• 2018-07
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • VX-745 In contrast to drospirenone dydrogestrone acts rather


    In VX-745 to drospirenone dydrogestrone acts rather neutral at the aldosterone-, glucocorticoid- and androgen-receptor [12]. This indicates that the assessment of a ‘net-overall effect’ on the vascular system is very difficult based on the often discussed ‘partial effects’ of the progestogens. Thus, currently receptor-neutral progestogens such as dydrogesterone can be recommended especially for cardiovascular risk patients. For an advanced differentiated assessment of the progestagenic action in vascular systems the research currently is strongly focussed on the so-called ‘vascular active biochemical markers’, since it is expected that risk assessment before therapy and monitoring during therapy is possible by means of simple and cost-saving measurement of blood concentrations of these biological mediators, comparable to the measurements in the lipid and carbohydrate system. The main mechanism of the cardioprotection of estrogens appears to be a direct effect on the vasculature resulting in an improvement of endothelial function and inhibition of atherogenesis [1], [13], [14]. Studies assessing direct vascular effects seem to be most important. For this reason research on biochemical markers may have a greater significance as compared to metabolic markers, which cannot or can only indirectly reflect the influence on the vascular system.
    Functional significance of vascular markers
    Effects of progestogens on the vascular system Progesterone increased NO generation in rat aortas which seems to be a rapid, non-genomic effect [31]. As yet it remains unclear as to whether progesterone and synthetic progestogens may attenuate the estrogen-induced beneficial effect on NO synthesis. MPA attenuated the estradiol-induced increase of nitrate/nitrite, surrogate markers for the production of the vasodilating nitric oxide, in postmenopausal women [32]. Intermittent addition of MPA for 10 days every 3 months to 17β-estradiol, however, did not inhibit an increase in plasma NO levels after 6 months [33]. For norethisterone, however, published data are scarce, but NETA diminished the estradiol-induced increase in nitrate/nitrite levels in postmenopausal women [34]. Long-term effects of oral and transdermal HRT using NETA were investigated by Ylikorkala et al. [35]. These authors found no changes in nitrate/nitrite levels after 1 year of treatment. No deteriorating effect of oral or transdermal addition of the progestogen norethisterone acetate sequentially added to oral or transdermal estradiol was found in terms of influencing urinary cGMP excretion [36]. In a further prospective randomized study we also found no negative effect with the new progestogen, dienogest, on cGMP excretion continuously combined with oral estradiol valerate [37]. We compared the effect of oral versus transdermal sequential estradiol/NETA replacement therapy in postmenopausal women on the prostacyclin to thromboxane ratio [36]. An increase of prostacyclin-metabolite during the estrogen phase, and an increase of thromboxane-metabolite during combined phases were observed with both oral and transdermal administration, failing to show significance possibly due to high interindividual variations. Conceivably speculative, but the decrease in the quotient of prostacyclin to thromboxane, which is decisive for the resulting effects on vessels and which occurred following oral addition of NETA, can clearly be explained by a vasoconstrictory progestogen effect, as progestogens are thought to exert a vasoconstrictory effect on vessels. Another research group has provided conflicting data on the effect of oral VX-745 or transdermal HRT on urinary prostanoid excretion [35], [38], [39]. Oral estradiol/desogestrel for 6 months and oral and transdermal E2/NETA application for 12 months did not change prostanoid excretion significantly compared to the pre-treatment values. However, in a third study these authors found an increase in thromboxane metabolites for oral E2/NETA but not for transdermal E2/MPA treatment after 12 months [38]. In our study investigating the continuous addition of dienogest to estradiol a significant effect on the ratio of prostacyclin to thromboxane was observed after 3 months [37].