Safety of estrogen/androgen regimens

A persistent view of testosterone as the "male hormone" deprives many clinically androgen deficient women of effective treatment, although data from the 1960s to the present have indicted the importance of androgens to libido and feelings of well-being in women, providing relief from vasomotor symptoms that are unresponsive to estrogen alone. The safety of androgen replacement therapy is reviewed in this article. The risk of androgen toxicity is influenced by dosage and route of administration. Most products developed for use in men produce androgen levels that are too high for safety in women. Low-dose androgen replacement therapy as used in women, 1.25 mg esterified estrogen (EE) + 2.5 mg methyltestosterone (MT), or a half-strength preparation, 0.625 mg EE plus 1.25 mg MT, is unlikely to produce commonly described side effects: liver dysfunction, adverse lipid effects or virilization, as reviewed in this article. The potential for adverse endometrial effects if used by women with uteri unless a progestogen is used is also discussed. Low-dose estrogen/androgen therapy offers beneficial cardiovascular effects, primarily regarding lipids, atherogenesis and vasodilation. Androgens may act independently on the cardiovascular system and may be mediated by estrogen metabolites (aromatization products) or by secondary effects of androgens on estrogen bioavailability and metabolism (sex hormone binding globulin [SHBG] effects). They may improve vasomotor stability and reduce triglyceride (TG) levels. The marked reduction in TG in the estrogen/androgen (E/A) regimen is of note because women who experience oophorectomy have significantly increased levels of TG as compared with women who are naturally menopausal. Androgens offer positive effects on bone. Various types of studies--including cell culture, preclinical and observational--have attempted to document potential associations between androgens and breast cancer. Androgen administration has been shown to induce down-regulation of mammary epithelial proliferation and estrogen receptor expression, suggesting that E/A therapy might reduce the risk of breast cancer associated with ERT. However, studies of the relation of breast cancer to elevated circulating androgen levels have yielded inconsistent results. Testosterone may have an indirect effect on breast cancer risk because of its association with estrogen levels. Testosterone's effect on estrogen bioavailability may be of importance since an increase in serum testosterone levels could lead to a decrease in the percent of estradiol bound to SHBG. For the surgically menopausal woman faced with significant symptoms and health risks associated with estrogen withdrawal, E/A supplementation offers a reasonable course of treatment.