p>BETHESDA, MD—Eight years ago, results from the Women’s Health Initiative (WHI) study on hormone replacement therapy raised serious concerns for post-menopausal women taking estrogen plus progestin, linking the therapy to increased risk of breast cancer and other health problems. At the time, the WHI’s findings were criticized by defenders of hormone replacement therapy, who cited flaws in the study design and suggested that, if followed over a longer period, the results would be different.

However, according to WHI researchers, the study’s findings have only been further substantiated over time.

Discovering the Danger of Hormone Therapy

WHI, a long-term national health study funded by NIH, began its work in 1993. The hormone therapy arm of the study was split into two separate trials: one looking at estrogen-alone versus placebo and one looking at estrogen plus progestin versus placebo. All of the 16,608 women in the study screened negative for cancer and heart disease.

“These were women who had no reason to think they’d be dead within three years,” explained Rowan Chlebowski, MD,PhD, WHI lead investigator, at a breast cancer research briefing on the NIH campus last month. “With hormone therapy alone, we anticipated to decrease coronary heart disease, decrease hip fractures, and increase breast cancer, but the cancers were anticipated to be diagnosed at early stages and have favorable characteristics and outcome.”

The trial, designed to go on for nine years, ceased in 2002 after six years. In the estrogen plus progestin group, study monitors saw significantly worse outcomes than they were expecting. “It looked like initially that there were going to be fewer breast cancers on estrogen plus progestin. But then the curves crossed and we actually had a significant increase in the estrogen plus progestin group,” Chlebowski explained. “We anticipated that there would be more lobular cancers. We didn’t see that. We thought there would be more low-grade cancers, and we didn’t see that.”

Researchers found that there were almost double the number of mammograms with abnormalities and double the number of biopsies in the estrogen plus progestin group compared to placebo. “What it boiled down to was that estrogen plus progestin was delaying breast cancer diagnosis and stimulating breast cancer growth,” Chlebowski said.

There was criticism by those defending the therapy that the WHI study participants were too old, and that women who started hormone therapy closer to the onset of menopause would fare better. However, according to Chlebowski, further examination of the results shows that those who began therapy closer to menopause had higher risk for cancer than those that began therapy later.

Findings Holding Out Over Time

The study received substantial media attention. As result, use of hormone replacement therapy dropped significantly between 2003 and 2004. Prior to the study’s findings, 40% of post-menopausal women were taking hormone replacement therapy. That number dropped to 30%, a decrease of 35 million prescriptions in one year.

“When we looked at the data, we saw that there was an immediate drop in breast cancer incidents, reversing a 20-year trend,” Chlebowski declared. The drop occurred most significantly in women aged 50 to 69. The overall decrease of breast cancer rates dropped 8.6% in that age group between 2001 and 2004. The decrease in this age group has been sustained through 2007—the latest year with available data.

Chlebowski admitted that there is no proof of causality, merely association. “But we think it’s linked to the drop in hormone therapy. We don’t see any other reason.”

He cited a study published in the Journal of Clinical Oncology that looked at women in certain California counties in 2001. The study showed that the cancer rate was higher among women taking hormone therapy. After WHI’s results were published, the rate of hormone replacement therapy went down to 10% and cancer risk went down across the board. Another study published in The Lancet in September showed that estrogen plus progestin also doubled lung cancer mortality, Chlebowski said.

And while there was initial evidence that the therapy actually decreased colorectal cancer by as much as 40%, follow-up of WHI study participants is showing that there is more colorectal cancer mortality in the estrogen plus progestin group.

More data is expected from WHI’s follow-up. An extension study was begun in 2005 and is set to last through this year. Nearly all of the original participants agreed to enroll in the follow-up study.

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