Diminished Cortisol Levels in Subordinate Female Marmosets Are Associated with Altered Central Drive to the Hypothalamic-Pituitary-Adrenal Axis

Background Female marmosets offer a promising primate model of stress-related hypocortisolism, as they undergo chronic reductions in circulating cortisol after becoming subordinate in a social group. In this study, we treated dominant and subordinate female marmosets with the cortisol synthesis inhibitor metyrapone and corticotropin-releasing factor (CRF) to characterize the effects of subordination on central regulation of the hypothalamic-pituitary-adrenal (HPA) axis. Methods Seven dominant and six subordinate female marmosets received CRF (6 μg/kg, intravenous [IV]), following pretreatment with metyrapone (75 mg/kg, by mouth [PO]) or water. Plasma adrenocorticotropic hormone (ACTH) and cortisol concentrations were determined before metyrapone or water treatment and before, 1 hour after, and 2 hours after CRF treatment. Results Following metyrapone treatment, subordinates had similar cortisol levels to dominants but significantly higher ACTH levels. During CRF challenges, cortisol concentrations were lower and ACTH concentrations higher in subordinates, although net integrated responses to CRF did not differ. Cortisol-to-ACTH ratios were consistently lower in subordinates. Conclusions These results confirm previous findings of low cortisol concentrations and blunted adrenal responsiveness in subordinates and suggest that when differences in cortisol levels are eliminated, subordinates exhibit exaggerated hypothalamic drive to the pituitary. These neuroendocrine alterations in subordinate marmosets resemble those in posttraumatic stress disorder patients and adult survivors of child abuse.