Robert A. Wild, MD, PhD, MPH
Davis SR, Moreau M, Kroll R, et al, for the APHRODITE Study Team. Testosterone for low libido in postmenopausal women not taking estrogen. N Engl J Med 2008;359:2005-2017.
Therapy with a testosterone patch placed on the abdomen and delivering 300 µg daily provides some benefit to postmenopausal women with hypoactive sexual desire disorder (HSDD) who are not using estrogen therapy (ET) or estrogen plus progestin therapy (EPT), according to this randomized, double-blind, placebo-controlled study. The Phase III Research Study of Female Sexual Dysfunction of Women on Testosterone without Estrogen was initiated to determine the efficacy and safety of the testosterone patch in postmenopausal women not receiving estrogen who are suffering from HSDD and included women from 65 centers in the United States, Canada, Australia, the United Kingdom, and Sweden. The trial was conducted for 52 weeks and included 814 healthy postmenopausal women (aged 20-70 y) who were randomly assigned to receive a patch delivering either 150 µg or 300 µg testosterone per day or placebo. Participants were seen at baseline and at weeks 6, 12, 24, 36, and 52.
Efficacy was measured through women's responses on a weekly sexual activity log for 24 weeks and their scores on a Profile of Female Sexual Function and a Personal Distress Scale that were completed at baseline and at weeks 12 and 24. Adverse events were assessed at each visit through week 52. Some women continued treatment for a second year to provide additional safety data. The primary endpoint was a change through week 24 in frequency of satisfying sexual episodes over 4 weeks.
Baseline scores for frequency of satisfying sexual events, sexual desire, and distress were similar among groups. By week 24, the increase in 4-week frequency of satisfying events was significantly greater in the group with the 300 µg/day patch, with an increase of 2.1 episodes versus 0.7 episodes for placebo; P < 0.001. There was an increase in satisfying episodes of 1.2 in 4 weeks for the group receiving 150 µg testosterone. Both groups receiving testosterone had significantly increased scores for sexual desire and decreased scores for distress by week 24. The overall incidence of adverse events among groups was similar, with incidence of androgenic events highest in the 300-µg group, mainly increased hair growth. Breast cancer occurred in three women in the testosterone groups by week 52 and in an additional woman receiving hormone in the extension phase.
Commentary by Robert A. Wild, Md, Phd, Mph
Prior clinical trials (typically lasting 3-6 mo) with exogenous testosterone have been well conducted. The majority of trials show modest overall improvement in desire, sexual responsiveness, and frequency of orgasm as well as the number of satisfying sexual episodes (an endpoint required by the Food and Drug Administration [FDA] as evidence of efficacy). The short duration of these trials has worried those concerned about potential for serious adverse effects. Studies have been restricted to postmenopausal women taking ET or EPT.
Here, Davis et al assess testosterone therapy in postmenopausal women presumably estrogen deficient for up to 2 years. Efficacy was shown in women who had natural menopause but not in those with surgically induced menopause (probably because of a lack of statistical power). It is reasonable to ask whether the absolute increase of satisfying sexual episodes of 2.1 per month (1.4 more events per month than in the placebo group) was of value. The article does not indicate whether the women were asked if this was meaningful for them. Baseline data suggest it probably was. The mean number of such episodes almost doubled for the high-dose group (84% vs. 28% for placebo).
All groups had reaction at the application site (49.5%-52.8%, which is high) and various androgenic events (acne, alopecia, and voice deepening in less than 8% of each group). A little more than half in each group completed 52 weeks. Reasons for dropping out are well illustrated. Increased unwanted hair growth was significantly more common with 300 µg of testosterone per day (19.9% vs. 10.5% in the placebo group). Of greater concern are the four cases of breast cancer in the groups receiving testosterone, including one case detected 3 months after the extension period ended, versus zero in the placebo group. This could simply be due to chance, yet it is potentially worrisome and cannot be ignored. Findings suggest the need for caution until we understand more about testosterone's possible link with breast cancer and until we are better able to predict which patients are more likely to have negative effects.
Transdermal testosterone is available in Europe for use in surgically postmenopausal women who have persistent symptoms of HSDD despite adequate nonconjugated ET. However, the FDA in the United States is concerned about potential adverse effects over the long term. Breast cancer risk and potential detrimental lipoprotein physiology with unknown cardiovascular disease risk, as well as androgenic side effects (well documented here), have been the major challenges. The reported lipid profiling in this study is reassuring yet not definitive. Small, dense lipoprotein particle concentrations are a better predictor of events but were not measured. The pharmaceutical industry sponsored and analyzed this multisite study.
Because of a lack of FDA-approved testosterone patches in the United States for women, compounding pharmacy preparations for transdermal testosterone are often prescribed. If this route is chosen, full disclosure of off-label use and documentation of the known and unknown risks is strongly recommended. With the breast cancer concern and the need for studies with large numbers of women enrolled to answer this concern, it is likely that the FDA will continue to be very conservative regarding this issue.
From the NAMS First to Know e-newsletter released December 23, 2008
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