Opposing Effects of Estrogen and Progestins on LDL Oxidation and Vascular Wall Cytotoxicity: Implications for Atherogenesis

Abstract

Estrogens are widely regarded as beneficial to arterial wall health. Among the mechanisms of this benefit are antioxidant effects on LDL and the arterial wall. Because progestins oppose the effect of estrogen in several systems, we asked if progestins oppose the antioxidant effect of estrogen. To study this question, LDL and various female sex hormones were incubated alone and combined in the absence or presence of bovine aortic endothelial cells, placental trophoblast, or macrophages, and LDL oxidation and cytotoxicity were quantitated. In the absence of cells, LDL incubated with copper in phosphate-buffered saline enhanced the oxidation of LDL. When 17beta-estradiol was added to this system, an antioxidant effect was observed. Progestins inhibited this protective estrogenic effect. In endothelial cell culture, progestins also opposed the antioxidant effect of estrogen, with the strongest antiestrogenic effect seen with the synthetic progestins, levonorgestrel and medroxyprogesterone acetate (MPA). Endothelial cell cytotoxicity was proportional to the enhanced lipid peroxide formation observed with progestins or estrogen. Similar opposing effects were seen when estrogen and progesterone were added to primary cultures of placental trophoblast or macrophages. Thus, three cell culture systems modeling circulating arterial blood contact with cell surfaces demonstrated opposing effects of estrogens and progestins on LDL oxidation and cell cytotoxicity. These studies are in keeping with published reports that female sex steroids influence LDL oxidation in vivo and consequent arterial wall injury.

Lipid peroxidation and nitric oxide inactivation in postmenopausal women

“…The addition of estrogens to a system of LDL oxidation mediated by copper showed an increase in the initiation time of LDL oxidation 26 . Several studies have shown the effect of the administration of estrogens on human LDL oxidation [50][51][52] .…”

“…In liver cells, cholesterol is transformed into bile acids, which, in turn, are excreted in bile. Under the influence of estrogens, the following events may occur: (i) plasma triglycerides increase due to an increase in VLDL production; (ii) LDL concentration is reduced due to an increase in the expression of LDL receptors; (iii) HDL is increased by 2 mechanisms: greater secretion of apolipoprotein A-1, and lower removal of its lipids, because estrogens lead to a reduction in hepatic lipase activity (revised by Zhu et al 26 ).…”

Oxidative damage and the pathogenesis of menopause related disturbances and diseases

“…During last decades, researchers hypothesized that menopause itself represents an important threat to women's health because it is accompanied by increased systemic OxS, triggered by the loss of E2 which has antioxidant activity in vitro on cell cultures, ex vivo and in animal models [14,[69][70][71][72][73][74]. The hypothesis of a protection by E2 against oxidative damage to cardiovascular, neuronal and bone tissue still waits a definitive scientific validation in human disease since epidemiologic studies failed yet to confirm the in vivo impact of these hormones in the systemic redox balance, as we discuss below.…”

Effects of an EE/CA compared with EE/CA-metformin on serum ADMA levels in women with polycystic ovary syndrome

“…Moreover, progestins have been reported to impair the cardioprotective effects of estrogen, as well as decrease serum NO levels and increase of plasma NO metabolites; nitrate and nitrite, even in the presence of high concentrations of 17b-estradiol [17]. Estrogen increases HDL-C whereas progestins can induce HDL-C levels fall in association with an increase in hepatic lipase activity.…”