i ntroduction d’androgènes en contraception orale ( androgen restored contraception-arc)
DESCRIPTION
I ntroduction d’androgènes en contraception orale ( Androgen Restored Contraception-ARC). J.M. Foidart *, A.Pintiaux *, A.Béliard * et H. Coeling - Bennink ** 12 èmes Journées Liégeoises de Gynécologie-Obstétrique, Liège, le 25 septembre 2009 * Université de Liège, Belgique - PowerPoint PPT PresentationTRANSCRIPT
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Introduction d’androgènes en contraception orale
(Androgen Restored Contraception-ARC)
J.M. Foidart*, A.Pintiaux*, A.Béliard * et H. Coeling-Bennink**
12èmes Journées Liégeoises de Gynécologie-Obstétrique,Liège, le 25 septembre 2009
*Université de Liège, Belgique** Pantarhei, Holland
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Rôle des androgènes
• Les androgènes sont des précurseurs essentiels des oestrogènes. et sont indispensables à la croissance folliculaire.
• Le maintien d’une balance androgènes/ oestrogènes précise au sein des follicules est essentiel pour la maturation folliculaire.
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• De nombreux tissus (SNC, muscles, os…) ont des récepteurs aux androgènes ce qui suggère que les androgènes puissent y jouer un rôle.
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Fonction cognitive • Le traitement de personnes ménopausées ou
ovariectomisées par des E ou des androgènes peut améliorer leurs émotions, leur bien-être, leur énergie, leur appétit et leurs fonctions cognitives. Dans plusieurs essais randomisés, en double aveugle, placebo-contrôle, un traitement par des E seul, des E+T ou un placebo a amélioré significativement les scores d’anxiété et de dépression des femmes traitées par E ou E+T.
• L’amélioration des scores présentait une tendance à être supérieure dans le groupe E+T par rapport au groupe E.
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Rôle dans le comportement sexuel
• La libido féminine dépend de nombreux facteurs, y compris psychologiques. Un équilibre entre oestrogènes et androgènes peut également être nécessaire au désir et à la réactivité sexuelle.
• L’administration de DHEA à de jeunes femmes insuffisantes surrénaliennes améliore leur sexualité.
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Certains traitements réduisent l’effet des androgènes
• La contraception orale, les glucocorticoïdes provoquent une chute relative des androgènes par freination surrénalienne et ovarienne.
• Les oestrogènes oraux même à faibles doses augmentent les taux de SHBG et réduisent la T libre.
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Coenen CM, et al Changes in androgens during treatment with four low-dose contraceptives. Contraception. 1996;53:171-6
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ARC- AMUSA Study
Study Design
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ARC - proof of concept
• Double-blind, randomised study in 138 young, healthy, female volunteers
• Before study: an oral OC for at least 3 menstrual cycles
• Study medication taken once daily for 105 days
• Lowette®: 20 µg ethinyl estradiol (EE)/ 100 µg levonorgestrel (Lng) • 50 mg DHEA (n=55) • placebo (n=55)
• Microgynon 30® : 30 µg EE/ 150 µg Lng• 50 mg DHEA (n=14)• placebo (n=14)
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ARC – proof of concept
Testosterone/SHBG ratio
Day 1 Day 105 Day 1 Day 105
DHEA Placebo
0
0.01
0.02
0.03
0.04
0.05OC -1
OC -2
Testosterone/SHBG ratio
Day 1 Day 105 Day 1 Day 105
DHEA Placebo
0
0.01
0.02
0.03
0.04
0.05OC -1
OC -2
0
0.01
0.02
0.03
0.04
0.05Free testosterone (nmol/L)
Day 1 Day 105 Day 1 Day 105
DHEA Placebo
OC -1
OC -2
0
0.01
0.02
0.03
0.04
0.05Free testosterone (nmol/L)
Day 1 Day 105 Day 1 Day 105
DHEA Placebo
OC -1
OC -2
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ARC – proof of concept (II)Increased testosterone levels after intake of 50 mg DHEA plus an oral contraceptive in 138 young healthy
women
30µg EE/Lng
20µg EE/Lng
Total testosterone (nmol/L)
Day 1 Day 105 Day 1 Day 105
50 mg DHEA Placebo
Normal physiological range
0
1
2
3
4
5
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Study Title
A double-blind, placebo controlled, randomized, comparative, mono-centre trial to assess the effects on the androgen metabolism
and its effects on biochemical parameters, mood, fat, muscle and bone of continuous
supplementation with dehydroepiandrosterone in women using a monophasic contraception containing drospirenone and ethinylestradiol
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Study ObjectivesPrimary objective: To assess the biochemical effects on androgen
metabolism, estradiol, lipid metabolism and bone turn-over of DHEA supplementation to EE/DRSP OC
Secondary objectives: To evaluate the effects of DHEA supplementation
on mood, quality of life, sexual functioning, menstrual symptoms and body composition
To evaluate general safety and acceptability of continuous DHEA supplementation
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Study Design (I)Design: A randomized, double-blind, placebo
controlled, comparative mono-centre trial
Subjects:100 subjectsCOC naive (> 3 months no COC use)age 18-35
Treatment: Group 1 - COC plus DHEA Group 2 - COC plus placebo
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Study Design (II)
COC plus placebo
Treatment period6 cycles
Randomisation
Run-in Period3 cycles COC only
Screening
COC plus DHEA
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ARC-AMUSA Run-in Period
Preliminary Results
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Total TestosteroneChange in Total T levels after 3 months of COC (Yasmin®)
use in 60 women
maximum
minimum
90th centile
10th centile
0
0.5
1
1.5
2
2.5
3
3.5
Prior to COC use after 3 months COC use
Duration of COC use
Tota
l T (n
mol
/L)
median P<0,0001
Source: ARC-AMUSA study (PRB data on file)
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Free TestosteroneChange in free T levels after 3 months of COC (Yasmin®)
use in 60 women
maximum
minimum
90th centile
10th centile
0
10
20
30
40
50
60
Prior to COC use after 3 months COC use
Duration of COC use
Free
Tes
tost
eron
e (p
mol
/L)
P<0,0001
median
Source: ARC-AMUSA study (PRB data on file)
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SHBG
median
maximum
minimum
90th centile
10th centile
0.0
50.0
100.0
150.0
200.0
250.0
300.0
350.0
400.0
450.0
Prior to COC use after 3 months COC use
Duration of OC use
SHBG
(pm
ol/m
L)
median
Source: ARC-AMUSA study (PRB data on file)
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Total T and SHBG
Change in Total T and SHBG levels after 3 months of COC (Yasmin®) use in 60 women
Total T (nmol/L) SHBG (pmol/mL)
0.0
50.0
100.0
150.0
200.0
250.0
300.0
350.0
400.0
450.0
Prior to COC use after 3 months COC use
Duration of COC use
SHBG
(pm
ol/m
L)
P<0,0001
median
P<0,0001
maximum
minimum
90th centile
10th centile
0
0.5
1
1.5
2
2.5
3
3.5
Prior to COC use after 3 months COC use
Duration of COC use
Tota
l T (n
mol
/L)
P<0,0001median
Source: ARC-AMUSA study (PRB data on file)
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Free T and SHBG
Change in Free T and SHBG levels after 3 months of COC (Yasmin®) use in 60 women
Free T (pmol/L), calc SHBG (pmol/mL)
0.0
50.0
100.0
150.0
200.0
250.0
300.0
350.0
400.0
450.0
Prior to COC use after 3 months COC use
Duration of OC use
SHBG
(pm
ol/m
L)
P<0,0001
maximum
minimum
90th centile
10th centile
0
10
20
30
40
50
60
Prior to COC use after 3 months COC use
Duration of OC use
Free
Tes
tost
eron
e (p
mol
/L)
median
P<0,0001
Source: ARC-AMUSA study (PRB data on file)
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Bioavailable Testosterone
minimum
90th centile
maximum
10th centile
0.00
0.20
0.40
0.60
0.80
1.00
1.20
1.40
1.60
Prior to COC use after 3 months COC use
Duration of OC use
Bio-
avai
l. Te
st. (
nmol
/L)
median
Source: ARC-AMUSA study (PRB data on file)
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Androstanediol glucuronide
maximum
minimum
90th centile
10th centile
0.00
5.00
10.00
15.00
20.00
25.00
Prior to COC use after 3 months COC use
Duration of OC use
andr
osta
nedi
ol g
lucu
roni
de (n
mol
/L)
median
Source: ARC-AMUSA study (PRB data on file)
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DHEA-S
maximum
minimum
90th centile
10th centile
0
2000
4000
6000
8000
10000
12000
Prior to COC use after 3 months COC use
Duration of OC use
DH
EA-S
(nm
ol/L
)
median
Source: ARC-AMUSA study (PRB data on file)
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Treatment Extension Prolongation Study Treatment: 6 months
Primary objective: To assess the effects of DHEA supplementation on
the bone mineral density
Secondary objective: To obtain long-term general safety and acceptability of
continuous DHEA supplementation