Quelle modulation du Recepteur des Oestrogènes pour quels bénéfices? Jean-Francois Arnal, MD, PhD
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1 Quelle modulation du Recepteur des Oestrogènes pour quels bénéfices? Jean-Francois Arnal, MD, PhD INSERM U1048, Equipe 9, CHU et Université de Toulouse III
2 Pleiotropic effects of estrogens : protective vs harmful Reproduction / sexual characters Breast Uterus CNS Testosterone aromatase Estradiol (E2) Immunity bone ER! ER" skin Cardio-vascular and metabolic homeostasis
3 Cardiovascular actions of estrogens (E) Epidemiological : Sex difference before menopause Cohort (Nurse!s) s) : Early Menopause No delay Women Health Initiative : Hysterectomized : E alone coronary events Men Women No treatment Hormone treatment E+P placebo E alone 52 years 63 years Endogenous E : Protective Early exogenous E+P : Protective Delayed E alone : inefficient
4 50-59 ans CEE better ans Placebo better ans
5 Question 1 : Are estrogens protective against atheroma and their thrombotic complications (acute coronary syndrome)
6 WHI 2004 : Relative Risk of Coronary Heart Desease of Estrogen alone / placebo early E almost protective but delayed E is not Importance of the timing
7 Very similar to the Monkey studies (Cardiovasc. Res. 2002) Endogenous E2 Surgical menopause Exogenous E2 No delay Delay = 6 post-menopausal years for women
8 Question 1 : Are estrogens protective against atheroma and their thrombotic complications (acute coronary syndrom) Endogenous and exogenous E are protective early : primary prevention in animal and humans. but not when delayed or in secondary prevention (Reviewed in Lenfant et al. Maturitas 2011)
9 Question 2 : Which estrogen receptor does mediate the vasculoprotective action of estrogen?
10 Respective roles of each Estrogen Receptors (ER) in the vascular actions of E2? N-ter C-ter ER! AF1 AF2 AF2 DBD LBD AF2 A/B C D E F ER" AF1 AF2 DBD LBD AF2 A/B C D E F DBD : DNA Binding Domain, LBD : Ligand Binding Domain, AF : Activation Function Pubmed : respective roles of ER! and ER" unclear
11 Estrogen receptor! mediates most of the protective / beneficial actions of E2 including : - arteries (atheroma, endothelial healing), - metabolism (accumulation of adipose tissue, insulino-resistance), - bone (demineralization, fractures). - prevention of hot flushes But also of the undesired / deleterious actions : - breast and endometrium (increased cancer risk) - VTE / oral route. Hepatic target
12
13 Question 3 : Is it possible to uncouple these benefical actions of estrogens from their deleterious actions? Already achieved by Selective ER Modulators (SERMs) such as tamoxifen : - prevents breast cancer - prevents osteoporosis but not vasculoprotective nor Type 2 diabetes
14 66 kd ER! AF1 AF2 AF2 DBD LBD AF2 N-ter A/B C D E F C-ter Mouse models : Molecular dissection of ER! functions ER! Neo «KO» 55 kd ER! AF1 AF2 DBD LBD AF2 ER! AF kd ER! AF1 AF2 DBD LBD AF2
15 Final goal : Uncoupling beneficial/desirable and deleterious actions of ER!. contribute to the design of SERMs (JF Arnal et al. Br. J. Pharmacol. 2011) ER! Atheroma (endothelium) AF1 Indep. AF2 Dependent. MISS? Obesity/Metab. Cortical bone Indep. Indep. Dependent. Dependent.?? Reendothelial. Indep. Indep. Sufficient Fertility Dependent Dependent? Uterine growth (endometrium) Dependent Dependent? Breast cancer Dependent In vitro (Flouriot et al.) Dependent?
16 Activation of Discrete ER! Functions=>new optimized SERMs Selective Extra-nuclear ER Activation or Selective AF-2 Activation ER_ A/B C D E (AF -1) ER_! * * * (AF-2) F Beneficial Detrimental Also? Breast Cancer Reproductive Tract Cancer Thrombosis Cardiovascular Protection Obesity, Insulin resistance Osteopenia
17 Activation of AF1 Activation of AF2 and/or MISS Deleterious Beneficial Enterolactone (ENL) Estetrol (E4)
18 P Chambon INSERM U858 Team 9 P. Gourdy F. Lenfant H. Laurell C. Fontaine L. Brouchet F. Trémollières C. Burgos M.J. Fouque F. Boudou JC. Albouys H. Berges A. Fabre A. Billon E. Riant C. Pequeux MC. Valera A. Abot S. Handgraff C. Chenu A. Vinel P. Monsarrat Tse: JC Guéry, R Burcelin, B Payrastre, M Laffargue R & A Salvayre, B Pipy Strasbourg : P Chambon, A Krust, D. Metzger Rennes : G Flouriot Bordeaux : AP Gadeau Angers : D. Henrion Lyon: M. Leromancer Paris : Z Mallat, A Tedgui, JB Michel, A Herbelin G Nickenig (Bonn) JM Foidart (Liège) KS Korach (NIH USA)
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