NEWS

Recent Studies Bring Risks, Benefits of Hormone Replacement Therapy Under Scrutiny

M.J. Friedrich

Over the years, estrogen replacement therapy has promised not only to spare a woman from menopausal symptoms but also to lower her risk for cardiovascular disease and osteoporosis and even possibly prevent the onset of Alzheimer’s disease and colon cancer.

Under close scrutiny, estrogen presents a more complex picture. Estrogen does alleviate menopausal symptoms and increase bone mineral density; however, it also increases the risk of endometrial cancer. To counteract this danger, progesterone—in the form of progestins—have been added to estrogen in the hormone replacement therapy mix.

But recent studies suggest that a woman’s breast cancer risk, which is slightly elevated when she is taking ERT, increases further when estrogen is coupled with progestins. Other trials raise questions about estrogen’s purported cardioprotective effects, so much so that the American Heart Association recently issued a statement advising that HRT not be prescribed for women for the sole purpose of preventing heart disease.

The situation remains ambiguous, and more definitive answers from ongoing studies are at least a few years away. Meanwhile researchers are teasing out the differential effects that estrogen and progestin have on various organs of the body, information that is contributing to the evolution of HRT’s risk-benefit equation.

Observational Studies

A number of large-scale observational studies that looked at combination therapy and the risk of breast cancer have been published in the last few years. Since the time progestins were added to HRT, controversy has emerged over whether they are harmful or beneficial to the breast, said Richard Santen, M.D., professor of medicine at the University of Virginia, Charlottesville.



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Dr. Richard Santen

 
"The original concept was that the breast and uterus respond similarly to progestins. More recently the major body of data suggests that progestins work differently in the breast than in the uterus and cause more breast cancer than with estrogens alone," Santen said. Breast cancer risk, which is modest with short-term HRT use, appears to increase with duration of use.

Ronald Ross, M.D., chair of preventive medicine at the University of Southern California Norris Comprehensive Cancer Center, Los Angeles, said that in the last year a lot has been learned about the effect of progestins on the breast, not only from epidemiologic studies but also from mammographic density and cell proliferation studies.



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Dr. Ronald Ross

 
"I think [these studies] have further enforced what I have believed all along—that certainly there’s no place for progestin in HRT in women without a uterus and that we really have to start thinking more about how to deliver progestin in the best possible way to women who have their uterus."

Ross noted that "the only organ that seems to like progestins postmenopausally is the endometrium, so why don’t we figure out a way to get it to just that organ?" There is reason to believe this can be done, he said. The issue is to figure out the delivery system.

Working on that problem is Malcolm Pike, Ph.D., professor of preventive medicine at USC/Norris Comprehensive Cancer Center. There are a number of ways to enhance uterine delivery of progestins to protect the endometrium while minimizing their systemic effects, said Pike. One approach is to administer them locally via vaginal creams or IUDs. Pike recently began a study involving vaginal cream to determine the dose necessary to control endometrial cancer.



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Dr. Malcolm Pike

 
Cardiovascular Concerns

Another important question raised about HRT is whether estrogen confers cardioprotective benefits, as many observational studies have indicated. A few randomized clinical trials have cast doubt on HRT’s protective effect on the heart. These studies indicate that HRT may actually increase the risk of cardiovascular events in women with coronary heart disease—at least in the first 1 to 2 years of use. And an interim analysis of the Women’s Health Initiative, which is examining the effects of HRT on heart disease, osteoporosis-related bone fractures, and breast and endometrial cancer, suggests there may be a short-term increase in risk for postmenopausal women who do not have coronary heart disease.

‘Not Living Up to Their Promise’

"Once these studies became available," said JoAnn Manson, M.D., director of clinical prevention at Brigham and Women’s Hospital, Boston, "it was clear these hormones were not living up to their promise to protect the heart. Not only that, but there appeared to be early harm."



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Dr. JoAnn Manson

 
The short-term increase in risk may have been missed by observational studies given their design, said USC’s Ross. Nevertheless, he said that he would be surprised if over the long term estrogen therapy is not shown to be cardioprotective in women with some established cardiovascular disease.

Until further data are in, Manson stressed that HRT should not be used for the express purpose of preventing heart disease. "Patients shouldn’t expect that these hormones will protect their hearts and clinicians shouldn’t be prescribing hormones for that purpose." Manson, an investigator on the Women’s Health Initiative, said results from the study, which will conclude in 2005, should help to clarify the issue.

Manson advocates dividing the decision-making process into short-term (less than 5 years) and long-term (5 years or greater) time frames. In her view, many women are good candidates for short-term therapy, but a much smaller number are appropriate for long-term therapy.

HRT is a reasonable choice for women with severe menopausal symptoms, since at this time no other alternative works as well, said Manson. Women around the age of menopause tend to have a fairly low baseline risk of heart disease, and the HRT/breast cancer studies suggest that short-term use of HRT does not contribute substantially to the risk of breast cancer in the majority of women.

"If you’re talking about a slight elevation in that risk—but you’re providing an important benefit of improved quality of life and reduced symptoms of menopause—then you can make a case [for HRT], especially if the woman prefers going that route," said Manson.

Medical Alternatives

University of Virginia’s Santen said many women decide to take HRT to relieve menopausal symptoms but then switch to medical alternatives after symptoms subside. A woman should discuss with her physician which problems she is facing—cardiovascular risk, osteoporosis, hot flashes, urogenital atrophy, or depression—and choose alternatives appropriately. "Many people say you can’t use five different drugs to take the place of estrogen," he said. "But the fact is, most women only have one or two of these problems."

Alternatives to HRT include bisphosphonates and selective estrogen-receptor modulators (SERMs, such as raloxifene) for osteoporosis; statins to prevent heart disease; soy and vitamin E to reduce mild to moderate hot flashes; and low-dose vaginal estrogen for vaginal symptoms of menopause. And, as a number of experts pointed out, menopause and estrogen depletion do not always need to be treated pharmacologically. Lifestyle changes, such as exercising, quitting smoking, or eating a healthy diet, may control symptoms without the need for medical intervention.

Perhaps in the future, said USC’s Ross, the ideal HRT will be a designer drug that has estrogen agonist properties for the organs that "like" the hormone and estrogen antagonist properties for those, such as the breast and endometrium, that do not. Until that time arrives—if it does—clinicians must help women consider the evolving picture of the risks and benefits of HRT so that each woman can reach a decision based on current evidence and her own preferences.



             
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