Estrogen: good, bad, or both?

S ex differences in the prevalence and progression of numerous cardiovascular diseases are well documented, with males typically exhibiting greater severity and progression of disease compared with age-matched females. In contrast, females are more likely to develop autoimmune disease compared with age-matched males, both clinically and experimentally. Nevertheless, there is growing evidence that certain autoimmune diseases, including systemic lupus erythematous (SLE), are associated with an increased risk of developing car-diovascular disease. 1 Based on the expanding literature linking the immune system with cardiovascular disease, the question arises if females lose their cardiovascular protection with immune dysfunction and the molecular mechanisms driving cardiovascular disease in SLE. Historically, female sex hormones have been thought to contribute to the lower incidence of cardiovascular disease in premenopausal women. However, despite numerous studies designed to investigate the role of female sex hormones in cardiovascular disease, data from both animal and clinical research remain controversial. Therefore, it was with great interest that we read the study by Gilbert et al 2 in the current issue of Hypertension, which was designed to determine whether estrogen has a causal role in the development of hypertension in adulthood in SLE, an autoimmune disease with high prevalence of hypertension and cardiovascular disease. Using an established mouse model of SLE (female NZBWF1), Gilbert et al 2 have directly confirmed a protective role for 17β-estradiol against SLE-mediated hypertension and proteinuria in adult female mice, in part, by reducing tumor necrosis factor-α. In this study, animals were ovariectomized at 30 weeks and studied at 34 weeks, and the results are in contrast to those obtained where estrogens potentiate the onset of SLE when mice are ovariectomized at <6 to 8 weeks. 3 Together, these studies suggest that female sex hormones may act as a double-edged sword in the development and progression of hypertension in SLE, with timing being the critical determinant of the inflammatory and cardiovascular impact of estrogen. The authors suggest that there are temporal effects of estrogens in SLE, with estrogens promoting humoral immunity during subclinical disease but protecting against inflammation and disease progression in adulthood. It is well established that 17β-estradiol binds to its cog-nate receptors (ie, estrogen receptorα and estrogen receptorβ) to initiate extranuclear cytosolic signaling pathways and nuclear expression of specific genes by associating with transcriptional cofactors. Nongenomic mechanisms trigger downstream signaling events through rapid post-translational modifications of numerous membrane and cytosolic signaling molecules, including mitogen-activated protein kinase, …