Wednesday, July 17, 2002

BY KITTA MacPHERSON
Star-Ledger Staff

Federal researchers have concluded that taking estrogen over an extended period of time could increase the risk of ovarian cancer in women, a finding certain to prolong the controversy over the safety of using hormones to treat menopause.

The study, to be published in today's issue of the Journal of the American Medical Association, follows the startling announcement last week that the combined use of estrogen and progestin increased the risk of heart disease and breast cancer in women who participated in a large study. Until now, medical treatment had been based on the widely held belief that estrogen warded off heart disease.

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An editorial in the same edition of the influential medical journal advises physicians to stop prescribing combined hormone treatments for long-term use. Physicians and patients had been confused about the practical impact of last week's study, released early in an electronic version placed on the journal's Web site.

The findings serve as a nasty one-two punch for Wyeth Pharmaceuticals in Madison, whose drugs, Prempro, a combined hormone treatment, and Premarin, an estrogen medication, are best sellers.

"The association between estrogen use and ovarian cancer should be worrisome enough for clinicians to consider carefully whether to suggest estrogen-only hormone replacement therapy," writes Kenneth Noller, an obstetrician-gynecologist at Tufts University in Boston, in an accompanying editorial.

Study author James Lacey Jr., an epidemiologist, and colleagues from the National Cancer Institute in Bethesda, Md., found evidence of the increase in ovarian cancer after conducting a follow-up study of 44,241 women. The women in the study had agreed to stay in touch with scientists after participating in the vast Breast Cancer Detection Demonstration Project, a mammogram-screening program that ran from 1973 to 1980 and involved more than 200,000 women.

"Because hormone therapy may influence so many conditions that affect women after menopause -- cardiovascular disease, osteoporosis, breast cancer, uterine cancer, gallbladder disease, blood clots and now potentially ovarian cancer -- we should no longer think of a woman basing her decision to use hormones on the potential risk of just one condition," Lacey said. "Women should continue to talk to their health care providers about whether hormones might be right for them."

Estrogen is already known to increase the risk of developing uterine cancer. The finding of an increased incidence of ovarian cancer, however, is significant because, though rare, it is a far more deadly form of cancer.

Victoria Kusiak, North American Medical Director for Wyeth, which makes the hormone pills implicated in the study, said the findings represented just one more conclusion of a melange of studies on the purported link between estrogen and ovarian cancer that have been "all over the map."

"This is an evolving story," said Kusiak, a physician. "We just have to stay tuned as to what comes out." Women now, she said, have "a better definition of the risks" of hormone therapy, which should help guide treatment.

The study, she said, is not definitive in that it was an observational study, based on self-reported facts by participants, rather than a more rigorous clinical trial.

Lacy, the federal epidemiologist who led the analysis, said that in the case of his study, a clinical trial would be unethical. Such trials are supervised medical experiments testing new drugs or procedures. "We don't do clinical trials to test harmful effects," Lacy said.

Lacy and the other authors concluded that while this study points to an association between long-term estrogen use and ovarian cancer, more research is needed to gauge the actual risks of taking estrogen.

All that may be left to medicine in order to perform further analysis, he said, are more big studies. Since ovarian cancer is so rare, it is necessary to gather data from very large groups, a factor that makes such studies expensive and cumbersome.

The federal Women's Health Initiative study, which found last week that combined hormone therapy did not guard against heart disease and may contribute to increased breast cancer risk, studied 16,000 women over five years. The study that forms the basis of the estrogen-ovarian cancer link included 44,000 women over 20 years.

"For a population three times as big over a time interval four times as long, we still only saw 329 ovarian cancers," Lacy said. "You need something large enough and long enough so we can be somewhat confident about the results."

Women who used estrogen had a 60 percent greater risk of developing ovarian cancer, according to the study, than women who had never taken hormones. The risk increased with length of estrogen use. Women who used the combined treatment did not appear to have a significantly increased risk of developing ovarian cancer, according to the study.

Between 1979 and 1998, the authors interviewed participants about the type of hormones used, age at first use of hormones, duration of use, form of administration and other possible risk factors that could contribute to the development of the disease.

By the time of the follow-up, the women in the study were all postmenopausal and were 56 years old on average. Some had hysterectomies. All had at least one ovary.

They asked participants whether they had been diagnosed with ovarian cancer, and then reviewed medical records, death certificates and state cancer registry data to confirm those diagnoses.

Among the 44,241 women who were interviewed in the follow-up, 329 developed ovarian cancer. The risk of ovarian cancer, the study found, increased with estrogen use among women with and without a hysterectomy, and the risk increased proportionately with a longer duration of hormone use.

Estrogen is a natural hormone produced primarily by the ovaries. After menopause, the ovaries produce lower levels of the hormones estrogen and progesterone. By the time natural menopause is complete -- usually between ages 45 and 55 -- hormone output decreases significantly.

As early as the 1940s, women began using estrogen in high doses to counteract some of the short-term discomforts of "the change of life" -- hot flashes, insomnia, vaginal drying and thinning, and urinary tract incontinence and infections. After it became clear in the 1970s that women who took estrogen alone had a six to eight times higher risk of developing uterine or endometrial cancer, doctors began prescribing progestin along with much lower doses of estrogen. Progestin is a synthetic form of the natural hormone progesterone.

Previous studies looking at the effect of postmenopausal hormones on ovarian cancer risk have been inconsistent. Some reported increased risk with estrogen use while others reported either no effect or a protective one.

Most of the earlier studies were small and limited by incomplete data about ovarian cancer risk factors.