Androgen Replacement Therapy in Women

Marie Lebbe; David Hughes; Nicole Reisch; Wiebke Arlt


Expert Rev Endocrinol Metab. 2012;7(5):515-529. 

In This Article

Long-term Side Effect Profile of Androgen Therapy

Most of the studies concerning androgen replacement in women have concentrated on potential effects on female libido and well-being and recorded androgenic effects on skin (acne, hirsutism and alopecia) and lipids. However, detailed data on potential androgen effects on insulin sensitivity, body composition, mineral bone density, cardiovascular events and cancer are much more scarce and often preliminary (Table 1). A recently published, 4-year follow-up study in 967 oophorectomized patients on estrogen replacement therapy, who received at least one application of 300-µg TTP, showed no meaningful changes in the safety or tolerability profile of TTP and observed, consistent with age-expected rates, three cases of invasive breast cancer.[109]

Associations with estrogens in the development of breast, ovarian and endometrial cancers have been well delineated.[110] Similarly, several prospective studies have linked circulating androgen levels to the risk of postmenopausal breast cancer.[111–115] Analysis of the data from the Nurses' Health Study and the Women's Health Initiative Observational Study concluded that naturally menopausal women using hormonal replacement therapy containing both estrogens and androgens were at greater risk of developing breast cancer compared to never users of postmenopausal hormone replacement.[116,117] However, cross-sectional analysis of these data revealed that androgen levels were related to certain risk factors for cancer, such as body mass index, alcohol intake and cigarette smoking, making exact cause–effect association difficult.[118] Reassuringly, Davis et al. reported no changes in mammographic density, one of the strongest risk factors for breast cancer, following 300 µg/day TTP for 52 weeks in postmenopausal women.[119] This finding has been confirmed by another large cross-sectional study in postmenopausal women.[120] There was no association between androgen levels and ovarian cancer risk across the five prospective studies published to date.[121–125] The European Prospective Investigation into Cancer and Nutrition concluded that there is a significantly increased risk of endometrial cancer in patients with high serum estrogen and free testosterone levels.[126]

Carotid artery intima–media thickness estimated via carotid ultrasonography is one of the most popular markers used to investigate the progression of atherosclerosis. Several studies have shown an inverse correlation of circulating androgen levels in postmenopausal women to intima–media thickness, providing some preliminary evidence suggesting a protective effect of androgens on the development of atherosclerosis.[127–134]

Studies of the lipid profile in females so far seem to be in agreement, since total serum testosterone levels and free androgen index in particular have been associated with higher LDL and lower HDL cholesterol levels.[129,134,135] Apolipoprotein CIII levels are decreasing in women receiving androgen therapy, and this is somewhat promising, since ApoCIII is an independent risk for cardiovascular disease.[136] Of note, obesity raises androgen levels, also observed in the context of the polycystic ovary syndrome and has had a confounding impact on many studies.