Dr. John Pittman

Estrogen Replacement

Risks, Benefits and Safety Issues

The history of estrogen replacement therapy goes back to the 1950’s when it first became possible to mass produce compounds with powerful estrogenic activity. The primary source of estrogen has been the urine of pregnant mares with the product being Premarin (conjugated equine estrogens), which at one time was the most prescribed medication on the planet. Initial use of this hormone resulted in women expressing their happiness over the return of normal function, with such women noting a reversal of hormone deficiency symptoms.

The initial interest in estrogen replacement was to control the symptoms of menopause and help women get through this change more comfortably, then to discontinue the hormones and age normally. When physicians began doing this with patients who had experienced benefits from estrogen replacement, there was nothing short of a revolt by many women who did not want to give up their estrogen. Longer term use of the hormone became commonplace and studies were begun to assess what health benefits, as well as potential risks, this treatment was providing.

The first “pill scare” in the world of hormone replacement therapy came in the mid 1970’s when reports were published indicating that women taking estrogen, without also taking progesterone, had an increased risk of developing endometrial cancer. This coincided with negative news about birth control pills. The effect was very similar to that seen in July 2002, when the Women’s Health Initiative study was released with negative findings in regards to the safety of Prempro.

It was quickly shown that the use of a progesterone-like compound, taken simultaneously with the horse urine-based estrogen, could significantly reduce the risk of developing endometrial cancer, thus the birth of Prempro. Prempro is a combination of Premarin, the horse urine estrogen, and Provera, which is the brand name for progestin, a synthetic form of progesterone. It is this product that has dominated the market and chosen by the Women’s Health Initiative (WHI) to be studied in clinical trials.

The WHI trial began in 1991 and involved 16,608 women ages 50 to 79 years with an intact uterus. It was a 15-year study addressing the most common causes of death, disability, and impaired quality of life in postmenopausal women. The study portion, involving estrogen and progestin, was stopped in July 2002 due to an increased risk of invasive breast cancer. The trial component found increases in coronary heart disease, stroke, and pulmonary embolism in study participants taking estrogen plus progestin, compared to women taking placebo pills.

One of the criticisms of this study is that the women who participated were too old when they started hormone replacement. For a woman to receive any significant benefit from hormones, and to prevent the degenerative effects of hormone deficiency from occurring, treatment must start as soon as possible after the onset of menopause, in some cases even before menopause if a woman’s estrogen levels are measured to be suboptimal.

Since the initial release of the study data, further analysis has supported the original conclusions of greater risk versus safety. Women in this study on Prempro had not only a higher incidence of breast cancer over those on placebo, but their cancer was diagnosed at a more advanced stage. It is important to remember that the WHI study looked at combined hormone replacement therapy, that is the use of Premarin along with medroxyprogesterone (Provera), a synthetic progesterone-like hormone and this appears to be the greater culprit in the increased risks than even the Premarin.

What is not being made clear is the fact that it takes 10 years for a cancer cell to grow from the point of mutation to where a tumor is large enough to be detected (about 1 cm). The WHI study was stopped after 10 years, with the average enrolled time for participants being 5.2 years. This indicates that women who developed cancer within the first 5 years of the study already had cancer cells growing in their breasts when they started the hormones, although the Prempro may have attributed to cancer acceleration. It was also clear from the data collected that women who had been on Prempro for longer periods of time did not have an increased incidence of cancer; the rate actually decreased the longer the women were on Prempro.

What was not measured by the WHI study was the quality of life women on hormone replacement therapy experience versus those only taking a placebo. Benefits include the almost immediate alleviation of the physical symptoms such as reduction/cessation of hot flashes and night sweats, improved sleep, improved memory and mood, and reduction in joint pain. Other not-so-obvious benefits include protection and reversal of osteoporosis, protection against the development of degenerative neurological disorders, and reduction in cholesterol levels.

In short, physicians owe it to their patients to understand these complexities and appropriately guide their patients to make informed decisions about the use of hormone replacement therapy. Small numbers of physicians, who have long championed a more progressive approach to healthcare, have been supplying patients with natural forms of bio-identical hormones (BHRT) since the early 1980’s. These forms of hormones are identical to those produced in the human body, and the doses are individually tailored to the biochemical individuality of the patient. Over these years, BHRT has been well tolerated with good long-term compliance, though there are no large trials comparable to the WHI.