Testosterone for Low Libido

Abstract & Commentary

By Leon Speroff, MD, Editor, Professor of Obstetrics and Gynecology, Oregon Health and Science University, Portland, is Editor for OB/GYN Clinical Alert.

Synopsis: A randomized, controlled trial concludes that transdermal testosterone at 300 µg per day modestly increases sexuality, but side effects are a concern.

Source: Davis SR, et al; Aphrodite Study Team. Testosterone for low libido in postmenopausal women not taking estrogen. N Engl J Med 2008;359:2005-2017.

Davis and colleagues report the results of a one-year, randomized, controlled clinical trial of 814 women not on estrogen therapy from 65 centers in the United States, Canada, Australia, the United Kingdom, and Sweden with hypoactive sexual desire disorder treated with transdermal testosterone, 150 or 300 µg per day, or placebo. A subgroup was followed for an additional year. This Phase III trial was supported by Proctor & Gamble Pharmaceuticals, maker of the Intrinsa patch, which was applied twice a week. In the 71% of participants who completed 24 weeks, the higher dose of testosterone increased sexuality (including desire, arousal, orgasm, and pleasure) by 1.4 episodes per month compared with placebo. This increase appeared as early as the second month of treatment. The lower dose did not differ from placebo, although both doses significantly increased desire per day. In the higher dose group, 30% reported unwanted androgenic effects (essentially an increase in facial hair). The frequency of acne, alopecia, and voice deepening was the same in all groups. There were 4 cases of breast cancer in the treatment groups and none in the placebo group.

Commentary

Hypoactive sexual desire disorder is defined as a decrease in sexual activity sufficient to cause distress. Previous clinical trials that concluded that the 300 µg transdermal dose of testosterone was effective for low libido consisted of women with either surgical (1172 women) or natural (549 women) menopause who also were being treated with estrogen.1,2 The magnitude of the impact on sexuality in this study was similar to the previous clinical trials with transdermal testosterone.

Pharmacologic levels of testosterone can stimulate sexuality; there is no debate over this. The concern is that this level of testosterone can produce unwanted consequences. There was a 30% incidence of increased facial hair in this trial with the effective dose. In addition, 1 woman in the low-dose group and 3 women in the high-dose group developed clitoral enlargement (the enlargement resolved in the woman receiving the low dose, but not in the high dose women). Remember that the trials with transdermal testosterone have been relatively short in duration. We have no idea what the long-term rate of side effects would be. It is certainly plausible that with longer exposure to the high dose, more and more women would develop androgenic side effects.

In this trial, there was a 10.6% incidence of vaginal bleeding in the women receiving the higher dose who had not undergone hysterectomy, compared with 2.6% in the placebo group and 2.7% in the low-dose group. Was this due to aromatization of testosterone in the endometrium? Furthermore, we already know that in the presence of a uterus, women receiving estrogen therapy plus testosterone still need progestational protection of the endometrium. The numbers and duration of the transdermal testosterone trials have not been sufficient to provide reliable data on this potential risk. There were no cases of endometrial hyperplasia or cancer in this trial, but again, a longer duration of exposure might have unwanted consequences. Two of the treated women had proliferative endometrium, but the authors chose to interpret the bleeding as an atrophying effect of the testosterone on the endometrium. This issue cannot be resolved without long-term data.

Breast cancer also is a concern because of the possibility of local breast tissue aromatization of the testosterone to estrogen. The potential for long-term exposure to unopposed and elevated local concentrations of estrogen continues to be worrisome despite studies that indicate inhibition of breast tissue proliferation by locally applied testosterone. In the 4 treated women who had breast cancer diagnosed in this trial, 1 was diagnosed after only 4 months of treatment and 1 had a bloody nipple discharge before the trial started.

A total of 132 women completed an additional year of follow-up. This left a small number of women in each treatment group, and the report provides no information regarding side effects in these women. The authors acknowledge that numbers and duration were not sufficient to provide long-term data on safety. The long-term effects on the cardiovascular system are unknown.

Response did not correlate with testosterone levels at baseline, and higher levels during treatment did not predict androgenic side effects. This is not surprising because measurement of free and bioavailable testosterone are subject to considerable inaccuracy and variability. For this reason, testosterone levels cannot be used to diagnose hypoactive sexual desire disorder.3 The current trial reports that all testosterone levels remained within the premenopausal ranges. However, the mean level of free testosterone was relatively high at 6.8 pg/mL, although within the reference range. According to the data in the supplemental appendix, available only on-line, the levels were at or above the upper end of the reference age. These are not physiological levels! Isn't the fact that 30% of the women receiving the high dose reported an increase in androgenic effects evidence of a pharmacologic effect? We don't know if it is possible to avoid unwanted consequences by careful monitoring of blood levels.

There is little doubt that the administration of pharmacologic amounts of testosterone can produce favorable effects on sexuality, but it remains doubtful that maintaining testosterone levels within the normal physiologic range can have a beneficial impact on health. Some women receiving pharmacologic amounts of testosterone develop very high circulating levels. The fundamental problem is that the long-term consequences of pharmacologic amounts of testosterone are totally unknown.

I am reluctant to support the pharmacologic use of testosterone given the difficulties in monitoring dosage and the lack of knowledge regarding the long-term effects on health. 17a-methyltestosterone is available in a commercial product, administered orally in combination with estrogen. The available doses are definitely pharmacologic. The problem is that this androgen is not demethylated in the body and cannot be measured by testosterone assays; therefore, it is impossible to monitor dosage. If a clinician and a patient choose to use supplemental androgens, my advice is to select a treatment that can be monitored with measurements of total testosterone in serum. The choices include the testosterone transdermal patch (not yet on the market), a testosterone skin gel (on the market for use in men), and testosterone compounded for individual use by a pharmacist.

We are left with this question: Is a modest increase of 1.4 episodes per month sufficient to offset the unanswered question of long-term safety? Some women would say yes, but the clinician has an obligation to avoid excessive doses and to educate the patient regarding the unanswered questions.

References

  1. Davis SR, et al. Efficacy and safety of a testosterone patch for the treatment of hypoactive sexual desire disorder in surgically menopausal women: A randomized, placebo-controlled trial. Menopause 2006;13:387-396.
  2. Shifren JL, et al. Testosterone patch for the treatment of hypoactive sexual desire disorder in naturally menopausal women: Results from the INTIMATE NM1 Study. Menopause 2006;13:770-779.
  3. Davis SR, et al. Circulating androgen levels and self-reported sexual function in women. JAMA 2005;294:91-96.