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Am Fam Physician. 2006;74(9):1501-1503

Clinical Scenario

A healthy 66-year-old woman has been taking combined continuous hormone therapy for menopausal symptoms for six months. She asks for how long she can safely continue taking the medication.

Clinical Question

In perimenopausal and postmenopausal women, is long-term, combined continuous hormone therapy safe and effective?

Evidence-Based Answer

Relatively healthy women taking combined continuous hormone therapy have higher risks of myocardial infarction and venous thromboembolism after one year, stroke after three years, and breast cancer after five years. In women who take hormone therapy continuously for five years, there is a lower incidence of fractures and colon cancer. Although it may be relatively safe and effective for short-term symptom control, hormone therapy should not be given routinely for prevention or chronic disease management.1

Practice Pointers

In the past, based on the results of multiple small observational studies, the health benefits of long-term hormone therapy for perimenopausal and postmenopausal women were thought to be numerous. However, the results of two large randomized controlled trials—the Heart and Estrogen/progestin Replacement (HER) study and the Women’s Health Initiative (WHI) study—showed there were significant risks to this approach. The Cochrane authors reviewed 15 double-blind, randomized trials comparing the effects of hormone therapy with placebo for at least one year.1 Nearly 50,000 women 41 to 91 years of age who were perimenopausal or postmenopausal participated in the studies. The two largest randomized controlled trials were the HER and the WHI studies.

The reviewers found that statistically significant benefits of long-term hormone therapy include the prevention of fractures in healthy women with no other previous osteoporosis risk factors (risk ratio [RR] = 0.78; 95% confidence interval [CI], 0.71 to 0.85) and the prevention of colon cancer. These benefits were noted only after five years of continuous use and were reported in the WHI study, but not the HER study.

The WHI study’s combined estrogen-progesterone arm showed a reduced incidence of colon cancer (RR = 0.62; 95% CI, 0.43 to 0.89); however, those in the treatment arm who subsequently were diagnosed with cancer showed evidence of more advanced disease at the time of diagnosis, offsetting the positive findings of possible prevention.

The HER and WHI studies also yielded information about the negative outcomes of long-term hormone therapy. Combined continuous hormone therapy increased coronary events (after one year: RR = 1.74; 95% CI, 1.05 to 2.89; after four years: RR = 1.37; 95% CI, 1.05 to 1.79). Women taking hormone therapy had a higher risk of stroke after three years (RR = 1.47; 95% CI, 1.02 to 2.11).2 The risk of venous thromboembolism was more than three times greater in women taking hormone therapy at one year, and the risk remained increased for more than five years. However, according to the WHI study, after five years of taking the medication, the absolute risk of venous thromboembolism for women 50 to 59 years of age was 0.5 percent for women of normal weight and 1.4 percent for women who were obese. Risk of breast cancer after five or more years of hormone therapy was increased (after a mean of 5.6 years: RR = 1.26; 95% CI, 1.02 to 1.56). There are no known benefits or risks from long-term hormone therapy with respect to the prevention of cognitive decline or dementia, quality-of-life assessments, or mortality. Rates of endometrial cancer and quality-of-life scores were similar for those taking hormone therapy and those taking placebo.

Cochrane Abstract

Background: Hormone therapy is widely used for controlling menopausal symptoms. It also has been used for the management and prevention of cardiovascular disease, osteoporosis, and dementia in older women, but the evidence supporting its use for these indications is largely observational.

Objectives:To assess the effect of long-term hormone therapy on mortality, heart disease, venous thromboembolism, stroke, transient ischemic attacks, breast cancer, colorectal cancer, endometrial cancer, ovarian cancer, gallbladder disease, cognitive function, dementia, fractures, and quality of life.

Search Strategy: The authors1 searched the following databases up to November 2004: the Cochrane Menstrual Disorders and Subfertility Group Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, and Biological Abstracts. Relevant nonindexed journals and conference abstracts also were searched.

Selection Criteria: Randomized, double-blind trials of hormone therapy (estrogens with or without progestogens) versus placebo, taken for at least one year by perimenopausal or postmenopausal women.

Data Collection and Analysis: Fifteen randomized controlled trials were included. Trials were assessed for quality and two review authors extracted data independently. They calculated risk ratios for dichotomous outcomes and weighted mean differences for continuous outcomes. Clinical heterogeneity precluded meta-analysis for most outcomes.

Primary Results: All the statistically significant results were derived from the two biggest trials. In relatively healthy women, combined continuous hormone therapy significantly increased the risk of venous thromboembolism or coronary event (after one year’s use), stroke (after three years), breast cancer (after five years), and gall-bladder disease. Overall, the only statistically significant benefits of hormone therapy were a decreased incidence of fractures and colon cancer with long-term use. Among relatively healthy women older than 65 years taking continuous combined hormone therapy, there was a statistically significant increase in the incidence of dementia. Among women with cardiovascular disease, long-term use of combined continuous hormone therapy significantly increased the risk of venous thromboembolism.

No trials focused specifically on younger women. However, one trial analyzed subgroups of 2,839 relatively healthy women 50 to 59 years of age taking combined continuous hormone therapy and 1,637 taking estrogen-only hormone therapy, versus similar-sized placebo groups. The only significantly increased risk reported was for venous thromboembolism in women taking combined continuous hormone therapy; their absolute risk remained very low.

Reviewers’ Conclusions: Hormone therapy is not indicated for the routine management of chronic disease. More evidence is needed on the safety of hormone therapy for menopausal symptom control, although short-term use appears to be relatively safe for healthy younger women.

These summaries have been derived from Cochrane reviews published in the Cochrane Database of SystematicReviews in the Cochrane Library. Their content has, as far as possible, been checked with the authors of the originalreviews, but the summaries should not be regarded as an official product of the Cochrane Collaboration; minorediting changes have been made to the text (

Data are more limited regarding the use of hormone therapy for relieving the symptoms of menopause in younger perimenopausal patients. However, in the WHI study, the subgroup of women 50 to 59 years of age taking combined continuous hormone therapy for five years had no adverse outcomes other than a slightly higher risk of venous thrombosis. The absolute risk of venous thrombosis for those taking hormone therapy is 19 per 10,000 women per year, compared with eight per 10,000 in women not taking therapy. Therefore, short-term use of hormone therapy in younger women is relatively safe. Because the WHI and HER studies reported an increased risk of cardiovascular events at one year, it is difficult to advise patients to take hormone therapy for longer than this. Future studies must assess the relationship between short-term hormone therapy use (i.e., three to six months) and perceived benefits in terms of quality of life for those with menopausal symptoms.3

These are summaries of reviews from the Cochrane Library.

This series is coordinated by Corey D. Fogleman, MD, assistant medical editor.

A collection of Cochrane for Clinicians published in AFP is available at

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