A Systematic Review of Randomized Controlled Trials Investigating the Efficacy and Safety of Testosterone Therapy for Female Sexual Dysfunction in Postmenopausal Women

Channa N. Jayasena; Fatima M. Alkaabi; Curtis S. Liebers; Thomas Handley; Stephen Franks; Waljit S. Dhillo

Disclosures

Clin Endocrinol. 2019;90(3):391-414. 

In This Article

Effects of Testosterone Supplementation on Sexual Function

Greenblatt et al in 1950 conducted the first randomized study of testosterone therapy (alone or in combination with oestrogen) in postmenopausal women. Since then, several randomized controlled trials have investigated the effects of testosterone therapy in postmenopausal women with symptoms of sexual dysfunction (Table 2). These trials have utilized different dosing regimens and routes of administration. Some trials have used testosterone replacement alone, whereas others have studied the effects of testosterone therapy during oestrogen replacement. Some studies have included women with age-associated ("natural") menopause, whereas others have included women with surgically induced menopause. All studies excluded women with psychological or medical conditions that could impact on their sexual function in keeping with the DSM-4 and DSM-5 diagnostic criteria. Furthermore, most studies were restricted to participants with long-term partners.

Most trials measured sexual function using validated symptom scores. Some authors[6,36,37] have used the modified McCoy's sex scale[38] which covers sexual experience and responsiveness during the last 30 days and contains seven items (eg, "Are you satisfied with your present frequency of sexual activity?" "How enjoyable is sex for you?" and "How often do you have an orgasm during sex?"). Some studies[39,40] used the female sexual function index (FSFI), which is a standardized questionnaire used to assess sexual function among postmenopausal women, and is an anonymous patient-based self-reported instrument.[41] Other authors[42,43,44,45,46,47,48] have used the following validated scales: Sexual Activity Log; Profile of Female Sexual Function; Personal Distress Scale. The result of testosterone administration in postmenopausal women has also been summarized in a recent Cochrane review.[49]

Transdermal Testosterone Administration

Several placebo-controlled double-blind studies have investigated whether testosterone improves sexual function in postmenopausal women taking oestrogen with or without progestin therapy. Most studies have investigated the effects of transdermal testosterone therapy. Three of the largest published studies randomized postmenopausal women with surgically induced menopause to daily dermal patch administration of placebo or 300 μg testosterone for 24 weeks of duration.[42,44,45] All women included in these trials had received oestrogen supplementation for at least 3 months before randomization. Simon et al[44] observed that in 562 women, testosterone administration significantly increased the frequency of total satisfying sexual activity (as measured by the SAL) from 2.82 to 4.92 episodes per 4 weeks, when compared with an increase from 2.94 to 3.92 episodes per 4 weeks in the placebo group (P = 0.0003). Libido was also increased significantly during testosterone supplementation when compared with placebo. Buster et al[42] observed in 533 women that testosterone increased total satisfying sexual activity when compared with placebo (1.56 episodes vs with 0.73 episodes per 4 weeks), and improved libido. Braunstein et al[45] randomized 447 women to one of 3 different daily doses of testosterone supplementation (150, 300 or 450 μg) or placebo; subjects receiving the 300 μg testosterone dose reached total serum testosterone levels of 91 ng/dL by week 24 and experienced a statistically significant increase in libido from baseline when compared with placebo (67% vs 48%; P = 0.05) and in frequency of satisfying sexual activity (79% vs 43%; P = 0.049); these results are concordant with similar smaller studies.[46,50] However, it is important to note the placebo response was substantial. No significant changes in libido or satisfying sexual activity were observed during 150-μg/d or 450-μg/d testosterone supplementation reaching total serum testosterone concentrations of 44.5 and 122.5 ng/dL, respectively, when compared with placebo in postmenopausal women. Shifren et al[47] studied the effects of testosterone patch in 549 women with natural menopause who were taking a stable dose of oral oestrogen (with or without progestin). Participants were randomized to placebo or transdermal testosterone patch (300 μg/d) twice weekly for 24 weeks. They were then followed up to measure a change from baseline in the number of satisfying sexual events using the SAL. Women allocated to testosterone reported a significantly greater increase in sexual events measured using SAL during testosterone when compared with placebo (placebo, 0.5 ± 0.23; testosterone, 2.1 ± 0.28, P < 0.0001 vs placebo). The largest RCT performed to date randomized 814 women with menopause (natural or surgical) and HSDD to placebo or testosterone patch at the doses 150 μg or 300 μg per day over a 24-week period.[48] Participants randomized to the 300 μg group, but not the 150 μg group reported significantly greater Satisfying Sexual Events (SSEs) over a 4-week period when compared with participants in the placebo group (episodes per 4 weeks: placebo, 0.7; 150 μg testosterone, 1.2, P = 0.11 vs placebo; 300 μg testosterone, 2.1, P < 0.001 vs placebo). Though not reported, it would be interesting to determine whether the effects of testosterone differed between women with a natural or surgical menopause.

Panay et al[43] conducted a 6-month placebo-controlled, double-blind trial (the ADORE study). They randomized 272 women to transdermal testosterone patch (TTP; 300 μg/d) or placebo, and used the SAL to measure satisfying sexual episodes as their primary end-point. Increases in Significant Sexual Events (SSEs; P = 0.0089), libido P = 0.0007 and reduced personal distress (P = 0.0024) were observed following 6 months of TTP administration when compared with placebo in menopausal women. In summary, several studies suggest transdermal testosterone increase sexual activity. Collectively, these multiple randomized placebo-controlled studies suggest that testosterone therapy significantly improves symptoms of sexual dysfunction in women with natural or surgical menopause. These conclusions are in keeping with two recent systematic reviews of the literature.[18,49] However, it is important to consider that symptoms of sexual dysfunction do not have a clear relationship with low level of circulating testosterone. Therefore, questions remain as to whether testosterone administration in postmenopausal women exerts pharmacological or physiological actions. It is also important to consider to what extent any effects of androgens on sexual function are attributable to aromatization to oestrogens. For instance in men, aromatase inhibition prevents testosterone administration from improving libido in GnRH agonist-induced hypogonadism.[51] Finally, it would be helpful to specifically investigate whether the testosterone therapy improves sexual function in postmenopausal women whose serum oestradiol levels are replete (eg, serum E2 levels 300-600 pmol/L) during HRT; this would suggest that testosterone is not simply acting to supplement bodily oestrogen exposure (via aromatization).

Other Routes of Testosterone Administration

Recent clinical trials have investigated the administration of nontransdermal application of testosterone in postmenopausal women. Urogenital topical application was investigated in 75 menopausal women (natural or surgical), who were randomized to placebo, oestrogen only or oestrogen with testosterone over a 12-week period.[6] McCoy Sexuality scores increased in all treatment groups, but were highest in the oestrogen with testosterone group (Percentage improvement in McCoy Sexuality score: placebo, 18.6; oestrogen only, 42.4, P < 0.05 vs placebo; oestrogen with testosterone, 147, P < 0.01 vs placebo). This implies that effects of sex hormones on sexual function may be partially mediated indirectly through improved vaginal lubrication.[20] Studies are needed to delineate the relative importance of vulvovaginal vs cerebral effects of sex steroids in sexual function in postmenopausal women. Similar increase in McCoy Sexuality score was observed in a 2002 study of 50 surgically menopausal women;[52] enjoyment of sex, satisfaction with frequency of sexual activity, interest in sex and total score all increased significantly with testosterone compared to placebo, as well as studies in 2006[36] and 2007.[37]

Tungmunsakulchai et al[40] investigated the effects of twice weekly administration of either oral placebo or testosterone undecanoate 40 mg in combination with oral oestrogen in a randomized double-blind study. Sexual function was significantly higher in the testosterone group when compared with placebo (FSFI scores: placebo, 28.6 ± 3.6; testosterone, 25.3 ± 6.7, P = 0.04 vs placebo).

Lobo et al[53] performed a double-blind randomized trial of 221 postmenopausal women receiving either oral combined esterified oestrogens/methyltestosterone or oral esterified oestrogens alone; changes in levels of sexual interest or desire as rated on the Sexual Interest Questionnaire were investigated. Treatment with the combination of esterified oestrogens and methyltestosterone significantly increased the concentration of bioavailable testosterone and suppressed SHBG. Scores measuring sexual interest or desire and frequency of desire increased from baseline with combination treatment and were significantly greater than those achieved with esterified oestrogens alone. Treatment with the combination was well tolerated.

Sherwin et al studied 10 premenopausal 43 surgical menopause who received either oestradiol 8.5 mg and testosterone 150 mg, oestradiol 8.5 mg, testosterone 150 mg or placebo 1 mol/L in a randomized control trial. They concluded that a combined oestrogen androgen therapy can enhance the quality of life for both naturally and surgically postmenopausal women and increase sexual arousal and libido. A randomized double-blind trial by Watts et al investigated 66 surgically menopausal women received either oral esterified oestrogens (1.25 mg), or esterified oestrogens (1.25 mg) combined with methyltestosterone (2.5 mg) daily for 2 years. Menopausal symptoms of somatic origin (hot flushes, vaginal dryness and insomnia) were improved significantly by both treatments. Also, both treatment regimens prevented bone loss at the spine and hip.[53,54,55] However, there was no significant difference in somatic symptoms between the treatment groups.

In another double-blinded randomized study by Huang et al,[56] 71 menopausal women who previously underwent hysterectomy with or without oophorectomy received a standardized transdermal oestrogen regimen during the 12-week run-in period, and were then randomized to receive weekly IM injections of placebo, or 3, 6.25, 12.5 or 25 mg testosterone enanthate for 24 weeks. Dose-dependent improvements in several domains of sexual function, lean body mass, chest-press power and loaded stair-climb power were observed, with the greatest improvements at the highest dose. Furthermore, a double-blind randomized study by Dobs and colleagues, with 40 naturally and surgically menopausal women, observed significant increases in upper and lower body strength with testosterone compared to placebo.[57] Whilst the majority of studies observed testosterone significantly increased sexual arousal/interest,[39,42,52,57,58] frequency of orgasms[13,39,57] and frequency of sexual activity[13,47,52] when compared to placebo, some suggest no significant difference between the treatment groups.[39,58,59,60,61] In conclusion, most but not all studies suggest that testosterone improves symptoms of sexual dysfunction regardless of the route of administration. Further studies are required to investigate whether the observed effects of testosterone administration on sexual function are truly dose dependent.

Comments

3090D553-9492-4563-8681-AD288FA52ACE

processing....