Menopause: Hormone Replacement Therapy
Until 2002, the "first-line" drug thought to be most effective to both prevent osteoporosis and coronary heart disease and to decrease the symptoms of menopause was estrogen replacement therapy (ERT). When used with a progestogen (progesterone or a progestin, a synthetic progesterone-like drug), the combined treatment is called hormone replacement therapy (HRT). But major findings from at least two recent studies, including the 1998 Heart Estrogen and Progestin Replacement Study (HERS) and the 2002 Women's Health Initiative study (WHI) call into question the benefit-risk balance of HRT. What is the evidence? What are the alternatives to hormone replacement?
Assessing the Benefits and Risks of Estrogen Use
Many studies have assessed the benefits and the risks of estrogen treatment for the diseases associated with menopause. (See separate table: Selected Epidemiological Studies of Hormone Therapy for Osteoporosis or Heart Disease.) With its first results published in July 2002, the WHI study is the largest and most extensive study on the benefits and risks of HRT. Here 16,600 healthy postmenopausal women were randomly assigned to take a placebo versus two hormones in combination: Premarinâ (conjugated equine estrogens) plus Proveraâ . Neither the women nor their doctors knew who was taking hormones and who was taking the placebo. The women were followed for 5 years on average and were monitored for clinical outcomes, including heart disease, stroke, blood clots, breast cancer, colon cancer, hip fracture and spine fracture. The women in the two groups were similar in age and health status, so the outcomes can be attributed more confidently to the use of the medication rather than characteristics of the women.
What are the main results of the WHI study?
None of the positive or negative clinical outcomes are different from what has been reported in various other studies, but the high quality of the study compels us to consider its conclusions. The women who took the hormones were more likely to experience heart attacks, strokes, other blood clots and invasive breast cancer. Women taking hormones were also less likely to experience hip and spine fractures and colon cancer. The increased or decreased number of cases of each condition was small, but statistical analysis shows that the differences were not likely due to chance. The study was stopped three years ahead of schedule because of the increase in breast cancer cases among the HRT users. Differences in several outcomes between the two groups became apparent after the first year of the study. Death rates were not different between the two groups.
The table below details the clinical outcomes in the WHI study, comparing the hormone and placebo groups, showing the frequency of each outcome that would occur among 10,000 women observed for one year.
Outcome | Hormone | Placebo | Annual number of extra cases in hormone users
| Annual number of fewer cases in hormone users
|
Coronary Heart Disease | 37 | 30 | 7 more | -- |
Stroke | 29 | 21 | 8 more | -- |
Other Blood Clots | 34 | 16 | 18 more | -- |
Invasive Breast Cancer | 38 | 30 | 8 more | -- |
Colon Cancer | 10 | 16 | -- | 6 fewer |
Hip and Spine Fracture | 10 | 15 | -- | 5 fewer |
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Benefits of HRT
Estrogen to Treat Perimenopausal Symptoms
Many studies show that estrogen decreases or eliminates hot flashes, maintains vaginal tone and lubrication, levels out mood, improves memory and other cognitive function, and maintains skin elasticity. These benefits continue to be evaluated in new studies.
Estrogen to Prevent Osteoporosis
Virtually all studies confirm this benefit of estrogen. A World Health Organization summary of studies regarding osteoporosis and hip fracture concluded that women who take estrogen for more than seven to 10 years have a 50% lower risk of hip or wrist fracture and a 75% lower risk of vertebral fracture.
Estrogen to Lower Risk of Colon Cancer
Several studies, including the Nurses' Health Study and the WHI showed that those currently using ERT or HRT have a significantly lower risk of colorectal cancer.
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Side Effects of HRT
Breast tenderness, menstrual bleeding, headaches and nausea can occur. Sometimes these symptoms are eased by changing the dose or kind of estrogen used.
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Risks of HRT
Estrogen and Coronary Heart Disease
At least 33 observational studies reviewed postmenopausal estrogen use and coronary heart disease. These studies compared women who chose to take hormones versus those who did not. Most studies show up to 50% lower rate of coronary heart disease for women using HRT. A major concern about these observational studies is whether the women who chose to take HRT differed from the non-hormone users in characteristics that would have affected their risk of coronary heart disease.
In contrast are two recent, randomized controlled trials, where comparable groups of women were assigned randomly to take HRT or placebo. In the HERS study, women with previous heart disease and taking HRT had more blood clots in the lungs and legs than women on placebo during the first three years of treatment, and lower rates of these complications by the fourth and fifth years of the study. In the WHI study described earlier, women without previous heart disease taking HRT had more heart attacks throughout the study, beginning during the first year of HRT.
Estrogen and Endometrial Cancer
Endometrial cancer (of the lining of the uterus) affects 3 women out of 100 not on estrogen. The median age of cancer detection is 68 years. Women who use ERT without progestogen have an increased risk of endometrial cancer, up to seven times higher than for women not on ERT. The endometrial cancer induced by estrogen is less likely to be fatal than that which occurs in women not taking estrogen. When a progestogen is added to ERT, there is no increased risk of endometrial cancer. Therefore, women who have a uterus and are prescribed estrogen during menopause are also given a progestogen to prevent endometrial cancer.
Estrogen and Ovarian Cancer
Ovarian cancer affects 1 out of 55 women, with 23,000 new cases each year in the United States. It accounts for 4% of all cancers in women but 20% of all cancer deaths in women.
A 2002 study reported ovarian cancer rates in women who had previously been enrolled in the Breast Cancer Detection Demonstration Project, comparing those who chose to take hormones (either ERT or HRT) versus those who chose not to take hormones. Increased rates of ovarian cancer were found among women using ERT for 10 years or more. Among 10,000 women observed for one year, this study found that ERT users would experience 7 ovarian cancers vs. 4 ovarian cancers among the women not taking hormones. Women who took HRT did not experience significantly more ovarian cancers.
HRT and Breast Cancer
Breast cancer affects approximately 1 in 9 American women, at an average age of 69. One-third of women diagnosed with breast cancer will die of the disease. For reasons not understood, women who develop breast cancer while on HRT have lower mortality than women not on hormones. In general, the risk of death is much greater in younger (premenopausal) women than in women who develop breast cancer later in life.
The WHI study of 2002 comparing placebo versus HRT was stopped early because of the increased number of invasive breast cancers found in the women taking HRT. The results indicated that among 10,000 women observed for one year, 37 cases of breast cancers would be detected among HRT users versus 30 among women taking placebo. However, another arm of this same study continues -- among women without a uterus, half taking ERT (estrogen without progestin) and half on placebo. In this ERT versus placebo group, there is no report to date of more breast cancers in either group. Final results should be ready in 2005.
The WHI study of HRT and breast cancer supports earlier findings from data pooled from many smaller studies about breast cancer risk, although some of these studies evaluated ERT while others evaluated HRT. The Collaborative Group on Hormonal Factors in Breast Cancer concludes that "the risk of having breast cancer diagnosed is increased in women using ERT and increases with longer duration of use. This effect ... largely ... disappeared ... about 5 years (after ceasing estrogen use)."
How much increased breast cancer risk?
The lifetime risk of getting breast cancer increases with the number of years on estrogen replacement therapy.
Years of Estrogen Use | Lifetime Risk of Developing Breast Cancer | Percent of Women Developing Breast Cancer |
None | 1 woman in 9 | 9 |
5 | 1 woman in 8 | 12 |
10 | 1 woman in 7 | 14 |
15 | 1 woman in 6 | 16 |
The Role of Progestins in Breast Cancer
The WHI study supports earlier findings that Provera® increases the risk of breast cancer beyond the risk conferred by estrogen alone. Women who have a uterus and take estrogen must take progesterone or a (synthetic) progestin to reduce their risk of endometrial cancer. We do not know if using newer versions of these agents or taking them on different schedules or doses will decrease the risk of breast cancer while continuing to protect against endometrial cancer.
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