Study That Discredited HRT Was Flawed, Experts Say

More research would be needed to overturn those findings, however

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By Kathleen Doheny
HealthDay Reporter

FRIDAY, Dec 16, 2005 (HealthDay News) -- The Women's Health Initiative was a landmark study involving 27,000 participants that caused many women to discontinue their use of hormone replacement therapy (HRT).

Researchers halted the study in 2002 after they found the regimen entailed more health risks -- most notably an increased risk for breast cancer and stroke -- than benefits.

But an expert who has conducted a new critique of the study contends it had major methodological flaws.

"I looked at the way they designed the study, and they did make some major mistakes," said Dr. Edward L. Klaiber, a consultant endocrinologist at the University of Massachusetts Medical Center. He is the lead author of the article, published in the December issue of Fertility and Sterility.

The estrogen/progestin arm of the Women's Health Initiative (WHI) was halted when researchers found the regimen increased the risk of invasive breast cancer and blood clots in the legs and lungs, in addition to not protecting women from heart disease and strokes.

Then, in 2004, the estrogen-only phase of the study was stopped because it was linked to an increased risk of stroke, with no reduction in women's risk for heart disease.

In the wake of the WHI study, the American Heart Association recommended that long-term hormone therapy not be used for cardiovascular disease prevention and that its use for other reasons "should be cautiously considered with the advice of a physician."

According to Klaiber, in the estrogen/progestin arm, 73 percent of the women -- who averaged 63 years of age -- had never taken HRT before. In the estrogen-only group, 52 percent of those women (also averaging 63 years of age) had not taken hormone therapy before.

Klaiber's major criticism of the WHI: "They were putting women in their 60s and 70s who hadn't been on hormones on hormones for the first time," he said. Because these women were older, they were already at greater risk of cardiovascular problems, he reasoned.

Another flaw? One of the two regimens in the study "used daily progesterone," said Klaiber, who prefers non-continuous administration of progesterone.

"That hormone pattern had never been tested at that time for its effect on breast cancer and heart disease," Klaiber said. The other regimen, administered to women who had had a hysterectomy, used only estrogen.

Klaiber argues that hormone replacement therapy in other doses or delivery forms is not only safe, but still has a positive health effect. He pointed to previous findings from the large-scale Nurses' Health Study, in which women were placed on hormone therapy earlier -- in their 40s and 50s -- and did not take the combination continuously. That study found a heart-protective effect, he said.

"The women in the Nurses' Study were not taking progestin daily," Klaiber said. "They took it cyclically, usually 10 to 12 days a month instead of daily."

The new review is basically a rehash of previous criticisms, said Dr. Nieca Goldberg, chief of women's cardiac care at Lenox Hill Hospital in New York City.

"It's a critique," she said. "It has no new information."

"Many of these issues were brought up a couple years ago," she added. "In order for them to prove any of these other things -- such as other forms [of HRT] would be better -- they need to do a study." Goldberg said Klaiber's article won't change the way she practices.

Klaiber agreed that more study is needed. He said one study, currently underway, is evaluating the worth of earlier intervention with hormones as a way to protect the heart.

The Massachusetts expert said he's convinced that transdermal estrogen, given in patch form, is superior to oral estrogen. "Oral estrogen passes through the liver and stimulates the blood-clotting factors too much, leading to heart attacks," he said. Not every woman who uses oral hormones will get a heart attack, he emphasized, but women who already have cardiovascular problems might be at raised risk.

Until more studies are done on other forms of therapy, Klaiber said, "the best evidence we have comes from the earlier studies." And those include regimens of estrogen and non-continuous progestin, he said.

More information

To learn more about hormone therapy, visit the Mayo Clinic.

SOURCES: Edward L. Klaiber, M.D., consultant endocrinologist, University of Massachusetts Medical Center, Worcester, Mass.; Nieca Goldberg, M.D., chief, women's cardiac care, Lenox Hill Hospital, New York City; December 2005 Fertility and Sterility

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