anatolia ivf and women’s health center department of ... · agonist and antagonist regimens for...

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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

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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

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iCOS Central Paradigm

Maximize Live Birth Minimize

risks/complications

Hypo-response Hyper-response

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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

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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®®


Day 2 or 3 Day 7Day 1

mensesmenses



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


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


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®®


Day 2 or 3

mensesmenses

Stop StimulationStop Stimulation



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

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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)

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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.

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iCOS-Goals P

opul

atio

n %

Inadequate

gonadotrophin

exposure

Iatrogenic

Poor response

Excessive

gonadotrophin

exposure

Iatrogenic

OHSS

Optimal

No. of oocytes

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PREDICTION OF OVARIAN RESPONSE

• Biomarkers • AMH

• AFC

- D3 FSH, E2

- Others Human Reproduction Update, Vol. 20, No.I pp 124 -140, 2014

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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

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AMH

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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

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AUTOMATED ASSAYS (Elecys-Roche; Access-Beckman Coulter)

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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

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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!

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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

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What about AFC?

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Dewailly, et al Hum Reprod Update 2011

2001 2009

The AFC assay has also changed..

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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

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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

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Who is who before iCOS?

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What about GnRH-ant cycles?

AUC-AMH=0.87 AUC-AMH=0.79

Hamdine et al. HR 2015

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Is not only about AMH and AFC…

AMH

AFC

AGE

BMI

ETHNICITY

OVARIAN RESPONSE

HYPERINSULUNISM

FSHR,LHR GENOTYPE

ANDROGEN LEVELS

SMOKING

INFERTILITY DIAGNOSIS

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AMH and AFC are not accurate for pregnancy prediction

Broer et al. Fertil Steril 2009 ; Broer et al. Hum Reprod Update, 17:46; 2011

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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

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Limited Predictive Accuracy of AMH for Implantation and Live Birth..

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Should IVF be withheld based on low/extremely low-AMH levels?

Kedem et al. Plos One 2013

(281 Patients; 769 cycles)

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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

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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

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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


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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

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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 %

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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

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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)

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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

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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

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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

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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

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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

anatolia ivf and women’s health center department of ... · agonist and antagonist regimens for...

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