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

Objective: 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. Methods: (1) Human umbilical vein endothelial cells were treated with medroxyprogesterone acetate (MPA), DNG, or P4 with or without estradiol (E-2), 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), E-2 alone, E-2 + MPA, and E-2 + DNG. The treatment groups were treated with transdermal E-2 (0.72 mg) for 2 days or E-2 + MPA (2.5 mg/d) or E-2 + 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. Results: (1) Although MPA attenuated E-2-induced NO production and phosphorylation of Akt, extracellular signal-regulated kinase, and endothelial NO synthase, neither DNG nor P4 inhibited E-2 effects. (2) A significant decrease in FMD was observed 1 week after the operation in all groups. E-2 significantly ameliorated endothelial impairment (FMD, 3.4% +/- 0.9% to 7.6% +/- 1.3%) in the E-2-alone group (P < 0.05), but E-2 + MPA could not ameliorate endothelial impairment (3.3% +/- 1.1% to 3.5% +/- 1.0%). However, FMD in the E-2 + DNG group significantly increased (2.9% +/- 0.5% to 8.7% +/- 1.0%; P < 0.05). Conclusions: These results suggest that DNG did not inhibit the restoration of vasodilatation by E-2. DNG may have an advantage compared with MPA on the endothelial function in postmenopausal women receiving hormone therapy.