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Janet Gray, Ph.D.
Janet Gray, Ph.D.

As author of our 2008 and 2010 State of the Evidence reports, Dr. Gray drives the science behind all our work.

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Hormone Replacement Therapy (HRT)

CATEGORY*: IARC known carcinogen; NTP: Estrogen-known carcinogen, progesterone-reasonably anticipated carcinogen

FOUND IN: Medications

THE GIST: HRT, a pharmaceutical hormone that often includes a combination of estrogen and progestin, is considered a known human carcinogen. Several major studies not only show that HRT increases risks for breast cancer, but also link the treatment to heart disease, stroke and blood clots.

State of the Evidence on Hormone Replacement Therapy

There is a long established link between lifetime exposure to steroid hormones and breast cancer. Thus it is not surprising that there are concerns over exposure to hormones through pharmaceuticals. The evidence from studies of women taking HRT has supported these concerns.

TIPS FOR PREVENTION

You can treat many of the symptoms of menopause with exercise and a healthy diet. If you decide to use HRT, try estrogen-only formulations and use it for as brief a time as possible.

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Between 1995 and 2000, several epidemiological studies indicated that use of combined estrogen-progestin hormone replacement therapy (HRT) treatments led to an increase in invasive breast cancer (Colditz, 1995; Magnusson, 1999; Ross, 2000; Schairer, 2000). In the decade since, combined HRT use has declined, as have rates of estrogen-receptor-positive (ER+) breast cancer in post-menopausal women (Krieger, 2010; Verkooijen, 2009).

A 2002 study designed to explore the benefits and risks of combined estrogen-progestin HRT (conjugated equine estrogens and medroxyprogesterone acetate) in post-menopausal women was halted three and a half years before the intended end of the study period. This project, called the Women's Health Initiative (WHI), enrolled more than 16,600 healthy women ages 50 to 79. The study was designed as a large randomized control trial, a method considered to be the most rigorous approach to studying clinical responses in human populations (Sibbald, 1998). Half the women took the combined estrogen-progestin HRT, while the other half took a placebo, and a number of health and disease outcomes were monitored. The WHI study was halted early because researchers observed a 26 percent increase in the relative risk of breast cancer (which equates to 38 women being diagnosed with breast cancer per 10,000 women who are taking the combined HRT per year as compared to 30 women per 10,000 who are not using HRT), in addition to statistically significant increases in the risk of heart disease, stroke and blood clots (Rossouw, 2002).

Since the results of the WHI were initially published, other large studies have supported its major conclusions. 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 combined estrogen-progestin HRT had three times the rate of recurrence or of new tumors compared to women who received other treatments for menopausal symptoms (Holmberg, 2004).

Also in 2003, researchers in the Million Women Study in the United Kingdom reported that the use of all types of post-menopausal HRT resulted in a statistically significant increase in the risk of breast cancer (Beral, 2003). Again, the risk was greatest among users of estrogen-progestin combination therapy. The study enrolled more than 1 million 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).

Other research has confirmed the basic result that use of combined estrogen-progestin HRT increases risk of breast cancer in post-menopausal women. Examination of cancer tissue in women taking combined HRT at the time of diagnosis reveals an increased presentation of breast cancer of lobular origin (Biglia, 2005; Borquist, 2007; Reeves, 2006), that have relatively low proliferation rates and favorable prognostic outcome (Reeves, 2006; Schuetz, 2007).

More recent analyses clarify that the increased risk of breast cancer in the Women’s Health Initiative study occurred in women taking the combined estrogen-progestin formula, but not in women taking estrogen-only HRT supplements (Anderson, 2004; Wood, 2008). When the studies were continued for the estrogen-only arms of the major studies, statistically significant decreases in breast cancer risk were noted in women who had been taking conjugated equine estrogen formulations (Anderson, 2012; LaCroix, 2011).

It is critical to note that the estrogen-only option can only be offered to women who have previously undergone surgical hysterectomies. Concurrent non-progestin treatment for women with intact uteri is not an acceptable option, because estrogen-only treatment leads to a statistically significant increased risk for uterine cancer (Montgomery, 2004). Additionally, data from the Million Women Study suggest that the benefits of the estrogen-only treatment might not apply to women at higher risk for a diagnosis of breast cancer (Anderson, 2012).

A follow-up of the women in the Women’s Health Initiative trial three years after all study participants stopped taking either the HRT or placebo treatments demonstrated increases in invasive cancers of all sorts (grouped together) in women who had been in the HRT arm of the trial. After three years, breast cancer rates remained slightly elevated in this group but were no longer statistically different from the placebo group (Heiss, 2008). These data suggest that the increased risk for breast cancer that accompanies use of HRT is reversible within a fairly short period following discontinuation of the treatment. This finding is consistent with the rapid drop in ER+ post-menopausal breast cancer incidence rates since 2002, a decrease that has been attributed to the precipitous drop in HRT prescriptions in white, middle/upper class post-menopausal women following the release of the data from these large studies (Krieger, 2010; Verkooijen, 2009).

*For chemicals that have been shown to be carcinogens, we provide classifications from two authoritative bodies: the International Agency for Research on Cancer (IARC, an international body) and the National Toxicology Program (NTP, a division of the U.S. Department of Health and Human Services). We have categorized endocrine-disrupting compounds where the body of peer-reviewed research indicates a strong foundation for doing so.