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Hum. Reprod. Advance Access published online on June 2, 2007
Human Reproduction, doi:10.1093/humrep/dem109
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© The Author 2007. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed: the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given: if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative word this must be clearly indicated. For commercial re-use, please contact journals.permissions@oxfordjournals.org

Drospirenone increases endothelial nitric oxide synthesis via a combined action on progesterone and mineralocorticoid receptors

T. Simoncini1, X-D. Fu, A. Caruso, S. Garibaldi, C. Baldacci, M.S. Giretti, P. Mannella, M.I. Flamini, A.M. Sanchez and A.R. Genazzani

Molecular and Cellular Gynecological Endocrinology Laboratory (MCGEL), Department of Reproductive Medicine and Child Development, Division of Obstetrics and Gynecology, University of Pisa, Via Roma 57, Pisa 56100, Italy

1 Correspondence address. Tel: +39-050-553412; Fax: +39-050-553410; E-mail: t.simoncini{at}obgyn.med.unipi.it

BACKGROUND: Progestins have actions on the cardiovascular system, which depend on the structure as well as on receptor binding characteristics. Drospirenone (DRSP) is a progestin that uniquely interferes with the signaling of the mineralocorticoid receptor (MR). Hormone therapy containing DRSP results in blood pressure reduction in hypertensive post-menopausal women.

METHODS: We describe the effects of DRSP on endothelial nitric oxide (NO) synthesis and compare them with those of progesterone (P) and of medroxyprogesterone acetate (MPA). In addition, we herein tested the relevance of the anti-mineralocorticoid activity of DRSP for NO synthesis.

RESULTS: DRSP results in rapid activation of the endothelial NO synthase (eNOS) through mitogen-activated protein kinases and phosphatidylinositol 3-kinase as well as in enhanced eNOS expression. These actions depend on P receptor. When the cells are exposed to aldosterone, a reduction of eNOS expression is found that is antagonized by DRSP. This action is not shared by P or MPA. In addition, DRSP does not interfere with the induction or activation of eNOS induced by estradiol, as opposed to MPA.

CONCLUSIONS: DRSP acts on endothelial cells via a combined action through the P and MRs. These results help to interpret the anti-hypertensive effects of hormonal therapies containing DRSP.

Key words: cardiovascular disease/endothelial cells/drospirenone/nitric oxide/endothelial nitric oxide synthase

Submitted on February 28, 2007; resubmitted on March 28, 2007; accepted on April 2, 2007.


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