Testosterone therapy for sexual dysfunction in postmenopausal women

CLIMACTERIC 2008;11:181 191 Testosterone therapy for sexual dysfunction in postmenopausal women Z. Hubayter* and J. A. Simon { *Division of Reproductive Endocrinology and Infertility, Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, MD; { Department of Obstetrics and Gynecology, The George Washington University School of Medicine,Washington, DC, USA Key words: MENOPAUSE, SEXUAL DESIRE DISORDER, TESTOSTERONE, ANDROGEN, ESTROGEN ABSTRACT Background After menopause, both surgical and natural, increases occur in the number of women experiencing sexual dysfunction. Although a direct link between sexual dysfunction and endogenous testosterone levels has not been clearly established, testosterone therapy is known to improve the signs and symptoms related to hypoactive sexual desire. However, testosterone supplementation is not approved in the United States for these clinical indications, primarily because of a lack of data evaluating the possible side-effects of these drugs. Method A MEDLINE search was performed, with a priority for well-designed studies (randomized, controlled trials, meta-analysis), for published data related to the efficacy and safety of testosterone therapy in postmenopausal women. Results Randomized trials have demonstrated an improvement in sexual function with testosterone in postmenopausal women with hypoactive sexual desire disorder, particularly after oophorectomies. Side-effects have been well tolerated and reversible upon discontinuation. Conclusion Exogenous testosterone treatment provides a rational therapeutic alternative to consider in women whose hypoactive sexual desire disorder negatively affects their quality of life and who have no biologic or psychosocial causes not related to decreased androgen levels for their sexual disorder. Women receiving testosterone should be monitored for clinical improvement and for adverse reactions. Transdermal patches and topical gels avoid the hepatic first-pass metabolism and are the preferred formulations. Testosterone therapy is usually administered concomitantly with estrogen therapy due to a lack of adequate safety and efficacy data on testosterone alone. INTRODUCTION Sexuality is an important aspect of general health and well-being of women. Sexual desire is affected by endocrinologic and psychosocial factors. Both estrogen and androgen are important for normal sexual desire 1. Psychosocial factors include age, depression, sensation of well-being, anxiety, fatigue, relationship conflicts, history of sexual and/or physical abuse, lack of privacy, medication use, chronic diseases, and body image. Correspondence: Dr J. A. Simon, 1850 M. Street, NW, Suite 450, Washington, DC 20036, USA REVIEW ª 2008 International Menopause Society DOI: 10.1080/13697130802162822 Received 07-04-2007 Revised 10-12-2007 Accepted 13-12-2007

Menopause is also associated with reduced sexual desire. In women aged 44 55 years, the frequency of sexual activity is significantly lower in postmenopausal women than in premenopausal women of the same age 2. Overall, up to 40% of postmenopausal women experience low sexual desire 3. For postmenopausal women diagnosed with sexual desire disorder who seek medical care, non-pharmacologic therapies are available. However, if symptoms fail to respond adequately, and in the absence of other identifiable potential causes, testosterone is one of the few pharmacologic therapies shown to produce positive results. This article will review the association between sexual dysfunction and testosterone production in postmenopausal women and evaluate the benefits and risks of testosterone therapy in this population. TESTOSTERONE LEVELS AND SEXUAL FUNCTION In reproductive-age women, testosterone is produced by three sources: the adrenal glands, the ovaries, and from peripheral conversion of circulating androgens to testosterone. The ovaries and adrenal glands each contribute 25% of testosterone, with the remaining 50% coming from peripheral conversion of the androgen androstenedione to testosterone 4. Of the testosterone present in the circulation, 99% is bound to proteins, primarily sex hormone binding globulin (SHBG) 5,6. As women age, androgen production from the adrenal glands declines, resulting in a progressive decline in serum testosterone production from peripheral conversion. In postmenopausal women, the ovary continues to secrete premenopausal levels of testosterone; however, it produces less androstenedione, resulting in a 50% drop in androstenedione levels. Subsequently, despite stable ovarian production of testosterone, serum testosterone levels decline due to a reduction in androstenedione production from both adrenal glands and ovaries and from the peripheral conversion component 7. As a result, testosterone levels decrease with age, and women in their fifth decade have around half the level seen during their third decade 8. However, it should be noted that women who undergo a bilateral oophorectomy (i.e. surgically induced menopause) have a sudden 50% drop in testosterone levels 9. Although postmenopausal women tend to report a decline in sexual interest, sexual satisfaction and coital frequency, there is no clear association between testosterone levels and sexual function. Observational studies have shown varying results. Most of these studies were limited by either the power of the study, the sample selection, the accuracy of testosterone assays, or the measurement of total testosterone instead of the free active component as the variable under evaluation. In a well-controlled longitudinal study of 438 women during their menopause transition, there was no association between a low serum testosterone level (total or free) and sexual function 10. More recently, a cross-sectional study of 1423 women between the ages of 18 and 75 years showed no relationship between low sexual function and total or free testosterone levels 11. In addition, a myriad of interrelated factors, both biologic and psychosocial, affect sexual desire in postmenopausal women, which complicates the determination of whether decreased sexual desire is due to a hypoandrogenic state. Furthermore, most commercially available clinical testosterone assays do not have the precision to reliably measure the relatively low testosterone levels in peri- and postmenopausal women. (Tests are more useful in determining high values seen in men or in androgen-producing tumors 12.) Thus, no clinical values have been established for diagnosing sexual dysfunction. Nevertheless, even though psychosocial factors may be more important than a hormonal cause, it is essential to determine if a biologic cause exists that can be treated. TREATMENT OF POSTMENOPAUSAL SEXUAL DYSFUNCTION General categories of female sexual dysfunction (FSD), as recognized by the Fourth Edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) 13, include desire disorders (i.e. hypoactive sexual desire disorder or HSDD), arousal disorders, orgasmic disorders, and sexual pain disorders. To meet the definition of each type of FSD, the problem must be persistent and result in distress. These disorders can occur individually or in combination and may be primary or secondary to another disorder or to other physical or psychiatric conditions. For example, dyspareunia can lead to hypoactive desire over time. Sexual dysfunction in postmenopausal women that causes personal distress (or distress in 182 Climacteric

the partner) should be treated. Both nonpharmacologic and pharmacologic therapies exist. Non-pharmacologic therapies include improving communication skills with their partner (discuss/share sexual preferences, videos, fantasies), education, exercising to strengthen the pelvic floor muscles, and changing the sexual routine. Several of these behavioral changes act through an increase in genital blood flow. If these modalities fail to restore a satisfactory sexual life, then pharmacologic therapy should be considered. In postmenopausal women, exogenous estrogen will increase vaginal blood flow and lubrication and prevent vaginal atrophy associated with lowered estrogen levels. Estrogen therapy also has been shown to improve several sexual components, including clitoral sensitivity, orgasm rates, sexual desire level, and sexual activity 14,15. However, estrogen has no major effect on sexual desire 16, and its value is mainly in treating women with hypoestrogenism. Regarding serum testosterone levels, estrogen therapy increases SHBG levels, which reduces the free testosterone level. Therapy with conjugated estrogens is associated with a 100% increase in SHBG, while the micronized form results in a 45% increase. Non-oral forms, such as transdermal estrogen, are associated with only a 12% increase 17. However, in a study by Simon and colleagues 18, combined methyltestosterone and estrogen therapy significantly decreased SHBG levels after a 3-month treatment. The increase in bioavailable hormones in the combined therapy group correlated with increased relief of their somatic symptoms. In another study, Lobo and colleagues 19 found that women receiving estrogen with methyltestosterone had higher bioavailable testosterone and lower SHBG than those receiving esterified estrogens alone. They also had an improvement in their sexual desire, suggesting a possible relation between bioavailable testosterone, SHBG and libido. Therefore, when compared to estrogen alone, combined estrogen and androgen replacement appears to be superior by two mechanisms: a reduction in SHBG levels and an increase in testosterone levels. TESTOSTERONE THERAPY FOR POSTMENOPAUSAL SEXUAL DYSFUNCTION In randomized, controlled trials, testosterone therapy has been shown to enhance sexual function in postmenopausal women experiencing sexual dysfunction. The data support a general consensus that exogenous testosterone therapy increases sexual desire, sexual responsiveness and the frequency of sexual activity. In this review, the serum levels achieved for total or free testosterone will be reported, if available, since it is important to correlate these levels not only with the improvement in sexual function but also in the incidence of side-effects. Because different trials used different assays, the serum androgen levels will be reported as a percentage of the upper limit of the reference range for the method used 20. Free testosterone levels also will be reported, given that the total testosterone level may not be an accurate reflection of the bioavailable testosterone. A prospective cross-over study reported in 1985 investigated the effect of testosterone injections (200 mg testosterone enanthate) on sexual function in 53 surgically induced postmenopausal women 21. Women were randomized to testosterone alone, estrogen alone, testosterone plus estrogen, or placebo. Testosterone significantly improved sexual desire and arousal and increased the frequency of sexual fantasies compared with estrogen alone or placebo. Of note, this is one of very few trials with a testosterone-alone arm; in most other trials, testosterone was combined with estrogen. The total testosterone reached 111% of the upper normal range 20. Additional trials support the conclusion that the combination of testosterone and estrogen is superior to estrogen alone, indicating that testosterone has a role in improving sexual function independent of estrogen. The efficacy of testosterone implants was investigated in postmenopausal women (natural or surgically induced) in two single-blind trials. Burger and colleagues 22 compared subcutaneous implants containing 50 mg testosterone and 40 mg estradiol against those containing estrogen alone in 20 postmenopausal women. Testosterone recipients had significant improvements in libido and sexual pleasure after 6 weeks, and these findings persisted until the end of the 24-week trial. In women receiving androgens, the serum testosterone levels were slightly above the upper level of normal (117%) 20,22. Davis and colleagues 23 compared implants containing doses of 50 mg estradiol and/or 50 mg testosterone in 34 women. They found that women receiving testosterone had significant increases in sexual activity, pleasure, satisfaction and frequency of orgasms compared with those receiving estrogen Climacteric 183

alone. During the study, serum testosterone levels remained within the normal range 20,23. Several trials used oral testosterone formulations. In the largest trial 19, 218 natural or surgically induced postmenopausal women receiving baseline estrogen therapy and experiencing hypoactive sexual desire were randomized in a double-blind protocol to 4 months of either 0.625 mg oral esterified estrogens alone or combined with 1.25 mg methyltestosterone. Testosterone recipients had a significant increase in their sexual desire and interest; however, their sexual function scores did not improve. Testosterone recipients also had increased concentrations of free testosterone and decreased SHBG levels. The free and total testosterone levels were 109% and 38% of the upper limit of the reference range, respectively 19,20. In another double-blind trial, Sarrel and colleagues 24 randomized 20 women receiving oral estrogen therapy at baseline to oral esterified estrogen therapy (1.25 mg), either with or without oral methyltestosterone therapy (2.5 mg). At 8 weeks, testosterone recipients had significantly improved sexual desire and satisfaction compared with baseline, while the estrogen-alone group showed no improvement. In a double-blind, cross-over trial, Floter and colleagues 25 added oral testosterone undecanoate (40 mg/day) to oral estradiol valerate (2 mg/day) therapy in 50 women. Testosterone recipients had significantly improved overall sexual function, which included greater interest in and enjoyment of sexual activity, compared with estrogen-alone recipients. The free testosterone levels obtained with testosterone undecanoate in this study were supraphysiologic, reaching 231% of the upper limit value 20,25. Several trials have evaluated the effect of testosterone patches. In a double-blind, cross-over study by Shifren and colleagues 26, 75 surgically induced postmenopausal women taking at least 0.625 mg oral conjugated estrogens were randomly assigned to a 12-week regimen with one of the following: 150 mg of testosterone patch, 300 mg of testosterone patch, or placebo. Women receiving the higher dose of testosterone (but not the lower dose) had higher scores for frequency of sexual activity and pleasure-orgasm than those receiving placebo. Mean serum free testosterone levels were three times higher than placebo in women receiving 150 mg and nearly five times higher in women receiving 300 mg; however, these levels remained within the normal range. The free testosterone was only 57% of the upper normal limit when the lower dose was used (compared to 87% with the 300 mg dose) 20,26. At higher doses, women had more sexual fantasies, masturbated more, and engaged more frequently in sexual intercourse (up to three times/week). Testosterone recipients also had a greater sense of positive wellbeing and lower depressed mood than placebo recipients 26. In a larger double-blind trial, Buster and colleagues 27 randomly assigned 533 surgically induced postmenopausal women with hypoactive sexual desire to receive either the 300 mg testosterone patch or placebo, in addition to either oral or transdermal estrogen. At 24 weeks, women receiving testosterone had a significant improvement of one additional episode of sexual activity per 2.5 weeks. Women receiving a placebo had one additional episode every 5.5 weeks. The free testosterone level was 42% of the upper normal value of the reference range used 20,27. Simon and colleagues 28 performed a multicenter, double-blind, placebo-controlled trial in 562 surgically induced postmenopausal women aged 26 70 years with hypoactive sexual desire. Along with estrogen therapy, women were assigned to receive either a 300 mg/day patch or placebo. At 24 weeks, the testosterone group had a significant increase in satisfying sexual activity of 2.1 episodes per 4 weeks versus 0.98 episodes per 4 weeks in the placebo group. The testosterone group also had a significant improvement in sexual desire and a decrease in distress. In this trial, the free testosterone level was 55% of the upper limit 20,28. In another multicenter, double-blind trial 29, 318 surgically induced postmenopausal women receiving oral estrogen were randomized to either placebo or testosterone patches of varying doses twice per week (150 mg/day, 300 mg/day, or 450 mg/day) for a 24-week period. Doses higher than 300 mg/day resulted in a significant increase in sexual desire and in frequency of sexual activity. There were no significant differences between those receiving the 300 mg/day and those on the 450 mg/day dose. Women receiving the 150 mg/day dose had no benefit. Similar to the other patch studies reported, the free testosterone level was within the normal range (51% of the upper normal value) 20,29. OTHER EFFECTS OF TESTOSTERONE THERAPY In addition to enhancing sexual function, clinical trials have found that testosterone has a beneficial 184 Climacteric

effect on several systems in postmenopausal women. Vasomotor symptoms In women experiencing climacteric symptoms, adding testosterone implants (100 mg) to implants containing estradiol (50 mg estradiol) resulted in significant improvement in hot flushes, depression, and libido 30. The effects were not related to absolute hypoestrogenism but to the hormonal changes occurring in climacteric women. This is not surprising given that testosterone production is substantially reduced by an oophorectomy. Other studies failed to show any improvement. In a study by Dow and colleages 31, 40 postmenopausal women with declining sexual desire were randomized to receive one of two hormone implant regimens: 50 mg estradiol alone or 50 mg estradiol plus 100 mg testosterone. Results showed that testosterone had no effect on menopausal symptoms, defined as psychological, somatic, and vasomotor symptoms on the Greene Climacteric Scale. Currently, there are no indications to start testosterone for control of vasomotor symptoms in women. Well-being In trials, testosterone has shown some beneficial effects on well-being in postmenopausal women compared with placebo 26,32 34. Montgomery and colleagues 32 found a trend for improved wellbeing in testosterone estrogen recipients compared with estrogen placebo at 2 months; however, at 4 months, there were no significant differences between the groups. In a study by Sherwin 33, surgically induced postmenopausal women receiving intramuscular injection of estrogen alone or in combination with androgen had improvement in their mood status. Furthermore, women receiving the combination therapy felt more energetic, elated, and had more appetite than those on estrogen only. Another report also showed that sensation of well-being was more prevalent in surgically postmenopausal women receiving androgen therapy 31. In the study by Shifren and colleagues 26, women treated with testosterone patches containing 300 mg/day (but not the 150 mg/day dose) had significant improvements in their well-being. Cognitive function In a study by Regestein and colleagues 35, women receiving estrogen methyltestosterone had a faster mean reaction time when compared with those on estrogen alone or on no therapy. Bone density Several studies have shown that testosterone has a beneficial effect on the bone density of postmenopausal women. In a prospective, non-randomized study of 20 women on oral estrogen 36, ten were switched to a combination of estrogen and testosterone implants. After 1 year of therapy, testosterone recipients had significant increases from baseline in bone density at the spine (5.7%) and at the neck of the femur (5.2%); oral estrogen recipients had no change in bone density. In another study 37, 66 surgically induced postmenopausal women were treated with either oral esterified estrogen (1.25 mg) alone or combined with methyltestosterone (2.5 mg). Both hormonal therapies had a protective effect on bone (along with improvement in hot flushes, vaginal dryness and insomnia), with a significant increase in the bone density of the spine in women receiving additional testosterone therapy (3.4%; standard deviation,+1.2%). The treatment was well tolerated over the 2-year length of the study. Even though this suggests testosterone has a favorable effect on bone, no randomized, controlled trials have studied its effect on fracture risk. RISKS AND SIDE-EFFECTS Several side-effects have been associated with androgen therapy, some of which have not been proven in clinical trials to be of significant value. Cardiovascular system Testosterone has been shown to adversely affect the lipid profile. In a literature review assessing the effect on the cardiovascular system of testosterone when added to estrogen therapy, it was concluded that testosterone blocks the beneficial effect of estrogen on high density lipoprotein (HDL) 38.Ina randomized, double-blind, controlled study involving 26 women, total cholesterol, HDL, and apolipoprotein A1 were reduced more with testosterone estrogen therapy than with estrogen alone 39. Lobo and colleagues also concluded that testosterone reduces HDL levels 19. Climacteric 185

The adverse effects of testosterone therapy on the cardiovascular system have only been observed with oral administration these effects are not seen with non-oral testosterone formulations, even at higher doses 26,40,41. In a study with parenterally administered hormonal therapy, there were no differences in total cholesterol, triglyceride, HDL, or low density lipoprotein (LDL) levels in women who received only estrogen and those receiving estrogen and testosterone 42. More recently, two large, randomized, controlled trials over 24 weeks found no significant effect of transdermal testosterone on HDL 27,28. Regarding other cardiovascular effects, one study reported that women receiving 6-week parenteral testosterone (50 mg implant) therapy had improved arterial vasodilation 43. Testosterone therapy is not associated with increased plasma viscosity 27,28. Hirsutism and acne Testosterone therapy in women may result in some cosmetic effects, including acne, hirsutism, deepening of the voice, and clitoromegaly. If given at an appropriate dose, these side-effects tend to be minimal. In a double-blind, randomized, controlled trial by Watts and colleagues 37 comparing estrogen alone versus estrogen and methyltestosterone, women receiving the latter formulation had a significantly higher risk of hirsutism and acne. Other side-effects were comparable among the two groups. Women were followed over 2 years and these unwanted side-effects resolved spontaneously upon discontinuation of the therapy. Most studies in this review reported that testosterone therapy was well tolerated, with mild hirsutism seen in approximately 20% of recipients. However, these trials were not followed over a long period to better determine the risk of longterm use on hirsutism and acne development. Weight In a study evaluating the effect of long-term use of estrogen and testosterone implants, there was no significant difference in weight, blood pressure, or liver function after 3 years of use 44. Most studies mentioned in this review did not show a significant increase in body weight with the use of testosterone. Breast cancer No randomized trials have been of sufficient duration to show an association between breast cancer and testosterone therapy. A review of both human and animal studies did not find a breast cancer risk associated with testosterone estrogen therapy 45. In a retrospective observational study in 508 postmenopausal women 46, breast cancer incidence was not different for estrogen alone, estrogen testosterone, or no hormones for a mean follow-up of 5.8 years. In addition, there is evidence that testosterone might actually have a protective effect 47,48. Dimitrakakis and colleagues showed that physiologic levels of exogenous testosterone blocked the stimulatory effect of estradiol on mammary cell proliferation 49. Moreover, in women with polycystic ovarian syndrome who typically have hyperandrogenism, the relative risk of breast cancer is decreased to 0.52 50. On the other hand, epidemiologic data from 29 breast cancer cases showed that women receiving estrogen and testosterone had a higher risk of breast cancer than those receiving estrogen alone 51. However, all women in this study had prior use of estrogen replacement therapy. CANDIDATES FOR TESTOSTERONE THERAPY Due to the unreliability of testosterone assays and to the multifactorial causes of sexual dysfunction, it is a challenge to determine who will benefit the most from testosterone replacement. As noted, there is no single discriminatory value for free testosterone below which testosterone should be supplemented to improve sexual desire. Therefore, the decision to initiate testosterone is based on a case-by-case evaluation of the woman s signs and symptoms. Women complaining of hypoactive sexual desire should have an extensive history and physical examination to rule out all potential causes not attributable to androgen deficiency. These include depression, social and relationship factors, fatigue due to anemia, thyroid diseases, hyperprolactinemia, as well as an atrophic vagina and vulvodynia 52. Women should be counseled regarding the many biologic and psychosocial factors that can cause sexual disorders, and the need to treat them before considering testosterone therapy. They also should be made aware of all possible risks associated with therapy. Contraindications for testosterone therapy include androgenic alopecia, seborrhea, acne, hirsutism, pregnancy, lactation, and history of polycystic ovarian syndrome. It is also preferable not to supply testosterone to women with dyslipidemia and liver disorders 52,53, requiring lipid profile and liver function testing before initiating therapy. 186 Climacteric

Once other causes have been ruled out, testosterone therapy for decreased sexual desire is appropriate in women with bilateral oophorectomies, those who experienced premature menopause, and in postmenopausal women already on estrogen replacement. Premenopausal women with low sexual interest may also benefit from testosterone therapy. A 2005 position statement by the North American Menopause Society (NAMS) 53 concluded that postmenopausal women are candidates for testosterone therapy if they present with symptoms of decreased sexual desire associated with personal distress and have no other identifiable cause for their sexual problems. In a contrasting opinion, the US Endocrine Society recommends against testosterone use in women primarily because studies assessing longterm safety are lacking and there are no established clinical and laboratory parameters that define an androgen deficiency syndrome treatable by testosterone 54. While it is true that additional research is needed, available clinical trial data do support as a reasonable and sound clinical decision the use of testosterone in a carefully selected population of postmenopausal women suffering from hypoactive sexual desire. TESTOSTERONE THERAPIES Currently, no testosterone products are approved by either the United States or the Canadian government for use in treating sexual dysfunction in women. Most testosterone products are for use in men, but are being used off-label in women. The exact dose needed to treat postmenopausal sexual dysfunction is not known, particularly because there are several different products on the market. Compounded formulations are available in pharmacies, but these do not have strict controls for quality, and their side-effects and effectiveness have not been studied. The following is an overview of the available testosterone therapies. Oral testosterone Micronized testosterone is not well absorbed when ingested and, thus, can result in erratic serum testosterone concentrations from the same dose. However, methyltestosterone is more readily absorbed. The FDA-approved drugs are Estratest (combined 1.25 mg esterified estrogen plus 2.5 mg methyltestosterone) and Estratest HS (0.625 mg esterified estrogen plus 1.25 mg methyltestosterone). Estratest products are approved for the treatment of vasomotor symptoms. These medications undergo a first-pass hepatic metabolism, which can adversely affect the lipoprotein profile and ultimately reduce HDL, a finding only observed during oral administration 20. Testosterone undecanoate is a type of oral testosterone absorbed via the lymphatic system. It is available in Canada and Europe. Dosing requirements in women are not known. Testosterone undecanoate is rapidly absorbed and can result in high testosterone levels within few hours followed by a rapid turnover. The unpredictable absorption and the wide variation among different subjects make it less useful in women 55. Transdermal testosterone patches Currently, the only products approved by the Food and Drugs Administration (FDA), Androderm (2.5 5.0 mg/day) and Testoderm (5.0 mg/day), are for use by men; there are no appropriate doses for these patches to be used by women. However, several studies have shown that patches providing 300 mg/day are safe and well tolerated in women for up to 6 months of use. Additional studies of these 300 mg/day patches are ongoing with some data available for use as long as 3 years. Sublingual/buccal testosterone These formulations do not undergo first-pass hepatic metabolism but will undergo rapid absorption and turnover. They are not FDAapproved for use in women. Intramuscular testosterone As a non-oral formulation, these products do not undergo a first-pass metabolism. However, their use in women often results in supraphysiologic levels. They also tend to produce low serum levels following the peak after administration. Furthermore, this route is associated with discomfort. In Canada, Climacteron is approved for surgically or naturally postmenopausal women who have vasomotor symptoms or estrogen-induced osteoporosis. This formulation includes testosterone enanthate, estradiol dienanthate, and estradiol benzoate. An injection every month is needed. Subcutaneous testosterone pellets Testosterone pellets are not approved for use in the United States or Canada. However, they are more commonly used world-wide and have been Climacteric 187

Table 1 Different testosterone formulations and phase of development for hypoactive sexual desire disorder Formulation Product name Manufacturer Trial status Availability Oral methyltestosterone Estratest Solvay Pharmaceuticals, phase 2/3 available (US) (with esterified estrogens) Inc Testosterone patch Intrinsa Procter & Gamble phase 3 Pharmaceuticals Testosterone cream Androsorb Novavax, Inc. phase 2 Testosterone gel Tostrelle Cellegy Pharmaceuticals phase 2/3 Testosterone gel (plus estrogen) LibiGel Biosante Pharmaceuticals phase 2/3 Testosterone spray (metered Testosterone Vivus, Inc phase 2 dose transdermal system) MDTS Vaginal ring no product name Warner Chilcott phase 2 on the market for several decades. In North America, custom-compounded testosterone pellets are available. In some areas, they are the only available androgen therapy. Subcutaneous testosterone pellets are particularly suitable for women who have had a hysterectomy and are receiving estrogen replacement through an estrogen implant. Even though this formulation will result in a stable level, supraphysiologic levels can occur. Furthermore, a minor surgical procedure is needed to implant and remove the pellet should a complication (i.e. infection) occur. Testosterone gels and emulsions These products can be applied to any body surface; however, absorption is erratic, and initial clinical monitoring is needed. The most commonly used applications are 1% testosterone gel or cream or 0.5 g/day ointment. Most women apply the medication on the genital surface because it is believed that it enhances sensitivity. (Rubbing the medication against the clitoris is probably similar to a masturbatory effect.) However, in a randomized, double-blind, placebo-controlled study by Goldstat and colleagues, testosterone cream at a dose of 10 mg/day was applied to non-genital skin in premenopausal women 56. Results showed that this type of androgen replacement resulted in a testosterone level in the high normal range and an improvement in well-being, mood and sexual function. The most common complaints are that these formulations are messy and can cause local irritation. Several other formulations are under study (see Table 1). Monitoring Monitoring should be performed on all women prescribed testosterone therapy. The physician should evaluate for any improvement in sexual desire and satisfaction, as well as for any signs or symptoms of androgen excess (hirsutism, acne). A lipid profile should be drawn before starting an oral preparation and repeated after 3 months of therapy. If no safety concerns are noted, it can be repeated on a yearly basis. The free testosterone index may be useful in monitoring whether the drug has caused an appropriate rise in androgen levels 53. Concomitant estrogen therapy Testosterone therapy is most commonly administered with estrogen-containing therapy. This preference is based on the lack of data establishing the short- or long-term safety and efficacy of testosterone therapy in women not using concomitant estrogen. With the exception of a testosterone-alone arm in one study 21 that provided no adverse events data, all trials combined testosterone with estrogen therapy. The NAMS position statement does not recommend use of testosterone therapy without concomitant estrogen therapy 53. Clinical trials of testosterone without estrogen are ongoing. CONCLUSION Sexual desire disorders associated with menopause are affected by the lower endogenous estrogen and androgen levels observed in postmenopausal women. Exogenous estrogen has an excellent effect on improving vaginal epithelium and increasing genital blood flow. Exogenous testosterone, on the other hand, has been shown to improve sexual desire, arousal and satisfaction, although endogenous testosterone levels have not been empirically linked to sexual dysfunction in women. The lack of objective tests for measuring endogenous androgen levels combined with the subjectivity of sexual desire complicate the 188 Climacteric

patient selection process. In general, clinical trial evidence indicates that peri- and postmenopausal women with sexual disorders leading to personal distress, and in whom other causes not related to androgen levels have been excluded, are appropriate candidates for testosterone therapy. Women should be counseled regarding the multifactorial aspect of sexual disorders and the importance of identifying and treating all biological and psychosocial causes not attributable to endogenous androgen levels. They also should be educated regarding all possible risks associated with testosterone therapy. Testosterone therapy without concomitant estrogen-containing therapy is not recommended since there are no adequate data on the safety and efficacy of testosterone replacement in women not receiving concomitant estrogen at present 53. A wide variety of formulations are available and several more are being studied, but none is FDAapproved for use in treating sexual dysfunction. In most randomized trials, side-effects were primarily mild hirsutism and acne, which resolved after therapy was discontinued. Data on lipid profiles, cardiovascular diseases and breast cancer, although limited, have shown no major complications. Nevertheless, testosterone therapy is contraindicated in women with cardiovascular or liver disease and those with a history of breast or uterine cancer. Women receiving testosterone therapy should be monitored closely for subjective assessment of sexual satisfaction and for potential side-effects. Conflict of interest J.A.S. has acted as consultant, as a member of advisory boards and as a speaker for a number of pharmaceutical companies; Z.H. Nil. Source of funding J.A.S. has received grants and research support from a number of pharmaceutical companies. References 1. Hutchinson KA. Androgens and sexuality. Am J Med 1995;98:111 15S 2. Dennerstein L, Dudley E, Burger H. Are changes in sexual functioning during midlife due to aging or menopause? Fertil Steril 2001;76:456 60 3. Sarrel PM. Sexuality and menopause. Obstet Gynecol 1990;75:26 30S 4. Longcope C. Adrenal and gonadal androgen secretion in normal females. Clin Endocrinol Metab 1986;15:213 28 5. Dunn JF, Nisula BC, Rodbard D. Transport of steroid hormones: binding of 21 endogenous steroids to both testosterone-binding globulin and corticosteroid-binding globulin in human plasma. J Clin Endocrinol Metab 1981;53:58 68 6. Speroff L, Fritz MA. Clinical Gynecologic Endocrinology and Infertility, 7th edn. Baltimore, MD: Lippincott Williams & Wilkins, 2004 7. Adashi EY. The climacteric ovary as a functional gonadotropin-driven androgen producing gland. Fertil Steril 1994;62:20 7 8. Zumoff B, Strain GW, Miller LK, Rosner W. Twenty-four-hour mean plasma testosterone concentration declines with age in normal premenopausal women. J Clin Endocrinol Metab 1995;80:1429 30 9. McCoy NL, Davidson JM. A longitudinal study of the effects of menopause on sexuality. Maturitas 1985;7:203 10 10. Dennerstein L, Randolph J, Taffe J, Dudley E, Burger H. Hormones, mood, sexuality, and the menopausal transition. Fertil Steril 2002;77: S42 8 11. Davis SR, Davison SL, Donath S, Bell R. Relationships between circulating androgen levels and self reported sexual function in women. JAMA 2005;294:91 6 12. Taieb J, Mathian B, Millot F, et al. Testosterone measured by 10 immunoassays and by isotopedilution gas chromatography-mass spectrometry in sera from 116 men, women, and children. Clin Chem 2003;49:1381 95 13. American Psychiatric Association. DSM-IV: Diagnostic and Statistical Manual of Mental Disorders, 4th edn. Washington, DC: American Psychiatric Association, 1994 14. Sarrel PM. Sexuality and menopause. Obstet Gynecol 1990;75:26 30S 15. Nathorst-Boos J, Wiklund I, Mattsson LA, et al. Is sexual life influenced by transdermal estrogen therapy? A double blind placebo controlled study in postmenopausal women. Acta Obstet Gynecol Scand 1993;72:656 60 16. Myers LS, Dixen J, Morrissette D, et al. Effects of estrogen, androgen, and progestin on sexual psychophysiology and behavior in postmenopausal women. J Clin Endocrinol Metab 1990; 70:1124 31 Climacteric 189

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