Hypothalamic-pituitary-adrenal axis in corticosteroid-resistant bronchial asthma.

Abstract

We have examined whether the lack of clinical response to corticosteroids seen in corticosteroid resistant (CR) bronchial asthma is reflected in abnormalities of endogenous cortisol secretion and in the sensitivity of the hypothalamic-pituitary-adrenal (HPA) axis in CR subjects by using a modification of the standard dexamethasone suppression test (DST) in response to 0.25 and 1 mg oral dexamethasone. Five corticosteroid-sensitive (CS) and five CR asthmatic subjects were studied on two occasions 1 mo apart. In the first limb of the study subjects received 0.25 mg of oral dexamethasone, and in the second limb they received 1 mg. Urinary cortisol was measured by fluorimetry after extraction, and plasma cortisol and adrenocorticotropic hormone (ACTH) concentrations were estimated by enzyme-linked immunosorbent assay (ELISA) and immunoradiometric assays, respectively. On Day 1, a 24-h urine sample was collected for estimation of urinary free cortisol. On Day 2, a fasting blood sample was taken at 9:00 A.M. for estimation of plasma cortisol and ACTH. At 11:00 P.M., 0.25 mg (1 mg) of dexamethasone was taken orally by each subject. On Day 3, blood was taken at 9:00 A.M. and 3:00 P.M. for similar estimations. The levels of urinary free cortisol (nmol/24 h) and predose plasma ACTH (ng/L) and cortisol (nmol/L) were 199 +/- 42, 27.4 +/- 5.7, and 300 +/- 48 (mean +/- SEM), respectively, in the CS group, and 210 +/- 74, 23.4 +/- 6.7, and 263 +/- 32 (mean +/- SEM), respectively, in the CR group (p > 0.05 for all comparisons). Plasma ACTH and cortisol concentrations were not significantly suppressed in either group after 0.25 mg dexamethasone, but were equally suppressed in both groups to undetectable levels by 1 mg dexamethasone. We conclude that CR asthma is not reflected in an altered secretory rate of endogenous cortisol or in an altered sensitivity of the HPA axis to dexamethasone suppression.

Difficult asthma

“…Indeed, treatment with glucocorticoids should be discontinued, as these patients do develop systemic side-effects to corticosteroids (presumably mediated via the normally functioning endocrine and metabolic pathways) [81]. Long-acting inhaled β 2 -agonists may be useful in these patients.…”

Effect of inhaled corticosteroids on bones and growth

“…The potential for systemic effects of inhaled corticosteroids is considered to be reflected in their activity of suppressing the hypothalamic-pituitary-adrenal (HPA) axis [7]. However, the clinical relevance of such suppression has been questioned [8] and concerns have been raised concerning the possible effects of inhaled corticosteroids on bones [9] and growth [10]. This review examines the effects of inhaled corticosteroids on bone metabolism, bone density and growth in adults and children with asthma, in view of the recent availability of a substantial amount of new information from clinical trials.…”

Personalised prescribing for asthma - is pharmacogenetics the answer?

“…The mechanism for glucocorticoid resistance is not fully understood, although it has been extensively examined. In summary, the defect does not appear to be due to impaired bioavailablity of glucocorticoids (May et al 1980); the secretion of endogenous cortisol or sensitivity of the hypothalamic±pituitary±adrenal axis is not altered (Lane et al 1996); finally, no abnormalities in receptor nuclear translocation, density or binding affinity have been demonstrated (Lane & Lee 1991).…”