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The WHI and the Postmenopausal Woman: No Magic Bullet

Take-home points from the WHI's hormone therapy, dietary modification, and calcium/vitamin D trials.

INTRODUCTION

The Women’s Health Initiative (WHI) is the largest women’s health study in U.S. history. Begun in 1993 and completed in 2005, with follow-up scheduled through 2010, the WHI included over 161,000 postmenopausal women aged 50–79 years who were recruited into three large clinical trials and an observational study.^1,2 Participants had to agree to a commitment of at least 5 years, during which they returned for follow-up multiple times, filled out detailed questionnaires, provided blood samples, and agreed to be randomized to treatment or placebo groups. The research program focused on strategies for preventing the most common health problems in postmenopausal women: heart disease, breast and colorectal cancer, and skeletal fractures. The clinical trials centered on three approaches: hormone therapy, dietary modification, and calcium/vitamin D supplementation.

HORMONE THERAPY

The hormone therapy (HT) trial focused on whether oral estrogen, alone or with progestin, was beneficial in preventing heart disease and whether this therapy increased the risk for breast cancer. Earlier observational studies, such as the Nurses’ Health Study,³ had suggested that estrogen therapy begun at menopause reduced the incidence of heart disease.

In one arm of the HT trial, more than 16,000 women with an intact uterus were randomized to receive either estrogen plus progestin (E+P) or placebo. After an average of 5 years’ follow-up, the trial was stopped because the overall risks exceeded the benefits: Women taking E+P had more heart attacks, strokes, blood clots, and breast cancers than women taking placebo (Table 1). Age at the start of HT did not appear to affect these risks. The HT group did have fewer hip fractures and colorectal cancers. Overall, there were no significant differences between the two groups in the number of deaths. (See Journal Watch Women’s Health Aug 7 2002.)

In the other arm, more than 10,000 women without a uterus were randomized to either estrogen alone or placebo. This arm was stopped after an average of 7 years because of an increased risk for stroke, with no evidence of heart disease protection, among women taking estrogen. The estrogen-alone group also had a greater risk for blood clots, but fewer hip fractures. In contrast to the findings of the E+P arm, the estrogen-alone group had no increase in heart attacks and a possible decrease in breast cancers (Table 1; see also Journal Watch Women's Health Jun 9 2004 and Apr 4 2006). This latter finding makes the WHI the largest randomized trial to show that breast cancer risk is not affected by long-term estrogen therapy. A subgroup of women older than 65 was also followed for development of dementia⁴: In both arms, HT-treated women had a higher incidence of dementia and no improvement in global cognition measures when compared with women who received placebo (Journal Watch Women’s Health Sep 9 2004).

Together, the WHI HT trials suggest that there are distinct differences in risks between E+P and estrogen alone. In both arms, however, strokes and blood clots were increased in estrogen users, and there was no evidence in either trial to show that estrogen reduces heart disease.^{5,6,7,8,9,10,11,12}

View this table: [in a new window]   Table 1. Risks and Benefits for Hormone Therapy in the WHI Hormone Trial

 

LOW-FAT DIETARY INTERVENTION

A high dietary intake of fat, along with reduced intake of fruits, vegetables, and grains, has been associated with the development of breast cancer, colorectal cancer, and heart disease. The WHI Dietary Modification Trial examined the effect of a diet low in fat (i.e., 20% of calories from fat) and high in fruits, vegetables, and grains on the incidence of these diseases in nearly 50,000 women. In the dietary intervention group, total fat intake was reduced from 38% of calories to 24% after 1 year, while a control group continued to average 35%–37%. After 8 years, there were no significant differences between the two groups in the incidence of heart disease, stroke, colorectal cancer, or breast cancer. These findings suggest that there is insufficient evidence to recommend a lower fat intake for reducing breast or colorectal cancer risk. However, lower trans fat intake and higher fruit and vegetable intake may have an impact on cardiovascular risk, and longer term follow-up may still reveal the benefits of a low-fat diet. (See also Journal Watch Women’s Health Mar 21 2006.)

CALCIUM AND VITAMIN D SUPPLEMENTATION

Low calcium and vitamin D intake has been associated with increased risk for colorectal cancer and fractures. In the WHI Calcium and Vitamin D (CaD) trial, more than 36,000 women were randomized to receive either 1000 mg of calcium and 400 IU of vitamin D₃ daily, or placebo. After an average of 7 years, the CaD recipients had higher bone densities but similar numbers of hip fractures. There was no difference in the risk for colorectal cancer. Among women older than 60, CaD supplementation was associated with a 21% decreased risk for hip fracture compared with placebo. The relatively small effect of CaD may be due to the relatively low baseline fracture risk of this cohort, the doses of supplement used, or a confounding effect of some placebo-treated women taking their own supplements. (See also Journal Watch Women’s Health Mar 21 2006.)

TAKE-HOME LESSONS FROM THE WHI

(1) Estrogen, alone or with progestin, does not reduce the incidence of heart disease, and increases the risk for strokes and blood clots. Women on estrogen plus progestin have a slightly increased risk for breast cancer.

(2) Users of estrogen alone did not have more breast cancers.

(3) Estrogen reduces the risk for fractures.

(4) Estrogen should be used judiciously in women with moderate-to-severe hot flashes, at the lowest effective dose, with periodic reevaluation of symptoms to determine the need for continuing therapy.

(5) Reducing dietary intake of fat and increasing intake of fruits, vegetables, and grains may or may not reduce breast or colorectal cancer risk. However, longer-term follow-up may yet reveal lasting benefits, particularly for breast cancer.

(6) Calcium and vitamin D supplements are effective in increasing bone density, and may be effective in reducing fracture risk in women over 60.

— James H. Liu, MD

Dr. Liu is Arthur H. Bill Professor and Chair of the Department of Reproductive Biology, Case School of Medicine, University MacDonald Women’s Hospital, Cleveland.

Published in Journal Watch Women's Health May 2, 2006

Citation(s):

1. The Women’s Health Initiative participant website. Accessed at http://www.whi.org/updates on April 26 , 2006.

2. NHLBI Women’s Health Initiative update. Accessed at http://www.nhlbi.nih.gov/whi/update.htm on April 26 , 2006.

3. Clinical Trial. Nurses’ Health Study. Accessed at http://www.clinicaltrials.gov/show/NCT00005152 on April 26 , 2006.

4. Women’s Health Initiative Memory Study. Accessed at http://www.wfubmc.edu/whims on April 26 , 2006.

5. Women's Health Initiative Steering Committee. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: The Women's Health Initiative randomized controlled trial. JAMA 2004 Apr 14; 291:1701-12.

• Original article (Subscription may be required)
• Medline abstract (Free)

6. Manson JE et al. Estrogen plus progestin and the risk of coronary heart disease. N Engl J Med 2003 Aug 7; 349:523-34.

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7. Chlebowski RT et al. Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: The Women's Health Initiative randomized trial. JAMA 2003 Jun 25; 289:3243-53.

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• Medline abstract (Free)

8. Wassertheil-Smoller S et al. Effect of estrogen plus progestin on stroke in postmenopausal women: The Women's Health Initiative: A randomized trial. JAMA 2003 May 28; 289:2673-84.

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9. Cushman M et al. Estrogen plus progestin and risk of venous thrombosis. JAMA 2004 Oct 6; 292:1573-80.

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10. Chlebowski RT et al. Estrogen plus progestin and colorectal cancer in postmenopausal women. N Engl J Med 2004 Mar 4; 350:991-1004.

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11. Cauley JA et al. Effects of estrogen plus progestin on risk of fracture and bone mineral density: The Women's Health Initiative randomized trial. JAMA 2003 Oct 1; 290:1729-38.

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12. Margolis KL et al. Effect of oestrogen plus progestin on the incidence of diabetes in postmenopausal women: Results from the Women's Health Initiative hormone trial. Diabetologia 2004 Jul; 47:1175-87.

• Medline abstract (Free)