Efficacy of Intravaginal Dehydroepiandrosterone (DHEA) on Moderate to Severe Dyspareunia and Vaginal Dryness, Symptoms of Vulvovaginal Atrophy, and of the Genitourinary Syndrome of Menopause

Fernand Labrie, MD, PhD; David F. Archer, MD; William Koltun, MD; Andrée Vachon, MD; Douglas Young, MD; Louise Frenette, MD; David Portman, MD; Marlene Montesino, MD; Isabelle Côté, BSc; Julie Parent, PhD; Lyne Lavoie, MSc; Adam Beauregard, BSc, MBA; Céline Martel, PhD; Mario Vaillancourt, BSc, MBA; John Balser, PhD; Érick Moyneur, BSc, MA; the members of the VVA Prasterone Research Group

Disclosures

Menopause. 2016;23(3):243-256. 

In This Article

Results

Demographics and Baseline Characteristics

A summary of the demographics and baseline characteristics of the safety population is presented in Table 1 . The demographics and baseline characteristics of the women enrolled in the two treatment groups were similar, considering the 2:1 ratio of the DHEA-to-placebo distribution. Overall, the average age of women enrolled in the study was 59.5 years (median 59.0 y; range 40-80 y). Similar age distributions were observed in both treatment groups.

Moreover, women assigned to the two treatment groups had similar reproductive histories: an average of 13.9 years (from 13.4 y [placebo] to 14.1 y [0.50% DHEA]) had elapsed between their last menses and their participation in this study. Menstrual cycles ceased naturally in 64% of the population (from 63% [0.50% DHEA] to 67% [placebo]). The average age at which the women had their last menstrual period ranged from 48.6 years (0.50% DHEA) to 48.9 years (placebo) in women who had a natural menopause, and from 39.8 years (0.50% DHEA) to 40.6 years (placebo) in women who had surgical menopause.

As illustrated in Figure 2, the percentage (%) of parabasal cells in the placebo group decreases from 51.7±3.00% at baseline to 39.7±2.68% at 12 weeks for a decrease of 12.0±2.36% (−23.2%) versus baseline. In contrast, the % of parabasal cells decreases from 54.3±2.14% at baseline to 12.7±1.02% at 12 weeks in the 0.50% DHEA group (−76.6% vs baseline). In the ANCOVA model, with the treatment group as the main factor and the baseline value as the covariate, the least square mean difference shows a value for the DHEA group of −27.7% at 12 weeks over placebo (P<0.0001).

Figure 2.

Effect of Prasterone on parabasal cells (ITT). Effect of daily intravaginal application of 0.0% (n=157) and 0.50% (n=325) dehydroepiandrosterone (DHEA; Prasterone) for 6 and 12 weeks on the percentage (%) of vaginal parabasal cells in postmenopausal women. Data are expressed as means±SEM; the P value for the Prasterone dose is compared with placebo at all time intervals. ITT, intention to treat.

In the same groups, the % of superficial cells increases in the placebo group from 1.04±0.11% at baseline to 2.78±0.27% at 12 weeks (+167%), whereas in the DHEA group, the % of superficial cells increases from 1.02±0.08% at baseline to 11.2±0.56% at 12 weeks (+1000%). In the ANCOVA test, the 5.8-fold greater effect of DHEA over placebo is measured at a P value less than 0.0001 (Figure 3).

Figure 3.

Effect of Prasterone on superficial cells (ITT). Effect of daily intravaginal application of 0.0% (n=157) and 0.50% (n=325) dehydroepiandrosterone (DHEA; Prasterone) for 6 and 12 weeks on the percentage (%) of vaginal superficial cells in postmenopausal women. Data are expressed as means±SEM; the P value for the Prasterone dose is comparison with placebo at all time intervals. ITT, intention to treat.

When vaginal pH is examined (Figure 4), a small decrease is observed in the placebo group from 6.32±0.05 pH units at baseline to 6.05±0.07 pH units at 12 weeks (−4.3%), whereas the pH decreases from 6.34±0.04 at baseline to 5.39±0.05 pH units at 12 weeks in the 0.50% DHEA group (−15.0%). When comparing to placebo in the ANCOVA test, there is a 3.4-fold greater effect of DHEA (P<0.0001 vs placebo).

Figure 4.

Effect of Prasterone on vaginal pH (ITT). Effect of daily intravaginal application of 0.0% (n=157) and 0.50% (n=325) dehydroepiandrosterone (DHEA; Prasterone) for 6 and 12 weeks on vaginal pH in postmenopausal women. Data are expressed as means±SEM; the P value for the Prasterone dose is comparison with placebo at all time intervals. ITT, intention to treat.

When the change of the moderate to severe pain at sexual activity (dyspareunia) is examined, the symptom evaluated by all women as being their MBS of VVA, it can be seen in Figure 5 that the severity score decreased from 2.56±0.04 units at baseline in the placebo group to 1.50±0.08 unit at 12 weeks (−1.06 unit). In the DHEA group, on the contrary, the severity score decreased from 2.54±0.03 units at baseline to 1.13±0.05 units at 12 weeks (−1.42 units). In the ANCOVA test, there is a 0.36-unit greater decrease of the intensity score in the DHEA group compared with the placebo group (þ34%) (P =0.0002 vs placebo).

Figure 5.

Effect of Prasterone on pain at sexual activity (ITT). Effect of daily intravaginal application of 0.0% (n=157) and 0.50% (n=325) dehydroepiandrosterone (DHEA; Prasterone) for 6 and 12 weeks on pain at sexual activity in postmenopausal women. Data are expressed as means±SEM; the P value for the Prasterone dose is comparison with placebo at all time intervals. ITT, intention to treat.

It is of interest to see in Table 2 that of the 482 women who had moderate (n=217, 45%) or severe (n=265, 55%) pain at sexual activity (dyspareunia) as their most bothersome VVA symptom at baseline, 283 (59%) women had moderate and 122 (25%) had severe vaginal dryness.

Since the moderate to severe symptoms of VVA, at least for dyspareunia, vaginal dryness, and irritation/itching, respond similarly if the moderate to severe symptom is considered most bothersome or not by the women,27 it is of interest to see in Figure 6 that the severity score of moderate to severe vaginal dryness decreases from a severity score of 2.30±0.04 units at baseline to 1.13±0.08 unit at 12 weeks (−1.17 units) in the placebo group, whereas, in the DHEA-treated group, the severity score decreased from 2.30±0.03 units to 0.86±0.05 units (−1.44 units). In the ANCOVA test, the difference due to treatment groups shows a 0.27 severity score unit superiority of DHEA compared with placebo (þ23.1%; P=0.004 vs placebo).

Figure 6.

Effect of Prasterone on vaginal dryness (ITT with moderate to severe dryness at baseline). Effect of daily intravaginal application of 0.0% (n=132) and 0.50% (n=273) dehydroepiandrosterone (DHEA; Prasterone) for 6 and 12 weeks on vaginal dryness in postmenopausal women. Data are expressed as means±SEM; the P value for the Prasterone dose is comparison with placebo at all time intervals. ITT, intention to treat.

To further assess the effect of treatment on the vaginal mucosa, visual vaginal examination with a speculum was performed at baseline and after 6 and 12 weeks of randomized treatment. The index of vaginal secretion decreased from 2.63±0.05 to 2.24±0.06 units in the placebo group, compared with a decrease from 2.70±0.04 to 1.97±0.04 units at 12 weeks in the DHEA-treated group, for a difference of −0.34 (þ87%) in favor of DHEA (P<0.0001 over placebo) (Figure 7).

Figure 7.

Effect of Prasterone on vaginal secretions (ITT). Effect of daily intravaginal application of 0.0% (n=157) and 0.50% (n=325) dehydroepiandrosterone (DHEA; Prasterone) for 6 and 12 weeks on vaginal secretions in postmenopausal women. Data are expressed as means±SEM; the P value for the Prasterone dose is comparison with placebo at all time intervals. ITT, intention to treat.

Vaginal epithelial integrity, on the other hand, decreased in the placebo group from 2.43±0.06 at baseline to 2.06±0.06 units at 12 weeks, whereas, in the DHEA-treated women, the decrease was from 2.45±0.05 to 1.75±0.04 units for a DHEA superiority of −0.32 (+86%) severity score unit (P<0.0001 vs placebo) (Figure 8). Evaluation of the epithelial surface thickness has shown a decrease from 2.76±0.05 units at baseline to 2.41±0.05 units at 12 weeks, whereas the decrease was in the DHEA group from 2.83±0.03 units at baseline to 2.09±0.04 at 12 weeks, for a superiority of−0.38 units (+106%) in favor of DHEA (P>0.0001 vs placebo) (Figure 9). Similarly, vaginal color decreased from 2.67±0.05 at baseline to 2.34±0.05 units at 12 weeks in the placebo group, whereas, in the DHEA-treated group, the score went from 2.75±0.03 units at baseline to 2.03±0.04 units at 12 weeks for a difference of −0.40 units (+121%) in favor of DHEA compared with placebo (P<0.0001) (Figure 10).

Figure 8.

Effect of Prasterone on vaginal epithelial integrity (ITT). Effect of daily intravaginal application of 0.0% (n=157) and 0.50% (n=325) dehydroepiandrosterone (DHEA; Prasterone) for 6 and 12 weeks on vaginal epithelial integrity in postmenopausal women. Data are expressed as means±SEM; the P value for the Prasterone dose is comparison with placebo at all time intervals. ITT, intention to treat.

Figure 9.

Effect of Prasterone on vaginal epithelial surface thickness (ITT). Effect of daily intravaginal application of 0.0% (n=157) and 0.50% (n=325) dehydroepiandrosterone (DHEA; Prasterone) for 6 and 12 weeks on vaginal epithelial surface thickness in postmenopausal women. Data are expressed as means±SEM; the P value for the Prasterone dose is comparison with placebo at all time intervals. ITT, intention to treat.

Figure 10.

Effect of Prasterone on vaginal color (ITT). Effect of daily intravaginal application of 0.0% (n=157) and 0.50% (n=325) dehydroepiandrosterone (DHEA; Prasterone) for 6 and 12 weeks on vaginal color in postmenopausal women. Data are expressed as means±SEM; the P value for the Prasterone dose is comparison with placebo at all time intervals. ITT, intention to treat.

Safety

Table 3 indicates the most frequently reported treatment-emergent AEs (TEAE) (>3% in one or both the treatment groups) presented by primary system organ class (SOC). Almost half (42.8% in the placebo group and 47.9% in the 0.50% DHEA group) experienced at least one TEAE of any nature.

The most frequently affected SOC ( Table 3 ) was "infections and infestations," with 10.6% and 14.2% in the placebo and DHEA groups, respectively. No relevant difference in frequencies of the MedDRA terms was observed between the two groups. On the basis of the known metabolism and local action of DHEA, the application site discharge is the only AE which can reasonably be drug-related. This is due to melting of the vehicle in the vagina at body temperature with the possible addition of increased vaginal secretions due to treatment. This was reported in 5.6% of women in the placebo group and 6.1% in the DHEA group. Two women discontinued treatment due to this AE.

No clinically significant abnormality was observed in the hematology, blood chemistry, or urinalysis. Serum DHEA and its main metabolites (namely DHEA-S, Testo, DHT, 4-dione, 5-diol, E1,E2,E1-S, ADT-G, and 3α-diol-17G) measured at baseline and week 12 (or at discontinuation visit, if applicable) by validated liquid chromatography tandem mass spectrometry[28,30,31,32,33] remained well within the normal postmenopausal values.

Compliance

In the ITT population, 152/157 (97%) of those receiving placebo have completed the study, whereas 96% (311/325) have completed the study in the DHEA group.

Comments

3090D553-9492-4563-8681-AD288FA52ACE

processing....