Early hormone therapy in menopause doesn't seem to affect atherosclerosis progression

Hormone therapy begun early in menopause improved some markers of cardiovascular disease (CVD) risk but did not appear to affect atherosclerosis progression, a study found.

Researchers performed a randomized, controlled trial at 9 U.S. academic medical centers to examine CVD risk factors and progression of atherosclerosis after hormone therapy was begun in early menopause. Healthy menopausal women who were 42 to 58 years of age and were 6 to 36 months from their last menses were included. Other inclusion criteria were no previous CVD events, a coronary artery calcium score below 50 Agatston units, and at least 90 days without receipt of estrogen or lipid-lowering drugs.

The patients were randomly assigned to receive oral conjugated equine estrogens (o-CEE), 0.45 mg/d, plus 200 mg of oral progesterone for 12 days each month; transdermal 17beta-estradiol (t-E₂), 50 mcg/d, plus 200 mg of oral progesterone for 12 days each month; or placebo. Duration of treatment was 48 months. The primary end point was annual change in carotid artery intima-media thickness, while secondary end points included changes in CVD risk markers. The study results were published early online July 29 by Annals of Internal Medicine.

Seven hundred twenty-seven women were randomly assigned, 230 (31.6%) to the o-CEE group, 222 (30.5%) to the t-E₂ group, and 275 (37.8%) to the placebo group. The mean age was 52.7 years, and patients were an average of 1.4 years past menopause. Among those who reported education and income, 72% had college degrees or higher and 62% earned more than $60,000 annually. Of the 727 women in the study, 89.3% had at least one follow-up measurement of carotid artery intima-media thickness and 79.8% had carotid artery intima-media thickness measured at 48 months. The mean increase in carotid artery intima-media thickness, 0.0076 mm/year, was similar across the study groups. Changes in blood pressure from baseline were not observed in either active treatment group compared with placebo.

A total of 85.7% of women reported hot flushes at baseline. At 6 months, moderate or severe hot flushes were reported by 28.3% of women in the placebo group, compared with 4.2% and 7.4%, respectively, in the o-CEE and t-E₂ groups (P<0.001). Levels of low- and high-density lipoprotein improved in patients taking o-CEE, and levels of C-reactive protein and sex hormone-binding globulin increased; however, levels of interleukin-6 did not. Patients taking t-E₂ experienced a decrease in insulin resistance.

Although the placebo group reported more vasomotor symptoms throughout the study, the differences between those taking hormones and those taking placebo attenuated, and the t-E₂ group no longer differed significantly from the placebo group at 48 months. Over 48% of the women in the study reported at least 1 adverse event, most commonly skin and hair changes. Sixteen, 9, and 12 women, respectively, withdrew from the o-CEE, t-E₂, and placebo groups after experiencing adverse events, half of which were considered possibly or probably study-related in the t-E₂ and placebo groups and almost two-thirds of which were considered possibly or probably study-related in the o-CEE group.

The authors noted that their study was too short and too small to allow them to determine the implications of clinical CVD or other adverse events. In addition, they said, the study's power for the end point of coronary artery calcium score was limited, and other factors associated with CVD risk such as oxidation, inflammation, and thrombosis, were not considered. They also pointed out that their study sample, which included mainly well-educated white women, was not fully representative of the overall postmenopausal population in the U.S. Because the women in the current study were relatively healthy, moreover, the results may not apply to those at higher risk for CVD, such as women who smoke.

The authors concluded that in women who have low CVD risk and who have recently become menopausal, 4 years of therapy with low-dose oral or transdermal estrogen and cyclic oral progesterone improved vasomotor symptoms of menopause with no deleterious effects on blood pressure and no apparent effect on progression of atherosclerosis. They pointed out that these findings provide reassurance of the relative cardiovascular safety of hormone therapy for relief of menopausal symptoms recommended in guidelines by the North American Menopause Society and other groups in women with low risk for CVD complications.

“Although some markers for CVD improved, [menopausal hormone therapy] neither improved nor worsened atherosclerosis progression,” the authors wrote. “The long-term effects of early initiation of [menopausal hormone therapy] on risk for CVD are uncertain.”