Studies on Women's Health by Ashok Agarwal Nabil Aziz & Botros Rizk

Author:Ashok Agarwal, Nabil Aziz & Botros Rizk
Language: eng
Format: epub
Publisher: Humana Press, Totowa, NJ

11.4.2 Selective Estrogen Receptor Modulators

SERMs are a class of compounds that act on the estrogen receptor, with the possibility to selectively stimulate or inhibit the effects of estrogen in various tissues. Raloxifene was the first SERM to be used to prevent and treat osteoporosis [9]. The compound functions in the breast and uterus as an estrogen antagonist [9, 48]. Raloxifene shares properties similar to those of estrogen, particularly in its capacity to reduce oxidative stress. The antioxidant activity of raloxifene is attributed to the presence of phenolic rings in its structure [9, 49]. The mechanism of action targets NADPH oxidase, an enzyme responsible for generating free radicals [9]. In normal physiologic conditions, NADPH oxidase requires activation of a particular subunit by GTPase rac 1. Raloxifene was shown to downregulate rac1 protein expression in the aortic membrane, further reducing the activity of GTPase rac1. The effects of raloxifene to ultimately decrease NADPH oxidase activity result in a less oxidative stress due to hindered ROS production [50].

Raloxifene was shown to reduce blood pressure and improve endothelial dysfunction in male spontaneously hypertensive rats. Furthermore, treatment was seen to cause a significant increase in SOD levels and the release of NO and upregulation of endothelial NOS in spontaneously hypertensive rats [48]. Raloxifene has also been shown to prevent the accumulation of cholesterol in ovariectomized cholesterol-fed rabbits and inhibit macrophage lipid oxidation [51]. A recent study by Ozbasar et al. [52] studied the effect of daily raloxifene administration in a group of 24 postmenopausal women who were undergoing long-term hemodialysis for the treatment of chronic renal failure. A regimen of 60 mg per day for 3 months lead to significantly lower levels of serum MDA and NO levels, with favorable effects on the lipid profile. The results of these studies illustrate the protective effect of raloxifene on the vascular endothelium.

Oviedo et al. [49] reported that levels of myeloperoxidase and F2α -isoprostane, markers of oxidative stress, did not change in a cohort of 30 postmenopausal women treated with raloxifene, at a dose of 60 mg per day for a 6 month period. However, the results of this study should be taken with caution as myeloperoxidase and F2α -isoprostane have not yet been proven to be reliable indicators of oxidative stress [49].

Based on the evidence, raloxifene is thought to serve a vasoprotective role by decreasing blood pressure levels and improving endothelial function as well as providing preventing hypogonadal bone loss. These effects are mediated via estrogen-receptor pathways and may result in protection against oxidative stress.

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