Estrogen, Testosterone, and Breast Cancer in the Nurses' Health Study

Abstract & Commentary

By Leon Speroff, MD, Editor, Professor of Obstetrics and Gynecology, Oregon Health and Science University, Portland, is Editor for OB/GYN Clinical Alert.

Synopsis: The Nurses' Health Study reports that the postmenopausal use of testosterone increases the risk of invasive breast cancer.

Source: Tamimi RM, et al. Combined estrogen and testosterone use and risk of breast cancer in postmenopausal women. Arch Intern Med. 2006;166:1483-1489.

The nurses' health study reported the risk of invasive breast cancer associated with the use of combined estrogen and testosterone. At the beginning of this cohort study, only 33 women reported testosterone use, but over the next 10 years this number increased to 550. Compared to never users and after adjusting for multiple risk factors, users of estrogen plus testosterone had an increased relative risk of invasive breast cancer (1.77; CI = 1.22-2.56). This risk was greater than that reported by the Nurses' Health Study for users of estrogen alone and for users of estrogen-progestin. There was no increase in past users.

Commentary

This report from the Nurses' Health Study is complicated by the same problem in other breast cancer reports from this cohort: the hormone users (in this case, estrogen and testosterone) differ substantially from never users. This requires multiple statistical adjustments, a process that is further influenced by the number of cases involved. This analysis is limited by relatively small numbers; there were only 29 cases of breast cancer among the estrogen-testosterone users. Nevertheless, the results should raise caution in this day of increasing postmenopausal use of androgens.

If testosterone affects breast tissue, does it do so directly or is it aromatized locally into estrogen? The majority of studies indicate that testosterone inhibits proliferation of breast cancer cell lines in vitro, suggesting that aromatization is of greater concern. The women in the Nurses' Health Study in the testosterone group were mainly (90%) using the combination of esterified estrogen and methyltestosterone. For years, I have tried to find out if methyltestosterone is aromatized to estrogen or whether the methyl group protects it against this conversion. There is nothing in the literature, and conversations with pharmaceutical people and biochemists have not provided the answer. Other testosterone preparations such as implants and transdermal applications do carry the risk of target tissue aromatization, perhaps raising local estrogen levels to high levels in breast tissue.

The long-term consequences of androgen administration are unknown. Besides the potential effect on the breast, there is also concern regarding cardiovascular disease. We should do our best to limit duration of androgen exposure and to avoid doses that are clearly pharmacologic. Testosterone assays have no utility for the diagnosis of sexual problems, but they can be used to avoid overdosing.