International Journal of Impotence Research (2007) 19, 458–463 & 2007 Nature Publishing Group All rights reserved 0955-9930/07 $30.00 www.nature.com/ijir

REVIEW therapy in women: its role in the management of hypoactive sexual desire disorder

RT Abdallah and JA Simon

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 , and deepening of the voice along with changes in lipid profiles. While less well understood, concern after increased risks for 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. International Journal of Impotence Research (2007) 19, 458–463; doi:10.1038/sj.ijir.3901558; published online 21 June 2007

Keywords: testosterone; female sexual dysfunction; sexual desire

Introduction Physiology

Although the word is derived from the Clinically, five and androgen precursors Greek words ando (man) and genein (to produce), are thought to be the most important: testosterone androgens are known to play many roles in women, (T), (DHT), including those related to bone mineral density, (A), (DHEA) and dehydroe- energy and overall well-being, menopausal symp- piandrosterone sulfate. In women, androgens are toms, lean body mass, and sexual function. This produced in the ovaries and adrenal glands. The article will review the physiologic effects of andro- adrenal glands and ovaries contribute equally to gens, the effect of testosterone therapy, especially on testosterone production, approximately 25% each, sexual function, the side effects of testosterone except around ovulation when ovarian contribution therapy, and the commercially available testosterone increases by 10–15%. The other 50% of circulating products, focusing primarily on those products avail- testosterone comes from peripheral conversion of able in the United States. Given that disorders of androgen produced by the adrenals or ovaries. The sexual function occur in up to 43% of women rate of testosterone production in normal female (although most are relatively minor complaints),1 subjects is 0.2–0.3 mg/day. and that hypoactive sexual desire is the most common Routine assays measure total T, but only free T has of these complaints, an emphasis will be placed on a clinical effect. Approximately 80% of testosterone the effect of testosterone therapy on hypoactive sexual is bound to sex hormone-binding globulin (SHBG), desire disorder (HSDD) in women. 19% to albumin and 1% is free and physiologically active.2 SHBG production increases, and thus free T levels usually decrease, with pregnancy, therapy use (such as oral contraceptives) and Correspondence: Dr JA Simon, Department of Obestrics and Gynecology, George Washington University, 1850 M hyperthyroidism. In contrast, SHBG production is Street, NW, Washington, DC 20036, USA. decreased by insulin and androgen and by obesity E-mail: [email protected] and menopause. The decreases in SHBG levels at Received 28 September 2006; revised 21 February 2007; menopause, when ovarian production of estrogen accepted 14 March 2007; published online 21 June 2007 decreases, can explain why the concentration of free Testosterone therapy in women RT Abdallah and JA Simon 459 T remains the same or increases slightly during explained on the basis of testosterone levels, which perimenopause. remain fairly steady during the menopausal transi- The decline in measurable total testosterone tion. Mushayandebvu et al.6 proposed that the production at menopause is a function of aging decrease in sexual interest at perimenopause may and not natural menopause. Testosterone concentra- be caused by a blunting of the periovulatory rise in tions actually begin to decline during the late 20 or both testosterone and androstenedione seen in 30 s. Levels of testosterone, androstenedione and younger women. DHEA all continue falling at a constant rate, reach- The lower estrogen levels associated with meno- ing a level of about 50% of their peak by the time of pause do not directly affect sexual desire, even menopause. The postmenopausal ovary appears to though estrogen therapy may improve sexual func- continue producing testosterone after menopause. tion in postmenopausal women by decreasing However, a bilateral oophorectomy decreases testo- vaginal dryness and pain. However, prescribing sterone production by about 50%.3,4 estrogen, particularly oral estrogen, to relieve me- nopausal symptoms leads to an increase in SHBG, thus, further decreasing the level of free T, which may, in turn, affect sexual desire. Sexual dysfunction and HSDD

The sexual response can be divided into three stages: Evaluation desire, arousal and orgasm. Sexual dysfunction occurs When evaluating a woman with decreased , it if any of these stages is affected or if sexual pain (that is important to note the duration of the problem. A is dyspareunia) is present and if the symptoms persist long history starting in adolescence or early adult- and cause personal distress. The National Health and hood should be referred to a mental health profes- Social Life survey found that 43% of US women 1 sional. However, a short history or a history experience sexual dysfunction versus 31% of males. associated with a specific date is more likely to be Low sexual desire, or HSDD, is the most common related to a specific event (for example, social, sexual dysfunction complaint, accounting for approxi- psychological or hormonal). Only after ruling out mately 22% of cases. The term hypoactive sexual social causes (for example, marital problems, desire disorder is defined as a chronic or recurrent depression, anorexia, bulimia), physical factors deficit in or absence of desire for sexual activity that (for example, vestibulitis, vulvodynia, pelvic infla- causes personal distress, in which lack of desire is not mmatory disease, endometriosis) and other hormo- due to another condition or circumstance. The term nal deficiencies (for example, low estrogen leading female androgen insufficiency was defined by the to vaginal dryness) should testosterone deficiency Princeton consensus as a pattern of clinical symptoms be considered. in the presence of decreased bioavailable testosterone 5 Given the lack of reliability and precision and normal estrogen levels. The most commonly of many commercially available free T assays when reported clinical symptoms are decreased libido and used in menopausal women and the rapid fluctuation sexual pleasure, a diminished sense of well-being, and of endogenous testosterone concentrations, it is persistent unexplained fatigue. difficult to accurately measure testosterone in clinical Sexual dysfunction can be caused by general practice. Measuring free and total T levels in medical conditions, such as diabetes mellitus, menstruating women between menstrual cycle hypothyroidism, congestive heart disease, hyper- days 7–10 will avoid both the very low free and prolactinemia, Addison’s disease, Cushing’s disease, total T levels that occur early in the cycle as well temporal lobe lesions or menopause. Medications, as the preovulatory peak in testosterone; however, such as chemotherapy, selective-serotonin reuptake this approach cannot compensate for the basic inhibitors and antihypertensives, can cause sexual imprecision of the testosterone assay, nor the poor dysfunction. There are psychological and social correlation between testosterone levels and sexual causes, such as depression, unresolved sexuality function. If a validated commercial assay is available and marital problems. Other conditions that can be with proven normal ranges for women, then choosing associated with a decrease in sexual desire include an arbitrary cutoff of the upper two-thirds of medical conditions treated with corticosteroids, normal premenopausal range (to represent ‘normal’) such as asthma, rheumatoid arthritis and connective may avoid over or under treatment based on the tissue diseases. poor sensitivity of available assays. 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 Testosterone therapy for HSDD in women common for perimenopausal women who still maintain functional ovulatory cycles to experience Recent studies have shown that testosterone therapy decreased sexual desire. However, this cannot be improves sexual function in postmenopausal

International Journal of Impotence Research Testosterone therapy in women RT Abdallah and JA Simon 460 women. Testosterone therapy can improve arousability, multicenter . Investigators enrolled 562 sexual desire and fantasy, frequency of sexual women aged 26–70 who had undergone a bilateral activity and orgasm, and satisfaction and pleasure oophorectomy and hysterectomy at least 6 months from the sexual act. Davis et al.7 also showed that before screening. All women had satisfying sexual testosterone improves libido, generalized fatigue, relationships before the surgery and reported a overall sense of well-being and quality of life. In bothersome loss of sexual desire and activity after another randomized, placebo-controlled study by the surgery. All participants were in a monogamous Shifren et al.,8 75 women aged 31–56 years old who relationship with a partner who had normal sexual had undergone oophorectomy and hysterectomy function. The women had no other medical, psy- received conjugated equine plus placebo chological or social factor that would explain their or 150 or 300 mg/day of testosterone transdermally decrease in sexual desire and function. They had all for 12 weeks. Outcome measures included scores on been receiving a stable dose of estrogen for more the Brief Index of Sexual Functioning for Women than 3 months. (BISF-W), the Psychological General Well-Being Participants were randomized to either testoster- Index (PGWB), and a sexual function diary. The one patches (300 mg/day applied twice a week) or mean serum-free T concentration increased from placebo. After 24 weeks, there was a significant 1.2 pg/ml during placebo treatment to 3.9 and 5.9 pg/ (P ¼ 0.0003) increase in the frequency of total ml during treatment with 150 and 300 mg/day of satisfying sexual activity of 2.1 episodes per 4 weeks testosterone, respectively. The higher testosterone compared with 0.98 episodes per 4 weeks. The dose resulted in further increases in scores for frequency of sexual episodes and orgasm also frequency of sexual activity and pleasure-orgasm increased in the treatment group. More importantly, on the BISF-W (P ¼ 0.03 for both comparisons versus a significant correlation was noted between total placebo). At the higher dose, the percentages of and free T levels and the frequency rate. Withdrawal women who had sexual fantasies, masturbated, or rates owing to side effects were 19% in placebo and engaged in sexual intercourse at least once a week 24% in the control group. There was no significant increased two to three times from baseline. The increase in androgen-related side effects (for exam- positive well-being, depressed-mood and composite ple, acne, hirsutism, balding, lipid profiles) in the scores on the PGWB also improved at the higher testosterone group. 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 Androgen effects on BMD, hot flashes, lean et al.9 evaluated the efficacy of transdermal testo- body mass, energy and overall well-being sterone in premenopausal women. In this rando- mized, placebo-controlled, crossover study, 34 Bone mineral density premenopausal women aged 30–45 years who Davis et al.,7 in a prospective, single-blind trial, reported diminished sexuality applied testosterone randomized 34 postmenopausal women to implants cream 10 mg/day (or placebo) for 12-week periods containing 50 mg either alone or with separated by a 4-week washout period. The women 50 mg testosterone. Cyclical oral progestins were all had early morning total T levels of o2.2 nmol/l. taken by women who still had their uterus. The Women with relationship problems, dyspareunia, study noted that BMD increased more rapidly in depression, high testosterone levels and various the testosterone-treated group at all sites: total body medical problems were excluded from the study. (Po 0.008), vertebral L1–L4 (Po 0.001) and Mean T levels in the treatment group were at the high trochanteric (Po 0.005) measurements. end of the normal premenopausal range, while In an open-label study by Raisz et al.,11 28 post- estradiol levels were unchanged. Although results menopausal women were treated for 9 weeks with from the Beck Depression Inventory were not sig- either 1.25 mg of conjugated equine estrogens or nificantly changed by testosterone treatment (2.8 1.25 mg combined with 2.5 mg decrease; P ¼ 0.06), this therapy resulted in significant (MT). Both groups had similar improvements in the composite scores of the PGWB decreases in urinary of bone resorption (12.9; P ¼ 0.003) and the Sabbatsberg Sexual Self- markers. The group treated with estrogen alone had Rating Scale (15.7; P ¼ 0.001) compared with placebo. commensurate decreases in serum markers of bone In addition, 46% of the participants reported a 50% or formation. In contrast, the group treated with more increase in their total sexual self-rating score in combined estrogen/androgen therapy had an in- the treatment group versus 19% in the placebo group. crease in these bone formation markers. The study No adverse effects were reported. concluded that administering testosterone with Simon et al.10 evaluated the efficacy and safety estrogen might reverse the inhibitory effects of of testosterone patches on surgically menopausal estrogen on bone formation. women with HSDD in a randomized, double- It should be noted that these were small studies and blind, parallel-group, placebo-controlled 24-week larger randomized control trials are needed to conclu-

International Journal of Impotence Research Testosterone therapy in women RT Abdallah and JA Simon 461 sively determine the effect of testosterone on BMD in reduction in high-density lipoprotein (HDL) choles- women. It has been know for many years that androgen terol and triglyceride levels in postmenopausal therapy could improve bone mineral density in men. women receiving oral estrogen therapy.19–25 Dimitrakakis et al.,26 in a retrospective observational study of 508 postmenopausal women who received Hot flashes testosterone in addition to estrogen therapy, showed Androgen therapy was first described for its use to that testosterone did not increase the incidence of relieve hot flashes in postmenopausal women. breast cancer, but it may have lowered the incidence Testosterone acts directly on testosterone receptors of hormone-associated breast cancer cases to equal in the brain and in the skin, but it can also act those of the untreated population. While it remains indirectly by conversion to estradiol (via aromatase) possible that long-term use of testosterone in addition and, thus, could have estrogen-like effects. During to estrogen therapy may increase the risk of breast the 1940s and 1950s, numerous reports described cancer, adequately designed and powered studies the effectiveness of estrogen–androgen combination have not been completed. A review of the impact of androgens on the breast, including breast cancer risk, therapy for improving the overall feeling of well- 27 being and quality of life for postmenopausal wo- has recently been published. men.12 However, more recent studies have shown There are no data from randomized controlled trials testosterone therapy has no benefit in alleviating to evaluate the effect of testosterone therapy on menopausal symptoms.13,14 Dow et al.13 showed myocardial infarction, stroke or venous thromboem- that testosterone implants had no beneficial effect bolic events. Although randomized clinical trials have on menopausal symptoms, and Regestein et al.14 notdemonstratedanincreaseintheseendpoints found that oral testosterone (1.25 mg) had no beyondwhatwouldhavebeenattributedtoestrogen significant effect on the menopause index defined alone, none of these studies has been adequately by the Menopause-Specific Quality of Life Ques- powered to statistically evaluate these end points in tionnaire. Simon et al.15 demonstrated that the the early menopausal populations investigated. addition of non-aromatizable androgen to estrogen Few randomized controlled trials have addressed therapy could increase the efficacy of the estrogen the side effect of hirsutism in women treated with therapy on vasomotor symptoms, and suppression testosterone. Two crossover studies with no washout of . The suppression of SHBG by this periods reported no increase in hirsutism or acne from testosterone undecanoate17 or transdermal tes- oral androgen with a resultant increase in free 8 24 estradiol was postulated as the mechanism. tosterone. Another 4-month trial by Lobo et al. reported no differences in hirsutism or acne between the group treated with testosterone and estrogen as Energy and overall well-being compared with the group treated with estrogen alone. 19 In the randomized, placebo-controlled, crossover A 24-month study by Barrett-Connor found that efficacy trial by Goldstat et al.,9 testosterone therapy hirsutism is uncommon with the use of oral MT. resulted in statistically significant improvements in the composite scores of the PGWB (P ¼ 0.003). Another well-designed crossover study using Commercially available testosterone 300 mg/day testosterone patch plus oral estrogen in products surgically menopausal women8 showed improve- ment in positive well-being, less depressed mood Testosterone is available in oral, transdermal and improved composite scores. However, four (patches, gels, creams or ointments), subcutaneous other randomized controlled trials showed that pellets, intramuscular, sublingual and buccal forms. testosterone in oral or injectable forms had no effect 14,16–18 Although a few testosterone-containing products are on psychological well-being. government approved for use by women, none are Food and Drug Administration (FDA) approved for Side effects the treatment of sexual dysfunction.

The potential side effects of testosterone therapy include hirsutism, acne and deepening of the voice, Oral testosterone but the most important changes are those that affect Methylation of testosterone is needed to make it lipid profiles, long-term breast cancer risks and more bioavailable in an oral formulation. Only one cardiovascular factors. Simon et al.10 reported that oral tablet containing MT is FDA approved for the serum lipid profile was similar between women women: Estratest (2.5 mg MT plus 1.25 mg esterified receiving testosterone patches and placebo at 24 estrogens or 1.25 mg MT plus 0.625 mg esterified weeks. This appears not to be true for oral testoster- estrogens). Estratest is indicated for treatment of one owing to its ‘first pass’ effects. Clinical severe vasomotor symptoms, but it is also commonly trials have shown that oral testosterone leads to a prescribed for sexual dysfunction in women.

International Journal of Impotence Research Testosterone therapy in women RT Abdallah and JA Simon 462 Andriol () is government potential risk of delivering supraphysiologic approved in for male . amounts. There is no FDA-approved testosterone However, it is used in women at a dose of 40 mg/day; pellet. The side effects include those from supra- the optimal dose is not known. physiologic amounts of androgen of any form, After ingestion, all oral formulations undergo infection from the implantation procedure, and the first-pass effect in liver, which increases the side inconvenience of the minor surgical procedures effects on the liver (hepatoma, hepatocellular carci- necessary to insert the pellets. nomas) and lipid profiles (reduced HDL and triglyceride levels in estrogen-treated women). Intramuscular testosterone In the United States, the only FDA-approved Transdermal testosterone gels, lotions, ointments intramuscular testosterone formulations are ap- and patches proved for men. In Canada, the product Climacteron Androgel, a hydroalcoholic gel used in hypogonadal (a combination of 150 mg/ml testosterone enanthate, men, is commonly adapted for women by reducing 7.5 mg/ml estradiol dienanthate and 1 mg/ml estra- the standard male dose by approximately 90%. diol benzoate), administered 0.5–1.0 ml IM every 4– Custom-compounded gels, lotions and ointments 6 weeks, is approved to treat postmenopausal are also used for this purpose. The nominal delivery symptoms. However, it is used off label to treat rate of these dosage forms should be between 100 symptoms of HSDD. Side effects include reaching and 300 mg/day to be consistent with normal supraphysiologic levels immediately after injection premenopausal production. Newer gels and lotions and tachyphylaxsis and suboptimal clinical efficacy specifically intended for use in women are in despite these supraphysiologic levels over time. As development. with all IM formulations, there is a small potential Androderm and Testoderm are testosterone risk of infection and nerve injury. 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– Sublingual and buccal testosterone 300 mg/day) are being investigated for use in women. No sublingual formulation is FDA approved for use Shifren et al.8 and Simon et al.10 reported that in women. A buccal formulation (Striant) is FDA testosterone patches delivering 300 mg/day for 3–6 approved for use in men with deficiency or absence months are safe and effective for the treatment of of endogenous testosterone associated with hypogo- sexual desire disorder in surgically menopausal nadism. The most common side effect is gum or women receiving concomitant estrogen therapy. mouth irritation (9.2%) and bitter taste (4.1%).

Subcutaneous testosterone pellets Testosterone products in development Although some of the pellet formulations deliver Table 1 lists the testosterone products under devel- constant levels of testosterone, most consisted of opment for treatment of female sexual desire compressed crystalline testosterone, which has the 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) Estratest Phase 2/3 Solvay Pharmaceuticals Inc. Testosterone patch Intrinsa Phase 3 Procter & Gamble Pharmaceuticals Testosterone cream Androsorb Phase 2 Esprit Pharma, Inc. Testosterone gel Tostelle Phase 2/3 Cellegy Pharmaceuticals Testosterone gel (plus estrogen) LibiGel Phase2/3 Biosante Pharmaceuticals Testosterone spray (metered dose transdermal system) Testosterone MDTS Phase 2 Vivus Inc. Vaginal ring (No product name) Phase 2 Warner Chilcott

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