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Review
. 2012 Aug;62(3):210-8.
doi: 10.1016/j.yhbeh.2012.02.024. Epub 2012 Mar 3.

Stress-induced sex differences: adaptations mediated by the glucocorticoid receptor

Chase H Bourke  1 , Constance S Harrell, Gretchen N Neigh
Affiliations
Review

Stress-induced sex differences: adaptations mediated by the glucocorticoid receptor

Chase H Bourke et al. Horm Behav. 2012 Aug.

Abstract

Clinical evidence has indicated that women are more susceptible to stress-related and autoimmune disorders than men. Although females may be more susceptible to some disease states, males do not escape unscathed and are more susceptible to metabolic dysfunction. The hypothalamic-pituitary-axis plays a pivotal role in the sexually dimorphic effects of chronic stress through alterations in negative feedback. Recent evidence has implicated the glucocorticoid receptor and its co-chaperones in the etiology of psychiatric and somatic diseases. Gonadal hormones heavily interact with both glucocorticoid receptor expression and glucocorticoid receptor action either through direct or indirect effects on proteins in the chaperone and co-chaperone complex. Diverse systems including the hypothalamic-pituitary-axis, the immune system, and metabolism are affected differently in males and females, possibly through the glucocorticoid receptor system. New considerations of glucocorticoid regulation through the co-chaperone complex in the brain will be vital to the development of treatment strategies for men and women afflicted by neuropsychiatric and somatic disorders.

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Conflict of interest statement

Conflicts of Interest

CH Bourke and CS Harrell declare that they have no conflicts of interest.

GN Neigh receives grant funding from NIMH, AHA, NARSAD, GSK, and Emory University.

Figures

Figure 1
Figure 1
The hypothalamic-pituitary-adrenal axis. External stressors cause initiation of the HPA axis by first stimulating CRF neurons in the hypothalamus. Corticotropes in the pituitary release ACTH that activates adrenal output of cortisol. Negative feedback inhibition loops return the system towards homeostasis. The hypothalamus also controls the pituitary-gonadal axis. In males, stress has been shown to activate androgen release that plays a direct or indirect role in negative feedback (A). Estrogens and proestogens in females may activate the HPA axis or disrupt negative feedback in females (B).
Figure 2
Figure 2
Involvement of hormones in the regulation of glucocorticoid receptor translocation. Corticosterone/cortisol (CORT) binds the homodimer of GR. Estradiol (E2) can decrease (−) GR expression. Progesterone (P4) acts as an agonist (+) of FKBP5 that can in turn block GR translocation. BAG1 blocks GR translocation (−) but PPID may act in opposition to facilitate GR translocation (+). Once GR is shuttled into the nucleus, it binds to SRC1 (+) at the glucocorticoid response element (GRE) to facilitate gene expression. GRE facilitated gene expression plays diverse roles in physiological mechanisms.
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