A study reported in the July 17 Journal of the American Medical Association (JAMA Vol. 288, No.3: 334-341) said that using estrogen therapy alone can increase the risk of ovarian cancer.

This follows a study reported on July 9 by the Women's Health Initiative confirming that combined hormone therapy with estrogen and progesterone increases the risk of breast cancer in women.

In the new report, James V. Lacey Jr., PhD, and associates from the National Cancer Institute in Bethesda, Md., examined information obtained from more than 44,000 women who participated in the Breast Cancer Detection Demonstration Project in 1979 and 1980. They followed these women through 1998.

The researchers reported that there was an increased risk of cancer of the ovary in women who said they had used estrogens compared to women who never used any hormones.

The longer the women used estrogens, the greater their risk of developing ovarian cancer. For women who used estrogens alone for more than 20 years, the risk of ovarian cancer was over three times the risk of women who had not used estrogens.

Most of the women who reported long-term estrogen use for menopausal symptoms had a prior hysterectomy, according to the report. Among the women who had a hysterectomy and used estrogens for 10 to 19 years, the risk of ovarian cancer was double that of women who never used estrogen.

Stopping estrogens after 10 years or more still resulted in an increased risk of ovarian cancer.

For women who used estrogen with progesterone, there was no increased risk of ovarian cancer. Using combination therapy for a long period of time also did not increase the risk in these women.

Why would estrogens affect the risk of ovarian cancer? The authors noted that several recent studies showed that estrogen can stimulate cells from the ovaries, and that there are estrogen receptors on ovarian cells.

The authors said, "In this large prospective study, women who used estrogen replacement therapy, particularly for 10 or more years, were at significantly increased risk of ovarian cancer." They also noted that women who switched from estrogens alone to estrogens in combination with progesterone had an increased risk of ovarian cancer.

In an editorial which accompanied the article (JAMA Vol. 288, No. 3:368-369), Kenneth L. Noller, MD, from Tufts New England Medical Center in Boston, wrote, "For a short time, estrogen replacement was viewed as the perfect solution for many health problems in postmenopausal women. The benefits of preserving bone and reducing menopausal symptoms were already well-known.

"It is not surprising the pharmaceutical industry developed numerous estrogenic agents, which could be swallowed, placed in the vagina, applied with a patch, or rubbed into the skin, and that these agents have been prescribed for and are now used by millions of women," he said.

Noller continued, "However, recent…studies provide compelling evidence that there is no protection against further cardiovascular [heart and blood vessel] events for women with coronary heart disease who take hormone replacement therapy, and there may be real harm."

"Estrogen replacement therapy certainly is not the panacea it once appeared. Physicians counseling women about hormone replacement therapy must consider the unique needs of each patient, and attempt to weigh the benefits and risks on an individual basis," Noller said.

"Based on the information in the study by Lacey [and colleagues] the risks now include ovarian cancer," he said.

Carolyn Runowicz, MD, vice chairman of the department of obstetrics and gynecology at St. Lukes-Roosevelt Hospital Center in New York City and a nationally recognized expert on ovarian cancer, said, "This is a significant study that has followed lots of women. There has been increasing evidence that this makes sense."

"There have also been animal studies suggesting that progesterone may have a preventive effect on ovarian cancer,” said Runowicz, who serves on the national board of the American Cancer Society (ACS) and is a member of the ACS’ gynecological cancer advisory group.

This may explain why the women on combined hormonal therapy did not have an increased risk of ovarian cancer, according to Runowicz.

However, for women who have had hysterectomies, Runowicz does not recommend they stop taking estrogen. "This risk is small, and should come out in the informed consent," she said, noting that it is important for women taking estrogen to discuss this study with their doctors.

Runowicz emphasized strongly that she would absolutely avoid using any hormone therapy in women with either a history of ovarian or breast cancer.

What about the confusion this report will cause in light of the recent breast cancer study showing that women should avoid combination hormone therapy with estrogen and progesterone?

Runowicz said that in the breast cancer study women were treated with combination hormones where the estrogen and progesterone were combined in a single pill. The other option is taking them in sequence where the estrogen is taken for several weeks and followed by progesterone for a few days.

"Sequential hormone treatment may be preferable, and may not have the same effects on the breast," she said. "The pendulum doesn’t have to swing completely the other way. The truth is probably somewhere in the middle."