Abstract
Evaluation of: van Anders SM, Chernick AB, Chernick BA et al.: Preliminary clinical experience with androgen administration for pre- and postmenopausal women with hypoactive sexual desire. J. Sex Marital Ther. 31, 173–185 (2005).
There has been significant debate about the potential role of androgens in the treatment of hypoactive sexual desire in women. In this study, pre- and postmenopausal women with hypoactive sexual desire were age-matched with women without such complaints (n = 33). The treatment group received 100 mg of testosterone cypionate intramuscularly once a month for 3 months. Measures of salivary testosterone indicated no difference between groups at baseline, with an increase in testosterone levels in the hypoactive sexual desire group post-treatment. While significant differences existed between the two groups at baseline in scores on the Sexual Desire Inventory, the treated women demonstrated a significant increase in sexual desire post-treatment, with no difference in Sexual Desire Inventory scores at study end point. This study suggests that supplemental testosterone may improve sexual desire in women with hypoactive sexual desire without hypoandrogenism.
Androgens have been proposed to improve libido in women who complain of low sexual desire [1]. However, studies have not clearly documented the serum testosterone level below which low sexual desire might occur and how such numbers might vary with pre- [2] versus postmenopausal status [3]. Studies have not consistently demonstrated a relationship between free testosterone levels and sexual desire through the menopausal transition [4]. However, declines in sexual desire may begin long before the age of 45 years, when most studies evaluating the perimenopause begin. Conflicting reports exist on the relationship between decreased levels of androgens and low sexual desire in women experiencing surgical menopause [5,6]. This discrepancy may be explained by continued androgen production in the adrenals and conversion of prohormones in adipose or other peripheral tissues, inaccurate assays of testosterone levels or sexual function, or differences in the criteria used to define hypoactive sexual desire (HSD). It may be the relationship of sex steroids to each other or the levels of hormones other than testosterone, such as dihydroepiandrosterone sulfate (DHEA-S), that are associated with low sexual desire in women [7]. Studies that have demonstrated improvements in sexual desire with transdermal testosterone in surgically menopausal women have required concomitant use of estrogen replacement [8]. Estrogen may increase levels of sex hormone-binding globulin, which reduces levels of bioavailable testosterone. Thus, estrogen replacement without testosterone (the status of the placebo-treated group) may actually decrease sexual desire by increasing sex hormone-binding globulin and lowering free testosterone [9].
Another issue is the definition of the treatment group. Complaints of low sexual desire are common in the general female population under the age of 60 years, with prevalence rates estimated to be from a quarter to a third of the sample [10]. However, far fewer women meet the criteria for hypoactive sexual desire disorder, which requires persistent diminished or absent sexual fantasies and desire, plus marked associated distress [11]. Different definitions of the study population might lead to significantly different results. In addition, very few published reports have utilized a validated measure of sexual functioning and comparisons across studies are not possible when a different validated instrument has been used in each one. Furthermore, relational factors play a role, and are difficult to control for in a population-based study or clinical trial.
Despite the similarities between men and women in the physiology of sexual function, there have been few studies examining circulating levels of free testosterone in women with and without complaints of low sexual desire, ensuring accuracy of the testosterone assay at physiologic levels in women, establishing the relationship between various sex steroids affecting desire and examining the response to endogenous testosterone in women with free testosterone levels either within the current normal range or in women with hypoandrogenism. This may reflect a bias against the use of androgens in women, or may be the result of low priorities in funding studies of sex differences [12]. Thus, failure to demonstrate a relationship between low testosterone levels and low sexual desire in women should not necessarily limit studies of the effects of supplemental androgens in women with HSD.
Results
Women who presented with complaints of HSD were offered enrollment in the study. Unfortunately, documentation that the criteria for HSD disorder were met was not indicated in the paper. Instead, the reader is left to assume that these women complained of low libido, and that perhaps voicing this complaint or agreeing to participate in the study reflected significant distress. With a total of 33 women completing the study, the numbers in the 4 cells varied from 3 to 14, with postmenopausal women predominating. Salivary testosterone levels were used rather than serum free testosterone levels, with the authors citing high correlations between saliva and serum free testosterone concentrations. Women were excluded if they had a major health condition, sexual dysfunction other than HSD, or were using medications that might lower androgen levels and/or diminish sexual desire, such as hormonal contraceptives, estrogen replacement therapy or psychotropic medications. Dropout from the study was low, at only 4 of 37 subjects. Pre- and postmenopausal, age-matched women without complaints of sexual dysfunction were recruited when they presented for their annual pelvic examination.
Open-label treatment with monthly intramuscular testosterone cypionate 100 mg in oil was administered for 3 consecutive months in the women with HSD. Saliva samples for testosterone levels were collected in the HSD women at baseline, at the time of the first and third androgen injections and 1 month after the third injection. The reference subjects provided saliva for assay at corresponding time points in the 3-month study period, two pretreatment and two post-treatment, at consistent times during the menstrual cycle in the premenopausal women. Most of the samples were collected between 8:30 am and 9:45 am, before eating, drinking or smoking, and after rinsing the mouth with water. All specimens were assayed in duplicate, with the values reported representing the mean of the duplicate samples. The Sexual Desire Inventory [13], a validated instrument, plus one additional question on the frequency of sexual thoughts in the preceding month, was completed by the women at baseline and at the study end point.
Results of the testosterone assay revealed no difference in pretreatment means, but significantly higher levels in the HSD women post-treatment compared with pretreatment values for their group, and compared with the post-treatment mean for the reference group. Sexual desire did not change across the study in the reference group. HSD women had lower desire as indicated by Sexual Desire Inventory scores at pretreatment measures than post-treatment, and when compared with the pretreatment scores for the reference group. There were no differences in sexual desire between the two groups at the post-treatment measurements. The desire for self- stimulation and partnered sexual activity was equivalent between the two groups following treatment. Premenopausal women with HSD demonstrated a larger increase in sexual desire than did postmenopausal HSD women, and had a greater interest in partnered sexual activity.
Significance of the results
The results demonstrate improvement in sexual desire with the administration of supplemental testosterone in women with HSD, both from their baseline and in comparison to women without sexual desire complaints. Surprisingly, this change was greater in premenopausal women, who have higher androgen levels than postmenopausal women. In addition, this benefit occurred in women whose testosterone levels at baseline did not differ from those of women without HSD and were considered within the normal range. Furthermore, the testosterone improved sexual desire in the HSD women to the point where they could not be distinguished from the reference group women on a measure of sexual desire. It appears that multiple factors may influence the onset of diminished sexual desire. As such, hypoandrogenism should not be a requirement for further studies of testosterone supplementation in women with HSD.
Reviewer's perspective
Further studies are needed to establish the normal range of testosterone levels in women at different ages, the relationship between levels of sex steroids and sexual desire, and the response to supplemental androgens in women with HSD. Salivary testosterone levels may allow for measurements of androgen status in large populations of women, and for repeated measures that might better define the range of normal levels within a specific group (for example, premenopausal women aged 20–30, women who are within 2–5 years following cessation of menses etc.). Larger, double-blind, placebo-controlled trials of androgen supplementation via different routes (i.e., intramuscular, transdermal, inhaled) and of different hormones or formulations are also necessary. Bias and fear should not limit the options offered to women who are distressed by their level of sexual desire.