Stress and the function of the hypothalamicpituitaryadrenal axis

The hypothalamic—pituitary—adrenal (HPA) axis regulates the secretion of cortisol. The net result of the output of cortisol from the adrenals is dependent on central stimulatory events and feedback inhibitory mechanisms. The central regulation takes the shape of a diurnal rhythm, which in humans consists of high activity in the early morning hours and low activity in the afternoon/evening. This basic pattern is changed by the experience of a variety of factors which are often grouped together under the common description of 'stress'.

'Stress' may be defined as factors which disturb the homeostasis of several neuroendocrine and autonomic systems. A more recent definition is the disturbance of allostasis. An example of allostasis is the maintenance of a normal adaptation of blood pressure to posture, or insulin secretion after a meal (McEwen 1998). Stress reactions have been defined by Henry & Stephens (1977) and may be divided into two distinct classes. One is the fight—flight reaction where a challenge is met by a typical neuroendocrine—autonomic reaction, primarily involving the sympathetic nervous system with elevation of heart rate and blood pressure. When the threat is dealt with successfully additional hormonal changes are occurring, which in males include an increase in testosterone production.

Another type of reaction is a depressive, defeat reaction, also described as a situation of helplessness. This reaction is seen when the threat is perceived as overwhelming and cannot be coped with. Mental depression also follows this reaction as well as typical neuroendocrine—endocrine reactions, including activation of the HPA axis with elevated cortisol secretion. When this is frequently repeated or chronic, other consequences follow. A primary reaction seems to be a delayed 'down-winding' of the response, with cortisol elevation remaining for longer than normal after a challenge. A second step is diminished responsiveness of the HPA axis. An early consequence of this seems to be decreased morning cortisol levels in humans. Finally a low, poorly responsive HPA axis results. Such neuroendocrine 'burn-out' has been described in war veterans and holocaust victims (McEwen 1998).

Along this pathway other neuroendocrine and autonomic adaptations are occurring. The growth hormone and hypothalamo—pituitary—gonadal axes are inhibited by the elevated HPA axis activity at several levels (Chrousos & Gold 1992). This results in decreased secretion and low concentrations of sex steroid and growth hormones. In addition, when the activity of the HPA axis is sufficiently down-regulated there seems to be a parallel activation of the sympathetic nervous system, which might be seen as a compensatory adjustment in an attempt to maintain homeostatic conditions (Plotsky et al 1989).

The activity of the HPA axis is controlled by a feedback inhibition mechanism where central glucocorticoid receptors are involved. When cortisol is bound to these receptors the activity of the HPA axis is diminished. When challenged with repeated activation of the HPA axis this control mechanism becomes less efficient, first apparently by a decrease of glucocorticoid receptor (GR) density and later by structural changes, including atrophy of the dendrites coupled to the inhibitory mechanism of the GR. Eventually brain substance loss occurs, which is visible as atrophy and the formation of lacunae. This is seen in Cushing's syndrome (with severe, constant overproduction of cortisol), in melancholic depression (another condition with chronically elevated cortisol), and in war veterans (presumably as a result of long-term, severe stress reactions in the battlefield). At which stage such

FIG. 1. The associations between stress reactions and pathways to disease generation. Activation of the HPA axis is followed by Cortisol secretion, particularly when insufficiently controlled by the feedback loop involving central glucocorticod receptors (GRs). Androgens, probably partly of adrenal origin, are important in women. When prolonged, this activation causes insulin resistance and visceral accumulation of body fat, both cornerstones of the metabolic syndrome. A parallel activation of the central sympathetic nervous system is followed by hypertension and increased mobilisation of free fatty acids (FFA), which amplify insulin resistance. For details, see Bjorntorp (1996, 2002). CRH, corticotropin-releasing hormone; ACTH, adrenocorticotropic hormone; n.s., nervous system.

FIG. 1. The associations between stress reactions and pathways to disease generation. Activation of the HPA axis is followed by Cortisol secretion, particularly when insufficiently controlled by the feedback loop involving central glucocorticod receptors (GRs). Androgens, probably partly of adrenal origin, are important in women. When prolonged, this activation causes insulin resistance and visceral accumulation of body fat, both cornerstones of the metabolic syndrome. A parallel activation of the central sympathetic nervous system is followed by hypertension and increased mobilisation of free fatty acids (FFA), which amplify insulin resistance. For details, see Bjorntorp (1996, 2002). CRH, corticotropin-releasing hormone; ACTH, adrenocorticotropic hormone; n.s., nervous system.

changes are reversible is not certain, but it seems unlikely that severe topographic losses can be normalized (McEwen 1998).

As described above, the reaction to stress involves a large number of reactions where the central sympathetic nervous system and the HPA axis are primary players. The inhibitions of other central neuroendocrine axes are probably secondary to the activation of the HPA axis but form an integrated part of the stress reaction participating in the damaging somatic consequences.

Both of these reaction types are often mixed, particularly in humans, and it may be difficult to separate one from the other. The peripheral consequences of stress reactions are therefore often a mixture of neuroendocrine/endocrine and autonomic reactions. As will be described later, such prolonged reactions are damaging to bodily systems and may end up in serious diseases (see schematic summary in Fig. 1).

0 0

Post a comment