Controlled ovarian stimulation in IVF

1. Benha University Hospital, Egypt
Aboubakr Elnashar

2. 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
Aboubakr Elnashar

3. MethodsAimPrevious
terminology
Recommended
terminology
No medicationSingle
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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4. 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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5. 2. DRUGS
Gonadtrophins
GnRha
GnRhan
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6. 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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7. Aboubakr Elnashar

8. 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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9. Aboubakr Elnashar

10. Types of GnRHa
PriceEPcompanyDoseRouteNamePreparation
750
1550
540
Abbot3.75 mg/4w
11.25 mg/12 w
2.8 ml, 1 ml daily
IM, SC
IM, SC
Lupron
Lucrin
Leuprorelin
500Astrazenica3.6 mgSCZoladexGoserelin
605
266(7syr)
FerringCR: 3.75mg,
0.1mg then 0.05 mg
IM, SCDecapeptylTriptolerin
Sanofi0.5 mg then 0.2 mgNasal, SCsuperfactBuserelin
Pfaizer0.2 mg bidnasalSynarelNafarelin
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11. PriceCompanyRouteTradeGeneric
2500.25 mg
3 mg
SeronoSCCetrotideCetrorelix
192
0.25 mgMSD
MSD
SCGanirelix
Orgalutran
Ganirelix
Types of GnRhan
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12. Aboubakr Elnashar

13. 3. GNRHa PROTOCOLS
GnRHa
Produced by
Modification of the native GnRH decapeptide at 6 &
10 positions
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14. 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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15. 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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16. (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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17. 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 cycleAboubakr Elnashar

18. 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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19. 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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20. 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
ay 1
GnRHa 0.1mg/day
3rd day
TVS
E2
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21. 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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22. Follicular phase
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23. Luteal support
hCG
5-10000 IU
75-300 IU / FSH/day
Long GnRHa Protocol (luteal phase)
TVS
E2
34 h.
OPU20th day
previous
cycle
TVS >18 ml
E2
GnRHa 0.1mg/day
< 50 pg/ml
TVS
E2
FSH
2 weeks
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24. -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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25. 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

26. ,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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27. Depot Vs daily
No differences PR.
Depot:
longer duration
higher doses of Gnt
more luteal support depot
(Cochrane review 2002)
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28. 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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29. Aboubakr Elnashar

30. 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

31. Aboubakr Elnashar

32. 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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33. Aboubakr Elnashar

34. 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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35. 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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36. Aboubakr Elnashar

37. 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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38. 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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39. 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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40. 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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41. 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

42. 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

43. 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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44. 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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45. 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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46. 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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47. 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 responseLow
response
16 or more4 or lessTotal AFC
3.5 or more0.8 or less
AMH
ng/ml
4 or less8.9 or moreFSH IU/L Aboubakr Elnashar

48. 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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49. 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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50. 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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51. SELECTION OF PROTOCOL ACCORDING TO
OVARIAN ReserveReserve ‘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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52. Benha University Hospital
E-mail: elnashar53@hotmail.com
Aboubakr Elnashar