Testosterone production by the ovaries and adrenal glands plays an important role in maintaining women's sexual health. Loss of libido, diminished feelings of well-being, and fatigue are associated with decreased testosterone levels.1 The frequency of sexual activity and sexual desire in menopausal women are closely linked to testosterone.2 The ovaries and adrenal glands account for 50% of circulating testosterone; the remainder is from the peripheral conversion of androgen precursors.3,4 Women who undergo bilateral oophorectomy experience a 40% to 50% reduction in testosterone from presurgical levels and approximately 30% to 50% of these patients report a decrease in libido.5–7 At this time, more than 10 million women in the United States are surgically menopausal (Mattson Jack Group. Epidemiology of surgical menopause, 2004).
Low sexual desire was the most prevalent female sexual problem reported in the National Health and Social Life Survey,8 and it is estimated that 40% of postmenopausal women experience decreased libido.9 A survey of women in the United States found that 50% of the women who reported low sexual desire experienced distress due to this loss (Leiblum SR, European Federation of Sexology, 2004). Even with adequate estrogen therapy to ameliorate vasomotor symptoms, such as vaginal atrophy and dryness, after oophorectomy, many women experience persistent decreases in libido.10 Hypoactive sexual desire disorder, or loss of libido associated with distress, is one of the 4 types of female sexual dysfunction recognized by the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV).11 The International Consensus Development Conference on Female Sexual Dysfunction defined hypoactive sexual desire disorder as the persistent deficiency (or absence) of sexual fantasies or thoughts or desire for or receptivity to sexual activity, which results in personal distress.12
Studies involving testosterone therapy in the form of oral preparations,13,14 intramuscular injections,15,16 and subcutaneous implants17–19 have demonstrated significant improvement in sexual desire in postmenopausal women. However, many of these studies included small sample sizes and were of short duration, warranting large-scale, longer-term trials of testosterone therapy in women. Several products specifically designed for women with hypoactive sexual desire disorder are in development. For example, testosterone administered by a patch at 300 μg/d increased sexual function and well-being in a phase 2 trial of oophorectomized women with impaired sexual function who were receiving concomitant estrogen therapy.20
The INTIMATE SM 2 study (Investigation of Natural Testosterone In Menopausal women Also Taking Estrogen in Surgically Menopausal women), a randomized, double-blind, placebo-controlled, multicenter, multinational, phase III trial, was designed to further investigate the efficacy and safety of the 300 μg/d testosterone patch for the treatment of hypoactive sexual desire disorder in women with surgically-induced menopause concurrently receiving oral or transdermal estrogen therapy.
MATERIALS AND METHODS
Five hundred thirty-three women from 53 sites in the United States, Canada, and Australia were enrolled in the study between June 2002 and December 2003. All participants had undergone hysterectomy and bilateral salpingo-oophorectomy at least 6 months before screening and had been receiving a stable dose of approved oral or transdermal estrogen therapy for at least 3 months before enrollment. Participants were required to be in a stable monogamous relationship for at least 1 year to a sexually (both psychologically and physically) functional partner who was available for sexual activity at least 50% of each month during the study. All patients demonstrated evidence of hypoactive sexual desire disorder by reporting a meaningful loss in the desire for sex and a decrease in sexual activity since their oophorectomy. They expressed concern regarding these changes and expressed a desire to increase their level of interest for sexual activity. Women were excluded from the study if they had received oral, sublingual, topical, or transdermal androgen therapy during the past 3 months, injectable or implantable androgen during the past 7 months, or medications known to impair sexual function in the past 12 weeks such as selective serotonin reuptake inhibitors, tricyclic antidepressants, antiandrogens, progestins, and β-blockers. Patients also were excluded if they exhibited dyspareunia, severe dermatologic problems, history of sexual trauma, breast cancer, estrogen-dependent neoplasia, relationship disturbances, significant psychiatric disorders, alcohol or drug dependency, diabetes, cerebrovascular disease, or other serious medical conditions. Women qualifying for the study gave written informed consent to participate. The Institutional Review Board or Independent Ethics Committee at each study site approved the clinical protocol.
Patients visited the research centers twice during the 8-week pretreatment period to evaluate their eligibility to participate in the study. A physical examination, including breast and pelvic examination, was performed. Blood samples were collected for determination of serum chemistry, hematology, lipid profile, carbohydrate metabolism, and renal and liver function. Free, total, and bioavailable testosterone; sex hormone-binding globulin (SHBG); free and total estradiol (E2); and estrone levels also were measured.
If eligible, patients were randomly assigned in a 24-week, double-blind, parallel-group, placebo-controlled trial. Patients were stratified based on their use of oral or transdermal estrogen therapy. Within each stratum and site, the method of random permuted blocks was used to randomly allocate women to either the placebo or testosterone (300 μg/d) matrix patches. The random allocation sequence was implemented using a central telephone system. Both groups applied an identical-appearing patch twice weekly to be worn for 3 to 4 days on the abdomen. All participants, investigators, and study personnel were blinded to treatment assignment. Patients returned to the clinical research center at weeks 4, 8, 12, 16, 20, and 24 for assessments of efficacy and safety. Medical histories and physical examinations were obtained periodically during follow-up visits, as well as evaluations of serum hormone levels, lipid levels, liver function, and carbohydrate metabolism. Clinical assessments of alopecia, scalp hair, facial depilation, and facial acne also were made periodically during the study.
The efficacy tools for measuring testosterone treatment effect on sexual functioning relative to placebo included the Sexual Activity Log (Derogatis L, Rust J, Golombok S, Kuznicki J, Rodenberg C, McHorney C. A patient based diary to measure sexual activity in menopausal women with HSDD. Presented at the International Society for the Study of Women's Sexual Health; October 28-31, 2004; Atlanta, Georgia), the Profile of Female Sexual Function,21,22 and the Personal Distress Scale (Derogatis L, Rust J, Golombok S, Kuznicki J, Rodenberg C, McHorney C. A patient-generated, multinational inventory to measure distress associated with low desire. Presented at the International Society for the Study of Women's Sexual Health; October 28-31, 2004; Atlanta, Georgia). The Sexual Activity Log measured the frequency of sexual activity, with and without intercourse, orgasms from this activity, and frequency of satisfying sexual activity over the previous week. Patients were instructed to complete the Sexual Activity Log diary at the end of each 7-day period. The clinical phenomenology of hypoactive sexual desire disorder and its effects on patients’ thoughts, feelings, and behaviors were assessed with the Profile of Female Sexual Function, which measured 7 different domains of sexual function including sexual desire, sexual pleasure, sexual arousal, orgasm, sexual responsiveness, sexual concerns, and sexual self-image over the previous 4 weeks. The Personal Distress Scale measured patients’ personal distress related to their lack of interest in sex. Study participants completed the Profile of Female Sexual Function and Personal Distress Scale at baseline and at weeks 4, 8, 12, and 24.
Safety was evaluated by monitoring adverse events throughout the study, clinical laboratory tests, vital signs, and physical examinations. Patients were asked a series of questions regarding changes in medication regimens, voice, facial and scalp hair pattern, frequency of depilation, recent hospitalizations, and skin reaction during each visit. Hair was evaluated using the facial portion of the Lorenzo pictorial rating scale.23 Severity of acne was evaluated using a scale developed by Palatsi et al.24
Serum samples collected during the study were analyzed for free, total, and bioavailable testosterone, SHBG, E2, and estrone using validated immunoassay methods. All assays had a coefficient of variation of less than 13.2%. Reference ranges for hormones were generated by Quest Diagnostics Nichols Institute (San Juan Capistrano, CA) based on data from premenopausal women.
Assuming a 2-tailed test (alpha = 0.05), a sample of 230 patients per arm was determined to provide 90% power to detect a between-group mean difference of approximately 0.34 times per week. The standard deviation for the change from baseline in mean weekly rate of total satisfying sexual activity was estimated in phase II as 1.13 times per week. Because it was assumed that 90% to 95% of the patients would contribute postbaseline efficacy data to be used in the primary analysis, the sample size was increased to 250 patients per treatment arm. Analyses were performed using an intent-to-treat approach, with all patients who received at least 1 application of study medication included in the analyses. A last-observation-carried-forward approach was used to account for patients who did not complete the study. All hypothesis tests were 2-tailed, and treatment differences were assessed at the 0.05 significance level. Analyses were performed using SAS 8.2 software (SAS Institute, Cary, NC).
The primary efficacy endpoint was the change from baseline in the 4-week frequency of total satisfying episodes during weeks 21 through 24. The treatment effect of the testosterone patch was compared with placebo using a Wilcoxon rank sum test. The Profile of Female Sexual Function domains, in particular sexual desire, distress as measured by the Personal Distress Scale, total sexual activity, and total orgasms measured by the Sexual Activity Log were key secondary efficacy endpoints. Comparisons of the testosterone patch with placebo for the Profile of Female Sexual Function domains and the Personal Distress Scale were made using an analysis of covariance, adjusting for baseline response, concomitant estrogen therapy, age, and pooled site. (Pooled site refers to the pooled data from multiple clinical sites in the same geographical region when the number of patients at individual sites was small.) The secondary efficacy endpoints of total sexual activity and total orgasms were performed in a manner similar to the primary efficacy analysis.
The number of adverse events and percent of patients reporting adverse events as categorized by the Medical Dictionary for Regulatory Activities were summarized by treatment group as well as the severity and causality. Laboratory test findings, vital signs, and body weight were summarized at week 24 or study exit with descriptive statistics by treatment group in addition to the change from baseline. Change from baseline in androgenic assessments of upper lip and chin hair, facial depilation frequency, and facial acne were summarized at week 24 or exit by treatment group. Hormone concentrations were summarized by visit. To assess whether serum concentrations for free, total, and bioavailable testosterone were consistent at weeks 12 and 24, a repeated measures analysis was performed using log-transformed concentrations.
Two hundred sixty-six women were randomly assigned to the placebo group, and 267 women were randomly assigned to the testosterone patch group (Fig. 1). Of the 533 patients in the study, 417 (78%) completed the 24-week trial, whereas 115 (22%) patients discontinued. One patient who was randomly assigned to the testosterone patch failed to receive the study medication and was excluded from the intent-to-treat population. Characteristics of the patients in the 2 study groups were similar (Table 1).
Total satisfying sexual activity increased significantly at 24 weeks in the testosterone patch group compared with placebo based on the Wilcoxon rank sum test (Fig. 2A). Patients receiving the testosterone patch had a mean increase of 1.56 satisfying episodes per 4 weeks (corresponding to a 51% increase over the baseline mean) compared with a mean increase of 0.73 for the placebo group (P = .001). The median change from baseline was 1 satisfying episode per 4 weeks in the testosterone group compared with 0 in the placebo group. Statistically significant differences in total satisfying sexual activity in the testosterone patch group compared with placebo were observed beginning at week 5 (P = .03), with a maximal effect reached by week 12 and sustained through the remainder of the 24-week study. Total sexual activity in the testosterone patch group increased significantly from baseline compared with the placebo group at week 24 (P = .013) (Fig. 2A). Furthermore, total orgasms increased from baseline compared with placebo in the testosterone patch group (P < .001), corresponding to a 68% increase over baseline.
All 7 domains of sexual function including sexual desire, pleasure, arousal, orgasm, concerns, responsiveness, and self-image (measured by the Profile of Female Sexual Function) showed significant improvement in the testosterone patch group (Fig. 2B) compared with placebo at week 24. Mean changes from baseline in sexual desire were 4.29 and 10.57 in the placebo and the testosterone patch groups, respectively. The mean change in the test group corresponded to a 49% increase over baseline (P < .001). Sexual desire for patients in the testosterone patch group showed statistically significant improvement compared with placebo beginning at week 8 (P < .05) and was sustained through week 24. Arousal and orgasm also were improved relative to placebo. The mean change in the test group for arousal corresponded to a 74% increase over baseline (10.77 compared with 20.26, P = .001) and for orgasm corresponded to a 35% increase over baseline (5.65 compared with 12.87, P = .002). Patients’ improvement in sexual concerns (indicated by an increase in the Profile of Female Sexual Function sexual concerns score) was significantly improved in the testosterone patch group compared with placebo (22.30 compared with 11.97, P = .001), corresponding to a 65% change over baseline. Statistically significant differences in the testosterone patch group compared with placebo were observed beginning at week 8 for arousal (P = .028) and week 12 for orgasms (P < .001) and sexual concerns (P = .002).
The decrease in personal distress scores in the testosterone group at 24 weeks was significantly greater than the decrease in the placebo group (mean change from baseline, testosterone, −22.72; placebo, −16.05; P = .009). This mean change in the testosterone group corresponded to a 68% change from baseline. The difference in personal distress scores between groups first achieved statistical significance at week 24 (P < .05).
The overall incidence of adverse events and withdrawals due to adverse events were similar between the treatment groups (Table 2). The most common adverse events reported were application-site reaction, upper respiratory infection, facial hair, and headache. Most of the adverse events reported in both treatment groups were assessed as mild by the investigators and were considered doubtfully related to the study drug. A total of 11 serious adverse events (placebo, 6 [2.3%]; testosterone, 5 [1.9%]) were reported during the trial. All events in the testosterone patch group were classified by the investigator as doubtfully related to study drug (appendicitis, central line infection, complications from abdominal surgery, cellulitis, blocked salivary gland, and vertigo) and did not represent any serious safety risk with the testosterone patch use over 6 months. The overall incidence of androgenic adverse events was higher for the testosterone patch group (19.5%) compared with placebo (11.3%). Most of the androgenic adverse events were assessed as mild in severity. Two (0.8%) patients in the placebo group and 6 (2.3%) in the testosterone patch group withdrew due to androgenic adverse events. There were no statistically significant differences between the groups in any objective assessments of androgenic effects on the skin (facial hair, frequency of depilation, and degree of acne). More than 93% of the patients in both treatment groups had no change in scores at each facial area (Lorenzo pictorial rating scale23) during the 24 weeks. Using the Palatsi24 scale, very few patients in the placebo and the testosterone patch groups reported a change in the degree of facial acne during the study.
No meaningful changes in mean levels of lipids, lipoproteins, carbohydrate metabolism markers, renal function, liver function, or hematology measures were observed in either group (data not shown). The median serum concentrations of free, total, and bioavailable testosterone were similar between treatment groups at baseline and increased in the testosterone patch group at weeks 12 and 24 (Table 3). The total testosterone level was higher than the upper limit of the reference range (median at 24 weeks, 65.5 ng/dL; range, 12 to 50 ng/dL); however, the free testosterone level was not (median at 24 weeks, 3.1 pg/mL; range, 0.9 to 7.3 pg/mL) (Table 3). Although a decreased testosterone level was not a trial entry criterion, baseline levels of testosterone in both groups were at the lower end of the reference range; median (10th, 90th percentiles) free testosterone levels were 0.7 pg/mL (0.3, 1.6) and 0.7 pg/mL (0.3, 1.8) in the placebo and testosterone patch groups, respectively. The serum concentration of E2 (free and total) and estrone also were similar at baseline and showed no appreciable changes after treatment with the testosterone patch. The median serum concentration of free E2 increased slightly in the testosterone patch group at week 12 compared with placebo; however, levels were the same in each group at week 24. The baseline median SHBG levels were similar between the 2 groups. Within the testosterone patch group, SHBG levels were similar throughout the study. Significant correlations were observed between changes in serum total, bioavailable, and free testosterone levels at week 24 and changes in the frequency of satisfying activity (Spearman's rank correlation of 0.16 to 0.18; P < .05), in sexual desire (0.20 to 0.25; P < .05), and in personal distress (−0.11 to −0.17, P < .05).
The marked reduction of testosterone after bilateral oophorectomy is often associated with low sexual desire in women.2,3,25 Recent studies have focused on the efficacy, safety, and route of testosterone therapy for treating declining sexual desire. In this study, the 300 μg/d testosterone patch provided an effective and well-tolerated treatment of hypoactive sexual desire disorder in surgically menopausal women on concomitant oral or transdermal estrogen therapy. A positive treatment effect was observed for all total sexual activity endpoints of the Sexual Activity Log, all domains of the Profile of Female Sexual Function, and the Personal Distress Scale at 24 weeks. Mean increases observed in total satisfying sexual activity at 24 weeks suggest that women receiving the testosterone patch engaged in 1 additional sexual episode per 2.5 weeks, whereas those receiving placebo engaged in 1 additional sexual episode per 5.5 weeks. Importantly, there was also a corresponding increase in desire and a decrease in personal distress. The consistency of findings across a range of efficacy endpoints and the decrease in distress associated with low desire provide evidence that these changes are clinically meaningful in addition to being statistically significant.
Treatment with the testosterone patch was well tolerated in surgically menopausal women receiving concomitant oral or transdermal estrogen therapy, consistent with the findings of Shifren et al.20 Androgen-related adverse events were assessed as mild, were readily observed by patients, and did not require clinical monitoring. Although the incidence was higher in the testosterone patch group compared with placebo, the percentage of patients who withdrew from the trial due to an androgenic adverse event was low. It is important to note that this trial evaluated a fairly narrow population of women with hypoactive sexual desire disorder and these results should not be applied to other groups, such as premenopausal women, naturally menopausal women, or postmenopausal women not receiving estrogen. Because it was limited to 24 weeks, this study cannot address the safety of use beyond this duration. Additional data will be required to address the risks of longer-term use.
Similar to other trials of patient-centered outcomes, the placebo group in the current trial demonstrated improvement in sexual function.20,26 The awareness associated with seeking help for their complaint, frequent contact with healthcare professionals, and visibility of the transdermal patch by the patients and their partners may have influenced response in the placebo group.
Treatment with the testosterone patch resulted in increases in free, total, and bioavailable testosterone concentrations, with no significant change in free and total E2 or SHBG. The median total testosterone level was above the upper limit of the reference range. However, because most patients were receiving oral estrogens, the median SHBG level was also high. As a result, much of the total testosterone was bound and biologically inactive. Free and bioavailable testosterone both remained within the normal reference range. The lack of effect on E2 levels suggests that the 300 μg/d testosterone patch treatment is not associated with a detectable increased peripheral aromatization of androgens. Some previous studies have found a positive correlation between endogenous testosterone levels and sexual activity in women,2,27 whereas others have not.28,29 In this study, we found statistically significant correlations between the changes in testosterone levels and changes in efficacy measures.
Although there are no Food and Drug Administration–approved therapies for hypoactive sexual desire disorder at this time, the INTIMATE SM 2 study supports the effectiveness of testosterone in surgically postmenopausal women with low sexual desire and distress. The administration of testosterone by injection or implant may be effective for increasing sexual desire in women, but results in supraphysiological doses.15,17 These modes of administration are plagued by variable and unpredictable levels of testosterone.30,31 Oral preparations undergo first-pass hepatic metabolism, potentially leading to decreased levels of high-density lipoprotein cholesterol.13,14 The testosterone patch used in this trial is specific for women, contains a low dose, and has a continuous delivery of testosterone to provide consistent serum levels.32 The transdermal delivery of hormones avoids this first-pass metabolism.33 In the current trial, 24 weeks of 300 μg/d of testosterone delivered by a transdermal patch, in oophorectomized women with hypoactive sexual desire disorder who were receiving estrogen treatment, increased frequency of satisfying sexual activity and desire, decreased distress, and was well tolerated.
1. Sherwin BB. Changes in sexual behavior as a function of plasma sex steroid levels in post-menopausal women. Maturitas 1985;7:225–33.
2. McCoy NL, Davidson JM. A longitudinal study of the effects of menopause on sexuality. Maturitas 1985;7:203–10.
3. Laughlin GA, Barrett-Connor E, Kritz-Silverstein D, von Muhlen D. Hysterectomy, oophorectomy, and endogenous sex hormone levels in older women: the Rancho Bernardo Study. J Clin Endocrinol Metab 2000;85:645–51.
4. Abraham GE. Ovarian and adrenal contribution to peripheral androgens during the menstrual cycle. J Clin Endocrinol Metab 1974;39:340–6.
5. Judd HL, Judd GE, Lucas WE, Yen SS. Endocrine function of the postmenopausal ovary: concentration of androgens and estrogens in ovarian and peripheral vein blood. J Clin Endocrinol Metab 1974;39:1020–4.
6. Zussman L, Zussman S, Sunley R, Bjornson E. Sexual response after hysterectomy-oophorectomy: recent studies and reconsideration of psychogenesis. Am J Obstet Gynecol 1981;140:725–9.
7. Nathorst-Boos J, von Schoultz B. Psychological reactions and sexual life after hysterectomy with and without oophorectomy. Gynecol Obstet Invest 1992;34:97–101.
8. Laumann EO, Paik A, Rosen RC. Sexual dysfunction in the United States: prevalence and predictors. JAMA 1999;281:537–44.
9. Sarrel PM. Sexuality and menopause. Obstet Gynecol 1990;75:26S–30S.
10. Simon J, Klaiber E, Wiita B, Bowen A, Yang HM. Differential effects of estrogen-androgen and estrogen-only therapy on vasomotor symptoms, gonadotropin secretion, and endogenous androgen bioavailability in postmenopausal women. Menopause 1999;6:138–46.
11. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV). Washington (DC): American Psychiatric Association; 2000.
12. Basson R, Berman J, Burnett A, Derogatis L, Ferguson D, Fourcroy J, et al. Report of the international consensus development conference on female sexual dysfunction: definitions and classifications. J Urol 2000;163:888–93.
13. Barrett-Connor E, Young R, Notelovitz M, Sullivan J, Wiita B, Yang HM, et al. A two-year, double-blind comparison of estrogen-androgen and conjugated estrogens in surgically menopausal women: effects on bone mineral density, symptoms and lipid profiles. J Reprod Med 1999;44:1012–20.
14. Lobo RA, Rosen RC, Yang HM, Block B, Van Der Hoop RG. Comparative effects of oral esterified estrogens with and without methyltestosterone on endocrine profiles and dimensions of sexual function in postmenopausal women with hypoactive sexual desire. Fertil Steril 2003;79:1341–52.
15. Sherwin BB, Gelfand MM. The role of androgen in the maintenance of sexual functioning in oophorectomized women. Psychosom Med 1987;49:397–409.
16. Sherwin BB, Gelfand MM, Brender W. Androgen enhances sexual motivation in females: a prospective, crossover study of sex steroid administration in the surgical menopause. Psychosom Med 1985;47:339–51.
17. Burger H, Hailes J, Nelson J, Menelaus M. Effect of combined implants of oestradiol and testosterone on libido in postmenopausal women. Br Med J (Clin Res Ed) 1987;294:936–7.
18. Burger HG, Hailes J, Menelaus M, Nelson J, Hudson B, Balazs N. The management of persistent menopausal symptoms with oestradiol-testosterone implants: clinical, lipid and hormonal results. Maturitas 1984;6:351–8.
19. Davis SR, McCloud P, Strauss BJ, Burger H. Testosterone enhances estradiol's effects on postmenopausal bone density and sexuality. Maturitas 1995;21:227–36.
20. Shifren JL, Braunstein GD, Simon JA, Casson PR, Buster JE, Redmond GP, et al. Transdermal testosterone treatment in women with impaired sexual function after oophorectomy. N Engl J Med 2000;343:682–8.
21. Derogatis L, Rust J, Golombok S, Bouchard C, Nachtigall L, Rodenberg C, et al. Validation of the profile of female sexual function (PFSF) in surgically and naturally menopausal women. J Sex Marital Ther 2004;30:25–36.
22. McHorney CA, Rust J, Golombok S, Davis S, Bouchard C, Brown C, et al. Profile of Female Sexual Function: a patient-based, international, psychometric instrument for the assessment of hypoactive sexual desire in oophorectomized women. Menopause 2004;11:474–83.
23. Lorenzo EM. Familial study of hirsutism. J Clin Endocrinol Metab 1970;31:556–64.
24. Palatsi R, Hirvensalo E, Liukko P, Malmiharju T, Mattila L, Riihiluoma P, et al. Serum total and unbound testosterone and sex hormone binding globulin (SHBG) in female acne patients treated with two different oral contraceptives. Acta Derm Venereol 1984;64:517–23.
25. Longcope C, Hunter R, Franz C. Steroid secretion by the postmenopausal ovary. Am J Obstet Gynecol 1980;138:564–8.
26. Walsh BT, Seidman SN, Sysko R, Gould M. Placebo response in studies of major depression: variable, substantial, and growing. JAMA 2002;287:1840–7.
27. Persky H, Dreisbach L, Miller WR, O'Brien CP, Khan MA, Lief HI, et al. The relations of plasma androgen levels to sexual behaviors and attitudes of women. Psychosom Med 1982;44:305–19.
28. Dennerstein L, Dudley EC, Hopper JL, Burger H. Sexuality, hormones, and the menopausal transition. Maturitas 1997;26:83–93.
29. Cawood EH, Bancroft J. Steroid hormones, the menopause, sexuality, and well-being of women. Psychol Med 1996;26:925–36.
30. Lobo RA, March CM, Goebelsmann U, Krauss RM, Mishell DR Jr. Subdermal estradiol pellets following hysterectomy and oophorectomy: effect upon serum estrone, estradiol, luteinizing hormone, follicle-stimulating hormone, corticosteroid binding globulin-binding capacity, testosterone-estradiol binding globulin-binding capacity, lipids, and hot flushes. Am J Obstet Gynecol 1980;138:714–9.
31. Chu MC, Lobo RA. Formulations and use of androgens in women. Mayo Clin Proc 2004;79:S3–S7.
32. Mazer NA. Testosterone deficiency in women: etiologies, diagnosis, and emerging treatments. Int J Fertil Womens Med 2002;47:77–86.
© 2005 The American College of Obstetricians and Gynecologists
33. Burkman RT. The transdermal contraceptive system. Am J Obstet Gynecol 2004;190:S49–S53.