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The idea that frequent or persistent challenges of the HPA axis may constitute a base for pathophysiological consequences in the periphery of the body stems from the central role played by the HPA axis in homeostatic processes. Although biologically plausible, this complex hypothesis has been difficult to study in humans (17), presumably as a result of several inherent problems.

The pattern of ACTH and cortisol variations shows an early morning peak, declining levels during the daytime and minimal secretory activity in the evening. This secretory pattern is brought about by the nervous system. There is, however, no sharp distinction between the endocrine and nervous systems, and in the hypothalamus and the pituitary there is a close connection between these two systems that integrates the two into one control unit. The CRH-secreting neurons, located within the paraventricular nuclei (PVN) (18), receive afferent regulatory signals from different parts of the brain. Stimulatory inputs arise from the suprachiasmatic nucleus (the regulator of circadian rhythms), the amygdala and the raphe nuclei (19,20), while inhibitory inputs on CRH secretion arise in the hippocampus and in the locus coeruleus. The CRH

neurons are excitatory, influenced by cholinergic and serotoninergic central pathways (21). Inhibitory effects are exerted by y-aminobutyric acid (GABA) (20). Catecholamines can exert both inhibitory and excitatory effects (22). Furthermore, stimulation of hypothalamic opioid peptide (POMC-producing) neurons will inhibit the release of CRH from the PVN (23).

In summary, the central nervous system provides inputs in terms of registrations by the senses, modified by experience and coping ability, and the integrated resulting signals transferred to the hypothalamus. These afferent signals are balanced by endocrine feedback regulation, mediated via glucocorticoid receptors (GR) in the hippocampus and the amygdala (24-26). Feedback information allows the HPA axis to adjust appropriately the cortisol secretion from the adrenals.

When measurements are performed aimed at elucidating the natural, spontaneous, everyday activity of the HPA axis, several prerequisites have to be considered. The regulation of the HPA axis is greatly affected by environmental disturbances. For instance, the artificial milieu of a laboratory or a hospital may distort normal activity, and even minor venepuncture per se can significantly increase cortisol concentration in serum. Urinary cortisol measurements offer a tool to circumvent this source of bias. However, urinary measurements do not reveal the secretory pattern of cortisol, which is, as will be seen in the following, vital information. Moreover, the technique is usually restricted for practical reasons to inpatients.

The assessment of cortisol in saliva provides several advantages over blood cortisol measurements, as the collection procedure is non-invasive and stress free, making it ideal for use in psychoneuroen-docrinological research. Since salivary cortisol sampling is laboratory independent, it can be applied under a variety of field settings. It is well documented that salivary cortisol provides the clinician with a reliable tool for examination of pathological conditions characterized by abnormal cortisol secretion (27-30). Cortisol is lipid-soluble which enables the molecule to diffuse rapidly to the acinar cells of the salivary glands via the bloodstream, and then pass easily through these cells into saliva. Neither maximal stimulation of saliva flow (28) nor minimal secretion of saliva following medication with anticholinergic side effects influences the concentration of cortisol in saliva (27). Moreover, corti sol in saliva represents the unbound ('free') hormone fraction, and reflects accurately the free fraction of cortisol in plasma, despite the conversion of cortisol to cortisone in saliva by 11ft-hydroxys-teroid dehydrogenase (31).

To obtain a biochemical evaluation of the HPA axis activity and regulation that is as complete as possible several details are essential. A normal diurnal variation is a pattern in which cortisol levels are high and varying in the morning and from 1600 hours to midnight less than 75% of the morning values. This must be recorded together with the total cortisol levels. Since the HPA axis is subject to periodic or cyclic changes (19), the measurement of cortisol levels at various times of the day to determine the presence or absence of a circadian rhythm is crucial. Furthermore, the response to external stimuli is informative, and the physiological input by food intake can be measured, if the stimulus is standardized. Various centrally occurring challenges of the HPA axis, in terms of stress, are of fundamental importance, and as stressors are perceived differently, individual coping ability has to be taken into account. This is accomplished by reports by the proband of perceived stress.

In addition to these measurements of basal and stimulated HPA axis activity, the response to exogenous glucocorticoids is required to detect abnormal feedback regulation of ACTH and cortisol secretion (32). Conventionally dexamethasone is given in a dose of 1 mg, which is usually followed by a complete inhibition of ACTH and cortisol secretion, except in subjects with Cushing's syndrome. Preliminary examinations showed that utilizing a low dose (0.5mg x 1) of dexamethasone (33) reveals mild abnormalities in the ability of the central glucorticoid receptor (GR) to control the HPA axis by feedback inhibition that cannot be discovered with the conventional dose of 1 mg (15).

In summary, these different characteristics of the HPA axis activity and regulation were measured by a series of saliva sampling during the day, in which cortisol levels were measured. A sample was obtained in the morning (0800-0900 hours), then at 1145 hours, and 30, 45 and 60 minutes after a standardized lunch at 1200 hours, 1700 hours, and finally just before bedtime. Within these periods, relatively small changes in unstimulated cortisol values occur and therefore a satisfactory estimation of the circadian rhythm can be acquired (34). The cir-cadian rhythm of cortisol secretion was estimated as the variability of cortisol secretion. By addition of all measured values, a measurement of total cortisol secretion was obtained. The response to lunch was calculated as the peak of cortisol after lunch. Stress-related cortisol secretion was calculated as the response of cortisol to simultaneously reported perceived stress. Finally, the low dose (0.5 mg x 1) dexamethasone suppression test was performed similarly at home.

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