Testosterone and the postmenopausal breast : aspects on cell proliferation and mammographic density

The breast is a target organ for sex steroids, and hormonal treatments have been associated with a risk of breast cancer. There is increasing interest in androgen treatment for postmenopausal women. Testosterone has been shown to improve bone density, body composition, mood, psychosexual function and general well-being. Little is known about the effects of testosterone on the breast.

The aims of this thesis were: to study the effects of testosterone addition to combined estrogen/progestogen treatment on breast cell proliferation and mammographic breast density; to assess possible relations to breast symptoms; to compare the effect of tibolone and combined hormone therapy on circulating sex steroids, binding proteins and their relationship to mammographic density; to explore the expression of androgen receptor (AR) and Syndecan-1 in primate breast tissue after long-term hormonal treatments. Postmenopausal, healthy women were recruited for prospective, randomized, placebo- controlled trials.

Tibolone and combined estrogen/progestogen treatment caused distinct differences in estrogen/androgen status and blood levels of possible breast mitogens. Treatment with tibolone resulted in elevated free testosterone levels. There was a negative association between free testosterone and mammographic density. This can be one mechanism to explain why tibolone has less influence on the breast than combined HT.

The fine needle aspiration biopsy technique is a useful tool to evaluate the proliferative response to hormonal treatments. During combined estrogen/progestogen treatment there was on average a four to five fold increase in breast cell proliferation. In contrast, when testosterone was added, no such increase was seen.

Mammographic density, a strong and independent risk factor for breast cancer, showed no significant difference between the treatment groups. Thus testosterone addition had a seemingly neutral effect on breast density. Breast symptoms of soreness and pain were found to increase during treatment, with a peak at 2 months. There was a correlation between symptoms and increase in mammographic density.

In a monkey model, long- term treatment with estrogen/progestogen resulted in a suppression of AR expression and a concomitant increase in Syndecan-1. After treatment with tibolone AR levels were markedly increased and around ten-fold higher than after estrogen/progestogen. The effects on Syndecan-1 expression were quite similar. After treatment with estrogen alone, values for both AR and Syndecan-1 expression did not differ from those in untreated monkeys.

In conclusion, testosterone and other androgens may have a protective influence on the breast.

List of scientific papers

I. Hofling M, Carlström K, Svane G, Azavedo E, Kloosterboer H, Von Schoultz B (2005). "Different effects of tibolone and continuous combined estrogen plus progestogen hormone therapy on sex hormone binding globulin and free testosterone levels--an association with mammographic density." Gynecol Endocrinol 20(2): 110-5
https://pubmed.ncbi.nlm.nih.gov/15823831

II. Hofling M, Hirschberg AL, Skoog L, Tani E, Hägerström T, von Schoultz B (2007). "Testosterone inhibits estrogen/progestogen-induced breast cell proliferation in postmenopausal women." Menopause 14(2): 183-90
https://pubmed.ncbi.nlm.nih.gov/17108847

III. Hofling M, Lundström E, Azavedo E, Svane G, Hirschberg AL, von Schoultz B (2007). "Testosterone addition during menopausal hormone therapy: effects on mammographic breast density." Climacteric 10(2): 155-63
https://pubmed.ncbi.nlm.nih.gov/17453864

IV. Hofling M, Ma L, Sahlin L, Haglund C, Nordling S, von Schoultz B, Cline JM (2008). "Expression of the Androgen receptor and Syndecan-1 in breast tissue during different hormonal treatments in cynomolgus monkeys." Climacteric (Submitted)