Testosterone and Sexuality

Abstract & commentary

Source: Shifren JL, et al. Transdermal testosterone treatment in women with impaired sexual function after oophorectomy. N Engl J Med 2000;343:682-688.

Shifren and colleagues report the results of a multi-center trial examining the effect of transdermal testosterone treatment in 75 women who had undergone oophorectomy and hysterectomy. All of the subjects were receiving daily estrogen therapy. They were randomized to placebo and patch treatment with either 150 mg testosterone or 300 mg testosterone daily. Duration of the study was 12 weeks. Outcome measurements were determined for sexual functioning and psychological well-being. Results were available for 65 women after 18 withdrawals. The 300 mg transdermal dose of testosterone was associated with a statistically significant increase in the scores for sexual functioning in the following categories: composite score, frequency of sexual activity, and pleasure-orgasm. The psychological well-being scores significantly increased with the 300 mg dose in the following categories: composite score, depressed mood, and positive well-being. Hirsutism and acne scores did not change during treatment, but one would not expect to see an effect within 12 weeks. There were no significant effects on the lipid profile, but again, this was only a short-term study. Shifren et al concluded that transdermal testosterone improves sexual function and psychological well-being.

Comment by Leon Speroff, MD

For a long time, there has been no doubt that pharmacologic amounts of testosterone can increase sexuality and perhaps psychological well-being in women who have experienced surgical menopause. An important unanswered question has been whether treatment with testosterone to produce relatively normal testosterone levels, that is, normal for reproductive age women, would produce any beneficial effects. Shifren et al concluded that transdermal testosterone improves sexual function and psychological well-being. However, it is clear to me that this observation was limited to the high-dose treatment. Within the paper, Shifrin et al argues that the 300 mg transdermal treatment, the high-dose treatment, increased free testosterone levels to what they called high normal values. This is derived from their interpretation of the free testosterone levels as being within the normal range. Both the 150 mg and 300 mg transdermal treatments increased free testosterone levels. The average free testosterone level with the 150 mg treatment was 3.9 pg/mL, and it was 5.9 pg/mL with the 300 mg transdermal treatment. Total testosterone levels increased to a normal range with the 150 mg dose, but exceeded the normal range of 20-80 ng/dL with the 300 mg dose.

The sexual and psychologic effects achieved with the lower dose, 150 mg, were equal to those achieved with placebo. This emphasizes two things: the need for placebo controls in studies of this nature, and the powerful placebo response most individuals experience.

A statistically significant beneficial effect was demonstrated only with the higher dose that, in my view, produced pharmacological levels of circulating testosterone. The long-term consequences of such levels are at this time unknown, but presumably one would expect an effect on cardiovascular disease. There also exists a concern that aromatization of testosterone within breast tissue might produce exceptionally high estrogen levels and affect the risk of breast cancer. I would expect with time that the higher dose treatment would be associated with a significant percentage of hirsutism and acne. In the discussion, Shifren et al attribute the elevated testosterone levels to the effect of the concomitant treatment with estrogen raising sex hormone-binding globulin (SHBG). However, the increase in free testosterone levels indicates the SHBG effect was overwhelmed by the treatment.

In most women, sexual dysfunction is due to psychological problems. In those women in whom clinician and patient decide testosterone treatment is worthwhile, data thus far indicate that only super physiological testosterone can produce sexuality and psychological effects. In the absence of data on long-term consequences, I am reluctant to promote this pharmacologic use of testosterone. I have used an approach in my own patients in which we agree to monitor testosterone levels and to maintain levels within the normal reproductive range of 20-80 ng/dL. This study would support the contention that treatment associated with those levels is yielding mainly, if not totally, a placebo response. There is nothing wrong with that, especially if the patient is happier, and I am certainly happier in being comfortable that long-term adverse consequences would be less likely at those levels. The transdermal testosterone method of treatment helps provide us with an option that is easily monitored by testosterone levels. (Dr. Speroff is Professor of Obstetrics and Gynecology, Oregon Health sciences University, Portland, Ore.)