Women’s Health Initiative: the final outcome

Following publication of the Women’s Health Initiative (WHI) and Million Women Study (MWS) many women stopped oestrogen-based hormone replacement therapy (HRT)

[1.2]. The main concerns were an increased risk of breast cancer and cardiovascular disease. They turned to alternative strategies such as changing diet to stay healthy after the menopause. The Women’s Health Initiative has now reported on randomised controlled trials of the effects of calcium and vitamin D supplements and low fat diets, as well as detailed analyses of oestrogen-progestogen and oestrogen-alone HRT.

Calcium and vitamin D were hypothesized to reduce the risk of hip fracture and colorectal cancer. 18,176 women received 500 mg of elemental calcium as calcium carbonate with 200 IU of vitamin D3 twice daily (1000 mg of elemental calcium and 400 IU of vitamin D3) and 18,106 received a matching placebo for an average of 7.0 years [3,4]. No effect on the incidence of colorectal cancer or hip fracture was found and there was an increased risk of kidney stones.

A low fat diet was hypothesized to reduce the risk of breast and colorectal cancer and cardiovascular disease [5,6,7]. 19, 541 women were assigned to a diet with reduced total fat intake (20% total energy) and increased intakes of vegetables, fruits, and grains. The comparison group of 29, 294 women did not have any dietary changes. Mean follow-up was 8.1 years. The dietary intervention did not significantly reduce the risk of coronary heart disease (CHD), stroke, cardiovascular disease, breast or colorectal cancer.

The initial report [1] of an increased risk of CHD with combined HRT in WHI was at variance with observational studies such as the Nurses’ Health Study. Reanalysis of the Nurses’ Health Study has found that women beginning HRT near menopause had a significantly reduced risk of coronary heart disease (RR = 0.66, 95% CI 0.54-0.80 for oestrogen alone; RR = 0.72, 95% CI 0.56-0.92 for combined HRT) [8]. In the subgroup of women demographically similar to those in the WHI, no significant relation was found between HRT and coronary heart disease among women who initiated therapy at least 10 years after menopause for both types of HRT. These data support the possibility that timing of starting HRT in relation to the menopause or to age might influence coronary risk. This concept is also supported by the findings of the observational WHI trial of combined HRT [9]. Detailed analysis [10] of the WHI randomised trial of combined HRT showed that there was no overall significant increase in CHD, with a significant increase being seen only in the first year of treatment but a significant trend downwards thereafter. Detailed analysis [11] of the WHI oestrogen-alone study showed a non-significant reduction in CHD, which was most marked in the younger (50-59 years) age group. In this sub-group, there was a significant reduction in a composite of coronary events and procedures, and there were no significant increases in events in the older age groups.

Most women seeking HRT to treat menopausal symptoms are aged less than 60 years and thus these analyses on cardiovascular disease are reassuring. The role of diet seems to be very limited. Any effect of calcium and vitamin D is most likely to be limited to elderly institutionalized women [12].

Although the WHI and MWS initially highlighted concerns about breast cancer risks with HRT [1,2], resulting in regulatory authorities issuing urgent revisions of its recommended use [13], the more detailed WHI analyses [14,15] demonstrate that these reactions were inappropriate. With combined HRT, there was a (just) significant increase in invasive breast cancer incidence when all women were grouped together, but no increase in in situ breast cancer. This increase in invasive cancer was seen only after 5 years use in women who had previously been exposed to HRT for more than 5 years; there was no increased risk in women who had not previously used HRT. With oestrogen-alone HRT, there was a non-significant reduction in invasive breast cancer when all women were grouped together, but a significant reduction in those women with no previous HRT exposure. There was also a significant reduction in ductal cancer. Thus it appears that an increased breast cancer risk is in fact confined to those women who have been exposed to combined HRT for more than 10 years, and these clinical trial findings are completely contradictory to the reported findings from the observational MWS.

The initial findings of WHI were seized upon by those wishing to condemn HRT as showing it was unsafe because of increases in breast cancer and coronary heart disease. We have subsequently learnt that the risk of breast cancer is small and apparently confined to those women with a very long exposure to a combined HRT regimen, whilst oestrogen alone may actually reduce the risk. There is no overall increased risk for coronary disease, and again oestrogen alone may actually be of benefit in younger postmenopausal women. Dietary interventions did not produce any health benefits for either breast cancer, colon cancer or coronary disease. Although many criticisms may be made of the WHI trials (wrong doses of HRT, wrong doses of vitamin D, wrong diets), the overall message from them should be that HRT is in fact a purveyor of health benefits rather than risks.

Margaret Rees
John Stevenson
24 April 2006

References

1. Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women’s Health Initiative randomized controlled trial. JAMA 2002; 288:321-33.
2. Million Women Study Collaborators. Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet 2003; 362: 419-427.
3. Wactawski-Wende J, Kotchen JM, Anderson GL, et al; Women’s Health Initiative Investigators.
Calcium plus vitamin D supplementation and the risk of colorectal cancer. N Engl J Med 2006;354:684-96.
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5. Prentice RL, Caan B, Chlebowski RT, et al. Low-Fat Dietary Pattern and Risk of Invasive Breast Cancer: The Women’s Health Initiative Randomized Controlled Dietary Modification Trial
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6. Beresford SAA, Johnson KC, Ritenbaugh C, et al.Low-Fat Dietary Pattern and Risk of Colorectal Cancer: The Women’s Health Initiative Randomized Controlled Dietary Modification Trial
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11. Hsai J, Langer RD, Manson JE, et al. Conjugated equine estrogens and coronary heart disease. Arch Intern Med 2006; 166:357-65.
12. Management of the Menopause: the Handbook. 2006 Eds Rees M, Purdie DW. Royal Society of Medicine Press for the British Menopause Society.
13. Stevenson JC. HRT, osteoporosis and regulatory authorities. Hum Reprod 2006 Mar 23; [Epub ahead of print] 14. Chlebowski RT, Hendrix SL, Langer RD, et al. Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women. JAMA 2003; 289:3243-53.
15. Stefanic ML, Anderson GL, Margolis KL, et al. Effects of conjugated equine estrogens on breast cancer and mammography screening in postmenopausal women with hysterectomy. JAMA 2006; 295:1647-57.