HORMONE REPLACEMENT THERAPY

We hope that by now most women have heard that the first part of a large, long-term, government-sponsored clinical trial evaluating hormone replacement therapy (HRT), the Women’s Health Initiative (WHI), was halted prematurely. The bottom line from this trial is that long-term, HRT’s risks outweigh its benefits. The part, or arm, of the trial that was first stopped involved 16,608 women who were taking conjugated estrogens (PREMARIN) with medroxyprogesterone (PROVERA) or a combination of the two as a single pill, with the brand name PREMPRO.

The main reason for stopping was an increased risk of invasive breast cancer in women receiving HRT after 5.2 years of treatment. This increase in breast cancer, combined with an increase in cardiovascular events that began in the first year of HRT treatment and persisted, clearly outweighed the benefits, among which were a reduced incidence of colon cancer and hip fractures.

A breakdown of the risks and benefits of HRT is given in the table below. The type of risk is shown in the left-hand column. The middle column gives the size of the risks of HRT, all serious and potentially life-threatening. The numbers represent the increased number of women out of 10,000 using HRT for one year who will experience one of the listed health events compared to those women taking an inactive placebo. The right-hand column shows the benefits of HRT. The numbers represent women who will not experience the listed health events compared to those taking a placebo.

The risk of harm to an individual woman is not that large, but the risks are extremely serious. There are 31 serious adverse effects per 10,000 women using HRT per year. On the other hand, there are 11 fewer cases of colorectal cancer and hip fracture per 10,000 women taking HRT per year. Clearly, there are almost three times as many negative outcomes as positive ones.

At the time of the WHI, approximately 38% of postmenopausal women in the United States were using HRT, and from a public health perspective, the harm is quite substantial. For every 1 million women using HRT for one year, there is an increase of 3,100 potentially life-threatening adverse events, namely heart attacks, strokes, blood clots, and breast cancer. A conservative estimate of the total number of women who have been using HRT is 5 million. This translates to an increase of 15,500 of these serious adverse events per year because of the use of HRT.

After the initial results from the WHI, new data from the same study found that HRT significantly increased the risk of dementia, and the FDA subsequently requested manufacturers to update labeling for hormone therapy products (estrogen and combination estrogen and progestin products) for use by postmenopausal women with data from the Women’s Health Initiative Memory Study (WHIMS). WHIMS reported an increased risk of dementia in women 65 and older and also showed that estrogen with progestin (PREMPRO) failed to prevent mild cognitive impairment (memory loss). (WHIMS is a substudy of the WHI conducted by the National Institutes of Health.)

Most recently, the part of the WHI that involved giving estrogen alone was also halted and then published. These were women who had had a hysterectomy and therefore did not need the protection from estrogen-induced uterine cancer provided by adding a progesterone-like drug to the estrogen.

For the outcomes significantly affected by estrogen alone, there was an absolute excess risk of 12 additional strokes per 10,000 person-years and an absolute risk reduction of 6 fewer hip fractures per 10,000 person-years. The conclusion was that estrogen alone should not be recommended for chronic disease prevention in postmenopausal women.

The adverse economic impact of HRT on the health care system because of all of the diseases caused by HRT is enormous. This cost must be added to the amount spent each year on HRT. In 2001, the combined sales for conjugated estrogens and conjugated estrogens in combination with medroxyprogesterone exceeded $2 billion.

The FDA-approved uses for hormone replacement therapy include relief of menopausal symptoms and prevention of osteoporosis but do not include treatment of osteoporosis. Long-term use has been in vogue to prevent a range of chronic conditions, especially heart disease. The use of HRT to prevent chronic diseases are referred to as “off-label” uses because data have not been presented to the FDA to show that the drug is safe and effective for these conditions.

How Did the Estrogen Vogue Begin and Why Did It Continue?

The New York Times explored this question in a July 10, 2002, article. Robert Wilson, MD (who died in 1989), wrote a best seller in 1966 with the title Feminine Forever. He traveled around the country promoting the book, telling doctors and women that estrogen could keep women young, healthy, and attractive. The logic was simple, and when uncritically accepted, it was taken to mean that women need only top up with a little estrogen to be young again.

In the Times article, Dr. Wilson’s son was quoted as saying that Wyeth-Ayerst, the manufacturer of Premarin and Prempro, had paid all the doctor’s expenses of writing Feminine Forever and furthermore paid him to lecture to women’s groups. Contacted for confirmation, Wyeth-Ayerst said it could not confirm the story because it was so long ago.

In 1990, Wyeth-Ayerst requested FDA approval for Premarin to be used as protection against heart disease. The company’s request was not based on randomized controlled trials such as the Women’s Health Initiative’s, but rather on observational research, a study design that is excellent for raising research questions that, in turn, must be validated by randomized controlled trials. The FDA’s advisory committee recommended approval, but the FDA refused the advice, saying that better data were needed.

Reliance on the positive results of observational studies elevated HRT to the status of a standard of practice for preventing heart disease, and HRT remained one of the most frequently prescribed drugs in the United States year after year.

The overdue demise of long-term HRT has sparked new activity on the part of the medical marketplace jackals, alternative medicine practitioners, compounding pharmacists, and the dietary supplement industry, all ready to offer women “proven” natural substitutes for HRT.

Shortly after the results of the Women’s Health Initiative study were made public, one particularly disreputable and unethical compounding pharmacist posted a press release on her Web site with the following caption:

Natural Hormones—Safe and Effective Alternative to Prempro

Remarkably, a number of women have apparently embraced such “pitches” with no or significantly less evidence of safety and effectiveness than there was for HRT. Medically, if a drug sounds too good to be true, it usually is.

You should not be using hormone replacement therapy for any reason other than its very short-term use to control the symptoms of menopause, for as short a time as possible. Otherwise, the benefits are outweighed by the increased risks of heart attacks, strokes, breast cancer, and blood clots in the lungs.