Published online before print February 7, 2008, doi: 10.1161/HYPERTENSIONAHA.107.106575
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(Hypertension. 2008;51:1197.)
© 2008 American Heart Association, Inc.
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Medroxyprogesterone Abrogates the Inhibitory Effects of Estradiol on Vascular Smooth Muscle Cells by Preventing Estradiol Metabolism
From the Department of Obstetrics and Gynecology (R.K.D., B.I., M.R.), Clinic for Reproductive Endocrinology, University Hospital Zurich, Zurich, Switzerland; Zurich Center for Integrative Human Physiology (R.K.D.), University of Zurich, Zurich, Switzerland; Center for Clinical Pharmacology (R.K.D., E.K.J., D.G.G., L.C.Z.) and Departments of Medicine (R.K.D., E.K.J., D.G.G., L.C.Z.) and Pharmacology (E.K.J., L.C.Z.), University of Pittsburgh Medical Center, Pa; and the Inselspital (D.W.), Frauenheilkunde, University Hospital, Bern, Switzerland.
Correspondence to Raghvendra K. Dubey, Department of Obstetrics and Gynecology, Clinic for Reproductive Endocrinology (NORD-1, D217), University Hospital Zurich, Zurich, 8091-CH, Switzerland. E-mail Raghvendra.dubey{at}usz.ch
Sequential conversion of estradiol (E) to 2/4-hydroxyestradiols and 2-/4-methoxyestradiols (MEs) by CYP450s and catechol-O-methyltransferase, respectively, contributes to the inhibitory effects of E on smooth muscle cells (SMCs) via estrogen receptor–independent mechanisms. Because medroxyprogesterone (MPA) is a substrate for CYP450s, we hypothesized that MPA may abrogate the inhibitory effects of E by competing for CYP450s and inhibiting the formation of 2/4-hydroxyestradiols and MEs. To test this hypothesis, we investigated the effects of E on SMC number, DNA and collagen synthesis, and migration in the presence and absence of MPA. The inhibitory effects of E on cell number, DNA synthesis, collagen synthesis, and SMC migration were significantly abrogated by MPA. For example, E (0.1µmol/L) reduced cell number to 51±3.6% of control, and this inhibitory effect was attenuated to 87.5±2.9% by MPA (10 nmol/L). Treatment with MPA alone did not alter any SMC parameters, and the abrogatory effects of MPA were not blocked by RU486 (progesterone-receptor antagonist), nor did treatment of SMCs with MPA influence the expression of estrogen receptor-
or estrogen receptor-β. In SMCs and microsomal preparations, MPA inhibited the sequential conversion of E to 2–2/4-hydroxyestradiol and 2-ME. Moreover, as compared with microsomes treated with E alone, 2-ME formation was inhibited when SMCs were incubated with microsomal extracts incubated with E plus MPA. Our findings suggest that the inhibitory actions of MPA on the metabolism of E to 2/4-hydroxyestradiols and MEs may negate the cardiovascular protective actions of estradiol in postmenopausal women receiving estradiol therapy combined with administration of MPA.
Key Words: estradiol • progestins • cytochrome P450 • metabolism • cardiovascular disease • vascular remodeling