Child maltreatment and HPA axis dysregulation: relationship to major depressive disorder and post traumatic stress disorder in females

Summary

A history of child maltreatment increases the vulnerability to the development of Major Depressive Disorder (MDD) and/or Posttraumatic Stress Disorder (PTSD), especially in females. Both MDD and PTSD are associated with a dysregulation of the Hypothalamic-Pituitary-Adrenal (HPA) axis. Dysregulation of the HPA axis may be an important etiological link between child maltreatment and subsequent psychiatric disorder, yet little is known about the relationship between exposure and outcome. The aim of this review is to explore the role of HPA axis dysregulation in the link between child maltreatment and MDD/PTSD among women. Studies of females with MDD frequently indicate a hyperactivity of the HPA axis, and contribute to our understanding of the underlying mechanisms involved in mood dysregulation. Evidence for HPA axis dysregulation in PTSD is less convincing and suggests that timing of the stressful experience as well as the type of the trauma may influence the outcome. The strongest evidence to date suggesting that the development of the HPA axis may be affected by early life stressful experiences comes from pre-clinical animal studies. Together these studies add to our understanding of the role of the HPA axis in psychiatric disorders in relation to stress. The literature on HPA axis function in both children and adults following child maltreatment further highlights the potential relevance of early stress to later onset of major psychiatric disorders. Such knowledge may also contribute to the development of early interventions targeted at primary prevention.

Introduction

It is now widely accepted that psychological stress may alter the internal homeostatic state of an individual. During acute stress, adaptive biochemical responses occur, which include increased adrenocortical secretion of hormones, primarily cortisol (Chrousos and Gold, 1992, Wolkowitz et al., 2001). These responses help an individual to cope with the stressor, but may be detrimental when stressful experiences are extreme or chronic, particularly when these experiences occur early in life (Heim and Nemeroff, 2001).

The stress and trauma of child maltreatment (including child physical abuse (CPA), child sexual abuse (CSA), emotional abuse, and neglect) have therefore drawn the attention of researchers. Child maltreatment may occur as a one-time exposure, or in the form of a chronic stressor, and can be associated with serious psychiatric impairment (MacMillan et al., 2001). Specifically, it is a major risk factor for major depressive disorder (MDD) and posttraumatic stress disorder (PTSD) (Kessler et al., 1997, Kendler et al., 2000, Heim et al., 2001). These disorders are twice as common in females than in males (Kessler et al., 1995, Kessler and Walters, 1998). Many females who develop MDD/PTSD have a childhood history of maltreatment suggesting that the traumatic experiences may be etiologically important to the later development of psychiatric disorders (MacMillan et al., 2001).

Preclinical studies demonstrate that early life stress can influence the development of the hypothalamic–pituitary–adrenal (HPA) axis (Meaney et al., 1996, Liu et al., 2000, Kalinichev et al., 2002). HPA axis dysregulation has also been documented in humans. Patients with MDD have been reported to have elevated cortisol levels while in an episode (Posener et al., 2000, Young et al., 2001). Conversely, in patients with PTSD cortisol levels are reported as both increased (Rasmusson et al., 2001) and decreased (Yehuda et al., 1995, Gelernter et al., 1999). It is suggested that this type of HPA axis dysregulation may be the basis for an important etiological link between child maltreatment and subsequent mood and anxiety disorders (Kendall-Tackett, 2000).

The HPA axis is one of the stress response systems of the body (the other is the sympathetic-adrenal-medullary system), which consists of the hypothalamus, the pituitary gland and the adrenal gland (See Fig. 1). The HPA axis activates and coordinates the stress response by receiving and interpreting information from other areas of the brain (the amygdala and the hippocampus) as well as from the autonomic nervous system (Holsboer, 2001). A hormonal cascade is initiated in response to the stressor with the release of corticotropin releasing hormone (CRH) from the hypothalamus, which stimulates the release of adrenocorticotropin releasing hormone (ACTH) from the pituitary gland. ACTH then triggers the breakdown of pregnenolone within the adrenal cortex into the glucocorticoid, cortisol, which is subsequently secreted into the blood circulation (Fig. 1). Glucocorticoids provide negative feedback at the level of the hypothalamus, the pituitary, and the hippocampus, thereby shutting off the stress response (See Figure 1, Figure 2). The HPA axis provides the adaptive mechanisms needed to maintain homeostasis in times of increased stress. Although, these responses are protective in acute situations, they can be damaging if the hormones are overproduced or dysregulated over long periods of time (McEwen, 2002).

In humans, cortisol is the principal glucocorticoid and is the primary regulator of resting activity of the HPA axis by its negative feedback effects on ACTH and CRH. It is secreted from the adrenal cortex into the blood circulation as a free hormone, where it binds to the plasma protein, corticoid-binding globulin (CBG). Under basal conditions, about 5% of total cortisol is in the free, unbound form and it is this amount that can pass across the blood-brain barrier and is measurable in saliva (Herbert et al., 1982, Goodyer et al., 1996). Thus, the unbound portion of cortisol represents the amount that is biologically active. Free and bound proportions are in dynamic equilibrium, but when cortisol levels are high, CBG capacity becomes limited and the free fraction that can enter the brain will increase dramatically (Herbert et al., 1982). In addition to stress-related increases, cortisol levels may be affected by factors such as: gender (Kirschbaum et al., 1999, Wolf et al., 2001, Netherton et al., 2004); estradiol treatment, use of oral contraceptives and menstrual cycle phase (Kirschbaum et al., 1995, Kirschbaum et al., 1996, Kirschbaum et al., 1999); pubertal status (Angold et al., 1998, Angold et al., 1999); exercise (Kanaley et al., 2001); cigarette smoking (Kirschbaum et al., 1992, Kirschbaum et al., 1993b), and time of day (Weitzman et al., 1971, Kanaley et al., 2001).

Although glucocorticoids are adaptive in the short-term, they can also be detrimental. A disrupted circadian rhythm of cortisol has been frequently reported in depressed patients (Sachar et al., 1973, Posener et al., 2000). High levels of corticoids can induce atrophy in cells in the hippocampus (Sapolsky, 1996, Lupien et al., 1998), an area of the brain, which has a high density of glucocorticoid receptors and is particularly important for (episodic) memory and learning. Studies suggest that glutamate release is increased by elevated glucocorticoid levels, which may increase neurotoxicity to hippocampal cells (McEwen, 2000, Venero and Borrell, 1999). It has been reported that hippocampal volume and performance on a delayed memory test decrease in aging subjects with elevated cortisol levels (Lupien et al., 1998). Increased cortisol levels are therefore associated with decreased hippocampal volume and may endanger the function integrity of the brain, thereby contributing to cognitive dysfunction. A dysregulation of normal glucocorticoid secretion can be harmful and examination of the associated psychopathophysiology is warranted.

This paper explores the role of HPA axis dysregulation in the link between child maltreatment and MDD and PTSD among women. Females are discussed exclusively because they are at greater risk than males for the development of MDD and PTSD.