Acute improvement of peripheral endothelial function in postmeno- pausal women with coronary artery disease after single oral intake of 17β-estradiol valerate

Summary:

Chronic estrogen supplementation is known to improve endothelial function in postmenopausal women. We studied the acute effect of a single dose of orally administered 17β-estradiol valerate (E2) on the peripheral endothelial dependent and independent vasodilatation in postmenopausal women with coronary artery disease (CAD). 20 postmenopausal women (age: 64.9 (7.2) y, height: 1.61 (0.04) m, weight: 68.6 (10.6) kg) with angiographically confirmed CAD were randomly examined for flow-associated vasodilatation (= FAD%, a marker for endothelial dependent vasodilatation) and for glyceryltrinitrate (400 μg, p.o.) induced vasodilatation (=GTN%, representing endothelial independent vasodilatation) two hours after placebo controlled, randomized crossover intake of 4 mg E2 p.o. After placebo FAD% was impaired (3.5 (1.7)%) compared to historic controls. After the oral intake of 4 mg E2, FAD% improved to 5.0 (2.8) % (P = 0.02). GTN% was not significantly influenced by the oral E2 (E2: 12.6 (5.7) v placebo: 11.2 (6.9) %, P = 0.14). Endothelial dysfunction can partially be restored by a single oral dose of 4 mg E2. This indicates an acute vasoprotective effect of E2 beyond its genomic and lipid modifying actions. It remains to be investigated if estrogen might play a beneficial role in the acute treatment of symptomatic coronary artery disease such as angina pectoris or preinfarct syndrome.

Abbreviations: CAD coronary artery disease, DBP diastolic blood pressure, E2 17β-estradiol valerate, FAD% flow associated (vaso)dilatation derived as percentage change during reactive hyperemia relative to the baseline scan at rest (100%), GTN Glyceryltrinitrate, GTN% glyceryltrinitrate induced (vaso)dilatation derived as percentage change relative to the baseline scan at rest (100%), SBP systolic blood pressure.

Key words:

Postmenopause - endothelial function - oral application - 17β-estradiol valerate - acute effect

References

• 1 Anderson T J, Uehata A, Gerhard M D, Meredith I T, Knab S T, Delagrange D, Lieberman E L, Ganz P, Creager M, Yeung A C, Selwyn A P. Close relation of endothelial function in the human coronary and peripheral circulations.  J Am Coll Cardiol. 26 1235-1241 1995; 
• 2 Celermajer D S, Sorensen K E, Gooch V M, Spiegelhalter D J, Miller O I, Sullivan I D, Lloyd J K, Deanfield J E. Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis.  Lancet. 340 1111-1115 1992; 
• 3 Collins P, Rosano G MC, Sarrel P M, Ulrich L, Adamopoulos S, Beale C M, McNeill J G, Poole-Wilson P A. 17beta-Estradiol attenuates acetylcholine-induced coronary arterial constriction in women but not men with coronary heart disease.  Circulation. 92 24-30 1995; 
• 4 Davies P F, Tripathi S C. Mechanical stress mechanisms and the cell.  An endothelial paradigm. Circ Res. 72 239-245 1993; 
• 5 Enderle M D, Balletshofer B M, Schmuelling R M, Haering H U, Pfohl M. Early Detection of Atherosclerosis in Type 2 Diabetic Patients Using High Resolution Ultrasound.  Ultraschall Med. 19 16-21 1998; 
• 6 Enderle M D, Benda N, Schmuelling R M, Haering H U, Pfohl M. Preserved endothelial function compared with healthy subjects in IDDM patients, but not in NIDDM patients.  Diabetes Care. 21 271-277 1998; 
• 7 Enderle M D, Schroeder S, Ossen R, Meisner C, Baumbach A, Haering H U, Karsch K R, Pfohl M. Comparison of peripheral endothelial dysfunction and intima media thickness in patients with suspected coronary artery disease.  Heart. 80 349-354 1998; 
• 8 Hayashi T, Ishikawa T, Yamada K, Kuzuya M, Naito M, Hidaka H, Iguchi A. Biphasic effect of estrogen on neuronal constitutive nitric oxide synthase via Ca(2+)-calmodulin dependent mechanism.  Biochem Biophys Res Commun. 203 1013-1019 1994; 
• 9 Joswig M, Hach-Wunderle V, Ziegler R, Nawroth P P. Postmenopausal Hormone replacement Therapy and the Vascular Wall: Mechanisms of 17beta-estradiol's effects on vascular biology.  Exp Clin Endocrinol Diabetes. 107 477-487 1999; 
• 10 Kim-Schulze S, Lowe W L, Schnaper W. Estrogen stimulates delayed mitogen-activated protein kinase activity in human endothelial cells via an autocrine loop that involves basic fibroblast growth factor.  Circulation. 98 413-421 1998; 
• 11 Mendelsohn M E, Karas R H. Estrogen and the Blood Vessel Wall.  Curr Opin Cardiol. 9 619-626 1994; 
• 12 Morales D E, McGowan K A, Grant D S, Maheshwari S, Bhartiya D, Cid M C, Kleinman H K, Schnaper W. Estrogen promotes angiogenic activity in human umbilical vein endothelial cells in vitro and in a murine model.  Circulation. 91 755-763 1995; 
• 13 Pearce M, McIntyre T, Prescott S, Zimmerman G, Whatley R. Shear stress activates cytosolic phospholipase A2 (cPLA2) and MAP kinase in human endothelial cells.  Biochem Biophys Res Commun. 218 500-504 1996; 
• 14 Reis S E, Gloth S T, Blumenthal R S, Resar J R, Zacur H A, Gerstenblith G, Brinker J A. Ethinyl Estradiol Acutely Attenuates Abnormal Coronary Vasomotor Responses to Acethlcholine in Postmenopausal Women.  Circulation. 89 52-60 1994; 
• 15 Rosano G MC, Peters N S, Lefroy D, Lindsay D C, Sarrel P M, Collins P, Poole-Wilson P A. 17 beta-estradiol therapy lessens angina in postmenopausal women with syndrome X.  J Am Coll Cardiol. 28 1500-1505 1996; 
• 16 Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s.  Nature. 362 801-809 1993; 
• 17 Sullivan J M, Fowlkes L P. Estrogens, menopause, and coronary artery disease.  Cardiol Clin. 14 105-116 1996; 
• 18 Taddei S, Virdis A, Ghiadoni L, Mattei P, Sudano I, Bernini G, Pinto S, Salvetti A. Menopause is associated with endothelial dysfunction in women.  Hypertension. 28 576-582 1996; 
• 19 Tseng H, Peterson T E, Berk B C. Fluid shear stress stimulates mitogen-activated protein kinase in endothelial cells.  Circ Res. 77 869-878 1995; 
• 20 Wendelhag I, Gustavsson T, Suurkula M, Berglund G, Wikstrand J. Ultrasound measurement of wall thickness in the carotid artery: fundamental principles and description of a computerized analysing system.  Clin Physiol. 11 565-577 1991;