Clinical Review

HRT and cancer: quantifying the risk

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Until recently, hormone replacement therapy was hailed for its many benefits in postmenopausal women, but findings from the Women’s Health Initiative and other trials have altered the landscape. Here, the authors sift the data on HRT and the risk of various cancers.



  • Hormone replacement therapy (HRT) may be associated with an increased risk of breast cancer.
  • Although the increased risk of breast cancer with HRT use is minimal, it may be advisable for some women to avoid this therapy altogether, especially those at high risk of breast cancer.
  • The long-term use of unopposed estrogen is associated with epithelial ovarian cancer.
  • The data on the risk of colorectal cancer with HRT use demonstrate a protective effect.
  • Unopposed estrogen use is associated with the development of endometrial carcinoma.
To say that the body of research on hormone replacement therapy (HRT) and the risk of cancer in postmenopausal women is rife with ambiguity is an understatement. Not only have recent studies challenged earlier findings, but the popular press often has generalized highly specific data into ubiquitous truths. Even so, we are gradually discerning who should and should not take the therapy, particularly in regard to the increased risk of cancer or its recurrence. With this article, we aim to objectively cite what is known about HRT in menopause and offer guidelines on how this information can be individualized to patients.

HRT and breast cancer

The most controversial risk associated with HRT is developing or aggravating breast cancer. Estrogen therapy—alone or in combination with progesterone—has been shown to increase production of the estrogen and progesterone receptors in breast tissue.1 When activated, these receptors enhance breast density. In fact, a relationship between increasing breast density and breast cancer has been detected in several studies.2,3

Endogenous hormones also may heighten the risk of breast cancer. Risk factors such as early menarche, late menopause, and high postmenopausal serum estradiol levels appear to be significantly associated with the development of breast cancer, as does obesity that persists after menopause (with presumed high estrogen levels secondary to peripheral androgen conversion to estrogen).4 In addition, an in vitro study suggests that breast-cell growth is stimulated with low doses of estrogen (but restricted at high doses).5

A recent prospective study found a significantly higher risk of invasive breast carcinoma among women who had ever used HRT (5 or more years).6 No association was noted between use of HRT and ductal carcinoma in situ (DCIS) or invasive ductal or lobular carcinoma. Nor was any association found between current HRT use and DCIS or invasive ductal or lobular carcinoma, regardless of the duration of use. Holli and colleagues corroborate these findings.7

In the Nurses’ Health Study, Colditz et al detected a significant association between breast cancer and the use of unopposed estrogen, estrogen in combination with progesterone, or progesterone alone.8 Current HRT users who were 55 to 59 years of age had a significantly increased risk of breast cancer, as did women age 60 to 64 who had taken HRT more than 5 years. The authors recommended that the use of any form of HRT be considered carefully, on a patient-by-patient basis, especially after 55 years of age.

In the Breast Cancer Detection Demonstration Project, Schairer et al found that the risk of breast cancer increased with the duration of HRT use among postmenopausal women.9 With unopposed estrogen, the risk of breast cancer in nonobese women increased after 8 or more years of use. With estrogen-progesterone, the risk was elevated after 4 years of use. When Schairer and colleagues analyzed different types of breast cancer, they found estrogen-progesterone was associated with a significantly increased risk of ductal and/or lobular disease with 4 or more years of use. In contrast, unopposed estrogen was associated with an increase in ductal and/or lobular disease after 8 to 16 years of use. Pike and Ross also found a statistically significant association between the risk of breast cancer and the use of estrogen-progesterone, compared with the use of estrogen alone.10

Researchers found a significant association between HRT use of 5 to 10 years and the development of invasive breast cancer, but no significance for prior use exceeding 10 years.

We now have data from the estrogen-progestin arm of the Women’s Health Initiative (WHI), which was halted after a mean follow-up of 5.2 years.11 One reason this arm of the trial was interrupted was the emerging evidence that combination HRT is associated with invasive breast cancer. Researchers found a significant association between HRT use of 5 to 10 years and the development of invasive breast cancer (confidence interval [CI], 1.01-21.02). However, prior use exceeding 10 years was not significantly associated with breast cancer (CI, 0.60-5.43). This trial involved only 1 form and dose of HRT: conjugated equine estrogen 0.625 mg and medroxyprogesterone acetate 2.5 mg. It did not consider the use of lower doses of estrogen and progesterone or different formulations.


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