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

Abstract and Introduction

Abstract

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.

Introduction

Atrophy of the epithelial surface of the vaginal mucosa is accompanied at menopause by reduced fluid secretion, reduced levels of lactobacilli, and increased vaginal pH.[1] These epithelial changes are responsible for the best known symptoms of vulvovaginal atrophy (VVA) or genitourinary syndrome of menopause (GSM),[2] namely vaginal dryness, pain at sexual activity, and irritation/itching.[3,4,5] Bleeding associated with sexual activity, pain and burning during urination (dysuria), and urinary tract infections with vaginal discharge commonly accompany VVA. In addition to the local negative effects in the vagina, VVA is frequently associated with emotional distress and reduced quality of life,[6,7,8] with extension to the sexual partner.[9] The VVA symptoms are reported in up to approximately 60% of postmenopausal women.[7,10,11]

Despite their benefits on vasomotor symptoms, 40% of women receiving systemic estrogen therapy have persistent vaginal symptoms.[12] Consequently, local estrogen therapy is recommended over systemic administration, except if other symptoms of menopause, especially hot flushes, are present. All intravaginal estrogens apparently have comparable efficacy for the treatment of VVA.[13] As per the data of the Women's Health Initiative Study,[14] the recommendation has been to use the lowest dose of intravaginal estrogen possible for the shortest duration of treatment possible.[13,15,16]

Significant changes recently took place in our understanding of sex steroid physiology in women. Whereas it was well known that the ovary stops making estrogens at menopause, thus resulting in very low and biologically inactive serum estradiol (E2) levels,[17] it was important to recognize that the adrenal and, to a small extent, the ovary[18] secrete in the blood a compound inactive by itself, namely dehydroepiandrosterone (DHEA), which is the exclusive precursor of all sex steroids after menopause.[18] Thus, acting through the mechanisms of intracrinology, DHEA provides estrogens and/or androgens only to the cells/tissues which possess the required enzymes to transform DHEA.[19]

The secretion of DHEA markedly decreases with age, with an average 60% loss between the age of 30 years and the menopause at about 50 years.[20,21,22,23] This marked reduction in the secretion of DHEA[23] results in a parallel fall in the formation of androgens and estrogens in peripheral target tissues—a situation most likely responsible for the hormone deficiency-related symptoms and signs of menopause. In addition to markedly decreasing with age, the serum levels of DHEA are highly variable, with some women having barely detectable serum concentrations of DHEA, whereas others have values of up to 9 to 10 ng/mL in the normal premenopausal range.[18,20]

Our recent placebo-controlled, randomized, double-blind, and prospective clinical trials have shown clinical and statistically significant benefits of daily intravaginal administration of DHEA on the maturation index (MI) of the vaginal cells, vaginal pH, as well as on moderate to severe dyspareunia, considered as the most bothersome symptom (MBS), as well as on moderate to severe vaginal dryness.[5,24,25,26,27] The objective of the present clinical trial, performed in 558 postmenopausal women enrolled with moderate to severe dyspareunia as their most bothersome VVA symptom, is to confirm the previous data obtained with daily intravaginal administration of DHEA for 12 weeks while reaching the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)-required number of 1,500 women exposed to the intravaginal DHEA treatment and the US Food and Drug Administration (FDA) guidelines.[28]

Comments

3090D553-9492-4563-8681-AD288FA52ACE

processing....