Effect of dienogest on estrogen-induced nitric oxide production in human umbilical vein endothelial cells and endothelium-dependent vasodilatation in postmenopausal women

Abstract

We investigated the effects of dienogest (DNG), which has a profile similar to that of natural progesterone (P4), on the favorable effects of estrogen in endothelial function. (1) Human umbilical vein endothelial cells were treated with medroxyprogesterone acetate (MPA), DNG, or P4 with or without estradiol (E2), and then we examined nitric oxide (NO) production, phosphorylation of Akt, ERK, and endothelial NO synthase. (2) Twenty women with surgical menopause were randomly allocated to four groups: control (no treatment), E2 alone, E2 + MPA, and E2 + DNG. The treatment groups were treated with transdermal E2 (0.72 mg) for 2 days or E2 + MPA (2.5 mg/d) or E2 + DNG (2 mg/d) for a week starting 1 week after the operation; the control group did not use hormone. We examined the changes in the flow-mediated dilatation (FMD) of the brachial artery using ultrasonography. (1) Although MPA attenuated E2-induced NO production and phosphorylation of Akt, extracellular signal-regulated kinase, and endothelial NO synthase, neither DNG nor P4 inhibited E2 effects. (2) A significant decrease in FMD was observed 1 week after the operation in all groups. E2 significantly ameliorated endothelial impairment (FMD, 3.4% +/- 0.9% to 7.6% +/- 1.3%) in the E2-alone group (P < 0.05), but E2 + MPA could not ameliorate endothelial impairment (3.3% +/- 1.1% to 3.5% +/- 1.0%). However, FMD in the E2 + DNG group significantly increased (2.9% +/- 0.5% to 8.7% +/- 1.0%; P < 0.05). These results suggest that DNG did not inhibit the restoration of vasodilatation by E2. DNG may have an advantage compared with MPA on the endothelial function in postmenopausal women receiving hormone therapy.