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Benha University Hospital, Egypt Aboubakr Elnashar
Benha University Hospital, Egypt Aboubakr Elnashar

Benha University Hospital, Egypt

Aboubakr Elnashar

Benha University Hospital, Egypt Aboubakr Elnashar

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CONTENTS

TYPES OF OVARIAN STIMULATION FOR IVF

DRUGS

GNRHa PROTOCOLS

GNRHan PROTOCOLS

TRIGGERING OF OVULATION

CYCLE CANCELLATION

INDIVIDUALIZATION OF COS

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GNRHa PROTOCOLS GNRHan PROTOCOLS TRIGGERING OF OVULATION CYCLE CANCELLATION INDIVIDUALIZATION OF COS Aboubakr Elnashar

1. TYPES OFOVARIAN STIMULATION FOR IVF

Recommended

Previous

Aim

Methods

terminology

terminology

1.

Natural cycle

Unstimulated,

Single

No medication

 

spontaneous

oocyte

cycle

2. Modified natural cycle

Semi-natural, controlled natural cycle IVF

Single

hCG only GnRHan and FSH/HMG add-back

oocyte

3.

Mild

Soft, minimal stimulation, ‘friendly’ IVF

2-7

Low dose FSH/HMG, oral compounds and GnRHan

 

oocytes

4. Conventional

Standard, routine,

> 8

GnRHa or antagonist

COS

oocytes

conventional FSH/HMG dose

International Society for Mild Approaches in Assisted Reproduction

(ISMAAR), 2007

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Protocols of ovarian stimulation in IVF

 

GnRHa

 

GnRHan

No GnRH

   

analogue

long

Short

Ultra

Standard

Mild

Modified

Mini

Natural

short

natural

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2. DRUGS

Gonadtrophins

GnRha

GnRhan

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I. Types of Gnt

I. Urinary Gonadotropins

Preparation

1. HMG

2. H.P.HMG

3. Purified

FSH

4. H.P.FSH

5.

HCG

6.

H.P.HCG

Trade name

Route

U.pr

FSH

LH

Company

PriceEP

Pergonal,

IM

95%

75

75

Serono

 

Humegon,

Organon

Menogon

Ferring

Ibsa

66

Merional

Menopur

SC

<5%

   

Ferring

118

Gonapur

SC

<5%

M pharm

85

Metrodine

IM

<5%

75

<0.1

Serono

 

Urofillotropin

Fostimon

SC,

<5%

75

<0.001

Ibsa

55

Metrodine HP Bravelle

IM

Urofillotropin

Serono

Ferring

70

Pregnyl

IM

95%

   

Organon

 

Profasi

Serono

Choriomon

SC,IM

<5%

   

Ibsa

33

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II. Recombinant Gonadotropins

Preparation

Trade name

Route

Upr

FSH

LH

Price

Company

1.

FSH

Puregon

SC, IM

-

50

-

 

Organon

 

(follitropin),

-

100

-

180

Serono

Gonal F (follitropin)

75

150

2. HCG

Ovitrelle

SC

-

     

Serono

Choriogonadotropin

3. LH

Luveris

SC

-

     

Serono

lutotropin

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Types of GnRHa

Preparation

Name

Route

Dose

company

PriceEP

Leuprorelin

Lupron

IM, SC

3.75 mg/4w

Abbot

750

Lucrin

IM, SC

11.25 mg/12 w

1550

2.8 ml, 1 ml daily

540

Goserelin

Zoladex

SC

3.6

mg

Astrazenica

500

Triptolerin

Decapeptyl

IM, SC

CR: 3.75mg,

Ferring

605

0.1mg then 0.05 mg

266(7syr)

Buserelin

superfact

Nasal, SC

0.5 mg then 0.2 mg

Sanofi

Nafarelin

Synarel

nasal

0.2

mg bid

Pfaizer

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Types of GnRhan

Generic

Trade

Route

Company

 

Price

Cetrorelix

Cetrotide

SC

Serono

0.25

mg

250

3 mg

Ganirelix

Ganirelix

SC

MSD

0.25

mg

 

Orgalutran

MSD

 

192

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3. GNRHa PROTOCOLS

GnRHa

Produced by

Modification of the native GnRH decapeptide at 6 &

10 positions

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Effects of GnRha

Flare effect: Within 12 h and lasting 24-48 h

: 5 fold increase of FSH

10 fold rise in LH &

4 fold elevation in E2.

Continuous administration

: opposite effects:

internalization of the agonist /receptor complex & decrease in

the number of receptors

(down-regulation).

: paradoxical suppression of the pituitary Gnt synthesis &

liberation

(desensitization).

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The decreased levels of FSH & LH:

1. Arrest of follicular development 2. Decrease in sex steroid levels to castrate levels. The pituitary blockade persist during agonist tt but it is reversible after therapy.

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(a)action of native GnRH on a gonadotroph; binding of GnRH to the receptor results in FSH and LH secretion. FSH and LH, in turn, stimulate the gonads to produce steroid hormones.

(b) Binding of a GnRH agonist to the

gonadotroph receptor produces an initial

stimulation of FSH and LH, but subsequently

suppression of gonadotropins occurs, with the

resulting suppression of gonadal steroid

production.

(c) Binding of a GnRH antagonist to the

gonadotroph receptor stimulates an immediate downregulation and desensitization, with resulting suppression of gonadotropin secretion and gonadal steroid

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Protocols

Ultra-short (sequential):

Based on initial stimulatory effect of GnRHa on Gnt secretion [flare- up effect] lasts for 1-2 days promotes simultaneous maturation of several follicles. GnRHa: from the 1 st to 3 rd day of the cycle. Gnt: from the 3 rd day of the cycle Aboubakr Elnashar

No evidence of a difference in the outcome of LBR

in a comparison of GnRHa long, short or ultrashort protocols.

PR was significantly higher in Long vs short protocols

(Maheshwari A et al 2011. Cochrane , 2011)

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Short (Flare):

GnRHa: from the 1 st day of the cycle until the day of ovulation induction.

Gnt: from the 3 rd day of the cycle.

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Short GnRHa protocol

TVS

E

2

TVS > 18 ml

E

2

FSH 75-300 IU 34 h. Leuteal support
FSH 75-300 IU
34 h.
Leuteal support

GnRHa 0.1mg/day

ml E 2 FSH 75-300 IU 34 h. Leuteal support GnRHa 0.1mg/day 3 r d day

3 rd day

ycle

ay 1

75-

300/day

IU /FSH

0.1mg/day 3 r d day ycle ay 1 75- 300/day IU /FSH OPU Ovulation 5.000-10.000 IU
0.1mg/day 3 r d day ycle ay 1 75- 300/day IU /FSH OPU Ovulation 5.000-10.000 IU

OPU

Ovulation

5.000-10.000 IU

hCG

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Long:

GnRHa:

From:

1 st day (follicular) or middle of the luteal phase (D19-21)

{1. inhibition of the pituitary function can be achieved earlier. 2. Higher fertilization & PR than therapy started on the 1 st day of the cycle}.

until a sufficient inhibition of Gnt release (10-14

days)

Gnt while GnRHa therapy is maintained.

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Follicular phase

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Long GnRHa Protocol (luteal phase)

TVS

E

2

< 50 pg/ml

Long GnRHa Protocol (luteal phase) TVS E 2 < 50 pg/ml TVS TVS > 18 ml

TVS

TVS >18 ml

E 2 E 2
E 2
E 2
75-300 IU / FSH/day
75-300 IU / FSH/day

Luteal support

34 h.

GnRHa 0.1mg/day

E 2 75-300 IU / FSH/day Luteal support 34 h. GnRHa 0.1mg/day OPU 2 weeks 20
E 2 75-300 IU / FSH/day Luteal support 34 h. GnRHa 0.1mg/day OPU 2 weeks 20
E 2 75-300 IU / FSH/day Luteal support 34 h. GnRHa 0.1mg/day OPU 2 weeks 20
E 2 75-300 IU / FSH/day Luteal support 34 h. GnRHa 0.1mg/day OPU 2 weeks 20

OPU

2 weeks

20 th day previous

cycle

hCG

5-10000 IU

FSH

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-Criteria of suppression:

Hormonal: E2 <50 pg/ml

Progesterone < 1 ng/m

LH <5 IU

US: No ovarian cysts

Endometrial thickness <6 mm

predicts down regulation in 95% of cases

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Advantages:

long protocol Vs Short & ultrashort

(Cochrane review, 2000)

superior in terms of

1.

follicular development &

2.

fertilization rate

3.

number of embryos suitable for transfer

4.

PR

5.

more units of GN were needed

Midluteal is the optimal Gnt suppression & oocytes

(Roman et al 1992,Huirne et al,2004)

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rFSH Vs other GN (HMG, hp-FSH, p-FSH), no

,

evidence of difference in LBR or OHSS

42 trials, 9606 couples

Further research on these comparisons is unlikely

to identify substantive differences in effectiveness or

safety

(Cochrane Database Syst Rev. 2011, Wely et al)

Use either u or rec Gnt for ovarian stimulation

(NICE, 2013)

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Depot Vs daily

No differences PR.

Depot:

longer duration higher doses of Gnt

more luteal support depot

(Cochrane review 2002)

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4. GNRHan PROTOCOLS

GnRHan

Produced by

Modification at 6, 10, & 1, 2, 3, 8 positions

Effects

Inhibition of LH & FSH immediately without the initial

flare up effect of the Gnta.

Mechanism of action

Competitive receptor blockade.

The suppression of LH is dose related.

Larger doses of antagonist is associated with marked

reduction of pregnancy rate in IVF cycles

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Protocols

1. Small daily dose (LubecK):

HMG or FSH:

From day 2 or 3 of the cycle &

Cetrorelix or Ganirelix: 0.25 mg daily SC: from

stimulation day 5 or 6 (fixed protocol) or

leading follicle14 mm (Flexible protocol) onwards until

the day of HCG (Diedrich et al,1994).

Advantages:

1.

Prevents premature LH surge

2.

effective in terms of CPR/cycle & /ET (22% &

27%).

3.

safe in terms of a low incidence of patients

hospitalized due to OHSS. Aboubakr Elnashar

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2. Single dose(French):

HMG or FSH:

from day 2 or 3 of the cycle

Cetrorelix:

single dose, 3 mg SC, on stimulation day 7

(Olivennes et al,1998).

HCG is given when the follicles are mature by U/S &/or E2.

GnRha single dose can be given instead of HCG to

reduce incidence of OHSS {shorter half life of the agonist compared to HCG}.

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Single Vs multiple (Olivennes et al,2003)

Similar efficacy & safety

Recommendations of GnRHan Consensus

Workshop Group)

No increase starting dose of Gnt

Fixed antagonist appears superior to flexible.

Optimal timing for HCG administration

Agonist for triggering Luteal phase supplementation is required

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Agonists Vs Antagonists

LBR after COS for IVF does not depend on the type of analogue used for pituitary suppression

(SR: Kolibianakis et al,2006)

Antagonist protocol:

short, simple with significant decrease in severe OHSS & amount of GN. CPR, OPR/LBR were lower in antagonist group

(Cochrane Database Systematic Review Al-Inany et al., 2006)

No evidence of a difference in LBR

(Cochrane Database Syst Rev. 2011, Al-Inany et al, 2011)

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5. TRIGGERING OF OVULATION

1. HCG

Rational:

The structure & action of HCG are very similar to

those of LH. HCG induces final follicular maturation.

Ovulation follow:

IM injection of HCG at 37 h.

Accordingly follicular puncture is performed earlier i.e.

32-34 h or 35 h after hCG administration.

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Usual dose:

10,000 IU administered 34-36 h before the scheduled time of oocyte retrieval.

When:

. At least 3 follicles >18 mm

.

E2: 150 pg/ml per >15mm follicles.

.

Endometrium: Thickness >8mm, Triple line

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Risk: OHSS

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).

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Do not trigger ovulation with the intention of fresh

ET in women who have:

E2>3500 pm/l or >20 follicles on US

(NICE, 2013)

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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 A new treatment option reducing risk of developing OHSS in high responders cycle cancellation. Aboubakr Elnashar

6. CYCLE CANCELLATION

Define:

discontinuation of ovarian stimulation prematurely

without oocyte retrival.

Incidence

12% of all IVF cycles are cancelled before egg

collection.

Womens age

Cancellation rate

Less than 35

7.7-10%

35-37

11.6-14.7%

38-40

14.6-19.5%

The main reasons 1.No or poor egg production (83%)

2.Patient’s personal reasons (10%) 3.Excessive response to ovarian stimulation and risk of developing OHSS (5%)

4.Medical illness (1%).

(SART 2005 and HFEA 2006 Reports).

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Indications

1. Follicular growth is delayed:

ovarian stimulation over 10 days:

< 3 follicles > 16 mm & E2 < 600 pg/ml.

2. Basal LH is elevated:

LH > 10 IU/l or a premature LH surge occurs

3. Elevated serum P4:

>1.5 ng/ml is detected prior to ovulation induction.

4.OHSS is suspected:

each ovary contains > 10 follicles < 16 mm &

E2 > 3500 pg/ml

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7. INDIVIDUALIZATION OF COS

What?

I.

Selection of protocol

II.

Selection of Gnt starting dose.

cCOS

Repeated cycle

Outcome of previous cycles: If good: same protocol.

1 st cycle:

a. Empirical:

based on either the clinician’s or a centre’s

preference. b. Clinical criteria:

Age, BMI, PCOS

(Homburg and Insler, 2002; Arslan et al., 2005).

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FSH starting dose (IU/day)

(Tronson & Gardner, 2000)

1st cycle

<37 yr old: 150= 2 amp

& PCOS: 112.5= 1.5 amp

37-39 yr: 225= 3 amp

>40 yr: 300= 4 amp

Previous

Normal response(>4 follicles):

same

OHSS: 75= 1 amp

Poor response: 450= 6 amp Adjust dose

BMI>30 Kg/m (PCO excluded): as cycle monitoring proceeds

increase by 75= 1 amp

Severe endometriosis:

increase by 75= 1 amp

with U/S & E2.

Do not use a dose of

FSH>450 IU/d

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I. Individualization of stimulation protocol Correct prediction of ovarian response

(especially extremes: poor and hyper response).

By most sensitive markers of ovarian reserve.

Ovarian reserve testing before the first IVF cycle categorize patients (NICE, 2013)

Total AFC

AMH

ng/ml

FSH IU/L

Low

response

4 or less

0.8 or less

8.9 or more

High response

16 or more

3.5 or more

4 or less

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A. Expectant low responder: Antagonist protocol 1. No evidence of superiority of one approach

over another (Pu et al., 2011; Sunkara et al., 2013).

2. Antagonist is associated with

Reduced discomfort and treatment burden

(Nelson et al. ,2009)

Fewer days of Gnt stimulation (10 Vs 14 d)

(Pandian et al., 2010): improve patient compliance.

Lower Gnt consumption: lower cost

Drop in cycle cancellation

Prognosis remained poor, with CPR 16% with GnRHan Vs 11% with the GnRHa

(Nelson et al., 2009).

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B. Expectant high responders: Antagonists

Reduction of: high response {OHSS, cycle cancellation

{risk of OHSS} (Al-Inany et al., 2007, 2011; Hosseini et al., 2010; Lainas et al., 2010; Tehraninejad et al., 2010).

La marca et al,

2013

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II. Individualization of Gnt Starting Dose:

A. Simple models

One or 2 parameters

1.

AMH

2.

AFC and age

3.

AFC

B. Complex models: > 2 parameters

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SELECTION OF PROTOCOL ACCORDING TO

Reserve

OVARIAN Reserve

‘Low’

‘Average’

AFC

<7

7-14

AMH

<1.1 ng/ml

1.1-3.5

Starting FSH

375

225

dose IU

Amp

5

3

Protocol

- Antagonist

-Long

-Microdose flare

protocol

-Agonist stop

-Antagonist

-GH

-Natural -Modified natural

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‘High’

>14

>3.5

150

2

-Long

protocol

-Antagonist

Benha University Hospital E-mail: elnashar53@hotmail.com Aboubakr Elnashar
Benha University Hospital E-mail: elnashar53@hotmail.com Aboubakr Elnashar

Benha University Hospital

E-mail: elnashar53@hotmail.com

Aboubakr Elnashar