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Testosterone Patch Increases Sexual Activity and Desire in Surgically Menopausal Women with Hypoactive Sexual Desire Disorder

Women’s Health Research Center (J.S.), Laurel, Maryland 20707; Cedars-Sinai Medical Center (G.B.), Los Angeles, California 90048; New York University School of Medicine (L.N.), New York, New York 10016; Rapid Medical Research (W.U.), Cleveland, Ohio 44122; Katz, Kade, and Hewitt, Inc. (M.K.), Cincinnati, Ohio 45219; S. A. M. Clinical Research Center (S.M.), San Antonio, Texas 78229; Downtown Women’s Health Care (A.W.), Denver, Colorado 80202; Clinique RSF, Inc. (C.B.), Quebec, Canada G1S 2L6; St. Michael’s Hospital Health Center (C.D.), Toronto, Canada M5B 1W8; Procter & Gamble Pharmaceuticals Health Care Research Center (A.B., C.R., J.L.), Mason, Ohio 45040; The Jean Hailes Foundation, Research Unit (S.D.), Clayton, Australia VIC 3168; and Department of Medicine (S.D.), Monash University, Praham, Victoria, Australia VIC 3800

Address all correspondence and requests for reprints to: Dr. James Simon, 14201 Laurel Park Drive Suite 104, Laurel, Maryland 20707. E-mail: jasimon{at}whrc.net.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Context: Hypoactive sexual desire disorder (HSDD) is one of the most common sexual problems reported by women, but few studies have been conducted to evaluate treatments for this condition.

Objective: The objective of this study was to evaluate the efficacy and safety of a testosterone patch in surgically menopausal women with HSDD.

Design: The design was a randomized, double-blind, parallel-group, placebo-controlled, 24-wk study (the Intimate SM 1 study).

Setting: The study was performed at private or institutional practices.

Patients: The subjects studied were women, aged 26–70 yr, with HSDD after bilateral salpingo-oophorectomy who were receiving concomitant estrogen therapy. Placebo (n = 279) or testosterone 300 µg/d (n = 283) was administered. There were 19 patients who withdrew due to adverse events in the placebo group and 24 in the 300 µg/d testosterone group.

Intervention: Testosterone (300 µg/d) or placebo patches were applied twice weekly.

Main Outcome Measure(s): The primary end point was the change in the frequency of total satisfying sexual activity at 24 wk. Secondary end points included other sexual functioning end points and safety assessments.

Results: At 24 wk, there was an increase from baseline in the frequency of total satisfying sexual activity of 2.10 episodes/4 wk in the testosterone group, which was significantly greater than the change of 0.98 episodes/4 wk in the placebo group (P = 0.0003). The testosterone group also experienced statistically significant improvements in sexual desire and a decrease in distress. The overall safety profile was similar in both treatment groups.

Conclusion: In the Intimate SM 1 study, the testosterone patch improved sexual function and decreased distress in surgically menopausal women with HSDD and was well tolerated in this trial.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
HYPOACTIVE SEXUAL DESIRE disorder (HSDD) is defined as a chronic or recurrent deficit in or absence of desire for sexual activity that causes personal distress (1). Investigators have noted that up to 50% of postoophorectomy patients report a decrease in sexual desire after surgery (2, 3). It is hypothesized that this decrease may be associated with lower levels of circulating androgens due to removal of the ovaries. Women who have undergone bilateral oophorectomy typically experience a drop of 50% in their circulating testosterone levels (4). Treatment with oral estrogens after surgery frequently increases SHBG levels, which may exacerbate the effects of a low testosterone level, because a greater proportion of circulating testosterone is bound to SHBG and does not enter target tissues (5).

Study findings have suggested that libido can be improved for women with HSDD through the use of postoperative estrogen and testosterone therapy, and this combination therapy has been found to be more effective than estrogen alone (6, 7, 8). Testosterone delivered by a transdermal patch may have advantages over other dosage forms, because it bypasses first-pass metabolism and can provide consistent levels of hormone over time. A 12-wk, placebo-controlled trial of a testosterone transdermal matrix patch showed that administration of 300 µg/d produced increases in sexual functioning and well-being in oophorectomized women with low libido receiving concomitant oral conjugated equine estrogens (9). We undertook this phase III study to investigate the efficacy and safety of 300 µg/d testosterone administered by this patch in women with HSDD after surgically induced menopause.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Study design and patients

This trial enrolled women at 52 centers in the United States, Canada, and Australia and consisted of a 24-wk, double-blind, placebo-controlled treatment period, followed by a 28-wk, open-label, safety follow-up period. This manuscript reports results of the placebo-controlled treatment period. Participants were required to be 20–70 yr of age, in good health, have a normal mammogram if age 40 yr or older, have a normal Pap smear, have undergone bilateral salpingo-oophorectomy and hysterectomy at least 6 months before screening, and have no physical impediment to sexual function. All women were also receiving a stable dose of estrogen therapy (oral or transdermal patch) for at least 3 months before screening and in a stable, monogamous relationship with a partner who was sexually functional, based on the assessment of the woman. The goal in requiring a functional partner was to ensure that a woman’s sexual activity was not limited by impairment of the partner. No medical information was collected regarding the partner.

To be eligible to participate, a woman had to report having a satisfying sex life before oophorectomy and a meaningful loss of sexual desire and decrease in sexual activity after surgery and being bothered or concerned about this decrease in desire for sexual activity. Women were excluded if they had other conditions that could impact sexual function, including dyspareunia; major life change interfering with sexual function; a psychiatric disorder, including depression [Beck Depression Inventory II score (10) of 14 or greater]; or drug or alcohol dependency, or were taking medications known to affect sexual function, including androgens, phytoestrogens, selective serotonin reuptake inhibitors, systemic ß-blockers, raloxifene, tamoxifen, and sildenafil. Women were also excluded if they had a history of breast cancer or estrogen-dependent neoplasia, significant organic disease that could affect the outcome of the study, active gall bladder disease, diabetes, history of cerebrovascular disease or thromboembolic disorders, or abnormal levels of TSH, serum creatinine, or liver enzymes.

Women were stratified by route of concomitant estrogen therapy (transdermal or oral) and were then randomly assigned in a 1:1 ratio to receive placebo or 300 µg testosterone daily for 24 wk in the form of a twice weekly patch worn on the abdomen. The placebo and testosterone patches were identical in appearance. Patients and all study personnel were blinded to treatment assignments. Study participants visited the sites at baseline and every 4 wk during the 24-wk, double-blind study period.

The treatment of human subjects was consistent with the principles outlined in the Declaration of Helsinki. All patients gave written, informed consent to participate, and the appropriate ethic committees or institutional review boards approved both the protocol and patient consent form.

Efficacy measurements

The primary efficacy end point, the change in frequency of total satisfying sexual activity over a 4-wk period evaluated at 24 wk, was assessed using a weekly diary, the sexual activity log (SAL). The SAL was completed for 8 wk before and for the 24 wk of study treatment and questioned patient physical health status, partner availability, and the frequency of sexual activity during the preceding 7 d. Women were asked to record the frequency of sexual activity, the number of orgasms, and whether the activity was satisfying. As specified in the SAL, sexual activity included sexual intercourse, masturbation (with or without the partner), giving or receiving oral sex, or any other sexual activity. This allowed patients to include whatever sexual practices in which they chose to engage, but still to count episodes of sexual activity as a common unit for comparison. All episodes of sexual activity in the last 4 wk were included when calculating the frequency of total sexual activity; only episodes that the woman considered satisfying were included when calculating the frequency of total satisfying sexual activity.

Secondary efficacy measurements included evaluation of changes in the profile of female sexual function (PFSF), a 37-item questionnaire that has been developed and validated in postmenopausal women (11, 12). The PFSF measures seven different domains of sexual function: sexual desire, sexual pleasure, sexual arousal, orgasm, sexual responsiveness, sexual concerns, and sexual self-image. Each item in every PFSF domain had six scoring levels, ranging from always (1) to never (6). In addition, a question regarding the patient’s overall satisfaction with her sexuality had to be completed. The possible responses to this question were: 1 = poor, 2 = fair, 3 = good, 4 = very good, and 5 = excellent. Domain scores were computed by summing the scores for items within a domain. Each raw domain score was then transformed to a 0–100 scale using the following formula: transformed score = [(actual raw score – lowest raw domain score possible)/(highest raw domain score possible – lowest raw domain score possible)] x 100. Scores of 0, 20, 40, 60, 80, and 100 on each domain of the PFSF correspond, on the average, to the following categories of response: never, seldom, sometimes, often, very often, and always, respectively. Note that an increase in the sexual concerns score indicated a decrease in patients’ concerns related to sexuality.

The level of patient distress was evaluated using the Personal Distress Scale (PDS), which consisted of seven questions concerning level of distress associated with decreased interest in sex. Each item of the PDS had six scoring options, ranging from always (score of 1) to never (score of 6). The PDS score was the sum over the scores for the items on the scale. The raw score was transformed to a 0–100 scale using the same formula shown above. Scores of 0, 20, 40, 60, 80, and 100 on the PDS correspond, on the average, to the following categories of response: never, seldom, sometimes, often, very often, and always distressed about a lack of interest in sex, respectively. A decrease in PDS score indicated a decrease in patient distress. The PFSF and PDS were administered at baseline and after 4, 8, 12, and 24 wk of treatment.

Safety assessments

Adverse event reports were collected from the time of first application of study drug (either placebo or testosterone patch) until the patients exited the study. Women experiencing any clinically significant adverse event were to remain under medical supervision until the event resolved, stabilized, or was no longer serious enough to warrant follow-up. All adverse events were categorized using the Medical Dictionary for Regulatory Activities coding dictionary. The Medical Dictionary for Regulatory Activities is a registered trademark of the International Federation of Pharmaceutical Manufacturers Associations.

Any report of a reaction at the patch application site volunteered by a participant was recorded as an adverse event; in addition, the site of most recent patch application was examined at each clinic visit. Application site adverse events were rated as mild, moderate, or severe depending upon the degree of erythema, pruritis, or other symptoms.

At each clinic visit, study personnel assessed the degree of lip or chin hair using the facial portion of the Ferriman-Gallwey/Lorenzo scoring system (13). Facial acne was evaluated using the scale developed by Palatsi et al. (14) Women also were asked whether they had experienced any change in scalp hair or voice and positive responses were recorded as adverse events.

Blood samples were collected 8 and 4 wk before treatment and 24 wk after initiation of treatment for determination of serum chemistry, hematology, lipid profile, carbohydrate metabolism, renal and liver function, and coagulation parameters (Quintiles Laboratories, Smyrna, GA).

Hormone measurements

Blood samples were collected at baseline and after 24 wk of treatment for determination of hormone levels using validated methods (Quest Diagnostics, Inc., San Juan Capistrano, CA).

The analysis of total testosterone was performed by RIA after sample extraction and column chromatography. The lower limit of quantification (LLOQ) for the testosterone measurement was 2 ng/dl, and the interassay coefficient of variation (CV) was 12.5% or less for all quality control samples analyzed with the study samples. The percent free testosterone was determined by equilibrium dialysis using radiolabeled tracer techniques. Free testosterone concentrations were calculated by multiplying the total testosterone by the percent free testosterone.

The concentration of dihydrotestosterone was measured by RIA after sample extraction and column chromatography; tritiated dihydrotestosterone was used as an internal standard to correct for recovery. The LLOQ was 3 ng/dl (0.10 nmol/liter), and the CV was 14.2% or less.

Androstenedione measurements were performed by RIA after sample extraction for which tritiated androstenedione was used as an internal standard. For the androstenedione measurements, the LLOQ was 3 ng/dl (0.10 nmol/liter), and the CV was 11.2% or less.

The concentrations of SHBG were determined using a sandwich immunoassay. The LLOQ was 2 nmol/liter, and the interassay CV was 8.1% or less for all quality control samples.

The analyses of total estradiol and estrone were performed by RIA after sample extraction and column chromatography. For the total estradiol assay, the LLOQ was 2 pg/ml (7.34 pmol/liter), and the CV was 12.5% or less. The corresponding values for the estrone assay were 10 pg/ml (37 pmol/liter) and 9.6% or less.

Statistical methods

Assuming a two-sided test, a minimum of 230 patients/arm were estimated to be necessary to provide approximately 90% power to detect a difference between treatment groups of 0.34 satisfying sexual activities/wk. Analyses were performed using an intent to treat approach, with all patients who received at least one 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. The sample size was increased to 250 patients/arm, because it was assumed that 5–10% of the patients would not contribute data for inclusion in the primary efficacy analysis. All hypothesis tests were two-sided, and treatment differences were assessed at the 0.05 significance level. Analyses were performed using SAS 8.2 software (SAS Institute, Inc., Cary, NC).

The primary efficacy end point was the change from baseline in the 4-wk frequency of total satisfying episodes during wk 21–24. Treatment groups were compared using an analysis of covariance model, adjusting for route of administration of concomitant estrogen therapy, baseline rate of activity, age, and pooled center. Model assumptions were assessed qualitatively by visual inspection of the residuals. Similar methods were used to analyze the secondary efficacy end points. Correlations between changes from baseline in hormone levels and efficacy assessments were evaluated using Spearman correlation coefficients.

The number of adverse events and the percentage of patients reporting adverse events through wk 24 were summarized by treatment group. Laboratory test findings, vital signs, and body weights were summarized by treatment group using descriptive statistics. Lip and chin facial hair scores, facial depilation frequency, and facial acne scores were summarized using frequency tables. Changes in lipids by treatment group were summarized using descriptive statistics.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Patient characteristics and disposition

Baseline characteristics were similar for the treatment groups (Table 1). Baseline PFSF scores for sexual desire corresponded to the seldom interested in sex category, whereas baseline PDS scores were reflective of patients who were often distressed by their lack of desire.

Efficacy measures

At 24 wk, the increase in the 4-wk frequency of total satisfying sexual activity was significantly greater in the testosterone group compared with the placebo group (P = 0.0003; Table 2). A statistically significant increase in the change in frequency of total satisfying sexual activity in the testosterone group compared with placebo was observed in the 4-wk period beginning at wk 5 (i.e. wk 5–8), with a consistent effect maintained from wk 12 on (Fig. 1). Testosterone patch treatment also resulted in statistically significant increases compared with placebo in frequency of total sexual episodes and orgasm (Table 2).

View larger version (16K): [in this window] [in a new window]   FIG. 1. Changes in 4-wk frequency of total satisfying activity, sexual desire score, and PDS in the testosterone and placebo groups over 24 wk. , Testosterone; , placebo. *, P 0.05 vs. placebo.

The decrease in personal distress scores in the testosterone group at 24 wk was significantly greater than the decrease in the placebo group (P = 0.0006; Table 2). A significant decrease in personal distress in the testosterone group compared with placebo was observed at wk 4 and at all subsequent time points throughout the study (Fig. 1).

Testosterone-treated women also experienced significantly more favorable changes compared with placebo-treated women in all other domains of the PFSF (Fig. 2).

View larger version (29K): [in this window] [in a new window]   FIG. 2. PFSF domain scores: values at baseline and wk 24 in the testosterone and placebo groups. P values are for comparison of changes from baseline in testosterone vs. placebo groups. Note that the higher score for the sexual concerns domain reflects a decrease in patient concern.

The overall adverse event profiles were similar in the two treatment groups (Table 3). The majority of adverse events were mild and classified by the investigator as doubtfully related to testosterone treatment. A total of 14 patients [placebo, seven patients (2.5%); testosterone, seven patients (2.5%)] reported serious adverse events during the trial. All but two of the seven testosterone patients had events that were classified by the investigator as doubtfully related to study drug (a transient ischemic attack in one patient; diaphoresis, increased heart rate, nausea, and other symptoms in a second patient). These two patients had resolution of the events while remaining on testosterone treatment. The incidence of application site reactions, the most commonly reported adverse event, was comparable in the testosterone and placebo groups. Most of these skin reactions were mild; 22 women [placebo, 13 patients (4.7%); testosterone, nine patients (3.2%)] discontinued treatment for this reason. The adverse events reported most commonly and by a higher percentage of patients receiving testosterone patch were headaches, upper respiratory tract infections, and acne. However, the difference between the treatment groups in the percentage of patients reporting these events was small. A higher percentage of patients reported migraine headache in the testosterone group (12 patients, 4.2%) than in the placebo group (four patients, 1.4%). Eight of the 12 patients in the testosterone group who reported migraines had a history of migraines before entering the study.

Serum hormone levels

The median serum concentrations of free and total testosterone were similar in both treatment groups at baseline and were increased in the testosterone-treated group after 24 wk of treatment; no change in SHBG levels was observed with testosterone treatment (Table 5). There were no appreciable changes from baseline observed in serum estradiol (free and total) or estrone in either treatment group.

Statistically significant correlations were observed between changes in most efficacy end points of the SAL, PFSF, and PDS and changes in testosterone serum concentrations (total, free, and bioavailable testosterone) after 24 wk of treatment (Table 6). No other correlations between efficacy end points and estrogen-related serum concentrations (i.e. free and total estradiol, estrone, or SHBG) were statistically significant, except for a correlation between sexual arousal and SHBG. Similar correlations were observed when efficacy end points were compared with actual hormone concentrations, rather than the changes in hormone concentrations.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

Female sexual function and associated distress were measured in our study using three patient-based instruments (the PFSF, PDS, and SAL) previously developed specifically to evaluate sexual function in surgically and naturally menopausal women with low libido. Of the aspects of sexuality captured by these measures, changes in sexual desire and distress are of particular interest, because both are defining properties of HSDD. The testosterone patch treatment produced significant favorable changes not only in both of these parameters but also in the frequency of total satisfying sexual activity. Satisfying sexual activity was a composite end point, including a variety of sexual activities, including sexual intercourse, masturbation, and oral sex as well as other sexual activities.

All PFSF, PDS, and SAL end points demonstrated statistically significant changes from baseline in the testosterone group compared with placebo after 24 wk of treatment. The magnitude and consistency of this response suggest that the testosterone patch produced a clinically meaningful change in overall sexual functioning, as measured across many aspects of sexual function and activity in this study. Statistically significant increases in some end points were evident within 4 wk of the start of treatment, and these increases were maintained throughout the treatment period.

The placebo response in this study is consistent with that in other reports related to sexual functioning (9, 15). All women enrolled in our study stated at baseline that they desired an improvement in their sex lives, and participating in the study may have increased dialogue regarding sexual satisfaction between the study subjects and their partners. We observed statistically significant changes with testosterone treatment even compared with the response in the placebo group.

The testosterone patches used in the study demonstrated a favorable safety profile in this population of women with low sexual desire. Adverse events, including androgenic adverse events, occurred with similar frequency in the placebo- and testosterone-treated groups. We saw no clinically important effects on vital signs, clinical chemistry, or hematology. About 30% of women in our study experienced application site reactions; however, most of these reactions were mild, and less than 5% of each patient group discontinued study participation due to these events. The incidence of application site reaction or discontinuation due to application site reactions observed in this study appears similar to those observed in some other studies with patches (16, 17).

Serum concentrations of free and total testosterone were similar between the treatment groups at baseline, and women receiving transdermal testosterone had increases in these concentrations at the end of 24 wk of treatment. No appreciable changes in the serum concentrations of estradiol or estrone occurred after treatment with transdermal testosterone. It should be noted that even though patients were selected on the basis of clinical symptoms of HSDD rather than on the basis of testosterone levels, the baseline testosterone levels in these oophorectomized women were low. These findings suggest that measurement of testosterone at baseline is not necessary in oophorectomized women with HSDD who are being considered for testosterone treatment.

The majority of women included in this study were Caucasian; therefore, fewer data are available regarding the effects of testosterone transdermal therapy on patients of other racial backgrounds. Only surgically postmenopausal women were enrolled in this clinical trial, and all were receiving concomitant estrogen therapy, so other studies will be needed to evaluate this therapy in naturally menopausal women or in women without concomitant estrogen therapy. This study also evaluated only short-term use (24 wk). Given concerns with long-term safety of estrogen and progestin therapy raised by the Women’s Health Initiative study (18), it will be important to obtain additional data to assess the longer-term safety of testosterone.

Conclusions

In this large, randomized, placebo-controlled trial, the transdermal testosterone patch was demonstrated to be an effective therapy for the treatment of HSDD in surgically menopausal women receiving concomitant estrogen therapy. Treatment was well tolerated, and no serious safety concerns were identified during 24 wk of therapy.

	Acknowledgments

 
We thank Procter & Gamble Pharmaceuticals, Inc. (Cincinnati, OH) for statistical analysis of study results and assistance with the preparation of the manuscript. We also thank all of the other investigators who participated in this trial: P. Bearnson, Phase II Center for Women’s Health (Salt Lake City, UT); E. Bieber, Geisinger Medical Center (Danville, PA); P. Bowen, The Emory Clinic (Atlanta, GA); F. Cole, Fayette Medical Clinic (Fayetteville, GA); G. Connor, Radiant Research–Birmingham, (Birmingham, AL); L. Derogatis, J. H. Center for Sexual Health and Medicine (Lutherville, MD); J. Dietrich, M. T. Health Research Institute (Billings, MT); J. Eden, Sydney Menopause Center at Royal Hospital for Warren Randwick (Randwick, Australia); J. Ervin, The Center for Pharmaceutical Research (Kansas City, MO); A. Goldstein, The Sexual Wellness Center (Annapolis, MD); S. Gordon, ICSL Clinical Studies (Atlanta, GA); M. Greenwald, Desert Medical Advances (Palm Desert, CA); R. Harlin, Coastal Clinical Research, Inc. (Mobile, AL); B. Hecht, Mercy Medical Center (Canton, OH); M. Heuer, Clinical Science International, Inc. (Ocala, FL); J. Abernethey (Gainesville, FL); V. Jorgensen, ICSL (Philadelphia, PA); R. Kagan, The Foundation for Osteoporosis Research and Education (Oakland, CA); N. Kakos, QUEST Research Institute (Southfield, MI); B. Kessel, The Queen’s Medical Center (Honolulu, HI); L. Komer, The Center for Womens’ Health Urgent Care Canada (Burlington, Canada); R. Kroll, Women’s Clinical Research Center (Seattle, WA); S. Levine, The Center for Marital and Sexual Health, Inc. (Beachwood, OH); A. Luciano, New Britain General Hospital Center for Fertility and Women’s Health (New Britain, CT); A. Marcadis, Comprehensive NeuroScience (Boynton Beach, FL); M. McDermott, Radiant Research–Austin (Austin, TX); J. McKenney, National Clinical Research (Richmond, VA); B. Miller, Radiant Research–Scottsdale (Scottsdale, AZ); P. Miller, Greenville Hospital System (Greenville, SC); M. Moreau, Montreal Clinical Study Center, Inc., Centre Detude Clinique Montreal, Inc. (Montréal, Canada); K. Muse, University of Kentucky (Lexington, KY); T. Poling, Heartland Research Associated, LLC (Wichita, KS); J. Redmon, University of Minnesota (Minneapolis, MN); H. Reisman, Atlanta North Gynecology P.C. (Roswell, GA); M. Reynolds, Radiant Research–Dallas North (Dallas, TX); L. Romanzi (New York, NY); S. Rosenblatt, Irvine Center for Clinical Research (Irvine, CA); J. Rothman, Tampa Bay Medical Research (Clearwater, FL); C. Saffer, Radiant Research–San Diego (San Diego, CA); B. Troupin, Radiant Research–San Diego (San Diego, CA); R. Weinstein, Diablo Clinical Research, Inc. (Walnut Creek, CA); N. Watts, University of Cincinnati Osteoporosis Center (Cincinnati, OH); P. Whitsitt, Paradigm Clinical Trials, Inc. (Oshawa, Canada); and C. Yuen, Manitoba Clinic (Winnipeg, Canada).

	Footnotes

 
This work was supported by grants from Procter & Gamble Pharmaceuticals, Inc. (Cincinnati, OH).

First Published Online July 12, 2005

Abbreviations: CV, Coefficient of variation; HSDD, hypoactive sexual desire disorder; LLOQ, lower limit of quantification; PDS, Personal Distress Scale; PFSF, Profile of Female Sexual Function; SAL, Sexual Activity Log.

Received September 1, 2004.

Accepted June 30, 2005.

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