The Long-Term Effects of Oral and Transdermal Postmenopausal Hormone Replacement Therapy on Nitric Oxide, Endothelin-1, Prostacyclin, and Thromboxane

Abstract

Objective: Oral postmenopausal hormone replacement therapy (HRT) decreases the risk of cardiovascular disorders, but the mechanisms of this protection are largely unknown. We compared the long-term effects of sequential 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 against cardiovascular disorders. Design: Prospective, randomized study. Setting: Department of Obstetrics and Gynecology at a university hospital. 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 μg/d of estradiol on days 1–28 followed by 250 μg/d of norethisterone acetate on days 14–28; n = 21) for 1 year. Ten female smokers received transdermal HRT for 1 year. Main Outcome Measure(s): Plasma levels of nitrate as an index of nitric oxide production, endothelin-1, and urinary output of the prostacyclin metabolite (2,3-dinor-6-keto-PGF 1α) and that of the thromboxane A 2 metabolite (2,3-dinor-thromboxane B 2) were measured before and during the combined phases of the 2nd, 6th, and 12th treatment months. Result(s): Both regimens increased plasma estradiol levels and alleviated vasomotor symptoms. Neither regimen caused significant changes in nitrate, endothelin-1, prostacyclin, or thromboxane A 2 in nonsmoking women. Female smokers had significantly higher levels of endothelin-1, which were significantly reduced by transdermal HRT at 6 months of treatment. Conclusion(s): Nitric oxide, endothelin-1, prostacyclin, and thromboxane A 2 are not of primary importance in the protective effect of sequential oral HRT against cardiovascular disorders in otherwise healthy nonsmoking postmenopausal women. In this regard, transdermal HRT appears comparable to oral HRT. Postmenopausal female smokers have high levels of endothelin-1 that are reduced by transdermal HRT.