The menopausal transition has been associated with decreased sexual responsiveness independent of age [22]. Several studies have shown that women who underwent surgical menopause experience greater deterioration of sexual function compared to naturally menopausal women [23–25]. Indeed, women who have undergone bilateral oophorectomy (resulting in low serum testosterone levels) report impaired sexual function even on estrogen therapy [26, 27], suggesting that androgens play an important role in the regulation of libido in women. In 2000, the first female testosterone transdermal patch was manufactured by Procter & Gamble called Intrinsa. This patch is available in 150 ug and 300 ug doses applied to the abdomen twice weekly, providing equivalent to 50 and 100 % daily testosterone production in premenopausal women, respectively [28].

In the last decade, there have been several clinical trials in surgically menopausal women demonstrating improvements in sexual function with physiologic transdermal testosterone replacement that increase serum testosterone levels into the mid- to high-normal range for healthy young women [8, 9, 11, 12]. The first randomized placebo-controlled trial using the patch was published in 2000 [8]. This study was a 12-week trial of 75 surgically menopausal women (ages 31–56) with impaired sexual function (based on the Brief Index of Sexual Functioning for Women Questionnaire) on 0.625 mg of oral estrogen (for at least 2 months) who were randomized to placebo, 150 ug or 300 ug testosterone patch. The mean total testosterone levels increased from 21 ng/dl to 65 ng/dl and 102 ng/dl in the 150 ug and 300 ug groups, respectively. Sexual function (measured by the Brief Index of Sexual Functioning for Women Questionnaire) only improved in the 300 ug-treated group compared to placebo; despite a large placebo response, improvements in sexual thoughts–desire, frequency, pleasure–orgasm, and well-being were seen. Specifically, there was a two- to threefold increase from baseline in percentage of women who had sexual fantasies, masturbated, or engaged in sexual intercourse at least once a week. There was no differences in androgenic (hirsutism, acne) adverse events nor metabolic profile between the groups [29]. Indeed, several follow-up well-designed randomized, controlled studies in both surgically and naturally menopausal women (most trials included women on estrogen replacement) with hypoactive sexual desire disorder (HSDD) have reported that administration of transdermal testosterone resulted in modest improvement in some domains of sexual function such as sexual desire, satisfaction, and frequency [8–12]. Davis and colleagues conducted a trial using the testosterone patch (150 or 300 ug per day vs. placebo) in 814 non-estrogen-treated postmenopausal women (natural and surgical) for 24 weeks [11]. A significant increase by an additional 2.1 satisfying sexual encounters per month was seen only in the 300 ug group versus 0.7 satisfying sexual encounters in the placebo group. There were no significant differences in the adverse side effect profile among the groups.

Despite several studies having demonstrated efficacy and short-term safety of physiologic transdermal androgen therapy for sexual dysfunction in postmenopausal women, the improvements seen have been modest and limited by large placebo effects. Furthermore, recently, two large phase III trials using a transdermal testosterone gel (LibiGel, BioSante, Inc.) failed to meet their primary endpoints of improvements in sexual function (sexual desire and total number of satisfying sexual events) in women with HSDD compared with placebo (data not published). In a recent dose–response study of intramuscular testosterone administration (ranging from physiologic to supraphysiologic doses) in 71 estrogen-treated hysterectomized postmenopausal women (ages 41–62 years) who did not have impaired sexual functioning at baseline, testosterone administration was associated with concentration-dependent improvements in sexual thoughts and desires, sexual activity scores, and arousal, but not in other domains of sexual function [30]. However, these improvements were observed only in women who were assigned to the highest testosterone dose (Fig. 10.4).

Although these clinical trials have demonstrated some efficacy of testosterone in the treatment of sexual dysfunction in postmenopausal women, long-term safety of testosterone therapy remains unclear. In 2004, the FDA voted not to approve the transdermal testosterone patch for the treatment of hypoactive sexual desire due to lack of long-term safety data. In 2006, the Endocrine Society recommended against making a diagnosis of androgen deficiency in women due to lack of a well-defined syndrome and normative data for testosterone levels and also recommended against generalized use of testosterone supplementation in women as evidence of safety in long-term studies is lacking [31]. The most updated 2014 Endocrine Society Guidelines on androgen therapy in women continue to recommend against making a diagnosis of FADS and generalized use of testosterone. They also recommended against the use of testosterone therapy in sexual dysfunction, the exception being a postmenopausal women with HSDD, and in the absence of any contraindications, for whom the guidelines suggest a 3- or 6-month trial of testosterone. However, approved testosterone preparations for women are not available in many countries including the United States. Approved testosterone products are available for women in Australia and in some European countries; clinicians in the United States are limited to off-label testosterone preparations, since no testosterone product is FDA approved for use in women.

In women, the menopausal transition has been associated with an accelerated loss of muscle mass and strength and decrease in physical function [32, 33]. Although the negative impact of low estrogen on bone health is well established, there is limited evidence on whether this loss of estrogen significantly influences muscle mass and physical function [34–36].

Menopause is associated with an increase in fat mass and a decrease in lean body mass [37, 38]. Conversely, free serum testosterone levels are associated with increased lean mass in older women [39]. The Study of Women’s Health Across the Nation (SWAN) found higher rates of physical limitation in surgically menopausal women compared to women undergoing natural menopause [40]. Indeed, the age-related decline in serum testosterone levels in older women has been associated with frailty [41]. Thus, it is conceivable that women who have undergone surgical menopause and have low testosterone levels may be at a greater lifetime risk for physical disability. Clinical trials using various formulations and doses of testosterone and other androgens have reported some improvements in lean mass and muscle strength, although with few demonstrating improvements in physical function [42–45]. One trial reported modest increase in lean mass in women (aged 19–50 years) with hypopituitarism in response to physiologic testosterone replacement [46]. Another 16-week double-blind randomized controlled trial of 40 postmenopausal women (natural and surgical) who were randomized to either oral 1.25 mg esterified estrogen + 2.5 mg methyltestosterone versus estrogen alone showed that the combined estrogen–androgen group experienced a significant increase in lean mass and muscle strength as well as reduction in total fat mass compared to estrogen alone [42].

Testosterone therapy has also shown beneficial effects on body composition in women who are androgen deficient as a result of another medical condition. Indeed, a study of transdermal testosterone replacement (4 mg/patch) in HIV-infected women with androgen deficiency and 10 % weight loss for 6 months resulted in increases in muscle mass and strength as well as improved muscle function [47]; however, these results have not been confirmed in other studies of women with HIV [48]. In another study of relatively healthy estrogenized postmenopausal women without physical dysfunction at baseline, testosterone administration via intramuscular injections at supraphysiologic doses was associated with significant gains in lean mass, chest press power, and loaded stair climb power; these improvements were observed only at the highest dose (25 mg weekly), with nadir testosterone concentrations of 200 ng/dl [30] (Fig. 10.5). Additional studies are needed to explore the role of androgens in the regulation of body composition, muscle performance, and physical function in various subsets of women (postmenopausal with chronic diseases) with low testosterone levels.

Epidemiologic studies have suggested that serum testosterone levels in women are associated with specific aspects of cognition, although data regarding the association of circulating testosterone concentrations and cognitive function are inconsistent across studies [49–52]. Testosterone is aromatized to estradiol, both in the periphery and in the brain; in addition to its direct effects via androgen receptor, some effects of testosterone administration might thus be mediated via its aromatization to estradiol [53]. For example, premenopausal women with polycystic ovary syndrome (PCOS) who have higher serum testosterone levels were noted to perform better on spatial tasks and worse on verbal tasks compared to controls [54, 55]. Similarly, endogenous testosterone levels during the menstrual cycle are positively correlated with visuospatial ability and negatively with verbal fluency in healthy women [49, 56]. Similar findings have been noted in some [50], but not in other association studies of endogenous sex hormones and cognition in healthy postmenopausal women [51, 52], and trials of testosterone administration assessing cognitive performance in postmenopausal women have yielded inconsistent results [57, 58]. A 12-week crossover study did not show improvement in cognitive function in surgically menopausal women receiving estrogen alone versus estrogen and intramuscular testosterone [57]. In short-term studies using oral testosterone, improvement in executive function (attention) was noted in one study [59]; however, other studies did not show any cognitive benefits [60, 61]. A recently conducted 24-week dose–response study of testosterone intramuscular injections in estrogen-treated postmenopausal women aged 41–62 years neither showed improvement nor worsening of cognitive performance in a number of domains of cognitive function (spatial reasoning, verbal memory, verbal fluency, and executive function) over a wide range of testosterone doses and concentrations, including doses that achieved supraphysiologic serum testosterone concentrations [62]. In a mechanistic study exploring the role of aromatization on cognition, 71 postmenopausal women who were already receiving transdermal estrogen for 12 weeks were given transdermal 0.5 % testosterone gel and were then randomized either to aromatase inhibitor (letrozole 2.5 mg) or placebo for 16 weeks [63]. Significant improvements in visual and verbal memory were seen with testosterone therapy, and the results were unaffected by aromatase inhibition. These findings suggest that testosterone may have direct cognitive effects independent of its conversion to estradiol. On the contrary, a recently conducted 24-week dose–response study of testosterone replacement in estrogen-treated postmenopausal women neither showed improvement nor worsening of cognitive performance in a number of domains of cognitive function (spatial reasoning, verbal memory, verbal fluency, and executive function) over a wide range of testosterone doses and concentrations, including doses that achieved supraphysiologic serum testosterone concentrations [62].

Contrastingly, some studies have suggested that testosterone therapy may have negative effects on cognitive performance in postmenopausal women. In a study of surgically menopausal women, significant worsening of verbal memory was seen in the group receiving both testosterone and estrogen compared to estrogen alone [58]. Similarly, though in a different context, administration of supraphysiologic doses of testosterone to female-to-male transsexuals has been shown to worsen verbal fluency while improving spatial memory [64]. Long-term, adequately powered trials are needed to evaluate the cognitive effects of testosterone therapy in women. Furthermore, whether testosterone might be beneficial in women with baseline cognitive deficits remains to be investigated.

In women, serum testosterone levels are correlated with trabecular and cortical bone mineral density (BMD), particularly in the older postmenopausal women [39, 65]. Postmenopausal women treated with combined estradiol and testosterone implants for 2 years experienced significantly greater increases in hip and lumbar spine BMD compared to those receiving estradiol implants alone [44]. Two randomized controlled trials in surgically menopausal women compared the effects of a combination of estrogen and methyltestosterone therapy with estrogen therapy alone [66, 67]. One study showed improvement only in the spine BMD in the group receiving testosterone [66], while the other showed improvements at both sites [67]. On the contrary, another study of estrogenized surgically menopausal women who were administered with oral testosterone undecanoate 40 mg daily for 24 weeks did not improve BMD at any of the studied skeletal sites [68]. In yet another small trial of 25 surgically menopausal women on estradiol implants, addition of testosterone for 16 weeks had no significant effects on serum bone markers compared to estrogen alone [69], suggesting that testosterone does not augment the positive effects of estrogen on bone. These results are consistent with studies in young women with primary ovarian insufficiency (who have profound estrogen and testosterone deficiency) where the addition of transdermal testosterone replacement to estrogen did not provide additional benefit [70]. In contrast, another study in postmenopausal women showed that short-term administration of methyltestosterone with estrogen increased markers of bone formation [71].

In summary, data from some, but not all, testosterone intervention studies demonstrate improvement in BMD in postmenopausal women; however, it is unclear whether or not testosterone itself can provide further benefits in the prevention of osteoporosis in adequately estrogenized women. Importantly, the efficacy of testosterone on fracture rates in postmenopausal women remains unknown.

Currently a combination of oral methyltestosterone and estrogen is FDA approved only for the treatment of moderate to severe menopausal vasomotor symptoms that are not improved by estrogen alone [72]. While the majority of studies have not shown a benefit of methyltestosterone over estrogen [59, 66, 71, 73, 74] in reducing postmenopausal somatic symptoms, two studies have reported greater benefit in menopausal symptoms with methyltestosterone and estrogen combination than estrogen alone [75, 76]. Sherwin et al. reported greater improvements in somatic symptoms in surgically menopausal women treated with combined testosterone and estrogen injections compared with estrogen alone [77]. A large uncontrolled study in 300 pre- and postmenopausal women with symptoms of androgen deficiency showed that continuous testosterone alone, delivered by subcutaneous pellets, was effective in relieving psychological, somatic, and urogenital symptoms, measured by a validated Menopause Rating Scale (MRS) [78]; however this study is limited by a lacking control group for comparison.

In summary, because of the small number of studies and limitation of study design, more evidence is needed to support the efficacy of the addition of testosterone to estrogen in improving menopausal symptoms in both surgically and naturally menopausal women.

Potential adverse androgenic effects of testosterone therapy include hirsutism, acne, alopecia, clitoromegaly, and voice deepening. In the majority of randomized placebo-controlled studies of testosterone administration in postmenopausal women [9, 10, 12, 29, 30, 79], the frequency of androgenic events (mainly hirsutism and acne) was higher in the testosterone-treated groups versus placebo; however, most androgenic events were mild in nature. Furthermore, few women withdrew from these studies because of androgenic adverse events [11, 30]. Four cases of clitoral enlargement were reported in one trial of transdermal testosterone patch (one woman receiving 150 ug/day; three receiving 300 ug/day dose), but all were classified as mild by the investigators [11]. None of these women withdrew from the study and clitoromegaly either resolved or remained stable throughout the trial. However, most of the abovementioned androgenic events were collected by subjective report with only a few studies using validated assessment tools. In one dose–response study of 71 estrogen-treated postmenopausal women, androgenic adverse effects were objectively monitored using validated instruments: hair growth using the Ferriman–Gallwey scale, sebum production using Sebutape, acne using the Palatsi scale, clitoral size using a caliper scale, and voice changes using functional acoustic testing [30, 80]. In this trial, clitoral size, Palatsi score, and sebum production rate did not differ significantly between any of the testosterone dose groups (ranging from physiologic to supraphysiologic) versus placebo. However, there were small increases in Ferriman–Gallwey scores in the two highest dose groups (12.5 and 25 mg testosterone enanthate). In the same trial, testosterone administration in women was also associated with dose- and concentration-dependent reduction in average pitch in the higher dose groups [80]. Interestingly, these changes were measureable even though the participants did not report any subjective changes in voice. Early changes in acoustic parameters prior to clinical manifestation have also been reported in patients with Parkinson’s disease, in whom changes in vocal frequency can be detected a decade prior to the clinical diagnosis [81], supporting the notion that detection via functional acoustic testing can be an early marker for subsequent clinical voice changes during testosterone administration. Future clinical trials addressing safety of testosterone therapy should include both subjective and objective evaluations of androgenic side effects.

In summary, the incidence of adverse androgenic side effects of testosterone administration in postmenopausal women at physiologic doses appears to be low and infrequent, and if they do occur, they are generally tolerable.

In women with PCOS, endogenous serum testosterone levels are positively associated with fat mass, proatherogenic dyslipidemia, and insulin resistance [60, 82]. Similarly, in postmenopausal women, higher serum testosterone levels have also been associated with insulin resistance, metabolic syndrome, and coronary heart disease [39, 83]. The data from epidemiologic studies have been extrapolated to suggest that exogenous testosterone administration may also worsen metabolic outcomes in women.