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It is increasingly axiomatic that depression has widespread adverse physiological effects and, conversely, that a variety of physiological systems impact the risk for developing depression. This convergence of depression and altered physiology is particularly dramatic during midlife—a time during which reproductive failure presages dramatic increases in prevalence of both heart disease and depression. The potentially meaningful and illuminating links between estrogen deficiency, cardiovascular disease (CVD), and depression have largely been obscured, first by assertions, subsequently repudiated, that the perimenopause was not a time of increased risk of depression, and more recently by the denegration of hormone replacement therapy by initial reports of the Women's Health Initiative. Increasingly, however, research has led to unavoidable conclusions that CVD and depression share common, mediating pathogenic processes and that these same processes are dramatically altered by the presence or absence of estrogen (E2). This review summarizes data supporting these contentions with the intent of placing depression and estrogen therapy in their proper physiologic context. Depression and Anxiety 28:E1–E15, 2011. © 2011 Wiley-Liss, Inc.