Serum steroid concentrations remain within normal postmenopausal values in women receiving daily 6.5 mg intravaginal prasterone for 12 weeks. Issue 159 (May 2016)

• Record Type: Journal Article
• Authors: Martel, Céline; Labrie, Fernand; Archer, David F.; Ke, Yuyong; Gonthier, Renaud; Simard, Jean-Nicolas; Lavoie, Lyne; Vaillancourt, Mario; Montesino, Marlene; Balser, John; Moyneur, Érick
• Is Part Of: Journal of steroid biochemistry and molecular biology. Issue 159(2016)
• Page Start: 142
• Page End: 153
• Publication Date: 2016-05
• Subjects: Vulvovaginal atrophy -- Prasterone -- Menopause -- Dehydroepiandrosterone (DHEA) -- Estradiol -- Androgens; Steroid hormones -- Periodicals; Biochemistry -- Periodicals; Hormones -- Periodicals; Molecular Biology -- Periodicals; Hormones stéroïdes -- Périodiques; Steroid hormones; Periodicals; 572.579
• DOI: 10.1016/j.jsbmb.2016.03.016
• Languages: English
• ISSNs: 0960-0760

Abstract

Highlights: Intravaginal 0.50% (6.5 mg) DHEA (prasterone) was administered daily for 12 weeks in postmenopausal women with VVA symptoms (n = 723, prasterone; n = 266, placebo) (ITT-S population) . Eleven steroids were measured in serum at baseline and 12 weeks by validated liquid chromatography tandem mass spectrometry. Serum DHEA and its ten derived steroids remained well within normal postmenopausal values. At 12 weeks, serum estradiol was 19% below normal postmenopausal values while serum estrone sulfate, the best known marker of total estrogenic activity, was 5% below normal values (cITT-S population). These combined steroid data further illustrate the mechanisms of intracrinology or the strictly intracellular sex steroid formation, action and inactivation following intravaginal DHEA. Intravaginal DHEA exerts a strictly local activity without biologically significant systemic exposure, as developed by evolution for menopause. Abstract: This study integrates all data obtained in women aged 40–80 years enrolled with moderate to severe symptoms of vulvovaginal atrophy (VVA) who received daily intravaginal administration of 0.50% (6.5 mg) dehydroepiandrosterone (DHEA; prasterone) for 12 weeks (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-3β, 17β-diol (5-diol), testosterone, dihydrotestosterone (DHT), androstenedione (4-dione), estrone (E1 ), estradiol (E2 ), estrone sulfate (E1 -S), androsterone glucuronide (ADT-G), and androstane-3α, 17β-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 12 weeks of treatment at 3.36 pg/ml (cITT-S population) or 19% below the normal postmenopausal value of 4.17 pg/ml. On the other hand, serum E1 -S, the best recognized marker of global estrogenic activity, shows an average value of 209 pg/ml at 12 weeks compared to 220 pg/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 (6.5 mg) 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.