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      Incidence of Adrenal Insufficiency and Cushing’s Syndrome After Long-Term Epidural Steroid Injections Over Six Months or Longer: A Preliminary Study

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          Endocrinological complications of an epidural steroid injection (ESI) are rare but dangerous. Nevertheless, despite the associated risks, repeated long-term ESIs are indispensable in some clinical situations. However, only a few reports to date have assessed the safety of this procedure. In this study, we evaluate the incidence of adrenal insufficiency (AI) and Cushing’s syndrome after long-term ESIs.


          This clinical observational study enrolled herniated nucleus pulposus or spinal stenosis patients who had received ESIs over a period of six months or longer. The adrenocorticotropic hormone (ACTH) stimulation test was performed to confirm AI and the late-night salivary cortisol (LNSC) test was performed to diagnose Cushing’s syndrome. To evaluate the hypothalamus pituitary adrenal axis suppression, salivary cortisol (SC) levels were measured on days 0, 1, 7, 21, 28, 35, and 42.


          This study included 17 patients. Among these, two patients (11.8%) developed AI, but no cases of Cushing’s syndrome were reported. There was no predictor for the development of AI. The SC levels tended to increase with time after an ESI (β = 0.003). The slope of the mixed effect model between the AI and non-AI groups showed a significant difference (p value = 0.015). However, the differences in mean SC levels at each time point between the two groups were not significant (adjusted p value = 0.053).


          Long-term ESI use may be associated with AI development. An unexpected adrenal crisis due to AI could be life threatening. Therefore, regular monitoring of adrenal function in patients who have received long-term ESIs may be prudent.

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          Most cited references 23

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          Diagnosis and management of adrenal insufficiency.

          Adrenal insufficiency continues to be a challenge for patients, their physicians, and researchers. During the past decade, long-term studies have shown increased mortality and morbidity and impaired quality of life in patients with adrenal insufficiency. These findings might, at least partially, be due to the failure of glucocorticoid replacement therapy to closely resemble physiological diurnal secretion of cortisol. The potential effect of newly developed glucocorticoid drugs is a focus of research, as are the mechanisms potentially underlying increased morbidity and mortality. Adrenal crisis remains a threat to lives, and awareness and preventative measures now receive increasing attention. Awareness should be raised in medical teams and patients about adrenal insufficiency and management of adrenal crisis to improve clinical outcome.
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            Salivary cortisol determined by enzyme immunoassay is preferable to serum total cortisol for assessment of dynamic hypothalamic--pituitary--adrenal axis activity.

            The aim of this study was to determine whether salivary cortisol measured by a simple enzyme immunoassay (EIA) could be used as a surrogate for serum total cortisol in response to rapid changes and across a wide range of concentrations. Comparisons of matched salivary and serum samples in response to dynamic hypothalamic-pituitary-adrenal (HPA) axis testing. Subjects Healthy women (n=10; three taking oral oestrogens) and men (n=2), aged 23--65 years, were recruited from the community. Measurements Paired saliva and serum samples were obtained during three protocols: 10 min of exercise at 90% of maximal heart rate (n=8), intravenous administration of corticotrophin-releasing hormone (CRH; n=4), and dexamethasone suppression (n=7). Cortisol was measured in saliva using a commercial high-sensitivity EIA and total cortisol was measured in serum with a commercial radioimmunoassay (RIA). Results The time course of the salivary cortisol response to both the exercise and CRH tests paralleled that of total serum cortisol. Salivary cortisol demonstrated a significantly greater relative increase in response to the exercise and CRH stimuli (697+/- 826%vs. 209+/- 150%, P=0.04 saliva vs. serum). A disproportionately larger increase in free cortisol, compared with total, would be expected when the binding capacity of cortisol-binding globulin (CBG) is exceeded. In response to dexamethasone suppression, relative decreases in cortisol were not significantly different between the two media (-47+/- 56%vs.-84+/- 8%, P=0.13 saliva vs. serum). Although a significant linear correlation was found for all paired salivary and serum total cortisol samples (n=183 pairs, r=0.60, P<0.001), an exponential model provided a better fit (r=0.81, P<0.001). The linear correlations were strengthened when data from subjects on oral oestrogens (n=52 pairs, r=0.75, P < 0.001) were separated from those not taking oestrogens (n=131 pairs, r=0.67, P<0.001). Conclusions Salivary cortisol measured with a simple EIA can be used in place of serum total cortisol in physiological research protocols. Evidence that salivary measures represent the biologically active, free fraction of cortisol includes: (1) the greater relative increase in salivary cortisol in response to tests that raise the absolute cortisol concentration above the saturation point of CBG; (2) the strong exponential relationship between cortisol assessed in the two media; and (3) the improved linear correlations when subjects known to have increased CBG were analysed separately. Thus, an advantage of measuring salivary cortisol rather than total serum cortisol is that it eliminates the need to account for within-subject changes or between-subject differences in CBG.
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              Diagnosis of adrenal insufficiency.

               C Qualls,  L M Crapo,  J Dorin (2003)
              The cosyntropin stimulation test is the initial endocrine evaluation of suspected primary or secondary adrenal insufficiency. To critically review the utility of the cosyntropin stimulation test for evaluating adrenal insufficiency. The MEDLINE database was searched from 1966 to 2002 for all English-language papers related to the diagnosis of adrenal insufficiency. Studies with fewer than 5 persons with primary or secondary adrenal insufficiency or with fewer than 10 persons as normal controls were excluded. For secondary adrenal insufficiency, only studies that stratified participants by integrated tests of adrenal function were included. Summary receiver-operating characteristic (ROC) curves were generated from all studies that provided sensitivity and specificity data for 250-microg and 1-microg cosyntropin tests; these curves were then compared by using area under the curve (AUC) methods. All estimated values are given with 95% CIs. At a specificity of 95%, sensitivities were 97%, 57%, and 61% for summary ROC curves in tests for primary adrenal insufficiency (250-microg cosyntropin test), secondary adrenal insufficiency (250-microg cosyntropin test), and secondary adrenal insufficiency (1-microg cosyntropin test), respectively. The area under the curve for primary adrenal insufficiency was significantly greater than the AUC for secondary adrenal insufficiency for the high-dose cosyntropin test (P 0.5) for secondary adrenal insufficiency. At a specificity of 95%, summary ROC analysis for the 250-microg cosyntropin test yielded a positive likelihood ratio of 11.5 (95% CI, 8.7 to 14.2) and a negative likelihood ratio of 0.45 (CI, 0.30 to 0.60) for the diagnosis of secondary adrenal insufficiency. Cortisol response to cosyntropin varies considerably among healthy persons. The cosyntropin test performs well in patients with primary adrenal insufficiency, but the lower sensitivity in patients with secondary adrenal insufficiency necessitates use of tests involving stimulation of the hypothalamus if the pretest probability is sufficiently high. The operating characteristics of the 250-microg and 1-microg cosyntropin tests are similar.

                Author and article information

                J Pain Res
                J Pain Res
                Journal of Pain Research
                24 June 2020
                : 13
                : 1505-1514
                [1 ]Department of Anesthesiology and Pain Medicine, College of Medicine, The Catholic University of Korea , Seoul, Republic of Korea
                Author notes
                Correspondence: Ho Sik Moon Department of Anesthesiology and Pain Medicine, Eunpyeong St. Mary’s Hospital, College of Medicine, The Catholic University of Korea , 1021, Tongil-ro, Eunpyeong-gu, Seoul03312, Republic of KoreaTel +822-2030-3864Fax +822-2030-3861 Email mhsjshgma@gmail.com
                © 2020 Park et al.

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                Page count
                Figures: 4, Tables: 6, References: 28, Pages: 10
                Funded by: solely from department sources
                Support was provided solely from department sources.
                Original Research


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