Hormone Replacement Therapy (HRT)

Over the past several decades, pharmaceutical companies have developed a variety of mixtures of natural and synthetic ovarian hormones used mainly for contraception or post-menopausal hormone replacement therapy (HRT). The International Agency for Research on Cancer (IARC) has listed estrogens as known human carcinogens since 1987, and their component hormones since 1976. In 2002, the National Toxicology Program (NTP) added HRT and estrogens used in oral contraceptives to the list of known human carcinogens.

These classifications confirm scientific evidence that has been collected since the 1930s linking steroidal estrogens to increased cancer risk. Data now show that when a woman’s natural estrogens are supplemented by oral contraceptives and/or HRT, her risk of breast cancer increases. Women who previously used oral contraceptives and later received HRT face an even greater breast cancer risk than those who have not used either or who have used only one. The effect may be most pronounced for pre-menopausal women who have taken both oral contraceptives and hormone therapy.

In 2002, a large study designed to explore the benefits and risks of combined estrogen plus progestin HRT in post-menopausal women was halted before the end of study period. This project, called the Women’s Health Initiative (WHI), enrolled more than 16,000 women ages 50 to 79. Half the women took Prempro, a combination of estrogen plus progestin. The other half took a placebo. Researchers halted the WHI study after five years because they saw a 26 percent increase in the relative risk of breast cancer (38 women with breast cancer versus 30 women per 10,000 person years), in addition to significant increases in the risk of heart disease, stroke and blood clots.

However, during the course of the WHI study, 42 percent of the participants withdrew. When the researchers reanalyzed the data based on the number of women actually treated with HRT, the relative risk of breast cancer increased from 26 percent to 49 percent (43 women with breast cancer versus 30 women per 10,000 person-years). Other health risks also increased in the women taking HRT.

More recent analyses clarify that the increased risk of breast cancer in the WHI study is found for women taking the combined estrogen-progestin formula, but not for those women taking estrogen only HRT supplements.

In 2003, Swedish researchers halted a study of HRT in women with a history of breast cancer. Originally planned as a five-year study, the Swedish trial was stopped after two years because women taking HRT had three times the rate of recurrence or new tumors compared to women who received other treatments for menopausal symptoms.

Also in 2003, researchers in the Million Women Study (MWS) in the United Kingdom reported that the use of all types of postmenopausal HRT significantly increased the risk of breast cancer. Again, the risk was greatest among users of estrogen-progestin combination therapy. The study enrolled more than 1million women ages 50 to 64. Researchers estimated that women who used estrogen-progestin HRT for 10 years were almost four times more likely to develop breast cancer than women who used estrogen-only HRT (19 additional breast cancers per 1,000 women compared to five per 1,000).

Use of HRT by women ages 50 to 64 in the U.K. over the past decade has resulted in an estimated 20,000 extra breast cancers, 15,000 of them associated with estrogen-progestin combination; the extra deaths cannot yet be reliably estimated.

Several other studies have confirmed the basic result that use of combined HRT increases risk of breast cancer in post-menopausal women. Examination of cancer histology in women taking combined HRT at the time of diagnosis reveals an increased presentation of breast cancer of lobular origin, but also of cancers with low proliferation rates (mitotic indices) and favorable prognostic outcome.

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For references, see State of the Evidence 2008.