Effect of Oral Postmenopausal Hormone Replacement on Progression of Atherosclerosis

Abstract

Abstract-Postmenopausal hormone replacement therapy (HRT) is associated with low cardiovascular morbidity and mortality in epidemiological studies. Yet, no randomized trial has examined whether HRT is effective for prevention of coronary heart disease (CHD) in women with increased risk. bservational studies consistently found a 30% to 35% decreased risk of coronary heart disease (CHD) among postmenopausal women who use hormone replacement therapy (HRT). 1,2 There is no evidence that HRT influences the risk of stroke. 3 Several effects of estrogen on the cardiovascular system suggest a potential for protection. 4 The only randomized trial with clinical end points (Heart and Estrogen/ progestin Replacement Study, HERS) failed to demonstrate the efficacy of estrogen plus medroxyprogesterone for secondary prevention in women with CHD. 5 Among other reasons, medroxyprogesterone acetate, which is known to attenuate some of the beneficial effects of estrogen, 6 -9 has been discussed as a cause for the unexpected results of HERS. 10 Initiation of HRT after myocardial infarction is no longer recommended. 11 To date, no randomized trial has addressed the efficacy of HRT for women with increased risk for CHD who potentially benefit most, as indicated by epidemiological data. 1,12 Intima-media thickness (IMT) of the carotid arteries correlates with the presence, extent, and severity of atherosclerosis in coronary and other arteries. [13][14][15][16][17] IMT of the carotid arteries consistently and partially independently of traditional risk factors predicts future myocardial infarction and stroke. 18 -22 Change of carotid IMT is currently an established intermediate end point for clinical trials that study the inhibitory effect of an intervention on atherogenesis. 23,24 The present randomized, controlled, observer-blind trial investigated the hypothesis that HRT with estrogen and progestin inhibits progression of carotid artery IMT in postmenopausal women with increased IMT as a sign of subclinical disease and increased risk for CHD and stroke. It was further hypothesized that the inhibitory effect of estrogen balanced with low-dose progestin would be superior to the combination with high-dose progestin. Methods SubjectsBetween March 1995 and September 1996, women living in the greater Munich area who heard about the study through the local media contacted us for more detailed information (Figure). They were eligible if they had passed natural (cessation of bleeding) or surgical menopause for Ն1 year or, in case of hysterectomy, had follicle-stimulating hormone (FSH) levels Ͼ40 IU/L, were between 40 and 70 years old, had Ͼ1 mm IMT in Ն1 of the predefined segments of the carotid arteries, and gave informed consent. (For exclusion criteria, please see supplemental Methods section at

Effect of postmenopausal hormone replacement on atherosclerosis in femoral arteries

“…However, there are no trials with clinical endpoints to corroborate this concept. We and other workers have recently shown that HRT does not slow progression of carotid atherosclerosis in clinically healthy women [7,25]. Pooled data from randomized trials that focused mostly on bone-related outcome measures in primarily healthy women showed a non-significantly higher odds ratio for cardiovascular events in women taking HRT compared with those taking placebo [26].…”

“…Sample size estimation was based on similar assumptions as for the study on carotid atherosclerosis progression [7]: with reference to what had been demonstrated in another primary prevention trial, the annual atherosclerotic progression rate of IMT was estimated to be 0.049 0.04 mm in untreated women [17]. HRT was estimated to result in a 50% slowing of progression.…”

“…The change of IMT in the femoral arteries was the secondary outcome measure. The study design and the results of the primary outcome measure have been reported in detail elsewhere [7].…”

“…Only the far wall was considered for calculation of outcome measures since ultrasound measurement of the near wall underestimates the true histological thickness and proper visualization is often difficult [5,15]. The measurement of the carotid IMT has been described previously [7]. In brief, for the common and internal carotid artery and the carotid bifurcation, left and right side, the maximum IMT of the far wall was determined at study start and at study end, using the same angles of interrogation.…”

“…Some epidemiological studies suggested a reduced risk for angiographically significant coronary artery disease [1], and for atherosclerosis in the carotid arteries [2][3][4], whereas others observed no beneficial effect of HRT [5]. Randomized controlled trials demonstrated that oestrogen alone or combined with different doses of progestogen does not inhibit progression of atherosclerosis in coronary or carotid arteries of postmenopausal women [6,7].…”