Effect of Estrogen Plus Progestin on Progression of Carotid Atherosclerosis in Postmenopausal Women With Heart Disease

Abstract

Objective-The Heart and Estrogen/Progestin Replacement Study (HERS) found no overall effect of estrogen plus progestin (compared with placebo) on coronary event rates in 2763 postmenopausal women with established coronary disease (mean 4.1 years of follow-up). In addition to the events trial, a carotid ultrasound substudy was established in 1993 to be conducted concurrently to determine whether hormone therapy affects the progression of the underlying atherosclerotic process. Methods and Results-Within the larger HERS, a subset of 362 participants underwent carotid B-mode ultrasound examinations at baseline and the end of follow-up. Progression of carotid atherosclerosis was measured as the temporal change in intimal-medial thickness (IMT). Conclusions-IMT progressed in the hormone treatment and placebo groups, although there was no statistical difference between the rates: IMT progressed 26 m/y (95% CI 18 to 34 m/y) in the hormone group and 31 m/y (95% CI 21 to 40 m/y) in the placebo group (Pϭ0.44). There were also no significant treatment effects when the results were examined by carotid segment or were adjusted for covariates. These data support the American Heart Association recommendation that women with established coronary disease should not initiate hormone therapy with an expectation of atherosclerotic benefit. Key Words: women Ⅲ secondary prevention Ⅲ hormone therapy Ⅲ carotid artery disease Ⅲ atherosclerosis N umerous observational studies have documented that compared with nonusers, users of postmenopausal hormone replacement have lower rates of coronary events 1-3 and less extensive coronary and carotid atherosclerosis. 4 -7 Estrogen therapy can decrease LDL cholesterol (LDL-C), increase HDL cholesterol (HDL-C), improve endothelial function, and favorably affect other factors thought to play a role in the pathogenesis of atherosclerosis. 8 -11 Estrogen also inhibits the development of atherosclerosis in animal models. 12,13 Despite the abundance of data from observational studies suggesting that estrogen should be beneficial for the prevention of coronary heart disease (CHD), the Heart and Estrogen/ Progestin Replacement Study (HERS), the first large randomized trial examining secondary prevention with hormones in women, found no effect of estrogen plus progestin (EϩP) on the rate of CHD events in women with established coronary disease over an average treatment period of 4.1 years. 14,15 It was originally noted that within the overall null effect, there were more coronary events in the hormone-treated group in the first year of follow-up and fewer coronary events in years 3 through 5. In an extended posttrial observational follow-up, however, there was no evidence of differences in CHD outcomes between the 2 treatment groups. 16 To examine the effects of estrogen plus medroxyprogesterone acetate on the progression of atherosclerotic disease, a prespecified substudy was established in 1993 in which a subset of HERS participants underwent carotid B-mode ultrasound examinations at baseline and at th...

Surrogate Markers for Cardiovascular Disease

“…Consider also the report of the neutral effect of HRT on the progression of carotid atherosclerosis. 62 This result is dissonant with the fact that women using active HRT had a poorer clinical outcome, perhaps related to other actions of HRT not affecting atherosclerosis. Thus, despite examples of concordance between outcome trials and carotid atherosclerosis regression trials, the net benefit of any given therapy is determined by a variety of factors that may not be reflected in changes or lack of changes in carotid IMT.…”

“…3,[52][53][54] Carotid IMT has been used as an end point in clinical trials of several drug classes, including lipid-lowering drugs, [55][56][57][58][59] antihypertensive agents, 60,61 and hormone replacement therapy (HRT). 62 However, use of change in surrogate end points to predict clinical outcome is statistically and mechanistically complex. Many studies show that statins reduce events and reduce carotid atherosclerosis.…”

Estrogen Plus Progestin and the Risk of Peripheral Arterial Disease

“…[2][3][4] Randomized trials have provided variable results. Trials using conjugated estrogens with medroxyprogesterone acetate, 5 estradiol with gestodene, 6,7 and estradiol with norgestrel 8 found no effect on carotid or femoral artery intimamedia thickness. In contrast, unopposed estradiol did reduce progression of ultrasonographic carotid disease.…”

Short-term oral progesterone administration antagonizes the effect of transdermal estradiol on endothelium-dependent vasodilation in young healthy women

“…The administration of estradiol has also been demonstrated to increase FMD compared with hormone-suppressed values (5,10,11,25,26,47). However, cardiovascular responses to different types of exogenous progestogen administration widely vary (1,7,23,36). Our laboratory has previously shown that levonorgestrel, desogestrel, and medroxyprogesterone acetate (MPA) all antagonized the effects of ethinyl estradiol on FMD (25,26,47).…”