ABSTRACT
Context
Screening morning serum cortisol is used to select patients for ACTH stimulation testing to diagnose adrenal insufficiency (AI) but may be affected by pre‐analytical factors. Careful consideration to discontinue confounding medications beforehand may preclude the need for subsequent stimulation testing.
Objective
To determine whether serum cortisol collected after discontinuation of confounding medications is more predictive of AI compared to screening morning cortisol without mandatory medication adjustment.
Methods
Retrospective chart review of 835 patients with ACTH stimulation testing (Short Synacthen Test [SST]). Linear regression to compare Roche Cortisol II immunoassay screening cortisol versus optimally collected cortisol measurements after removal of confounding medications. Receiver operating characteristic (ROC) curve analyses to identify 100% sensitivity threshold for AI.
Results
The majority of patients passed the SST (n = 756; 90.5%). There was a poor correlation between screening morning cortisol and optimally collected cortisol measurements, r = 0.34 (95% CI, 0.25–0.42). Real‐world screening morning cortisol measurements had moderate discrimination for the diagnosis of AI (AUC 0.80; 95% CI, 0.77–0.82; p < 0.001) with a 100% sensitivity threshold for AI of 262 nmol/L. Applying this threshold would save 112 SSTs (13.4% of all tests). In contrast, an optimally collected serum cortisol had strong discrimination for AI (AUC 0.89; 95% CI, 0.87–0.91; p < 0.0001) and the threshold with 100% sensitivity for the diagnosis was 246 nmol/L which would save another 4.8% of all tests.
Conclusion
Careful attention to pre‐test patient preparation and implementation of a lower cortisol threshold may significantly reduce the number of stimulation tests needed to screen for AI.
Keywords: adrenal cortex diseases, adrenal cortex hormones, adrenal gland disease, adrenal insufficiency, adrenocorticotropic hormone, endocrine testing nurses, reducing unnecessary testing, screening test optimization
1. Introduction
Adrenal insufficiency (AI) is a potentially life‐threatening disease [1, 2]. Initial screening for AI with a morning serum cortisol typically shows that lower values are associated with a higher probability of disease [3]. If there is uncertainty about the diagnosis after initial screening, the ACTH stimulation test (also called the short Synacthen test [SST]) can be used to evaluate adrenal reserve. This test accurately diagnoses both primary and chronic secondary AI [1, 2]. A normal response to the SST makes future development of adrenal crises highly unlikely [4, 5], thereby offering both diagnostic and prognostic information.
As a dynamic endocrine test, the SST is feasible to perform in a hospital setting but may require admission. A dedicated nurse‐led endocrine testing unit (ETU) is an ideal solution to facilitate outpatient SST but may face a high demand for services. Ideally, a process whereby requests for SST are pre‐screened and filtered could ensure the most appropriate patients are tested promptly and unnecessary test requests are declined.
Clinicians commonly select patients for SST using morning cortisol [3]. The optimal threshold for interpretation of this screening cortisol approach is method‐ and assay‐dependent [6, 7, 8, 9]. However, less attention has been paid to the impact of pre‐analytical factors such as patient preparation and medication or supplement profile that may also affect the results of the screening serum cortisol. Knowing that clinicians frequently fail to attend to pre‐analytical test conditions [10], a real‐world, pre‐analytical optimization study of screening serum cortisol prior to SST is needed which can be compared to the predictability of a serum cortisol after appropriate preparation.
Since 2016, the regional ETU in Calgary, Alberta has utilized a specialized nurse‐led process whereby referrals for SST are systematically screened for appropriateness. Each patient referred for SST typically has a screening cortisol performed under unknown conditions by the referring physician; however, prior to performing SST, the ETU nurses pay careful attention to minimize pre‐analytical confounders. The basal zero‐minute cortisol (post‐nursing intervention) drawn on the morning of the SST visit simulates a repeat screening cortisol with attention to pre‐analytical confounders. Based upon these data, we performed a retrospective cohort study to determine the correlation between the screening cortisol measured by a physician prior to the referral and the basal zero‐minute cortisol measured after fastidious nurse‐led patient preparation. We evaluated the association of each of these to the final diagnosis of AI based on the SST result.
2. Methods
2.1. Endocrine Testing Unit Referrals
This study was approved by A pRoject Ethics Community Consensus Initiative (ARECCI) as a quality improvement and research initiative and waiver of individual participant consent was granted. The Calgary ETU serves Southern Alberta with a catchment of ~2 million people. The clinic does not offer stimulation tests to patients with screening cortisol levels ≥ 350 nmol/L on the grounds that this already constitutes normal adrenal function, based upon locally validated and published data using the Roche Cortisol II immunoassay [11].
2.2. Testing Protocol
Upon referral, nursing staff booked the patient for SST which was performed prior to noon. Patients were advised to hold all multivitamins, non‐essential or biotin‐containing supplements for 48 h or more prior to the test [12]. Inhaled, intranasal or topical steroids were withheld for 48–72 h prior to the test. Oral corticosteroids were also held for a minimum of 24 h, if clinically permissible. Opioids were also withdrawn for 24 h, if feasible. The vast majority of patients were able to safely comply with temporary medication withdrawal.
After obtaining consent, an intravenous line was placed with saline lock and patency of the IV was confirmed. Then, 2 mL of 0.9% Sodium Chloride Injection USP was added to a vial of Cortrosyn to yield a concentration of 250 mcg/2 mL [13]. Baseline zero‐minute serum cortisol was drawn. Cortrosyn 2 mL (250 mcg) was then administered by IV push over 2 min followed by 5 mL of 0.9% sodium chloride flush. Cortisol levels post‐Cortrosyn administration were drawn at 30‐ and 60‐min following injection [14]. For a 1 mcg ACTH stimulation test, the identical procedure was performed except that Cortrosyn 250 mcg (2 mL) was added to a 250 mL 0.9% Sodium Chloride IV bag, mixed and then 1 mL of solution was removed to obtain the final dose of 1 mcg. Serum cortisol was measured using the Roche Cortisol II assay (Roche Diagnostics GmBH, Mannheim, Germany) on the Roche Cobas 8000 instrument according to the manufacturer's specifications. If also performed at baseline, plasma ACTH was measured using a solid‐phase, two‐site sequential chemiluminescent immunometric assay on the Immulite 2000 system (Siemens, Germany).
2.3. Data
We reviewed all paper and electronic charts of patients referred to the ETU who received the SST (1 or 250 μg) between 6 April 2016 and 31 October 2023. The main study inclusion criterion, which matched the clinic referral protocol, was that the patient must have had a serum cortisol drawn at 1000 h or earlier within 3 months prior to the ETU referral and this value was < 350 nmol/L on the Roche Cortisol II assay. If multiple screening morning cortisol tests were performed, the value closest to the testing date was recorded. We excluded cases where the screening morning cortisol had been performed: (a) > 3 months prior to the date of the stimulation test, (b) after 1000 h or (c) using a cortisol assay other than the Roche Cortisol II. Charts that lacked any written medical records or had incomplete laboratory results were also excluded. The date of testing, age, sex, indication for SST, screening morning cortisol, and history of any exogenous corticosteroid or opioid preparation taken by the patient within 3 months of the test date was recorded.
For the 250 μg SST, the basal 0‐, 30‐ and 60‐min cortisol levels were collected. For the 1 mcg SST, only the 0‐ and 30‐min cortisol samples were drawn. A normal response to the SST was deemed to be a serum cortisol at any time point of ≥ 350 nmol/L. An abnormal or failed test was defined when all cortisol values were < 350 nmol/L.
2.4. Analysis
Baseline demographics were presented using descriptive statistics using mean and standard deviation or median and interquartile ratio as appropriate. Categorical variables were presented as number and frequencies; χ 2 tests were used to compare proportions where appropriate. Linear regression was used to compare the real‐world screening cortisol versus zero‐minute cortisol measurements. Then, receiver operating characteristic (ROC) curve analyses were used to identify the thresholds of the screening cortisol and zero‐minute cortisol associated with 100% sensitivity for identifying true AI [15] in order to identify the highest cortisol threshold where no cases of AI were missed. The presence of AI was determined based on categorizing each patient according to whether they had normal or abnormal results on the SST. The area under the curve (AUC) and 95% confidence intervals of each ROC curve was determined. To compare the two AUC, we used the Hanley and McNeil method which accounts for non‐independence between the data sets. Using the aforementioned ROC‐derived thresholds, we modelled the percentage of ACTH stimulation test referrals that might be avoided if the nurse‐prepared, zero‐minute cortisol had been the initial screening cortisol test, compared to the traditional screening threshold of < 350 nmol/L, where cortisol was also collected in the community without systematically controlled standardization of pre‐analytical factors.
3. Results
A total of 1112 SSTs were performed between 6 April 2016 and 31 October 2023. One patient who had rapidly evolving Addison's disease was excluded on account of marked disease progression during the interval between screening and testing, making the cortisol levels non‐comparable. After other exclusions by study protocol, there were a total of 835 unique test patients for analysis. Most of the patients were female (Table 1). The median age was 46 years (range 17–92 years). In total, 678 (81.2%) of the tests were performed using 250 mcg of ACTH and 501 (60.0%) of the tests were performed without any previous history of steroid or opioid administration.
Table 1.
Baseline characteristics.
| Number (%) | |
|---|---|
| Number of tests | 835 (100) |
| Female | 531 (63.6) |
| Male | 304 (36.4) |
| Age (median, range) | 46 years (17–92) |
| 250 mcg tests | 678 (81.2) |
| 1 mcg tests | 157 (18.8) |
| No steroids, no opioids | 501 (60) |
| Steroids and/or opioids | 334 (40) |
Table 2 illustrates test results for the whole cohort (n = 835) as well as for the subgroups of interest, including those who received the 250 mcg SST (n = 678), the 1 mcg SST (n = 157), patients with no history of glucocorticoid or opioid use (n = 501), and those who have received glucocorticoids and/or opioids (n = 334). The majority of patients passed the SST (n = 756, 90.5%). Among those who received the 250 mcg dose, 91.6% passed, in comparison to 86.0% who received the 1 mcg dose of ACTH (p = 0.04). As shown in Figure 1, when the physician‐ordered screening morning serum cortisol was below 100 nmol/L (n = 130), 86 (66.2%) patients still passed whereas 44 (33.8%) failed.
Table 2.
ACTH stimulation testing (SST) results for the whole cohort and subgroups.
| Whole cohort | 250 mcg tests | 1 mcg tests | No steroids/opioids | Steroids and/or opioids | |
|---|---|---|---|---|---|
| Number of tests (% of all tests) | 835 (100%) | 678 (81.2%) | 157 (18.8%) | 501 (60.0%) | 334 (40.0%) |
| Pass (any time ≥ 350 nmol/L) | 756 (90.5%) | 621 (91.6%) | 135 (86%) | 483 (96.4%) | 273 (81.7%) |
| Fail (all times < 350 nmol/L) | 79 (9.5%) | 57 (8.4%) | 22 (14%) | 18 (3.6%) | 61 (18.3%) |
| Zero‐time cortisol ≥ 350 nmol/L | 90 (10.8%) | 69 (10.2%) | 21 (13.4%) | 51 (10.2%) | 39 (11.7%) |
| 30 min cortisol ≥ 350 nmol/L | 738 (88.3%) | 603 (88.8%) | 135 (86%) | 474 (94.6%) | 264 (79.0%) |
| 60 min cortisol ≥ 350 nmol/La | 620 (91.3%) | 620 (91.3%) | 404 (97.1%) | 216 (82.4%) | |
| Highest screen am cortisol: Fail (nmol/L) | 262 | 239 | 262 | 214 | 262 |
| Lowest screen am cortisol: Pass (nmol/L) | 5 | 5 | 36 | 14 | 5 |
| Highest zero‐time cortisol: Fail (nmol/L) | 245 | 245 | 229 | 229 | 245 |
| Lowest zero‐time cortisol: Pass (nmol/L) | 2 | 2 | 2 | 2 | 2 |
250 mcg tests only.
Figure 1.
Pass or fail ACTH stimulation testing (SST) by the range of serum morning cortisol.
The correlation between the physician‐ordered screening morning cortisol (drawn prior to the referral) and the basal zero‐minute cortisol (drawn in the ETU after the nursing intervention) within the next 3 months was low (r = 0.34; 95% CI, 0.25–0.42; Figure 2).
Figure 2.
Comparison of screening and basal zero‐minute serum cortisol.
The physician‐ordered screening morning cortisol (representative of a real‐world measurement) was moderately able to discriminate the diagnosis of AI (AUC of 0.80; 95% CI, 0.77–0.82; p < 0.001). The basal zero‐minute cortisol (collected after discontinuation of potentially confounding medications) had stronger discrimination (AUC of 0.89; 95% CI, 0.87–0.91; p < 0.0001). The difference was statistically significant (Figure 3; difference in AUC of 0.099; 95% CI, 0.05–0.15; p = 0.0003).
Figure 3.
ROC curves for screening serum cortisol and basal zero‐minute cortisol (n = 835).
In Table 3, details from the ROC curve analysis are shown; the minimum screening cortisol threshold where there was 100% sensitivity for AI was 262 nmol/L (i.e., where no cases of AI were missed). For the optimally collected, basal zero‐minute, nurse‐prepared cortisol, the corresponding threshold with 100% sensitivity to detect AI was 246 nmol/L.
Table 3.
Test performance characteristics from ROC curve data.
| Study cohort | 100% sensitivity threshold, nmol/L | Specificity at 100% sensitivity | PPV at 100% sensitivity | NPV at 100% sensitivity |
|---|---|---|---|---|
| Full cohort n = 835 | 262 | 15% | 11% | 100% |
| No GC/opioids n = 501 | 215 | 32% | 5% | 100% |
| GC and/or opioids n = 334 | 262 | 13% | 20% | 100% |
Note: Prevalence of AI in our study: 9.5% failed the ACTH stimulation test in full cohort (n = 835).
We then performed a sex‐stratified secondary analysis. When we analyzed female patients only (n = 531) and compared these to the male patients (n = 304), there was no difference between groups (p = 0.86). Furthermore, when all pre‐menopausal women were excluded, the ROC AUC was 0.78 (0.71–0.85), p < 0.0001, the same as in the full cohort.
3.1. Simulation of Optimized Threshold Screening Cortisol Values and ETU Referral Impact
We then estimated the number of patients who could potentially be safely directed away from SST if an optimally collected cortisol was measured (with a threshold of < 262 nmol/L required) for patients to be eligible for the SST. There were 112 patients who had a screening cortisol between 262 and 350 nmol/L. Therefore, lowering the cortisol threshold from 350 to 262 nmol/L for SST eligibility would result in 13.4% (112/835) fewer patients requiring testing.
To model the potential impact of a screening cortisol performed with strict attention to pre‐analytical preparation, as represented by the nurse‐facilitated cortisol measurement at time zero on the day of SST, 100% of patients with a cortisol threshold ≥ 246 nmol/L would pass the SST. Thus, setting a threshold screening cortisol at < 246 nmol/L would safely avert 18.2% (152/835) of SST requests.
4. Discussion
In this study, < 10% of 835 patients who had a screening morning immunoassay cortisol under 350 nmol/L failed the ACTH stimulation test (SST). This indicates that only a small fraction of patients considered to have some form of adrenal compromise ultimately have confirmation of the diagnosis with dynamic testing. However, the resource demand for such testing is not insignificant. We estimated that nearly 20% of requests for SST could be safely averted, if pre‐analytical confounding medications were discontinued and/or by instituting a lower test indication threshold. This dynamic test obligates patients to attend our testing unit for 90 or more minutes, requires highly skilled nursing staff to prepare the patient and administer the test, intravenous access, and multiple cortisol measurements. Moreover, even without controlling for pre‐analytical conditions, we found that lowering the screening morning cortisol cut‐off to < 262 nmol/L on the current immunoassay would still identify 100% of the patients with AI.
We described a marked discrepancy between the screening morning cortisol drawn through usual clinical care and the basal zero‐time serum cortisol drawn before ACTH administration on the day of the test. In theory, if both measures were done within a short time frame and with appropriate attention to pre‐test patient preparation, these two cortisol values should be well correlated. In contrast, we found that these were poorly correlated. The basal zero‐minute result was much higher in nearly all cases, arguing against random variation in repeat results. Plausibly, the testing nurse's standardized pre‐test instructions to hold all inhaled, intranasal or topical steroids and vitamins for 48–72 h and oral glucocorticoids or opioids for 24 h prior to the test likely accounted for this difference. If clinicians advised their patients to follow similar, standardized pre‐test instructions to hold potentially confounding agents before ordering a morning serum cortisol, it is likely that similar basal zero‐minute cortisol data could be reproduced, allowing even more ETU referrals (18.2%) to be safely avoided. This would lead to a substantial reduction in resource utilization in patients, most of who are ultimately not diagnosed with adrenal disease.
A screening cortisol < 100 nmol/L is considered by many clinicians and authors to be diagnostic of AI [3, 16]. Our experience does not support this. In our study, 130 patients (representing 15.6% of all tests) had a screening morning serum cortisol < 100 nmol/L, yet two‐thirds of these patients passed the SST. The majority of those patients who passed (62.1%) had prior opioid or exogenous glucocorticoid exposure, a known confounder to the interpretation of basal or random cortisol measures. Our data thus suggest that when clinically feasible, formal evaluation with the SST is still important even when morning cortisol values are < 100 nmol/L to avoid mis‐labelling patients and potentially treating them unnecessarily with lifetime glucocorticoid replacement. The exception to this is any patient with low basal cortisol and high (more than double normal) plasma ACTH, in which case Addison's disease/primary AI should be strongly considered and may need treatment instituted without delay.
The Roche Cortisol II assay is one of the most popular assays in North America [17]. Prior, smaller studies have shown results similar to what we have described, using the same cortisol assay. Barbar and colleagues described a retrospective analysis of a cohort of 595 patients, all of whom were at risk for secondary AI from pituitary lesions, surgery or radiation [18]. All underwent 250 mcg IV ACTH stimulation, about half using the Roche Cortisol II assay. The other half were analyzed using the older Roche Cortisol assay but results converted to estimated Cortisol II values using a validated regression equation [19]. In their experience, 51/595 failed the stimulation test after applying a high diagnostic threshold of < 420 nmol/L. Using the time‐zero cortisol measure as a surrogate for pre‐test screening, in contrast to our real‐world study of actual pre‐test cortisol screening, they estimated that a basal cortisol measured before ACTH stimulation of ≥ 237 nmol/L would maintain a 100% sensitivity to diagnose AI without the need to proceed to dynamic stimulation. No details were provided on the use of glucocorticoids or opioids prior to testing. A subsequent study from the same centre looked at 60 SSTs on 58 chronic low‐dose glucocorticoid therapy patients with rheumatologic disease. Exogenous glucocorticoids were held for 48 h prior to the test. In total, 100% of patients with serum morning cortisol values above 237 nmol/L achieved cortisol results ≥ 420 nmol/L on SST [20]. Our study provides some external validation to these studies with the additional advantage of employing a more conservative, assay‐specific diagnostic threshold for the SST [11] and by including results from pre‐test patient screening results.
The cardinal strength of our study is the inclusion of consecutive, unselected patients over 7.5 years who were referred to a regional ETU with a catchment of over 2 million people and near‐complete capture of all ACTH stimulation tests performed. This permitted us to examine the impact of standardized pre‐test counselling by a consistent, experienced and skilled endocrine testing nurse team. We used the same well‐validated and commonly utilized cortisol immunoassay for all tests. Subgroup analyses of all female patients, and specifically post‐menopausal females and male patients, yielded virtually identical results for the ability of a screening morning cortisol to predict success on SST.
Our study had some limitations, notably that this was a retrospective analysis and there were oftentimes limited details about clinical symptoms and signs provided in the chart. Results from the SST could not be correlated to patient outcomes or final clinical diagnoses. But neither of these were outcomes of interest; for this study, our aim was to evaluate the correlation between baseline cortisol and SST results, not clinical interpretation of results. Our focus was to identify ways to improve ETU resource utilization and to safely reduce low‐value testing for a commonly ordered endocrine dynamic test. Our results may not be generalizable to centres using other cortisol immunoassays or mass spectrometry measures. Sbardella and colleagues reported SST results using three different cortisol immunoassays. They showed significant variation for diagnostic cortisol thresholds in test interpretation, each of which was assay‐specific [3]. Therefore, each centre must take care to use cortisol assay‐specific interpretation thresholds. Our results for suggested screening serum cortisol should not be used to exclude AI which is due to acute hypothalamic/pituitary disease or related to rapidly evolving primary AI [21]. In these situations, clinical suspicion must always take precedence to guide testing and/or empiric therapy. Finally, there is no published evidence to our knowledge to support that withholding opioids for 24 h will fully alleviate a suppressive effect on the hypothalamic–pituitary–adrenal axis but anecdotal clinical experience would suggest that it is reasonable. Clinicians are reminded that a normal SST result does not exclude the possibility of AI in those who resume or continue exogenous glucocorticoids or narcotics.
5. Conclusions
The ACTH stimulation test (SST) is one of the most frequent dynamic endocrine tests ordered by endocrinologists and medical generalists alike. A low threshold for consideration is required to ensure that AI, a potentially life‐threatening diagnosis, is not missed. However, in the absence of acute pituitary injury or rapidly progressing primary adrenal failure, a screening morning cortisol may help to define which patients might need dynamic SST for diagnosis. Using the Roche Cortisol II immunoassay, a morning cortisol ≥ 262 nmol/L predicts normal results on subsequent ACTH stimulation testing with high certainty and in the presence of modern interpretive thresholds. If the screening cortisol is measured after careful attention to pre‐test patient preparation variables that may affect measured cortisol results, an even greater number of dynamic tests may potentially be avoided. This study highlights the value of an experienced endocrine testing nursing team who may assist in patient preparation and test resource utilization.
Funding
The authors received no specific funding for this work.
Conflicts of Interest
The authors declare no conflicts of interest.
Acknowledgements
The authors would like to acknowledge the invaluable work, dedication to detail and exemplary patient care by their endocrine testing unit nurses: Brenda Niquet, Jena Holtby, Elaine Coté and Brenda Polzin.
Data Availability Statement
Restrictions apply to the availability of some or all data generated or analyzed during this study to preserve patient confidentiality or because they were used under license. The corresponding author will on request detail the restrictions and any conditions under which access to some data may be provided. The data that support the findings of this study are available on reasonable request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
Restrictions apply to the availability of some or all data generated or analyzed during this study to preserve patient confidentiality or because they were used under license. The corresponding author will on request detail the restrictions and any conditions under which access to some data may be provided. The data that support the findings of this study are available on reasonable request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.