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Wed 13 Feb 2008 04:00 AM

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Revisiting hormone therapy’s risks and benefits

A more nuanced picture may emerge as researchers re-examine data from massive postmenopausal hormone trials.

A more nuanced picture may emerge as researchers re-examine data from massive postmenopausal hormone trials.

Hormone therapy has long been the standard treatment for relieving menopausal symptoms: hot flashes, night sweats, and vaginal dryness.

Until 2002, many clinicians were also recommending it long term to prevent chronic health problems, including heart disease, stroke, and osteoporosis.

Some scientists now suggest that the cardiac risk and benefit of hormone therapy may depend on a woman’s age.

There was some evidence that oestrogen might contribute to breast cancer, but except for women at especially high risk for that disease, cardiovascular disease was a more serious concern - a far greater cause of death and disability.

For that reason, most health organisations recommended that postmenopausal women consider taking hormone therapy.

Then, in 2002, the hormonal approach to averting women's later-life ills screeched to a halt. Researchers had to stop the Women's Health Initiative (WHI) randomised trial of oestrogen and progestin (in the form of Prempro) because the hormone combination was actually causing more heart attacks and strokes than a placebo, as well as more blood clots and breast cancer.

Two years later, the WHI's trial of oestrogen alone (Premarin), also ended early, after it became apparent that oestrogen increased the rate of strokes and blood clots without conferring any benefits on the heart.

Although there were some benefits - fewer fractures in both trials and a reduced risk for colon cancer in the combined-hormone trial - they didn't outweigh the risks.

That left hormone therapy back where it started, as a short-term treatment for menopausal symptoms.

Impact and critique of the WHI

Hormone therapy is still the most effective treatment for hot flashes and night sweats. But the WHI results - and the associated media firestorm - left women worried and confused about even such short-term use.

They were told to use hormones only for short periods and at low doses, and hormone therapy prescriptions plummeted. (One study reported a 75% drop between 2002 and 2006.) Yet menopausal women looking for symptom relief shouldn't misinterpret the WHI findings.

These studies were not about short-term management of menopausal symptoms. Moreover, the results aren't above criticism.

New questions have arisen as scientists try to reconcile the findings of earlier observational studies with those of the WHI - a randomised, placebo-controlled trial, considered the "gold standard" type of clinical investigation.

Some critics argue that the WHI results may not apply to the typical woman considering hormone therapy because most of the 27,347 participants were in their 60s and 70s - well past the perimenopausal transition and early menopause (the usual time for starting hormone therapy).

Others say that the risks were overstated. Each year, for example, the women taking Prempro had only six more heart attacks per 10,000 than the women taking a placebo; among younger women, the difference was even less.

Because of these and other concerns, scientists have been re-examining the WHI data and undertaking new trials.

Researchers are also reappraising earlier studies that suggested hormone therapy could prevent cardiovascular disease.

Some scientists now suggest that the cardiac risk and benefit of hormone therapy may depend on a woman's age, particularly the age at which she starts taking hormones.

This new hypothesis doesn't change current recommendations (see chart), but it may reassure perimenopausal and newly menopausal women who are considering short-term hormone treatment for symptom relief.

Heart risk: a matter of timing?

The lack of heart benefits in the WHI contradicts findings from observational studies, such as the Nurses' Health Study, in which participants are followed for years but are not asked to take medications or do anything differently.

In those studies, women have tended to start taking hormones closer to the onset of menopause.

Researchers have observed that these women suffer fewer of the heart problems caused by atherosclerosis (for example, angina and heart attacks) than women who don't take hormones.

The idea that hormone therapy might help protect women from atherosclerosis was biologically plausible.

It's long been recognised that women develop atherosclerosis-related heart problems at an older age than men - after menopause and the decline in oestrogen.

In animal studies, oestrogen has been shown to slow development of atherosclerosis.

So why might oestrogen then increase the risk of heart disease in women who start taking it at an older age? Evidence indicates that oestrogen can destabilise atherosclerotic plaques, the artery-clogging accumulations of cholesterol and debris that are a major source of heart disease.

Oestrogen appears to make plaques more vulnerable to rupture, which can result in a heart attack. Older women are more likely to have developed plaques.

So for them, oestrogen might do more harm than good. It may be that hormone therapy is good for the heart only during a fairly narrow window, when plaques are starting to form but are not fully developed.

Nurses' Health Study researchers found some support for this hypothesis in 2006 in a study undertaken to shed light on the discrepancies between the WHI results and earlier research.

They found a 30% reduction in risk for heart disease among women who began hormone therapy within about four years of menopause, but little or no cardiac benefit for women who started hormones either after age 60 or 10 or more years after menopause.

A reanalysis of the WHI data turned up similar evidence that timing may be a factor.

Investigators reporting in the Journal of the American Medical Association (April 4, 2007) found no increased risk for heart disease among hormone users ages 50 to 59 and a suggestion of reduced risk among women who started hormone therapy within 10 years after menopause.

Thereafter, the greater the gap between onset of menopause and start of hormone therapy, the greater the risk for heart disease, especially in those with a history of hot flashes and night sweats.
Stroke remained a problem, regardless of time since menopause, for women receiving either oestrogen alone or combined therapy.

The risk for breast cancer rose after five years in women taking combined hormones, although not in those taking oestrogen alone.

Hormone therapy should be taken only for symptoms and, like any drug, for the shortest time possible and at the lowest effective dose.

In an ancillary study, WHI investigators assessed coronary artery calcium, which is a marker for atherosclerosis, in 1,064 women ages 50 to 59 who'd had a hysterectomy before entering the WHI oestrogen-only trial.

The women took their study medications for an average of 7.4 years and then, a year after the trial ended, they underwent CT scans of the heart.

Results, published in the June 21, 2007, issue of The New England Journal of Medicine, showed that the oestrogen-takers had less calcified plaque in their arteries than the placebo takers, suggesting a reduced risk for future cardiovascular events.

But it's not known how long this benefit would have lasted - or whether it would have actually led to fewer heart attacks or strokes - if the women had continued taking oestrogen.

According to WHI investigator (and the study's lead author) Dr. JoAnn Manson, these findings lend support to the idea that oestrogen, when it's started near menopause, may slow the early stages of plaque build-up.

"But oestrogen's effects are complex, and it has other known risks," Dr. Manson points out, so it "shouldn't be used for the express purpose of preventing cardiovascular disease."

Also, this study did not include older women, so there's no indication of whether age makes a difference in the way oestrogen affects plaque build-up. Only a randomised trial can test the "timing" hypothesis, and until then it remains unproven.

What about breast cancer?

Initial results from the WHI's oestrogen-only trial indicated that oestrogen alone reduced the risk for breast cancer by 23% over about seven years.

The effect was not statistically significant (meaning that it could have been due to chance), but it was still surprising in light of the increased risk found in the combined-hormone trial after four years, so investigators decided to take a closer look.

In a final report - published in the April 12, 2006, issue of the Journal of the American Medical Association - they concluded that the women taking oestrogen alone were at no greater risk for breast cancer than those taking a placebo.

The difference in risk between oestrogen alone versus combined oestrogen and progestin is one of the unanswered questions about hormone therapy and breast cancer.

In the WHI, the oestrogen-only takers had undergone hysterectomy, which is different from natural menopause.

Also, we don't know yet whether the time when hormone therapy starts influences breast cancer risk in the way it does heart disease risk.

WHI investigators will soon report on a follow-up study of women in the oestrogen-plus-progestin trial who continued to have annual mammograms after stopping their study medications in 2002.

This could shed light on how long it takes for breast cancer risk to return to normal after women stop taking combined hormone therapy.

In the meantime, several groups of researchers reported in 2007 that the rate of new breast cancers began to decline in 2003, the year hormone therapy prescriptions fell off sharply.

What it means

Women in early menopause with troublesome hot flashes or night sweats can take short-term hormone therapy without increasing their risk for heart disease.

Hormone therapy should be taken only for symptoms and, like any drug, for the shortest time possible and at the lowest effective dose (although we don't know whether lower doses are actually safer).

Studies suggest that oestrogen patches may be less likely to cause blood clots in the legs than oral oestrogen.

For some women, the major menopausal complaint is vaginal dryness, which may persist for many years. Low-dose vaginal oestrogen is an effective treatment for this symptom with negligible systemic effects.

When it comes to prevention, hormone therapy reduces the chances of fractures and colon cancer. Whether its adverse effect on the heart is related to timing still needs more study.

But you can reduce these risks in other ways without increasing your odds for breast cancer, blood clots, and stroke.

Avoid tobacco; exercise at least 30 minutes a day; adopt a healthy eating plan; and control your blood pressure, cholesterol, and blood sugar - with medications, if necessary.

Be sure to get adequate calcium (1,200 milligrams per day) and vitamin D (800 to 1,000 IU per day).

And if you're at high risk for osteoporosis, there are many medications to choose from that curb bone loss.

Recommendations regarding hormone therapy (HT) useU.S.Preventive Services Task Force (USPSTF):recommends against the routine use of HT to prevent chronic conditions in postmenopausal women.

North American Menopause Society:moderate to severe vasomotor symptoms (hot flashes and night sweats) are the main use for systemic HT.

Food and Drug Administration: HT should be used at the lowest dose and for the shortest time needed to reach treatment goals, although it's not known how low you should go to reduce the risk of serious side effects.

When hormone therapy is prescribed only for vaginal symptoms, consider topical vaginal products.

AmericanCollegeof Obstetricians and Gynaecologists:estrogens are the most effective treatment for menopausal vasomotor symptoms (hot flashes and night sweats).

Their use (with or without a progestin) should be reassessed yearly. The lowest effective dose should be used for the shortest possible time to alleviate symptoms.

American Society for Reproductive Medicine: low-dose oestrogen is a valid option for many seeking short-term relief from menopausal symptoms. HT does not provide additional health benefits that would justify its use beyond the immediate relief of menopausal symptoms.

HT is not indicated for the primary or secondary prevention of coronary artery disease events.

Canadian Task Force on Preventive Health Care

HT should not be used for the primary prevention of chronic diseases in postmenopausal women. To maintain heart health, women should use other preventive strategies, such as increased exercise, smoking cessation, and blood pressure control.

There's not enough evidence to make a recommendation on HT regarding stroke and death from stroke.

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