Hypothalamic-Pituitary-Adrenal Axis Suppression and Inhaled Corticosteroid Therapy

Abstract

In the first part of this two-part review it was noted that inhaled corticosteroids had become the mainstay of treatment for chronic asthma and yet the effects of long-term use of these compounds on the hypothalamic-adrenal-pituitary (HPA) axis were largely being determined by testing methods of limited reliability, especially by morning plasma cortisol measurements. It was established in our examination of the published literature and in our presentation of current knowledge of the structure and function of the HPA axis that safe, accurate and discriminating techniques to assess the functional status of the HPA axis were available. It was concluded that two state-of-the-art tests that have been insufficiently used were the ACTH stimulation test and measurement of the 24-hour integrated serial plasma cortisol concentrations. These two tests can detect adrenal suppression before the appearance of clinical effects. For part 2 of this review we conducted an exhaustive search of the English language clinical and pharmacological literature on the use of inhaled corticosteroids from 1988 until the present time to identify studies in which one or both of these testing methods have been used. We present our analysis of this limited number of studies to determine what accurately can be known of the HPA axis safety profile of three of the most commonly used and investigated inhaled corticosteroids – beclomethasone dipropionate, budesonide and fluticasone propionate. The first finding of significance was that only 50 reports were identified in which information on the HPA axis safety effects of orally inhaled steroids in asthma patients or in clinical pharmacological studies met our inclusion requirements. By analysis of the data presented in these reports we were able to reach the following conclusions: (1) inhaled corticosteroids administered chronically, and prudently, within recommended dose ranges do not endanger the functioning of the HPA axis, (2) the increasing tendency to use higher doses of inhaled corticosteroids on the assumption that there are clear dose-response benefits and no adverse HPA axis effects from long-term high-dose regimens is misguided and not supported by reliable published information, (3) the corollary – that higher corticosteroid potencies (as measured, for example, by skin-blanching activity) can have greater therapeutic effect in lung tissue without greater concomitant systemic activity – is a flawed concept, and (4) the limited clinical and pharmacological data support our part 1 conclusions that discriminating techniques to assess the functional HPA axis status should be an integral part of the drug development process and that further HPA axis function studies are required on existing inhaled corticosteroids – if they lack a rigorous testing history or long-term record of clinical safety.

The “Steroid Dementia Syndrome”: A Possible Model of Human Glucocorticoid Neurotoxicity

“…Although inhaled steroids are substantially less likely to cause systemic side effects than oral or i.v. steroids, systemic effects can occur, especially at high doses (Bender, Ikle, DuHamel, & Tinkelman, 1998;Chrousos & Harris, 1998;Lipworth, 1999;Allen et al, 2003). Only one largescale study, to our knowledge, has systematically assessed the neuropsychological effects of chronically administered nasal beclomethasone in the dose used by BB (Bender et al, 1998).…”

Effects of ciclesonide and fluticasone propionate on allergen-induced airway inflammation and remodeling features

“…It is not excluded that these changes might be related to generalized weight change and are closely related to bone marrow and hormone suppression. 34,35 Corticosteroids have regulatory effects on ASM proliferation induced by mitogens. 36 Suppression of ASM proliferation at less than the baseline level, even at 0.01 mg/kg of both steroids, indicates that ASM proliferation is more susceptible and sensitive to steroid regulation compared with other parameters.…”

Adrenal Insufficiency and Growth Failure Secondary to Inhaled Corticosteroids

“…It has a large volume of distribution, a strong relative binding affinity for the glucocorticoid receptor (18 times that of dexamethasone), and a prolonged receptor binding half-life (10.5 hours), all of which make it more likely to cause adrenal suppression from chronic use. 8 Prolonged treatment with fluticasone can also decrease adrenocortical reserve (as demonstrated by low-dose ACTH stimulation test) even in cases where normal basal cortisol levels are maintained. 8 Our cases are unusual in that the patients paradoxically developed manifestations of adrenal insufficiency while still on treatment with ICS, while at the same time not manifesting any Cushingoid features or signs of glucocorticoid excess.…”

“…8 Prolonged treatment with fluticasone can also decrease adrenocortical reserve (as demonstrated by low-dose ACTH stimulation test) even in cases where normal basal cortisol levels are maintained. 8 Our cases are unusual in that the patients paradoxically developed manifestations of adrenal insufficiency while still on treatment with ICS, while at the same time not manifesting any Cushingoid features or signs of glucocorticoid excess. A suggested explanation for this paradoxical complication is that some patients show differential tissue sensitivity to corticosteroids and that polymorphisms of the glucocorticoid receptor affect corticosteroid sensitivity in a tissue-specific manner.…”