Estradiol as an antioxidant: incompatible with its physiological concentrations and function

Abstract

Estradiol has been documented to inhibit the oxidation of low density lipoprotein (LDL). We show that physiological concentrations of estradiol do not inhibit the oxidation of LDL by copper. LDL samples isolated from a ) premenopausal and postmenopausal women and from b ) women at different time periods during their menstrual cycle, who differ vastly in plasma estradiol levels, were also oxidized at the same rates by copper. In contrast, LDL samples isolated from c ) women who were hyperstimulated during in vitro fertilization (IVF), with estradiol concentrations above 2000 pg/ml, were resistant to oxidation by copper. However, these LDL samples were also oxidized at a higher rate by peroxidases. More importantly, subjects with high estradiol levels also showed an increase in myeloperoxidase (MPO) protein in the plasma. Based on these results, we conclude that at physiologic concentrations, it is unlikely that estradiol could act as an antioxidant. In fact, the ability of estradiol to induce MPO and become a prooxidant might instead suggest that MPO-mediated oxidative clearance of LDL from plasma by liver might favorably influence the outcome of atherosclerosis.-

Antiphospholipid antibodies are induced by in vitro fertilization and correlate with paraoxonase activity and total antioxidant capacity of plasma in infertile women

“…30 Furthermore, it has been suggested that in fact, at physiological concentrations, oestrogens might bear pro-oxidant activity through myeloperoxidase activation. 31 In this way, we suggest that IVF treatment could induce a rise in plasma oxidation that would lead to an increase in oxidation of the membrane phospholipids and the consequent triggering of anti-PL antibody production. These antibodies have been correlated with a reduction in PON activity in patients with APS, 24 enhancing in this way the oxidation levels of plasma that in turn would further increase the oxidation of membrane phospholipids, hence perpetuating this condition.…”

17β-Estradiol acts separately on the LDL particle and artery wall to reduce LDL accumulation

“…Studies utilizing physiological doses of estradiol are conflicting. Recent work by Santanam et al (41) suggested that at physiological concentrations, estradiol did not function as an antioxidant and protect LDL from Cu ϩ2 -mediated oxidation. Conversely, work by Shwaery and colleagues (14) showed that physiological levels of estradiol associated with LDL and also, incubation of estradiol with LDL in the presence of plasma protected against aqueous peroxyl radical-mediated oxidation.…”

Oxidants and antioxidants in atherogenesis: an appraisal

“…Recently, the induction of heme oxygenase (which would generate potent antioxidants such as bilirubin and biliveridin) (133)(134)(135), catalase (136) (O. Meilhac, unpublished observations) and glutathione (137,138) by vascular cells under oxidative stress has been described. These findings raise an inescapable conclusion that a mild oxidative stress might itself lead to the body's antioxidant defense, a conclusion that might be supported by circumstantial studies from in vivo studies (116,139,140). These studies indicated that beginning exercisers suffer an oxidative stress whereas conditioned exercisers are well protected, as determined by the susceptibility of isolated LDL to oxidation (140).…”

“…More importantly, whether the observed effects could be attributed to pro-or antioxidant effects could not be established. The probability of a phenolic antioxidant to become a prooxidant is well illustrated by estradiol (116). Not only does it have the ability to become a prooxidant in the presence of peroxidases, its increased presence is also associated with an increased neutrophil activation and release of myeloperoxidase (MPO) (117).…”

“…The contribution of the "prooxidant" effect of estrogens needs to be carefully evaluated. Estradiol might "help" to oxidize and clear LDL rapidly from plasma, induce antioxidant enzymes such as nitric oxide synthase in the endothelium in the arterial cells, and might have other effects (116,120). The recent HERS report has alerted us to the potential negative consequences of estrogen replacement ther-apy for menopausal women with potential for atherogenesis (121,122).…”