Sexually Dimorphic Actions of Glucocorticoids Provide a Link to Inflammatory Diseases with Gender Differences in Prevalence

Abstract

Males and females show differences in the prevalence of many major diseases that have important inflammatory components to their etiology. These gender-specific diseases, which include autoimmune diseases, hepatocellular carcinoma, diabetes, and osteoporosis, are largely considered to reflect the actions of sex hormones on the susceptibility to inflammatory stimuli. However, inflammation reflects a balance between pro- and anti-inflammatory signals, and investigation of gender-specific responses to the latter has been neglected. Glucocorticoids are the primary physiological anti-inflammatory hormones in mammals, and synthetic derivatives of these hormones are prescribed as anti-inflammatory agents, irrespective of patient gender. We explored the possibility that sexually dimorphic actions of glucocorticoid regulation of gene expression may contribute to the dimorphic basis of inflammatory disease by evaluating the rat liver, a classic glucocorticoid-responsive organ. Surprisingly, glucocorticoid administration expanded the set of hepatic sexually dimorphic genes. Eight distinct patterns of glucocorticoid-regulated gene expression were identified, which included sex-specific genes. Our experiments also defined specific genes with altered expression in response to glucocorticoid treatment in both sexes, but in opposite directions. Pathway analysis identified sex-specific glucocorticoid-regulated gene expression in several canonical pathways involved in susceptibility to and progression of diseases with gender differences in prevalence. Moreover, a comparison of the number of genes involved in inflammatory disorders between sexes revealed 84 additional glucocorticoid-responsive genes in the male, suggesting that the anti-inflammatory actions of glucocorticoids are more effective in males. These gender-specific actions of glucocorticoids in liver were substantiated in vivo with a sepsis model of systemic inflammation.

Sex-specific effects of estrogen and androgen on gene expression in human monocyte-derived osteoclasts

“…Sex differences in response to therapeutic agents based on both pharmacokinetic and pharmacodynamic factors are being increasingly recognized [Chen et al, 2007;Franconi et al, 2007]. There are sexually dimorphic effects of glucocorticoids on gene expression in rat liver, effects potentially relevant to sex differences in susceptibility to inflammatory disease [Duma et al, 2010]. These findings indicate that a more complete understanding of the mechanisms of sex differences of responses at the gene level will be an important step in developing the most effective personalized therapies.…”

Human Glucocorticoid Receptor β Regulates Gluconeogenesis and Inflammation in Mouse Liver

“…In this study, we took advantage of an AAV-mediated gene transfer method to study the function of hGR␤ in mouse liver, a classic glucocorticoid-responsive organ (20). We subcloned Flagtagged hGR␤ cDNA into an AAV vector carrying liver hepatocytespecific hAAT promoter to achieve hepatocyte-specific hGR␤ expression ( Fig.…”

CDC23 regulates cancer cell phenotype and is overexpressed in papillary thyroid cancer

“…This suggests that the difference in CDC23 expression level by gender is not likely to be due to sex hormone difference between women and men. Other possible reasons for the difference in CDC23 expression in PTC by gender may be due to activating oncogenic changes which may occur at different frequencies by gender, differential effect of environmental and dietary factors by gender, and secondary changes that occur differently during cancer progression by gender (Nakagawa et al 2009, Duma et al 2010, Rahbari et al 2010, Lista et al 2011, Sighoko et al 2011. The complex possible mechanisms that may regulate CDC23 expression would need to be studied in the future to explain why this gene is differentially expressed in PTC by gender.…”