This study is the first to investigate the effects of testosterone use over 18 months among HIV-infected women. Similar to other shorter-term studies 6, 10, 11
, we now show that testosterone is well-tolerated over a long treatment period. In addition, we demonstrate that testosterone use among HIV-infected women with relatively low androgen levels, weight and bone density resulted in a significant increase in lean mass, weight, bone density at the hip and trochanter, and improvement in quality of life indices. Prior data demonstrate that low androgen levels are common among HIV-infected women 1, 2, 3, 4
suggesting a sizable population that might benefit from testosterone administration. Low androgen levels are seen among HIV-infected women even in the current era of HAART, as 31/35 women met the criterion for relative androgen deficiency in this study and at least 50% met a definition of relative androgen deficiency in a prior study 6
Subjects randomized to testosterone experienced a significant increase in both free and total testosterone levels without simultaneous effects on estradiol. This suggests that minimal testosterone was aromatized to estrogen, consistent with prior investigations of transdermal testosterone use at this dose 11, 12
. Contrary to the findings of a prior study with the same testosterone dose 6
, transdermal testosterone use in our study had no significant effect on lipid levels, including HDL, and the number of women receiving lipid lowering medications did not differ between treatment groups.
Study related adverse events were similar between groups, without significant differences in hirsutism score, hair pattern, acne or skin irritation, or changes in menstrual pattern. The frequency of adverse events was consistent with that seen in other studies utilizing transdermal testosterone at similar or lower doses in HIV-infected women 1, 11
, and none of the subjects withdrew related to such events, except for one women receiving placebo who withdrew for a change in menstrual pattern. Immune function remained stable.
Testosterone use resulted in a significant increase in lean mass in this long-term study. Prior testosterone treatment studies of a lower dose and/or shorter duration did not show an effect on lean mass among HIV-infected women 1, 3, 6
. A significant effect of testosterone given at the same dose as used in this study was shown in a longer-term study of HIV-negative women, over a 12 month period 11
. We selected patients who were at normal to low weight, and therefore, more likely to have lost lean body mass at baseline. Moreover, we chose patients based on low androgen levels. Indeed, 91% of HIV-infected women screened demonstrated a testosterone level below the cutoff chosen, with mean baseline levels very close to the lower end of the normal range. Women chosen for this study, with relatively low testosterone, may have been more likely to benefit than HIV-infected women with higher androgen levels.
Weight also increased within the testosterone group over 18 months. The women were of stable, relatively low weight at baseline, and the increase in BMI may be related to the increase in lean mass. In addition, this increase in BMI did not adversely affect insulin levels, potentially because subjects were at relatively low weight to begin the study. Indeed, those randomized to testosterone actually demonstrated a significant reduction in fasting glucose compared to placebo over 18 months, suggesting an improvement in overall glucose homeostasis. This improvement may relate to increased muscle mass for glucose disposal, but further studies are needed to verify this effect and determine its mechanism. Caloric intake did not change significantly between the groups over the course of the study.
Our study demonstrates beneficial effects of testosterone on bone density among HIV-infected women. Prior investigations have reported reduced bone density among women with HIV and androgen deficiency 13, 14
, although no study to date has been long enough to examine the effects of testosterone treatment on bone density in this population. Bone density was reduced at all sites among the women in this study at baseline, consistent with prior data demonstrating that HIV-infected women with low androgen levels are at greater risk for bone loss. We demonstrate that testosterone use increased BMD at the hip and tronchanter, though no effect was seen for the lumbar spine. Similar results were seen among non HIV-infected women with hypopituitarism treated with the same testosterone dose for 12 months 11
. These data suggest that cortical, rather than trabecular bone may be more responsive to testosterone administration. Estradiol levels did not increase in response to testosterone, arguing against increased estradiol levels as a mechanism for increased bone density. The effects on bone density may be directly related to the anabolic effects of testosterone on bone 15, 16
or via indirect effects, related to increased lean body mass and weight seen in response to testosterone 13, 14, 17
A significant effect on mood and problems effecting sexual function was seen among those in the testosterone treatment group. At baseline, mean scores on the BDI were consistent with “mild to moderate” depression. A significant improvement was seen in response to testosterone with mean scores suggesting “no or minimal” depression in the testosterone group after 18 months, though individual responses varied. A beneficial effect of testosterone on depression and mood scores was not seen in prior studies of testosterone administration among women with HIV 1
, although a lower dose of testosterone was used for only 6 months. In contrast, a beneficial effect of testosterone administration on mood was reported among androgen deficient women with hypopituitarism over 12 months 11
. In our study, testosterone use resulted in a significant decrease in the number of problems affecting sexual function, though did not have an effect on or other domains present in the questionnaire. Testosterone use in postmenopausal women has also been associated with improvement in some aspects of sexual function, though studies are limited 18
. Other studies of testosterone use (300 mcg) have showed improvement in libido and sexual function among women with bilateral oophorectomy 12
, and also among women with hypopituitarism 11
This study has a number of limitations. Although testosterone was well tolerated over 18 months, without signs of virilization, and patients with low levels were specifically chosen, testosterone levels did rise above the normal range in a number of the subjects. The levels achieved were similar to those reported in the investigator brochure and in the recent study of Davis et al. among non HIV-infected women 19
. Transdermal testosterone administration is not approved for use in the United States. A transdermal testosterone product identical to the one used in this study is approved for the treatment of sexual dysfunction in oophorectomized women in Europe, though is not approved for other indications or for use in HIV infected women. Though these data from a relatively small, but long-term pilot study are very encouraging, the long-term safety of such a strategy needs to be investigated and confirmed in larger studies before it can be recommended clinically. Future studies will need to assess effects of long-term testosterone on risk for breast cancer, endometrial cancer, hirsutism and menstrual pattern. We assessed pregnancy tests frequently in the current study, as testosterone use is potentially harmful to pregnant women.
Women with HIV are known to have reduced bone density, lean body mass, and reduced quality of life. Low androgen levels are common in this population, and may contribute to such changes, yet no treatment strategies exist for women and research investigating gender specific treatment strategies in HIV-infected women has been very limited. In contrast, among male HIV-infected men, treatment of hypogondism is routine and improves body composition, bone and depression 20, 21
. Data from this study suggest that testosterone (300 mcg twice weekly) is well-tolerated over 18 months, and results in significant effects on body composition, BMD, and quality of life indices. Further studies of long-term testosterone are necessary in women with HIV, as this treatment strategy may ultimately prove useful for the large numbers of such women with low androgen levels, bone loss and reduced quality of life.