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

<p>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.</p><p>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.</p><p>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.</p><p>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.</p><p>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.</p><p>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.</p><p>In conclusion, testosterone and other androgens may have a protective influence on the breast.</p><h3>List of scientific papers</h3><p>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 <br><a href="https://pubmed.ncbi.nlm.nih.gov/15823831">https://pubmed.ncbi.nlm.nih.gov/15823831</a><br><br></p><p>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 <br><a href="https://pubmed.ncbi.nlm.nih.gov/17108847">https://pubmed.ncbi.nlm.nih.gov/17108847</a><br><br></p><p>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 <br><a href="https://pubmed.ncbi.nlm.nih.gov/17453864">https://pubmed.ncbi.nlm.nih.gov/17453864</a><br><br></p><p>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)</p>