Individual glucocorticoid sensitivity in the human

Sammanfattning: The expanding use of inhaled and intranasal glucocorticoid (Gc) preparations for treatment of mildto-moderate asthma and allergic rhinitis has in the last decade greatly increased the number of adults and children chronically exposed to exogenous glucocorticoids. In general, current topical glucocorticoid therapies appear to be well tolerated. However, clinical impressions exist that the response to glucocorticoid therapy varies between individuals, and that there may be individual differences in glucocorticoid sensitivity. We investigated the regulation and functional limitation of the hypothalmic-pituitary-adrenal (HPA) axis in a normal healthy population, and assessed possible markers of tissue-specific glucocorticoid sensitivity. The first study (I) addressed the question whether topical glucocorticoids administrated intranasally affected specific glucocorticoid receptor regulated genes in circulating lymphocytes, as well as affected the HPA axis as measured by 24-hour urinary free cortisol (UFC) and serum cortisol. Serum osteocalcin was also measured. We found effects on all measured parameters, which were receptordependent and reversible, indicating systemic effects within a biological and physiological range. Although the HPA axis was suppressed, the adrenal response remained intact as indicated by insulin tolerance test. Expression levels of GR and MTIIa mRNA in nasal mucosa were evaluated in the second study (II) and found to be potential tissue-specific markers of glucocorticoid sensitivity, exhibiting differences in patterns of response between individuals. To provide basic information concerning the normal functional state of the HPA axis in relation to pubertal development, growth and gender, we investigated in the third study (III) the basal serum cortisol circadian rhythm in a group of 238 healthy normal boys and girls with an age-range between 2.2 and 18.5 years. The study provided evidence of a large inter- individual variability and intraindividual stability of serum cortisol levels. No correlation was found between cortisol and age, gender, weight, height, body composition or pubertal stage. In the fourth study (IV), we evaluated the suitability of the low-dose 0.2 mg dexamethasone suppression test (DST) and the low-dose adrenocorticotropin hormone (ACTH) stimulation test in assessing individual feedback sensitivity of the HPA axis. We found that both tests adequately differentiated individual response patterns, and provided evidence that the HPA axis has an intrinsic activity that appears to be set for a given individual. In the fifth study (V), we found an inversed correlation between the magnitude of cortisol response to ACTH stimulation and basal cortisol concentrations, indicating an enhanced cortisol response associated with lower basal cortisol concentrations and/or a blunter or subsensitive response associated with higher basal cortisol concentrations. In summary, within the normal healthy population there are differential neuroendocrine responsesto stimulation and suppression that may lead to or be derived from differences in glucocorticoid negative feedback sensitivity. Evaluations of tissue-specific GR regulation linked with 14PA axis activity may be a way to further explore Gc sensitivity in the human and the pathophysiology of inflammatory disease. A better knowledge of the covariance between central regulatory mechanisms and tissue-specific responses may be contributive to the optimal treatment of inflammatory disorders, as well as in the selection of agents, doses, and/or schedules for individual therapies.