Dydrogesterone and 20-alpha-dihydrodydrogesterone activity on nitric oxide synthesis in human endothelial cells.

P. MANNELLA; A.M. SANCHEZ; M.S. GIRETTI; A. CARUSO; AR.GENAZZANI; T. SIMONCINI

May 19-23, Madrid, España

Congreso; 12th World Congress on the Menopause.; 2008

INTERNATIONAL MENOPAUSE SOCIETY

Objective: To investigate the effects of progesterone, medroxyprogesterone acetate, dydrogesterone and 20- -dihydrodydrogesterone on endothelial synthesis of nitric oxide and characterize the signaling events recruited by these compounds. Design & Method: Human endothelial cells from umbilical vein treated with Progesterone, medroxyprogesterone acetate, dydrogesterone and 20-alpha- dihydrodydrogesterone. We measured NO release, endothelial nitric oxide synthase (eNOS) activity and expression, and activation of ERK 1/2 and Akt. Results: The administration of dydrogesterone alone or in combination with estrogen to endothelial cells results in neutral effects on nitric oxide synthesis and on the activity and expression of eNOS. In parallel, the stable metabolite 20-alpha-dihydrodydrogesterone acts similarly to natural progesterone, enhancing the expression of eNOS and inducing rapid activation of the enzyme through the regulation of the ERK 1/2 mitogen-activated protein kinase cascade. 20-alpha-dihydrodydrogesterone and P also potentiate eNOS induction by estrogens. On the contrary, medroxyprogesterone acetate does not trigger eNOS enzymatic activation and decreases the extent of eNOS induction by estrogen. Conclusions: These findings support the concept that synthetic progestins act differently on vascular cells and that hormonal preparations may differ as to their cardiovascular effects.