title: Serum steroid concentrations remain within normal postmenopausal values in women receiving daily 6.5mg intravaginal prasterone for 12 weeks.
abstract: 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-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 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.
authors.affiliation: EndoCeutics Inc., Quebec City, QC G1V 4M7, Canada.
authors.forename: Céline
authors.initials: C
authors.lastname: Martel
authors.affiliation: EndoCeutics Inc., Quebec City, QC G1V 4M7, Canada. Electronic address: fernand.labrie@endoceutics.com.
authors.forename: Fernand
authors.initials: F
authors.lastname: Labrie
authors.affiliation: CONRAD Clinical Research Center, Norfolk, VA, USA.
authors.forename: David F
authors.initials: DF
authors.lastname: Archer
authors.affiliation: EndoCeutics Inc., Quebec City, QC G1V 4M7, Canada.
authors.forename: Yuyong
authors.initials: Y
authors.lastname: Ke
authors.affiliation: EndoCeutics Inc., Quebec City, QC G1V 4M7, Canada.
authors.forename: Renaud
authors.initials: R
authors.lastname: Gonthier
authors.affiliation: EndoCeutics Inc., Quebec City, QC G1V 4M7, Canada.
authors.forename: Jean-Nicolas
authors.initials: JN
authors.lastname: Simard
authors.affiliation: EndoCeutics Inc., Quebec City, QC G1V 4M7, Canada.
authors.forename: Lyne
authors.initials: L
authors.lastname: Lavoie
authors.affiliation: EndoCeutics Inc., Quebec City, QC G1V 4M7, Canada.
authors.forename: Mario
authors.initials: M
authors.lastname: Vaillancourt
authors.affiliation: EndoCeutics Inc., Quebec City, QC G1V 4M7, Canada.
authors.forename: Marlene
authors.initials: M
authors.lastname: Montesino
authors.affiliation: Veristat, Southborough, MA, USA.
authors.forename: John
authors.initials: J
authors.lastname: Balser
authors.affiliation: StatLog Consulting Inc., Quebec, QC, Canada.
authors.forename: Érick
authors.initials: É
authors.lastname: Moyneur
mesh_terms: D000282:Administration, Intravaginal; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001284:Atrophy / Q000188:drug therapy; D003687:Dehydroepiandrosterone / Q000008:administration & dosage* / Q000493:pharmacokinetics; D004958:Estradiol / Q000097:blood*; D005260:Female; D020249:Hormone Replacement Therapy; D006801:Humans; D008875:Middle Aged; D017698:Postmenopause / Q000097:blood*; D013739:Testosterone / Q000097:blood*; D014623:Vaginal Diseases / Q000188:drug therapy*
chemical_list: D013739:Testosterone; D003687:Dehydroepiandrosterone; D004958:Estradiol
keywords: Androgens; Dehydroepiandrosterone (DHEA); Estradiol; Menopause; Prasterone; Vulvovaginal atrophy