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.

A low dose (6.5 mg) of intravaginal DHEA permits a strictly local action while maintaining all serum estrogens or androgens as well as their metabolites within normal values.

OBJECTIVE: Serum concentrations of estradiol (E2) and testosterone (testo) measured by mass spectrometry-based assays should remain below the 95th centile measured at 9.3 pg/mL for E2 and 0.26 ng/mL for testo in normal postmenopausal women in order to avoid the risk of non-physiological systemic exposure to elevated serum concentrations of these two sex steroids. METHODS: Serum E2 and testo, as well as dehydroepiandrosterone (DHEA) and nine of its other metabolites, were measured at 10 time intervals over 24 h on the first and seventh days of daily intravaginal administration of 0.50% (6.5 mg) DHEA by validated mass spectrometry-based assays. RESULTS: No biologically significant change in the individual serum concentrations of E2, testo or DHEA was observed. Most importantly, estrone sulfate (E1-S) and the glucuronidated androgen metabolites also remained within normal values, thus confirming the absence of biologically significant systemic exposure in line with intracrinology. Using data from the literature, comparison is made with serum E2 above normal postmenopausal values following administration of 10-µg E2 tablets. CONCLUSION: While the clinical program on vulvovaginal atrophy has shown the efficacy and safety of intravaginal 6.5 mg of DHEA (prasterone), the present data illustrate in detail the serum levels of the individual sex steroids and their metabolites derived from DHEA. The data obtained are in line with the physiology of intracrinology and confirm an action limited to the vagina as the serum concentrations of all sex steroids are maintained within the normal values of menopause, thus protecting the uterus and most likely other tissues.

Metabolism of DHEA in postmenopausal women following percutaneous administration.

The marked decline in serum dehydroepiandrosterone (DHEA) with age is believed to play a role in health problems associated with aging, these health issues being potentially preventable or reversible by the exogenous administration of DHEA. In the present study, liquid chromatography/mass spectrometry/mass spectrometry (LC/MS/MS) and gas chromatrography/mass spectrometry (GC/MS) were used to measure the serum levels of DHEA and 11 of its metabolites in seventy-five 60-65-year-old Caucasian women who received 3g of 0.1%, 0.3%, 1.0% or 2.0% DHEA cream or placebo applied twice daily on the face, upper chest, arms and legs. The serum levels of DHEA increased 574% over control at the 2.0% DHEA dose while the sum of the androgen metabolites androsterone glucuronide (ADT-G), 3alpha-androstenediol-3G (3alpha-diol-3G) and 3alpha-diol-17G increased by only 231%. On the other hand, serum testosterone and dihydrosterone were increased by 192% and 275%, respectively, above basal levels compared to 139% and 158% for estrone and estradiol. Such data show that the transformation of exogenous DHEA in postmenopausal women is preferentially into androgens rather than into estrogens. On the other hand, the present data indicate that serum DHEA measurements following DHEA supplementation in postmenopausal women are an overestimate of the formation of active androgens and estrogens and suggest a decreased efficiency of transformation of DHEA into androgens and estrogens with aging.