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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 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. Labrie F, Archer D, Bouchard C, Fortier M, Cusan L, Gomez J‐L, Girard G, Baron M, Ayotte N, Moreau M, Dube R, Cote I, Labrie C, Lavoie L, Gilbert L, Martel C, and Balser J. Lack of influence of dyspareunia on the beneficial effect of intravaginal prasterone (dehydroepiandrosterone, DHEA) on sexual dysfunction in postmenopausal women. J Sex Med 2014;11:1766–1785.

Objective To examine the effect of intravaginal dehydroepiandrosterone (DHEA) on pain at sexual activity (dyspareunia) identified as the most bothersome symptom of vaginal atrophy in postmenopausal women at both screening and day 1. 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 severity of dyspareunia in 114 postmenopausal women who had identified dyspareunia as their most bothersome symptom of vaginal atrophy, while meeting the criteria for superficial cells � 5% and pH4 5.0 at both screening and day 1. Results At the standard duration of 12 weeks of treatment, increasing doses of 0.25%, 0.5% and 1.0% DHEA decreased the percentage of parabasal cells by 48.6+ 6.78%, 42.4+ 7.36% and 54.9+ 6.60% (p5 0.0001 vs. placebo for all) with no change with placebo (p ¼ 0.769). The effects on superficial cells and pH were also highly significant compared to placebo at all DHEA doses. The severity score of pain at sexual activity decreased by 0.5, 1.4, 1.6 and 1.4 units in the placebo and 0.25%, 0.5% and 1.0% DHEA groups, respectively, with the p value of differences from placebo ranging from 0.0017 to 5 0.0001. Conclusions Intravaginal DHEA, through local estrogen and androgen formation, causes a rapid and highly efficient effect on pain at sexual activity without systemic exposure of the other tissues, thus avoiding the recently reported systemic effects of estrogens.

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

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.

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 T 5.31 (P G 0.0001 vs placebo) decrease in the percentage of parabasal cells, a 6.8 T 1.29% (P G 0.0001) increase in superficial cells, a 1.3 T 0.13 unit (P G 0.0001) decrease in vaginal pH, and a 1.5 T 0.14 score unit (P G 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.

Intravaginal DHEA (dehydroepiandrosterone, prasterone), the exclusive precursor of androgens and estrogens in postmenopausal women, has previously been shown to improve all the domains of sexual function by a strictly local action in the vagina. The well recognized female sexual function index (FSFI) questionnaire was used in the present study.The long-term effect of 52-week treatment with daily intravaginal 0.50% (6.5 mg) DHEA was evaluated on the various domains of female sexual function using the FSFI questionnaire at baseline, Week 26 and Week 52.One hundred and fifty-four postmenopausal women with at least one mild to severe symptom of vulvovaginal atrophy (VVA) and who have completed the FSFI questionnaire at baseline and at least one post-baseline timepoint were included in the analysis.The FSFI domains desire, arousal, lubrication, orgasm, satisfaction and pain were increased by 28%, 49%, 115%, 51%, 41% and 108%, respectively (pAs the serum levels of DHEA and all its metabolites, including estradiol and testosterone, show no meaningful change, the present clinical data indicate a stimulatory effect of intravaginal DHEA through a strictly local action in agreement with the preclinical data showing that the androgens made locally from DHEA in the vagina induce an increase in local nerve density.

This study aims to evaluate the effects of intravaginal dehydroepiandrosterone (DHEA, prasterone) on the endometrium in postmenopausal women.Intravaginal DHEA (6.5 mg) was administered daily for 52 weeks to 422 women who had endometrial biopsy at baseline and end of study, whereas 15 women were similarly treated for 26 to 52 weeks. Participants in three other studies received 3.25 mg (n = 126), 6.5 mg (n = 129), or 13 mg (n = 30) of DHEA for 12 weeks; women similarly had baseline and end-of-study biopsies. Endometrial biopsy samples were available for 668 women at baseline and end of study, with sufficient material for analysis.Endometrial atrophy or inactive endometrium (668 women) was found in all women treated with intravaginal DHEA. Similar atrophy was observed in 119 of 121 participants with sufficient material for analysis who received placebo.After cessation of estradiol secretion by the ovaries at menopause, the estrogens made by mechanisms of intracrinology are inactivated intracellularly at their site of formation and action, thus maintaining serum estradiol at biologically inactive concentrations to avoid stimulation of the endometrium. The absence of enzymes that are able to transform DHEA into estrogens in the endometrium explains the typical endometrial atrophy in all normal postmenopausal women in the presence of variable concentrations of circulating endogenous DHEA. According to these mechanisms, the inactive sex steroid precursor DHEA administered intravaginally acts exclusively in the vagina, whereas all serum sex steroids remain well within the biologically inactive postmenopausal reference range, thus avoiding any stimulation of the already atrophic endometrium.

An objective was to analyze the time course of efficacy of daily intravaginal administration of 0.5% (6.5mg) DHEA (prasterone) for 52 weeks on the moderate to severe (MS) symptoms and signs of vulvovaginal atrophy (VVA).Five hundred twenty-one postmenopausal women were enrolled and received daily intravaginal administration of 0.5% DHEA in an open-label phase III study. The severity of the VVA symptoms examined in detail in the different groups.A parallel improvement of pain at sexual activity was observed in women who had moderate to severe (MS) dyspareunia as their most bothersome symptom (MBS) (n=183) or not MBS (n=240) and MS without being MBS (n=57) with a 1.70 severity unit change in the MBS group for a decrease of 66.1% from baseline (p0.0001 versus baseline) over 52 weeks. A further improvement of dyspareunia, namely 0.33 severity unit (19.4%), was observed with continuing treatment from 12 weeks to 52 weeks. Similar results were observed on vaginal dryness and irritation/itching. Highly significant beneficial effects (p0.0001 versus baseline for all) were observed at gynecological examination on vaginal secretions, color, epithelial integrity and epithelial surface thickness.The present study shows, in addition to the parallel benefits on the three symptoms of VVA, that the choice of any of the MS symptoms as being or not being MBS by women has no influence on the observed therapeutic effect (NCT01256671).

This multicenter study compared the contraceptive efficacy, cycle control, and safety of a new triphasic norgestimate (180/215/250 microg)/ethinyl estradiol 25 microg regimen (Ortho Tri-Cyclen Lo) (n = 1,723) with that of norethindrone acetate 1 mg/ethinyl estradiol 20 microg (Loestrin Fe 1/20) (n = 1,171). Healthy women were treated for up to 13 cycles. Demographics were similar between regimens. Contraceptive efficacy was comparable for Ortho Tri-Cyclen Lo and Loestrin Fe 1/20. The overall and method failure probabilities of pregnancy through 13 cycles were 1.9% and 1.5%, respectively, with Ortho Tri-Cyclen Lo and 2.6% and 2.4%, respectively, with Loestrin Fe 1/20. Breakthrough bleeding and spotting was reported by a significantly lower percentage of participants in the Ortho Tri-Cyclen Lo group compared with the Loestrin Fe 1/20 group. At representative Cycles 1, 3, 6, 9, and 13, breakthrough bleeding and spotting rates were 16.3, 11.5, 10.3, 7.9, and 7.7%, respectively, in the Ortho Tri-Cyclen Lo group and 34.9, 22.9, 22.2, 15.9, and 13.1%, respectively, in the Loestrin Fe 1/20 group. Compliance and safety data were similar for the two regimens.

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.

OBJECTIVE The aim of this study was to evaluate the effects of a constant-estrogen, intermittent-progestogen hormone replacement regimen (Ortho-Prefest, Ortho-McNeil Pharmaceutical, Raritan, NJ, USA) on menopausal symptoms measured by the Kupperman Index and on quality of life measured by the Menopause Quality of Life-Intervention questionnaire. DESIGN This was a randomized, double-blind, placebo-controlled multicenter study of 90 days' duration. Nonhysterectomized, postmenopausal women with vasomotor symptoms and at least 6 months' amenorrhea were eligible. On completion of the placebo-controlled portion of the study, participants could elect to receive active treatment for an additional 90 days. RESULTS The study enrolled 119 participants, 59 and 60 in the Prefest and placebo groups, respectively. A marked reduction of menopausal symptoms, as measured by the Kupperman Index, was observed in the active treatment group compared with the placebo group after 45 days' treatment (mean reduction, 14.8 v 7.2 points, respectively), which was sustained to day 90 (16.8 v 7.8 points; < 0.001). Similarly, greater improvement in quality of life, as measured by the Menopause Quality of Life summary score, was also observed in the active treatment group for the same period (improvement of up to 1.6 points v 0.7 points; < 0.001). The adverse event profile was unremarkable. Of the 114 participants who received the active treatment, 6 withdrew because of adverse events. CONCLUSIONS The constant-estrogen, intermittent-progestogen regimen was highly effective in relieving menopausal symptoms and in improving quality of life and was well received by the study participants.