EFFECTS ON HYPOTHALAMO-PITUITARY-ADRENAL (HPA) AXIS

ICS have been found to affect the hypothalamo-pituitary-adrenal axis [4]. Exogenous corticosteroids act on the hypothalamus and anterior pituitary gland, and cause a negative feedback which attenuates the release of cortisol from the adrenal cortex [5]. This hypo-stimulation causes shrinkage of the adrenals due to disuse. This suppressive effect of corticosteroids is only problematic if the exogenous stimulus is removed suddenly (i.e. inhalers discontinued), or if a greater cortisol response is required during the introduction of stressful stimuli e.g. infection, surgery, or trauma. The lack of an adequate endogenous glucocorticoid response (due to adrenal atrophy) would result in an adrenal insufficiency crisis.

Several studies have compared the effects of different ICS on the HPA axis and have assessed for a dose response relationship. Low dose ICS (0.4 mg/day), regardless of the device or drug, have not shown to cause adrenal suppression [6]. Contrasting results do exist however as these studies were conducted over a short period of only two weeks [7] and one of these was not blinded [8] leading to potential confounders.

With higher doses (>0.4 mg/day), Clark et al. showed fluticasone administered to asthmatic children via a large volume spacer caused adrenal suppression as measured by urinary cortisol. Budesonide however at the same dose did not have this effect [9]. In a similar test in asthmatic adults comparing fluticasone and budesonide administered via metered-dose inhalers, only 8.3% patients had low urinary cortisol levels with budesonide, whilst 58% of patients on fluticasone were seen to have low urinary cortisol levels [10].

On comparing high dose ICS given via the same device, fluticasone propionate and beclomethasone dipropionate have more of an effect on the HPA axis than budesonide [9, 11]. Thus it can be concluded that fluticasone is more potent at inhibiting the HPA axis than budesonide and also this suppression is dose related.

In order to assess whether patients on ICS would be able to mount a response to stressful situations, stimulation with high dose exogenous corticotropin such as cosyntropin is required. Such studies have been conducted with long term beclomethasone dipropionate with no concomitant use of oral corticosteroids. Of the 11 patients on higher doses of ICS, 4 had low serum cortisol levels pre- and post- cosyntropin test [12]. Thus ICS at higher doses upset the response required to stressful stimuli.

Todd carried out a survey to inquire whether ICS caused adrenal crisis in children and adults. Of the 28 children meeting the study criteria, 22 had an episode of acute hypoglycemic events where they presented with reduced conciousness, coma or convulsions. In one case, the child’s death was thought to be caused by adrenal insufficiency as demonstrated by adrenal hemorrhages and cushingoid features. In the study population (n=33), 30 subjects were found to have an impaired response to the short synacthen stimulation test. Moreover there were 37 episodes of adrenal crisis. The cause was found to be related to cessation or a reduction in the ICS dose [13]. This observation is consistent with the studies that prove ICS diminish the ability of the adrenals to mount a response to stress. 76% of adrenal crisis episodes in this survey were in patients on high dose ICS. In addition most of the episodes include the use of fluticasone despite it being the least prescribed ICS in the patient population [14, 15]. This is consistent with a meta-analysis showing that fluticasone was more effective in suppressing the adrenals vs budesonide [5, 15]. The higher lipophilic properties and longer half-life [16] of fluticasone may explain this difference. Fluticasone is able to distribute effectively due to its highly lipophilic nature, and its long half-life means it is able to exert its adrenal suppressive effects for an extended period [17]. This may also explain why fluticasone can be used to wean patients off oral corticosteroids i.e. high dose fluticasone has systemic effects comparable to that of oral corticosteroids [18].

With the abundance of data suggesting that ICS do affect the HPA axis, clinicians should regularly assess adrenal function particularly in patients on high doses of fluticasone [13]. Though budesonide may have a lesser effect on HPA, ciclesonide and flunisolide, which are newer ICS molecules, have been assessed for effects on the HPA, and have been found to possess reduced effects on the HPA [19, 20] and may be better treatment options in patients where this is of concern.

Top 18 why are inhaled steroids used to treat asthma and copd edit by Top Q&A

Top 19 why is olipop so expensive

Top 15 why is abbott in a wheelchair

Top 20+ why are schools closed today