Is HRT safe?

Source: Best Health Magazine, September 2008

The many studies on hormone replacement therapy (HRT) that have been reported in the news seem to contradict one another, and figuring out what it all means is enough to make your head hurt. So what is actually going on and why does medical opinion seem so divided? Here are the answers.

Menopause 101

Most women stop menstruating sometime between the ages of 45 and 54. Their ovaries release lower amounts of estrogen and progesterone, and these hormonal changes associated with menopause can cause a variety of symptoms such as hot flushes (as they are referred to by the medical community), night sweats, difficulty sleeping, mood swings, irritability or anxiety. Women may also have trouble concentrating and remembering things. Sex can become painful, and vaginal or urinary infections may occur more frequently.

Nobody ever died of menopause, but for some women the symptoms are pretty unpleasant, and some doctors will prescribe HRT for relief. For most women, this means taking estrogen combined with progesterone or progestin. But is HRT safe?

A history of HRT

1960s: HRT started getting popular in 1966 with the book Feminine Forever, by American gynecologist Robert Wilson, which touted the benefits of estrogen. Thirty years later, 22 percent of Canadian women between the ages of 45 and 64 (about 648,000) reported using some form of hormonal therapy.

1970s: In the 1970s, studies showed that estrogen alone leads to an overproduction of the cells lining the uterus, possibly causing endo­metrial cancer. After these studies came out, progesterone or progestin was added to avoid this problem. Women who had had their uterus removed didn’t face this risk, of course, and could take estrogen by itself.

1980s: By the mid-1980s, ‘the main reason to use hormone therapy was for hot flush control and for vaginal dryness,’ according to Dr. Robert Reid, a professor of obstetrics and gynecology and chair of the division of reproductive endocrinology and infertility at Queen’s University’and one of Canada’s leading experts on HRT. But then several studies appeared indicating that HRT also reduced the risk of heart disease in post-menopausal women. One of the most influential was the U.S. Nurses’ Health Study, a large research project that began in 1976 and followed more than 120,000 nurses, investigating their risks for various diseases. In 1985, it compared the health of those who happened to be taking hormones with those who were not. It found that nurses taking hormones had lower rates of heart attacks. Because of this, some doctors began to prescribe HRT for just this reason’to prevent heart disease. HRT was also shown to reduce the risk of osteoporosis. It looked as if women might benefit from taking HRT not just for a few years, but on a long-term basis.

1990s: However, by 1991, the U.S. National Institutes of Health (NIH) realized there was a problem with the Nurses’ Health Study. Reid describes it as the ‘healthy user effect.’ Women who sought out hormone therapy tended to be health-conscious, watched their weight and got more exercise than the women who didn’t seek it out. So it wasn’t really clear what was responsible for the nurses’ healthy hearts‘the hormones they were taking or their lifestyles.

The NIH decided to try to settle the matter, launching a series of studies called the Women’s Health Initiative (WHI). One tested 16,000 women and looked at combination HRT; another tested 10,000 women who did not have a uterus and looked at estrogen-only HRT. To avoid the criticisms of the Nurses’ Health Study, it used controlled experiments in which women were randomly assigned HRT or a placebo.

2000s: In 2002, the results of the trial on the risks of combined HRT were released’and they surprised everyone. It seemed HRT wasn’t heart protective at all. In fact, women on estrogen plus progestin had higher rates of heart attacks as well as stroke, and more blood clots in their lungs and legs. The researchers stopped the study three years early. A year later, they published further negative findings, namely that older women on combined HRT were at a heightened risk of developing dementia.

Certainly, the increased risks the WHI found were small. For example, the higher incidence of heart attacks meant that out of 10,000 women, 37 taking HRT would have a heart attack compared to 30 on placebo. Still, because so many women were taking combination HRT in Canada, there was a possibility that the incidence of heart attacks would rise considerably.

In March 2004, the second WHI report on estrogen-alone treatment was released. It found a significant increase in the rates of stroke and blood clots. The treatment did not affect heart disease, breast cancer or colorectal cancer rates either positively or negatively, but there was a slight increase in dementia in a subgroup of older women. This study was also stopped early.

Both WHI studies found that women taking hormones had lower rates of bone fractures. The rate of hip fracture among women taking combination HRT was 10 out of 10,000; in women on placebo, it was slightly higher: 15. But women and their doctors were scared by HRT and by 2005, scores of women had stopped using it.

How we view HRT today

More research has been done to settle the issue. First, it seemed that a woman’s risk of breast cancer rose after five years of combined HRT. In other words, it wasn’t affected by short-term use. Second, the heart problems highlighted by the WHI may have resulted partly from a skew in the study design. ‘A perfect study would take women at age 50, randomly assign a placebo or hormones, then follow them for 30 years,’ says Reid. This would allow us to see what happens as they age. But such a study would be expensive’and we wouldn’t get results for 30 years. Participants in the WHI studies ranged in age from 50 to 79, and there’s evidence that prescribing HRT to older women is not a good idea. There may be an increased risk of coronary artery disease in women starting HRT many years past menopause.

Some older American research on monkeys, from Wake Forest University’s school of medicine, backs up this concern. In 1988, it found that when monkeys had their ovaries removed and then were immediately given estrogen, their arteries stayed healthy. But when the treatment was delayed, it wasn’t able to reverse damage to the arteries. The work led researchers to think that while estrogen can inhibit disease in healthy arteries, it may be ineffective, or harmful, if problems already exist. The hypothesis is that a woman who starts HRT several years past menopause might develop problems she wouldn’t have had if she had gotten the therapy right away.

In response, the WHI researchers went back, looked at their data and released a new analysis in the spring of 2007. They focused on women who started HRT early on in their menopause, rather than those who were recruited into the trials at a more advanced age. It appeared that the early starters had a lower risk of heart attack. Researchers also found a lower rate of death overall among women ages 50 to 59 who were using HRT.

In June 2007, a report by WHI researchers published in The New England Journal of Medicine found that younger post-menopausal women who had been assigned estrogen only in the trials had less coronary artery calcification than their counterparts taking placebo. And in March 2008, experts at the International Menopause Society’s First Global Summit on Menopause-Related Issues concluded that HRT in the early post-menopausal period is safe.

The last word on HRT

Reid helped to write the guidelines on HRT use for the Society of Obstetricians and Gynaecologists of Canada (SOGC) as well as The North American Menopause Society (NAMS). He reports: ‘Both organizations have said that for newly menopausal women, the risks of hormonal therapy are very small and the benefits may be substantial. For most women with hot flushes, the benefits are going to outweigh the risks.’

Neither the SOGC nor NAMS advocates long-term use of hormones to prevent heart disease or bone fractures. But HRT’s earlier purpose, which was to ease menopausal symptoms, appears to stand up.

Says Reid: ‘Women should be reassured that if they need short-term hormone therapy to help them through that distressing transition, they should consider it.’

This article was originally titled “Midlife Crisis,” in the September 2008 issue of Best Health. Subscribe to Best Health today and never miss an issue!