Testosterone's Impact on Postmenopausal Women and Breast Cancer

By Janna Gordon, R.Ph., MBA
March 2007

Loss of libido, fatigue, and anorgasmia are common testosterone related symptoms women experience as their natural production of hormones starts to decline during perimenopause and menopause. The loss of testosterone is often a concern for patients and their physicians, and many are asking, "Should testosterone be used as supplementation in postmenopausal patients?" Additionally, there is worry with the effects of testosterone on women with breast cancer.

Testosterone is an androgen or male hormone found in low levels in the female body. It is a steroid produced in the ovaries, the adrenal gland, and from conversion of other steroid hormones, such as androstenedione and dehydroepiandrosterone (DHEA).^1,2,3

Testosterone’s role in the body is to build muscle and promote muscle tone, increase libido, strengthen bone and in some will improve mood and metabolism. Testosterone levels typically decline as we age due to declining ovarian and adrenal function.² Another possible driver of decreased testosterone is an elevated level of a binding protein called sex hormone-binding globulin (SHBG). SHBG binds to both estradiol and testosterone and inactivates the function of these hormones while they are bound to it. An elevated level of SHBG lowers the bioavailability of testosterone and can be an issue for patients on hormone replacement therapy because oral estrogen therapy has been associated with increases in SHBG.^2,3 While currently there is not a commercially available testosterone supplement for women, supplementing a women’s testosterone level into a normal range has been shown to improve their sexual enjoyment and libido.⁴ Numerous women will also testify to the positive effects they experience once their testosterone and other hormone levels are returned to a normal range with hormone supplementation.

When evaluating testosterone’s impact on breast cancer, it is unclear if testosterone is a singular causative agent or if breast cancer is a result of other hormonal stimulation such as estrogens or synthetic progestins. Several clinical studies have attempted to answer this question with results suggesting that there is more to the equation than testosterone. A study that followed 508 postmenopausal women receiving testosterone in addition to usual hormone therapy, evaluated the role of testosterone in hormone replacement therapy. The observations began in 1987 and ended in 1999. Participants received testosterone implants 50-150mg, with a common dose of 100mg, every 5 months in addition to estrogen or estrogen and progestin treatment. The testosterone dose was titrated to relieve symptoms, improve bone mineral density, and decrease possible adverse effects. Seven invasive cases of breast cancer were seen throughout the study. Six out of the seven cases were seen in the estrogen/progestin/testosterone arm. In contrast, only one case was seen in the estrogen/testosterone arm of this study.³ In comparison, the incidence of breast cancer was 2-3 times higher among the estrogen/progestin arm of The Women’s Health Initiative study (WHI). One might possibly surmise that the common thread in these results was the progestin therapy, not the estrogen/testosterone therapy, although this has not been clinically proven.

It has been shown that estrogen therapy may disrupt the balance between estrogen and androgens; therefore, lead to estrogenic stimulation of the breast cells.³ The increased stimulation may lead to cell proliferation, differentiation and ultimately to breast cancer. Estrogen therapy has been shown in an animal study to decrease ovarian production of testosterone by inducing a negative feedback loop in the ovary where luteinizing hormone levels are decreased, leading to decreased production of testosterone and ultimately estradiol; therefore, changing the balance of estrogen and testosterone.⁵ Experimental data from rodents and monkeys suggest that conventional estrogen treatment may upset the normal estrogen/androgen balance and stimulate estrogen in the mammary epithelium.³ Therefore, increasing a patient’s chance of developing breast cancer.

Clinical studies have provided conflicting results when looking for a clear correlation between testosterone blood levels and breast cancer in postmenopausal women.^6,8 As of to date, there aren’t any unbiased trials of sufficient size and duration to evaluate the effect of testosterone in breast cancer. A review of published studies did not find an adverse effect from estrogen/testosterone therapy when evaluating testosterone’s effect on breast cancer. In addition, one study concluded that testosterone may decrease the risk of breast cancer when conventional hormone therapy (i.e. estrogen and progesterone) includes testosterone.³ Another study looked at androgen receptor antagonist in primates and concluded that endogenous androgens (such as testosterone) inhibit mammary proliferation, thus potentially decreasing its impact on breast cancer.

There is an abundant amount of information supporting and rejecting the supplemental use of testosterone in hormone replacement therapy for postmenopausal women. Theoretically it makes sense that replacing all hormones that are decreased during menopause, including testosterone, would have some benefit. Data has suggested that adding testosterone to conventional hormone therapy in postmenopausal women might reduce the hormone therapy-induced breast cancer risk in this population.³

Further evaluation is needed to clearly determine the role of testosterone in postmenopausal women. Testosterone supplementation has not been conventionally recommended if there’s a family history of breast cancer, although some physicians believe that there may be a benefit in maintaining normal levels through supplementation. In addition, testosterone supplementation is generally warranted in women complaining of low libido and sexual problems.

For questions and further information, contact Bellevue Pharmacy Solutions.

References

1. Lillie EO, Bernstein L, Ursin Giske. The Role of androgens and Polymorphisms in the Androgen Receptor in the Epidemiology of Breast Cancer. Breast Cancer Res. 2003;5: 164-173.
2. The Role of Testosterone Therapy in Postmenopausal Women: Position Statement of The North Americal Menopause Society. Menopause. 2005;12(5):497-511.
3. Dimitrakakis C, Jones RA, Liu A, Bondy CA. Breast Cancer Incidence in Postmenopausal Women Using Testosterone in Addition to Usual Hormone Therapy. Menopause. 2004;11(5):531-535.
4. BurgerHG, Hailes J, Nelson J, Menelaus M. Effect of Combined Implants of Estradiol and Testosterone on Livido in Postmenopausal Women. BMJ. 1987;294:936-937.
5. Leung P CK, Goff AK, Kennedy TG, Armstrong DT. An Intraovarian Inhibitory Action of Estrogen on Angrogen Production in vivo. Biology of reproduction. 1978;19: 641-647.
6. Missmer SA, Eliassen AH, Barbieri RL, Hankinson SE. Endogenous Estrogen, Androgen, and Progesterone Concentrations and Breast Cancer Risk Among Postmenopausal Women. J Natl Cancer Inst. 2004;96(24):1856-1865.
7. Cauley JA, Lucas FL Kuller LH, Stone K, Browner W, Cummings SR. Elevated Serum Estradiol and Testosterone Concentrations are Associated with a High Risk for Breast Cancer. Ann Intern Med. 1999;130:270-277.
8. Adly L, Hill D, Sherman ME, Sturgeon SR, Fears T, Mies C, Ziegler RG, Hoover RN, Schairer C. Serum concentrations of estrogens, sex hormone-binding globulin, and androgens and risk of breast cancer in postmenopausal women. Int J Cancer. 2006 Nov 15;119(10):2402-7.

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