Abstract
Evaluation of: Davis SR, Moreau M, Kroll R et al. Testosterone for low libido in postmenopausal women not taking estrogen. N. Engl. J. Med. 359(19), 2005–2017 (2008).
Use of testosterone in older woman with hypoactive sexual-desire disorder (HSDD) is controversial. One concern about existing testosterone therapies for HSDD is the common recommendation to concomitantly administer estradiol because of the known risks of such therapy in postmenopausal women. This large, year-long, double-blind, placebo-controlled trial of testosterone therapy in postmenopausal women examined the hypothesis that testosterone alone would be efficacious in improving HSDD. The results of this trial confirm the improvement in sexual function for postmenopausal women seen in earlier studies using testosterone in combination with estradiol, implying that estradiol administration may not be essential for the beneficial effects of testosterone. However, this study raised some concerns regarding testosterone therapy on the risk of breast and endometrial cancer, highlighting the need for further long-term trials to better assess the long-term safety of this approach for the treatment of HSDD in women.
In November 2008, the New England Journal of Medicine published a large, placebo-controlled, double-blind trial of 814 women with hypoactive sexual-desire disorder (HSDD) randomized to placebo or one of two doses of a daily testosterone patch Citation[1]. HSDD is defined as a deficiency or absence of sexual fantasies and desire for sexual activity that causes marked distress or interpersonal difficulty, and cannot be attributed to another psychological disorder or the effects of a general medical condition Citation[2]. The prevalence in postmenopausal women of low sexual desire alone has been reported to be as high as 50%, but only 8.3% meet the stricter criteria for HSDD Citation[3].
Current therapies for HSDD are limited. Treatment guidelines encourage the use of cognitive–behavioral therapy, mindfulness techniques and sex therapy to address women’s concerns. Testosterone therapy is approved for the treatment of HSDD in some countries, but the US FDA did not approve the testosterone patch, Intrinsa® (by Proctor and Gamble), in part, owing to the relatively limited long-term data on safety. One of the goals of the trial by Davis and colleagues was to provide additional data on the safety of testosterone in postmenopausal women. This study examined surgically or naturally postmenopausal women who were not taking estrogen and the efficacy and safety of testosterone treatment.
Methods
Women from 65 international centers were recruited to participate in this trial. Subjects were postmenopausal for at least 1 year if surgically menopausal, or at least 2 years if naturally menopausal. Women were required to have normal baseline sex hormone-binding globulin levels, a normal mammogram if appropriate to their age, normal Papanicolaou smear, and be in a stable, monogamous relationship with a sexually functional partner. Women had to meet criteria for HSDD based on the criteria in the Diagnostic and Statistical Manual of Mental Disorders (4th Edition) in order to participate Citation[2].
Patients were stratified by hysterectomy status, and then randomly assigned to receive placebo, testosterone 150 or 300 µg per day for 52 weeks. Efficacy was measured through week 24, safety measured through week 52, and patients had the option of continuing their blinded treatment through 104 weeks of follow-up. Efficacy was measured with three different scoring instruments: the weekly Sexual Activity Log, the Profile of Female Sexual Function and the Personal Distress Scale. Adverse events assessed included facial hair growth, facial acne, change in voice, quantity and pattern of scalp hair and patch-site symptoms, as well as breast and endometrial symptoms. Analysis was performed on an intention-to-treat basis.
Results
Over 1300 women were screened and 814 women enrolled. Of the enrolled women, 71% completed 24 weeks of treatment and 57% completed the full 52 weeks of treatment. Drop-out rates were similar among all three groups and the majority discontinued the drug owing to either adverse events or personal choice.
The primary outcome was the change in the number of sexually satisfying events per month during the last month of the efficacy phase. Among women in the 300-µg group, there was a significant increase in number of events compared with placebo (an increase of 2.1 vs 0.7 events/month [p < 0.001]), but a significant increase was not present in women in the 150-µg group. This increase is similar to that reported in other studies of testosterone in postmenopausal women Citation[4,5].
In addition, women in both testosterone groups had significant increases in scores for sexual desire and decreases in scores of personal distress compared with the placebo group. The effect on sexual desire and personal distress scores were similar between women who underwent surgical versus natural menopause. However, the change in the frequency of sexually satisfying events did not increase among women with surgical menopause on either treatment dose, probably owing to low power in this subgroup.
The safety data highlighted several important results. Rates of adverse events were similarly high among all three treatment groups (84.3–87.7%). The most common adverse events were application-site reactions and increased hair growth. More concerning, however, was an increase in vaginal bleeding among women in the 300-µg group compared with the other groups, which affected approximately 10% of women in this group. While most cases were considered mild bleeding, all the women with bleeding required either an endometrial biopsy or a transvaginal ultrasound for evaluation. Two of the women in the 300-µg group were found to have proliferative endometrium but there were no cases of endometrial hyperplasia or carcinoma identified.
In addition, of serious concern were the four cases of breast cancer identified among women in the testosterone-treatment groups. Three cases were diagnosed during the study, one from the 150-µg group and two from the 300-µg group. A fourth case of breast cancer was identified in a patient who completed the extension period and was diagnosed 3 months after study completion. By comparison, there were no cases of breast cancer identified in the placebo group.
Discussion
This study demonstrates that testosterone, without concomitant estradiol therapy, is an effective treatment for postmenopausal women with HSDD. Testosterone therapy has a beneficial impact on the frequency of sexually satisfying episodes, results in improvements in sexual function and decreases in levels of personal distress. Interestingly, the magnitude of the beneficial effect on sexual function is similar to that of earlier trials using combined estrogen and testosterone therapy, implying that estradiol administration may not be necessary for the beneficial effects of testosterone, and arguing against the need for cotreatment, especially in women with relative contraindications to estradiol therapy.
However, the increased number of breast and/or endometrial events observed in the treatment groups in the study is concerning. While the absolute risk of breast cancer among the study subjects was low (0.5% incidence rate), the appearance of four cases in the treatment arms compared with none in the placebo arms is worrisome. Concerns about an increased risk of breast cancer secondary to testosterone therapy have previously been raised in studies of combined estrogen and testosterone therapy Citation[6]. This safety signal could be seen as validating the FDA’s original position that longer studies of women on testosterone therapy were required before this treatment could be approved for nonexperimental use in the USA. In countries where testosterone is already used for HSDD, women need to be made aware of this potential risk.
A plausible mechanism exists to explain why testosterone might increase the risk of breast cancer. Testosterone is aromatized to estradiol in vivo and can, thereby, increase estrogen concentrations. While the serum estradiol concentrations in this study were not markedly different between the treatment and placebo groups, serum estradiol concentrations may not accurately reflect hormone concentrations within the target tissue. Aromatase enzymes are known to be present in breast and endometrial tissues; therefore, if aromatization occurs in situ, serum estradiol concentrations may not accurately reflect tissue estradiol concentrations. Alternatively, testosterone may exert a direct effect on breast tissue as androgen receptors are found on breast cells. However, in vitro data have shown the effect of testosterone to be primarily antiproliferative on breast tissue, not stimulatory Citation[7]. The increase in vaginal bleeding and endometrial proliferation in the treatment groups is also concerning. Unopposed estrogen is known to increase endometrial proliferation and the risk of endometrial cancer, which could be caused by the conversion from testosterone.
Nonhormonal treatments for HSDD are currently under investigation, including other pharmacologic approaches. Transdermal testosterone applied before sex may provide help for women with HSDD, but would avoid prolonged exposure to androgens, thereby minimizing side effects Citation[8]. Other therapies such as selective androgen receptor modulators, serotonin–dopamine agonists or direct application of clitoral stimulation, may also help women with HSDD with potentially fewer risks Citation[9]. Finally, although the prevalence rates of sexual dysfunction are high, it seems that fewer women are severely distressed by their lack of sexual desire than meet diagnostic criteria for HSDD Citation[10]. Therefore, clinicians should discuss whether treatment with a medication is the best approach.
In summary, this study improves our understanding of the relative roles of testosterone and estradiol therapy in the treatment of HSDD. This study demonstrates that testosterone therapy alone can improve sexual function in postmenopausal women with HSDD. However, the study further highlights the concerns that testosterone therapy may pose risks to women with regard to breast and endometrial health. It is likely that more data on the safety of testosterone therapy for HSDD will be required before it will be approved for use outside of research studies in the USA.
Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
References
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- American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (4th Edition). DSM-IV-TR. Washington, DC, USA (2000).
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