Women’s Health Initiative: Another look at hormone therapy

Risk for heart disease increased with age and years since menopause, stroke risk remained in all groups taking hormone therapy.

Issue: May 2007

In a secondary analysis of the Women’s Health Initiative, researchers found that women who started hormone therapy closer to menopause tended to have a reduced risk for coronary heart disease compared with women who started hormone therapy later after menopause. The difference, however, was not statistically significant.

Although HT is associated with an increased risk for stroke regardless of age or the time since menopause, younger women with moderate to severe menopausal symptoms can benefit from HT, according to the researchers.

The analysis was performed by Jacques Rossouw, MD, chief, Women’s Health Initiative Branch, National Heart, Lung, and Blood Institute, and colleagues. Their findings were published in the Journal of the American Medical Association.

“In these women, it works well for treatment of symptoms, but even in this group, there is some increased risk for stroke and breast cancer, particularly with the combination therapy,” Rossouw told Endocrine Today. “But if you look at the overall risks as shown by the global index, or total mortality in that group, [CHD] is not increased. This is somewhat reassuring for women, even those with severe symptoms, who might have been scared of taking [HT]. It’s a reasonable option if you’re using it close to menopause, for four to five years.”

The WHI study consisted of two trials conducted during a period of five to seven years. The first trial comprised 10,739 postmenopausal women who had a hysterectomy. The researchers randomly assigned these women 0.625 mg/day conjugated equine estrogens (CEE) or placebo.

The second trial comprised 16,608 postmenopausal women who had not had a hysterectomy. The researchers randomly assigned estrogen plus progestin (0.625 mg/day CEE plus 2.5 mg/day medroxyprogesterone acetate [MPA]) or placebo. The age range of the women was 50 to 79.

The researchers looked at whether the effects of HT on the risk for CHD varied by age or years since menopause. The participants were categorized by age range (50 to 59, 60 to 69 and 70 to 79 years) and years since menopause (<10, 10 to 19 and >20 years).

Results, HT effects

In all participants, the HR for CHD was lower for those taking CEE than for those taking CEE plus MPA (0.95 vs. 1.23; P=.02 after adjusting for risk factors). An increased risk for stroke in all participants (HR=1.32; 95% CI, 1.12-1.56) was found in the combined trials, with no difference between the individual trials.

Although adverse events increased as age increased, HT did not contribute to any statistically significant effect by age for any outcome in the combined trials. The HR for CHD was 0.93 in the 50 to 59 age group, 0.98 in the 60 to 69 group and 1.26 in the 70 to 79 age group (95% CI, 1.00-1.59) compared with placebo. Cardiovascular disease tended to be reduced by hormones in younger women, but the reduction was insignificant.

The trends in HR for CHD were slightly more pronounced in women without previous cardiovascular disease, (0.91 in the 50 to 59 age group, 0.97 in the 60-69 group and 1.33 in the 70 to 79 group; 535 cases; P=.10) compared with those in women with previous CVD (0.99 in the 50 to 59 age group, 0.98 in the 60 to 69 group and 1.12 in the 70 to 79 group; 214 cases; P=.72).

Years since menopause

The researchers suggested that years since menopause was a greater determinant of hormone effects on CHD than was chronological age. The closer women were to menopause, the lower the HR for CHD (0.76 in women with <10 years; 1.10 for women with 10 to 19 years; and 1.28 for women with >20 years since menopause; P=.02)

Alternately, the effect of HT on stroke risk was similar in all ranges of years since menopause, with a HR of 1.77 in women with <10 years, 1.23 in women with 10 to 19 years, and 1.26 in women with >20 years since menopause.

Not for everybody

The researchers noted that the higher risks in women more removed from menopause were concentrated in a subset of women with moderate or severe vasomotor symptoms. “It is possible that vasomotor symptoms in recently menopausal women represent the reaction of vessels with normal endothelial function to estrogen withdrawal, but persistent symptoms may signify something different in older women,” the researchers wrote.

“Five to 10% of women, up to their 70s, may have severe hot flashes and night sweats and those women might be tempted to take [HT] because it works in them as well as it works in younger women,” Rossouw said. “But these older women are the ones at really high risk and they should focus on identifying and treating their risk factors, which are more likely to be elevated if they have symptoms.

“Women who had an early menopause, because they’ve had an oophorectomy … most of them get severe symptoms and lose a lot of bone mass,” he said. “Those women need hormones up to the age when they would naturally become menopausal.” – by Carey Cowles

For more information:
Rossouw J, Prentice R, Manson J, et al. Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. JAMA. 2007;297:1465-1477.