Benha University Hospital, Egypt Aboubakr Elnashar
Jul 12, 2015
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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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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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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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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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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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). 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
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