Individualisation of controlled ovarian stimulation

11/2/2021
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ABOUBAKRMOHAMED ELNASHAR
INDIVIDUALIZATION OF
CONTROLLED OVARIAN STIMULATION
Prof. Aboubakr Elnashar
Benha university Hospital, Egypt
11/2/2021
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CONTENTS
1. INTRODUCTION
2. WHY?
3. WHAT?
4. HOW?
1. ORT
2. PREDICTION MODELS
5. PREDICTED POOR RESPONDERS
6. PREDICTED HIGH RESPONDERS
 CONCLUSION
1. INTRODUCTION
 Most medical treatments
 are designed for the average patient, with a one-size-fits all-
approach.
 Though successful for many, this approach may not benefit
all patients.
 Personalized medicine:
 Tailored approach to disease prevention & TT that considers
interindividual differences in patients.
 An improved understanding of the function of genes,
proteins, metabolites, personal &environmental factors

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 “individualization” in IVF.
 In recent years, has been evolved
 Individualization of COS
 The crucial step for good oocyte retrieval&
couple's prognosis
 Based on ovarian reserve.
2. WHY?
Objectives of individualization
Offer every single woman the best TT tailored to her
unique characteristics:
 Maximizing success
 Eliminating OHSS
 Minimizing cycle cancellation:
 Reduced costs
 Reduce dropping out from TT
 Improve patient compliance
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3. WHAT?
I. Selection of protocol:
 Agonist or antagonists
 Type of gonadotrophin
 Triggering for oocyte maturation
 Adjuvant therapies
II. Selection of Gnt starting dose.
 {variability in ovarian reserve is very wide} (Monget et
al., 2012):
 Standard fixed dose of Gnt is not suitable for all
women.
 Extremely important, fundamental.
 Low Gnt dose: mono follicular development, not
desired in IVF cycles.
 Excessive Gnt dose: excessive ovarian
response: OHSS.

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4. How?
i. Ovarian Reserve tests
 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
25
0.8 or less
5.4
AMH
ng/ml
pmol/l
Conversion ratio:7
4 or less
8.9 or more
FSH IU/L
1. Serum FSH
 Measured on day 3-5 of the menstrual cycle, and E2
 Limitation:
1. FSH is an indirect marker of ovarian reserve& its serum
levels are out of range only when ovarian reserve is
severely compromised: large percentage of patients
with normal values
2. Suboptimal sensitivity & specificity for predicting ovarian
response to GnT.
3. Various cut-off values (from 10 to 15 IU/L) have been
proposed for predicting poor ovarian response
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2. AMH and AFC
 Measure the real ovarian follicle pool very
accurately.
 The pool of 2 to 9 mm antral follicles is the same
that produces AMH
 Highly correlated
 Superior in predicting both hyporesponse (≤5
oocytes) or excessive response (>15 oocytes)
than other ORT
 Same performance in evaluating follicle quantity
ii. Prediction models
 The prediction of a poor or hyper response:
 Allow clinicians to give women more information
on possible
 Protracted treatment
 Cycle cancellation
 OHSS
 Reduced success.

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1. Simple models
One or 2 parameters
1. AMH
2. AFC & AGE
3. AMH & WEIGHT
4. AFC
1. AMH:
3 studies have been
published reporting
simple models for Gnt
dose selection
A. Nelson et al.(2009)
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B. Yates et al.(2011)
C. Leao et al (2013)

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2. AFC & AGE (La Marca et al., 2013)
3. AMH & WEIGHT: (Andersen, 2017)
 RCT, multicenter;1,329
 Individualized vs. standard 150–450 IU/d
 More targeted ovarian response
 Less poor response
 Less excessive response
 Less OHSS
 Same oocyte number
 Same ongoing pregnancy rate

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B. Complex models
> 2 parameters
1. Popovic-Todorovic et al.(2003)
2. Howles et al.(2006)
1. Age
2. BMI
3. AFC
4. D3 FSH
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3. Olivennes et al.(2009).
The CONSORT dosing algorithm individualizes FSH
doses, assigning 37.5 IU increments acc to:
1. Age
2. BMI
3. AFC
4. D3 FSH
 Olivennes, 2015
 RCT, multicenteric, n= 200
 Consort calculator (25–450 IU/d), vs. ‘‘standard’’
(150 IU/d) in standard IVF patients
 Lower daily & total FSH doses
 Fewer oocyte retrieved
 Same CPR
 Less OHSS

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4. Biasoni et al (2011)
1. Age
2. BMI
3. AFC
4. D3FSH
5. Yovich et al, 2012
1. Age
2. BMI
3. Smoking
4. AFC
5. D2 FSH
6. AMH
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6. Oliveira et al (2012):
Ovarian Response Prediction Index (ORPI)=
AFCXAMH/Age

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7. La Marca et al.(2012)
1. Age
2. FSH
3. AMH
 Allegra, 2017
 RCT, single center; 191
 Individualized dosing (nomogram involving age,
FSH, AMH; 75–225 IU/d) vs. age based standard
dose (150–225 IU/d)
 More often optimal oocyte number retrieved
 Same CPR
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8. La Marca et al.(2013)
1. Age
2. AFC
3. FSH
5. PREDICTED POOR RESPONDERS
Bologna Criteria 2011
At least 2 of 3 features must be present:
1. Age (≥40 y) or any other risk factor for POR
2. Previous POR
(≤3 oocytes with a conventional stimulation protocol)
3. Abnormal ORT
(AFC <5–7 follicles or AMH <0.5–1.1 ng/ml).
 2 episodes of POR
after maximal stimulation in absence of advanced maternal age
or abnormal ORT.

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 Criticisms
1. Population was too heterogenous in
1. Woman ’s age
2. Oocyte competence
3. Risk factors .
2. No clear cut-off of AFC& AMH
Values ranging from 5-7 for AFC&0.5- 1.1 ng/mL for AMH
3. Use of “other cause of POR” as one of criterion:
these criteria imprecise.
{as ovarian surgery or history of chemotherapy should be
evaluated separately not included in the same category}.
POSEIDON (Humaidan et al, 2017)
(Patient-Oriented Strategies Encompassing IndividualizeD Oocyte Number)
The group comprises 12 opinion leaders in reproductive medicine from 7 countries
 More detailed stratification for patients by
 Reduced ovarian reserve or
 Low response to ovarian stimulation.
 Moving from a poor ovarian response to a low
prognosis concept
 Considering not only the
 Number of oocytes retrieved, but also
 Age -related aneuploidy rate and
 Ovarian ‘sensitivity’ to GnT
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4 groups based on oocyte quantity& quality
ABOUBAKR ELNASHAR
Treatment According To The POSEIDON
Stratification (Drakopoulos et al, 2020)
Group 1&2
 Issue: Unexpected poor response:
 Hyposensitivity of granulosa cells to standard
FSH doses
 FSH receptor polymorphisms

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I. COS:
1. Protocol
 Both GnRH long agonist& antagonist protocols
may be used {studies has shown comparable
efficacy}
 They perform better compared with the short
flare-up protocol
 Dual stimulation
 {higher oocyte yield is required to obtain an euploid
embryo}.
 Maximizing the total number of oocytes in one
menstrual cycle: higher probability to get a
genetically normal embryo: the cumulative LBR
would be increased.
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 Dual stimulation in a menstrual cycle (DuoStim)
{Multiple follicular waves during one menstrual cycle has
offered new possibilities for ovarian stimulation}
2. Type of gonadotropins
 To retrieve more oocytes, a more “potent” GnT.
 Several RCTs&MA: rFSH: significantly more
oocytes compared with urinary preparations (Devroey
et al, 2012; Santi et al, 2017): rFSH may be the GnT of
choice for Poseidon groups 1 and 2.

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3. Dose: Increase of initial dose of stimulation
 An increase in the stimulation dose of the second
IVF cycle: significantly higher oocyte yield.
 An increase by 50 units in the initial dose: one more
oocyte.
 Each additional oocyte may increase the LBR by
5% (Martin et al, 2010)
II. Adds on
 rLH.
 To
 stimulate early stages of follicular growth
 improve FSH receptor expression in granulosa cells
 improve the sensitivity to FSH dose& recruitability
 Mainly benefits patients who are carriers of LH–β&
present ovarian resistance to GnT.
 showing a benefit in terms of oocyte yield & PR
 2:1 ratio of rFSH:LH, (75–150 IU once daily)
 Starting at
 Mid-follicular phase in an attempt to rescue the ongoing cycle or
 From day 1 of the following IVF cycle.
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 Androgens supplementation
 DHEA supplementation for 8 ws before COS were
found to have significantly higher LBR & lower
miscarriage rate (Tartagni et al, 2013)
Group 3& 4
 Issue
Depletion of ovarian reserve in terms of AFC
I. COS
1. Protocol
 Antagonist protocol with Synchronizing follicle wave
before starting COS with
1. E2 for 5 days prior to menses
2. Short GnRHan pre-treatment at beginning of the
cycle
3. Oral contraceptives
4. Progestins for 12–14 days as pretreatment

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 Dual stimulation in a menstrual cycle (DuoStim)
{Multiple follicular waves during one menstrual cycle has
offered new possibilities for ovarian stimulation}
2. GnT type:
 insufficient evidence to favor the use of one type of
GnT rather than another in POR (ESHRE, 2019), making
this decision subject to availability, convenience&
costs.
3. GnT dose: [Berkkanoglu et al, 2010].
 FSH 300 IU daily.
 Higher doses will never compensate the absence
of follicles {GnT can only support the cohort of follicle
responsive to the stimulation, but cannot generate follicles
denovo}
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II. Adds on
 Adding LH: (Alviggi et al, SR 2018)
 benefit was more pronounced in
 unexpected PORs
 women 36–39 years of age
 CoQ10: 2 m prior to COS (Zhang et al., RCT2020 ) in POSEIDON
group 3
 significantly higher number of retrieved oocytes
 Significantly less consumed FSH
 {CoQ10 would reduce mitochondrial oxidative stress:
improved oocyte competence}
 Insignificant improve the ovarian reserve.
 Growth hormone [Eftekhar et al, 2013]
 DHEA [Yeung et al, 2016]
 Testosterone [Bosdou et al, 2016]

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6. PREDICTED HIGH RESPONSE
 Define: retrieval of>15 oocytes following standard COS protocol.
 The prevalence rate in IVF cycles:
 7%
 decreases with the woman’s age.
 Predictors:
 Suggestive
 Young age,
 Long menstrual cycles,
 PCOS, and
 Hyper response in a previous cycle
 Stronger: AMH and AFC.
 AMH cut-off levels for the prediction of hyper response
 vary according to the assay used (DSL, IBC or
AMH gen II)
 AMH serum levels >3.5 ng/mL have good
sensitivity and specificity.
 An AFC value of >16 has been shown to be the most
appropriate cut-off for hyper response.
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1. GnRH antagonist protocol
 Reduction in
 OHSS
 Cycle cancellation and patient hospitalization
 Costs.
 Recommended for women with PCOS or predicted high
responders, with regards to improved safety&equal efficacy
(ESHRE, 2019)
 Risk of severe OHSS can be reduced by using GnRHa
trigger final oocyte maturation. (I-B)
 PR are not affected when using GnRHa trigger in GnRHan
protocols when embryos are frozen for later transfer. (II-2)
2. HMG
a. Lower doses:
 to decrease the risk of OHSS (ESHRE, 2019)
 Low starting dose of 75-150 IU for all patients at
possible risk of OHSS, irrespective of their age
 GnT dosing should be individualized acc to: Age,
BMI, AFC, and previous response to GnT. (II-3B)
b. Type: Rec FSH make no difference to the
incidence of OHSS. (I)

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Fischer et al, 2016 ABOUBAKRMOHAMED ELNASHAR
3. GnRHa trigger
Requires use of GnRHan protocol.
Recommended
in women at risk of OHSS (ESHRE, 2019)
over hCG where no fresh transfer (ESHRE, 2019)
induces surges of endogenous LH and FSH, with similar
luteal phase length & progesterone levels than hCG.
Short half-life (4 h): eliminates the risk of OHSS in non
conception cycles {hCG has a half life of about 34 h}
Should be followed by LPS with LH-activity (ESHRE, 2019)
hCG (1500 IU) on the day of OR: excellent CPR, while not
compromising the ability of GnRHa to prevent severe
OHSS.
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4. Freeze all embryos:
Avoiding pregnancy by freezing all embryos will
prevent severe prolonged OHSS in patients at high
risk. (II-2)
 Recommended to eliminate the risk of late-onset
OHSS and is applicable in both GnRH agonist and
GnRH antagonist protocols (ESHRE, 2019)
5. Blastocyst transfer
Decreased
Multiple pregnancy
Moderate or severe OHSS (Xin et al, 2013)
6. Elective single ET
recommended in patients at high risk for OHSS.
(III-C)
7. Use of different medications after the egg retrieval,
such as cabergoline

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CONCLUSIONS
It is now very clear that the ‘one size fits all’ approach
is not recommended.
Individualizing of Gnt starting dose is extremely
important
 iCOS is based on correct prediction of ovarian
response (especially the extremes (poor and hyper
response) by most sensitive markers of ovarian
reserve (Age, AFC and AMH) .
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Individualization, will lead to a
 Reduction in:
 inappropriate ovarian response
 cycle cancellations
 withdrawals from treatment
 OHSS
 Cycles with poor prospects for success
 Improvement in:
 overall cost-effectiveness.

Individualisation of controlled ovarian stimulation

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