Hormone Replacement Study a Shock to the Medical System

[Guest guest]

Hormone Replacement Study a Shock to the Medical System

Wed Jul 10, 9:09 AM ET

By GINA KOLATA with MELODY PETERSEN The New York Times

The announcement yesterday that a hormone replacement regimen taken

by six million American women did more harm than good was met with

puzzlement and disbelief by women and their doctors across the

country.

A rigorous study found that the drugs, a combination of estrogen and

progestin, caused small increases in breast cancer ( news web sites), heart

attacks, strokes and blood clots. Those risks outweighed the drugs' benefits

a small decrease in hip fractures and a decrease in colorectal cancer. Many

of the 16,000 women in the study, supported by the National Institutes of

Health ( news - web

sites), opened letters yesterday telling them to stop the drugs. In light of

the findings, the study had come to a halt.

Hearing the news, some said the findings had persuaded them.

" I may have taken my last pill this morning, " said Dr. Deborah Bublitz, a

pediatrician in Littleton, Colo.

Others agonized over the consequences of suddenly stopping drugs that help

prevent bone loss and relieve menopause symptoms. Would they suffer

torrential night sweats and embarrassing hot flashes? Or were the scientists

simply exaggerating the risks, which were, after all, minuscule for an

individual woman?

Until recently, medical authorities were telling doctors to encourage almost

every woman who had not had a hysterectomy to start taking the drugs when

she reached menopause and to take them for years, even for life. Now the

growing consensus seems to be that women should carefully consider whether

they want to start the drugs at all. Those who take them for more than a few

years should be aware of the risks, which, if slight, are real.

The news of the study's findings came as such a surprise that doctors were

inundated yesterday with calls from patients. Some medical experts on the

hormone therapy said they had given up and taken their phones off the hook.

" I'm just letting all my calls go onto the answering machine, " said Dr. Wulf

Utian, executive director of the North American Menopause Society.

But for Dr. Utian and others, this was a defining moment in medical history.

This is the biggest bombshell that ever hit in my 30-something years in the

menopause area, " Dr. Utian said.

It was a powerful scientific counterattack to years of strong promotion of

hormone replacement. There were reams of scientific papers. Many fell short

of absolute rigor, but in sum they pointed mostly in one direction, that of

benefit. There were compelling marketing campaigns by drug companies. There

was also the eager adoption of the drug combination by doctors and women who

wanted to believe it worked.

The new study was different from the rest because it involved thousands of

healthy women and had a

control group, with half the women taking dummy pills. In addition, it

looked for evidence of disease

like heart attacks and cancer rather than indirect indicators like

cholesterol levels, which can be

misleading.

" This is definitive evidence, " said Dr. Deborah Grady, who directs the

Mount Zion Women's Health

Clinical Research Center at the University of California in San Francisco.

The tale of estrogen therapy began in 1966, when an enthusiastic doctor,

, wrote a

best-selling book. He called it " Feminine Forever " and flew around the

country promoting it, telling

women and doctors alike that estrogen, the feminine hormone, could keep

women young, healthy and

attractive. It was just so natural women would be replacing a hormone they

had lost at menopause just

as diabetics ( news - web sites) replace the insulin their pancreas fails

to make.

" At age 50, there are no ova, no follicles, no theca, no estrogen truly a

galloping catastrophe, " Dr.

wrote in 1972 in The Journal of the American Geriatric Society,

referring to the eggs and

surrounding tissue. But, he continued, estrogen can save these women.

" Breasts and genital organs will

not shrivel. Such women will be much more pleasant to live with and will

not become dull and

unattractive. "

Dr. died in 1981, but his son, , said yesterday that

Wyeth-Ayerst had paid all

the expenses of writing " Feminine Forever " and financed his father's

organization, the Research

Foundation, which had offices on Park Avenue in Manhattan.

Mr. , who lives in Cary, N.C., said the company had also paid his

parents to lecture to women's

groups on the book. Wyeth said it could not confirm the account because it

was so long ago.

By 1975, Wyeth's product, Premarin, had become the fifth leading

prescription drug in the United

States, said Nadine F. Marks, an associate professor at the University of

Wisconsin at Madison, who

co-wrote a research paper on hormone therapy. " Even textbooks for

gynecologists and obstetricians in

the 1960's would explain how a woman's life could be destroyed if she

didn't have estrogen in her

body, " Dr. Marks said.

During that time, however, two major studies published in 1975 in The New

England Journal of

Medicine ( news - web sites) indicated that estrogen substantially

increased the risk of cancer of the

lining of the uterus. Soon, doctors and drug companies found an

alternative. They began giving

estrogen with progestin, which counteracts the effects on the uterine

lining, leading to monthly bleeding

that resembles a menstrual period. Women who had had a hysterectomy could

take estrogen alone.

Women who had a uterus could take the hormone combination. The problem was

solved, or so most thought.

Sales soared again in the 1980's, Dr. Marks said, after a major

advertising initiative by the company,

which promoted the hormones for the prevention of osteoporosis.

There was no doubt that the drugs helped many women through a difficult

time when their sleep was

disrupted by night sweats and their days by hot flashes.

" There is nothing else out there that addresses the symptoms of

menopause, " said Dr. Kusiak,

vice president of global medical affairs at Wyeth.

But scientists and doctors were saying something more that it could be

used for disease prevention.

Many were impressed by evidence from dozens of observational studies in

which women who

happened to take estrogen were compared to women who did not. The drawback

to these studies,

however, is that women who decide to take estrogen, studies have shown,

tend to be different from

those who do not. They are healthier, leaner, less likely to smoke. The

question is, does estrogen make

women healthy, or do healthy women take estrogen?

Nevertheless, many of the studies indicated that those who took the drugs

had fewer heart attacks and

fewer strokes, that they had stronger bones and fewer fractures. There

were also laboratory studies

demonstrating effects on animals and cells that seemed to support the

observations.

" There was all this mechanistic stuff, " Dr. Grady said. " I have six inches

of papers suggesting that it

improves coronary vasodilation, that it prevents atherosclerosis. " In

fact, she said, the accumulating

evidence for a heart disease benefit, although indirect, seemed

overwhelming.

Even a large study by the National Institutes of Health seemed to support

the notion of benefit. It

looked not at disease but at markers for disease, cholesterol levels and

bone density. Women who

took hormones had better cholesterol levels and denser bones than those

taking a placebo.

" If you look at this evidence and it's part of the mind-boggling aspect of

this whole story boy, the

evidence for estrogen looked really strong, " Dr. Grady said. She and other

experts were so persuaded

that they wrote guidelines for the American College of Physicians

recommending that women at high

risk of heart disease take estrogen after menopause.

Dr. Marcia Stefanick, the principal investigator of the new federal study,

said that not long ago medical

groups were recommending that as soon as a woman turned 50, she should

have a frank discussion

with her doctor about hormone replacement therapy and that her doctor

should encourage her to take

the drugs.

" This was what every 50-plus woman should do to prevent the disease of

aging, " Dr. Stefanick said.

" They linked up a very beneficial product for treating menopausal symptoms

to the answer for treating

all of a woman's aging problems. "

Even when some observational studies indicated that estrogen, and more so

the combination of

estrogen and progestin, might increase the risk of breast cancer, doctors

were not dissuaded.

" A lot of people thought it was outrageous that women should worry about

breast cancer risk when the

heart disease risk is so much higher, " Dr. Stefanick said.

Even as some scientists and advocates for women began arguing that at

least there should be a more

vigorous test of the estrogen hypothesis, it retained its power.

Dr. Stefanick said that when the new study was being planned, doctors and

researchers said it was

unethical because in the most rigorous studies, a group of women would be

taking placebos. They

would be denied the benefits of the hormones, these critics said.

All along, as hormone therapy grew in popularity, some refused to be

convinced. One group, the

National Women's Health Network, said it was offended by the message and

questioned the data.

The message, said Pearson, executive director of the network, " was

sexist and ageist. " It had a

constant refrain, she added. " Stay young. Stay healthy. Stay sexually

vital. Be less of a pain to your

husband. "

" The claims were too good to be true, " Ms. Pearson said. " Each time there

was anything negative

about the drug, a new claim arose to keep it alive. "

" The science was accurate but it was extrapolated beyond imagination, " Ms.

Pearson said. " We started

saying: Not proven, not proven, not proven. "

In 1990, when Wyeth, the leading maker of estrogen, went before the Food

and Drug Administration (

news - web sites) with a request to label the drug as protective against

heart disease, Ms. Pearson was

there.

" We stood there and said, Hello? You couldn't approve a drug for healthy

men without a randomized

clinical trial. Even aspirin had to have a randomized controlled trial

with healthy men, " she said, alluding

to the data that persuaded the F.D.A. to allow aspirin makers to market

their product as protective

against heart attacks. In a randomized controlled trial, patients are

divided at random into groups, with

each group taking a different treatment or placebo. They are considered

the gold standard of scientific

evidence.

The agency's advisory committee recommended that the company be able to

market estrogen as

protective against heart disease, but the panel was overruled by the

agency, which said better data

were needed.

In the end, Wyeth began a randomized controlled study that most doctors

and researchers assumed

would prove estrogen's beneficial effects on the heart. The study, known

as HERS, involved women

who had already had heart disease, a group in whom effects should be

easiest to find.

At the same time, amid lobbying by women's groups and criticism by

congresswomen about the lack of

attention paid to women's health, Congress appropriated money for a new

research initiative at the

National Institutes of Health. That led to the latest huge and expensive

study of hormone replacement

therapy.

The emerging data from both that study, the Women's Health Initiative and

HERS are sobering. HERS

found that far from protecting women against heart attacks, the

combination therapy actually increased

their risk in the first few years of taking the drugs.

The Women's Health Initiative includes a group of women who have had

hysterectomies and who are

taking estrogen alone. That part of the study is continuing because the

data have not shown significant

risk or significant benefit from the hormone.

The other part of the study, of women taking the hormone combination, was

the part that was halted. It

found that if 10,000 women take the hormones for one year, eight more will

develop invasive breast

cancer than a similar group not taking the hormones, seven more will have

heart attacks, eight more will

have strokes and eight more will have blood clots in their lungs. The

benefits are six fewer instances of

colorectal cancers and five fewer hip fractures.

There is no one overwhelming danger, said Dr. Claude Lenfant, director of

the National Heart, Lung

and Blood Institute. " It is a global risk. "

Dr. Grady says she is absolutely convinced by the new evidence. " This is

such compelling evidence that

women and their physicians ought to be finding a way to get off estrogen, "

she said. But, she added,

she is not sure that is what will happen.

Many questions remain and it is possible that future studies will find

that benefits outweigh risks,

perhaps with different combinations or formulations of hormones. The study

did not look at estrogen

patches, which deliver just estrogen, through the skin. There are also

different formulations of

progestin.

Dr. Utian of the Menopause Society said he was not surprised that an

active debate seemed to be

emerging.

" There are an awful lot of interests at stake here beyond women's health, "

he said. " There are

investigators with research grants, N.I.H. grants and grants from the

pharmaceutical industry. There are

academics with careers to build. " Added to that, he said, are medical

specialists gynecologists are

comfortable with hormones, internists with statins to lower cholesterol

and protect against heart

disease, bone experts with drugs like bisphosphonates to protect against

osteoporosis.

" It's not just a matter of what the data says, " Dr. Utian added. " Truth is

opinion. "

_________________________________________________________________

Send and receive Hotmail on your mobile device: http://mobile.msn.com