The above subgroups of the functional status of the HPA axis represent extremes in terms of the resiliency of the HPA axis. Although strongly genetically determined (71), environmental and social factors also affect the circadian rhythm of the HPA axis (72). The question arises whether there are time- and stress-related changes in patterns of HPA axis activity and regulation, and if it is possible to tentatively define stages of such HPA axis affliction. A first stage then would be a normal function of the HPA axis, defined as a normal circadian rhythm with high morning and low afternoon-evening cortisol levels, and normal feedback control of GRs. Total cortisol output is regulated within the normal range and this is associated with optimal health. A second stage is seen upon acute stress where central regulation of HPA axis rhythm is maintained as well as the feedback control. The growth and reproductive axes are not affected. Cortisol secretion will, however, be elevated with peripheral consequences if prolonged. A third stage appears when frequently repeated stress challenges the central regulation of HPA axis function. The GRs will be downregulated (26,73), resulting in a poor feedback control of ACTH and cortisol secretion. The elevated cortisol secretion will then eventually become low. This prolonged activation of the HPA axis will also suppress the GH and sex steroid secretions (23). The peripheral consequences will now be a full-blown metabolic syndrome. A fourth and final stage is that of chronic stress, with a 'burn-out' of central regulatory systems (25,26,74), resulting in a net decrease of cortisol output and inhibition of other endocrine axes resulting in a metabolic syndrome. These stages are summarized in Table 23.2.
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