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Hakan Yarali Anatolia IVF and Women’s Health Center Department of Obstetrics and Gynecology Hacettepe University, School of Medicine Ankara, Turkey
Declared receipt of honoraria or consultation fee from Merck Serono
www.excemed.org
IMPROVING THE PATIENT’S LIFE THROUGH
MEDICAL EDUCATION
9th IVF Preceptorship: current practice in the 21st century
24-25 September 2015
Madrid and Alicante, Spain
3
Individualized Controlled Ovarian Stimulation (iCOS): Tools for matching
patients and protocols
Professor Hakan Yaralı, MD Anatolia IVF and Women’s Health Center
& Hacettepe University, School of Medicine, Dept. of OB/GYN
4
iCOS Central Paradigm
Maximize Live Birth Minimize
risks/complications
Hypo-response Hyper-response
5
Patients are the main variable associated with response to COS
The patient individual factors of response to stimulation are: • Demographics and anthropometrics (Age, BMI, Race)
• Genetic profile
• Health status
• Cause of Infertility
• Years on Infertility
• Nutrition
6
Increase dose of FSH and add-back LH
Lupron 0,5 mg day 1 0,1 mg day 3 day 12-14
r-FSH 300-450 + 150-300 hMG/rLH Crinone qd
E2<75pcg Menses
Step up/down
Day 6 8 10
r-HCG
250 mcg
P4 oil bid
day 17-19 29-31
Transfer
day 15-17E2 level control & Usound
Short (Flare) ProtocolShort (Flare) Protocol
recFSH and LH/recFSH and LH/hMGhMG
Daily Daily LupronLupron®® (co-flare: 1mg X 2d, then 0.5 mg)
Start StimulationStart Stimulation hCGhCG
Day 2 or 3Day 1
mensesmenses
hCG criteria based on follicle sizehCG criteria based on follicle size
Apx. 10 DaysApx. 10 Days
Ultrashort (Ultrashort (miniflareminiflare or Lupronor Lupron®® Stop) ProtocolStop) Protocol
FSH FSH
LupronLupron®®
Start StimulationStart Stimulation hCGhCG
Day 2 or 3 Day 7Day 1
mensesmenses
hCG criteria based on follicle sizehCG criteria based on follicle size
Apx. 10 DaysApx. 10 Days
Agonist- Antagonists Protocol
Lupron® 40mcg BID Antagonist 3 mg or 250 ug / day
hCG
Day 3
Day 5
Exogenous recFSH +/- hMG
Endogenous FSH/LH
Risk of LH Peak
Stop Lupron Protocol
Lupron® 0.5mg/day Stop Lupron®
7 – 8 days after documented ovulation
hCG
Day 21
Day 28
Day 2 or 3
recFSH +/- hMG
Endogenous FSH/LH
21 22 23 ….. 27 28 1 2 3 4 …………………………... 9 101 2 3 4 5
Agonist and Antagonist Regimens for IVFAgonist and Antagonist Regimens for IVF
GnRH AntagonistGnRH Antagonist
GnRH AgonistGnRH Agonist
Agonist started Agonist started
1mg/0.5 mg1mg/0.5 mgAgonist Dose adjusted 0.5 mg/0.25 mgAgonist Dose adjusted 0.5 mg/0.25 mg
Standardized Standardized
DoseofDoseof FSHFSH
Day 1 Day 1 of rFSHof rFSH
Day 6Day 6
of rFSHof rFSHDayDay
of hCGof hCG
7 7 –– 8 days8 days
after estimated ovulationafter estimated ovulation
Standardized Standardized
Dose of FSHDose of FSHIndividualized DosingIndividualized Dosing
0.25 mg/day of 0.25 mg/day of
AntagonistAntagonist
Day 6Day 6
or follicles 12or follicles 12--15mm15mm hCGhCGDay 1 Day 1
mensesmenses
mensesmensesmensesmenses
// // //
Individualized Dosing Individualized Dosing
hCG criteria based on follicle sizehCG criteria based on follicle size
Antagonist and Agonist Treatment Antagonist and Agonist Treatment
Regimens with OC PillsRegimens with OC PillsGnRH AntagonistGnRH Antagonist
GnRH AgonistGnRH Agonist
Agonist startedAgonist started
hCGhCG
hCGhCG
Day 4 post Day 4 post OCPOCP
Individualized DosingIndividualized Dosing
Agonist Dose adjustedAgonist Dose adjusted
StandardizedStandardized
DoseofDoseof FSHFSH
mensesmenses
Standardized Standardized Dose of FSHDose of FSH
Individualized Individualized
DosingDosing
0.25 mg/day of 0.25 mg/day of
AntagonistAntagonistmensesmenses
OCP 14OCP 14--25 days25 days
OCs for 14OCs for 14--25 days25 days
21 22 23 ….. 27 28 1 2 3 4 ……………………….….. 9 101 2 3 4 5 // // //
mensesmenses
hCG criteria based on follicle sizehCG criteria based on follicle size
Multiple protocols of stimulation and drugs from different sources
Gonadotropins – Low dose FSH
Gonadotropin with IUI/Timed IntercourseGonadotropin with IUI/Timed Intercourse
Set Dose of FSHSet Dose of FSHIndividualized Dosing of Individualized Dosing of
FSHFSHSet Dose of FSHSet Dose of FSH
Individualized Dosing of Individualized Dosing of
FSHFSH
mensesmenses
IUIIUI
oror
IntercourseIntercourse
hCGhCG
36 hours
hCG criteria based on follicle sizehCG criteria based on follicle sizeXStandard Long Luteal Lupron Protocol
Lupron 0,5 mg day 1 day 3 day 12-14
E2<75pcg Menses
r-FSH 150-225
Step up/down
Day 6 8 10
E2 level control & Fol Usound
hCG
Crinone qd
P4 oil bid
day 17-19 29-31
Transfer
day 15-17
VOR
Mini (Micro) LupronMini (Micro) Lupron®® Flare Protocol for Poor Flare Protocol for Poor
RespondersResponders
recFSH recFSH
OCPOCP’’s for 21 dayss for 21 daysSynchronize Follicle WavesSynchronize Follicle Waves
20 or 40ug BID of Lupron20 or 40ug BID of Lupron®®
Start StimulationStart Stimulation hCGhCG
Day 2 or 3
mensesmenses
Stop StimulationStop Stimulation
Apx. 10 DaysApx. 10 Days
hCG criteria based on follicle sizehCG criteria based on follicle size
GnRH Antagonist Protocol
recFSH/hMG recFSH or hMG continues
hCGDay 1
of recFSH or hMG
Day 2 or 3
Fix on Day 6 of stimulationFlexible when fols >12-14mm
Endogenous FSH/LH 250 ug per day of Antagonists
Steroid Hormones:
Progesterone
Estradiol
Testosterone
DHEA
Gonadotropins:
Recombinant FSH/LH/hCG
Urinary FSH/LH/hCG
GnRH Analogues:
Agonists brands
Antagonists brands
Adjuvant co-treatment
Aromatase Inhibitors
Growth hormone
7
We want an optimal oocyte yield
Sunkara, et al Hum Reprod 2011
UK 15 oocytes US
n = 400,135 fresh cycles
Steward et al Fertil Steril 2014
n = 256,381 fresh cycles (US registry 2008-2010)
8
How many oocytes are needed to optimize PR?
• Van der Gaast et al-2006 - 13 oocytes; below and above PRs are compromised (n=7,422)
• Verberg et al-2009 - 5 for mild stimulation and 10 oocytes for conventional stimulation (meta-
analysis ; mild-313 cycles; conventional-279 cycles)
• McAvey et al-2011 - Yielding >6 M-II oocytes does not further improve live birth rates (n=737)
• Bosch et al-2011 - LBR increase up to 15 oocytes maximize the chances of pregnancy (n=7954)
• Sunkara et al-2011 - LBR increase up to 15 oocytes; plateaus between 15-20 and decline steadily beyond 20
(n=400,135)
• Ji et al-2013 Optimum - 6-15 oocytes for LBR below and above PRs are compromised; however, cumulative LBR
increase with increasing oocyte number (n=2,455)
• Fatemi et al-2013 - A high ovarian response 18 oocytes does not jeopardize LBR in fresh ET’s and even is
associated with increased cumulative PR (Engage; n=1,506)
• Steward et al-2014 - Retrieval of >15 oocytes significantly increases OHSS risk without
improving LB rate in fresh autologous IVF cycles.
9
iCOS-Goals P
opul
atio
n %
Inadequate
gonadotrophin
exposure
Iatrogenic
Poor response
Excessive
gonadotrophin
exposure
Iatrogenic
OHSS
Optimal
No. of oocytes
10
PREDICTION OF OVARIAN RESPONSE
• Biomarkers • AMH
• AFC
- D3 FSH, E2
- Others Human Reproduction Update, Vol. 20, No.I pp 124 -140, 2014
11
BOTH AFC AND AMH CORRELATE WELL WITH PRIMORDIAL FOLLICLE NUMBER
Scatter plots and correlations for log10 primordial follicle (PF) counts vs ovarian reserve test results
Hansen et al-2011
12
AMH
13
Our confidence has been shaked..
DSL assay
25,000 women
AM
H (
pmol
/L)
Age (years)
Gen II assay
11,000 women
AM
H (
pmol
/L)
Age (years)
Gen
II –
DS
L as
say
(pm
ol/L
)
Age (years)
Nelson, et al Fertil Steril 2011
Nelson, et al Fertil Steril 2013
14
AUTOMATED ASSAYS (Elecys-Roche; Access-Beckman Coulter)
15
Robust to
type of collection
Elecsys AMH serum (ng/ml)
Ele
csys
AM
H L
i Hep
arin
(ng
/mL)
Robust to sample
storage temperature
Ele
csys
AM
H s
erum
str
esse
d
Elecsys AMH serum fresh
Robust to short
and long-term storage
Ele
csys
AM
H L
i Hep
arin
str
esse
d
Elecsys AMH serum fresh
Gassner and Jung Clin Chem Lab Med 2014
A robust automated assay
16
20% lower than AMH Gen II
AMH Gen II (ng/mL)
Ele
csys
AM
H (
ng/m
L)
Y=0.81x – 0.046
Gassner and Jung Clin Chem Lab Med 2014
New reference ranges again..
Y=0.781x + 0.128
Nelson et al. Fertil Steril 2015
AMH Gen II (ng/mL) A
cces
s A
MH
(ng
/mL)
10-15% lower than AMH Gen II
ASSAY-SPECIFIC INTERPRETATION IS REQUIRED!
17
Menses Follicular Ovulation Luteal
AM
H (
ng/m
L)
4.5
1.0
0.5
4.0
3.5
3.0
2.0
2.5
1.5
5.0
0.0
≤20 years
21–25
26–30
31–35
>35
Kissell, et al Hum Reprod 2014
AM
H (
ng/m
L)
Menses Follicular Luteal
4.0
3.5
3.0
2.0
2.5
1.5
AMH
Oestradiol
Progesterone
Ovulation
We can measure AMH on any day of the cycle
18
What about AFC?
19
Dewailly, et al Hum Reprod Update 2011
2001 2009
The AFC assay has also changed..
20
Healthy
control
women
Year of data collection
Fol
licle
num
ber
per
ovar
y
Max
Transducer
Freq (MHz)
2
4
6
8
10
12
14
16
1992 1994 1996 1998 2000 2002 2004 2006 2008 2010 2012
6 7 7.5 8 8.5 9 12
Dewailly, et al Hum Reprod Update 2013
Normal is now <25 follicles per ovary
21
AFC
Moderate to Low Inter-cycle Variation van Disseldorp et al, Hum Reprod 2010;25:221
ICC: 0.71 (95% CI: 0.63–0.77); 29% individual cycle variation
High Inter- and Intra-observer Reproducibility Scheffer et al. Ultrasound Obstet Gynecol 2002;20:270
22
Who is who before iCOS?
23
What about GnRH-ant cycles?
AUC-AMH=0.87 AUC-AMH=0.79
Hamdine et al. HR 2015
24
Is not only about AMH and AFC…
AMH
AFC
AGE
BMI
ETHNICITY
OVARIAN RESPONSE
HYPERINSULUNISM
FSHR,LHR GENOTYPE
ANDROGEN LEVELS
SMOKING
INFERTILITY DIAGNOSIS
25
AMH and AFC are not accurate for pregnancy prediction
Broer et al. Fertil Steril 2009 ; Broer et al. Hum Reprod Update, 17:46; 2011
26
Does AMH predict Implantation and Live Birth? – Meta-analysis
Implantation Clin Preg-Unspecified OR
Clin Preg-DOR Clin Preg-PCOS
Tal et al-FS 2015
27
Limited Predictive Accuracy of AMH for Implantation and Live Birth..
28
Should IVF be withheld based on low/extremely low-AMH levels?
Kedem et al. Plos One 2013
(281 Patients; 769 cycles)
29
4 Major Categories of Patients
Hyper- responder
Definition
Profile
Therapy
Normo-
responder
Definition
Profile
Therapy
Low-
responder
Definition
Profile
Therapy
Sub-optimal
responder
Definition
Profile
Therapy
iCOS to maximize efficacy & safety and minimize patient burden
Antonio La Marca and Sesh Kamal Sunkara, Human Reprod. Update, Vol. 20, No. 1 pp.124-140, 2014
30
Hyper- responder
Definition
Profile
Therapy
Definition
• > 15 oocytes
Profile
• AMH > 4 ng/mL
• AFC > 20
• PCOS type; mostly younger
• History of OHSS/multiple oocytes harvested in previous therapy
Therapy
• Antagonist
• 75-150 IU/d starting dose of rFSH
• GnRH-agonist trigger
Incidence 15 %
SEGMENTATION OF PATIENTS FOR iCOS
31
Definition
• 10 - 15 oocytes
Profile
• AMH: 2 - 4 ng/mL
• AFC: 10 – 20
• Mostly 30 – 40 yr old
• History of normal response in previous therapy
Therapy
• Agonist / Antagonist
• 150-200 IU/d starting dose of rFSH
Incidence 55 %
Normo-
responder
Definition
Profile
Therapy
SEGMENTATION OF PATIENTS FOR iCOS
32
SEGMENTATION OF PATIENTS FOR iCOS
Definition
• 4 - 9 oocytes
Profile
• AMH 1 - 2 ng/mL
• AFC 5 - 10
• Mostly 35 – 40 yr old
• History of low-response in previous therapy
Therapy
• Agonist/Antagonist ?
• 225-300 UI/d starting dose of rFSH with rLH add-back?
Incidence 15 %
Sub-optimal
responder
Definition
Profile
Therapy
33
SEGMENTATION OF PATIENTS FOR iCOS
Definition
• ≤3 oocytes
Profile
• AMH < 1 ng/mL
• AFC < 5
• Mostly > 40 yr-old
• History of previous poor response
Therapy
• Protocol of choice?
• 300 UI/d starting dose of rFSH with rLH add-back
• Adjuvant therapy?
• Oocyte/embryo accumulation ?
Low-
responder
Definition
Profile
Therapy
Incidence 15 %
34
What about iCOS for normo-responders?
Agonist vs Antagonist: No difference
Al Inani et al, 2011; Xiao et al, 2014
rFSH vs hMG in long protocol: No difference
Andersen et al, 2006 (MERIT)
rFSH vs hMG in antagonist prootocol: No difference
Bosch et al, 2008; Devroey et al, 2012 (Megaset)
rLH supplementation in long protocol: No difference
Kolibianakis et al, 2006
rLH supplementation in antagonist protocol: No difference
Griesinger et al, 2005; Bosch et al, 2010
Mild vs conventional stimulation: No difference
Hohmann et al, 2003
Long acting vs daily FSH: No difference
Devroey et al, 2009
150 vs 200 IU/day of rFSH: No difference
Out el al, 2004
35
What about sub-optimal responders? (4-9 oocytes)
• 43.3% of the entire cohort • 20-30% lower Live Birth Rate
compared to normo- responders (10-15 oocytes)
36
Why patients may demonstrate a sub-optimal response to ovarian stimulation ?
Human FSH Receptor Mutations
Locus FSHR (680) polymorphic variability
• Three genotypes:
• Asn/Asn (45%)
• Ser/Ser (26%)
• Asn/Ser (29%)
Perez-Mayorga, et al. 2000.
- NH2
- COOH
Ala189Val
Asp567Gly??
(Asn191Ile) Ile160Thr Asp224Val
Arg573Cys
Leu 601Val
Ala419Thr
Pro346Arg Val341Ala
*
Pro519Thr Thr307Ala
Ser680Asn
*
FSH-R: Ser680 genotype
Additional sulphated sugar at asn-13
The common Trp8Arg/Ile15Thr LH
β1 12
1
Y 3
0
Trp8Arg
Ile15Thr
LH-variant
LH
β1 121
Y
30
Trp8Arg Ile15Thr
To the native molecule
Worldwide occurrence Percent V/V + V/WT
0
0 10 20 30 40 50 60
13.6%
Australia/Aboriginals Finland (Lapp) Finland Faroe Islands Iceland Greenland Estonia Poland Sweden (Stockholm) South Africa (black) United Kingdom United States (black) The Netherlands China Sweden (Göteborg) Italy Thailand Jordan Jordan United States (Hispanic) Spain (Vasco) Mexico (Mayan) Western India (Kota)
37
Which protocol/gonadotropin for sub-optimal responders to improve live birth rate?
Future Prospect
38
Ovarian response & FSH dose
Hypo-response = Poor Outcome
Hyper-response = Danger
“Optimal response” 10-15 oocytes
FSH dose
Ova
rian
res
po
nse
39 Sterrenburg et al. HRU 17: 184-96, 2011
Daily Dose of rFSH in Presumed Normal Responders <39 yr Meta-analysis
40
Fine tuning of Daily Dosing of rFSH Multi-variate models
• Popovic-Todorovic et al-2003 • RCT; Standard patients (n=262)
• 150 IU vs calculated Dose; Agonist
• AFC, Ovarian V; Doppler score; Female Age; Smoking habit
• Olivennes et al-2009 • CONSORT; Prospective uncontrolled
• Calculated dose; Agonist
• Basal FSH, BMI, Female age and AFC
• La Marca et al-2012, 2013 • Female age, AMH/AFC, FSH
41
We can use AMH to stratify care
Antagonist
hCG/GnRHa trigger
Standard
treatment
Maximise
oocyte yield
40
20
7
1 Pre-AMH
Live
birt
h ra
te (
%)
30
25
20
15
10
Post-AMH Nelson, et al Hum Reprod 2009
Yates, et al Hum Reprod 2011
42
OC Pre-treatment – GnRH-ant Cycles
• Griesinger et al-Fertil Steril 2010 (Meta-analysis; 6 RCTs) • Ongoing PR (Rate difference: -5%; 95%CI, -10% to -1%)
• Criticism.. • Normal (5) and poor responders (1) included
• Limited sample size
• Different types of OCPs used
• Different duration of administration (14-28 days)
• Different pill-free interval of 2-5 days
43
Conclusions
• AMH and AFC are currently the best biomarkers to predict ovarian response to iCOS
• iCOS guided by such biomarkers is aimed to maximize the beneficial effects of treatment while minimizing complications and risks
• iCOS results in a better cycle final outcome and a more cost-effective approach