Testosterone Effects on the Breast: Implications for Testosterone Therapy for Women

Abstract

Androgens have important physiological effects in women. Postmenopausal androgen replacement, most commonly as testosterone therapy, is becoming increasingly widespread. This is despite the lack of clear guidelines regarding the diagnosis of androgen insufficiency, optimal therapeutic doses, and long-term safety data. With respect to the breast specifically, there is the potential for exogenous testosterone to exert either androgenic or indirect estrogenic actions, with the latter potentially increasing breast cancer risk. In experimental studies, androgens exhibit growth-inhibitory and apoptotic effects in some, but not all, breast cancer cell lines. Differing effects between cell lines appear to be due primarily to variations in concentrations of specific coregulatory proteins at the receptor level. In rodent breast cancer models, androgen action is antiproliferative and proapoptotic, and is mediated via the androgen receptor, despite the potential for testosterone and dehydroepiandrosterone to be aromatized to estrogen. The results from studies in rhesus monkeys suggest that testosterone may serve as a natural endogenous protector of the breast and limit mitogenic and cancer-promoting effects of estrogen on mammary epithelium. Epidemiological studies have significant methodological limitations and provide inconclusive results. The strongest data for exogenous testosterone therapy comes from primate studies. Based on such simulations, inclusion of testosterone in postmenopausal estrogen-progestin regimens has the potential to ameliorate the stimulating effects of combined estrogen-progestin on the breast. Research addressing this is warranted; however, the number of women that would be required for an adequately powered randomized controlled trial renders such a study unlikely.

Exemestane's 17-hydroxylated metabolite exerts biological effects as an androgen

“…Androgens regulate growth of normal and neoplastic mammary cells in a cell type-specific manner, either by inhibiting or stimulating growth (44). However, the mechanisms by which androgens via AR regulate breast cancer growth remain elusive.…”

“…Not all androgens are metabolized by aromatase to estrogens; for instance, dihydrotestosterone cannot be converted to an estrogen by aromatase (44). Thus, a possible mechanism for failure of AI therapy in the clinic is androgen-stimulated breast cancer growth, a largely unrecognized alternative mechanism.…”

Age at first childbirth and oral contraceptive use are associated with risk of androgen receptor-negative breast cancer: the Malmö Diet and Cancer Cohort

“…Androgens exert stimulating effects directly on breast cancer cells through binding to the AR, as well as indirect effects through androgen aromatization into estrogens, which in turn bind to the ER (19)(20)(21). The levels of circulating androgens are most likely affected by hormonal factors, such as reproductive history and anthropometric measures (22,23).…”

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“…testosterone, dihydrotestosterone (DHT)) blocked proliferation of breast cells in vitro, caused by oestrogens as well as expression of oestrogen receptor genes (87,88,89,90,91). The antiproliferative and proapoptotic actions of androgens are probably mediated through the androgen receptor, despite the potential of testosterone to metabolise to oestrogens (79). Before these interrelations were known, advanced stages of mammary gland carcinoma had even been treated with testosterone from the 1940s until the 1970s (92).…”