Glossary

Type a term:

Hormone Replacement Therapy (HRT) & Oral Contraceptives (OC)

HRTC In recent years, there have been numerous reports about breast cancer risk and hormone supplements, including both Hormone Replacement Therapy (HRT) and oral contraceptives. Some of the stories present conflicting and confusing information. In fact, results from large studies looking at HRT use and breast cancer risk are fairly consistent in demonstrating an increased risk of cancer with recent use of HRT. On the other hand, results of studies looking at the effects of oral contraceptives use are much more varied.

Overview

Why is HRT prescribed?

HRT is commonly prescribed to offset some of the common symptoms of menopause including hot flashes, vaginal dryness, and mood fluctuations. HRT is also often prescribed to decrease the probability of several diseases that are found more often in postmenopausal women, especially osteoporosis.

What are the most common types of HRT?

  • Estrogen only replacement therapy
  • Combination HRT: the addition of a synthetic progestin to the estrogen base. This can be done in two ways:
    • Continuous Combined Replacement Therapy (CCRT) adds the progestin for the entire monthly cycle.
    • Sequential Estrogen plus Progestin Replacement Therapy (SEPRT) adds the progestin usually for 7-10 days of the monthly cycle.

Why might HRT be associated with increased breast cancer risk?

HRT leads to sustained higher levels of estrogen and progestin hormones. In turn, exposure of breast tissue to these hormones, especially at high levels, is known to increase risk for breast cancer.

Evidence

In general, studies show that the longer a postmenopausal woman is taking HRT, the greater her risk is of breast cancer. In addition, several studies have shown that HRT supplements that contain both estrogen and progestin components lead to a significant increase in breast cancer risk. (We should also note, though, that there may be an increased risk of endometrial cancer for women taking the estrogen only HRT.)

Study summaries

Several recent large studies support the conclusion that the use of HRT, especially the combined estrogen-progestin form, increases risk for breast cancer.

1. A summary of nearly every study to date of hormone replacement therapy and breast cancer was published in 1997. The analysis explored the experience of more than 52,000 women with breast cancer and twice as many women without cancer from 21 countries. The researchers found that women who used HRT for five or more years increased their risk of breast cancer by about 35%. The risk lasted as long as the woman took hormones but disappeared within five years after she stopped hormone use. The study also reported that each year of HRT use increased the risk by 2.3%, similar to the increased risk observed (2.8%) for each additional year of menstruation (extra year before menopause). In other words, these data suggest that the increase risk due to use of HRT is comparable with the effect on breast cancer of delaying menopause [Collaborative Group on Hormonal Factors in Breast Cancer, 1997].

2. In 2000, two large studies demonstrated that progestins seem to increase breast cancer risk beyond that of estrogen taken alone. One of these studies showed that HRT in general was associated with a 10% higher breast cancer risk for each five years of use. Risk was substantially higher for CHRT use than for estrogen-only therapies, and the risk estimate for use of SEPRT was higher than for CHRT, but not significantly. This study provides evidence that the addition of a progestin to HRT significantly enhances the risk of breast cancer relative to estrogen use alone [Ross et al., 2000]. The second study echoes these results, showing that the relative risk of breast cancer increased by 1% with each year of estrogen-only use and by 8% with each year of combined estrogen-progestin use [Schairer et al., 2000]. Again the data suggest that the estrogen-progestin regimen increases breast cancer risk beyond that associated with estrogen alone.

3. The Women’s Health Initiative (WHI) is a set of clinical trials that enrolled 161,809 postmenopausal women in the age range of 50 to 79 years. Among the many health issues examined were the effects of postmenopausal use of HRT. One of the trials tested the combined estrogen and progestin replacement therapy in women who had not had hysterectomies (surgical removal of their uteri). The trial was stopped early based on the surprising observation that health risks of taking the HRT exceeded the benefits over an average follow-up of 5.2 years. One of the adverse health effects was a 26% increase in invasive breast cancer in women taking the combined HRT [Women’s Health Initiative Investigators, 2002].

4. The Million Women Study was set up to investigate, among other health-related issues, the effects of specific types of HRT use on the incidence of and death rate from breast cancer. This report was based on more than a million women aged 50-64 years from the United Kingdom. Participants in the study provided information about their personal and health histories, including their use of HRT. They were then followed for later breast cancer incidence and death. It was found that use of HRT was associated with a significantly increased risk of both measures. The effect was substantially greater for use of estrogen-progestin combinations than for other types of HRT [Million Women Study Collaborators, 2003].

5. In another large epidemiologic study (10,874 female nurses 45 years of age or older), an increased risk of breast cancer was found for current use of estrogen-only therapy, as well as for the combined used of estrogen and progestin therapy. The highest risk was found for the use of continuous combined estrogen and progestin [Stahlberg et al., 2004].

6. A study of 35,456 postmenopausal Norwegian women also demonstrated the increased risk of breast cancer in current users of HRT, with the risk increasing with longer duration of use and with the use of a regimen of combined estrogen-progestin therapy. According to the authors, the results suggest that HRT could be considered a major factor in the increasing incidence of breast cancer in Norway [Bakken et al., 2004].

7. Other recent studies have confirmed 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 [Biglia et al., 2005, Borgquist et al., 2007, Reeves et al., 2006, Schuetz et al., 2007].

8. A follow-up of the women in the WHI 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. While breast cancer rates remained elevated in this group, a trend over time toward rates similar to those found in the placebo group made these effects non-significant [Heiss et al., 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 post-menopausal breast cancer incidence rates since 2002, a decrease that has been attributed to the precipitous drop in HRT prescriptions following the release of the data from these large studies [Verkooijen et al., 2009].