Long Term Hormone Replacement Therapy (HRT): The Demise of a Standard of Practice

We hope that by now women have heard that one part of a large, long term, government sponsored clinical trial, the Women’s Health Initiative, evaluating hormone replacement therapy (HRT) was halted prematurely. The bottom line from this trial is that long term HRT’s risks outweigh its benefits.

The Women’s Health Initiative enrolled 27,000 women between 1993 and 1998 and was scheduled to conclude in 2005. The goal was to see if HRT would help prevent heart disease and hip fractures. Another goal was to see if those possible benefits were greater than possible risks of breast cancer, endometrial cancer, and blood clots. The part, or arm, of the trial that was 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 fact, combined with an increase in cardiovascular events that began in the first year of HRT treatment and persisted, 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 health event is listed in the left hand column. The middle column gives the risks of HRT, all of which are serious and potentially life threatening. The numbers represent the number of women out of 10,000 using HRT for one year that 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 small. 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.

Approximately 38 percent of postmenopausal women in the U.S. use HRT and from a public health perspective, the harm is substantial. For every 1 million women using HRT for one year there are 3,100 potentially life threatening adverse events. A conservative estimate of the total number of women who have been using HRT is 5 million. This translates to 15,500 serious adverse events per year.

The adverse economic impact of HRT on the health care system 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, M.D. (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, 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 protective 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 which, 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 U.S. 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 captioned:

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.

In 1991, the Health Research Group published the Women’s Health Alert. The largest chapter in the book was on HRT. By then, the evidence was clear that these drugs caused breast cancer and very serious doubts had been raised about their ability to protect against heart disease. The first sentence in this chapter began:

Female replacement hormones may someday be remembered as the most recklessly prescribed and dangerous drugs of this century.

This prediction has come to pass with the results of the Women’s Health Initiative.

What You Can Do

You should not be using hormone replacement therapy for any reason other than its very short term use to control the symptoms of menopause.