Shift in Hormone Science Leaves Women in Lurch

For many women, it felt like a slap in the face.

They had been given hormones for years at menopause to gain relief from hot flashes and night sweats. But as the years went by they were told something far grander: By continuing to take the drugs well past menopause, they could not only lessen their risk of osteoporosis but also possibly of heart disease, the leading cause of death for women.

Now it seems the promise was not so bright. They are grappling with the news that a five-year study of 16,608 women released Tuesday showed that the long-term use of the hormones estrogen and progestin actually increased the risk of heart disease, as well as breast cancer, strokes and blood clots in the lungs and legs, although only slightly.

As millions of women wrestle now with the decision of whether to continue their therapy--used for varying durations by an estimated 38% of post-menopausal women--many are wondering: How could science be so wrong? Why were so many hormones dispensed for so long?

One reason was simply that drugs weren’t tested nearly as rigorously in the 1930s, when the therapy was introduced. “It got grandmothered in, as it were,” said Dr. Stephen Hulley, chairman of the department of epidemiology at UC San Francisco.

Economics and sociology played their parts too. Pharmaceutical companies poured millions of dollars into marketing a product that could be used by tens of millions of women, who were receptive to a chemical that could relieve the distressing symptoms of menopause and perhaps help them ward off old age.

But a front-and-center player was the subtlety of the truths that science was trying to unearth and the very limitations of that science. For more than seven decades, scientists conducted thousands of studies to try to tease out what the hormones did--good and bad--to women’s bodies. They accrued a wealth of information but were never able to mount a study big enough, long enough and controlled enough to find the truth.

The truth, as it turned out, amounted to eight extra cases of breast cancer, seven heart attacks, eight strokes and 18 more cases of blood clots each year per 10,000 women.

It is a subtle effect indeed, but enough to have upset the balance of risks and benefits that women have weighed for so many years.

It is still not an easy decision. Hormone replacement therapy really does help, experts stress. It alleviates menopausal symptoms such as hot flashes, atrophy of the vagina and genitourinary tract, and bone loss. The study released Tuesday confirmed that hormones help ward off fractures in older women. And many women just feel better taking hormones.

“Some women do require hormones for quality of life, and I don’t think they should be told they can’t have it,” said Dr. Elizabeth Barrett-Connor, an epidemiologist and internist at UC San Diego.

The suggestion that sex hormones might be therapeutic stretches back long before they were discovered. The ancient Egyptians ate extracts of ovaries as an elixir against aging. By the late 19th century, scientists had already seen that extracts of ovaries could alleviate hot flashes.

Hormone replacement therapy began in the 1930s and gained momentum with the introduction of Premarin, a drug that contained a mix of estrogens obtained from pregnant mares’ urine. Even then, there were hints that estrogen replacement could have benefits for the bones and heart in post-menopausal women.

But it was a more audacious promise that launched post-menopausal estrogen therapy into the mainstream.

In the 1960s, New York gynecologist Robert A. Wilson penned “Feminine Forever.” In that instant bestseller, Wilson wrote of the “tragedy of menopause” and of his own mother’s transformation from “vital, wonderful woman” to “pain-racked, petulant invalid.”

Estrogen, he wrote, would keep women sprightly, firm-breasted, smooth-skinned and straight-backed into old age. Women began to clamor for the drug.

Drug companies helped fund Wilson’s efforts and have ever since made sure that women and their doctors knew about hormones and what they could do for a woman’s well-being through ads in magazines and journals.

“The pharmaceutical companies play a large role” in the adoption of hormone therapy, said Dr. Susan Love, adjunct professor of surgery at UCLA and an outspoken critic of the treatment. “They support our medical meetings. They pay for most of our continuing medical education--even pay for the pizza.”

But there was certainly science to back the notion that estrogen could help preserve a woman’s health. In one landmark paper in 1976, scientists reported that women who had had their ovaries removed--and thus were severely estrogen-deficient--could prevent osteoporosis by taking estrogen.

Reams of data, from studies of people and monkeys, suggested that hormone replacement therapy, or at least estrogen alone, would protect women against heart disease--findings now placed in question.

For instance, scientists noticed that women have fewer heart attacks than men--but that after menopause, the risk started to climb. That seemed to track the rise and fall of estrogen.

They found estrogen improved a woman’s blood cholesterol and increased the tone of blood vessels.

And there was other, compelling evidence from studies examining large numbers of women.

“Virtually all of these have shown that taking estrogens lowered your risk of heart disease,” recalled Dr. Howard Judd, chief of the department of obstetrics and gynecology at Olive View-UCLA Medical Center. They lowered that risk by about 40%.But not all the news was good. Estrogen was also linked to increased rates of blood clots, strokes and breast cancer.

Equally smart scientists, even colleagues who have worked side by side, have argued fiercely about the heft of all these data.

Some thought the case for estrogen protecting the heart was so overwhelming that a major, long-term trial would be unethical--because half the women would be given a placebo and be deprived of the hormones’ benefits.

Others were much less convinced, worried, always, that the seeming benefit to the heart observed in so many studies could be put down to causes unlinked to the hormones’ biological effects.

What, they asked, if the women who chose to take hormones were healthier to begin with than those who did not?

One of the skeptics was Barrett-Connor, the epidemiologist at UC San Diego. She became convinced she was tracking an illusion in the women she was studying. It looked as if the women choosing estrogen were richer, healthier and more likely to take their medicines and vitamins.

“We were worried that estrogen was getting the credit,” she said.

In the end, there was only one solution: large, long-term clinical trials in which women would be randomly assigned to take hormones or a placebo.

Scientists finally got their trials in 1993, half a century after hormone use began. But the findings of last week’s trial, part of a massive, government-funded effort called the Women’s Health Initiative, were so unsettling that the effort was halted abruptly three years short of its scheduled end.

And after all the planning, recruitment of women, money spent, and pills and placebos swallowed, there are still many unanswered questions.

Were the findings so gloomy because the dosage of hormones was wrong, or were they caused by adding progestin?

Did women start on estrogen too long after menopause?

But the continuing scientific debate has less relevance for women who are now struggling to decide whether to continue their treatment or throw their pills down the toilet. There is anger too at being led down a riskier road than they had bargained for.

“When people have time to read [about this study], look back to other articles written earlier ... they’ll have to make up their own minds whether people were deliberately misled or not,” Barrett-Connor said. “I know physicians acted in the best interest of their patients. They believed in their hearts that they were doing the right thing.”

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Times staff writer Ronald D. White contributed to this report.