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Hormones and disease

Certain diseases, such as heart disease, breast cancer, and osteoporosis, have long been linked to menopause because of their connection with hormone levels. Currently, most major health organizations (including the U.S. Preventive Services Task Force, the American College of Obstetricians and Gynecologists, the American Heart Association, and the North American Menopause Society) recommend against using hormone therapy to prevent chronic disease. Findings from the Women's Health Initiative have helped clarify the complex relationship between hormones and disease. However, our understanding of the complex and interrelated effects of menopause and aging is still evolving. The following discussion summarizes the current thinking about how menopause and its treatments influence common (and less common) health conditions.

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The hormone studies: The Women's Health Initiative

How can women best protect themselves against common, chronic diseases such as heart disease, breast and colon cancer, and osteoporosis? The Women's Health Initiative (WHI), a 15-year, multimillion-dollar project, set out to answer this broad question. Begun in the early 1990s by the National Institutes of Health, this far-reaching study involves more than 161,000 women between ages 50 and 79.

The WHI is actually a compendium of several major studies. To date, the most widely publicized is the one involving hormone therapy. Most previous studies of hormone therapy were cohort or observational studies, meaning that researchers compared the medical records and histories of women who used hormones with those who did not. Those studies suggested that over all, hormone therapy seemed to have beneficial health effects. But the most reliable, conclusive evidence comes from randomized clinical trials — like the WHI — in which researchers randomly assign women to take either a drug treatment or a fake pill known as a placebo and compare the two groups after a period of time.

The WHI trial included two parts. The Estrogen-Plus-Progestin (E+P) arm included 16,608 women who had not had hysterectomies and were given either combined hormone therapy (Prempro) or placebo. The Estrogen-Only (E-Only) arm included 10,739 women who had undergone hysterectomies and who were given either estrogen (Premarin) or a placebo. In July 2002, researchers stopped the Prempro trial early, after an average follow-up of 5.2 years instead of the planned 8, when it became clear that hormone users had a higher risk of breast cancer, heart disease, stroke, and potentially fatal blood clots compared with women not taking the hormones. Although hormone users were less likely to fracture a hip or develop colorectal cancer, these positives did not outweigh the negative heath effects. Still, the added risks are quite small.

Two years later, the E-Only arm was also stopped early, after an average of 6.8 years of follow-up instead of 8 as planned. Again, the evidence suggested that the hormone treatment's risks outweighed the benefits, although with a somewhat different pattern. Like women who used combination Prempro, estrogen-alone users were more likely to have strokes but less likely to fracture a hip. However, researchers found no significant differences in the risk of heart disease or breast or colon cancer between the estrogen and placebo groups.

Since then, researchers have continued to analyze data from both trials. Below are some of the other key findings:

Urinary incontinence. Contrary to conventional wisdom, in the studies, both E-Only and Prempro increased the risk of stress incontinence. This problem — leaking of urine when a person coughs, laughs, sneezes, lifts, stands, or exercises — is the most common form of incontinence. Women with no history of incontinence were more likely to develop the problem if they took hormones. And those with previous incontinence problems tended to develop worse incontinence if they took hormones.

Dementia and cognitive function. Despite expectations that hormones might protect against cognitive problems such as memory loss, the results revealed a slightly higher risk of dementia (including Alzheimer's disease, the most common form of dementia) among older E-Only and Prempro users.

Diabetes. Women who took Prempro had a slightly lower risk of developing diabetes than women not taking the hormones, but experts don't feel this benefit outweighs the other health risks from hormones.

Quality of life. Compared to women taking placebos, women who took Prempro reported slightly higher scores on certain measures of quality of life, such as better physical functioning, less sleep disturbance, and less pain, but only during the first year of the study. After three years, these slight advantages had vanished.

Despite the strengths of this study, it has some limitations. Critics of the WHI point out that the study involved only one form of estrogen and progestogen, Prempro. It's not clear whether other forms of estrogen and progestogen have these same risks or benefits. Also, the average age of participants was 64, which is older than the traditional age of women who've taken hormones in the past, so their risks for certain disease differed from those of younger women. Finally, women with severe menopausal symptoms were discouraged from being in the study.

Studies such as the WHI provide information about a group of people but often don't directly address the issues of an individual. The results of the WHI tell us about the average outcomes and side effects for a large group of women. However, not only is each woman's body different, but each woman has different personal priorities. Use the WHI study results as a guide rather than a cookbook.

Researchers will continue to monitor women from these studies until 2010, which will help determine whether the pros and cons from taking hormones continue or disappear over time among women who stopped taking the hormones. Other arms of the WHI are continuing as well. The Dietary Modification component will evaluate how a diet low in fat and high in fruits, vegetables, and grain products affects risk for breast and colon cancers and heart disease. The Calcium/Vitamin D component will evaluate the effect of those nutrients on risk for osteoporosis and colon cancer. Another arm, called the Observational Study, focuses on the relationship between lifestyle, health, and risk factors and specific disease outcomes.

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Heart disease

Besides relieving menopausal symptoms, one major reason for using hormone therapy in the 1990s was the belief that it protected against heart disease. Over the years, a number of large studies revealed that estrogen lowers total blood cholesterol and harmful LDL cholesterol, while increasing beneficial HDL cholesterol. That's good, because high LDL cholesterol is a major risk factor for heart disease, and HDL is protective. Studies published in the 1980s and early 1990s that surveyed large groups of women showed that women using combined hormone therapy had a 40% lower risk of heart disease than women who didn't use it. These findings, from the long-term Nurses' Health Study among others, contributed to millions of American women receiving prescriptions for hormone therapy in the belief that it could prevent heart disease.

That notion changed when findings from the Heart and Estrogen/Progestin Replacement Study (HERS) appeared in 1998. This was the first large randomized placebo-controlled clinical trial of hormone replacement therapy in women with heart disease. After four years, the results showed no difference in the number of heart attacks or strokes between randomly chosen women who took Prempro and those who did not. In fact, HERS showed that postmenopausal hormones raised the risk of heart disease and blood clots during the first year or two that women took them. Even more recent, short-term data from the Nurses' Health Study show the same pattern. It's important to note that most of the heart-related problems occurred within the first two years of using the combined hormone therapy. So, why did the earlier Nurses' Health Study data show that taking hormones reduced heart disease? One reason may be that the women who were taking hormones were healthier to begin with.

The age at which a woman begins hormone therapy may make a difference. For example, the WHI results that showed an increase in heart attacks for women taking combined hormone therapy included mainly older women with an average age of 64 — about a decade past menopause. At that age, women are more likely to have clogged arteries and are therefore more likely to have a heart attack. But the Nurses' Health Study looked at women who started hormone use at or soon after menopause. It's possible, as some experts believe, that hormones may be beneficial in early menopause and harmful when started late after menopause. Reexamination of the WHI data looking at women by age supports this hypothesis

Several studies seeking to untangle these distinctions are currently under way, including a five-year, multicenter trial privately funded by the Kronos Longevity Research Institute. Researchers are testing whether hormone therapy prevents the progression of atherosclerosis in women ages 42–58. Women in the study will take either a placebo or a transdermal patch or pill that contains estrogen plus a different progestogen than the one used in WHI.

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Stroke and blood clots

Hormones appear to increase the blood's tendency to clot, an observation that ties in with the slightly higher risk of stroke and blood clots seen in women who take hormones. Numerous studies have documented a slight increase in ischemic stroke (the type caused by a blood clot that blocks blood flow to the brain) among women who take hormones. (The other, less common type of stroke, known as a bleeding or hemorrhagic stroke, doesn't appear to be more common among hormone users.) These observations were upheld by the WHI findings: Both types of therapy (estrogen alone and combined hormone therapy) boosted the risk of stroke by about 40%. That is, an additional 7 women in 10,000 had a stroke each year.

Blood clots can also lodge in the deep veins of the legs (deep-vein thrombosis) and the lungs (pulmonary embolism). These dangerous conditions are also slightly higher among hormone users, as documented in earlier studies and the WHI results. Risk of clotting problems doubled for women in the WHI who took combined hormone therapy but increased by less than half for estrogen-only users.

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Breast cancer

Well before the WHI results, a number of studies suggested a link between hormone replacement therapy and breast cancer. Researchers have long known that estrogen promotes cell division in breast tissue. In addition, cell division in the breast surges in tandem with the highest levels of progesterone during the menstrual cycle. Progesterone tends to prevent cancer in the uterus, but it may stimulate it in the breast.

Researchers have observed that hormones cause dense breasts, and postmenopausal women with dense breasts have more cancers. Also, women with osteoporosis, thought to be associated with low estrogen, have less breast cancer than those with stronger bones. Additional early evidence for the link between breast cancer and hormone therapy came from the Nurses' Health Study, in which researchers followed 120,000 women over a period of several years. The women periodically filled out questionnaires about their diet, exercise, and medical histories, including hormone use. The researchers observed a 9% increase in breast cancer risk in women taking combined hormone therapy and a 3.3% increase in those taking estrogen alone. Risk increased the longer women took the hormones but returned to normal once they stopped.

Conflicting studies were also published. But the WHI results corroborated earlier findings, showing a 26% increased risk of breast cancer among combined hormone users. In addition, women who took hormones tended to have larger and more advanced cancers than those seen in the placebo users. Surprisingly, the findings from the E-Only arm of the study showed no increased risk of breast cancer, which lends further support to the idea that progestogen might be fueling at least some of the increased breast cancer risk.

Findings from a major study in the United Kingdom, the Million Women Study, support those of the estrogen/progestogen arm of WHI. Data from more than one million women showed that current users of combined estrogen and progestogen had a twofold higher risk of developing breast cancer. However the risk of women who took estrogen alone was 1.3 times higher. What's more, the risks were similar for all forms of the medication — oral, transdermal, or implanted — and for both continuous and cyclical patterns of use.

For many women, the risk of breast cancer is one of the most important considerations in deciding whether to take hormone therapy. Risk assessment models are available through your physician or on the National Cancer Institute Web site. You will have to weigh your risk profile — such as if you have a family history of breast cancer — with the severity of your menopausal symptoms to arrive at an informed decision. And keep in mind that, so far, doctors don't fully understand how combined hormone therapy's risk of breast cancer interacts with a woman's other risk factors.

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Colon cancer

This area hasn't been a topic of widespread research, but existing studies show that estrogen appears to confer a moderate reduction in the risk of colon cancer. When estrogen is stopped, however, the protective effect diminishes and eventually disappears altogether.

Although the reason for this is not clear, it may be that estrogen therapy can slow the production of bile acids and lower the level of the growth hormone IGF-1. Both IGF-1 and bile acids are known to stimulate cancerous growths in the colon.

The Nurses' Health Study found that while women are taking hormone therapy, they are about 35% less likely to develop colon cancer than women who have never taken the hormones. The WHI showed a 37% reduction in colon cancer risk among women taking combined hormone therapy. Interestingly, the estrogen-only arm of the WHI did not show any colon cancer protection, and experts are uncertain why.

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Ovarian cancer

Again, conclusive data are lacking, but a large-scale study sponsored by the American Cancer Society showed a small increase in the risk of ovarian cancer in women who had taken postmenopausal hormones. The longer hormones were taken, the greater the risk, with a twofold increase among current users who had been taking hormones for at least 10 years. Findings from the WHI upheld these results, showing a 58% increased risk of ovarian cancer among Prempro users. Keep in mind that the risk of ovarian cancer is small to begin with, so a small increase still does not pose a threat to most women.

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Uterine cancer

Estrogen-only hormone therapy more than doubles the risk of uterine (or endometrial) cancer, and the risk stays high five or more years after stopping. For this reason, women who have not had a hysterectomy are advised to take estrogen in combination with a progestogen, which counteracts this increased risk. Earlier research, as well as the WHI findings, found no increased risk for uterine cancer in women who took combined hormone therapy.

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Osteoporosis

A woman's bones are constantly remodeling throughout her lifetime. Most women reach peak bone density around age 30. If no attention is given to maintaining strong bones, bone density will slowly decline until menopause. With menopause, bone loss accelerates for the next 6 years. Then the pace slows again, but bone density will continue to decline throughout the rest of life.

In this area, the findings appear to be fairly clear-cut: Estrogen can prevent and partially reverse the postmenopausal bone loss that leads to osteoporosis. Doctors don't recommend taking hormones solely for this purpose because of the health risks posed by hormone therapy. In some cases, however, hormone therapy may make sense in managing bone health for a variety of reasons.

Osteoporosis is very common: In the United States, a 50-year-old woman has a 40%–50% lifetime chance of having a broken bone because of osteoporosis. Bone loss begins during perimenopause. In the early postmenopausal years, women lose bone mass at an average rate of 3% per year. Estrogen protects against bone loss by inhibiting osteoclasts, the cells that break down bone, and stimulating osteoblasts, the cells that build new bone. Only a few studies, including the WHI, have examined the effects of combined estrogen and progestogen on fractures, but these studies show that combined hormone therapy is effective in reducing fractures even in an average-risk population.

For women taking estrogen, the greatest protection against osteoporosis has been shown in women who take it sooner rather than later in the postmenopausal years and stay on it for at least 7–10 years. However, the protective effect stops when a woman stops taking hormones, and taking hormones for longer than four or five years confers increased risk of breast cancer.

Other, newer medications are usually used to treat osteoporosis, such as bisphosphonates, selective estrogen receptor modulators (SERMs), and parathyroid hormone. These prescription drugs help prevent bone loss in postmenopausal women without increasing the risk of breast cancer or heart disease. Talk with your doctor about your medical history and health risks and possible benefits and side effects of your options.

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Dementia and Alzheimer's disease

Early studies suggesting that hormones seem to have a positive effect on cognition, including memory and reasoning skills, led to a widespread assumption that hormones might protect against dementia and Alzheimer's disease. But subsequent studies — most notably the WHI — showed that hormones seem to increase the risk of probable dementia or cognitive problems in women over age 65 who take estrogen alone or in combination with progestogen. However, there are estrogen receptors in the brain, and some experts think estrogen given right after menopause might have a preventive role. At this point, the answer is far from clear.

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Gallbladder disease

Estrogen raises the level of cholesterol in bile, a substance produced by the liver and stored in the gallbladder. This promotes the growth of gallstones. Data from the Nurses' Health Study found that taking estrogen, with or without progestogen, increased the likelihood of needing cholecystectomy (surgery to remove the gallbladder). The higher the dose of hormone therapy and the longer its use, the more likely a woman was to have the surgery. Five years after they stopped, women who had used hormones still had a higher risk of having cholecystectomy than women who never had taken hormones. The WHI findings corroborated these results, showing an increased risk that more than doubled after five years of hormone use.

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Review Date: 2008-05-01

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