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Lack of effect of intravaginal dehydroepiandrosterone (DHEA, prasterone) on the endometrium in postmenopausal women

Portman, David J. MD1; Labrie, Fernand MD, PhD2; Archer, David F. MD3; Bouchard, Céline MD4; Cusan, Leonello MD, PhD5; Girard, Ginette MD6; Ayotte, Normand MD7; Koltun, William MD8; Blouin, François MD9; Young, Douglas MD10; Wade, Anthony MD11; Martel, Céline PhD2; Dubé, Robert MD12other participating members of the VVA Prasterone Group

doi: 10.1097/GME.0000000000000470
Original Articles
Editorial

Objective: This study aims to evaluate the effects of intravaginal dehydroepiandrosterone (DHEA, prasterone) on the endometrium in postmenopausal women.

Methods: Intravaginal DHEA (6.5 mg) was administered daily for 52 weeks to 422 women who had endometrial biopsy at baseline and end of study, whereas 15 women were similarly treated for 26 to 52 weeks. Participants in three other studies received 3.25 mg (n = 126), 6.5 mg (n = 129), or 13 mg (n = 30) of DHEA for 12 weeks; women similarly had baseline and end-of-study biopsies. Endometrial biopsy samples were available for 668 women at baseline and end of study, with sufficient material for analysis.

Results: Endometrial atrophy or inactive endometrium (668 women) was found in all women treated with intravaginal DHEA. Similar atrophy was observed in 119 of 121 participants with sufficient material for analysis who received placebo.

Conclusions: After cessation of estradiol secretion by the ovaries at menopause, the estrogens made by mechanisms of intracrinology are inactivated intracellularly at their site of formation and action, thus maintaining serum estradiol at biologically inactive concentrations to avoid stimulation of the endometrium. The absence of enzymes that are able to transform DHEA into estrogens in the endometrium explains the typical endometrial atrophy in all normal postmenopausal women in the presence of variable concentrations of circulating endogenous DHEA. According to these mechanisms, the inactive sex steroid precursor DHEA administered intravaginally acts exclusively in the vagina, whereas all serum sex steroids remain well within the biologically inactive postmenopausal reference range, thus avoiding any stimulation of the already atrophic endometrium.

1Columbus Center for Women's Health Research, Columbus, OH

2EndoCeutics Inc, Quebec City, QC, Canada

3CONRAD Clinical Research Center, Norfolk, VA

4Clinique de Recherche en Santé des Femmes, Quebec City, QC, Canada

5Clinique de Recherche en Traitements Hormonaux, Quebec City, QC, Canada

6Diex Recherche Montréal Inc, Montreal, QC, Canada

7Clinique de Gynécologie, Shawinigan, QC, Canada

8Medical Center for Clinical Research, San Diego, CA

9Pro-Recherche, St-Romuald, QC, Canada

10Northern Califonia Research, Sacramento, CA

11Maritime Research Center, Bathurst, NB, Canada

12Centre Hospitalier Universitaire de Quebec, Quebec City, QC, Canada.

Address correspondence to: Fernand Labrie, MD, PhD, EndoCeutics, 2795 Laurier Blvd, Suite 500, Quebec City, QC, Canada G1 V 4M7. E-mail: Fernand.Labrie@endoceutics.com

Received 31 October, 2014

Revised 5 March, 2015

Accepted 5 March, 2015

Funding/support: This research was sponsored by EndoCeutics.

Financial disclosure/conflicts of interest: All authors received financial support from EndoCeutics. F.L. and C.M. are employees of EndoCeutics. D.J.P. reports consultancy for TherapeuticsMD, Shionogi, Actavis, Pfizer, Teva, Sprout, and Palatin, and membership in speakers bureau for Pfizer, Shionogi, and Actavis. D.F.A. reports consultancy for Abbvie, Agile Therapeutics, Ascend Therapeutics, CHEMO, Exceltis, Shionogi, and TherapeuticsMD, and grants from Abbvie, Bayer Healthcare, Merck, and TherapeuticsMD. C.B. reports grants from Bayer and membership in speakers bureau for Merck and Actavis.

© 2015 by The North American Menopause Society.