Progestins and cardiovascular risk markers

Several risks are attributed to progestins as a class-effect; however, the progestins used in hormone replacement therapy (HRT) have varying pharmacologic properties and do not induce the same side effects. Natural progesterone (P) and some of its derivatives, such as the 19-norprogesterones, do not exert any androgenic effect and, hence, have no negative effect on the lipids. On the other hand, the 19-nortestosterone derivatives and even some 17-hydroxyprogesterones have a partial androgenic effect, which may explain some of the negative effects observed on surrogate markers of cardiovascular risk. The relevance of the lipid changes induced by sex steroids has been questioned, and studies in the female cynomolgous monkey have not shown a direct relationship to atherosclerosis. Results suggest that estrogens (E) have antiatherogenic effects and that P does not reverse the beneficial effect of estradiol. Also, sex hormones modulate the vasomotor response of the main arteries. E preserves the normal endothelium-mediated dilation of coronary arteries, and P does not reverse this potential cardioprotective mechanism. In the same animal model, the addition of cyclic or continuous medroxyprogesterone acetate (MPA) to E inhibited vasodilatation by 50%, while nomegestrol acetate did not diminish the E-induced vasodilatation. Not all progestins act similarly on vasomotion or affect cardiovascular risk factors in the same way. Progestins, such as MPA or norethisterone acetate (NETA), exert a partial detrimental effect on the beneficial actions of estrogens with regard to lipid changes, atheroma development, or vasomotion. In contrast, progesterone itself does not have this inhibitory effect on lipid changes and vascular reactivity in animal models or on exercise-induced myocardial ischemia in humans. Nonandrogenic molecules of P itself and of derivatives, such as 19-norprogesterones, would appear neutral on the vessels. Several ongoing randomized controlled trials of HRT are focusing on primary or secondary prevention of coronary heart disease. Unfortunately, most of these large trials have selected the same HRT regimen for their study design. Further studies with other treatment regimens are thus needed and should consider the various steroids used in different countries.