Medroxyprogesterone acetate versus norethisterone: effect on estradiol-induced changes of markers for endothelial function and atherosclerotic plaque characteristics in human female coronary endothelial cell cultures.
OBJECTIVE
Progestin addition to estradiol (E(2)) replacement therapy may lead to a deterioration of beneficial effects on the vasculature. The effect of the two clinically most common progestins, medroxyprogesterone acetate (MPA) and norethisterone (NET), during continuous combination with E(2) on the synthesis of markers for coronary endothelial function, atherosclerotic plaque initiation, and plaque formation was investigated in human female vascular cell cultures and compared with that of E(2) alone.


METHODS
Endothelial cell cultures from human female coronary arteries were used to evaluate the effect of progestin addition to E(2) on the production of the following endothelial markers: prostacyclin, endothelin, plasminogen activator inhibitor-1, E-selectin, intercellular adhesion molecule-1, monocyte chemoattractant protein-1 (MCP-1), and the precursor of matrix metalloproteinase-1 (pro-MMP-1). E(2) was tested at 0.1 microM, 1 microM, and 10 microM alone and in equimolar combinations with MPA or NET. The markers were determined by enzyme immunoassays in the cell supernatant.


RESULTS
E(2) induced a significant increase of endothelial prostacyclin production and was able to significantly decrease the synthesis of endothelin, plasminogen activator inhibitor-1, E-selectin, and intercellular adhesion molecule-1. Neither MPA nor NET addition negatively interfered with these E(2)-induced benefits. However, MPA antagonized the E(2)-induced significant reduction of MCP-1 synthesis, with the difference between both progestins being significant (p < 0.01). Interestingly, an enhancement of the positive E(2)-effect on pro-MMP-1 production was observed by the addition of both MPA and NET (p < 0.01).


CONCLUSIONS
E(2) can positively influence various markers of endothelial function. Addition of MPA or NET can elicit different effects, which has been demonstrated for the first time in human coronary cell cultures. No impact was found on markers representing primarily vasotonus and thrombogenicity. In terms of MMP-1, which is crucial for atherosclerotic plaque stability, an enhancement of the beneficial E(2) effect was observed. However, regarding MCP-1, contrary effects of progestins cannot be excluded. This indicates that progestins may differ in their effects, particularly in the early stages of atherosclerosis, which has also been supported by other studies.
Mueck
Alfred O
AO
Section of Endocrinology and Menopause, Department of Obstetrics and Gynecology, University of Tuebingen, Tuebingen, Germany. endo.meno@med.uni-tuebingen.de
Seeger
Harald
H
Wallwiener
Diethelm
D
D015415:Biomarkers / Q000032:analysis*; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000032:analysis; D016001:Confidence Intervals; D003324:Coronary Artery Disease / Q000188:drug therapy / Q000503:physiopathology*; D003331:Coronary Vessels / Q000166:cytology / Q000187:drug effects; D019040:E-Selectin / Q000032:analysis / Q000187:drug effects; D016232:Endothelins / Q000032:analysis / Q000187:drug effects; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects*; D011464:Epoprostenol / Q000032:analysis; D005260:Female; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000032:analysis / Q000187:drug effects; D020781:Matrix Metalloproteinase 1 / Q000032:analysis / Q000187:drug effects; D017258:Medroxyprogesterone Acetate / Q000494:pharmacology*; D009640:Norethindrone / Q000494:pharmacology*; D011336:Probability; D012680:Sensitivity and Specificity
D015415:Biomarkers; D018932:Chemokine CCL2; D019040:E-Selectin; D016232:Endothelins; D018799:Intercellular Adhesion Molecule-1; D017258:Medroxyprogesterone Acetate; D011464:Epoprostenol; D020781:Matrix Metalloproteinase 1; D009640:Norethindrone