Benha University Hospital, Egypt

Aboubakr Elnashar

CONTENTS

1. TYPES OF OVARIAN STIMULATION FOR IVF

2. DRUGS

3. GNRHa PROTOCOLS

4. GNRHan PROTOCOLS

5. TRIGGERING OF OVULATION

6. CYCLE CANCELLATION

7. INDIVIDUALIZATION OF COS

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Methods Aim Previous

terminology

Recommended

terminology

No medication Single

oocyte

Unstimulated,

spontaneous

cycle

1. Natural cycle

hCG only

GnRHan and FSH/HMG

add-back

Single

oocyte

Semi-natural,

controlled natural

cycle IVF

2. Modified

natural cycle

Low dose FSH/HMG,

oral compounds and

GnRHan

2-7

oocytes

Soft, minimal

stimulation,

‘friendly’ IVF

3. Mild

GnRHa or antagonist

conventional

FSH/HMG dose

> 8

oocytes

Standard, routine,

COS

4. Conventional

International Society for Mild Approaches in Assisted Reproduction

(ISMAAR), 2007

1. TYPES OFOVARIAN STIMULATION FOR IVF

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GnRHa GnRHan No GnRH

analogue

long Short Ultra

short

Standard Mild Modified

natural

Mini Natural

Protocols of ovarian stimulation in IVF

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2. DRUGS Gonadtrophins

GnRha

GnRhan

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Preparation Trade name Route U.pr FSH LH Company PriceEP

1. HMG Pergonal,

Humegon,

Menogon

Merional

IM 95% 75 75 Serono

Organon

Ferring

Ibsa

66

2. H.P.HMG Menopur

Gonapur

SC

SC

<5%

<5%

Ferring

M pharm

118

85

3. Purified

FSH

Metrodine IM <5% 75

Urofillotropin

<0.1 Serono

4. H.P.FSH Fostimon

Metrodine HP

Bravelle

SC,

IM

<5% 75

Urofillotropin

<0.001 Ibsa

Serono

Ferring

55

70

5. HCG Pregnyl

Profasi

IM 95% Organon

Serono

6. H.P.HCG Choriomon SC,IM <5% Ibsa 33

I. Types of Gnt

I. Urinary Gonadotropins

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Aboubakr Elnashar

II. Recombinant Gonadotropins

Preparation Trade name Route Upr FSH LH Price Company

1. FSH Puregon

(follitropin),

Gonal F (follitropin)

SC, IM -

-

50

100

75

150

-

-

180

Organon

Serono

2. HCG Ovitrelle

Choriogonadotropin

SC - Serono

3. LH Luveris

lutotropin

SC - Serono

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Aboubakr Elnashar

Types of GnRHa

PriceEP company Dose Route Name Preparation

750

1550

540

Abbot 3.75 mg/4w

11.25 mg/12 w

2.8 ml, 1 ml daily

IM, SC

IM, SC Lupron

Lucrin

Leuprorelin

500 Astrazenica 3.6 mg SC Zoladex Goserelin

605

266(7syr)

Ferring CR: 3.75mg,

0.1mg then 0.05 mg

IM, SC Decapeptyl Triptolerin

Sanofi 0.5 mg then 0.2 mg Nasal, SC superfact Buserelin

Pfaizer 0.2 mg bid nasal Synarel Nafarelin

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Price Company Route Trade Generic

250 0.25 mg

3 mg

Serono SC Cetrotide Cetrorelix

192

0.25 mg MSD

MSD

SC Ganirelix

Orgalutran

Ganirelix

Types of GnRhan

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Aboubakr Elnashar

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 1st to 3rd day of the cycle.

Gnt: from the 3rd 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 1st day of the cycle until the day of

ovulation induction.

Gnt: from the 3rd day of the cycle.

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Leuteal support

FSH 75-300 IU

Ovulation

5.000-10.000 IU

hCG

Short GnRHa protocol

75-

300/day

IU /FSH

34 h.

OPU

TVS > 18 ml

E2

Cycle

day 1

GnRHa 0.1mg/day

3rd day

TVS

E2

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Long: GnRHa:

From:

1st 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 1st 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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Luteal support

hCG

5-10000 IU

75-300 IU / FSH/day

Long GnRHa Protocol (luteal phase) TVS

E2

34 h.

OPU 20th day

previous

cycle

TVS >18 ml

E2

GnRHa 0.1mg/day

< 50 pg/ml

TVS

E2

FSH

2 weeks

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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) Aboubakr Elnashar

, 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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Aboubakr Elnashar

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.

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Aboubakr Elnashar

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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Aboubakr Elnashar

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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Aboubakr Elnashar

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). Aboubakr Elnashar

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.

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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%

Over 40 19.1-24.6% Aboubakr Elnashar

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.

1st 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

BMI>30 Kg/m (PCO excluded):

increase by 75= 1 amp

Severe endometriosis:

increase by 75= 1 amp

Previous

Normal response(>4 follicles):

same

OHSS: 75= 1 amp

Poor response: 450= 6 amp

Adjust dose

as cycle monitoring proceeds

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)

High response Low

response

16 or more 4 or less Total AFC

3.5 or more

0.8 or less

AMH

ng/ml

4 or less 8.9 or more FSH IU/L Aboubakr Elnashar

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

OVARIAN Reserve Reserve ‘Low’ ‘Average’ ‘High’

AFC <7 7-14 >14

AMH <1.1 ng/ml 1.1-3.5 >3.5

Starting FSH

dose IU

Amp

375

5

225

3

150

2

Protocol - Antagonist

-Microdose flare

-Agonist stop

-GH

-Natural

-Modified natural

-Long

protocol

-Antagonist

-Long

protocol

-Antagonist

Aboubakr Elnashar

Benha University Hospital

E-mail: elnashar53@hotmail.com

Aboubakr Elnashar