Predictive Factors of Ovarian Response

Colin M Howles Vice President Scientific Affairs Global Medical Affairs Merck Serono International SA, Geneva

What I would like to do in this 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 this 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 place over a 6 month period

ESHRE Capri Workshop Fertility and Aging Hum Reprod Update 2005

Age-related germ cell loss
Germ cells (millions)
7 6

Baker, 1972
5 4 3 2 1 0.6 0.3
Birth

3 6 9 Months p.c

5 10

20 30 Years

40 50

Age

There is a steep decline in the population of human ovarian follicles after 35 years of age
106
105

Follicular counts

104 103 102 101 100

0

10

20

30

40

50

60

70

80

Age (years)
Gougeon et al. Biol Reprod 1994 50:653-663

Intervene before FSH driven recruitment phase

What I would like to do in this 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 fall 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 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 comparing r-hFSH vs r-hFSH + r-hLH (>= 35 yrs)

Engrand and Loumaye 2003

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

Favours r-hFSH

Favours r-hFSH + r-hLH
(Mochtar MH, Cochrane Database, 2007)

What I would like to do in this lecture
• • •
Briefly review ovarian physiology Markers of ovarian reserve and factors affecting ovarian response Discuss development of predictive models and application in ART

to

Chance of spontaneous pregnancy

• Identify Predictive factors • Construct a Prediction Model • Validate Model using similar group of patients from another centre using a standardised stimulation protocol

Hunault 2004 Steures 2004 Custer 2007 Templeton 1996 Popovic 2003 Howles 2006

Probability of pregnancy after IUI
− −

Probability of pregnancy after IVF

Prediction of ovarian response in ART
− −

OI Response to stimulation (CC/FSH) and pregnancy
− − − −

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

Model to predict ovarian response in ART Popovic-Todorovic et al. 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 Popovic-Todorovic B et al. Hum Reprod 2003;18:781–7 .1 (150 IU/day) Popovic-Todorovic B et al. Hum Reprod 2003;18:2275–82 .2

• • • • • • • •

15 routinely measured parameters were analysed from FSH only stimulated cycles (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
(Howles et al 2006)
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

Most important predictive factors:
1. 2. 3. 4.

Basal FSH BMI Age Antral follicle count

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

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

• 161 patients received an individualized starting
75 IU n=48 112.5 IU n=45 150 IU n=34 187.5 IU n=24 225 IU n=10

dose between 75 IU and 225 IU (ITT population)
n=161

CONSORT ART study results: Demographics
75 IU n Age, years BMI, kg/m2 Basal FSH, IU/L Number of antral follicles <11 mm 48 29.1
(3.5)

112.5 IU 45 31.4
(2.3)

150 IU 34 32.2
(1.8)

187.5 IU 24 32.2
(1.8)

225 IU 10 33.3
(1.9)

All 161 31.3
(2.9)

21.6
(2.7)

22.3
(2.2)

22.8
(2.7)

23.1
(3.1)

23.2
(2.3)

22.4
(2.7)

5.79
(1.4)

6.57
(1.7)

6.14
(1.3)

7.34
(1.4)

8.10
(2.0)

6.46
(1.6)

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: Treatment
(ITT population)
112.5 IU (n=45) 1287
(447)

75 IU (n=48) Total FSH dose, IU FSH duration days Oocytes retrieved No. cycles cancelled (%) 1102
(672)

150 IU (n=34) 1632
(341)

187.5 IU (n=24) 2044
(276)

225 IU (n=10) 2573
(552)

All (n=161) 1498
(648)

12.5
(4.4)

11.0
(2.9)

10.6
(1.8)

11.0
(1.4)

11.5
(2.4)

11.4
(3.1)

8.3
(4.5)

9.6
(6.5)

12.1
(6.4)

12.7
(4.3)

8.3
(3.8)

10.3
(5.7)

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: Outcome
(ITT population)
75 IU 112.5 IU 150 IU 187.5 IU (n=48) (n=45) (n=34) (n=24) Embryos transferred No. clinical pregnancies (rate per cycle, %) No. multiple pregnancies (rate per cycle, %) Implantation rate (%) 1.9
(0.9)

225 IU All (n=10) (n=161) 1.4 (1.1) 2
(20.0)

1.8 (0.7) 14
(31.1)

2.0 (0.8) 12
(35.3)

2.0 (0.6) 12
(50.0)

1.9 (0.8) 55
(34.2)

15
(31.3)

3
(20.0)

2
(14.3)

4
(33.3)

3
(25.0)

0
(0.0)

12
(21.8)

36.5
(42.8)

24.3
(35.0)

28.2
(38.9)

37.1
(40.5)

11.9
(20.9)

29.8
(38.5)

All values mean (SD) unless stated otherwise Implantation rate = number of gestational sacs/total number of embryos transferred by patient

Oocytes Retrieved in Original Database and CONSORT ART study
ORIGINAL DATABASE

CONSORT ART STUDY

What’s the future of the CONSORT 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 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 Calculator

CONSORT clinical investigators and expert panel
Study group P 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 Expert panel A Borini (Italy); M Germond (Switzerland); F Olivennes (France); (G Trew (UK); M Wikland (Sweden); F Zegers (Chile Merck Serono project participants C Howles, H Saunders, P Engrand, V Alam, S Bustion, S Gerin

Predictive Factors of Ovarian Response
Summary
• 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 AMH, AFC in predictive models have now been shown to have high predictive value more studies needed to validate models

• Combinations of factors in particular bFSH, BMI,

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