Michèle Moreau

Testosterone for Low Libido in Postmenopausal Women Not Taking Estrogen

BACKGROUND The efficacy and safety of testosterone treatment for hypoactive sexual desire disorder in postmenopausal women not receiving estrogen therapy are unknown. METHODS We conducted a double-blind, placebo-controlled, 52-week trial in which 814 women with hypoactive sexual desire disorder were randomly assigned to receive a patch delivering 150 or 300 microg of testosterone per day or placebo. Efficacy was measured to week 24; safety was evaluated over a period of 52 weeks, with a subgroup of participants followed for an additional year. The primary end point was the change from baseline to week 24 in the 4-week frequency of satisfying sexual episodes. RESULTS At 24 weeks, the increase in the 4-week frequency of satisfying sexual episodes was significantly greater in the group receiving 300 microg of testosterone per day than in the placebo group (an increase of 2.1 episodes vs. 0.7, P<0.001) but not in the group receiving 150 microg per day (1.2 episodes, P=0.11). As compared with placebo, both doses of testosterone were associated with significant increases in desire (300 microg per day, P<0.001; 150 microg per day, P=0.04) and decreases in distress (300 microg per day, P<0.001; 150 microg per day, P=0.04). The rate of androgenic adverse events - primarily unwanted hair growth - was higher in the group receiving 300 microg of testosterone per day than in the placebo group (30.0% vs. 23.1%). Breast cancer was diagnosed in four women who received testosterone (as compared with none who received placebo); one of the four received the diagnosis in the first 4 months of the study period, and one, in retrospect, had symptoms before undergoing randomization. CONCLUSIONS In postmenopausal women not receiving estrogen therapy, treatment with a patch delivering 300 microg of testosterone per day resulted in a modest but meaningful improvement in sexual function. The long-term effects of testosterone, including effects on the breast, remain uncertain. (ClinicalTrials.gov number, NCT00131495.)

Testosterone patch for the treatment of hypoactive sexual desire disorder in naturally menopausal women: Results from the INTIMATE NM1 Study

Objective: To evaluate the efficacy and safety of a testosterone patch for the treatment of women with hypoactive sexual desire disorder after natural menopause. Design: A multicenter, randomized, double-blind, placebo-controlled, parallel-group trial was conducted in naturally menopausal women with hypoactive sexual desire disorder receiving a stable dose of oral estrogen with or without progestin (N = 549). Women were randomized to receive testosterone 300 &mgr;g/day or placebo patches twice weekly for 24 weeks. The primary efficacy measure was change from baseline in frequency of total satisfying sexual activity over a 4-week period (weeks 21-24). Results: A total of 483 women (88%) were included in the primary analysis population (those with baseline sex hormone binding globulin levels ≤160 nmol/L). The change from baseline in number of total satisfying sexual episodes was significantly greater for testosterone compared with placebo (participants with baseline sex hormone binding globulin levels ≤160 nmol/L, mean change of 2.1 ± 0.28 versus 0.5 ± 0.23 episodes/4 weeks; P < 0.0001; intent-to-treat population, mean change from baseline of 1.9 ± 0.26 versus 0.5 ± 0.21 episodes/4 weeks, P < 0.0001). Testosterone also produced statistically significant improvements compared with placebo in all secondary efficacy measures, including sexual desire and personal distress. The testosterone patch was well tolerated. Conclusions: Testosterone patch treatment increased the frequency of satisfying sexual activity and sexual desire, decreased personal distress, and was well tolerated in naturally menopausal women with hypoactive sexual desire disorder.

Effect of intravaginal dehydroepiandrosterone (Prasterone) on libido and sexual dysfunction in postmenopausal women

Objective: The objective of this study was to provide evidence that the transformation of DHEA into both androgens and/or estrogens locally in cells of the three layers of the vagina (epithelium, lamina propria, and muscularis) would have effects of greater impact, including effects on sexual function, than only effects on superficial epithelial cells as achieved with estrogens. Methods: This prospective, randomized, double-blind, and placebo-controlled phase III clinical trial has evaluated the effect of daily local intravaginal application of Prasterone (dehydroepiandrosterone; DHEA) for 12 weeks on the domains of sexual dysfunction, namely, desire/interest, arousal, orgasm, and pain at sexual activity, in 216 postmenopausal women with moderate to severe symptoms of vaginal atrophy. Results: A time- and dose-dependent improvement of the four domains of sexual function was observed. At the 12-week time interval, the 1.0% DHEA dose led, compared with placebo, to 49% (P = 0.0061) and 23% (P = 0.0257) improvements of the desire domains in the Menopause Specific Quality of Life and Abbreviated Sex Function questionnaires, respectively. Compared with placebo, the Abbreviated Sex Function arousal/sensation domain was improved by 68% (P = 0.006), the arousal/lubrication domain by 39% (P = 0.0014), orgasm by 75% (P = 0.047), and dryness during intercourse by 57% (P = 0.0001). Conclusions: By a local action in the vagina, DHEA applied daily at doses at which serum steroids remain well within normal postmenopausal values exerts relatively potent beneficial effects on all four aspects of sexual dysfunction. Such data indicate that combined androgenic/estrogenic stimulation in the three layers of the vagina exerts important beneficial effects on sexual function in women without systemic action on the brain and other extravaginal tissues.

Intravaginal dehydroepiandrosterone (Prasterone), a physiological and highly efficient treatment of vaginal atrophy

Objective: Because the secretion of dehydroepiandrosterone (DHEA), the exclusive source of sex steroids in postmenopausal women, is already decreased by 60% and continues to decline at the time of menopause, the objective of this study was to examine the effect of intravaginal DHEA on the symptoms and signs of vaginal atrophy. Methods: This prospective, randomized, double-blind and placebo-controlled phase III clinical trial studied the effect of Prasterone (DHEA) applied locally in the vagina on the signs and symptoms of vaginal atrophy in 216 postmenopausal women. Results: All three doses (0.25%, 0.5%, and 1.0%) of DHEA ovules applied daily intravaginally induced a highly significant beneficial change in the percentage of vaginal parabasal and superficial cells and pH as well as in the most bothersome symptom at 2 weeks. At the standard 12-week time interval, 0.5% DHEA caused a 45.9 ± 5.31 (P < 0.0001 vs placebo) decrease in the percentage of parabasal cells, a 6.8 ± 1.29% (P < 0.0001) increase in superficial cells, a 1.3 ± 0.13 unit (P < 0.0001) decrease in vaginal pH, and a 1.5 ± 0.14 score unit (P < 0.0001) decrease in the severity of the most bothersome symptom. Similar changes were seen on vaginal secretions, color, epithelial surface thickness, and epithelial integrity. Comparable effects were observed at the 0.25% and 1.0% DHEA doses. Conclusions: Local Prasterone, through local androgen and estrogen formation, causes a rapid and efficient reversal of all the symptoms and signs of vaginal atrophy with no or minimal changes in serum steroids, which remain well within the normal postmenopausal range. This approach avoids the fear of systemic effects common to all presently available estrogen formulations and adds a novel physiological androgenic component to therapy.

Ortho Evra™/Evra™ versus oral contraceptives: follicular development and ovulation in normal cycles and after an intentional dosing error

OBJECTIVE To compare the effects of the contraceptive patch to oral contraceptives (OCs) on follicular size and incidence of ovulation in normal cycles and after dosing errors. DESIGN Randomized, open-label. SETTING Twelve centers. PATIENT(S) One hundred twenty-four ovulatory women. INTERVENTION(S) Subjects received either the patch (groups 1 and 2) or one of three OCs. Correct dosing occurred in cycles 1, 2, 3, and 5. The following dosing errors were planned during cycle 4, a shortened 10-day cycle: [1] patch group 1 subjects wore one patch for 10 consecutive days; [2] for patch group 2 and OC subjects, 7 dosing days were followed by 3 drug-free days. MAIN OUTCOME MEASURE(S) Follicular size, as determined at each cycle by the maximum mean follicular diameter. RESULT(S) After a 3-day dosing error, follicular size was significantly smaller in the patch group (mean, 7.0 mm) vs. each OC group (range of means, 11.8-17.1 mm). Similar results were seen after proper dosing. The incidence of ovulation was significantly lower for the patch users than for women using OCs. CONCLUSION(S) Follicular size and incidence of ovulation were significantly reduced among contraceptive patch users compared with women using OCs in normal cycles and after planned dosing errors.

Serum steroid levels during 12-week intravaginal dehydroepiandrosterone administration.

Objective: Because a previous 1-week study has shown no or minimal changes in the serum levels of dehydroepiandrosterone (DHEA) and its metabolites after up to daily 1.8% (23.4 mg) intravaginal DHEA, the objective of the present study was to investigate the serum steroid levels during a 12-week daily intravaginal administration of 0%, 0.25%, 0.5%, and 1.0% DHEA (Prasterone) 1.3 mL ovules. Methods: In a double-blind, placebo-controlled phase III study, 218 postmenopausal women (age range, 42-74 y) were randomized to receive daily one of four DHEA concentrations intravaginally. Serum steroids were measured by a Good Laboratory Practice-validated mass spectrometry technology in samples obtained at time of visit. Results: The serum levels of DHEA and 11 of its metabolites measured at screening, day 1, and weeks 2, 4, 8, and 12 in women showed no or minimal changes during the whole observation period, with all values remaining well within the limits of normal postmenopausal women. No accumulation of the steroid metabolites nor change in DHEA bioavailability was detected. Conclusions: The present data show that local daily intravaginal DHEA administration at DHEA doses of 3.25-13 mg was able to rapidly and efficiently achieve correction of all the signs and symptoms of vaginal atrophy and improve sexual function and caused no or minimal changes in serum sex steroid levels, which all remain within the normal postmenopausal range, thus avoiding the risks of all estrogen formulations.

Preference for and satisfaction of Canadian women with the transdermal contraceptive patch versus previous contraceptive method: an open-label, multicentre study.

OBJECTIVE To document Canadian womens experience with the transdermal contraceptive patch, a method delivering 150 microg norelgestromin and 20 microg ethinyl estradiol daily. METHODS We conducted an open-label, multicentre, descriptive cohort study of the contraceptive patch over 9 cycles in 392 women requiring contraception. A single treatment cycle consisted of 3 consecutive 7-day patch applications followed by 1 patch-free week. At the final visit, overall satisfaction and preference for the patch was rated and compared with the previously used contraceptive method. RESULTS At baseline, 80.9% of participants were either very satisfied or somewhat satisfied with their previous contraceptive method, 89% having used oral contraceptives. At final observation, 60.6% of participants preferred the patch, 9.3% had no preference; and 30% preferred their previous method (n = 376). A total of 279 participants (71.2%) completed 9 cycles of patch use. Of these, 91% were satisfied with the patch and 74.9% preferred the patch to their previous contraceptive (43% strongly preferred and 31.9% preferred); 9% had no preference; and 16.1% preferred their previous method. Of those who preferred the patch, 82.7% preferred it because of its convenience or simplicity. Across all cycles, 88% of participants recorded perfect compliance. The most common adverse event was application site reactions (most of which were mild), experienced by 49% of participants: 33.7%, 16.5%, and 14.7% at cycles 1, 4, and 9, respectively. CONCLUSION Both preference for and satisfaction with the transdermal contraceptive patch were high. Most participants.

Lack of Influence of Dyspareunia on the Beneficial Effect of Intravaginal Prasterone (Dehydroepiandrosterone, DHEA) on Sexual Dysfunction in Postmenopausal Women

INTRODUCTION We have previously observed that intravaginal prasterone (dehydroepiandrosterone, DHEA) improved all domains of female sexual dysfunction (FSD). AIM Investigate the influence of moderate/severe pain at sexual activity (dyspareunia) (MSD) at baseline on FSD following prasterone administration. METHODS The effect of daily administration of prasterone (0, 3.25 mg, 6.5 mg or 13 mg) for 12 weeks on FSD in 215 postmenopausal women with or without MSD at baseline was evaluated in a prospective, randomized, double-blind, and placebo-controlled phase III clinical trial. MAIN OUTCOME MEASURES Differences were examined on desire, arousal and orgasm. RESULTS Comparable benefits were observed in women not having MSD (n = 56) vs. those having MSD (n = 159). The benefits over placebo in prasterone-treated women for desire, avoiding intimacy and vaginal dryness as well as for the total sexual domain of the MENQOL (Menopause Specific Quality of Life) questionnaire, ranged between 18.0% and 38.2% with P values of <0.05 or <0.01 except in one out of 12 subgroups. For the arousal/sensation, arousal/lubrication and summary score of the ASF (Abbreviated Sexual Function) questionnaire, in the MSD+ group, improvements of 64.2% (P = 0.01), 118% (P = 0.001) and 31.1% (P = 0.03) were observed over placebo, respectively, while similar differences (58.0%, 67.6% and 32.1%) did not reach statistical significance in the MSD- group having up to only 44 prasterone-treated women compared with 119 in the MSD+ group. CONCLUSIONS No MSD at baseline does not apparently affect the effects of intravaginal prasterone on sexual dysfunction. Knowing the absence of significant effects of estrogens on FSD, the present data suggest that vulvovaginal atrophy (VVA) and vulvovaginal sexual dysfunction (VVSD) are two different consequences of sex steroid deficiency at menopause which can respond independently. In addition, the present data seriously question the justification of pain being part of FSD as well as the separation of FSD into separate domains.

High internal consistency and efficacy of intravaginal DHEA for vaginal atrophy.

Following the compelling data obtained in a pivotal phase III clinical trial performed in 218 postmenopausal women suffering from vaginal atrophy who received daily intravaginal 0.25, 0.5 or 1.0% DHEA (dehydroepiandrosterone) ovules for 12 weeks, we have performed analysis of the four co-primary objectives at each site of that multicentre U.S. and Canadian trial. Comparison was made of the change in percentage of parabasal and superficial cells, vaginal pH and severity of the most bothersome symptom. The site-by-site (seven sites) analysis has shown that 10–13 women per group are generally sufficient to obtain a significant or highly statistically significant decrease in vaginal pH and percentage of parabasal cells and increased percentage of superficial cells at p values ranging from 0.02 to <0.0001. For vaginal pain as the most bothersome symptom, a statistically significant difference from baseline was found at six out of seven sites. The exceptionally high consistency between all sites in this phase III study and high potency of the compound permit to obtain a clinically and statistically significant to highly significant effect of treatment on all parameters of vaginal atrophy with the 0.5% DHEA daily intravaginal dose which does not significantly affect the serum levels of oestrogens, thus avoiding systemic risks.