Review Role of estrogen receptors in pro-oxidative and anti-oxidative actions of estrogens: A perspective Sukhdeep Kumar, Kusum Lata, Srirupa Mukhopadhyay, Tapan K. Mukherjee ⁎ Department of Biology, Indian Institute of Science Education and Research (IISER),Transit Campus, MGSIPA Complex, Sector 26, Chandigarh-160019, India abstract article info Article history: Received 4 February 2010 Received in revised form 23 March 2010 Accepted 21 April 2010 Available online 29 April 2010 Keywords: Estrogens Estrogen receptors Estrogen receptor related receptors Pro-oxidative action Anti-oxidative action Background: Estrogens are steroid hormones responsible for the primary and secondary sexual characteristics in females. While pre-menopausal women use estrogens as the main constituents of contraceptive pills, post-menopausal women use the same for Hormone Replacement Therapy. Estrogens produce reactive oxygen species by increasing mitochondrial activity and redox cycling of estrogen metabolites. The phenolic hydroxyl group present at the C3 position of the A ring of estrogens can get oxidized either by accepting an electron or by losing a proton. Thus, estrogens might act as pro-oxidant in some settings, resulting in complicated non-communicable diseases, namely, cancer and cardiovascular disorders. However, in some other settings the phenolic hydroxyl group of estrogens may be responsible for the anti-oxidative beneficial functions and thus protect against cardiovascular and neurodegenerative diseases. Scope of review: To date, no single review article has mentioned the implication of estrogen receptors in both the pro-oxidative and anti-oxidative actions of estrogens. Major conclusion: The controversial role of estrogens as pro-oxidant or anti-oxidant is largely dependent on cell types, ratio of different types of estrogen receptors present in a particular cell and context specificity of the estrogen hormone responses. Both pro-oxidant and anti-oxidant effects of estrogens might involve different estrogen receptors that can have either genomic or non-genomic action to manifest further hormonal response. General significance: This review highlights the role of estrogen receptors in the pro-oxidative and anti- oxidative actions of estrogens with special emphasis on neuronal cells. © 2010 Elsevier B.V. All rights reserved. 1. Introduction Estrogens are namely a group of steroid hormones secreted primarily from the ovaries of the females. Estrogens can be produced in both males and females but, the physiological levels of estrogens are significantly higher in females of reproductive age. A normal healthy woman of reproductive age daily produces 700 μg of 17-β- estradiol (E 2 ) until her menopause. E 2 is the predominant estrogen produced by the female body. E 2 has a half life of approximately 3 h and is thereby subjected to a very rapid and irreversible oxidation into the estrogen metabolites estrone (E 1 ) and estriole (E 3 ) [1]. At menopause, generation of estrogens in females is drastically reduced. Estrogens are termed for their so called importance in the oestrus cycle and are also involved in the thickening of uterine endometrium besides regulation of menstrual cycle. Estrogens are responsible for the development of female secondary sexual characteristics like mammary glands and loss of facial hair etc. [2]. Millions of pre-menopausal women worldwide use estrogens as the primary constituent of contraceptive pills. Post-menopausal women may also use estrogens as the major constituents of Hormone Replacement Therapy (HRT). The benefits of HRT include instanta- neous relief from the pre- and post-menopausal symptoms, cardio- vascular problems and delay in the onset of possible osteoporosis and Alzheimer's disease [3]. The vasoprotective and anti-oxidative properties of estrogens are responsible for at least some of the beneficial effects of estrogens in the neuronal cells [4]. Estrogens are potentially preventative against neurodegenerative diseases (Alzhei- mer's disease, Parkinsonism etc.) in part, by activating the anti- oxidant defense systems either by scavenging reactive oxygen species (ROS) or by limiting mitochondrial DNA and protein damage along with enhancing electron transport chain activity [5]. However, the initial results from the Women's Health Initiative (WHI) study conducted in July 2002 indicated quite the opposite and Biochimica et Biophysica Acta 1800 (2010) 1127–1135 Abbreviations: E 1 , estrone; E 2 , estradiol (also known as 17-β E 2 ); E 3 , estriol; 2-OH- E 1 , 2-hydroxyestrone; 2-OH-E 2 , 2-hydroxyestradiol; 4-OH-E 1 , 4-hydroxyestrone; 4- OH-E 2 , 4-hydroxyestradiol; 16α-OH-E1, 16α-hydroxyestrone; ERα, estrogen receptor alpha; ERβ, estrogen receptor beta; CE, catechol estrogens; HRT, Hormone Replacement Therapy; ROS, reactive oxygen species; ERE, estrogen response element; AD, Alzheimer's disease; ND, neurodegenerative disorders ⁎ Corresponding author. Tel.: +91 9876722596; fax: +91 172 2790188. E-mail address: tapan@iisermohali.ac.in (T.K. Mukherjee). 0304-4165/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.bbagen.2010.04.011 Contents lists available at ScienceDirect Biochimica et Biophysica Acta journal homepage: www.elsevier.com/locate/bbagen