Twenty-eight days of topical testosterone was associated with improved symptoms of vaginal atrophy in 20 women on AIs without raising estradiol levels. Clinical improvement waned but was not lost 1 month after therapy. The treatment was well tolerated. This is an important finding because vaginal atrophy is common among patients on AI therapy and current treatment strategies are either ineffective or pose potential risks.
The literature on the use of topical testosterone by women on AIs is limited. Recent reports support the use of androgens and testosterone in women with vaginal atrophy and research is ongoing into the effectiveness of pilocarpine, a nonselective muscarinic receptor agonist [32
]. A recently completed trial of intravaginal dehydroepiandrosterone (Prasterone) showed an effect on vaginal atrophy without elevation of estradiol or testosterone above usual postmenopausal levels [37
]. Preliminary results from one study of vaginal testosterone in women on AIs are available [30
]. Testosterone was applied at a dose of 500 μg daily for 2 weeks then three times per week for 10 weeks, which improved vaginal atrophy and sexual function. This supports our result on the clinical effectiveness of testosterone. However, modest elevations in estradiol were noted in some patients, even after treatment ceased. This underscores the importance of finding the lowest effective dose of testosterone in this population.
The lowest effective dose of testosterone is also important for its effect on serum testosterone levels. Although the association between testosterone therapy and elevated serum testosterone levels on initial and recurrent breast cancer risk is controversial, the elevation in testosterone levels in several patients in this study is concerning. The most significant increase in serum testosterone occurred in our first patient. Modifications in the application of the cream mediated levels and subsequent patients had either no or small increases in serum testosterone. Several studies suggest that a possible greater breast cancer risk associated with testosterone is indirectly mediated by greater conversion to estrogen. This would theoretically not occur in the presence of aromatase inhibition; however, other studies suggest that this effect is mediated directly by testosterone, which would not be countered by aromatase inhibition. Observational and case–control studies reviewing the association of higher levels of serum testosterone with more frequent and recurrent breast cancer diagnoses are conflicting [38
]. Testosterone prescribed for low libido is associated with a higher risk for an initial breast cancer diagnosis in some, but not all, studies [45
]. Data on testosterone levels in patients on AIs are lacking. Thus, it is prudent to closely monitor the effects of this treatment on serum testosterone in future studies of testosterone in this population.
The main limitation of this study is the lack of concurrent controls, which leaves our findings vulnerable to regression to the mean. The recruitment of subjects was not systematic, which may limit the generalization of this small sample of patients to other populations. Without concurrent controls, it is also not possible to judge how much effect was related to the cream base as opposed to the testosterone alone. Future studies will be randomized with a control arm of the cream or Replens® moisturizer.
One of the strengths of our study is the consistency of findings across a variety of measurements. Although the self-reported symptoms are subjective, they are supported by the pathologic improvement seen in the blinded comparison of vaginal cytology. The pathologic correlates of pH and the maturation index only improved significantly in the cohort on 300 μg testosterone. Interestingly, despite the lack of a pathologic response at the lower dose, there was no difference in symptom outcomes at the different doses of testosterone studied. Given the equivalent effect on symptoms, use of the lower dose may be prudent. Alternatively, the effect of the higher dose on the thinness of the vaginal epithelium may be associated with greater effectiveness, similar to the difference between symptom improvement with topical estrogens, which reverse the cytologic changes of vaginal atrophy, and with Replens, which does not [8
Our findings are preliminary and require confirmation in controlled studies before clinical recommendations can be made. The doses in this study, however, provide a reasonable starting point for further testing because we were able to demonstrate clinical efficacy and tolerance in this small cohort of subjects.