Bad News About Hormone Replacement Therapy

Many of us have been jaded by the constant onslaught of “the latest” medical news, much of which seems to contradict what we just heard or read about the week before.

But on July 9, millions of us – patients and health care providers alike – paid rapt attention when the federal government’s National Institutes of Health released findings from a major clinical trial, warning of the risks associated with a widely used type of hormone replacement therapy (HRT) that combines two female hormones, estrogen and progestin.

It’s estimated that 6 million postmenopausal American women currently take Prempro or similar combined estrogen-progestin drugs to ease menopause symptoms and to improve their health and well-being.

Risks Outweigh Benefit, Study Found
The study, called the Women’s Health Initiative (WHI), found that the combined drugs caused increases in breast cancer, heart attacks, strokes and blood clots. Although the risk to an individual woman may be small, the number of cases occurring in the population at large can be great, researchers said. And those risks outweigh the drugs' actual benefits – a small decrease in hip fractures and a decrease in cases of colorectal cancer. The study was released four years earlier than expected because of researchers’ concerns.

The WHI study is the first-ever long-term randomized controlled clinical trial – considered the gold standard by medical researchers – of hormone replacement therapy. The WHI was established in 1991 by the government to address the most common causes of death, disability and impaired quality of life in postmenopausal women. The Medical College of Wisconsin is one of 40 WHI clinical sites nationwide where study participants are seen and monitored.

The Women’s Health Initiative is a 15-year multimillion-dollar endeavor, and one of the largest US prevention studies of its kind. The study was designed to look at the effects not only of HRT, but also diet modification and vitamin and mineral supplements. Some 67,000 women from across the country, ranging in age from 50 to 79, are participating in the WHI clinical trials. In addition to those women, the study is also following the medical history and health habits of an additional 100,000 women to examine the relationship between lifestyle, health and risk factors with specific disease outcomes. Final results are due out in 2006.

More than 16,600 US women are participating in the combined estrogen-progestin portion of the trial, among them 438 women who are in the Medical College of Wisconsin group. They were sent letters telling them to discontinue taking those drugs. The WHI is continuing to study the effects of ERT, or estrogen-alone drugs, used by women who have had a hysterectomy. WHI has not stopped that portion of the study.

Jane Morley Kotchen, MD, Professor and Director of Epidemiology at MCW, is the principal investigator for MCW’s portion of the study. She admits she was caught by surprise by the early release.

"The breast cancer risks for women on the combined estrogen-progestin therapy are similar to risks that have been found in other studies,” she notes, although she says the cardiovascular findings were not anticipated. “A decreased risk of coronary heart disease had been hypothesized for women on active hormone therapy, so the finding of slightly greater risks for women on the active hormone therapy was unexpected. Overall, the health risks for women taking combined estrogen plus progestin therapy were found to outweigh the benefits. The trial was stopped because the risk-benefit balance, as indicated by a global indicator of overall risk, was unfavorable and the breast cancer risks crossed the predetermined safety boundaries."

The WHI’s Data and Safety Monitoring Board – an independent advisory committee charged with reviewing results and ensuring participant safety – set the limits of acceptable risk for breast cancer at an unusually low level of cases per thousand. When that level was reached, the trial was stopped and results were released early.

Another Medical College faculty member who served as a WHI investigator agreed that the early release of the findings was surprising. For Vanessa Barnabei, MD, PhD, the medical risks and benefits that caused such a national media furor when the WHI released its combined estrogen-progestin study results had been indicated by earlier patient studies, although earlier studies were regarded as “observational,” and had not met the strict standards of the WHI. Dr. Barnabei is an Associate Professor of Obstetrics and Gynecology at MCW and Director of MCW Physicians’ Division of General Obstetrics and Gynecology.

"Early harm from heart disease and stroke were suggested several years ago, and women in the study were informed about it at that time,” Dr. Barnabei says. “And the breast cancer risks have been suspected. The numbers and magnitude of risk are no different today than they were then.

Risk ‘Relatively Small’ for Individual Women
In a news release from the NIH on July 9, Jacques Rossouw, MD, acting director of the WHI, summarized the risk findings:

"The WHI results tell us that during one year, among 10,000 postmenopausal women with a uterus [as opposed to those who have had their uterus removed] who are taking estrogen plus progestin, eight more will have invasive breast cancer, seven more will have a heart attack, eight more will have a stroke, and 18 more will have blood clots, including eight with blood clots in the lungs, than will a similar group of 10,000 women not taking these hormones. This is a relatively small annual increase in risk for an individual woman,” he said.

Dr. Barnabei said that she found it interesting that the WHI has continued with the estrogen-only portion of the study. She says scientists have known that progestin can act to influence breast growth and development while reducing the risk of uterine cancer. And an article in the January 26, 2000, Journal of the American Medical Association reported that researchers at the National Cancer Institute had found that women who are current or recent users of combined estrogen and progestin had a higher relative risk of breast cancer than women who only take estrogen.

What Patients Should Know
Dr. Rossouw, the acting WHI director, offered this advice: “Women with a uterus who are currently taking estrogen plus progestin should have a serious talk with their doctors to see if they should continue it. If they are taking this hormone combination for short-term relief of symptoms, it may be reasonable to continue, since the benefits are likely to outweigh the risks. Longer term use or use for disease prevention must be re-evaluated, given the multiple adverse effects noted in WHI."

Dr. Barnabei says she always cautions patients about the potential for increased breast cancer risks. First, she rules out women who are not candidates for HRT– those with vaginal bleeding of an unknown cause, suspected breast cancer or history of breast cancer, history of endometrial cancer or certain cancers of the uterus, chronic liver disease such as cirrhosis or a history of blood clots.

For women who are eligible for HRT, the primary reason for HRT is symptom relief, she says, with less emphasis on using hormone therapy for disease prevention: “I explain the known risks and benefits. And I do remind them that the risk for breast cancer does increase naturally for all women as they age, along with heart disease and osteoporosis."

Dr. Barnabei tells her patients who want to stop HRT that they can certainly quit anytime. “First of all, with menopause, we’re not treating a disease,” she says. “Stopping HRT has no major consequences except perhaps a return of menopausal symptoms.”

Non-HRT Options Effective for Some
For both women who want to stop taking HRT and for women who choose not to start HRT, Dr. Barnabei discusses alternative therapies. “For almost everyone, there are other treatment options. I take them through all the major organ systems in the body that undergo change with menopause. I assess their personal risks and discuss options.”

For instance, she tells women they can reduce their risk of heart disease by stopping smoking and by keeping their weight, cholesterol levels and blood pressure under control. Prozac and some other antidepressants can relieve hot flashes. Biphosphonate drugs such as Fosamax help protect against osteoporosis. So can another prescription drug, Evista (raloxiphene HCl), which also claims to lower total cholesterol and prevent breast cancer. However, Dr. Barnabei says that because women on Evista experience more hot flashes, it raises questions about how that might affect the brain. Some researchers have suspected a link between hot flashes and Alzheimer’s. “We don’t have long-term data, so we don’t know.” And Evista has been found to exaggerate vaginal dryness, she says. Evista belongs to a class of drugs called SERMs, or Selective Estrogen Receptor Modulators. A SERM being used in Europe, tibolone, may be more effective without the side effects found in Evista.

Herbal Remedies: Effectiveness and Safety at Issue
As women have become more doubtful about HRT, many have grown interested in using herbal remedies instead. Dr. Barnabei urges women to be cautious: “Just because something is derived from a plant does not necessarily mean it’s safe. Some herbal remedies work a bit, but some don’t work at all. And many have potentially dangerous health risks. We have even less data on herbal remedies (which are not regulated by the government) than we do on HRT.”

A popular herbal remedy is black cohosh, which “seems safe for most women. But I have serious reservations about soy,” Dr. Barnabei says. “It’s not the panacea women would like to think it is. To get any relief from hot flashes, you’d have to consume a high quantity, about 40 grams per day or more, and that raises calorie intake issues.” Soy has gained popularity in the United States because it’s such a staple in the Japanese diet, where women generally have lower rates of breast cancer and menopausal symptoms. “However,” she notes, “Asian women do seem to be at higher risk for osteoporosis.”

Other widely used remedies for relief of menopausal symptoms are St. John’s Wort and wild yam. With St. John’s Wort, women typically take three tablets a day for two to three months before finding relief. Yams contain a protein or protein-like substance that is similar to the progesterone hormone. But, Dr. Barnabei says, “By itself it can’t have a hormone-like effect because our bodies lack an enzyme needed to convert it.”

Besides Drs. Kotchen and Barnabei, three other Medical College of Wisconsin faculty members are investigators of the WHI study: Joan M. Neuner, MD, MPH, Assistant Professor of Medicine; Mary Ann C. Gilligan, MD, MPH, Assistant Professor of Medicine; and Theodore A. Kotchen, MD, Professor of Medicine. Dr. Neuner’s focus is metabolism and nutrition; Dr. Gilligan’s area of interest is cancer prevention and genetic screening for cancer; Dr. Theodore Kotchen is an endocrinologist.

Although these early findings from the WHI raise some cautions and pose some questions, Dr. Kotchen says, “The most important thing about what we know is that women need to understand the risks and benefits so they can make informed choices.”

This article includes information from the Froedtert & Medical College Obstetrics and Gynecology Clinic.

MCW Health News presents up-to-date information on patient care and medical research by the physicians of the Medical College of Wisconsin.