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Date of release: 25 January, 2010

The effect of transdermal testosterone on mammographic density in postmenopausal women not receiving hormone therapy


In the article published by Susan Davis and colleagues in the Journal of Clinical Endocrinology & Metabolism of December 2009, the authors compared the effects of two doses of the testosterone transdermal patch (TTP) with placebo on mammographic density in postmenopausal women without concomitant estrogen/progestin therapy (EPT) over a period of 52 weeks [1].


 


Greater mammographic density is associated with increased breast cancer risk and reduced diagnostic mammographic sensitivity, as in the case in women receiving EPT. However, the effects of testosterone therapy on mammographic density in postmenopausal women on EPT are not known.


 


The study was a randomized, double-blind, placebo-controlled, parallel-group, multinational trial. Patients included 279 postmenopausal women randomized to placebo, or TTP at 150 μg/day, or TTP at 300 μg/day, stratified by menopause type (natural or surgical). A total of 250 women with paired mammograms for study at baseline and at termination (at week 52) were included in the primary analysis. There were no baseline differences between the groups. The mean changes from baseline (± SEM) in percentage of dense tissue for the placebo, TTP 150, and TTP 300 groups were small (0.05% ± 0.16, 0.06% ± 0.19, and 0.21% ± 0.17, respectively) and were not significantly different. Also, there were no statistically significant differences from placebo for total dense or non-dense area and no significant relationship between hormone levels and percentage of dense tissue after adjustment for body mass index. 


 


TTP therapy over 52 weeks appears to have no significant effect on digitally quantified absolute or percent dense mammographic area in postmenopausal women not using EPT.

Comment

In 2007, Hofling and colleagues published a study in Climacteric in which the effects on mammographic breast density of additional testosterone in women using postmenopausal oral hormone therapy were investigated [2]. It was a prospective, randomized, double-blind, placebo-controlled trial which included 99 women. The authors concluded that the addition of testosterone did not influence mammographic breast density in those women over a period of 6 months. 
 
Androgens have important physiological effects in women. Androgen levels decline in women before menopause and it is now accepted that many postmenopausal women may experience physical symptoms secondary to androgen deficiency, as well as physiological changes that affect their quality of life [3]. Postmenopausal androgen replacement, most commonly testosterone therapy, is becoming increasingly widespread. Since EPT may be associated with greater mammographic density, and increased mammographic density is associated with increased breast cancer risk, the question arises as to what would be the case in regard to androgen therapy. It is noteworthy that Birkhäuser and colleagues argued whether the increase in mammographic breast density secondary to EPT is directly linked to the increase in the risk for breast cancer in hormone users [3]. 
 
A comprehensive review on the effect of testosterone on the breast was published by Somboonporn and Davis [4]. Two cross-sectional studies which investigated the relationship between testosterone level and breast cancer in premenopausal women yielded inconsistent results. On the other hand, three observational studies looking at a possible association between testosterone therapy and breast cancer concluded that the incidence of breast cancer in postmenopausal women treated with testosterone was similar to that in the general population. Finally, several studies indicated that both testosterone and dihydrotestosterone may actually have some protective effect on the breast. In vitro and in vivo studies showed that both molecules had a predominantly inhibitory influence on the mitogenic and cancer-promoting effects of estrogen in breast cells and promoted apoptosis via the androgen receptor. Unfortunately, most clinical studies have used total testosterone as a measure of androgen exposure, and these generally have shown that higher total testosterone levels are associated with increased breast cancer risk. However, these findings may reflect higher levels of sex hormone binding globulin due to higher endogenous estrogen. There are few data pertaining to the relationship between free testosterone levels and breast cancer risk in humans using reliable assay methodology. Although studies in both premenopausal and postmenopausal women are inconclusive, there is no evidence that hyperandrogenism in women with polycystic ovary syndrome is associated with increased breast cancer risk. Data for the use of exogenous testosterone and breast cancer risk are limited. The strongest supporting data for exogenous testosterone therapy come from primate studies. Based on such simulations, inclusion of testosterone in postmenopausal estrogen–progestin regimens has the potential to ameliorate the stimulating effects of combined estrogen–progestin on the breast. Unless more specific data become available, the use of testosterone should be limited to women symptomatic of androgen insufficiency despite adequate estrogen replacement [4].

Comentario

Roberto Sano Ito
Internal Medicine and Infectious Diseases, President of the Peruvian Menopause Society

    References

  1. Davis SR, Hirschberg AL, Wagner LK, Lodhi I, von Schoultz B. The effect of transdermal testosterone on mammographic density in postmenopausal women not receiving systemic estrogen therapy. J Clin Endocrinol Metab 2009;94:4907-13.
    http://www.ncbi.nlm.nih.gov/pubmed/19850682

  2. Hofling M, Lundstrom E, Azavedo E, et al. Testosterone addiction during menopausal hormone therapy: effects on mammographic breast density. Climacteric 2007;10:155-63.
    http://www.ncbi.nlm.nih.gov/pubmed/17453864

  3. Birkhuser H, Panay N, Archer DF, et al. Updated practical recommendations for hormone replacement therapy in peri- and postmenopause. Climacteric 2008;11:108-23.
    http://www.ncbi.nlm.nih.gov/pubmed/18365854

  4. Somboonporn W, Davis SR; National Health and Medical Research Council. Testosterone effects on the breast: implications for testosterone therapy for women. Endocr Rev 2004;25:374-88.
    http://www.ncbi.nlm.nih.gov/pubmed/15180949