Stanford, CA - A new meta-analysis shows that hormone replacement therapy (HRT) reduces the risk of coronary heart disease events in younger postmenopausal women by 32% [1]. In older women, the risk is increased initially but then decreases over time. The lead author, internist Dr Shelley R Salpeter (Stanford University, CA), says that HRT is essential to protect against heart disease and other ailments, although she acknowledges that it does increase the risk of breast cancer.

The new results are reported by Salpeter and colleagues in the May 2006 issue of the Journal of General Internal Medicine and back up data from the observational Nurses' Health Study, reported in January, which found that women who began HRT near to menopause had a 30% reduced risk of CHD compared with those who did not use it. Taken together, these data indicate that HRT might have a primary preventive effect if taken before atherosclerosis develops, Salpeter told heartwire.

She adds that the warnings following the Women's Health Initiative (WHI) and Heart Estrogen/Progestin Replacement Study (HERS)—both of which are included in her new meta-analysis—has resulted in a time bomb waiting to explode.

We will start to see this damage in terms of heart disease . . . sometime in the future.

"There has been a 60% reduction in use of HRT, and we now have a large generation of women going into their older years without protection. We will start to see this damage in terms of heart disease and bone fractures sometime in the future." She estimates it will take at least 10 to 15 years before the full effects are appreciated.

Salpeter et al conducted a similar meta-analysis two years ago, as reported by heartwire, in which they showed a 40% reduction in total mortality with hormone replacement therapy vs placebo or no treatment in women younger than 60 years at baseline.

Now, Salpeter explains, because subgroup analyses have been performed in some of the trials, including separation of the WHI data into younger and older women, they have been able to use the more specific end point of CHD events—defined as myocardial infarction or cardiac death.

They divided the women in the trials into two groups: younger women (those less than 10 years from menopause or under the age of 60) and older women (those 10 years or more from menopause or over 60).

Younger women who took HRT had significantly reduced CHD events (odds ratio 0.68; p<0.05) compared with those who took placebo or no treatment and a similarly reduced risk compared with older women (OR 0.66; p<0.05).

In older women, there was no protective effect (OR 1.03; p=NS). In fact, in the older women, CHD risk increased in the first year of taking HRT (OR 1.47; p=0.004), but then events were reduced after two years (OR 0.79; p=0.004).

In addition, a significant time trend was seen of increased events progressing to decreased events (p=0.002), Salpeter notes. "This shows that an older woman on HRT for several years will pass the point of increased CHD risk and end up with a lower risk."

Salpeter explains these findings in the following way. "There is an initial prothrombotic risk with HRT in the first few years, but in younger women you don't see this manifesting itself—in fact, it is bypassed—because it's about the differential between the amount of hormones in your body and the amount you are putting in."

But after a couple of years use, HRT has metabolic benefits, she says, improving diabetes and lipid profiles and reducing central adiposity. (Her team published a paper on this subject last year in Diabetes, Obesity, and Metabolism [2].)

"If you take hormones perimenopausally, you will get reduced coronary heart disease risk, reduced risk of bone fractures, and reduced risk of colon cancer," she adds. "However, there is an increase in the risk of breast cancer."

But the increased risk of breast cancer—around 25%—is to some extent canceled out by an equal 25% reduced risk of invasive colon cancer, she notes. Nevertheless, the decision on whether to take HRT or not should always be made on an individual basis, taking into account the risks and benefits for each patient, she stresses.

For those who do decide to take HRT, Salpeter says new recommendations issued last year by the American College of Obstetricians and Gynecologists—to limit HRT use to a maximum of five years—are misguided.

Basically, she says, by taking HRT women are delaying menopause. "If they do not take hormones, there is a rapid change in metabolites and a rapid increase in CHD risk."

Look at me, and then look at all my friends not on hormones. They are all dead.

"Women should take HRT for 15 years, well into their 60s, so that they can live a long life without hip fracture or heart attack," she believes, adding, "I myself will be taking my hormones long term."

She also tells the tale of her mother-in-law, who is still taking a 0.625-mg dose of Premarin in her mid 80s. "I asked her whether we should consider stopping it, and she said, 'No. Look at me, and then look at all my friends not on hormones. They are all dead.' "

Salpeter said the only group of women for whom she does not currently prescribe HRT is older women who have never taken it. "If a woman stopped taking HRT, I would consider starting it again and would begin with a low dose. If they stay off hormones long term, their longevity will suffer," she stresses.