How women may benefit from bioidentical testosterone therapy

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[h=1]Testosterone Supplementation for Hypoactive Sexual Desire Disorder in Women[/h]C. Brock Woodis, Pharm.D, Amber N. McLendon, Pharm.D., Andrew J. Muzyk, Pharm.D.
Pharmacotherapy. 2012;32(1):38-53.
[h=3]Abstract and Introduction[/h] [h=4]Abstract[/h] Over 50% of women are believed to be affected by female sexual dysfunction (FSD). When particularly distressful, FSD is known as hypoactive sexual desire disorder (HSDD). In contrast to male sexual dysfunction that has been extensively researched, there is less evidence addressing the treatment of HSDD in women, particularly with regard to the use of androgen therapy. A variety of testosterone products, including oral, injectable, and transdermal preparations, has been prescribed for the treatment of HSDD in premenopausal women, as well as in those with naturally occurring or surgically induced menopause. Although studies have shown some benefit with testosterone supplementation in women with HSDD, conflicting evidence and debate regarding the clinical efficacy of testosterone remain. Because of concern over potential adverse events, additional studies with longer follow-up periods are necessary before use of testosterone in women with HSDD becomes widespread. Initiation of testosterone therapy must be considered on an individual basis after a thorough discussion with the patient about risks and benefits.
[h=4]Introduction[/h] Previous reports have estimated that by the year 2030, 1.2 billion women worldwide will be either menopausal or postmenopausal.[SUP][1][/SUP] Low libido has been a complaint routinely voiced by menopausal women, and current reports cite that 16 million women older than 50 years experience low sexual desire.[SUP][2][/SUP] Furthermore, female sexual dysfunction (FSD) is believed to affect over 50% of women.[SUP][3][/SUP] Female sexual dysfunction is a loss of desire for sexual activity that, in turn, causes significant distress and possible strain on interpersonal relationships. Diminished sexual arousal, dyspareunia, and difficulty achieving orgasm are also characteristics of FSD.[SUP][4, 5][/SUP] Hypoactive sexual desire disorder (HSDD) is the most common form of FSD and is characterized by low sexual desire that has become particularly distressful; HSDD is believed to affect approximately 1 out of 10 adult women in the United States.[SUP][6][/SUP]
Historically, the treatment of male sexual dysfunction has been addressed and investigated, but pharmacotherapeutic treatment for FSD has been somewhat controversial, and supporting evidence has been limited. Several pharmacologic options with varying levels of evidence exist for the treatment of HSDD in women, and the use of supplemental testosterone in some women has shown benefit, particularly by improving desire, responsiveness, orgasm, arousal, and satisfaction.[SUP][7][/SUP]
[h=3]Pathophysiology of Hypoactive Sexual Desire Disorder[/h] Understanding of the female sexual response has evolved since Masters and Johnson first introduced their model in the mid-1960s.[SUP][8][/SUP] Masters and Johnson characterized sexual response in four stages: excitement, plateau, orgasm, and resolution. Subsequent models, however, incorporated emotions and desires as well as response to sexual stimuli and intimacy. In addition, researchers have begun to better understand the influence of biologic factors on a woman's physical and psychological response to sex.[SUP][7-9][/SUP]
The pathophysiology underlying a woman's sexual response involves various regions of the brain, multiple neurotransmitters, sex hormones, and endogenous opioids, although the focal point for this response is the ventral tegmental area and its dopaminergic pathways.[SUP][7, 10, 11][/SUP] Following the efferent projections from the ventral tegmental area to other regions of the brain, mainly by means of the mesolimbic and mesocortical pathways, a clearer understanding of the interplay between the neurochemical and physical and psychologic responses to sex becomes apparent. The mesolimbic pathway innervates the limbic area structures, such as the nucleus accumbens, amygdala, hypothalamus, and hippocampus, connecting sexual response to emotional behavior, pleasure, reward, and memory.[SUP][12-14][/SUP] A study that used magnetic resonance imaging to compare women who had a diagnosis of HSDD with women who had no history of sexual dysfunction reported a decrease in response to erotic imagery and decreased ability in storage and retrieval of past sexual experiences in the women with HSDD.[SUP][15][/SUP] The results from this study suggest a hyperinhibition of dopamine reward pathways causing a lack of enjoyment to sexual stimuli.[SUP][10][/SUP]
The mesocortical pathway with projections to the prefrontal cortex integrates higher executive function processes, such as planning and decision making, into one's sexual emotions and mood.[SUP][12-14][/SUP] Support for dopamine's involvement in sexual response is found in the adverse-effect profiles of drugs that affect dopamine neurotransmission. Drugs that disrupt dopamine neurotransmission (e.g., antipsychotics) reduce sexual behaviors,[SUP][11, 16][/SUP] whereas those that improve dopamine neurotransmission (e.g., dopamine agonists or levodopa) are associated with increased sexual excitement and arousal.[SUP][11][/SUP]
However, the ventral tegmental area and its dopaminergic pathways do not exist as a closed system, receiving input from other neurotransmitters and sex hormones. Of these additional pathways involved in sexual response, the direct effect of serotonin (5-HT) on dopamine release may be the most important. Serotonin, released from neurons originating in the raphe nucleus, acts at postsynaptic 5-HT receptors located on various neurons, including dopamine neurons.[SUP][13, 14][/SUP] Stimulation of 5-HT[SUB]2A[/SUB] receptors located on dopamine neurons results in an inhibition of dopamine release.[SUP][10, 13][/SUP] This inhibitory effect of serotonin produces a state of "sexual satiety," which is necessary for body recuperation after sexual intercourse.[SUP][14][/SUP] However, a dysfunctional interaction between serotonin and dopamine, especially in the mesolimbic and mesocortical pathways, can greatly reduce sexual desire and pleasure. Serotonin neurons also directly innervate other brain regions involved in sexual response and descend down the spinal cord affecting spinal cord reflexes involved in achieving an orgasm.[SUP][13][/SUP]
A model to understand the role of serotonin on sexual function exists with the selective serotonin reuptake inhibitors (SSRIs). The SSRIs potently block serotonin reuptake from the synapse causing excessive serotonin to stimulate postsynaptic 5-HT receptors. This mechanism is necessary to improve depressive symptoms, but it can cause adverse effects such as sexual dysfunction.[SUP][11, 16][/SUP] Theoretically, a drug that stimulates 5-HT[SUB]1A[/SUB] receptors while antagonizing 5-HT[SUB]2A[/SUB] receptors would increase sexual response.[SUP][17, 18][/SUP]
The main role of sex hormones (testosterone, estrogen, and progesterone) may be to prime the body for sexual activity through a direct effect on neurotransmitters involved in sexual response.[SUP][14][/SUP] Low levels of estrogen (i.e., < 50 pg/ml) have been associated with a reduction in genital sensation and low vaginal lubrication, resulting in dyspareunia and a decrease in sexual desire and pleasure.[SUP][19, 20][/SUP] Estrogen replacement in postmenopausal women improves these measures.[SUP][21][/SUP] Studies of women throughout their ovulation cycle demonstrate an increased response to sexual stimuli in the follicular phase.[SUP][14, 22][/SUP]
Historically, androgen insufficiency (specifically testosterone) has been thought to be involved with sexual arousal, genital sensation, libido, and orgasm.[SUP][23-25][/SUP] The ovaries are responsible for roughly 50% of circulating testosterone, whereas peripheral conversion of adrenal precursors accounts for the remaining half.[SUP][23][/SUP] This peripheral conversion from dehydroepiandrosterone (DHEA) to testosterone is difficult to measure, and therefore obtaining free testosterone levels in women has not proved beneficial in treating HSDD.
Low circulating levels of testosterone in women may produce a similar decrease in sexual desire to that of patients with a diagnosis of androgen deficiency.[SUP][22][/SUP] Evidence for this direct relationship between low testosterone and diminished libido is supported in a study of 100 women taking four different low-dose progestin-containing oral contraceptives: ethinyl estradiol and norgestimate, ethinyl estradiol and gestodene, ethinyl estradiol and desogestrel, or ethinyl estradiol and desogestrel.[SUP][26][/SUP] The authors reported there was a reduction in all androgen parameters measured, including testosterone, free (unbound) testosterone, 5α-dihydrotestosterone, DHEA sulfate, and androstenedione, producing environmental changes in these women toward hypoandrogenism.
Sex hormones may also affect the release of vaginal nitric oxide synthase, an enzyme responsible for the production of nitric oxide.[SUP][25, 27][/SUP] In turn, nitric oxide promotes the production of cyclic guanosine monophosphate, leading to an increase in vaginal and clitoral muscle tone and relaxation. Sex hormones may also potentiate the function of norepinephrine and the neuropeptides melanocotrin and oxytocin in sexual response.[SUP][10, 14][/SUP] Although the exact role of norepinephrine remains unclear, its main role may be to arouse the body for sexual activity.[SUP][10][/SUP] Estradiol has been shown to enhance noradrenergic transmission.[SUP][14, 19][/SUP] The two neuropeptides are involved in sexual desire, arousal, and partner bonding.[SUP][10, 14][/SUP]
The last main component in sexual response is the role of endogenous opioids and cannabinoids.[SUP][14, 18][/SUP] These endogenous opioids and cannabinoids provide reward associated with sexual desire and intercourse. These chemicals also produce a state of sexual satiety after orgasm, which causes a dramatic decline in sexual desire and arousal.[SUP][14][/SUP]
[h=3]Medical Examination and Laboratory Work-up[/h] Each woman presenting with symptoms of HSDD should have a thorough examination to identify the underlying cause of her symptoms. The clinical evaluation should be composed of a psychosexual assessment, diagnostic assessment, medical history, physical and pelvic examination, and laboratory evaluation.[SUP][20, 22][/SUP]
A psychosexual assessment should probe for sexual abuse, quality of sexual relationship with a partner, sexual knowledge, and any stressors.[SUP][20, 21][/SUP] The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) lists the diagnostic criteria for HSDD as the following: persistently or recurrently deficient or absent sexual fantasies and desire for sexual activity; the disturbance causes marked distress or interpersonal difficulty.[SUP][28][/SUP] It is important to note that the HSDD cannot be attributed to either a psychiatric reason or to a drug or disease.[SUP][27][/SUP] Several diagnostic tools have been created to help screen for HSDD during physician visits. One of the more commonly used is the Decreased Sexual Desire Screener (DSDS). The DSDS is a validated brief screening tool that allows for assessment of HSDD by primary care clinicians.[SUP][29][/SUP] The DSDS contains four "yes/no" questions and a fifth compound question. An affirmative answer to any of the five questions should alert the clinician to discussing HSDD with the patient.
A review of a patient's medical history should screen for surgeries, medical disorders, and drugs that can cause a decrease in sexual interest and pleasure.[SUP][30][/SUP] Diabetes mellitus, cardiovascular disease, and psychiatric disorders are common illnesses that may cause sexual dysfunction.[SUP][21, 30][/SUP] In addition, the drugs used for these medical illnesses (e.g., antihypertensives, antidepressants, antipsychotics, antiepileptics, and anticholinergics) can also cause sexual dysfunction.[SUP][22][/SUP]
A gynecologic examination of a woman with a diagnosis of HSDD should evaluate the following: tone and control of pelvic floor muscles, vaginal atrophy, vaginal wall prolapse, presence of discharge, infection, epithelial disorders, and pain.[SUP][30][/SUP] A common laboratory work-up should include a basic metabolic panel, complete blood count, lipid panel, and thyroid panel.[SUP][20][/SUP] A detailed hormonal profile—follicle-stimulating hormone, luteinizing hormone, prolactin, total and free testosterone, serum hormone binding globulin, and estradiol levels—should be performed when clinically indicated.[SUP][20][/SUP]
[h=3]Treatment Options and Testosterone Literature Review[/h] Both nonpharmacologic and pharmacologic treatment options exist for HSDD. Psychotherapy is one possible nonphysical intervention available. This may include both basic counseling involving active listening, interrogation, and education, as well as cognitive behavioral therapy.[SUP][31][/SUP]
Current pharmacologic options include combinations of oral esterified estrogens and methyltestosterone, off-label use of testosterone products that have been used in men, and specialty compounded products. In addition, certain alternative therapies including ginkgo biloba, ginseng, L-arginine, and DHEA have been used historically in women with FSD, although limited data exist regarding effectiveness and long-term safety.[SUP][32][/SUP] Since androgen therapy (specifically testosterone) is one of the primary treatments for female HSDD used in clinical practice and is the focus of this review, additional treatment modalities will not be addressed further.
Testosterone therapy for use in women with diminished sexual desire has been evaluated in multiple clinical trials over the past several decades. summarizes the trials of oral, injectable, and transdermal testosterone therapies discussed in this article.[SUP][33–61][/SUP] Outcomes regarding sexual function are discussed first, followed by a discussion of specific adverse events.
[h=4]Table 1. Efficacy of Testosterone for the Treatment of Hypoactive Sexual Desire Disorder in Women[/h] ↑ = increase; ↓ = decrease; CEE=conjugated equine estrogens; HSDD=hypoactive sexual desire disorder; INTIMATE SM=Investigation of Natural Testosterone in Menopausal Women Also Taking Estrogen in Surgically Menopausal Women; CI=confidence interval.

[h=3]Effects of Testosterone Treatment on Sexual Function[/h] [h=4]Oral Testosterone[/h] The impact of testosterone treatment on sexual dysfunction was first described in the 1950s in studies of postmenopausal women who received testosterone in combination with estrogen.[SUP][33, 34][/SUP] Although sexual function was not a primary outcome of these trials, improved libido was self-reported by 23–42% of the subjects (significance not reported). Studies performed in the 1980s and 1990s further elucidated the role of testosterone therapy in female sexual behavior.
One of the earliest trials evaluating testosterone use in women was conducted in 40 naturally postmenopausal women randomly assigned to one of the following oral preparations: testosterone and estrogen combination (10 women), progesterone and estrogen combination (10), estrogen alone (10), and placebo (10).[SUP][35][/SUP] Participants were asked to keep a daily log for 10 weeks and quantify the number of times they experienced sexual desire, sexual thoughts, or sexual intercourse, and to participate in six laboratory sessions in which vaginal blood flow was measured. Testosterone treatment did not result in a significant change from baseline in vaginal blood flow or self-reports of sexual behavior; however, a significant difference for pleasure from masturbation was noted for women receiving the testosterone and estrogen combination compared with the other estrogen and placebo groups (p<0.046).
Another trial compared oral estrogens alone with the combination of estrogen and testosterone (esterified estrogens 1.25 mg and methyltestosterone 2.5 mg once/day) in 20 postmenopausal women taking estrogen at baseline.[SUP][36][/SUP] Objective sexual arousal was measured by using vaginal blood flow velocity and fingertip blood flow. This study did not find a significant impact of testosterone on either vaginal or fingertip blood flow velocity. However, a study of eight premenopausal women receiving a single dose of sublingual testosterone undeconate 0.5 mg in a double-blind, randomized, placebo-controlled, crossover design demonstrated increased vaginal blood flow (p=0.04), self-reported sensations (p=0.02) and sexual lust (p=0.01) on a visual analog scale within 5 hours of the testosterone dose.[SUP][37][/SUP] A small crossover trial in 10 postmenopausal women without sexual dysfunction demonstrated a benefit for methyltestosterone 5 mg on genital sexual response with increased vaginal blood flow 4.5 hours after the dose (p=0.03).[SUP][38][/SUP] However, the women did not report a subjective increase in sexual response with testosterone.
Although objective measurements of vaginal blood flow are useful in the evaluation of sexual behavior, these measurements are not currently used for diagnosis of HSDD Subjective reports offer more valuable information at this time as they correlate most closely with HSDD diagnosis and symptoms.
Testosterone has rarely been evaluated alone in postmenopausal women but has been investigated in several studies as an addition to estrogen therapy. Twenty postmenopausal women with menopausal or sexual symptoms unrelieved by estrogen were enrolled in a small, randomized, double-blind, parallel-group study to evaluate the effects of testosterone in addition to estrogen therapy.[SUP][39][/SUP] Participants were randomly assigned to either esterified estrogens 1.25 mg/day or estrogen plus methyltestosterone 2.5 mg/day for 8 weeks. The Sexual Activity and Libido Scale (11 questions) was completed weekly by each subject. This scale evaluates vaginal dryness, sexual desire, pain with intercourse, clitoral sensation, and sensitivity on a scale from 0–4; vaginal moisture, orgasm, sexual fantasy, sexual response in the last 24 hours as yes or no; and sexual intercourse as none, once, twice, 3 times, or 4 or more times/week. Sexual desire and clitoral sensation were significantly increased (p<0.01) from baseline at 8 weeks in the testosterone group. The frequency of sexual activity was significantly increased at week 4; however, this increase was no longer observed at 8 weeks.
A longer (16-wk), double-blind, randomized, parallel-group study comparing esterified estrogens 1.25 mg/day (19 women) with estrogen plus methyltestosterone 2.5 mg/day (18 women) was conducted to determine effects on fat and muscle mass and muscle strength.[SUP][40][/SUP] Sexual function was evaluated as a secondary objective by using three self-report questionnaires: the Brief Index of Sexual Functioning for Women ([BISF-W] 22 items of quantitative and qualitative data), Sabbatsberg Revised Sexual Self-Rating Scale (SRS), and the Sexual Interest Questionnaire ([SIQ] 10 items on a 7-point scale). A significant change from baseline was noted on each scale in the estrogen-testosterone group. A significant increase for pleasure/orgasm (p=0.041) was noted on the BISF-W and for interest in sex (p=0.014) on the SIQ scale in the estrogen-testosterone group.
Sexual function was the primary outcome in one crossover study involving 50 women with surgically induced menopause who were randomly assigned to estradiol 2 mg/day or estradiol and testosterone undecanoate 40 mg/day.[SUP][41][/SUP] McCoy's sex scale questionnaire, a 14-item scale evaluating the previous 30 days, was used to compare sexual function at baseline and after 6 months of treatment. No significant difference was found between treatment groups for lubrication, pain with intercourse, interest in sex, or sexual thoughts and fantasies. Although significant improvement from baseline was noted in the testosterone group on enjoyment (p<0.001), satisfaction with frequency of sexual activity (p<0.01), arousal (p<0.01), frequency (p<0.01) and satisfaction of orgasm (p<0.05), and feeling of attractiveness to partner (p<0.05), only the domains of enjoyment (p<0.05), satisfaction with frequency (p<0.05), and interest in sex (p<0.05) were significantly improved in the testosterone group compared with the other groups.
In 2003, testosterone was first investigated for use in women with HSDD, although the diagnosis was not determined by using DSM-IV-TR criteria.[SUP][42][/SUP] Hypoactive sexual desire was determined by using the BISF-W. Postmenopausal women previously taking estrogen were randomly assigned to either oral esterified estrogens 0.625 mg/day (111 women) or oral esterified estrogens plus methyltestosterone 1.25 mg/day (107 women) once/day for 4 months. Sexual outcomes were evaluated by using the SIQ. Women receiving the formulation with testosterone reported a significant increase in responsiveness (mean score 3.3 ± 5.6), which was more than twice that of women taking estrogen alone (1.3 ± 4.7, p=0.002). Sexual interest or desire (2.8 ± 1.6 vs 2.4 ± 1.4, p=0.05) and frequency of desire (p<0.01) were also greater in the testosterone combination group, with an increase noted at 4 weeks of therapy and maintained throughout 16 weeks. This study further solidified the role of testosterone in increasing sexual motivation in women with lack of sexual interest or desire.
[h=4]Injectable Testosterone[/h] In 1984, an implant of estradiol 40 mg and testosterone 100 mg was used in a small pilot study for 6 months in 17 postmenopausal women with decreased libido while taking oral estrogen.[SUP][43][/SUP] The testosterone implant demonstrated an improvement from baseline on self-reported libido and enjoyment of sex. At baseline, 94% of women reported absent or reduced libido compared with 43% of women 3 months after testosterone implantation (p<0.01). All women reported absent or reduced enjoyment of sex at baseline compared with 29% of women after 3 months (p<0.01). The effects returned to baseline levels 4 months after implantation. A placebo effect could not be ruled out due to the lack of a control group, but a follow-up study was published in 1987.[SUP][44][/SUP] This small 6-month study of 20 postmenopausal women with decreased libido while taking estrogen evaluated the effect of an estradiol 40 mg–testosterone 50-mg implant compared with estrogen alone and repeated the results of the pilot study with a significant effect of testosterone on self-reported libido (p<0.01) and enjoyment of sex (p<0.01). Sexual symptoms were rated by using a visual analog scale from 0–100. Across both trials, one woman reported hirsutism and weight gain, but no other significant adverse events were reported.
In 1985, another group of researchers also investigated the effect of testosterone on sexual function in women with surgically induced menopause.[SUP][45][/SUP] This small (54 women) crossover study compared intramuscular injections of hormonal preparations of testosterone 200 mg versus estrogen 10 mg versus estrogen 8.5 mg combined with testosterone 150 mg versus placebo once/month for 3 months. Both testosterone groups showed significant improvement in sexual desire (p<0.001), intensity of arousal (p<0.001), and frequency of sexual fantasies (p<0.01), as reported on the Daily Menopausal Rating Scale (DMRS) from 0–7. However, frequency of sex and orgasms were not significantly affected by testosterone, indicating testosterone affects the psychological aspects of sex rather than physical aspects. A follow-up study published in 1987 evaluated the impact of an estrogen 8.5 mg–testosterone 150 mg combination (22 women) versus estrogen 10 mg (11) and placebo (11) in women who had been receiving hormones once/month since their hysterectomy and oophorectomy 4 years earlier.[SUP][46][/SUP] Women who received the combination with testosterone reported significantly more sexual desire (p<0.01), arousal (p<0.01), fantasies (p<0.01), and coitus and orgasm (p<0.01) on the DMRS than women who received estrogen alone or placebo. The largest increase in coitus and orgasm was reported within the first 2 weeks of the estrogen-testosterone injection and decreased the following 2 weeks before the next injection. This suggests that the physical acts of sex may correlate with testosterone levels.
In 1995, an evaluation of a testosterone 50 mg– estradiol 50 mg implant (17 women) versus an estradiol 50 mg implant alone (16 women) every 3 months for 2 years in postmenopausal women was reported.[SUP][47][/SUP] Women who received the combination treatment with testosterone reported increased orgasm (p<0.035), sexual satisfaction (p<0.03), and sexual activity (p<0.03) on the SRS compared with women who received estrogen alone, demonstrating long-term effects for testosterone on sexual desire and function.
[h=4]Transdermal Testosterone[/h] Transdermal testosterone has been evaluated over the last decade for treatment of sexual dysfunction in women. A randomized, double-blind, placebo-controlled, crossover trial evaluated the use of transdermal testosterone for surgically induced postmenopausal women with low testosterone levels and decreased sexual desire.[SUP][48][/SUP] Seventy-five women with surgically induced menopause were randomly assigned to placebo, testosterone 150 μg/day patch applied twice/week and testosterone 300 μg/day patch applied twice/week for 12 weeks in addition to oral estrogen. The placebo group was noted to have an increase in the overall BISF-W score from 52 ± 27% of normal to 72 ± 38% over 12 weeks. The investigators determined that the transdermal testosterone 300-μg/day group had significantly improved frequency of sexual activity (p=0.03) and orgasm (p=0.03) on the BISF-W, but the 150-μg/day group did not differ significantly from the placebo group. This study indicates women with low testosterone levels have a positive physical sexual response to exogenous testosterone.
The testosterone patch was further evaluated in 447 surgically induced postmenopausal women with HSDD who were taking estrogen.[SUP][49][/SUP] HSDD was assessed using questions that compared sexual desire before and after menopause and an interest in increasing sexual activity. Women were randomly assigned to placebo (119 women) or testosterone patch 150 μg/day (107 women), 300 μg/day (110 women), or 450 μg/day (111 women) twice/week applied to the abdomen in a double-blind, parallel-group trial. Sexual function was evaluated on the Profile of Female Sexual Function ([PFSF], 37 items covering seven domains, scored 0–100 for each domain), which was validated in postmenopausal women with low sexual desire. At a dose of 300 μg/day over a period of 6 months, transdermal testosterone increased the frequency by 0.58 satisfying sexual episodes/week (p=0.049). The number of sexual events (p=0.01) and orgasms (p=0.02) on the PFSF were also increased along with desire (p<0.049) and arousal (p<0.04). The sexual desire score increased 67% from baseline in the 300-μg/day group compared with 48% in the placebo group. The other active groups did not demonstrate a significant change compared with placebo. These results demonstrate a positive effect on both the psychologic and physical aspects of sex with 300 μg/day of transdermal testosterone.
Further studies of the 300-μg/day testosterone patch in surgically induced postmenopausal women with HSDD demonstrated a benefit for testosterone on increasing total satisfying sexual activity by 1.5 (p=0.001) to 2 (p=0.0003) events over 4 weeks compared with placebo, although one study did not demonstrate an increase.[SUP][50-52][/SUP] Significant benefit was also demonstrated for other aspects of HSDD, including improved self-image, decreased personal distress, decreased concerns, and increased responsiveness. The studies also confirmed previous significant results indicating an increase of arousal, pleasure, desire, sexual activity, and orgasm ( ).
[h=4]Table 1. Efficacy of Testosterone for the Treatment of Hypoactive Sexual Desire Disorder in Women[/h] ↑ = increase; ↓ = decrease; CEE=conjugated equine estrogens; HSDD=hypoactive sexual desire disorder; INTIMATE SM=Investigation of Natural Testosterone in Menopausal Women Also Taking Estrogen in Surgically Menopausal Women; CI=confidence interval.

A phase III trial of the 300-μg/day testosterone patch was conducted in surgically induced postmenopausal women with HSDD.[SUP][53][/SUP] When asked if they found a "meaningful benefit" from the testosterone patch, 33 (52%) of 64 women who received the active patch reported "yes" compared with 21 (31%) of 68 women receiving placebo (p=0.025). The women also reported increased desire (p=0.041) and activity (p=0.011) and decreased personal distress (p<0.001 ).
Two additional studies that evaluated the efficacy and safety of transdermal testosterone in women who had undergone surgically induced menopause and also had HSDD were the Investigation of Natural Testosterone in Menopausal Women Also Taking Estrogen in Surgically Menopausal Women (INTIMATE SM) 1 and 2 trials.[SUP][54][/SUP] The INTIMATE SM 1 and 2 trials were conducted in the United States, Canada, and Australia, and both were 32 weeks in duration. Patients received either testosterone 300-μg patches twice/week (562 women in INTIMATE SM 1 and 532 women in INTIMATE SM 2) or placebo. The primary efficacy measure was the change in the frequency of total satisfying sexual activity over 24 weeks as assessed by means of the Sexual Activity Log (SAL). A significant increase in total satisfying sexual activity at 24 weeks was seen in both trials, with INITIMATE SM 1 showing a mean increase of 2.10 sexually satisfying event episodes/4 weeks with testosterone versus 0.98 events/4 weeks with placebo (p=0.0003), whereas INTIMATE SM 2 reported 1.56 and 0.73 episodes/4 weeks in the testosterone and placebo groups, respectively (p=0.001). Skin site reactions were the most commonly reported adverse effects.
In 2008, the use of transdermal testosterone for HSDD was reported in postmenopausal women who were not receiving concomitant estrogen.[SUP][55][/SUP] The Phase III Research Study of Female Sexual Dysfunction in Women on Testosterone Patch without Estrogen (APHRODITE) was a double-blind, randomized, placebo-controlled study that included both surgically induced menopausal women (aged 20–70 yrs) and women who entered menopause naturally (ages 40–70 yrs and had to be at least 2 yrs postmenopausal). Of the 814 patients who underwent randomization, the increase in the 4-week frequency of sexually satisfying episodes was significantly greater in the patients receiving 300 μg of testosterone (270 women, but three did not receive testosterone) versus placebo (277 women), with an increase of 2.1 vs 0.7 episodes (p<0.001) over a 24-week period. Of interest, the 150-μg testosterone patch did not have a statistically significant benefit (increase of 1.2 vs 0.7 episodes, p=0.11). In addition, sexual desire scores increased as personal distress scores decreased over 24 weeks compared with placebo. As early as 12 weeks, the testosterone 300-μg group showed a significant treatment effect versus placebo; however, the 150-μg group did not. Application-site reactions and androgenic adverse effects (specifically with the 300-μg dose) were the most commonly reported adverse events.
The A Study in Women with Low Sexual Desire to Evaluate the Efficacy and Safety of Oral Transdermal Testosterone Therapy in Naturally Menopausal Women Receiving Transdermal Estrogen Therapy (ADORE) study was a double-blind, parallel-group study investigating the use of a transdermal testosterone patch.[SUP][56][/SUP] The ADORE study randomly assigned naturally menopausal women taking either systemic transdermal estrogen, oral non–conjugated equine estrogens, or no estrogen therapy to either testosterone patch 300 μg/day (130 women) or placebo (142 women) twice/week and reported efficacy using the weekly SAL and the PFSF at weeks 12 and 24, respectively. Women assigned to testosterone patch 300 μg/day experienced a mean increase of 1.69 total sexually satisfying episodes/4-week period versus an increase of 0.53 episodes/4-week period in women who received placebo (p=0.0089). Overall, more adverse events were reported by women in the placebo group versus those in the testosterone patch 300-μg/day group (71.1% vs 62.3%). However, there were greater occurrences of both acne (4.6% vs 1.4%) and hair growth (18.5% vs 12%) in the testosterone patch 300-μg/day group versus the placebo group.
In surgically induced postmenopausal women with low sexual desire taking transdermal estrogen, a randomized, double-blind, placebo-controlled, crossover study was conducted to assess the efficacy of testosterone cream.[SUP][57][/SUP] Women with a BISF-W score indicating low sexual desire (36 women) were given testosterone cream 10 mg/day or placebo. Results on the BISF-W demonstrated improved sexual thoughts (p=0.024), receptivity and initiation of sex (p<0.001), and frequency of sex (p=0.039). Women who were having vaginal intercourse increased from 78% despite low desire before the study to 89% during testosterone treatment (significance was not reported).
In 2009, results from a phase III trial investigating the use of DHEA intravaginal ovule 0.25% (53 women), 0.5% (56 women), or 1% (54 women) at bedtime for 3 months versus placebo (53 women) were published.[SUP][58][/SUP] The trial was conducted in postmenopausal women with vaginal atrophy, which may itself contribute to a decrease in sexual desire. Use of the daily ovule demonstrated a significant benefit on orgasm for the 1% dose versus placebo (p=0.047) and arousal with lubrication (139–169% increase from baseline for all DHEA doses, p<0.0001). Vaginal dryness was reduced 53–58% with all DHEA doses versus placebo (p<0.005). Intimacy avoidance was reduced 51–53% with 0.5–1% DHEA versus placebo (p<0.05).
Men have the option of using drugs such as phosphodiesterase inhibitors as needed to improve sexual function; however, testosterone for female sexual function has most often been studied as a long-term treatment. A small, randomized, double-blind, crossover study evaluated the use of testosterone gel 50 mg applied to the abdomen and shoulders 4–8 hours before intercourse up to twice/week for 1 month in 10 premenopausal women with HSDD as diagnosed by a sexologist.[SUP][59][/SUP] Women were randomly assigned to testosterone or placebo for 4 weeks and then crossed over to the other treatment. After each sexual encounter, the Arizona Sexual Experience Scale (ASEX) was completed by the participant. On-demand use of testosterone was associated with an increase of arousal on the ASEX scale (p=0.034), but no significant difference from placebo was noted for desire, lubrication, orgasm, or satisfaction. One patient complained of tingling and one of hirsutism with testosterone gel.
[h=4]Efficacy in Premenopausal Women[/h] Although most studies investigated the use of testosterone in postmenopausal women, questions remain about the efficacy of testosterone in premenopausal women with decreased sexual desire. A small, randomized, double-blind, placebo-controlled crossover study of topical testosterone cream was evaluated in premenopausal women with low libido.[SUP][60][/SUP] Thirty-four women were given either testosterone 1% cream 10 mg/day or a placebo to apply daily. Testosterone cream demonstrated a significant effect versus placebo on the SRS score on sexual interest (p=0.001), satisfaction (p=0.004), pleasure (p=0.004), fantasy (p<0.001), activity (p=0.006), and orgasm (p=0.005). Although this study involved a small number of participants, these results suggest that women with low sexual desire may benefit from testosterone whether before or after menopause. Additional large, randomized, controlled trials are needed to assess benefit in premenopausal women.
In a 16-week study involving testosterone use in premenopausal women, patients at six Australian medical centers were randomly assigned to one of three doses of transdermal testosterone or placebo: two 90-μl sprays (67 women), one 90-μl spray (64 women), or one 56-μl spray (66 women), and the remainder of the patients (64 women) received a placebo spray.[SUP][61][/SUP] At week 16, the least-squares mean number of sexual side effects was statistically significantly greater for the one 90-μl spray group versus placebo (2.48, 95% confidence interval [CI] 1.92–3.21 vs 1.70, 95% CI 1.28–2.28, p=0.044). However, there were no statistically significant differences in secondary outcomes (i.e., self-rating and psychologic well-being scores) at study conclusion. No serious adverse events were reported, and hypertrichosis, acne, headache, and nausea were the most commonly cited adverse effects.
[h=3]Adverse Effects[/h] [h=4]Hirsutism[/h] Hirsutism is one of the most common adverse effects associated with testosterone use in women, although in many studies there was no difference in the amount of hirsutism in the testosterone group compared with the estrogen or placebo group.[SUP][48, 51, 55, 57, 58, 62][/SUP] Other studies have reported increased hair growth in 5–15% of women taking testosterone, with the higher percentages associated with oral therapy.[SUP][32, 40, 43, 49, 60, 63][/SUP] Transdermal testosterone is associated with a lower rate of hirsutism. A Cochrane review of testosterone use in women concluded the odds ratio for developing hirsutism was 1.52 (95% CI 1.07–2.17).[SUP][64][/SUP]
[h=4]Acne[/h] Another common issue associated with testosterone use in women is development or increased severity of acne. Acne was noted in 2–6% of women receiving testosterone therapy, including the testosterone patch.[SUP][41, 42, 49, 52, 62][/SUP] One study of oral testosterone in postmenopausal women with an intact uterus found 38% of subjects to have acne.[SUP][65][/SUP] A trial evaluating the testosterone patch found no difference in acne between the active treatment and placebo groups.[SUP][48][/SUP] The Cochrane Collaboration found the odds ratio for acne to be 1.52 (95% CI 1.07–2.14) in women taking testosterone in addition to estrogen.[SUP][64][/SUP]
[h=4]Lipid Level Changes[/h] An overall decrease in lipid levels is noted in menopausal and postmenopausal women taking testosterone. Postmenopausal women taking oral testosterone are noted to have decreases in total cholesterol, high density lipoprotein cholesterol (HDL), and triglyceride levels.[SUP][40, 66][/SUP] Total cholesterol decreased by 33 mg/dl and HDL decreased by 14 mg/dl in menopausal or postmenopausal women receiving methyltestosterone 1.25 mg/day.[SUP][63][/SUP] In contrast, one study found a significant increase in total cholesterol level by 3 mg/dl (p<0.01) and HDL by 3 mg/dl (p<0.01) in postmenopausal women taking methyltestosterone 1.25 mg/day.[SUP][42][/SUP] This study also noted a decrease in triglyceride levels of 17 mg/dl (p<0.01). No lipid changes were noted in patients receiving testosterone implants in combination with estrogen or patients using the testosterone 300-μg/day patch.[SUP][43, 48, 67][/SUP] The Cochrane Review found HDL levels to be decreased 19 mg/dl (95% CI –15 to –22 mg/dl) in women taking testosterone.[SUP][64][/SUP]
[h=4]Cardiovascular Disease[/h] A population-based prospective study of 651 postmenopausal women not taking estrogen evaluated the impact of testosterone on the development of cardiovascular disease over 19 years.[SUP][68][/SUP] No significant increase or decrease in cardiovascular disease was found in this population compared with the general population. Additional long-term evaluations of cardiovascular disease have not been performed in this population.
[h=4]Osteoporosis[/h] Testosterone is thought to decrease the risk of osteoporosis in postmenopausal women; however, data on fracture prevention are lacking. Bone mineral density (BMD) was significantly increased in surgically induced postmenopausal women receiving estrogen and testosterone 2.5 mg/day compared with estrogen alone (p<0.002).[SUP][62][/SUP] Total BMD was increased in postmenopausal women receiving estradiol and testosterone 50-mg implants every 3 months compared with women receiving estrogen alone (p<0.008), along with significant increases at the vertebrae (p<0.001) and hip (p<0.005).[SUP][47][/SUP] A small, prospective, randomized study of women receiving estradiol and testosterone implants found a 5.7% increase in spinal BMD and 5.2% in hip BMD (p<0.001).[SUP][69][/SUP]
[h=4]Breast Cancer[/h] Several reviews have been published to assess the impact of testosterone on breast cancer development. A review of five testosterone studies in postmenopausal women found inconsistent results of breast cancer risk.[SUP][70][/SUP] Two of the five studies demonstrated an increased risk, whereas three of the studies did not find an increased risk of breast cancer with testosterone treatment. A retrospective cohort of 631 women who ever received testosterone found 12 cases of breast cancer; this result was not significant.[SUP][71][/SUP] The authors determined there was no evidence of an association between testosterone use and breast cancer. Another retrospective observational study of 508 postmenopausal women taking testosterone evaluated the development of breast cancer.[SUP][72][/SUP] Seven cases of breast cancer were found, with no significant increase compared with untreated women.
Women who have undergone natural menopause and received testosterone were followed in the Nurse's Health Study for development of breast cancer.[SUP][73][/SUP] This study found an increased risk of breast cancer (relative risk 1.77, 95% CI 1.22–2.56) in the women taking testosterone over those who never used hormone therapy, but this was not significantly different from women taking estrogen and progestin. Women who were taking testosterone for less than 5 years had an 81% increase in breast cancer, but there was a nonsignificant difference for women who had received treatment for more than 5 years.
[h=3]Clinical Guidelines and Recommendations[/h] One of the earliest set of recommendations involving female androgen insufficiency was the Princeton consensus statement.[SUP][74][/SUP] Various representatives from medical disciplines including endocrinology, pharmacology, obstetrics and women's health, and psychiatry met in Princeton, New Jersey, in 2001, and formed a list of recommendations (as well as identified areas for research) concerning the role of androgens in women's health. The consensus statement included acknowledgment that large-scale epidemiologic studies involving androgens in women's health are needed, that current androgen assays lack reliability and sensitivity, that clinical symptoms and laboratory values should be considered when addressing female androgen insufficiency, and that androgen therapy should be used only when other diagnoses have been excluded and the risks and benefits of androgen therapy have been discussed with the patient.
In 2006, the Endocrine Society published guidelines regarding the use of androgen therapy in women.[SUP][75][/SUP] At that time, the Endocrine Society recommended against the generalized use of testosterone by women because of the lack of evidence supported by long-term studies. Areas for further development that were cited by these guidelines included defining specific conditions that have detrimental effects to women when androgens are not used, as well as defining appropriate clinical and laboratory markers to identify women with these conditions.
[h=3]Conclusion[/h] Although male sexual dysfunction has been studied more extensively than FSD, testosterone therapy has been evaluated for improvement of sexual function in women for over 60 years. During that time, the definition and assessment of sexual dysfunction have developed, as have delivery routes for therapy. Both the subjectivity of HSDD diagnosis and the numerous scales used to measure sexual improvement with testosterone therapy contribute to the challenge of managing HSDD. Currently, transdermal testosterone therapy has been evaluated in large, randomized, controlled trials and is most likely to be routinely used in women with HSDD. However, questions remain regarding which women are most likely to respond to treatment, as well as the safety with long-term use. Additional studies with longer periods of follow-up are necessary in order to determine the appropriate place in therapy of testosterone in the treatment of HSDD.
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