Hormone Replacement Therapy (HRT) - Now What to Do?

Summarized by Robert W. Griffith, MD
July 26, 2002 (Reviewed: July 16, 2004)

Introduction

Many women have been alarmed by the recent media reporting of the results of a large study of oral hormone replacement therapy (HRT). Over a third of postmenopausal women in the United States use HRT. While most of them take an estrogen drug, a large number (over 6 million) take an estrogen-plus-progestin pill.

A little history

The first drug to treat the symptoms of menopause (hot flashes, night sweats, irritability, vaginal dryness, are the main ones) was introduced over 50 years ago. It consisted of estrogens extracted from pregnant mare's urine, and it's still widely used today as estrogen replacement therapy (ERT).

The acceptance of ERT increased in the 1980s with the finding that estrogen replacement helps restore, or at least maintain, bone density that naturally declines in women after the menopause. Millions of women started taking estrogens to avoid the threat of osteoporosis, in addition to it's beneficial cosmetic effects.

Because estrogen was found to cause the buildup of the tissue lining the uterus, called the endometrium, it increased the risk of uterine cancer. This led to the need for women who still had their uterus to take progestin as well as estrogen; the progestin caused the excess endometrial tissue to be shed. Of course, women who had had a hysterectomy could continue to take estrogen alone without apparent risk.

In the 1990s several studies suggested that HRT might reduce the risk of developing heart disease and Alzheimer's disease. Certainly many women took it for cosmetic reasons, and for its beneficial effects on vaginal tissues.

Recently, several studies suggested a link between long-term use of estrogen-plus-progestin and breast cancer, and it's possible that the addition of progestin to estrogen may have increased that risk. In addition, results from surveys have shown that combined estrogen and progestin treatment increases the risk of coronary heart disease, at least in the first year; this may be due to progestin's action increasing thrombosis and inflammatory changes in the small arteries.

The new study

The Women's Health Initiative (WHI) conducted this study in over 16,500 women aged 50 to 79 with an intact uterus. They wanted to examine the effect of estrogen-plus-progestin on the occurrence of heart disease, hip fractures, breast and colon cancer. The study didn't address the short-term effects of HRT. In women who had lost their uterus (i.e. had a hysterectomy) estrogen alone was prescribed. Equal numbers of women were given HRT or a placebo.

Women were enrolled between 1993 and 1998 at over 40 clinical sites across the USA. In the years 2000 and 2001 safety assessments were done; at both times there was nothing to suggest an increased risk with HRT. However, in May 2002 the safety review showed that the number of cases of breast cancer in the estrogen-plus-progestin group was increased to a significant degree. It was decided that the study of estrogen-plus-progestin should be stopped immediately, and the results in these women fully analyzed.

What did the analyses show?

The 7,500-plus women taking estrogen-plus-progestin for an average of 5.2 years showed the following harmful changes, compared with a roughly equal number of women taking placebo:

• 26% increase in breast cancer
• 41% increase in stroke, 29% increase in heart attacks, and double the risk (i.e. 200% increase) of venous thromboembolism (blood clots)

Offsetting this, there were the following beneficial changes, compared with placebo:

• 37% reduction in colorectal cancer
• 24% reduction in all factures, with a one-third reduction in hip fractures

There was no difference in the total death rates between women on HRT and those taking the placebo.

What's to be done?

Although these numbers suggest considerable differences due to HRT, one must realize that the absolute risk of harm for an individual woman is very small. Put another way, the results mean that among 10,000 women taking estrogen-plus-progestin for a year, there will be 8 more strokes, 8 more pulmonary emboli (blood clots on the lung), and 8 more breast cancers, but 6 fewer colon cancers and 5 fewer hip fractures.

Over the 5.2 years of the study, the excess number of adverse events with HRT was approximately 1 in 100 women. So this is still a small risk, although not one to be taken lightly.

The authors of the study suggest that doctors should stop prescribing estrogen-plus-progestin combinations for long-term use, as the risks are greater than the possible benefits. There are alternative preventive strategies, including suitable medications, to prevent osteoporosis. Cardiovascular disease can be reduced by measures to combat high blood pressure, high blood cholesterol and obesity.

And the disabling symptoms produced by the menopause? The study does not address this question, but even the one-year results suggest that the combination slightly increases the risk for coronary heart disease and thromboembolism. HRT should really only be prescribed when the menopausal symptoms are intolerable, and even then only for a short period. Some symptoms can be treated with non-hormone medications, or alternative medicine (see links below).

Comment

The editorial in the Journal of the American Medical Association emphasizes that the results of the study are very persuasive -- the study was prospective (i.e. it randomly distributed a group of women to different treatments and measured the outcome over a period of time), rather than a retrospective survey. Moreover, numerous analyses of different sets of the results supported the overall conclusions.

The different roles of estrogen and progestin will be much clearer when the results of the estrogen-only study in women with hysterectomies are available; so far there is no indication that ERT - this type of HRT- carries an increased risk in hysterectomized women, but the findings over the next three years will be awaited with great interest.

Doctors will often tell their patients who ask what to do: "It's up to you to decide". That's fine, as long as you can make an informed decision. We hope the results of this study, as presented here, will have helped inform you enough to be able to make a good decision about starting, continuing, or stopping HRT. One should recognize that, for each individual, the likely benefits should clearly outweigh the possible risks.

Source

• Failure of estrogen plus progestin therapy for prevention. Editorial. SW. Fletcher, GA. Colditz, JAMA , 2002, vol. 288, pp. 366--368

Related Links
Treating Hot Flashes - Without Hormones
Alternative Medicine: Menopause
What is Your Cancer Risk?

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