(2007) 19, 458 463 & 2007 Nature Publishing Group All rights reserved 0955-9930/07 $30.00 www.nature.com/ijir REVIEW : its role in the management of hypoactive sexual desire disorder Department of Obsterics and Gynecology, George Washington University, Washington, DC, USA Disorders of sexual dysfunction occur in nearly half of women during their life, and hypoactive sexual desire disorder accounts for most of those complaints. Although the relationship between low endogenous testosterone levels and sexual desire disorders in women has not been empirically established, clinical trials have shown that exogenous testosterone therapy improves arousability, sexual desire and fantasy, frequency of sexual activity and orgasm, and satisfaction and pleasure from the sexual act. Its therapeutic role in bone mineral density, fatigue, well-being and hot flashes requires more study before specific recommendations can be made. Potential adverse effects of testosterone therapy include hirsutism, acne and deepening of the voice along with changes in lipid profiles. While less well understood, concern after increased risks for breast cancer and cardiovascular events has been raised about this therapy. Testosterone therapy is available in various formulations; the most commonly used are oral and transdermal, including patches, gels, creams and ointments. (2007) 19, 458 463; doi:10.1038/sj.ijir.3901558; published online 21 June 2007 Keywords: testosterone; female sexual dysfunction; sexual desire Introduction Although the word androgen is derived from the Greek words ando (man) and genein (to produce), androgens are known to play many roles in women, including those related to bone mineral density, energy and overall well-being, menopausal symptoms, lean body mass, and sexual function. This article will review the physiologic effects of androgens, the effect of testosterone therapy, especially on sexual function, the side effects of testosterone therapy, and the commercially available testosterone products, focusing primarily on those products available in the United States. Given that disorders of sexual function occur in up to 43% of women (although most are relatively minor complaints), 1 and that hypoactive sexual desire is the most common of these complaints, an emphasis will be placed on the effect of testosterone therapy on hypoactive sexual desire disorder (HSDD) in women. Correspondence: Dr JA Simon, Department of Obestrics and Gynecology, George Washington University, 1850 M Street, NW, Washington, DC 20036, USA. E-mail: jasimon@erols.com Received 28 September 2006; revised 21 February 2007; accepted 14 March 2007; published online 21 June 2007 Physiology Clinically, five androgens and androgen precursors are thought to be the most important: testosterone (T), dihydrotestosterone (DHT), androstenedione (A), dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate. In women, androgens are produced in the ovaries and adrenal glands. The adrenal glands and ovaries contribute equally to testosterone production, approximately 25% each, except around ovulation when ovarian contribution increases by 10 15%. The other 50% of circulating testosterone comes from peripheral conversion of androgen produced by the adrenals or ovaries. The rate of testosterone production in normal female subjects is 0.2 0.3 mg/day. Routine assays measure total T, but only free T has a clinical effect. Approximately 80% of testosterone is bound to sex hormone-binding globulin (SHBG), 19% to albumin and 1% is free and physiologically active. 2 SHBG production increases, and thus free T levels usually decrease, with pregnancy, estrogen therapy use (such as oral contraceptives) and hyperthyroidism. In contrast, SHBG production is decreased by insulin and androgen and by obesity and menopause. The decreases in SHBG levels at menopause, when ovarian production of estrogen decreases, can explain why the concentration of free
T remains the same or increases slightly during perimenopause. The decline in measurable total testosterone production at menopause is a function of aging and not natural menopause. Testosterone concentrations actually begin to decline during the late 20 or 30 s. Levels of testosterone, androstenedione and DHEA all continue falling at a constant rate, reaching a level of about 50% of their peak by the time of menopause. The postmenopausal ovary appears to continue producing testosterone after menopause. However, a bilateral oophorectomy decreases testosterone production by about 50%. 3,4 Sexual dysfunction and HSDD The sexual response can be divided into three stages: desire, arousal and orgasm. Sexual dysfunction occurs if any of these stages is affected or if sexual pain (that is dyspareunia) is present and if the symptoms persist and cause personal distress. The National Health and Social Life survey found that 43% of US women experience sexual dysfunction versus 31% of males. 1 Low sexual desire, or HSDD, is the most common sexual dysfunction complaint, accounting for approximately 22% of cases. The term hypoactive sexual desire disorder is defined as a chronic or recurrent deficit in or absence of desire for sexual activity that causes personal distress, in which lack of desire is not due to another condition or circumstance. The term female androgen insufficiency was defined by the Princeton consensus as a pattern of clinical symptoms in the presence of decreased bioavailable testosterone and normal estrogen levels. 5 The most commonly reported clinical symptoms are decreased libido and sexual pleasure, a diminished sense of well-being, and persistent unexplained fatigue. Sexual dysfunction can be caused by general medical conditions, such as diabetes mellitus, hypothyroidism, congestive heart disease, hyperprolactinemia, Addison s disease, Cushing s disease, temporal lobe lesions or menopause. Medications, such as chemotherapy, selective-serotonin reuptake inhibitors and antihypertensives, can cause sexual dysfunction. There are psychological and social causes, such as depression, unresolved sexuality and marital problems. Other conditions that can be associated with a decrease in sexual desire include medical conditions treated with corticosteroids, such as asthma, rheumatoid arthritis and connective tissue diseases. Even though many studies focus on diagnosis and treatment of sexual dysfunction in postmenopausal women, more sexual complaints are reported by women who are pre- or perimenopausal. It is common for perimenopausal women who still maintain functional ovulatory cycles to experience decreased sexual desire. However, this cannot be explained on the basis of testosterone levels, which remain fairly steady during the menopausal transition. Mushayandebvu et al. 6 proposed that the decrease in sexual interest at perimenopause may be caused by a blunting of the periovulatory rise in both testosterone and androstenedione seen in younger women. The lower estrogen levels associated with menopause do not directly affect sexual desire, even though estrogen therapy may improve sexual function in postmenopausal women by decreasing vaginal dryness and pain. However, prescribing estrogen, particularly oral estrogen, to relieve menopausal symptoms leads to an increase in SHBG, thus, further decreasing the level of free T, which may, in turn, affect sexual desire. Evaluation When evaluating a woman with decreased libido, it is important to note the duration of the problem. A long history starting in adolescence or early adulthood should be referred to a mental health professional. However, a short history or a history associated with a specific date is more likely to be related to a specific event (for example, social, psychological or hormonal). Only after ruling out social causes (for example, marital problems, depression, anorexia, bulimia), physical factors (for example, vestibulitis, vulvodynia, pelvic inflammatory disease, endometriosis) and other hormonal deficiencies (for example, low estrogen leading to vaginal dryness) should testosterone deficiency be considered. Given the lack of reliability and precision of many commercially available free T assays when used in menopausal women and the rapid fluctuation of endogenous testosterone concentrations, it is difficult to accurately measure testosterone in clinical practice. Measuring free and total T levels in menstruating women between menstrual cycle days 7 10 will avoid both the very low free and total T levels that occur early in the cycle as well as the preovulatory peak in testosterone; however, this approach cannot compensate for the basic imprecision of the testosterone assay, nor the poor correlation between testosterone levels and sexual function. If a validated commercial assay is available with proven normal ranges for women, then choosing an arbitrary cutoff of the upper two-thirds of normal premenopausal range (to represent normal ) may avoid over or under treatment based on the poor sensitivity of available assays. Testosterone therapy for HSDD in women Recent studies have shown that testosterone therapy improves sexual function in postmenopausal 459
460 women. Testosterone therapy can improve arousability, sexual desire and fantasy, frequency of sexual activity and orgasm, and satisfaction and pleasure from the sexual act. Davis et al. 7 also showed that testosterone improves libido, generalized fatigue, overall sense of well-being and quality of life. In another randomized, placebo-controlled study by Shifren et al., 8 75 women aged 31 56 years old who had undergone oophorectomy and hysterectomy received conjugated equine estrogens plus placebo or 150 or 300 mg/day of testosterone transdermally for 12 weeks. Outcome measures included scores on the Brief Index of Sexual Functioning for Women (BISF-W), the Psychological General Well-Being Index (PGWB), and a sexual function diary. The mean serum-free T concentration increased from 1.2 pg/ml during placebo treatment to 3.9 and 5.9 pg/ ml during treatment with 150 and 300 mg/day of testosterone, respectively. The higher testosterone dose resulted in further increases in scores for frequency of sexual activity and pleasure-orgasm on the BISF-W (P ¼ 0.03 for both comparisons versus placebo). At the higher dose, the percentages of women who had sexual fantasies, masturbated, or engaged in sexual intercourse at least once a week increased two to three times from baseline. The positive well-being, depressed-mood and composite scores on the PGWB also improved at the higher dose (P ¼ 0.04, 0.03 and 0.04, respectively, in comparison with placebo). While most studies for sexual dysfunction were conducted in postmenopausal women, Goldstat et al. 9 evaluated the efficacy of transdermal testosterone in premenopausal women. In this randomized, placebo-controlled, crossover study, 34 premenopausal women aged 30 45 years who reported diminished sexuality applied testosterone cream 10 mg/day (or placebo) for 12-week periods separated by a 4-week washout period. The women all had early morning total T levels of o2.2 nmol/l. Women with relationship problems, dyspareunia, depression, high testosterone levels and various medical problems were excluded from the study. Mean T levels in the treatment group were at the high end of the normal premenopausal range, while estradiol levels were unchanged. Although results from the Beck Depression Inventory were not significantly changed by testosterone treatment (2.8 decrease; P ¼ 0.06), this therapy resulted in significant improvements in the composite scores of the PGWB (12.9; P ¼ 0.003) and the Sabbatsberg Sexual Self- Rating Scale (15.7; P ¼ 0.001) compared with placebo. In addition, 46% of the participants reported a 50% or more increase in their total sexual self-rating score in the treatment group versus 19% in the placebo group. No adverse effects were reported. Simon et al. 10 evaluated the efficacy and safety of testosterone patches on surgically menopausal women with HSDD in a randomized, doubleblind, parallel-group, placebo-controlled 24-week multicenter clinical trial. Investigators enrolled 562 women aged 26 70 who had undergone a bilateral oophorectomy and hysterectomy at least 6 months before screening. All women had satisfying sexual relationships before the surgery and reported a bothersome loss of sexual desire and activity after the surgery. All participants were in a monogamous relationship with a partner who had normal sexual function. The women had no other medical, psychological or social factor that would explain their decrease in sexual desire and function. They had all been receiving a stable dose of estrogen for more than 3 months. Participants were randomized to either testosterone patches (300 mg/day applied twice a week) or placebo. After 24 weeks, there was a significant (P ¼ 0.0003) increase in the frequency of total satisfying sexual activity of 2.1 episodes per 4 weeks compared with 0.98 episodes per 4 weeks. The frequency of sexual episodes and orgasm also increased in the treatment group. More importantly, a significant correlation was noted between total and free T levels and the frequency rate. Withdrawal rates owing to side effects were 19% in placebo and 24% in the control group. There was no significant increase in androgen-related side effects (for example, acne, hirsutism, balding, lipid profiles) in the testosterone group. Androgen effects on BMD, hot flashes, lean body mass, energy and overall well-being Bone mineral density Davis et al., 7 in a prospective, single-blind trial, randomized 34 postmenopausal women to implants containing 50 mg estradiol either alone or with 50 mg testosterone. Cyclical oral progestins were taken by women who still had their uterus. The study noted that BMD increased more rapidly in the testosterone-treated group at all sites: total body (Po 0.008), vertebral L1 L4 (Po 0.001) and trochanteric (Po 0.005) measurements. In an open-label study by Raisz et al., 11 28 postmenopausal women were treated for 9 weeks with either 1.25 mg of conjugated equine estrogens or esterified estrogens 1.25 mg combined with 2.5 mg methyltestosterone (MT). Both groups had similar decreases in urinary excretion of bone resorption markers. The group treated with estrogen alone had commensurate decreases in serum markers of bone formation. In contrast, the group treated with combined estrogen/androgen therapy had an increase in these bone formation markers. The study concluded that administering testosterone with estrogen might reverse the inhibitory effects of estrogen on bone formation. It should be noted that these were small studies and larger randomized control trials are needed to conclu-
sively determine the effect of testosterone on BMD in women. It has been know for many years that androgen therapy could improve bone mineral density in men. Hot flashes Androgen therapy was first described for its use to relieve hot flashes in postmenopausal women. Testosterone acts directly on testosterone receptors in the brain and in the skin, but it can also act indirectly by conversion to estradiol (via aromatase) and, thus, could have estrogen-like effects. During the 1940s and 1950s, numerous reports described the effectiveness of estrogen androgen combination therapy for improving the overall feeling of wellbeing and quality of life for postmenopausal women. 12 However, more recent studies have shown testosterone therapy has no benefit in alleviating menopausal symptoms. 13,14 Dow et al. 13 showed that testosterone implants had no beneficial effect on menopausal symptoms, and Regestein et al. 14 found that oral testosterone (1.25 mg) had no significant effect on the menopause index defined by the Menopause-Specific Quality of Life Questionnaire. Simon et al. 15 demonstrated that the addition of non-aromatizable androgen to estrogen therapy could increase the efficacy of the estrogen therapy on vasomotor symptoms, and suppression of gonadotropins. The suppression of SHBG by this oral androgen with a resultant increase in free estradiol was postulated as the mechanism. Energy and overall well-being In the randomized, placebo-controlled, crossover efficacy trial by Goldstat et al., 9 testosterone therapy resulted in statistically significant improvements in the composite scores of the PGWB (P ¼ 0.003). Another well-designed crossover study using 300 mg/day testosterone patch plus oral estrogen in surgically menopausal women 8 showed improvement in positive well-being, less depressed mood and improved composite scores. However, four other randomized controlled trials showed that testosterone in oral or injectable forms had no effect on psychological well-being. 14,16 18 Side effects The potential side effects of testosterone therapy include hirsutism, acne and deepening of the voice, but the most important changes are those that affect lipid profiles, long-term breast cancer risks and cardiovascular factors. Simon et al. 10 reported that the serum lipid profile was similar between women receiving testosterone patches and placebo at 24 weeks. This appears not to be true for oral testosterone owing to its first pass liver effects. Clinical trials have shown that oral testosterone leads to a reduction in high-density lipoprotein (HDL) cholesterol and triglyceride levels in postmenopausal women receiving oral estrogen therapy. 19 25 Dimitrakakis et al., 26 in a retrospective observational study of 508 postmenopausal women who received testosterone in addition to estrogen therapy, showed that testosterone did not increase the incidence of breast cancer, but it may have lowered the incidence of hormone-associated breast cancer cases to equal those of the untreated population. While it remains possible that long-term use of testosterone in addition to estrogen therapy may increase the risk of breast cancer, adequately designed and powered studies have not been completed. A review of the impact of androgens on the breast, including breast cancer risk, has recently been published. 27 There are no data from randomized controlled trials to evaluate the effect of testosterone therapy on myocardial infarction, stroke or venous thromboembolic events. Although randomized clinical trials have not demonstrated an increase in these end points beyondwhatwouldhavebeenattributedtoestrogen alone, none of these studies has been adequately powered to statistically evaluate these end points in the early menopausal populations investigated. Few randomized controlled trials have addressed the side effect of hirsutism in women treated with testosterone. Two crossover studies with no washout periods reported no increase in hirsutism or acne from testosterone undecanoate 17 or transdermal testosterone. 8 Another 4-month trial by Lobo et al. 24 reported no differences in hirsutism or acne between the group treated with testosterone and estrogen as compared with the group treated with estrogen alone. A 24-month study by Barrett-Connor 19 found that hirsutism is uncommon with the use of oral MT. Commercially available testosterone products Testosterone is available in oral, transdermal (patches, gels, creams or ointments), subcutaneous pellets, intramuscular, sublingual and buccal forms. Although a few testosterone-containing products are government approved for use by women, none are Food and Drug Administration (FDA) approved for the treatment of sexual dysfunction. Oral testosterone Methylation of testosterone is needed to make it more bioavailable in an oral formulation. Only one oral tablet containing MT is FDA approved for women: Estratest (2.5 mg MT plus 1.25 mg esterified estrogens or 1.25 mg MT plus 0.625 mg esterified estrogens). Estratest is indicated for treatment of severe vasomotor symptoms, but it is also commonly prescribed for sexual dysfunction in women. 461
462 Andriol (testosterone undecanoate) is government approved in Canada for male androgen deficiency. However, it is used in women at a dose of 40 mg/day; the optimal dose is not known. After ingestion, all oral formulations undergo first-pass effect in liver, which increases the side effects on the liver (hepatoma, hepatocellular carcinomas) and lipid profiles (reduced HDL and triglyceride levels in estrogen-treated women). Transdermal testosterone gels, lotions, ointments and patches Androgel, a hydroalcoholic gel used in hypogonadal men, is commonly adapted for women by reducing the standard male dose by approximately 90%. Custom-compounded gels, lotions and ointments are also used for this purpose. The nominal delivery rate of these dosage forms should be between 100 and 300 mg/day to be consistent with normal premenopausal production. Newer gels and lotions specifically intended for use in women are in development. Androderm and Testoderm are testosterone patches FDA-approved for use in men. These patches should not be used in women, because they deliver high doses of testosterone far beyond the normal range for women. Lower-dose patches (150 300 mg/day) are being investigated for use in women. Shifren et al. 8 and Simon et al. 10 reported that testosterone patches delivering 300 mg/day for 3 6 months are safe and effective for the treatment of sexual desire disorder in surgically menopausal women receiving concomitant estrogen therapy. potential risk of delivering supraphysiologic amounts. There is no FDA-approved testosterone pellet. The side effects include those from supraphysiologic amounts of androgen of any form, infection from the implantation procedure, and the inconvenience of the minor surgical procedures necessary to insert the pellets. Intramuscular testosterone In the United States, the only FDA-approved intramuscular testosterone formulations are approved for men. In Canada, the product Climacteron (a combination of 150 mg/ml testosterone enanthate, 7.5 mg/ml estradiol dienanthate and 1 mg/ml estradiol benzoate), administered 0.5 1.0 ml IM every 4 6 weeks, is approved to treat postmenopausal symptoms. However, it is used off label to treat symptoms of HSDD. Side effects include reaching supraphysiologic levels immediately after injection and tachyphylaxsis and suboptimal clinical efficacy despite these supraphysiologic levels over time. As with all IM formulations, there is a small potential risk of infection and nerve injury. Sublingual and buccal testosterone No sublingual formulation is FDA approved for use in women. A buccal formulation (Striant) is FDA approved for use in men with deficiency or absence of endogenous testosterone associated with hypogonadism. The most common side effect is gum or mouth irritation (9.2%) and bitter taste (4.1%). Subcutaneous testosterone pellets Although some of the pellet formulations deliver constant levels of testosterone, most consisted of compressed crystalline testosterone, which has the Testosterone products in development Table 1 lists the testosterone products under development for treatment of female sexual desire disorders and their trial phase. Table 1 Testosterone products in development for female sexual desire disorders Formulation Product name, developer Trial status Oral methyltestosterone (plus esterified estrogens) Testosterone patch Testosterone cream Testosterone gel Testosterone gel (plus estrogen) Testosterone spray (metered dose transdermal system) Vaginal ring Estratest Solvay Pharmaceuticals Inc. Intrinsa Procter & Gamble Pharmaceuticals Androsorb Esprit Pharma, Inc. Tostelle Cellegy Pharmaceuticals LibiGel Biosante Pharmaceuticals Testosterone MDTS Vivus Inc. (No product name) Warner Chilcott Phase 2/3 Phase 3 Phase 2 Phase 2/3 Phase2/3 Phase 2 Phase 2
Summary and conclusion As women live long beyond their reproductive years, a phenomenon rare in the animal kingdom, they want to remain healthy, vital and most would also like to retain their sexual function. Since androgens are known to improve both vitality and sexual function, they have often been added to other therapies in an attempt to improve quality of life. Abundant epidemiological and emerging randomized clinical trial data have demonstrated that androgen therapy in both pre- and postmenopausal women can improve well-being, energy, sexual function and quality of life. Although not all women who suffer from low sexual desire, poor arousal or orgasmic dysfunction are androgen-deficient, those who are demonstrate a robust response to this therapy unless other interfering circumstances, illness or therapies are present. Side effects of testosterone therapy are usually mild, but depend on keeping doses in the normal premenopausal female range. 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