what is new in controlled ovarian stimulation?

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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ABOUBAKR ELNASHAR

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

ABOUBAKR ELNASHAR

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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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