Androgen replacement therapy in women

FERTILITY AND STERILITY威 VOL. 82, NO. 2, AUGUST 2004 Copyright ©2004 American Society for Reproductive Medicine Published by Elsevier Inc. Printed on acid-free paper in U.S.A. MODERN TRENDS Edward E. Wallach, M.D. Associate Editor Androgen replacement therapy in women Deborah R. Cameron, R.N.,a and Glenn D. Braunstein, M.D.a,b* Cedars-Sinai Medical Center, Los Angeles, California Objective: Review of literature with regard to androgen replacement therapy in women. Design: Review of the MEDLINE database and references from articles. Conclusions: Androgens affect sexual function, bone health, muscle mass, body composition, mood, energy, and the sense of well-being. Androgen insufficiency clearly has been demonstrated in patients with hypopituitarism, adrenalectomy, oophorectomy, and in some women placed on oral estrogen therapy which increases sex hormone-binding globulin (SHBG) levels and lowers the free and bioavailable forms of T. Symptoms of androgen insufficiency in women may include a diminished sense of well-being, low mood, fatigue, and hypoactive sexual desire disorder with decreased libido, or decreased sexual receptivity and pleasure that causes a great deal of personal distress. The preponderance of evidence from clinical trials supports the correlation of decreased endogenous androgen levels with these symptoms and alleviation of many of the symptoms with the administration of T or, in some cases, DHEA. There are no Food and Drug Administrationapproved androgen preparations on the market for treating androgen insufficiency in women. The safety profile of androgens in doses used for the treatment of hypoactive sexual desire disorder has been excellent with only mild acne and hirsutism being noted in a minority of patients. (Fertil Steril威 2004;82:273– 89. © 2004 by American Society for Reproductive Medicine.) Key Words: Androgen replacement therapy, androgen insufficiency syndrome, testosterone replacement, oophorectomy, female sexual dysfunction, hypoactive sexual desire disorder, libido Received October 13, 2003; revised and accepted November 14, 2003. Reprint requests: Glenn D. Braunstein, M.D., Department of Medicine, Plaza Level, Room 2119, Cedars-Sinai Medical Center, 8700 Beverly Blvd., Los Angeles, CA 90048 (FAX: 310-423-0437; Email: [email protected]). *Glenn D. Braunstein, M.D., is a Principal Investigator and a consultant for studies conducted by Procter & Gamble Pharmaceuticals, Inc. on a transdermal matrix delivery system of testosterone for women. a Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Cedars-Sinai Medical Center. b David Geffen School of Medicine at UCLA, Los Angeles, California. 0015-0282/04/$30.00 doi:10.1016/j.fertnstert.2003. 11.062 Female sexual dysfunction has been classified as four distinct disorders—sexual desire disorders (includes hypoactive and aversion disorders), sexual arousal disorder, orgasmic disorder, and sexual pain disorders (dyspareunia, vaginismus, and other causes) (1, 2). For some women, androgen insufficiency may result in hypoactive sexual desire disorder (HSDD), which is defined as a change in sexual function such as a persistent or recurring deficiency (or absence) of sexual fantasies or thoughts and desire for or receptivity to sexual activity that causes personal distress (1–3). For seven decades (4 –11), androgens have been used to treat menopausal symptoms including low libido and other manifestations of HSDD, but only recently have careful clinical trials established the beneficial effects of androgens in women with androgen insufficiency (12–15). This review focuses on the clinical constellation of symptoms that have been associated with androgen insufficiency, the relationship of androgens to female sexuality, and the efficacy and safety of androgen therapy in women. ANDROGENS IN WOMEN The biological activity of an androgen depends on its ability to bind to androgen receptors in target tissues and regulate gene transcriptional activity (i.e., its potency), the production rate, metabolic clearance rate, which includes various metabolic conversions and excretion, and the quantitative amount that is available to the target tissues. The metabolic clearance rate and amount of androgen that is bioavailable in the blood to be transported into cells is dependent to a great extent on the degree of binding to the low capacity and high affinity ␤-globulin, sex hormone-binding globulin (SHBG), and the high capacity but low affinity albumin (16 –21). The quantity of androgen in the blood that is not bound to serum proteins or weakly bound to albumin is considered to be bioavailable. Table 1 summarizes the relative potency, serum concentrations, and protein binding of the major androgens or precursors that are present in blood (16 –21). Taking into account the potency, concentration, and clinical correlations with hyper- and 273 TABLE 1 Relative potency; mean serum concentrations, and protein binding of major androgens or androgen precursors in women. Androgen Premenopausal serum concentrations (ng/dL) Postmenopausal serum concentrations (ng/dL) Relative potency % Unbound % Bound to albumin % Bound to SHBG 20 32 140 415 188,500 11 22 77 186 106,000 5 1 0.1 0.01 0.001 0.5 1.4 7.5 3.9 5.0 21 30.4 84.5 88.1 95.0 78 66 6.6 7.9 — DHT T A DHEA DHEAS Note: DHT ⫽ dihydrotestosterone; A ⫽ androstenedione; DHEA ⫽ dehydroepiandrosterone; DHEAS ⫽ dehydroepiandrosterone sulfate. Adapted from 16 –21. Cameron. Androgen replacement therapy in women. Fertil Steril 2004. hypoandrogenic states in women, T is a reasonable measure of the androgen status of women. The total T level is markedly influenced by the SHBG concentration. Sex hormonebinding globulin levels are decreased in obesity, hyperinsulinism, glucocorticoid or growth hormone excess, hypothyroidism, and hyperandrogenic states (17, 22). The levels are increased with oral estrogen therapy, hyperthyroidism, cirrhosis, and some antiepileptic medications (17, 22). Therefore, the free or bioavailable T level more accurately reflects androgen status than does the total T concentration. Free T is best measured by equilibrium dialysis and not by the various direct or analogue assays on the market (22, 23). The Free T Index (also called the Free Androgen Index) closely correlates with the free T measurement, and can be calculated from measurements of total T and SHBG (24). Androgens are directly secreted into the circulation by the ovaries and adrenals (25). In addition, various peripheral tissues, such as adipose tissue, muscle, and fat, convert androgens and androgen precursors from the ovaries and adrenals into androgens that then enter the circulation as part of the androgen pool. The relative contributions of these sources to androgen production in pre- and postmenopausal women are summarized in Table 2 (17, 26 –29). The circulating concentrations of the androgens may not reflect androgen action at a specific target tissue. For instance, the expression of the levels of 5␣-reductase, the enzyme that catalyzes the conversion of T to dihydrotestosterone (DHT), varies in different target organs and at different sites. Indeed, the term ‘intracrinology’ has been used to describe hormone production, metabolism, and effect occurring in the same local target tissue (30). This process allows androgens to be biologically available for physiologic effects, but unavailable for direct biologic measurement in serum. An indirect measurement of androgen status of peripheral tissues may be assessed by biological assay of DHT metabolites: androsterone-glucoronide (ADT-G), andro- TABLE 2 Relative contributions of ovarian, adrenal, or peripheral tissues in androgen production in premenopausal and postmenopausal women. Ovarian production (%) DHT T A DHEA DHEAS Adrenal production (%) Peripheral production (%) Premenopause Postmenopause Premenopause Postmenopause Premenopause Postmenopause Very small None Small Small 25% 40% 10% 0% 150% 220% 10% 0% 25% 50% 50% 90% 210% 170% 50% 90% Almost entirely from T 50% from A 10% from D 40% from DS 10% from D Almost entirely from T 240% from A 10% from D 40% from DS 10% from D Note: D ⫽ DHEA; DS ⫽ DHEAS; other abbreviations as in Table 1. Adapted from 17, 26 –29. Changes from the premenopausal to postmenopausal status are highlighted with arrows. Cameron. Androgen replacement therapy in women. Fertil Steril 2004. 274 Cameron and Braunstein Androgen replacement therapy in women Vol. 82, No. 2, August 2004 stane-3␣, 17␤-diol-glucoronide (3␣-diol-G), androstane-3␤, 17␤-diol-glucoronide (3␤-diol-G), and ADT-sulfate (31). Androgen production and serum levels decrease with age. Both T and androstenedione (A) levels decrease before menopause. One study in a small number of women noted that the mean serum T concentration at age 21 years was approximately twice that at age 40 years (32), whereas an approximate 25% decrease was noted between ages 42 and 50 years in the Study of Women’s Health Across the Nation (SWAN) (33). There is conflicting data, however, as to whether T levels decrease further during the menopause transition. Some studies suggest that an approximately 15% decline occurs (16, 34 –36). In contrast, the large longitudinal Melbourne Women’s Midlife Health Project, which studied women through the menopausal transition, did not demonstrate a decline in total serum T; indeed, a decrease in SHBG levels resulted in an increase in the calculated free androgen index (37). Similarly, the SWAN study did not find a reduction in T concentrations during the menopausal transition (33). There is no controversy surrounding the observations that production of the major androgen precursor from the adrenals, DHEA, and its sulfate peak during the third decade and then sharply decline between ages 30 and 60 years (37– 41). Between the ages of 20 and 80 years, serum DHT levels steadily decrease an average of 44% in association with a decrease between 48% and 72% of various conjugated metabolites (38). Thus, the relatively low androgen levels found in women after the menopause in comparison to women in their 20s and 30s reflects an age-related decrease, rather than a specific menopausal effect. ANDROGENS AND SEXUALITY The individual and combined effect of estrogens and androgens on female sexual function is controversial. Estrogens clearly decrease the vasomotor symptoms that can lead to sleep disturbances, which can affect mood, energy, and quality of life. Estrogens also improve vaginal mucus production, thereby reducing dyspareunia and the avoidance of sexual intercourse because of pain. These estrogen-mediated improvements may improve sexual receptivity, but they do not improve libido (42). The role of androgens has been difficult to discern. Libido, arousability, and frequency of sexual activity have been correlated with the mid-menstrual cycle increase in T (43– 47). Women with high normal T levels across the menstrual cycle are less depressed and experience more sexual gratification than do women with low normal T concentrations (44). In addition, several cross-sectional studies performed on women at various ages across the adult lifespan have shown positive correlations with T and sexual desire, arousal, initiation, responsiveness to sexual activity, and frequency of sexual gratification and intercourse (44, 48 –50). A longituFERTILITY & STERILITY威 dinal study (50), which followed women from approximately 2 years before until 2 years after the final menses, demonstrated a decline in coital frequency and sexual thoughts or fantasies, an increase in dyspareunia, and an increased dissatisfaction with their partners as lovers. In this study, E2 and T levels both showed significant (P⬍.002) declines, whereas T demonstrated closer correlation with coital frequency. In contrast, several studies (51–58) have not found a correlation of androgen levels to sexual function. The variables that are most problematic in attempts to correlate androgen levels to sexual function include insufficiently sensitive androgen assays, insufficient study power, and the lack of validated measures to assess sexual function (59). Even in the studies showing a positive association between androgens and parameters of sexual function, the correlations generally have not been very robust, indicating that in addition to androgens other factors such as relationship issues, attitudes, and general health as well as medication use by the patient and partner contribute to sexual function. ANDROGEN INSUFFICIENCY SYNDROME Androgen insufficiency has been well documented in four conditions: hypopituitarism, adrenalectomy/adrenal insufficiency, oophorectomy/premature ovarian failure, and after institution of oral estrogen replacement therapy (ERT) (10, 12, 19, 60 – 65). In a study of 55 estrogenized and nonestrogenized women with hypopituitarism (66), characterized by hypogonadism or hypoadrenalism, and 92 controls, serum total T, free T, A, and DHEAS were significantly decreased in the women with hypopituitarism as compared to the control group. The investigators reported that the severity of androgen insufficiency in these women was probably underestimated due to the limitations of androgen assays. In an early study (10), an abrupt loss of libido was observed in women after adrenalectomy with concomitant or prior oophorectomy as treatment for breast cancer. In this study, 17 of 29 women with a mean age of 51 years reported some sexual desire before surgery. Of the 17 women who were sexually active before surgery, all reported reduced frequency of intercourse, with almost half reporting cessation of sexual intercourse (Pⱕ.05) and 14 reported a decrease in desire of which 10 reported a total loss of desire (P ⫽ .01). Of the 12 women who were responsive in intercourse before surgery, 11 women experienced a decrease of which 9 reported a total loss of responsiveness (P ⫽ .01) after surgery. More recent studies have confirmed that women with adrenal insufficiency have reduced concentrations of a variety of serum androgens (10, 60, 61, 66, 67). Similarly, chronic administration of glucocorticoids may decrease androgen levels through suppression of DHEA production by the adrenals (68). Longitudinal hormone measurements after bilateral oophorectomy have shown an approximate 50% reduction in T 275 TABLE 3 Components of female androgen insufficiency syndrome. Symptoms Low libido with global decrease in sexual desire, fantasy, or arousability Persistent, unexplained fatigue Decreased sense of well-being Blunted motivation Flattened mood Signs Thinning or loss of public hair Decreased lean body mass Osteopenia or osteoporosis Other indications Onset after an event associated with decreased androgen production Other causes of symptoms have been evaluated and ruled out Symptoms persist despite having normal estrogen production if premenopausal or being on adequate estrogen replacement if hypogonadal Note: From 72. Cameron. Androgen replacement therapy in women. Fertil Steril 2004. levels and a 40%–50% reduction in A levels (62, 63, 69). The cross-sectional Rancho Bernardo study found that elderly postmenopausal women without ovaries had total and bioavailable T levels that were 40% lower and A levels that were 10% lower compared to postmenopausal women with intact ovaries (70). There is general agreement that ERT, especially by the oral route, may result in elevations of SHBG, which binds much of the circulating T, thereby reducing the free or biologically active fraction (19, 71). In women who are prone to exhibit low androgen levels because of oophorectomy, adrenal insufficiency, or hypopituitarism, estrogen administration may precipitate symptomatic androgen insufficiency. it is reasonable to consider a menopausal woman to have androgen insufficiency if she exhibits typical symptoms and has a free T or free T index level in the lowest quartile of the normal range or below the normal range for reproductive age women (3). In evaluating a woman suspected of having androgen insufficiency, it is important to eliminate other causes of the symptoms such as depression, iron deficiency, hypothyroidism, anemia, and medication use (especially glucocorticoids and selective serotonin reuptake inhibitors) from consideration (3). It is important to make sure that the woman is adequately estrogenized to eliminate dyspareunia with secondary avoidance of sexual activity. However, as noted, ERT can precipitate symptoms of androgen insufficiency by increasing the production and serum concentrations of SHBG, thereby reducing the concentration of free and bioavailable androgens. This is most commonly found with oral estrogen therapy, which directly stimulates the liver through a first pass effect. Therefore, before attempting androgen replacement therapy, the woman should be switched to a transdermal estrogen preparation, which results in lower SHBG concentrations (71). If these conditions are met, then a therapeutic trial of androgen replacement should be considered. EFFECTS OF ANDROGEN REPLACEMENT Testosterone Trials The symptom complex, which constitutes the androgen insufficiency syndrome, has been empirically derived from observations of patients who developed symptoms after an event, such as oophorectomy, that can precipitate a decrease in T (Table 3) (72). The frequently described symptoms are fatigue, low energy, decreased or absent sexual motivation, and desire, as well as a generalized decrease in the sense of well-being (3). These symptoms, which are consistent with the diagnosis of HSDD, often result in considerable personal distress in some women (1–3). Signs of androgen insufficiency, such as thinning or sparsity of pubic hair and decreased muscle mass may be seen (3, 73). Reduction of bone mineral density may be present on bone densitometry testing (74). Many, but not all, studies have demonstrated that exogenous androgen administration improves various sexual function parameters (coital frequency, desire and libido, arousal, pleasure, orgasm, thoughts or fantasy), and mood or the sense of well-being, as well as bone health, body composition, and muscle mass in women with symptomatic androgen insufficiency. There are a myriad of variables that make direct comparison between studies difficult. These include differences in study design (e.g., type of blinding, placebo, or estrogen control), duration of exposure to the androgen, whether the androgen level attained was physiologic or supraphysiologic, type of menopause (natural or surgical), selection criteria for inclusion of patients (no sexual dysfunction, low libido, mixture of menopausal symptoms), type of instrument for assessing sexual function and whether it has been psychometrically validated, type of sexual activity measured (with partner, self stimulation, intercourse only, or total sexual activity), and number of subjects in the study. These considerations are especially important as there may be a substantial placebo effect in these types of studies (12). In women who have hypopituitarism, hypoadrenalism, or who have undergone oophorectomy and present with symptoms of androgen insufficiency, free T levels and the free T index are low. According to a recent consensus conference, Nevertheless, as summarized in Table 4 and discussed in detail in the following paragraphs, the randomized, double blind, placebo, or estrogen-controlled trials in women with low libido after menopause that used well-validated tools to 276 Cameron and Braunstein Androgen replacement therapy in women Vol. 82, No. 2, August 2004 FERTILITY & STERILITY威 TABLE 4 Testosterone replacement clinical trials in women that measured sexual function and other psychological parameters. Trial Therapy N/avg. age Greenblatt et al. (9) Oral E, T, or E ⫹ T [5 mg MT q d] 102c/44 yr Sherwin et al. (75,76) IM E, T, or E ⫹ T [150 mg TE ⫹ E, or, 200 mg TE q mo] 43/46 yr Myers et al. (77) 40/⬃58 yr Shifren et al. (12) Oral E, E, ⫹ MPA, or E ⫹ MT [5 mg MT q d] E ⫹ Transdermal T [150 ␮g q d; 300 ␮g q d] Braunstein et al. (15) E ⫹ Transdermal T [150 ␮g q d; 300 ␮g q d; 450 ␮g q d] 447/49–50 yr Goldstat et al. (14) T 1% cream [10 mg q d] 31/40 yr Sarrel et al. (42) Oral E or E ⫹ T [2.5 mg MT q d] 20/52 yr Lobo et al. (13) Oral E or E ⫹ T [1.25 mg MT q d] 218/53 yr Dow and Hart (80) SC E or E ⫹ T [100 mg] 40/47 yr 65/47 yr Sexual function parameter improvement Other psychological parameter improvement Population/ prestudy sexual dysfunction Study design 1 mo Cross-over unk Interview 3 mo Cross-over Initially supraphysiologic DMRS 2 mo Parallel Initially supraphysiologic Daily logs SMP only/yes 3 mo Cross-over Physiologic free T, supraphysiologic total T BISF-W SMP only/yes 6 mo Parallel SAL, PFSF 3 mo Cross-over Physiologic free T (for 300 ␮g group) Physiologic total-T, supraphysiologic FAI 2 mo Placebo lead-in NR SALS 4 mo parallel Supraphysiologic SIQ, BISF-W 4 mo Parallel unk 7 pt. scale Randomized, double-blind, placebo-controlled trials 1Libidob,d 1Well-beingb,d ⬃72 NMP ⬃30 SMP/ “menopausal symptoms” 1Desirea 1Energya SMP only/unk 1Fantasya 1Well-beinga 1Arousala 2Psychological symptomsa 1Pleasure from No improvement 37 NMP masturbationa 3 SMP/no Effect of 300 ␮g dose 1Frequencya 1Pleasure–orgasma 1Desirea 1Satisfying activitya Effect of 300 ␮g dose: 1Well-beinga 1Mooda NR Dose effect on T (reproductive age range) Rx duration 1Interesta 1Positive well-beinga Pre-MP/yes 1Activitya 2Anxietya 1Satisfactiona 1Self-confidencea 1Pleasurea 1Vitality 1Fantasya 1Orgasma Randomized, double-blind, estrogen only comparison trials 1Frequency (at 4 Not tested 12 NMP wks)b 8 SMP/dissatisfied 1Sensationb with E alone Rx 1Desireb 1Interest or desirea Not tested 150 NMP 1Responsivenessa 68 SMP/yes Randomized, single-blind, estrogen only comparison trials 1“Psychological 1Orgasm at 2 6 NMP factor” at 4 monthsb 34 SMP/yes monthsb (low dyspareunia (low dyspareunia patients only) patients only) Sexual function tool SSSRS 277 278 Cameron and Braunstein T A B L E 4 Continued Trial Therapy Androgen replacement therapy in women Burger et al. (78) Davis et al. (79) SC E or E ⫹ T [50 mg] SC E or E ⫹ T [50 mg q 3 mo] Kupperman et al. (11) Burger et al. (81) Oral, IM, SC E⫹T [5 mg MT q d; 10 mg MT q d; 100 mg T cyclopentylpropionate q 2 wks; E ⫹ 150 mg T SC] SC E or E ⫹ T [100 mg] Sherwin et al. (83) IM E or E ⫹ TE [150 mg q mo] N/avg. age 20/43 yr (E ⫹ T) 32/57 yr (E ⫹ T) Sexual function parameter improvement 1Libidob 1Enjoymentb 1Activitya 1Satisfactiona 1Orgasma 1Pleasurea 1Relevancya 1Libidob 114 54 28 unk 17/42 yr 44/47 yr (E ⫹ T) 1Libidob 1Enjoymentb 1Climaxb 1Initiationb 1Desirea 1Arousala 1Fantasiesa 1Frequencya,e 1Orgasma,e Other psychological parameter improvement Not tested Not tested Other trials 1Physical vigorb 1“Joie de vivre”b 2Anxietyb 2Nervousnessb 1Well-beingb Population prestudy sexual dysfunction Rx duration Study design Dose effect on T (reproductive age range) Sexual function tool 14 NMP 6 SMP/yes 30 NMP 2 SMP/no 6 wk Parallel Supraphysiologic AS 2 yr Parallel Supraphysiologic SSSRS MP unk Not randomized, unk controlled, or blinded Self-report 2Tirednessb 1Concentrationb 6 NMP 11 SMP/yes 6 mo Pilot study Supraphysiologic AS 1Mooda 1Elationa 1Composurea 1Energya 2Depressionb 2Tirednessb 2Anxietyb SMP only/unk 2 yr 2 yr follow-up Supraphysiologic DMRS, MAS Vol. 82, No. 2, August 2004 Note: E ⫽ estrogen; T ⫽ testosterone; MT ⫽ methyltestosterone; 1 ⫽ increased/improved; 2 ⫽ decreased/improved; NMP ⫽ naturally menopausal; SMP ⫽ surgically menopausal; unk ⫽ unknown; TE ⫽ T enanthate; DMRS ⫽ Daily Menopausal Rating Scale; MPA ⫽ medroxyprogesterone acetate; BISF-W ⫽ Brief Index of Sexual Functioning for Women; NR ⫽ not reported; SAL ⫽ Sexual Activity Log; PFSF ⫽ Profile for Female Sexual Function; Pre-MP ⫽ premenopausal; FAI ⫽ free androgen index; SSSRS ⫽ Sabbatsberg Sexual Self-Rating Scale; SALS ⫽ Sexual Activity and Libido Scale; SIQ ⫽ Sexual Interest Questionnaire; AS ⫽ analog scale; MP ⫽ menopausal; NA ⫽ not applicable; MAS ⫽ marital adjustment scale. a Significant change between groups. b Significant change from baseline within group; or, self-report (11) of increase or improvement. c Only 22 participants crossed-over to all four treatment groups; 7 were surgically menopausal. d Data not provided in statistical terms; 67% preferred E ⫹ T compared to E alone due to increased sense of well-being and libido. 23.5% of E ⫹ T users reported an increase in libido; 42% of T alone users reported an increased libido. e Between-group significance during first 2 weeks after injection only. Cameron. Androgen replacement therapy in women. Fertil Steril 2004. measure sexual function have generally shown increased libido, satisfaction, and sexual activity with T therapy in comparison to the response seen with placebo or estrogen alone. In 1950, Greenblatt et al. (9) reported results of a randomized, double-blind, placebo-controlled clinical trial of oral 0.25 mg diethylstilbestrol (DES) daily alone, 5 mg methyltestosterone (MT) daily alone, combined DES and MT, and placebo in 102 women with postmenopausal symptoms after natural or surgical menopause. Each treatment was administered for 1 month in a cross-over fashion, and the effect of therapy was determined by vaginal smears and monthly interviews with regard to changes in bleeding, breast turgidity, pelvic congestion, acne, libido, hot flashes, insomnia, lubrication, and nervousness. The average age of participants was 44 years (range, 23 to 63 years). The investigators noted a carry-over effect of the prior treatment on the baseline assessment of the subsequent treatment, as well as a placebo effect. Of the 102 study participants, only 22 received all four treatments. Complete relief of menopausal symptoms was experienced by 90% of the women in the estrogen alone and combined treatment groups, but 67% of women preferred the combined therapy due to an increase in the sense of well-being. After 1 month of treatment, increased libido was reported by 2% in the placebo group, 12% in the estrogen alone group, 23% in the combined therapy group, and 42% in the MT alone group. Sherwin and Gelfand (75) and Sherwin et al. (76) studied a group of 43 premenopausal women with benign gynecological diseases and who subsequently underwent bilateral oophorectomy with total abdominal hysterectomy. The women were randomized in an 8-month cross-over study undergoing IM injections at 28-day intervals of estrogen plus androgen (n ⫽ 12; 150 mg of T enanthate, 7.5 mg of E2 dienanthate, and 1 mg of E2 benzoate), estrogen alone (n ⫽ 11; 10 mg of E2 valerate), androgen alone (n ⫽ 10; 200 mg of T enanthate), or placebo (n ⫽ 10) given in a double-blind fashion. Ten women who underwent hysterectomy without oophorectomy served as a second control group. There were four time periods—1 month of baseline monitoring, 3 months of the first hormone treatment, 1 month of placebo treatment, followed by a crossover to 3 months of the second hormone treatment. Serum T levels were significantly increased in the estrogen plus T or T alone treatment groups compared to the hysterectomy control group, estrogen alone group, and placebo group. In the same studies, Sherwin and colleagues found a significant (P⬍.01) correlation between the increased T levels of the estrogen plus T and T alone groups with improved energy level and well-being compared to the estrogen alone and placebo groups. This study measured sexual function on a daily basis with a questionnaire using a rating scale that included the domains of sexual desire, sexual arousal, sexual thoughts or fantasies, frequency of sexual encounters with FERTILITY & STERILITY威 the partner, and orgasm. Significant increases were demonstrated in sexual desire (P⬍.01), sexual fantasy (P⬍.01), and sexual arousal (P⬍.01) in the two T treatment groups as compared to the estrogen alone and placebo groups. Importantly, the investigators noted that sexual function of both the androgen groups did not differ from the ovary-sparing, hysterectomy-only control group. The investigators suggested that the lack of response with regard to coital frequency and orgasm may be due to partner variability or that androgens in women affect sexual motivation but not frequency and orgasm. Myers et al. (77) did not find an improvement in sexual function with androgen therapy in a randomized, doubleblind, placebo-controlled study of 40 predominantly naturally menopausal women (surgical menopause n ⫽ 3, natural menopause n ⫽ 37). The participants had not taken any hormones 3 months before receiving study treatment with either 0.625 mg of conjugated equine estrogens (CEE), 0.625 mg of CEE plus 5 mg of medroxyprogesterone acetate (MPA), 0.625 mg of CEE plus 5 mg of MT, or placebo for 8 weeks in parallel groups. There was a significant difference of total T levels in the combined estrogen and androgen group, but initially supraphysiologic levels decreased after several weeks of treatment to levels similar to the placebo group for the remainder of the 8-week treatment period. Myers and colleagues used daily logs for quantitative assessment of menopausal symptoms, mood state, sexual desire, sexual thoughts, and sexual activity. A seven-point Likert scale was used to assess mood states including anxiety, depression, energy level, irritability, and euphoria. Vaginal photoplethysmography provided assessment of physiologic sexual arousal. Perceived arousal to films and self-fantasy was assessed with a 10-point Likert scale. The investigators found no significant difference between groups for mood or sexual behavior. A significant improvement was found for pleasure from masturbation, but only a trend toward significance was found for frequency of masturbation and mean number of orgasms from masturbation. Shifren et al. (12) studied the effect of a transdermal T patch in 65 oophorectomized women who were on a stable dose of estrogen therapy of at least 0.625 mg of CEE daily for at least 2 months before study entry. In this double-blind, cross-over study, the women were randomized to three treatment groups for 12 weeks each of CEE plus 150 ␮g per day of T, CEE plus 300 ␮g of T, and CEE plus placebo. Serum total T levels were above the normal range, but the free and bioavailable T concentrations were within the normal range for young women, reflecting the fact that the majority of women receiving oral CEE had markedly elevated levels of SHBG. Shifren and associates measured sexual function at baseline and at the end of each 12-week treatment period, which included testing in the domains of sexual thoughts and desires, arousal, frequency of sexual activity, receptivity and 279 initiation, pleasure and orgasm, relationship satisfaction, and problems affecting sexual function. The investigators reported that the CEE plus 300 ␮g of T group demonstrated increased frequency of sexual activity (P ⫽ .03) and pleasure– orgasm (P ⫽ .03). A dose-dependent effect was demonstrated as there was an increased percentage of women with increased frequency of sexual fantasies, masturbation, and sexual intercourse in the CEE plus 300-␮g of T group as compared to the 150-␮g of T group. The sense of well-being (P ⫽ .04) and mood (P ⫽ .03) improved significantly in the 300-␮g of T group in comparison to the placebo group. There was a strong placebo response that was greater in the younger women. Women under the median study age of 48 years showed an increased composite score on the Brief Index of Sexual Function for Women during placebo treatment and no further improvement during T treatment. A recent trial conducted by Goldstat and colleagues (14), which investigated the use of T cream in premenopausal women, mean age of approximately 40 years, with low libido, demonstrated not only an improvement in sexual function, but also mood and well-being. Thirty-one women provided complete data using 10 mg of 1% T cream applied daily to the thigh. The study participants were randomized in a double-blind fashion to treatment or placebo for 12 weeks then crossed-over, after a 4-week wash-out time period, for another 12 weeks of treatment or placebo. The mean baseline serum T levels was near the lowest quartile of the normal range for reproductive age women. Serum total T levels increased with T treatment to the upper limit of the normal range, whereas the Free Androgen Index (total T/SHBG ⫻ 100) increased above the upper limit of normal. Of note, there was no change in serum E2 levels. Goldstat et al. found a significant improvement from baseline with T treatment as compared to placebo in the composite score (P ⫽ .001) on the Sabbatsberg Sexual Self-Rating Scale as well as significant improvement of individual sexual function domains of sexual interest (P ⫽ .001), sexual activity (P ⫽ .006), satisfaction of sexual life (P ⫽ .004), sexual pleasure (P ⫽ .004), sexual fantasy (P⬍.001), and orgasm (P ⫽ .005). That is, all sexual function domains on the Sabbatsberg Sexual Self-Rating Scale were significantly improved from baseline with T cream compared to placebo, except for the domain described as “importance of sex” (P ⫽ .108). In addition, T treatment demonstrated a significant improvement in the composite score on the Psychological General Well-Being Index (P ⫽ .004), which measures anxiety (P ⫽ .009), depressed mood (P ⫽ .053), positive well-being (P ⫽ .009), self confidence (P ⫽ .024), general health (P ⫽ .014), and vitality (P ⫽ .010). There was a beneficial decrease in the composite score on the Beck Depression Inventory, which did not reach significance (P ⫽ .062). Interestingly, this study did not demonstrate a placebo effect as did the trial conducted by Shifren and colleagues (12) involving surgically menopausal 280 Cameron and Braunstein women. Hirsutism scores using the Ferriman-Gallway Scale did not change and none of the participants developed acne. More recently, Braunstein et al. (15) reported in abstract form the results of a phase IIb, 6-month double-blind, placebo-controlled trial using varying doses of transdermal T delivered by a matrix delivery system patch in parallel groups of randomized surgically menopausal women (n ⫽ 447) receiving estrogen therapy with complaints of lowered libido after their oophorectomy. A 300-␮g daily transdermal dose was found to be optimal in this trial, which tested daily doses of 150 ␮g (n ⫽ 107), 300 ␮g (n ⫽ 110), and 450 ␮g (n ⫽ 111). Again, transdermal T demonstrated significant improvement in sexual desire with minimal side effects. There was a 30% increase (P⬍.05) in total satisfying sexual activity after 6 months of treatment with 300 ␮g of transdermal T compared to placebo and an 81% increase (P⬍.05) from baseline using a weekly Sexual Activity Log. The sexual desire score was also significantly increased 18% (P⬍.05) with T as measured by the Profile of Female Sexual Function. There was no difference in reports of adverse effects between the placebo and T groups. There are several controlled trials evaluating estrogen alone vs. estrogen plus T that support the benefits of androgen replacement. Sarrel et al. (42) studied a group of 20 naturally (n ⫽ 12) and surgically (n ⫽ 8) menopausal women, who were dissatisfied with their conventional hormone therapy, and were randomized to daily administration of oral estrogen, 1.25 mg of oral esterified estrogen (EE), alone (n ⫽ 11), or estrogen plus androgen, 1.25 mg of oral EE plus 2.5 mg of MT (n ⫽ 9) in a double-blind fashion. This study incorporated a 2-week, single-blind, placebo lead-in time period before an 8-week double-blind treatment time period. Sexual function was assessed weekly with the Sexual Activity and Libido Scale, which included items on vaginal moisture, level of sexual desire, frequency of sexual intercourse, pain with intercourse, clitoral sensation, clitoral sensitivity, orgasm, sexual fantasy, and sexual response. Sarrel and colleagues found that the EE plus MT group showed a significant improvement in the combined rating for sexual sensation and desire (P⬍.01 compared to previous estrogen therapy and previous hormone therapy; P⬍.01 compared to placebo) after 4 and 8 weeks of treatment. Frequency of sexual intercourse increased significantly after 4 weeks of the combined EE plus MT therapy compared to placebo, but was not significant at other assessment time periods. Serum levels of E2 and estrone (E1) increased in all groups in comparison to post-placebo levels. As expected, SHBG levels increased in the estrogen alone group and decreased in the estrogen plus androgen group. Although androgens were not measured in this study, the investigators concluded that the administration of estrogen plus androgen significantly improved sexual sensation and desire either as a direct result of the androgen or as an indirect result of decrease in SHBG levels, which increased the bioavailability Androgen replacement therapy in women Vol. 82, No. 2, August 2004 of T. Of interest, 13 study participants elected to continue with estrogen (0.625 mg EE daily) plus androgen (1.25 mg. MT daily) therapy after the trial was completed. Lobo et al. (13) performed a randomized, double-blind study with 218 postmenopausal women using a combined oral estrogen–androgen preparation (0.625 mg EE plus 1.25 mg MT; n ⫽ 107) and estrogen alone (0.625 mg EE; n ⫽ 111) during 4 months. Sexual function measurement was performed at 1, 2, 3, and 4 months of treatment, and both groups demonstrated increases in sexual interest after 1 month of treatment, with the increase in sexual interest or desire being greater for the combined therapy group. Combined therapy also effected greater sexual responsiveness (P ⫽ .002). There was no difference as to response related to age, race, or type of menopause. This study correlated the increases in sexual function parameters to significant increases (P⬍.01) in mean serum concentration of bioavailable T in association with significant decreases (P⬍.01) in SHBG levels in the combined treatment group compared to the control group. In the group of women with baseline SHBG in the normal range, there was a highly significant correlation between the change in bioavailable T to change in interest, responsiveness, and total Sexual Interest Questionnaire (SIQ) score. Burger et al. (78) studied the effect of implanted pellets containing estrogen alone (40 mg of E2) or estrogen (40 mg of E2) plus androgen (50 mg of T) on 20 postmenopausal women with “severe” loss of libido unresolved by conventional hormone therapy in a randomized, single-blind fashion. Supraphysiologic levels of T were noted in this study. After 6 weeks, the combined therapy group demonstrated improvement in libido (P⬍.01) and sexual enjoyment, whereas the estrogen alone treatment group did not demonstrate an increase in libido or sexual enjoyment. Also using implanted pellets, Davis et al. (79) performed a randomized, single-blind study involving 32 postmenopausal women. Unique to this study was the exclusion of women with low libido. The women received implants of either 50 mg of T combined with 50 mg of E2 or 50 mg of E2 alone every 3 months during 2 years. Supraphysiologic levels of T were also attained in this study. Sexual function including the domains of libido, activity, satisfaction, pleasure, fantasy, orgasm, and relevancy, were measured at baseline and at each 6-month period throughout the 2-year study. The results of this prospective study revealed that the women who received the combined therapy (E2 plus T) had a significantly greater improvement in sexual activity (P⬍.03), satisfaction (P⬍.03), orgasm (P⬍.035), relevancy (P⬍.05), and pleasure (P⬍.01) compared to the estrogen alone group. This study also measured bone mineral density (BMD) and body composition. The estrogen plus T treatment group showed a significantly greater improvement in total body, vertebral (L1–L4), and trochanter BMD. FERTILITY & STERILITY威 In contrast to the generally positive results found in these studies, Dow and Hart (80) reported a lack of a difference in restoration of sexual function in postmenopausal women (n ⫽ 40 [natural menopause n ⫽6; surgical menopause n ⫽ 34]) with a decline in sexual interest given 100 mg of T and 50 mg of E2 implants as compared to E2 implants alone. Participants self-rated using a seven-point scale for frequency of sexual interest, general satisfaction with the sexual relationship, general satisfaction with the marital relationship, frequency of orgasm, ease of responding to sexual stimulation, and frequency of dyspareunia before treatment and at 2 and 6 months after treatment in this randomized, single-blind trial. Although there was a significant improvement in all sexual function domains in each group compared to baseline, there was no significant difference found between groups. Therefore, the investigators stratified the two groups with regard to baseline measurement of dyspareunia. A significant increase in orgasm was noted only in the combined pellet group at 2 months in the patients with low dyspareunia. Several other studies bear noting, although they are of lower scientific quality than those summarized previously, because they are neither randomized, blinded, nor adequately controlled. In 1959, Kupperman and colleagues (11) gave 5 or 10 mg of oral MT or 100 mg of T cyclopentylpropionate intramuscularly along with estrogen to postmenopausal women and reported improvement in libido, “physical vigor,” and “joie de vivre,” as well as decreased anxiety and decreased nervousness. Also, these early investigators reported improved libido and well-being using implanted E2 and T. Burger et al. (81) conducted a pilot study with 17 postmenopausal women who were complaining of low libido, which was unresponsive to estrogen alone, using implanted pellets containing 40 mg of E2 and 100 mg of T. This study did not include estrogen alone or placebo control groups. Participants were assessed monthly with an analogue scale for libido and enjoyment of sex, and initiation of sexual activity and frequency of orgasm was assessed by interview and diary. Serum total and free T levels peaked after 1 month of treatment and remained at supraphysiologic levels at 6 months. Significant improvement in libido (P⬍.01) and enjoyment of sex (P⬍.01) was demonstrated compared to baseline assessments. The improvement in libido and enjoyment was cumulative and peaked after 3 months of therapy (n ⫽ 14). Improvement was maintained up to 6 months. Tiredness, ability to concentrate, change in hot flashes, sweats, and depression were assessed, but only tiredness (P⬍.01) and concentration (P⬍.05) showed significant improvements from baseline. Sherwin (82) and Sherwin and Gelfand (83) studied 44 women, who had undergone oophorectomy 2 years earlier, using monthly IM injections of estrogen and androgen (150 mg of T enanthate, 7.5 mg of E2 dienanthate, and 1 mg of E2 281 benzoate) or estrogen alone (10 mg of E2 valerate). A placebo group was not a part of the study design; however, a third group of women in this study who had been untreated since the time of surgery was used for control purposes. Supraphysiologic levels of T were achieved and maintained for 84 days in this study. Sexual function was measured daily by a rating scale in the domains of desire, number of fantasies, level of arousal during intercourse, orgasm, and frequency of intercourse. The estrogen plus androgen group showed significant improvement in comparison to the estrogen alone and control groups in the first 3 weeks (of 4 weeks) of therapy in the domains of sexual desire (P⬍.01), number of sexual fantasies (P⬍.01), and sexual arousal (P⬍.01). In the first 2 weeks of therapy, frequency of intercourse and orgasm was significantly better (P⬍.01) in the cotherapy group as compared to the monotherapy and untreated groups. However, by week 3 the frequency of intercourse and orgasm of the cotherapy group exceeded only the control group. These studies examined the effects of T treatment in menopausal or premenopausal women, whereas Tuiten et al. (84) studied eight women with hypothalamic amenorrhea and eight healthy menstruating women. The first phase of their investigation established that amenorrheic women had significantly decreased frequency of sexual thoughts, frequency of sexual desire, frequency of sexual activity, and low serum T levels. In the second phase of the study, these eight amenorrheic women were treated with 40 mg of T undecanoate for 8 weeks followed by a 28-day wash-out period and then a cross-over to placebo treatment for 8 weeks. Supraphysiologic serum levels of T were achieved. Only genital vasocongestion showed a significant difference between groups, being increased on T, whereas there were no significant mood or subjective sexual behavior effects noted between T and placebo treatment. DHEA Trials Because DHEA is converted into A and then T, several studies have examined the effects of DHEA administration on sexual function in women (Table 5). Morales and coworkers (85) conducted a 6-month, randomized, placebocontrolled, cross-over study using 50 mg of DHEA in 17 women, aged 40 to 70 years. Within 2 weeks of treatment, serum DHEA and DHEAS levels were within the normal range for reproductive age women and there was a twofold increase in A, T, and DHT. Although 84% of the women reported an improvement in well-being, there was no improvement in libido. It should be noted that 15 of the 17 women were menopausal and that only 7 were on conventional hormone therapy. Thus, it is possible that dyspareunia was present in some of the participants, which remained unaltered, as there were no changes in the serum levels of E1, E2, or SHBG with DHEA administration. Barnhart et al. (86) conducted a study with 60 symptomatic perimenopausal women with an average age of 48 years. 282 Cameron and Braunstein This randomized, double-blind, placebo-controlled, parallel group study used 50 mg of oral DHEA given daily for 3 months. There was no improvement in sexual or psychological domains over placebo. However, libido was assessed with only one question from the Hamilton Depression Rating Scale, which is insufficient to examine sexual function. Baulieu and colleagues (87) conducted a trial with 50 mg of daily, oral DHEA during 1 year in 140 women aged 60 to 79 years in a double-blind, randomized, placebo-controlled fashion. Serum androgens reached supraphysiogic levels after 6 months of therapy, but decreased to physiologic levels after 12 months of therapy. Estradiol levels increased significantly (P⬍.001), but did not exceed early follicular phase levels, after 6 months of treatment and were maintained through 12 months of treatment. Sexual attitudes, libido, activity (intercourse or masturbation), and satisfaction were measured with a questionnaire at baseline, 6 months, and 12 months. Baulieu and associates found that there was a significant improvement in sexual parameters in the women more than 70 years of age, but not less than 70 years of age. In the former, there was an increase in libidinal interest after 6 months of therapy that reached significance after 12 months of therapy. Of note, libido increased from baseline before the significant increases demonstrated in intercourse or masturbation (P⬍.03) and sexual satisfaction (quantitative and qualitative) (P⬍.01) after 12 months of therapy. As well, bone turnover improved in women who were more than 70 years old. Because the adrenals are a significant source of androgens in women, low serum androgen levels are found in patients with adrenal insufficiency. Arlt et al. (61) studied treatment with 50 mg of oral DHEA daily during 4 months in 24 women with adrenal insufficiency of whom 14 had primary adrenal insufficiency (11 had autoimmune adrenalitis and 3 had bilateral adrenalectomy) and 10 had secondary adrenal insufficiency (6 had pituitary surgery, 3 had Sheehan’s syndrome, and 1 had autoimmune hypophysitis). This study was randomized, double-blind, and placebo-controlled. Participants were randomized to treatment or placebo for 4 months with an intervening month for wash-out purposes in a crossover fashion. After 4 months, the DHEA treatment group demonstrated significant increases in serum levels of DHEA, DHEAS, A, T, and DHT compared to the placebo group. Of note, SHBG concentrations significantly decreased after 4 months of treatment compared to placebo. Serum concentrations of E1 and E2 did not change significantly between groups. In addition to the finding of significantly increased serum androgen levels between groups after 4 months of treatment, Arlt and colleagues noted an improvement in sexual function (increased frequency of sexual thoughts or fantasies, degree of sexual interest, and sexual satisfaction) and mood that correlated to the change in androgen levels. The improve- Androgen replacement therapy in women Vol. 82, No. 2, August 2004 FERTILITY & STERILITY威 TABLE 5 Oral DHEA replacement clinical trials in women that measured sexual function and other psychological parameters. Trial Morales et al.c (85) Arlt et al. (61) Barnhart et al. (86) Baulieu et al.c (87) Therapy N/average age (y) 50 mg q d 17/54 yr 50 mg q d 24/42 yr 50 mg q d 60/48 yr 50 mg q d 140/60–79 yr Hunt et al.c (66) 50 mg q d 24/26–69 yr Sexual function parameter improvement Other psychological parameter improvement Population/prestudy sexual dysfunction Randomized, double-blind, placebo-controlled trials 1Well-being 2 Pre-MP, 15 MP; 7 no HT/unknown 1Frequency of thoughts/ 1Mooda AI/unknown fantasiesa 2Exhaustiona 1Interesta 2Depressiona 1Satisfactiona 2Anxietya 2Hostilitya 2Obsessive–compulsive traitsa No improvement No improvement Peri-MP only/yes No improvement ⬎ 70 yrs only: Not tested 1libidob 1Intercourse–masturbationb 1Satisfactionb No improvement 1Self-esteema 1Evening mooda 2Evening fatiguea No improvement No improvement Johannsson et al. 30 mg if ⬍45 yr, 38/51 yr (88) 20 mg if ⬎ 45 (DHEA group) yr Lovas et al. (67) 25 mg q d 39/46 yr No improvement (DHEA group) No improvement Rx Duration Study design Dose effect on T (reproductive age Sexual function female range) tool 3 mo Cross-over Physiologic VAS 4 mo Cross-over Physiologic VAS 3 mo Parallel Physiologic MP/unknown 1 yr Parallel Initially supraphysiologic 1 question from Ham-D Questionnaire AI/unknown 3 mo Cross-over Physiologic Hypopituitarism/ unknown AI/unknown 6 mo ⫹ 6 mo Parallel open phase 9 mo Parallel GRISS Subnormal Self-report Physiologic MSQ (AS) Note: 1 ⫽ increased/improved; 2 ⫽ decreased/improved; Pre-MP ⫽ premenopausal; MP ⫽ menopausal; HRT ⫽ hormone replacement therapy; VAS ⫽ visual analog scale; AI ⫽ adrenal insufficiency; AS ⫽ analogue scale; Peri-MP ⫽ peri-menopausal; Ham-D ⫽ Hamilton Depression Rating Scale; GRISS ⫽ Golombok Rust Inventory of Sexual Satisfaction; DHEA ⫽ dehydroepiandrosterone; MSQ ⫽ McCoy’s sexuality questionnaire. a Significant change between groups. b Significant change from baseline within group. c Data reflects only female participants in the study. Cameron. Androgen replacement therapy in women. Fertil Steril 2004. 283 ment in sexual satisfaction (mental satisfaction [P ⫽ .009]; physical satisfaction [P ⫽ .02]) in the treatment group compared to the placebo group did not occur until 4 months of treatment, whereas the increases in the degree of sexual interest (P ⫽ .06) and frequency of sexual thoughts or fantasies (P ⫽ .07) was demonstrated after 1 month of treatment. Timing of effects coincided with the evaluation schedule as psychological assessments were performed after 1 and 4 months of treatment with both the placebo and DHEA treatments and 1 month after the completion of the second treatment in this cross-over trial. In addition, it should be noted that there was a significant carry-over effect with treatment in association with sexual interest effect (P ⫽ .05). The improvement in the sense of well-being occurred after 4 months of treatment. After 4 months, the DHEA treatment group demonstrated a significant decrease in depression (P ⫽ .05) and obsessive– compulsive traits (P ⫽ .03) compared to the placebo group. Anxiety (P ⫽ .01) and hostility (P ⫽ .03) decreased significantly in the DHEA treatment group compared to the absolute change from baseline in the placebo group. Mood (degree of unpleasantness, P ⫽ .008; degree of alertness, P ⫽ .03; and degree of restlessness, P ⫽ .01) improved significantly in the DHEA treatment group compared to the placebo group after 4 months of treatment. In contrast to these results, Hunt and co-workers (66) found no improvement in sexual function in 24 women, aged 26 to 69 years with adrenal insufficiency who received 50 mg of oral DHEA daily for 12 weeks in comparison to the response to 12 weeks of placebo in a randomized, doubleblind study. This cross-over study used a 1-month wash-out period between drug and placebo treatment periods. There was a significant increase in serum total T (P ⫽ .003) and a significant decrease in serum SHBG (P⬍.001) levels in the treatment group as compared to the placebo group. There were no differences in sexual interest or arousal, frequency of intercourse, or lubrication between the DHEA and placebo groups, but there was a significant improvement in self-esteem, evening mood, and a decrease in evening fatigue in the DHEA treatment group. phase. The mean ages of the placebo and DHEA groups were 50 and 51 years, respectively. Although levels of DHEAS, A, and T increased in the treatment group, the serum androgen levels remained subnormal at the completion of the study, and at 6 months there was no statistically significant differences in androgen levels compared to the placebo group. Johannsson and associates used patient reports at 6 and 12 months to measure changes in sexual interest and activity in three categories: reduced, unchanged, or increased. Quality of life was measured by the Psychological General WellBeing Index. A 12-item questionnaire was completed by the patients’ partners to assess mood and behavior changes. Of interest, there were no significant changes in sexual function as self-reported during the placebo-controlled phase of the study, although the patients’ partners reported an increase in sexual relations during this period. During the open phase of the study, increased sexual activity and interest was reported by 100% of the women with partners on 30 mg of DHEA and 41% of the women with partners on the 20-mg dose. There were no significant changes in the quality of life noted during either phase. Tibolone Trials Tibolone is a steroid hormone that possesses estrogenic, progestational, and androgenic properties. Although not available in the United States, it has had several decades of use in Europe and Asia. There are four randomized, placebocontrolled, single or double-blind trials using 2.5 mg of tibolone given orally each day. Kicovic and colleagues (89) studied 82 postmenopausal women for 16 weeks in each arm of a cross-over trial and noted that there was a 26% improvement in libido with tibolone compared to placebo. Nevinny-Stickel (90) also performed a cross-over trial for 16 weeks on active drug or placebo in 35 postmenopausal women and found no significant difference in effect on libido, which was the only sexual function domain examined. Similar negative results were found by Lovas et al. (67) who conducted a randomized, placebo-controlled study using 25 mg of oral DHEA daily for 9 months in 39 women with adrenal insufficiency. The serum T levels significantly increased from baseline to reach premenopausal levels. However, there was no effect on sexual function parameters. A single-blind, placebo-controlled trial was conducted by Palacios et al. (91) with 28 postmenopausal women using a questionnaire that measured several parameters of sexual function. At 12 months there was a significant improvement with tibolone compared to baseline and control in all parameters that included desire, frequency of arousability, intensity and frequency of orgasmic response, and coital activity. The effect of oral DHEA administration to women who were androgen deficient from hypopituitarism was studied by Johannsson and colleagues (88) who used an age-adjusted, dosing scheme of DHEA administration in 38 women, with 30 mg being given if the woman was less than 45 years of age and 20 mg if she was 45 years or older. The study was double-blinded, randomized, and placebo-controlled for a 6-month period followed by a 6-month open More recently, Laan and co-workers (92) studied 38 postmenopausal women for 12 weeks in a cross-over trial using sexual function questionnaires, daily diaries, and measurements of vaginal blood flow and lubrication. In comparison to placebo, tibolone significantly increased vaginal lubrication and blood flow, arousability, sexual fantasies, and sexual desire. There was no difference in the initiation of sexual activity, frequency of intercourse, or orgasm. 284 Cameron and Braunstein Androgen replacement therapy in women Vol. 82, No. 2, August 2004 As reviewed elsewhere (93, 94), multiple other trials with tibolone have been carried out that have either not been blinded, not randomized, or not had a prospective placebo control or have compared tibolone to estrogens or estrogen/ progesterone combinations. It is difficult to interpret the results because of the estrogenic and progestational activities of tibolone and the differences between the potency of tibolone and the comparators used in the studies. Also, because tibolone lowers SHBG, whereas estrogens increase this protein, differences in results may actually reflect alterations in the free endogenous androgen levels, rather than a direct androgenic activity of tibolone. ANDROGEN PREPARATIONS At the present time, there are no androgen preparations that have Food and Drug Administration approval for the treatment of HSDD. Many compounding pharmacies will prepare T pellets, creams, gels, drops, and lozenges by prescription. However, these generally have not been standardized with regard to absorption, duration of effect, or the range of serum levels achieved. There are numerous androgen products available for the treatment of male hypogonadism. However, normal serum T levels in men are 10 –20 times higher than those found in women, and, therefore, off-label use in women requires breaking tablets, diluting injectables, cutting patches, or trying to squeeze out just the right amount of gel, which generally leads to the administration of too much or too little androgen. The only T preparation produced by a pharmaceutical manufacturer that is made specifically for women is a combination product containing EE and MT (Estratest HS with 0.625 mg of EE plus 1.25 mg of MT or Estratest with 1.25 mg of EE and 2.5 mg of MT, both from Solvay Pharmaceuticals, Marietta, GA). The specific indication for these preparations are for the treatment of vasomotor menopausal symptoms not responsive to estrogens alone and not for the treatment of HSDD. However, as noted, the studies of Sarrel (42) and Lobo (13) and their co-workers have shown that this combination improves sexual function in women to a greater extent than that found with EE alone. Clinical trials are currently underway investigating T preparations that have been specifically designed to treat HSDD in women, but it is anticipated that it will still be several months to years before these complete the regulatory approval process and reach the market. Dehydroepiandrosterone is administered orally and has been used for androgen replacement in women with primary and secondary adrenal insufficiency. Doses more than 30 mg/day are usually required to produce a beneficial effect on sexual function. Dehydroepiandrosterone is considered a dietary supplement by the Food and Drug Administration, and as such is available in health food stores and markets. An investigation into the actual DHEA content of multiple overthe-counter DHEA products demonstrated a wide range with FERTILITY & STERILITY威 some containing no measurable DHEA to levels that were as much as 149% of the expected amount (95). Another preparation that theoretically could be used to provide androgen replacement therapy is androstenedione. Androstenedione, like DHEA, is considered a dietary supplement by the Food and Drug Administration. There have been two pharmacokinetic studies in women, which have not measured effect on sexual function parameters (96, 97). Kicman et al. (96) studied A administration in 10 healthy, premenopausal women aged 20 –32 years. Oral A in a single dose of 100 mg or placebo was administered in a doubleblind, cross-over fashion. Serum A and T levels were supraphysiologic at the 100-mg dose of A. Serum A levels in the treatment group were significantly different from placebo after 15 minutes to 24 hours, whereas T levels were significantly different from 30 minutes to 8 hours. Serum A levels plateaued between 2 and 4 hours. Leder et al. (97) studied oral A replacement in 30 postmenopausal women in single doses of 0 (n ⫽ 10), 50 (n ⫽ 10), and 100 (n ⫽ 10) mg, which resulted in significantly (P⬍.0001) increased serum T levels that were often supraphysiologic in the 50- and 100-mg treatment groups compared to the placebo group. There was considerable individual variability using this intermediate precursor of T. Androgen replacement therapies potentially lead to increases in the estrogen concentrations due to aromatization. In this study E1, but not E2, levels were increased, whereas oral DHEA administration has been shown to increase E2 levels. Because this study investigated the effect of a single oral dose, the adverse and beneficial effects, including sexual function parameters, with long-term administration of A is unknown in women. SAFETY OF ANDROGENS IN WOMEN The various studies that have investigated the administration of androgens in women have found that androgen replacement therapy is well tolerated and devoid of serious side effects. All may result in unwanted mild androgenic effects, such as acne and hirsutism, if supraphysiologic T concentrations are reached, but are rarely associated with more serious virilization. Acne has been found in 3%– 8% of patients with oral preparations of EE plus MT compared to 0%–7% in women receiving EE alone (13, 98 –101). An increase in acne was not found with IM or SC E2 plus T in comparison to the estrogen only control, or with transdermal T vs. placebo (12, 14, 15, 79, 82). The reported hirsutism rates with oral EE plus MT varied from 4.2% to 6%, which is not significantly different from patients receiving EE alone (13, 98, 100, 101). Of interest, in a group of 100 women who had no facial hair at baseline, 14% developed facial hair with 0.625 mg of EE plus 1.25 mg 285 TABLE 6 Blood lipid effects (% change from baseline) of T or DHEA replacement clinical trials in women. Trial Therapy Lobo et al. (13) Johannsson et al. (88) Arlt et al. (61) Barnhart et al. (86) Barrett-Connor et al. (101) Oral MT 1.25 mg q d Oral EE low dose Oral DHEA 30 or 20 mg q d N 106 110 38 Total cholesterol HDL Oral ⫺16.8 ⫺12.4 2.4 3.2 ⫹5.7 ⫹1.3 Shifren et al. (12) E ⫹ Transdermal T 300 ␮g q d 67 ⫺9.5a ⫺13.5a ⫺2.5 ⫺3.1 ⫹0.7 ⫹15.6 ⫹3.2 ⫹23.2 ⫺11.7 ⫺19.5 ⫺11.2 ⫺18.6 ⫺11.5a ⫺23.0a ⫺6.5 ⫹22.1a ⫺9.1 ⫺16.4a ⫺5.2 6.7a ⫺33.3 ⫺14.5 ⫺6.1 ⫹2.1 Transdermal ⫹3.2 NC Davis et al. (79) SC SC SC SC SC SC 16 17 20 17 14 17 Parenteral ⫺10.7 NC ⫺8.1 ⫹6.7 NS NS ⫺5.4* ⫹4.1 ⫺3.1 ⫹6.5* NC NC Raisz et al. (99) Watts et al. (103) Hickok et al. (102) Burger et al.b (78) Farish et al. (104) Burger et al. (81) Oral Oral Oral Oral Oral Oral Oral Oral Oral Oral Oral Oral DHEA 50 mg q d DHEA 50 mg q d EE low dose EE high dose EE ⫹ MT 1.25 mg q d EE ⫹ MT 2.5 mg q d EE ⫹ MT 2.5 mg q d EE EE ⫹ MT 1.25 mg q d EE EE ⫹ MT 1.25 mg. q d EE ⫹ MT 2.5 mg q d E E E E E E ⫹ T 50 mg q 3 mo or E ⫹ T 50 mg ⫻ 1 ⫹ T 100 mg ⫻ 1 ⫹ T 100 mg ⫻ 1 24 60 25 25 26 23 13 13 33 33 13 13 LDL Triglycerides Dose effect on T Rx Duration NC 1.0 ⫹3.7 ⫺31.1 ⫺7.5 ⫹1.6 Supraphysiologic 4 mo Subnormal 1 yr ⫺8.1 NC ⫺11.3 ⫺4.8 ⫺6.4 ⫺5.7 ⫺4.9 ⫺24.1a ⫹1.9 ⫺11.9 ⫺19.3a ⫺10.1 ⫺1.75 ⫺1.5 ⫹72.1 ⫹56.1 ⫺16.2 ⫺7.3 ⫺32.4a ⫹25.5a ⫺30.0* ⫹19.5 ⫹3.4 ⫹8.1 Physiologic Physiologic NR 4 mo 3 mo 2 yrs Physiologic 9 wks unk 2 yrs unk 6 mo ⫹5.1 NR Physiologic free T 3 mo Supraphysiologic 2 yrs Supraphysiologic Initially Supraphysiologic Supraphysiologic 6 wks 6 mo ⫺17.1 ⫺17.5 NS ⫺7.6* ⫺6.4 NSa ⫺10.5 ⫺5.5 NS ⫺14.2 ⫺8.1 ⫺0.2 5 mo Note: dosages are for T, low dose EE is 0.625 mg EE, high dose EE is 1.25 mg, dose effect on T comparison to normal reproductive age range. HDL ⫽ high-density lipoprotein; LDL ⫽ low-density lipoprotein; NC ⫽ no change; E ⫽ estrogen; NR ⫽ not reported; EE ⫽ esterified estrogen; MT ⫽ methyltestosterone; NS ⫽ not significant; unk ⫽ unknown. a Statistical significance. b Values for lipid profile not provided, but reported as no significant change. Cameron. Androgen replacement therapy in women. Fertil Steril 2004. of MT and 22% developed facial hair with 1.25 mg of EE plus 2.5 mg of MT at 12 months, most of which was reported as light or medium growth. In comparison, both the highdose and low-dose estrogen-only control groups had a 20% increase in facial hair growth (98). The hirsutism rates for IM or SC T administration, which results in supraphysiologic T levels, have been reported to vary between 0% and 20%, but has not been systematically compared to parental or SC estrogen-only therapy (82, 85). No difference in hirsutism incidence rates between transdermal placebo or T have been reported (12, 14, 15). Due to the first pass effect on the liver after absorption from the gastrointestinal tract, oral androgen preparations generally exhibit a greater degree of lowering of SHBG and, therefore, greater increase in the free androgen levels than do parental or transdermal androgens. This liver effect also leads to a reduction of high-density lipoprotein (HDL) cholesterol levels, which is usually not found with androgens given in replacement doses by a nonoral route. Table 6 (12, 286 Cameron and Braunstein 13, 61, 78, 79, 81, 86, 88, 99, 101–104) summarizes the effects on cholesterol found with the different androgen preparations that have been reported in the studies included in Tables 4 and 5. Fortunately, many of the adverse reactions listed in the product labels of the various androgen preparations and in the literature concerning androgen therapy for male hypogonadism, such as hepatic dysfunction, polycythemia, sleep apnea, and breast stimulation have not been found in women receiving replacement therapy. SUMMARY Clinical investigations attempting to correlate androgen levels and sexual function parameters are exceedingly difficult as sexual behavior is complex. Individual patterns of sexual expression do not have an exclusive determinant and are largely dependent on interrelational dynamics. Only small observational studies have attempted to correlate androgen levels with female sexual function and there are no Androgen replacement therapy in women Vol. 82, No. 2, August 2004 large studies that used validated questionnaires to confirm the correlation. The physiologic mechanisms of female androgen insufficiency syndrome and subsequent symptoms are not entirely clear. The decline of androgen production is well documented and probably a consequence of the effects of advancing age on the adrenals and the ovaries rather than menopause. It is clear that women with hypopituitarism, adrenal insufficiency, or oophorectomy are often androgen insufficient. Why some women become symptomatic, and others not, has yet to be determined. That some symptomatic women respond to androgen replacement is clear. Although androgen therapy has been used in the treatment of menopausal symptoms since the 1930s, the understanding of the importance of endogenous androgens as well as the benefits and risks of exogenous androgen replacement therapy in women is incomplete. Androgen therapy may be most beneficial to women with androgen insufficiency due to hypopituitarism, adrenal insufficiency, or subsequent to bilateral oophorectomy. However, as most women now live approximately one-third of their lives after menopause, the consideration of androgen therapy for symptomatic, naturally menopausal women has gained increasing support and attention in the lay and medical communities. In addition, because womens’ partners now have longer life expectancies and have therapies to address their sexual function, the quality of life of women increasingly includes the ability to enjoy a meaningful, intimate sexual relationship. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. Related to the consideration of androgen therapy in symptomatic postmenopausal women are issues of inadequate and excessive estrogen therapy. Loss of libido may be simply due to underestrogenization and therefore, aversion due to dyspareunia, or overestrogenization with resultant increase in SHBG and binding of T. The role of ET for menopausal women is currently undergoing reassessment in the wake of the Women’s Health Initiative and Heart and Estrogen/Progestin Replacement Study studies. Because the studies dealing with androgen replacement in women have been carried out on a background of estrogen replacement, it is unknown what the effect of androgen replacement will be on women who are not receiving estrogens. To be sure, more largescale, long-term, placebo-controlled clinical evaluations of androgen replacement therapy in women with both surgical and natural menopause, with and without systemic ET, which accurately measure serum androgens and sexual function with validated tools are urgently needed. 18. References 29. 1. American Psychiatric Association. DSM-IV. Diagnostic and Statistical Manual of Mental Disorders, 4th ed. Washington, D.C.: American Psychiatric Press, 1994. 2. Basson R, Berman J, Burnett A, Derogatis L, Ferguson D, Fourcroy J, et al. 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