Study Urges Use of 2nd Hormone in Estrogen Therapy

Taking estrogen alone produces such a substantial risk of uterine cancer that post-menopausal women opting for hormone therapy should strongly consider a protective regimen that includes progestin, according to the lead author of a new report on hormone therapy.

The findings, published in today’s Journal of the American Medical Assn., provide the most comprehensive, controlled look to date at how various hormone regimens affect the lining of the uterus. The paper is the second of three reports resulting from the Post-menopausal Estrogen/Progestin Intervention Study (PEPI), a multifaceted investigation to help women and their doctors make better decisions about hormone therapy.

The data published today reveal that women taking estrogen alone had high rates of endometrial hyperplasia, a condition in which the endometrium, the lining of the uterus, grows excessively. Hyperplasia is considered a precursor of uterine cancer.

Women taking any one of three regimens that combined daily estrogen with progestin, however, had low rates of hyperplasia, similar to those of women in a placebo group receiving no therapy.

“We’ve known that estrogen [causes hyperplasia]. But this is the first time that estrogen-only has been compared to a placebo,” said Dr. Howard Judd, a PEPI investigator and vice chairman of the department of obstetrics and gynecology at UCLA Medical Center. “It’s unequivocal that estrogen stimulates overgrowth.

“If a woman has a uterus and she considers hormone replacement therapy, our recommendation would be that she seriously consider the use of progestin,” he said.

Women sometimes prefer estrogen alone because combination therapy produces monthly vaginal bleeding. Moreover, some women experience side effects from progestin such as depression, premenstrual syndrome and headaches.

Physicians have routinely added progestin to hormone therapy because progestin is known to decrease the risk of uterine cancer. The data published today should help clarify the risk of uterine problems with respect to the four hormone regimens studied, Judd said.

“The endometrial issue is a safety issue. Our concern was that our patients would develop cancer,” he said. “This is the benchmark study.”

The PEPI study was a three-year, multi-center trial to assess the effects of four hormone regimens on heart-disease risk factors, endometrial hyperplasia, breast-cancer risk and osteoporosis.

Women were randomly assigned to receive a placebo or one of the four regimens: estrogen alone, daily estrogen plus a synthetic progestin taken 12 days a month, daily estrogen plus daily synthetic progestin, and daily estrogen plus natural progesterone taken 12 days a month. Neither the women nor the investigators knew to which group the women were assigned.

The uterine cancer risk segment of the study involved 596 post-menopausal women who were healthy and had a uterus. The women underwent regular examinations and diagnostic tests, including endometrial biopsies to look for changes in the uterus.

Of 119 women in the estrogen-only group, 74 (62.2%) developed some form of hyperplasia, from mild to severe. In comparison, only two of 119 women in the placebo group developed hyperplasia.

In the three estrogen-progestin combination groups, rates of hyperplasia also were low: six in 118, one in 120 and six in 120.

“Progestin really knocks it down to very acceptable rates of hyperplasia,” Judd said.

The women in the estrogen-only group also required far more unscheduled biopsies, 66.4% compared to 8.4% in the placebo group. The three combination therapy groups reported low rates of unscheduled biopsies as well: 13.6%, 7.5% and 11.7%, respectively. Unscheduled biopsies were performed when there was an indication of a problem, such as vaginal bleeding from hyperplasia.

Women in the estrogen-only group also required significantly more dilation and curettage procedures, in which the lining of the uterus is removed, and had a slightly increased rate of hysterectomy compared to the other four groups.

In November 1994, PEPI researchers announced that each of the four hormone regimens significantly lowered a woman’s risk of heart disease. Since that data showed that women on combination therapy still enjoy a cardiovascular benefit, the argument for using estrogen alone is a weak one, Judd said. But, he said, some women prefer estrogen over a combination therapy.

“If a woman cannot or will not take progestin, then we could see giving estrogen-only therapy. But we would recommend a biopsy [before beginning estrogen] and at yearly intervals,” Judd said.

The PEPI data on osteoporosis will be published later this year, giving women and their doctors the most well-rounded picture to date of the pros and cons of hormone therapy. But, Judd said, several key questions remain.

At least two of those questions will be tackled by a 10-year, nationwide study of 25,000 women, called the Women’s Health Initiative. It will attempt to determine whether hormone therapy prevents heart disease and whether it increases the risk of breast cancer. The PEPI study found no increased risk of breast cancer but was too short for that finding to carry much significance.

“Until we have answers to those two questions, there will continue to be confusion,” Judd said. “Until then, it will be a dilemma, and women will agonize over it. Hopefully, the Women’s Health Initiative will answer both.”