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  • Adding MPA or NETA we found no

    2020-10-14

    Adding MPA or NETA we found no impact on the estradiol-induced downregulation of serum-stimulated endothelin synthesis in vitro [40]. Progesterone was also able to inhibit the angiotensin II-induced increase in endothelin production [41]. Several clinical studies on the effect of oral or transdermal HRT have demonstrated a beneficial reduction of endothelin blood levels [42], [43], [44]. One study failed to confirm these results for oral and transdermal HRT in non-smoking women, but showed a reduction in smoking women for transdermal HRT [35]. In women with cardiovascular risk factors conflicting data have been presented. In hypercholesterolemic women oral and transdermal ERT reduced plasma endothelin values [45], whereas in women with Desfuroylceftiofur type 2 and metabolic syndrome no effect for oral HRT and transdermal ERT was found [46]. The increase in urinary serotonin excretion after 2 weeks of estradiol was negatively influenced by the addition of oral NETA, but not by the addition of transdermal NETA. In a further study comparing oral estradiol with continuous combined administration of estradiol plus dienogest, we found serotonin excretion being enhanced after 3 months unopposed estradiol [47]. This effect was not negatively influenced by the addition of dienogest. The estrogen-induced increase of CRP, observed for orally administration, appears to be attenuated by progestogens independent of the type [48], [49], [50], [51]. Concerning IL-6 most studies have found no changes for hormone replacement therapy, whereas a few found a reduction [50], [51], [52]. In vitro experiments indicate that there may be a difference between the various progestogens on the expression of stimulated cell adhesion molecules [53], [54], [55]. However, when combined with estrogens no detrimental effects seems to be observable [40]. In controlled clinical studies almost conclusive data have been observed in that HRT is able to reduce serum levels of cell adhesion molecules indicating no detoriating effect of the different progestogens [56], [57], [58], [59]. Even in women with coronary artery disease HRT appears to lower cell adhesion molecules [60], [61], [62]. To our knowledge there have been little investigations so far on the influence of sex hormones on cytokine-stimulated endothelial production of MCP-1. In recent investigations we were able to demonstrate that E2 can reduce TNFα-stimulated MCP-1 production [40]. This effect was not reinforced by the addition of MPA, but interestingly by the addition of NET. Thus, with respect to the synthesis of this endothelial marker, differences in progestogen action may exist. Clinical studies have shown that CEE combined with progesterone significantly lowered serum MCP-1 levels [63]. The same is true for 17β-estradiol combined with a progestogen [64]. Transdermal E2 combined with MPA significantly decreased MCP-1 serum levels [65]. Concerning PAI-1 progesterone inhibited PAI-1 concentrations in bovine aortic endothelial cells [66]. We found that neither MPA nor NET seem to exert an antagonistic effect on the E2-induced decrease of PAI-1 synthesis in human coronary aortic endothelial cells [40]. HRT using transdermal E2-gel and MPA or E2/progesterone found no decrease in PAI-1 levels [67], [68], whereas oral E2/P, CEE/P, CEE/MPA and E2/NETA reduced serum PAI-1 levels [68], [69], [70]. This effect was also observed for low dose CEE combined with a progestogen [71], [72]. In vitro experiments indicate that the addition of MPA as well as of NET to estradiol elicited an enhanced reduction of MMP-1 [40]. The addition of progestogens to estrogen replacement therapy seems to have no effect on the estrogen-induced changes in serum levels of matrix metalloproteinases. However, CEE alone or combined with MPA increased MMP-9 levels after 4 weeks in postmenopausal women with established CAD [73]. Combined oral hormone therapy seems to reduce homocysteine serum levels in most clinical studies, thus no negative effect of progestogen addition appears operative [74], [75], [76]. In contrast transdermal HRT has little or no effects [77], [78], [79].