Key Words

Breast cancer, postmenopausal hormone therapy, estrogen, testosterone. (Definitions of many terms related to cancer can be found in the Cancer.gov Dictionary.)

Summary

Use of postmenopausal hormone therapy that includes both estrogen and testosterone significantly increases the risk of breast cancer, according to a prospective, survey-based study. Women who used the combination of estrogen and testosterone had a greater risk of breast cancer than women who used estrogen-only or estrogen and progesterone hormone therapy.

Source

Archives of Internal Medicine, July 24, 2006 (see the journal abstract).
(Arch Intern Med. 2006 Jul 24;166(14):1483-9)

Background

During menopause, the ovaries gradually produce lower levels of the female hormones estrogen and progesterone. This change in hormone levels can cause uncomfortable symptoms, including hot flashes and vaginal dryness, and sometimes medical problems such as osteoporosis (bone loss).

Some women choose to take postmenopausal hormone (PMH) therapies to relieve the symptoms of menopause. Some women continue taking PMH after menopause, though the risks and benefits of long-term PMH, including an increased risk of breast cancer in women taking both estrogen and progesterone, must be compared for each individual woman. (See Menopausal Hormone Use and Cancer: Questions and Answers ¹.)

Based on studies suggesting that testosterone can improve mood, sexual functioning, and bone strength in postmenopausal women, the hormone is currently included in a small number of PMH regimens. However, no prospective studies had examined the breast cancer risk of testosterone therapy before its incorporation into these treatments.

The Study

Participants were taken from the Nurses’ Health Study, a prospective cohort study that between 1976 and 2002 sent questionnaires every two years to thousands of female registered nurses aged 30 to 55 years. Participating women were asked questions about lifestyle factors including smoking, pregnancy history, and diet. Their answers have been used to track risk factors for a variety of diseases. Beginning in 1978, the follow-up questionnaires asked women about the type of PMH they had used, if any.

The analysis described here included only postmenopausal women. Investigators recorded the cases of invasive breast cancer in postmenopausal women who took no PMH and those who did. Women took a variety of PMH therapies:

• Estrogen alone
• Progesterone alone
• Estrogen and progesterone
• Testosterone alone
• Estrogen and testosterone
• Other PMH use

Cases of invasive breast cancer were identified by the women’s self-reports and verified by a review of their medical records.

Results

Over 24 years, 4,610 cases of invasive breast cancer occurred in postmenopausal participants. Women who used estrogen and testosterone therapy had a 77 percent greater risk of developing breast cancer than women who never used any type of PMH. Compared to women who never used PMH, women who used estrogen alone had a 15 percent greater risk and women who used the estrogen and progesterone combination had a 58 percent greater risk.

Limitations

Data collection was hampered by the fact that the combination therapy of estrogen and testosterone was only a write-in option on the follow-up forms during some years of the study. Therefore, some women’s PMH use could have been misclassified as another type, leading to an underestimation of use of estrogen and testosterone therapy.

A larger limitation, explains Worta McCaskill-Stevens, M.D., a medical oncologist in the National Cancer Institute’s Division of Cancer Prevention, is that “very few women would go on [estrogen and testosterone] without having tried another [hormonal] agent.” This was the case in the Nurses’ Health Study, state the authors: “Because the use of E&T [estrogen and testosterone] therapy is a more recent clinical practice and the majority of current users were past users of other types of hormone therapy, there is the potential for confounding by past use of other therapies.”

To examine this possible limitation, the authors performed a secondary analysis that took into account the type and duration of previous PMH use. Although the data they had to work with were limited, explain the authors, the results supported their findings “that estrogen and testosterone use is associated with increased risk of breast cancer.”

Comments

Since the study was not a clinical trial, explains McCaskill-Stevens, the authors can’t make clinical recommendations about the duration of use of estrogen and testosterone therapies. However, the study is “basically telling us that [estrogen and testosterone therapy] is associated with a high risk of breast cancer,” she says.

The authors recommend caution when considering the use of hormone therapy: "Given the substantial evidence implicating combined E&P [estrogen and progesterone] therapy in breast cancer and the results of the present study regarding E&T [estrogen and testosterone] therapies, women and their physicians should reconsider use and, more specifically, long-term use of these therapies," they write.

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