Elsevier

Hormones and Behavior

Volume 43, Issue 1, January 2003, Pages 60-66
Hormones and Behavior

Regular article
Neuroendocrine aspects of hypercortisolism in major depression

https://doi.org/10.1016/S0018-506X(02)00016-8Get rights and content

Abstract

A consistent finding in biological psychiatry is that hypothalamic–pituitary–adrenal (HPA) axis physiology is altered in humans with major depression. These findings include hypersecretion of cortisol at baseline and on the dexamethasone suppression test. In this review, we present a process-oriented model for HPA axis regulation in major depression. Specifically, we suggest that acute depressions are characterized by hypersecretion of hypothalamic corticotropin-releasing factor, pituitary adrenocorticotropic hormone (ACTH), and adrenal cortisol. In chronic depressions, however, enhanced adrenal responsiveness to ACTH and glucocorticoid negative feedback work in complementary fashion so that cortisol levels remain elevated while ACTH levels are reduced. In considering the evidence for hypercortisolism in humans, studies of nonhuman primates are presented and their utility and limitations as comparative models of human depression are discussed.

Section snippets

HPA axis physiology in major depression

More than 40 years ago, researchers reported that patients diagnosed with major depression hypersecrete cortisol Board et al 1956, Gibbons and McHugh 1962. Since then, data from a variety of clinical studies clearly indicate that hormones of the HPA axis are dysregulated in patients with major depression Carroll et al 1976, Gold et al 1986; for a review see also Plotsky et al., 1995). Some reports suggest that chronic hypersecretion of cortisol is due to prolonged hypersecretion of

A model of hypercortisolism in monkeys

Although rodents often serve as valuable models in human biomedical research, in keeping with Selye’s initial observations (1946), it has been nearly impossible to produce in experimental studies of rodents a sustained endogenous adrenocortical response Bohus 1969, Daniels-Severs et al 1973, Sakellaris and Vernikos-Danellis 1975, Katz et al 1981, Vernikos et al 1982, Young and Akil 1985, Rivier and Vale 1987. This problem undoubtedly contributed to Selye’s formulation of an “exhaustion” phase

Adult grouping tendencies and cortisol responses to social separation

Squirrel monkeys are gregarious New World primates that typically live in social groups composed of males and females in all stages of life span development (Lyons et al., 1992). A salient characteristic of these groups is the segregation of males and females into same-sex subgroups. Around puberty at 2–3 years of age, juvenile males begin to associate primarily with other males, whereas juvenile females associate with other females Coe and Rosenblum 1974, Coe et al 1988. In free-ranging,

Separation-induced changes in adrenal responsiveness to ACTH

One explanation for the finding that squirrel monkeys hypersecrete cortisol when separated from social companions is that hypercortisolism reflects a deficiency in glucocorticoid-negative feedback mechanisms that normally inhibit the prolonged hypersecretion of ACTH Saltzman et al 1991, Mendoza et al 1992, Lyons and Levine 1994. To test this hypothesis, we initially examined longitudinal morning plasma samples collected from monkeys separated from social companions for evidence of prolonged

Glucocorticoid feedback and hypothalamic drive

As indicated above, social separations induce an initial hypersecretion of both ACTH and cortisol, whereas prolonged social separations result in hypersecretion of cortisol but hyposecretion of ACTH (see Fig. 2). To test the hypothesis that these low circulating levels of ACTH are maintained by glucocorticoid negative feedback, monkeys were separated from groups as in previous studies and longitudinal samples of plasma ACTH and cortisol concentrations were evaluated (Lyons et al., 1999).

Summary and conclusions

In squirrel monkeys, the unexpected loss of social companions mobilizes the HPA axis and results in acute hypersecretion of both plasma ACTH and cortisol (Lyons et al., 1999). However, following prolonged social separation, cortisol remains elevated above preseparation levels, whereas simultaneous reductions occur in ACTH Lyons et al 1995, Lyons and Levine 1994. Following ACTH challenge (with dexamethasone pretreatment), socially separated squirrel monkeys respond with greater, more prolonged

Acknowledgements

This work was supported by the Nancy Pritzker Network, a Stanford University School of Medicine Postdoctoral Dean’s Fellowship, and Public Health Service Grants MH47573 and MH50604.

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