GnRHa
Long acting FSH(Haydardedeoğlu , Kılıçdağ .2016)
Study:
45 pt:
long protocol: half-dose of depot GnRHa on D21 of
the preceding cycle and long acting FSH
49 pt:
GnRHan protocol: long acting FSH.
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Results:
1. Number of retrieved oocytes, fertilization rate,
number of transferred embryos:
similar .
2. CPR and IR:
similar
3. Number of injections depot-agonist injection:
significantly less
ART cycles
could be performed with fewer injections using
Long acting FSH and
half-dose of depot GnRHa.
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2. No routine antagonist protocolIoannis, 2016
Antagonist /other day Vs. daily
No differenceABOUBAKR ELNASHAR
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3. Progestagen to block the LH surgeKuang, 2014
Study group:
hMG and MPA (10 mg/d) were administered
simultaneously beginning on D3.
Triggering: GnRHa or GnRHa and hCG
Control group:
short protocol.
Viable embryos were cryopreserved for later transfer
in both protocols.
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In study group Vs Control group:
Number of oocytes retrieved: similar
Higher doses of hMGhMG duration (d): 8.4 ±2.2 vs. 9.3 ± 1.9 .00
hMG dose (IU): 1,636.7 ± 659.6 vs. 2,014.0 ± 451.7
LH suppression persisted during ovarian stimulation
CPR, IR,LBR: No statistically significant differences
MPA
An effective oral alternative for the prevention of
premature LH surge in woman undergoing COS.
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Zhu et al, 2015
Utrogestan (10 mg twice a day)
Utrogestan is an effective oral alternative for
preventing premature LH surges in women
undergoing COS
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Progestagen to block LH surge during COS in PCOS
MPA (10 mg/d) or uterogestan 10 mg twice daily with
HMG simultaneously from D3. (Wang et al, 2016; Zhu,2016)
Trigger
Freez all
The fertilization rate, CPR, and IR:
significantly higher
The incidence of OHSS:
Lower
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Massin 2017: literature review
The use of progesterone during ovarian stimulation
Effective in blocking the LH surge
Use in
General population of patients in IVF programs
Fertility preservation not related to oncology.
Its main constraint
it requires total freezing and delayed transfer.
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4. Flexibility in starting ovarian
stimulation at different phases of the menstrual
cycle
Traditional theory:
Single cohort of antral follicles grows only at the
beginning of the follicular phase,
Recently:
It has been demonstrated (through daily ultrasound
monitoring) that there are 2 or 3 waves of follicular
growth. (Baerwald et al. 2003)
Antral follicles in the luteal phase had similar
development potential
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1. Emergency fertility preservation(Bedoschi et al., 2010; Sonmezer et al., 2011).
Pregnancy outcomes in subsequent cryopreserved
embryo transfers is comparable(Kuang et al., 2013).
Random start or emergency IVF: fertility
preservation before chemotherapy
Rapid protocol for COS(Robertson et al, 2016)
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2. Luteal-phase ovarian stimulation vs.
conventional ovarian stimulation in
Normal ovarian reserve:
(Wang et al, 2016)
: Higher
IR
CPR
OPR and LBR compared with the short-term
protocol.
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3. Qin et al, 2016
Ovarian stimulation started in
Early follicular phase
Late follicular phase
Luteal phase.
Oocyte triggered: GnRHa and hCG.
Viable embryos were cryopreserved for subsequent
transfer.
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No differences in the 3 groups
number of mature oocytes retrieved
viable embryo rate per oocyte retrieved
CPR
IR
All three ovarian stimulation protocols were equally
effective.
Ovarian stimulation can be started on any day of the
menstrual cycle.
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5. Double (Dual, Duplex) ovarian stimulation
Poor responders
1. Shanghai protocol:
2 subsequent COS courses in the follicular and
luteal phase:
Retrieving more oocytes in COS2{COS1 exerts a priming effect that increases the ovarian
response to COS2}
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2. de Ziegler protocol(de Ziegler, 2015)
2 Antagonist protocols (with an FSH dose 300IU/d).
COS1
started on the 6th day post OCs.
COS2
started right after OR1.
Triggering: GnRHa in both COS1&2.
Similar number of oocytes and blastocysts in COS1
&2
Twice as many oocytes and blastocysts in a 4-week
time frame.
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6. Double trigger(Kasum et al, 2016)
What:
GnRHa together with
(reduced or standard dosage of) hCG
GnRHa and hCG:
40 and 34 h prior to OR respectively.
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Indications:
1. Treatment of empty follicle syndrome
2. Poor responder
statistically significant increase in
number of retrieved oocytes
mature oocytes
fertilized embryos
PR
IR
newborn/transferred embryo rate.(Oliveira et al, 2016)
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3. High responders
GnRHa with a reduced dose of hCG:
improved PR
4. Normal responders
GnRHa and a standard hCG:
significantly improved LBR
higher number of embryos of excellent quality
7. Individualization of starting FSH dose for
prevention of OHSS(Fischer et al, 2016)
1. PCOS
2. Age
3. AMH
4. BMI
5. History of previous OHSS
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CONCLUSIONS
Long acting FSH:
similar CPR
slightly higher OHSS compared with daily
rec FSH.
FSH Biosimilars
Cheaper
Biologically and clinically “non inferior” to the
originator product.
SC Progestagen
avoids the side effects of vaginal or IM
ABOUBAKR ELNASHAR
Further RCT are needed to confirm value
Minimal number of injections protocol
No routine antagonist
Progestagen to block the LH surge:
effective oral alternative
requires total freezing and delayed transfer
These protocols are valuable
Flexibility in starting ovarian stimulation
Double ovarian stimulation
Double triggering
Individualization of starting FSH dose for
prevention of OHSS
ABOUBAKR ELNASHAR
ABOUBAKR ELNASHAR
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