Common asthma steroids linked to side effects in adrenal glandsSuppression of the hypothalamo—pituitary—adrenal axis with the potential risk of adrenal crisis is adrenal insufficiency due to inhaled corticosteroids recognized complication of therapy. There are challenges to the use of the SST in routine clinical practice, including both the staff and time constraints and a significant recent increase in Synacthen cost. Methods We performed a retrospective analysis to determine ace tren trenbolone prevalence of adrenal suppression due to prescribed GCs and the insufifciency of a morning serum cortisol for rapid assessment of adrenal reserve adrenal insufficiency due to inhaled corticosteroids the routine clinical setting. Of patients taking oral, topical, intranasal or inhaled GC therapy for non-endocrine conditions, In patients taking inhaled Cirticosteroids without additional GC therapy, A basal serum cortisol concentration has utility in helping determine which patients should undergo dynamic assessment of adrenal function.
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Suppression of the hypothalamo—pituitary—adrenal axis with the potential risk of adrenal crisis is a recognized complication of therapy. There are challenges to the use of the SST in routine clinical practice, including both the staff and time constraints and a significant recent increase in Synacthen cost. Methods We performed a retrospective analysis to determine the prevalence of adrenal suppression due to prescribed GCs and the utility of a morning serum cortisol for rapid assessment of adrenal reserve in the routine clinical setting.
Of patients taking oral, topical, intranasal or inhaled GC therapy for non-endocrine conditions, In patients taking inhaled GCs without additional GC therapy, A basal serum cortisol concentration has utility in helping determine which patients should undergo dynamic assessment of adrenal function. Glucocorticoids GC have a diverse array of functions affecting every tissue in the body. GCs are essential for life, and both excess and deficiency are associated with increased mortality 1 , 2.
In patients with an intact hypothalamo—pituitary—adrenal HPA axis, endogenous secretion of cortisol from the adrenal cortex is under the control of adrenocorticotropic hormone ACTH from the anterior pituitary 3 , 4. The SST has been validated against the gold standard of insulin-induced hypoglycaemia to provide an accurate reflection of adrenal cortisol reserve 5 , therefore representing the most widely used tool for diagnosing adrenal insufficiency.
There are significant challenges to the use of the SST in clinical practice. These challenges include both the staff and time needed to perform the SST, a well-documented recent shortage of Synacthen and a subsequent significant increase in Synacthen cost.
Endocrine diseases affecting the adrenal or pituitary gland are important causes of primary and secondary causes of adrenal insufficiency respectively 6. However, prescribed GCs can also cause long-term suppression of the HPA axis and, consequently, adrenal atrophy and an inability to mount an adequate cortisol response to stress, rendering patients at an increased risk of adrenal crisis.
Adrenal crisis is a medical emergency necessitating hospital admission, resuscitation with i. The therapeutic indications and clinical benefit associated with GC treatment prescribed for underlying inflammatory conditions are not in doubt. Long-term prescription rates for oral GCs have increased, as has the use of inhaled GC therapy As a result, suppression of the HPA axis may be frequent and potentially overlooked.
Dynamic assessment of the HPA axis using the SST has not been widely reported in the literature in the setting of iatrogenic adrenal suppression.
Furthermore, the decision to undertake dynamic HPA axis testing in patients taking prescribed GCs is often based upon the presence of symptoms that may be suggestive of adrenal insufficiency, but these can be vague and often non-specific Importantly, there are currently no published data to help guide the clinician to decide in which patients to undertake assessment of adrenal cortisol reserve. Firstly, we have aimed to determine the prevalence of adrenal insufficiency in patients undergoing SSTs across all medical specialties, and specifically the prevalence of adrenal insufficiency due to prescribed GCs.
Secondly, we have analysed whether a morning serum cortisol can guide the clinician as to which patients are likely to have an intact HPA axis, and thus to rationalize further investigation and management.
In patients treated with oral GCs, these were suspended for h prior to testing. For patients with acute pituitary insult surgery or apoplexy , the SST was delayed for a minimum of at least 4 weeks after surgery or presentation, as earlier assessment can result in false positive passes, since adrenal atrophy only develops 4 weeks after the insult Clinical characteristics of individuals were recorded, including age, sex, indication for the SST and the use of GC medication including dose and route of administration.
Patients on GC replacement therapy as a consequence of adrenal or pituitary disease were classified according to their underlying endocrine condition rather than in groups associated with GC administration.
Similarly, patients with CNS disease including tumours were classified separately from those prescribed GC therapy due to the potential for the underlying disease process to impact upon endogenous HPA axis function. Serum cortisol was analysed on a standard automated competitive immunoassay platform Roche Modular system, Roche where there is no evidence for cross-reactivity with commonly prescribed inhaled GCs The basal and stimulated min cortisol samples were analysed in a single batch.
For comparison of single variables, t -tests have been used or non-parametric equivalents with paired analysis where appropriate. For analyses involving multiple comparisons, one-way ANOVA with Bonferroni's multiple comparison post-hoc correction or, for non-parametric data, Kruskal—Wallis with Dunn's multiple correction tests were used to determine statistical significance. To analyse basal cortisol as a predictor of passing the SST, receiver operator characteristic ROC curves were generated with true positive results sensitivity plotted against false positive 1-specificity.
We performed sub-group analysis in the following categories: To determine if the inclusion of repeat tests would influence the discriminatory value of a morning cortisol to predict adrenal reserve, a further analysis including the entire cohort of all SSTs was performed see Supplementary Table 1 , see section on supplementary data given at the end of this article.
Statistical analysis was performed using the GraphPad Prism 6. Overall, patients In cases where the SST had been performed without a confirmed endocrine diagnosis, or in patients not receiving GC therapy, failure rates were low 0—8. The results of SSTs in patients divided according to indication.
In total, SSTs were performed to determine adrenal reserve in patients who had been prescribed GC therapy indications 1 and 2 of Table 1. The prevalence of SST failure in this cohort was Patients with pituitary, adrenal and CNS disease indications 3—8 from Table 1 were then excluded.
Patients were further subdivided based upon their GC therapy status: However, failure rates were significantly higher in patients currently taking GC therapy In patients currently taking prescribed GCs, failure rates were highest in those patients taking oral therapy The impact of glucocorticoid therapy status upon SST results. Indications are as follows: SST failure rates were The min serum cortisol levels were significantly lower in patients on the highest doses of both beclometasone and fluticasone in comparison with those patients on lower doses Fig.
Excluding patients with underlying pituitary, adrenal or CNS disease, current glucocorticoid therapy is associated with increased rates of SST failure A. SST failure is common across all routes of glucocorticoid administration, although it is most frequent in patients on oral therapy B. The impact of inhaled glucocorticoid therapy on the prevalence of adrenal suppression C, D, E and F.
There were no significant differences in clinical characteristics in the patient cohorts when comparing across prescribed dose of inhaled GCs between different inhaled GCs or those who failed or passed the SST data not shown.
Baseline serum cortisol as a predictor of min cortisol levels during an SST. The AUC, best-fit cortisol value and cut-off cortisol values for respective specificities and sensitivities according to age, sex, menopausal status and other indications including endocrine diagnoses are presented in Supplementary Table 2 , see section on supplementary data given at the end of this article. In this study we have demonstrated a high prevalence of adrenal insufficiency associated with GC treatment in the largest cohort described to date, with an alarming prevalence in those patients taking GC therapy for non-endocrine disease.
Indeed, SST failure rates were higher in those taking GC therapy than in those with underlying pituitary disease. Furthermore, epidemiological data from general practice records has demonstrated a link between GC prescriptions and the risk of cardiovascular events and heart failure Some studies have suggested that adrenal suppression is not tightly linked to the duration and dose of oral GCs 16 , 21 ; however, this is not the case in all studies 22 and this may well reflect inter-individual variability in GC action and metabolism, including the activity of CYP3A4, the major pathway for the inactivation of most prescribed GCs 23 , 24 , 25 , The variability in results may reflect the use of inappropriate assessments of HPA axis and paucity of dynamic testing including SSTs; isolated measurements of serum cortisol are difficult to interpret and can be misleading.
Our data have shown a dose dependency in the SST response with inhaled GCs and are in agreement with evidence from the published literature suggesting that adrenal suppression is most frequent at the highest doses of inhaled GCs 31 , although we did observe suppression in some patients taking lower doses.
In addition, it is important to recognize that adrenal suppression can persist for prolonged periods after discontinuation of GC therapy Whilst we have been able to demonstrate the magnitude of a clinical problem that is more extensive than is widely appreciated, it is fundamentally important to understand its clinical consequences. Current clinical data in this regard are lacking. We have previously shown that decreased adrenal reserve as a consequence of inhaled GCs is associated with reduced quality of life in patients with bronchiectasis 30 and the use of inhaled GCs in patients with chronic obstructive pulmonary disease COPD is known to increase the risk of type 2 diabetes and pneumonia 11 , In the setting of intensive care, a significant proportion of patients have functional adrenal insufficiency and this has been associated with a poorer outcome Taken together, these observations raise the intriguing possibility that poor clinical outcome in patients on inhaled GCs may be due at least in part to HPA axis suppression, adrenal insufficiency and the consequent inability to mount an adequate cortisol stress response, and this has significant implications for the therapeutic approach to these patients Supplementary Table 3 and Supplementary Figure 1 , see section on supplementary data.
Routine screening for adrenal insufficiency in the context of inhaled GCs is not currently recommended. The magnitude of the clinical problem may be daunting, and making a case for routine assessment of HPA axis function in all patients on inhaled GCs may be prohibitive considering the workload and cost implications. To date, dynamic stimulation tests such as the SST and the ITT are considered mandatory for reliable investigation of adrenal reserve 13 , 35 , The utility of a basal cortisol in predicting adrenal reserve has been examined previously 37 , Using a single morning cortisol as the first screening step has the potential, in some circumstances, to reduce the need for dynamic tests and as a consequence to decrease cost and workload and reduce unnecessary tests for patients.
In addition, the recent well-publicized worldwide shortage of Synacthen has highlighted the role that alternative assessments of HPA axis function may play. Through our systematic approach to assessing adrenal function in a large cohort of patients, we are now able to propose an algorithm Fig.
In patients prescribed inhaled GCs and in the absence of symptoms of adrenal insufficiency, we recommend measuring annual baseline serum cortisol concentrations as a useful tool in assessing adrenal GC reserve. A similar approach could be used in patients with underlying adrenal or pituitary pathology, limiting unnecessary test and the potential for significant cost savings. Putative algorithm to aid in the rationalization of assessment of the HPA axis in patients taking inhaled glucocorticoids.
The management of patients with adrenal insufficiency in the context of endocrine disease has been reviewed extensively 6.
However, there are currently no guidelines or published studies that have determined the optimal management strategy for those patients with adrenal insufficiency due to prescribed GCs. For those on oral therapy, continuation of treatment as clinically indicated is appropriate, followed by weaning of the dose if the duration has been longer than 2 weeks.
For those patients taking inhaled GCs, the situation is more complex, as the inhaled GC cannot provide the adequate systemic actions that are needed at times of stress. A combined respiratory and endocrinology approach is appropriate. If possible, inhaled GC doses may be reduced, but this will be entirely dependent upon the underlying respiratory condition. Repeat SST should be performed, especially if modification to the inhaled GC therapy has been undertaken to assess the potential return of HPA axis function.
There are limitations with the current analysis, although it does represent a cross-sectional analysis of unselected clinical data across all medical specialties. The data are retrospective and the decision to perform the SST was based on clinical indication as assessed by the individual clinician leading to a potential positive selection bias that may overestimate prevalence rates.
Duration of GC treatment is likely to be important, as is the length of time since cessation of GC therapy. However, data from our electronic patient records does not allow accurate assessments of the duration of therapy or the time since therapy had been discontinued.
The cut-off levels in this paper relate specifically to the assay used, and interpretation of these data should be made in the context of local cortisol assays as well as the methodology for the SST i. We advocate utilising the i. In addition, robust longitudinal clinical outcome data was not available from our electronic database, which is of fundamental importance. The explanation for this is not clear and may relate to new diagnoses of endocrine or other, e. Importantly, some of these tests were performed in the intensive care setting where the underpinning mechanisms causing compromised adrenal reserve are still unknown.
In summary, the prevalence of adrenal insufficiency due to prescribed GCs is high and almost certainly represents the commonest cause of compromised adrenal function. Importantly, we have highlighted the potent, dose-dependent ability of inhaled GCs to suppress endogenous HPA axis function, and identified the utility of a morning cortisol level in guiding the clinician as to which patients may need dynamic assessment of adrenal reserve.
Futures prospective studies are needed to accurately define the clinical consequences of adrenal suppression for patients prescribed inhaled GC therapy and determine the optimal medical management for these patients. This is linked to the online version of the paper at http: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
C Boot and R Webster collected the biochemical data and helped to write the manuscript.