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Studying Side Effects of Hormone Therapy : Personal Health: A UCLA study seeks the best approach to hormone replacement therapy in postmenopausal women and its role in breast cancer and heart disease.

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TIMES HEALTH WRITER

Like many women, Anne Berkovitz had decided against taking hormones after menopause. But she often wondered whether she’d made the right decision. Among her friends, the topic was always a source of debate.

“You hear one person’s doctor say you must take it and another person’s doctor says you shouldn’t take it if you can get by without it,” says Berkovitz, 64, of Westwood. “I was feeling OK not taking hormones. But I had sort of wondered about it.”

Hormone replacement therapy is a drug treatment commonly prescribed to women after menopause to replace natural hormones the body has stopped manufacturing. The therapy is popular because it diminishes some uncomfortable side effects of menopause, such as hot flashes, and can reduce a woman’s risk of osteoporosis and, possibly, heart disease.

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But the treatment has drawbacks, including a possible increased risk of breast cancer.

The disparity led Berkovitz to enroll as a participant in one of the largest clinical studies on hormone replacement therapy, and the first drug trial to study its effects on heart disease. The study will begin soon at UCLA and six other research institutions. UCLA researchers hope to enroll another 75 women.

The Postmenopausal Estrogen/Progestin Interventions (PEPI) study should help define the dosage and combination of hormones that best reduce the risk of heart disease in women, the leading cause of death in women as well as men, says Dr. Howard Judd, executive director of the division of reproductive endocrinology at UCLA and Cedars-Sinai medical centers. PEPI is sponsored by the National Institutes of Health.

“Estrogen is such a powerful chemical; it impacts on so many systems in the body,” says Judd, who is directing UCLA’s part of the study. “Our hope is that we’ll be able to say, based on cardiovascular-disease risk factors, ‘this is the best way to take hormones.’ ”

While men and women share some risk factors for heart disease, such as a high-fat diet or family history, female hormones produced by the body apparently help protect women against heart disease before age 50--when men are at their peak risk.

But after menopause, when hormone production ceases, the rate of heart disease in women quickly climbs and eventually equals the rate in men.

“There is a lot of evidence now accumulating that estrogen plays a role in heart disease. How it does that is not clear,” Judd says. “We would suggest that an agent that may reduce the incidence of heart disease by 50%, maybe 60%, in more than half the population is worth studying. This is a very important question that needs to be answered. And I believe it will be.”

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Estrogen appears to lower the bad cholesterol (low-density lipoproteins) in the body and raise the good cholesterol (high-density lipoproteins) to reduce the chance of heart disease. But those possible benefits, while exciting, further complicate a therapy that is already enormously complex and the source of much consternation among postmenopausal women and their physicians.

Estrogen and progesterone are hormones produced by the ovaries; they regulate the menstrual cycle and fertility. At menopause, about age 45 to 50, the ovaries stop producing the hormones.

While the absence of a menstrual period is a welcomed event for many women, menopause can trigger uncomfortable symptoms such as hot flashes and thinning of the vaginal and urinary tissues. The drop in hormones also causes bone thinning and increases a woman’s risk of developing osteoporosis, a condition in which bones easily break or fracture.

Hormone replacement therapy resolves many of these problems. And, with the addition of possible cardiovascular benefits, it’s easy to see why hormone therapy--which usually consists of a mixture of estrogen and a progesterone-like chemical called progestin--is prescribed for 5 to 9 million women.

But, despite its popularity, the debate over hormone replacement continues.

“There are combinations of reasons and advantages for using estrogen,” says Dr. Ezra Davidson, president of the American College of Obstetricians and Gynecologists and chairman of obstetrics and gynecology at Drew Medical School. “In many instances, physicians are totaling those combined advantages and advising women of the benefits. But there is insufficient data about the risks.”

Besides minor side effects, such as menstrual bleeding, estrogen replacement is known to promote the growth of uterine tissue, called the endometrium, which can lead to cancer.

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Studies show that adding progestin to the regimen removes the risk of endometrial cancer, so physicians usually prescribe progestin for part of the month. But progestin therapy opens the door to a whole new set of complex side effects, says Barbara Hulka, an epidemiologist at the University of North Carolina and chairwoman of a government advisory committee on women’s health issues.

For example, progestin appears to erase the cardiovascular protection of estrogen. And some studies show progestin increases a woman’s risk of breast cancer.

“The quandary is basically the issue of taking estrogen alone versus estrogen plus progestin,” Hulka says. “Estrogen alone does cause a growth of the endometrial lining and does cause endometrial cancer in a significant number of women. That’s why it’s been recommended to add progestin for half the month.”

Fears that estrogen-progestin therapy will increase the risk of breast cancer were elevated last summer when a Swedish study revealed that women who took a combination of estrogen and progestin for more than six years were more than four times as likely as other women to develop breast cancer.

Other studies have not shown as great a risk, and the significance of the Swedish study is debated, Judd says.

“That data shows more risk than U.S. data,” Judd says. “Whether or not that will be substantiated or not, I don’t know. Many of us felt like (the Swedish) data were over-interpreted.”

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But the study did underscore the need for a better understanding of the risks and benefits of hormone therapy.

Earlier this year, the Food and Drug Administration approved new warnings regarding breast cancer risk on the labels of estrogen therapy drugs.

And, in a more controversial move, an FDA advisory panel concluded in July that estrogen taken alone (without progestin) helps prevent heart disease in women who have had hysterectomies. Because women who have had their uteruses removed do not run the risk of endometrial cancer, the committee deemed that estrogen alone would be beneficial in this group, says Davidson, who was a member of the panel.

“The committee made a prudent judgment based on the information on benefits, with the understanding that (the information) was limited about the long-term risks,” says Davidson, who added that some committee members had reservations about making any recommendations on estrogen therapy and heart disease.

The recommendation by the committee--which might persuade the FDA to allow a change in the labeling of estrogen to include protection against heart disease for women who have had hysterectomies--was criticized by some physicians and consumer health groups.

The National Women’s Health Network said in a statement that studies have not been done to verify that the potential protective effects of estrogen replacement therapy outweigh the risks.

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“It is alarming to think that millions of women may be given this drug before either its dangers or benefits are understood,” says Davi Birnbaum, a representative of the Washington-based women’s health organization.

The panel’s recommendation, which is only for women who have had hysterectomies, leaves postmenopausal women who have not had hysterectomies in limbo, says Dr. Diana Petitti of the University of California, San Francisco.

“The data on estrogen use alone in postmenopausal women are fairly consistent in showing a lower risk of coronary heart disease,” she says. “But most women are not put on estrogen alone. And the data to show whether or not the combination of estrogen and progestin also decrease the risk of coronary heart disease is essentially non-existent.”

The FDA advisory panel based its recommendations on a series of small observational studies, called epidemiological studies, not the expensive, clinical trials that are usually more conclusive, Judd says.

“I think (the advisory panel recommendation) is premature because it’s based exclusively on epidemiological studies,” he says. “You’ve got to do drug trials. For something this important that impacts on every woman in the country, we’ve got to spend money.”

The PEPI study was designed to fill this void, Judd says. In the study, 840 women will be randomly assigned to one of five drug regimens: a placebo; estrogen alone; the standard combination of estrogen and progestin widely prescribed in the United States; estrogen and a smaller, daily dose of progestin, and, estrogen with a new formulation of progestin created in Europe.

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Women will be followed for three years while their risk factors for heart disease, such as high blood pressure, and cholesterol levels are measured.

The study also will incorporate measurements of bone density to learn more about the prevention of osteoporosis. The PEPI study will not attempt to resolve the issue of breast cancer risks.

The results of the study are expected in 1994.

“It remains a question of what do you do in the interim between now and the time when we’ll have an answer,” Petitti says. “Do you want to take the risk of taking the drug and being wrong? Or do your take the risk of not taking the drug and being wrong? I consider it to be an incredibly hard choice.”

With so many questions remaining, physicians need to review each woman’s circumstances and fears before prescribing hormone replacement therapy, says Petitti.

“I think the clinicians who are trying to handle their patients on an individual basis are doing the best job,” she says. “Someone terrified of breast cancer may not want to take the potential risk of breast cancer. But someone has a mother or aunt who had a osteoporotic bone fracture may say ‘I don’t want that to happen to me and I don’t care as much about the risk of breast cancer.’ ”

Experts caution that it will take a long-term study, perhaps several decades, looking at causes of death among women to resolve whether hormone replacement therapy actually prolongs life or merely swaps one risk for another.

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“I think the PEPI study will be useful,” Petitti says. “But the bottom line will not be addressed by the PEPI study. The bottom line is, will it save our lives? I don’t think any single study will answer that question.”

Candidates Are Still Needed for UCLA Intervention Study

Individuals interested in volunteering for the Postmenopausal Estrogen/Progestin Interventions study must be healthy women, age 45-64, who have had a natural or surgical menopause and are willing to take hormones.

The participants will receive periodic free medical examinations over a three-year period.

For more information, call the UCLA Medical Center, Division of Reproductive Endocrinology, (213) 825-9502.

WOMEN AND HEART ATTACKS While heart disease in men often occurs in their 20s and 30s, heart disease in women soars after age 50. Medical experts believe this might be due, in part, to the loss of natural estrogen hormone during menopause. Age 29-44 Male: 123,000 Female: 3,000 Age 45-64 Male: 424,000 Female: 136,000 Age 65+ Male: 440,000 Female: 374,000 Source: American Heart Assn.

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