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IMS Menopause Live

The safety of postmenopausal testosterone therapy

16 October, 2012:

Testosterone therapy has been used in postmenopausal women for many years. However, it remains a contentious issue and few products are designed specifically for use in women. There are many potential benefits of testosterone replacement. Improvements in sexual function, mood, cognition, bone density and quality of life have all been demonstrated and testosterone has even been shown to improve outcomes in women with congestive cardiac failure [1-3]. Despite these potential benefits, many regulatory authorities remain unconvinced by the currently available safety data, particularly concerning the breast and cardiovascular systems. A recently published review [4] looks at the most recent data on postmenopausal testosterone therapy, focusing particularly on the effects of testosterone on breast, endometrium and cardiovascular health.

There are many inherent difficulties with studying the effects of testosterone in women and subsequently many of the available data have methodological flaws. For instance, concerns exist about the limitations of the different testosterone assays. There is also doubt whether systemic testosterone levels represent the true effect in the breast and cardiovascular system due to local tissue intracrinology. Variations in menopausal status, use of concomitant hormone therapy and the testosterone fraction used for analysis can limit comparisons between studies. Furthermore, many studies fail to adjust for estradiol, sex hormone binding globulin or body mass index, all of which can have a profound effect on risk factors.

It is difficult to give a definitive overview on the long-term safety of postmenopausal testosterone therapy because of the limitations discussed thus far and the absence of gold standard data [4]. Older studies using oral testosterone have shown an adverse effect on lipid metabolism, body composition and surrogate markers for cardiovascular disease. There has been a recent move to the use of transdermal preparations with a very different metabolic profile. Transdermal testosterone does not appear to affect cardiovascular risk factors such as body mass, blood pressure or lipid metabolism and low-dose subcutaneous therapy appears to have a beneficial effect on endothelial function [5]. However, robust data on cardiovascular risks are lacking; there are no sufficiently powered long-term, randomized, controlled trials (RCTs) investigating cardiac events with physiological transdermal replacement.

Similarly with breast cancer, there are no RCTs with exogenous testosterone investigating the risk of breast cancer as a primary outcome, so definitive conclusions cannot be drawn. Observational studies investigating the risk of breast cancer have shown conflicting results; although the majority have shown no increase in risk, two older trials investigating the effects of oral testosterone did show a small risk. Randomized, controlled trial data have shown no effect from transdermal testosterone on surrogate risk markers such as breast cell proliferation and mammographic density.

Comment

The available data do not show an increased risk of cardiovascular disease or breast cancer with transdermal testosterone preparations and support a move towards physiological replacement [6]. However, it must be acknowledged that, in the absence of large-scale, long-term RCTs, the regulatory authorities will be reluctant to approve androgenic products. There are no approved products for female androgen replacement in the USA, and in Europe the Intrinsa®testosterone patch was recently withdrawn for commercial reasons. Unfortunately, the large Libigel® cardiovascular study [7] has been terminated early, not due to safety concerns, and may fail to provide eagerly anticipated long-term breast and cardiovascular safety data.

Further studies, not only in postmenopausal but also in premenopausal women and in those not using concomitant estrogen therapy, would be welcome. Only the weight of cumulative reassuring data will convince the regulators of the efficacy and safety of testosterone for all these indications, thus encouraging the future licensing of female androgenic products.

Nick Panay
Editor-in-Chief (Europe) Climacteric, Imperial College, London, UK

and

Marie Gerval
Research Fellow, Imperial College, London, UK

and

Kate Maclaran
Research Fellow, Imperial College, London, UK

References

1. Al-Azzawi F, Bitzer J. Brandenburg U, et al. Therapeutic options for postmenopausal female sexual dysfunction. Climacteric 2010;13:103-20. http://www.ncbi.nlm.nih.gov/pubmed/19958161 

2. Maclaran K, Panay N. Managing low sexual desire in women. Women's Health (Lond Engl) 2011;7:571-81. http://www.ncbi.nlm.nih.gov/pubmed/21879825 

3. Panay N, Fenton A. The role of testosterone in women. Climacteric 2009;12:185-7. http://www.ncbi.nlm.nih.gov/pubmed/19437195 

4. Maclaran K, Panay N. The safety of postmenopausal testosterone therapy. Women's Health (Lond Engl) 2012;8:263-75. http://www.ncbi.nlm.nih.gov/pubmed/22554174 

5. Nachtigall L, Casson P, Lucas J, Schofield V, Melson C, Simon JA. Safety and tolerability of testosterone patch therapy for up to 4 years in surgically menopausal women receiving oral or transdermal oestrogen. Gynecol Endocrinol 2011;27:39-48.  http://www.ncbi.nlm.nih.gov/pubmed/21142609 

6. Davis SR, Braunstein GD. Efficacy and safety of testosterone in the management of hypoactive sexual desire disorder in postmenopausal women. J Sex Med 2012;9:1134-48. http://www.ncbi.nlm.nih.gov/pubmed/22304681 

7. White WB, Grady D, Giudice LC, Berry SM, Zborowski J, Snabes MC. A cardiovascular safety study of LibiGel (testosterone gel) in postmenopausal women with elevated cardiovascular risk and hypoactive sexual desire disorder. Am Heart J 2012;163:27-32. http://www.ncbi.nlm.nih.gov/pubmed/22172433 

 

Content updated 15 October 2012

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