Predictive Factors of Predictive Factors of Ovarian ResponseOvarian Response

Colin M HowlesColin M Howles

Vice President Scientific AffairsVice President Scientific Affairs

Global Medical AffairsGlobal Medical Affairs

Merck Serono International SA, GenevaMerck Serono International SA, Geneva

What I would like to do in What I would like to do in this lecturethis lecture

• Briefly review ovarian physiology

• Markers of ovarian reserve and factors affecting ovarian response

• Discuss development of predictive models and application in ART

What I would like to do in What I would like to do in this lecturethis lecture

• Briefly review ovarian physiology

• Markers of ovarian reserve and factors affecting ovarian response

• Discuss development of predictive models and application in ART

Follicle growth and maturation takes Follicle growth and maturation takes place over a 6 month periodplace over a 6 month period

ESHRE Capri Workshop Fertility and Aging Hum Reprod Update 2005

7

6

5

4

3

2

10.60.3

Age

3 6 9Months p.c Years

5 10 20 30 40 50

Germ cells(millions)

Birth

Baker, 1972

Age-related germ cell lossAge-related germ cell loss

There is a steep decline in the There is a steep decline in the population of human ovarian population of human ovarian follicles after 35 years of agefollicles after 35 years of age

Gougeon et al. Biol Reprod 1994 50:653-663

106

105

104

103

102

101

100

0 10 20 30 40 50 60 70 80

Age (years)

Fol

licul

ar c

ount

s

Intervene before FSH driven recruitment phase

What I would like to do in What I would like to do in this lecturethis lecture

• Briefly review ovarian physiology

• Markers of ovarian reserve and factors affecting ovarian response

• Discuss development of predictive models and application in ART

Predictors for ovarian response in ART Predictors for ovarian response in ART fall into three main categoriesfall into three main categories

• Clinical Age, cause of infertility, body mass index (BMI), Genetic

(e.g. Templeton & Morris, 1998; Hohmann et al., 2001; Salha et al., 2001; Howles et al 2006, Simoni et al 2007)

• Ultrasound Number of antral follicles (AFC), Doppler score (resistance), ovarian volume

(e.g. Lass et al., 1997; Fratterelli et al., 2000; Popovic-Todorovic et al., 2003; Hansen et al., 2003; Scheffer et al., 1999, 2003; Van Rooij, 2002; Bancsi, 2003, 2004; Seifer et al 2002; Hansen et al 2003; Muttukrishna et al 2005, Hendriks et al, 2005, 2007; Howles et al 2006; Kwee et al 2007)

• Hormone levels Basal FSH, inhibin B, oestradiol, anti-mullerian hormone (AMH)

(e.g. Toner et al., 1991; Scott, 1989, 1996; Fratterelli et al., 2000; Abdallah & Thum, 2004; Seifer, 2002; Rooij, 2002; Eldar-Geva, 2002; de Vet et al 2002; Fanchin, 2003; Bancsi, 2002, 2003, Akande et al 2002;Laven et al 2004;Hussein 2005; Howles et al 2006; Fleming et al 2006; Kevenaar et al 2007 a,b)

CDC Report for ART in USA; 2006

How do we optimise the response to How do we optimise the response to ovarian stimulation?ovarian stimulation?

• Take into account specific patient parameters

• Utilise different stimulation regimens GnRH antagonist / GnRH agonist

Different gonadotrophin regimens

Meta-analysis including 7 ART studies Meta-analysis including 7 ART studies comparing r-hFSH vs r-hFSH + r-hLH comparing r-hFSH vs r-hFSH + r-hLH (>= 35 yrs) (>= 35 yrs)

Engrand and Loumaye 2003

Patients who have suboptimal response Patients who have suboptimal response to r-hFSH benefit from addition of r-hLHto r-hFSH benefit from addition of r-hLH

Favours r-hFSH Favours r-hFSH + r-hLH

((Mochtar MH, Cochrane Database, 2007Mochtar MH, Cochrane Database, 2007))

What I would like to do in What I would like to do in this lecturethis lecture

• Briefly review ovarian physiology

• Markers of ovarian reserve and factors affecting ovarian response

• Discuss development of predictive models and application in ART

toto Chance of spontaneous pregnancy

Hunault 2004

Probability of pregnancy after IUI Steures 2004 Custer 2007

Probability of pregnancy after IVF Templeton 1996

Prediction of ovarian response in ART Popovic 2003 Howles 2006

OI Response to stimulation (CC/FSH) and pregnancy

Imani 1998, 1999, 2002 Mulders 2003 Van Wely 2005 Eijjkemans 2003

• Identify Predictive factors

• Construct a Prediction Model

• Validate Model using similar group of patients from another centre using a standardised stimulation protocol

Model to predict ovarian responseModel to predict ovarian responsein ART in ART Popovic-Todorovic Popovic-Todorovic et al.et al. 2003 2003

• Scoring system developed for calculating starting dose, based on four predictors:1

Total number of antral follicles Total Doppler score Serum testosterone Smoking status

• Prospectively tested in ART patients age < 39 years (n=262)2

Ongoing PR 36.6% with algorithm (100–250 IU/day)

Ongoing PR 24.4% with standard dose (150 IU/day)

1 .Popovic-Todorovic B et al. Hum Reprod 2003;18:781–72 .Popovic-Todorovic B et al. Hum Reprod 2003;18:2275–82

15 routinely measured parameters were 15 routinely measured parameters were analysed from FSH only stimulated cycles analysed from FSH only stimulated cycles

(Howles et al 2006)(Howles et al 2006)• Age

• Weight

• BMI

• Smoking history

• Type of infertility (primary/secondary)

• Duration of infertility

• Minimum cycle length

• Maximum cycle length

• Mean cycle length

• Previous ART treatment

• Number of previous ART attempts

• Basal FSH

• Antral follicle count (<11 mm) at screening

• Number of follicles >11 mm at screening

• Mean ovarian volume

CONSORT ART calculator CONSORT ART calculator (Howles et al 2006)(Howles et al 2006)

Most important predictive factors:1. Basal FSH

2. BMI

3. Age

4. Antral follicle count

Y (oocytes retrieved) = α + β 1 AGE + β 2 AGE 2 + β 3 BMI + β 4 FSH + β 5 FOLL_LT11 + β 6 DOSE

Therefore:

DOSE = (Y – (α + β 1 AGE + β 2 AGE 2 + β 3 BMI + β 4 FSH + β 5 FOLL_LT11)) / β 6

Computer model developed to predict FSH starting dose in women <35 years undergoing ART

Prospective study designProspective study design

• Phase IV, open-label, in 18 centres worldwide

• GnRH agonist daily (long protocol)

• r-hFSH treatment (GONAL-f® pen) fixed daily dose according to the CONSORT calculator

(allocated using IVRS) dose only to be reduced if risk of OHSS

• Set criteria for r-hCG triggering with a single sc 250 mcg injection of Ovidrel®

at least one follicle ≥18mm and 2 follicles ≥16mm

IVRS = interactive voice response system

Patient flow Patient flow

• Statistical plan required at least 5 patients/group for analysis

• 161 patients received an individualized starting dose between 75 IU and 225 IU (ITT population)

75 IU n=48

112.5 IU n=45

150 IU n=34

187.5 IU n=24

225 IU n=10

n=161

CONSORT ART study results: CONSORT ART study results: DemographicsDemographics

75 IU 112.5 IU 150 IU 187.5 IU 225 IU All

n 48 45 34 24 10 161

Age, years 29.1(3.5)

31.4(2.3)

32.2(1.8)

32.2(1.8)

33.3(1.9)

31.3(2.9)

BMI, kg/m2 21.6(2.7)

22.3(2.2)

22.8(2.7)

23.1(3.1)

23.2(2.3)

22.4(2.7)

Basal FSH, IU/L 5.79(1.4)

6.57(1.7)

6.14(1.3)

7.34(1.4)

8.10(2.0)

6.46(1.6)

Number of antral follicles <11 mm

13.4(5.5)

9.4(4.3)

7.8(3.5)

7.4(3.8)

8.2(4.9)

9.9(5.1)

All values mean (SD)

CONSORT ART study results: CONSORT ART study results: Treatment Treatment (ITT population)(ITT population)

75 IU

(n=48)

112.5 IU

(n=45)

150 IU

(n=34)

187.5 IU

(n=24)

225 IU

(n=10)

All

(n=161)

Total FSH dose, IU

1102(672)

1287(447)

1632(341)

2044(276)

2573(552)

1498(648)

FSH duration days

12.5(4.4)

11.0(2.9)

10.6(1.8)

11.0(1.4)

11.5(2.4)

11.4(3.1)

Oocytes retrieved

8.3(4.5)

9.6(6.5)

12.1(6.4)

12.7(4.3)

8.3(3.8)

10.3(5.7)

No. cycles cancelled (%)

12(25.0)

4(8.9)

4(11.8)

2(8.3)

2(20.0)

24(14.9)

All values mean (SD) unless stated otherwise

CONSORT ART study results: CONSORT ART study results: Outcome Outcome (ITT population)(ITT population)

75 IU(n=48)

112.5 IU(n=45)

150 IU(n=34)

187.5 IU(n=24)

225 IU(n=10)

All(n=161)

Embryos transferred

1.9(0.9)

1.8(0.7)

2.0(0.8)

2.0(0.6)

1.4(1.1)

1.9(0.8)

No. clinical pregnancies (rate per cycle, %)

15(31.3)

14(31.1)

12(35.3)

12(50.0)

2(20.0)

55(34.2)

No. multiple pregnancies (rate per cycle, %)

3(20.0)

2(14.3)

4(33.3)

3(25.0)

0(0.0)

12(21.8)

Implantation rate (%)

36.5 (42.8)

24.3 (35.0)

28.2 (38.9)

37.1 (40.5)

11.9 (20.9)

29.8 (38.5)

Implantation rate = number of gestational sacs/total number of embryos transferred by patient

All values mean (SD) unless stated otherwise

Oocytes Retrieved in Original Database Oocytes Retrieved in Original Database and CONSORT ART studyand CONSORT ART study

CONSORT ART STUDY

ORIGINAL DATABASE

What’s the future of the CONSORT What’s the future of the CONSORT calculator?calculator?

• Lowest starting dose 112.5 IU More data required to understand characteristics of

patients who respond to 75 IU

• More work to develop suitable tool for women >35 years of age

New CONSORT ART StudiesNew CONSORT ART Studies

CONSORT RCT in ART

• Comparison of Individualised GONAL-f dose using CONSORT calculator vs standard practice

CONSORT in ART Registry

• Test acceptability of CONSORT calculator via a web site

CONSORT ART Web-Based CONSORT ART Web-Based CalculatorCalculator

CONSORT clinical investigators CONSORT clinical investigators and expert paneland expert panel

Merck Serono project participantsC Howles, H Saunders, P Engrand, V Alam, S Bustion, S Gerin

Expert panelA Borini (Italy); M Germond (Switzerland); F Olivennes (France);

G Trew (UK); M Wikland (Sweden); F Zegers (Chile)

Study groupP Barri Rague, A Borini, G D’Amato, D De Ziegler, M Fernandez,

M Germond, T Hahn, JAM Kremer, JSE Laven, M Ludwig,N Macklon, A Obruca, F Olivennes, T Tanbo, H Tournaye, G Trew,

M Tsirigotis, M Wikland, Y Yang, F Zegers-Hochschild

• Currently there is no one single reliable predictor of ovarian reserve and hence response.

• The ‘ideal’ protocol for patients of advanced maternal age or poor response has still not been adequately defined

• Combinations of factors in particular bFSH, BMI, AMH, AFC in predictive models have now been shown to have high predictive value more studies needed to validate models

The CONSORT FSH starting dose calculator results are encouraging and deserve further investigation

Predictive Factors of Predictive Factors of Ovarian Response Ovarian Response

SummarySummary