Efficacy of intravaginal dehydroepiandrosterone (DHEA) on moderate to severe dyspareunia and vaginal dryness, symptoms of vulvovaginal atrophy, and of the genitourinary syndrome of menopause.

OBJECTIVE: The aim of this study is to confirm the local beneficial effects of intravaginal dehydroepiandrosterone (DHEA, Prasterone) on moderate to severe dyspareunia or pain at sexual activity, the most frequent symptom of vulvovaginal atrophy due to menopause or genitourinary syndrome of menopause (GSM). METHODS: In a prospective, randomized, double-blind, and placebo-controlled phase III clinical trial, the effect of daily intravaginal 0.50% DHEA (6.5 mg) (Prasterone, EndoCeutics) was examined on four coprimary objectives, namely percentage of parabasal cells, percentage or superficial cells, vaginal pH, and moderate to severe pain at sexual activity (dyspareunia) identified by the women as their most bothersome vulvovaginal atrophy symptom. The intent-to-treat population included 157 and 325 women in the placebo and DHEA-treated groups, respectively. RESULTS: After daily intravaginal administration of 0.50% DHEA for 12 weeks, when compared to baseline by the analysis of covariance test, the percentage of parabasal cells decreased by 27.7% over placebo (P < 0.0001), whereas the percentage of superficial cells increased by 8.44% over placebo (P < 0.0001), vaginal pH decreased by 0.66 pH unit over placebo (P < 0.0001), and pain at sexual activity decreased by 1.42 severity score unit from baseline or 0.36 unit over placebo (P = 0.0002). On the other hand, moderate to severe vaginal dryness present in 84.0% of women improved at 12 weeks by 1.44 severity score unit compared to baseline, or 0.27 unit over placebo (P = 0.004). At gynecological evaluation, vaginal secretions, epithelial integrity, epithelial surface thickness, and color all improved by 86% to 121% over the placebo effect (P < 0.0001 for all comparisons with placebo). Serum steroid levels remained well within the normal postmenopausal values according to the involved mechanisms of intracrinology. The only side effect reasonably related to treatment is vaginal discharge due to melting of the vehicle at body temperature and this was reported in about 6% of the participants. CONCLUSIONS: The daily intravaginal administration of 0.50% (6.5 mg) DHEA (Prasterone) has shown clinically and highly statistically significant effects on the four coprimary parameters suggested by the US Food and Drug Administration. The strictly local action of Prasterone is in line with the absence of significant drug-related adverse events, thus showing the high benefit-to-risk ratio of this treatment based upon the novel understanding of the physiology of sex steroids in women.

Concentration range of serum sex steroids in normal postmenopausal women and those with diagnosis of vulvovaginal atrophy.

OBJECTIVE: The aim of the study was to determine the range of serum sex-related steroids in normal postmenopausal women and in women of the same age with a diagnosis of vulvovaginal atrophy (VVA). METHODS: Validated mass spectrometry-based assays coupled to gas or liquid chromatography were used over a 10-year period for steroid measurements. Serum samples were obtained in up to 1,512 women aged 55 to 65 years. RESULTS: Serum estrone sulfate (E1S) and androsterone glucuronide (ADT-G), the main metabolites of estrogens and androgens, respectively, were 16.9% (P = 0.005) and 16.1% (P = 0.001) higher in women not diagnosed with moderate/severe VVA than those diagnosed with VVA. Serum estrone (E1) was 14.5% (P < 0.0001) higher in women with no diagnosis of VVA, whereas the other steroids did not show meaningful differences. The limited biological significance of serum estradiol (E2) and testosterone is supported by the lack of statistical significance in the serum concentrations of these two steroids between the two groups. Most importantly, for the women without a diagnosis of VVA, the normal upper limit (95 centile) of serum E2 was 9.15 pg/mL (n = 364) and 10.7 pg/mL (n = 67) for a weighted average of 9.99 pg E2/mL. A limit of 10 pg E2/mL has recently been found by two other laboratories. When comparing 50- to 59-year-old and 70- to 79-year-old women, serum E2, E1S, ADT-G, and DHEA were, respectively, 24.4%, 22.6%, 27.0%, and 85.9% higher in the younger group. CONCLUSIONS: Somewhat higher values, namely, 16.9% and 16.1%, are observed in the serum concentrations of the estrogen (E1S) and androgen (ADT-G) metabolites in normal compared with women with a diagnosis of VVA. Such data indicating a lower estrogenic and androgenic global exposure in women diagnosed with VVA offers an opportunity for the local intravaginal administration of DHEA to replace the deficiency in endogenous DHEA.

Combined data of intravaginal prasterone against vulvovaginal atrophy of menopause.

OBJECTIVE: To analyze the effects of intravaginal prasterone obtained in the three randomized clinical studies performed in postmenopausal women suffering from moderate to severe (MS) dyspareunia due to vulvovaginal atrophy (VVA). METHODS: In three independent 12-week prospective, randomized, double-blind, and placebo-controlled clinical studies, the effect of daily intravaginal 0.50% (6.5 mg) prasterone was examined on four co-primary objectives in women having MS pain during sexual activity (dyspareunia), identified as their most bothersome symptom (MBS) of VVA at baseline. RESULTS: In 436 women treated with 0.50% prasterone and 260 women who received placebo, an average 35.1% decrease over placebo in the percentage of parabasal cells (P < 0.0001), an average 7.7% increase in the percentage of superficial cells (P < 0.0001), and a mean 0.72 pH unit decrease in vaginal pH (P < 0.0001) were observed. The severity score of most bothersome symptom dyspareunia was decreased by a 0.46 unit (49%) (P < 0.0001 over placebo), whereas the severity score of MS vaginal dryness decreased by 0.31 unit (P < 0.0001 over placebo). A very positive evaluation was obtained on the acceptability of the technique of administration of the insert, whereas the male partners reported a very positive evaluation of the changes observed in their sexual partner. CONCLUSION: The efficacy data demonstrate highly positive effects on all the symptoms and signs of vulvovaginal atrophy with no significant drug-related side effects in line with the physiology of menopause and intracrinology.

Double-Blind, Placebo-Controlled, Randomized Phase I/IIa Study (Safety and Efficacy) with Buspirone/Levodopa/Carbidopa (SpinalonTM) in Subjects with Complete AIS A or Motor-Complete AIS B Spinal Cord Injury.

BACKGROUND: No drug treatment capable of restoring locomotor capabilities in patients suffering a motor-complete spinal cord injury (SCI) has ever been developed. We assessed the safety and efficacy of an activator of spinal locomotor neurons in humans, which were shown in paraplegic animals to elicit temporary episodes of involuntary walking. METHODS: Single administration of buspirone/levodopa/carbidopa (SpinalonTM), levodopa/carbidopa (ratio 4: 1), and buspirone or placebo was performed using a dose-escalation design in 45 subjects placed in supine position who had had an SCI classified as complete (AIS A) or motor-complete/sensory incomplete (AIS B) for at least 3 months. Blood samples before and at regular intervals (15, 30, 60, 120, 240 min) after treatment were collected for hematological and pharmacokinetic (PK) analyses. Electromyographic (EMG) activity of eight muscles (four per leg) was monitored prior to and at several time points after drug administration. RESULTS: SpinalonTM (10-35 mg buspirone/100-350 mg levodopa/25-85 mg carbidopa) displayed no sign of safety concerns - only mild nausea was found in 3 cases. At higher doses, 50 mg/500 mg/125 mg SpinalonTM was considered to have reached maximum tolerated dose (MTD) since 3 out of 4 subjects experienced related adverse events including vomiting. PK analyses showed comparable data between groups suggesting no significant drugdrug interaction with SpinalonTM. Only the SpinalonTM-treated groups displayed significant EMG activity accompanied by locomotor-like characteristics - that is with rhythmic and bilaterally alternating bursts. CONCLUSION: Therefore, this study provides evidence of safety and preliminary efficacy following a single administration of SpinalonTM in subjects with SCI.

Serum steroid concentrations remain within normal postmenopausal values in women receiving daily 6.5mg intravaginal prasterone for 12 weeks.

This study integrates all data obtained in women aged 40-80years enrolled with moderate to severe symptoms of vulvovaginal atrophy (VVA) who received daily intravaginal administration of 0.50% (6.5mg) dehydroepiandrosterone (DHEA; prasterone) for 12weeks (n=723; ITT-S population) as compared with placebo (n=266; ITT-S population). To this end, serum steroid levels (DHEA, DHEA-sulfate (DHEA-S), androst-5-ene-3ß, 17ß-diol (5-diol), testosterone, dihydrotestosterone (DHT), androstenedione (4-dione), estrone (E1), estradiol (E2), estrone sulfate (E1-S), androsterone glucuronide (ADT-G), and androstane-3α, 17ß-diol 17-glucuronide (3α-diol-17G)) were measured at Day 1 and Week 12 by liquid chromatography-tandem mass spectrometry (LC-MS/MS) following validation performed according to the FDA guidelines [1-6]. In agreement with the mechanisms of intracrinology where DHEA is exclusively transformed intracellularly into active sex steroids which act and are inactivated locally before being released as glucuronided or sulfated metabolites for elimination by the kidneys and liver, all sex steroids remained well within normal postmenopausal values following administration of intravaginal DHEA. Serum estradiol, the most relevant sex steroid, was measured after 12weeks of treatment at 3.36pg/ml (cITT-S population) or 19% below the normal postmenopausal value of 4.17pg/ml. On the other hand, serum E1-S, the best recognized marker of global estrogenic activity, shows an average value of 209pg/ml at 12 weeks compared to 220pg/ml in normal postmenopausal women. Moreover, serum ADT-G, the main metabolite of androgens, also remains well within normal postmenopausal values. The present data shows that a low daily intravaginal dose (6.5mg) of DHEA (prasterone) which is efficacious on the symptoms and signs of VVA, permits to achieve the desired local efficacy without systemic exposure, in agreement with the stringent mechanisms of menopause established after 500 million years of evolution where each cell in each tissue is the master of its sex steroid exposure.

Effect of intravaginal dehydroepiandrosterone (DHEA) on the female sexual function in postmenopausal women: ERC-230 open-label study.

OBJECTIVE: 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. DESIGN: 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. SUBJECTS: 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. RESULTS: The FSFI domains desire, arousal, lubrication, orgasm, satisfaction and pain were increased by 28%, 49%, 115%, 51%, 41% and 108%, respectively (p<0.0001 for all parameters) at 52 weeks vs. baseline, while the total score was increased from 13.4±0.62 at baseline to 21.5±0.82 (+60%, p<0.0001) at 52 weeks. CONCLUSION: As 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.

Efficacy of intravaginal dehydroepiandrosterone (DHEA) on moderate to severe dyspareunia and vaginal dryness, symptoms of vulvovaginal atrophy, and of the genitourinary syndrome of menopause.

OBJECTIVE: The aim of this study is to confirm the local beneficial effects of intravaginal dehydroepiandrosterone (DHEA, Prasterone) on moderate to severe dyspareunia or pain at sexual activity, the most frequent symptom of vulvovaginal atrophy due to menopause or genitourinary syndrome of menopause (GSM). METHODS: In a prospective, randomized, double-blind, and placebo-controlled phase III clinical trial, the effect of daily intravaginal 0.50% DHEA (6.5 mg) (Prasterone, EndoCeutics) was examined on four coprimary objectives, namely percentage of parabasal cells, percentage or superficial cells, vaginal pH, and moderate to severe pain at sexual activity (dyspareunia) identified by the women as their most bothersome vulvovaginal atrophy symptom. The intent-to-treat population included 157 and 325 women in the placebo and DHEA-treated groups, respectively. RESULTS: After daily intravaginal administration of 0.50% DHEA for 12 weeks, when compared to baseline by the analysis of covariance test, the percentage of parabasal cells decreased by 27.7% over placebo (P < 0.0001), whereas the percentage of superficial cells increased by 8.44% over placebo (P < 0.0001), vaginal pH decreased by 0.66 pH unit over placebo (P < 0.0001), and pain at sexual activity decreased by 1.42 severity score unit from baseline or 0.36 unit over placebo (P = 0.0002). On the other hand, moderate to severe vaginal dryness present in 84.0% of women improved at 12 weeks by 1.44 severity score unit compared to baseline, or 0.27 unit over placebo (P = 0.004). At gynecological evaluation, vaginal secretions, epithelial integrity, epithelial surface thickness, and color all improved by 86% to 121% over the placebo effect (P < 0.0001 for all comparisons with placebo). Serum steroid levels remained well within the normal postmenopausal values according to the involved mechanisms of intracrinology. The only side effect reasonably related to treatment is vaginal discharge due to melting of the vehicle at body temperature and this was reported in about 6% of the participants. CONCLUSIONS: The daily intravaginal administration of 0.50% (6.5 mg) DHEA (Prasterone) has shown clinically and highly statistically significant effects on the four coprimary parameters suggested by the US Food and Drug Administration. The strictly local action of Prasterone is in line with the absence of significant drug-related adverse events, thus showing the high benefit-to-risk ratio of this treatment based upon the novel understanding of the physiology of sex steroids in women.

Evaluation of the acceptability of intravaginal prasterone ovule administration using an applicator.

The objective of the study is to evaluate the acceptability of the intravaginal administration of ovules/suppositories of DHEA (dehydroepiandrosterone, prasterone) for the treatment of vulvovaginal atrophy (VVA) in women with moderate to severe dyspareunia who were administered daily for 12 weeks intravaginal 0.50% (6.5 mg) DHEA or placebo. There were a total of 373 women in the per-protocol population who responded to the questionnaire for both treatment groups. While it was planned that the applicator would be evaluated as suitable if at least 80% of participants have a global score ≤ 2 units, 99% and 100% of participants had a score ≤ 2 units in the placebo and DHEA groups, respectively, for the global score (mean of 5 questions). When asked about like and dislike the technique of drug administration, 284 comments were positive, while 114 women gave no comment. About 92-94% of women indicated that they were very confident to be able use the applicator successfully in the future. The survey shows a high degree of satisfaction and of confidence to use the applicator successfully in the future.

Effect of Intravaginal Prasterone on Sexual Dysfunction in Postmenopausal Women with Vulvovaginal Atrophy.

INTRODUCTION: Previous data have shown that intravaginal dehydroepiandrosterone (DHEA, prasterone) improved all the domains of sexual function, an effect most likely related to the local formation of androgens from DHEA. AIMS: To confirm in a placebo-controlled, prospective, double-blind and randomized study the benefits of daily intravaginal DHEA for 12 weeks on sexual function using the Female Sexual Function Index (FSFI) questionnaire. METHODS: Placebo was administered daily to 157 women while 325 women received 0.50% (6.5 mg) DHEA daily for 12 weeks. All women were postmenopausal meeting the criteria of vulvovaginal atrophy (VVA), namely moderate to severe dyspareunia as their most bothersome symptom of VVA in addition to having ≤5% of vaginal superficial cells and vaginal pH > 5.0. The FSFI questionnaire was filled at baseline (screening and day 1), 6 weeks and 12 weeks. Comparison between DHEA and placebo of the changes from baseline to 12 weeks was made using the analysis of covariance test, with treatment group as the main factor and baseline value as the covariate. MAIN OUTCOME MEASURES: The six domains and total score of the FSFI questionnaire were evaluated. RESULTS: The FSFI domain desire increased over placebo by 0.24 unit (+49.0%, P = 0.0105), arousal by 0.42 unit (+56.8%, P = 0.0022), lubrication by 0.57 unit (+36.1%, P = 0.0005), orgasm by 0.32 unit (+33.0%, P = 0.047), satisfaction by 0.44 unit (+48.3%, P = 0.0012), and pain at sexual activity by 0.62 unit (+39.2%, P = 0.001). The total FSFI score, on the other hand, has shown a superiority of 2.59 units in the DHEA group over placebo or a 41.3% greater change than placebo (P = 0.0006 over placebo). CONCLUSION: The present data show that all the six domains of the FSFI are improved over placebo (from P = 0.047 to 0.0005), thus confirming the previously observed benefits of intravaginal DHEA on female sexual dysfunction by an action exerted exclusively at the level of the vagina, in the absence of biologically significant changes of serum steroids levels.

Serum steroids remain within the same normal postmenopausal values during 12-month intravaginal 0.50% DHEA.

OBJECTIVE: Analyze the serum levels of DHEA (prasterone) and its metabolites after daily intravaginal 0.50% (6.5 mg) DHEA in postmenopausal women with vulvovaginal atrophy (VVA). METHODS: Serum samples were obtained at baseline and after 12, 26 and 52 weeks of treatment. The serum levels of DHEA, DHEA-sulfate (DHEA-S), androstene-3ß, 17ß-diol (5-diol), androstenedione (4-dione), testosterone, dihydrotestosterone (DHT), estrone (E1), estradiol (E2), E1-sulfate (E1-S), androsterone glucuronide (ADT-G) and androstane-3α,17ß-diol 17-glucuronide (3α-diol-17G) were measured by validated liquid chromatography-tandem mass spectrometry. RESULTS: A total of 435 women were exposed for 52 weeks. All serum steroids remained within normal values with no significant differences between lengths of treatment. For the most relevant estrogen-related compounds, namely E1, E2, and E1-S, a reliable marker of total estrogen exposure, the values in the DHEA-treated group at 52 weeks were -3.4%, -9.1% and +1.8%, respectively, compared to the normal postmenopausal values, thus clearly confirming the absence of significant systemic estrogen exposure. CONCLUSION: While confirming that all serum sex steroids originating exclusively from DHEA after menopause are maintained within the normal postmenopausal values, the present data show that the dose of intravaginal DHEA used is free from systemic exposure with no detectable change in metabolism up to 52 weeks of treatment.

Serum levels of sex steroids and metabolites following 12 weeks of intravaginal 0.50% DHEA administration.

The objective of the present phase III, placebo-controlled, double-blind, prospective and randomized study was to confirm the efficacy of daily intravaginal administration of 0.50% dehydroepiandrosterone (DHEA; prasterone) ovules for 12 weeks on moderate to severe dyspareunia (or pain at sexual activity) as most bothersome symptom of vulvovaginal atrophy (VVA) while having serum steroid concentrations within normal postmenopausal values. To this end, serum levels of DHEA, DHEA-sulfate (DHEA-S), Androst-5-ene-diol-3ß, 17ß-diol (5-diol), testosterone, dihydrotestosterone (DHT), androstenedione (4-dione), estrone (E1), estradiol (E2), estrone sulfate (E1-S), androsterone glucuronide (ADT-G), and androstane-3α, 17ß-diol 17-glucuronide (3α-diol-17G) were measured by validated liquid chromatography-tandem mass spectrometry (LC-MS/MS). In agreement with the mechanisms of intracrinology, all serum sex steroids and metabolites concentrations after 12 weeks of daily intravaginal administration of 0.50% DHEA remain well within the limits of normal postmenopausal women. More specifically, the 12-week serum E2 concentration was measured at 22% below the average normal postmenopausal value (3.26 versus 4.17 pg/ml), thus eliminating any fear of E2 exposure outside the vagina. In addition, serum E1-S, a particularly reliable indicator of global estrogenic activity, shows serum levels practically superimposable to the value observed in normal postmenopausal women (219 versus 220 pg/ml). Similarly, serum ADT-G, the major metabolite of androgens, remains within normal postmenopausal values. The present data confirm the intracellular transformation of DHEA in the vagina resulting in local efficacy without any systemic exposure to sex steroids, observations which are in agreement with the physiological mechanisms of menopause.