THE LONG-TERM EFFECTS OF ORAL AND TRANSDERMAL POSTMENOPAUSAL HORMONE REPLACEMENT THERAPY ON NITRIC-OXIDE, ENDOTHELIN-1, PROSTACYCLIN, AND THROMBOXANE

Objective: Oral postmenopausal hormone replacement therapy (HRT) decre ases the risk of cardiovascular disorders, but the mechanisms of this protection an largely unknown. We compared the long-term effects of se quential oral HRT and transdermal HRT on vasodilatory nitric oxide and prostacyclin as well as vasoconstrictive endothelin-1 and thromboxane A(2), all of which may be factors in the protective effect of HRT aga inst cardiovascular disorders. Design: Prospective, randomized study. Setting: Department of Obstetrics and Gynecology at a university hospi tal. Patient(s): Fifty-two healthy postmenopausal female nonsmokers (n = 42) or smokers (n = 10) who had climacteric symptoms. Intervention( s): The women received either oral HRT (2 mg of estradiol on days 1-12 , 2 mg of estradiol plus 1 mg of norethisterone acetate on days 13-22, and 1 mg of estradiol on days 23-28; n = 21) or transdermal HRT (50 m u g/d of estradiol on days 1-28 followed by 250 mu g/d of norethistero ne acetate on days 14-28; n = 21) for 1 year. Ten female smokers recei ved transdermal HRT for 1 year. Main Outcome Measure(s)): Plasma level s of nitrate as an index of nitric oxide production, endothelin-1, and urinary output of the prostacyclin metabolite (2,3-dinor-6-keto-PGF(1 alpha)) and that of the thromboxane A(2) metabolite (2,3-dinor-thromb oxane B-2) were measured before and during the combined phases of the 2nd, 6th, and 12th treatment months. Result(s): Both regimens increase d plasma estradiol levels and alleviated vasomotor symptoms. Neither r egimen caused significant changes in nitrate, endothelin-1, prostacycl in, or thromboxane A(2) in nonsmoking women. Female smokers had signif icantly higher levels of endothelin-1, which were significantly reduce d by transdermal HRT at 6 months of treatment. Conclusion(s): Nitric o xide, endothelin-1, prostacyclin, and thromboxane A(2) are not of prim ary importance in the Hospital. protective effect of sequential oral H RT against cardiovascular disorders in otherwise healthy nonsmoking po stmenopausal women. In this regard, transdermal HRT appears comparable to oral HRT. Postmenopausal female smokers have high levels of endoth elin-1 that are reduced by transdermal HRT.