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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 7
(millions)
6
Baker, 1972
5

1 Birth
0.6
0.3
3 6 9 5 10 20 30 40 50
Months p.c Years

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

105

104
Follicular counts

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
− Hunault 2004
• Identify Predictive ♦ Probability of pregnancy after IUI
factors
− Steures 2004
− Custer 2007
• Construct a Prediction ♦ Probability of pregnancy after IVF
Model − Templeton 1996
♦ Prediction of ovarian response in ART
− Popovic 2003
• Validate Model using − Howles 2006
similar group of patients ♦ OI Response to stimulation (CC/FSH)
from another centre and pregnancy
using a standardised − Imani 1998, 1999, 2002
stimulation protocol − 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
• Mean cycle length
• Weight
• Previous ART treatment
• BMI
• Number of previous ART
• Smoking history attempts
• Type of infertility • Basal FSH
(primary/secondary)
• Antral follicle count (<11 mm)
• Duration of infertility at screening
• Minimum cycle length • Number of follicles >11 mm
at screening
• Maximum cycle length
• 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. Basal FSH
2. BMI
3. Age
4. 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
dose between 75 IU and 225 IU (ITT population)

75 IU 112.5 IU 150 IU 187.5 IU 225 IU


n=48 n=45 n=34 n=10
n=161
n=24
CONSORT ART study results:
Demographics
75 IU 112.5 IU 150 IU 187.5 IU 225 IU All

n 48 45 34 24 10 161

Age, years 29.1 31.4 32.2 32.2 33.3 31.3


(3.5) (2.3) (1.8) (1.8) (1.9) (2.9)

BMI, kg/m2 21.6 22.3 22.8 23.1 23.2 22.4


(2.7) (2.2) (2.7) (3.1) (2.3) (2.7)

Basal FSH, IU/L 5.79 6.57 6.14 7.34 8.10 6.46


(1.4) (1.7) (1.3) (1.4) (2.0) (1.6)

Number of antral 13.4 9.4 7.8 7.4 8.2 9.9


follicles <11 mm (5.5) (4.3) (3.5) (3.8) (4.9) (5.1)

(All values mean (SD


CONSORT ART study results: Treatment
(ITT population)

75 IU 112.5 IU 150 IU 187.5 IU 225 IU All


(n=48) (n=45) (n=34) (n=24) (n=10) (n=161)
Total FSH 1102 1287 1632 2044 2573 1498
dose, IU (672) (447) (341) (276) (552) (648)

FSH duration 12.5 11.0 10.6 11.0 11.5 11.4


days (4.4) (2.9) (1.8) (1.4) (2.4) (3.1)

Oocytes 8.3 9.6 12.1 12.7 8.3 10.3


retrieved (4.5) (6.5) (6.4) (4.3) (3.8) (5.7)

No. cycles 12 4 4 2 2 24
cancelled (%) (25.0) (8.9) (11.8) (8.3) (20.0) (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 225 IU All
(n=48) (n=45) (n=34) (n=24) (n=10) (n=161)
Embryos 1.9 1.8 2.0 2.0 1.4 1.9
transferred (0.9) (0.7) (0.8) (0.6) (1.1) (0.8)
No. clinical 15 14 12 12 2 55
pregnancies (rate (31.3) (31.1) (35.3) (50.0) (20.0) (34.2)
per cycle, %)
No. multiple 3 2 4 3 0 12
pregnancies (rate (20.0) (14.3) (33.3) (25.0) (0.0) (21.8)
per cycle, %)
Implantation 36.5 24.3 28.2 37.1 11.9 29.8
rate (%) (42.8) (35.0) (38.9) (40.5) (20.9) (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
• 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