Summary
Context:
Overnight metyrapone test (OMT) is a dynamic test used to diagnose secondary adrenal insufficiency (SAI). Data on OMT use and its safety are scarce.
Objective:
To describe the indications and safety of outpatient OMT and compare OMT to the cosyntropin stimulation test (CST).
Design:
Single-center retrospective study of adult patients undergoing OMT between April 1st, 2018 -January 27th, 2023.
Measurements:
OMT-related adverse events, post-OMT diagnosis of SAI, and OMT comparison to CST.
Results:
OMT was performed in 114 patients (81, 71% women) at a median age of 48 (IQR 37–58). The pre-test probability for SAI was low in 52 (46%) patients, moderate in 48 (42%) patients, and high in 14 (12%) patients. Adverse events were reported in 7 (6.1%) patients and were mild except for one hospitalization. No baseline or OMT-related factors were associated with the development of adverse events. Prevalence of the OMT-based SAI diagnosis was 26 (23%) and 47 (46%) using 11-deoxycortisol cutoff <7 mcg/dL and <10 mcg/dL, respectively. Higher pre-test probability was associated with the OMT-based diagnosis of SAI. Post-OMT 11-deoxycortisol cutoff of 10 mcg/dL was used most to diagnose SAI. Compared to the OMT-based diagnosis of SAI (11-deoxycortisol cutoff of 10 mcg/dL), the specificity of CST was 100%, but the sensitivity was only 52%.
Conclusions:
OMT was well tolerated and used in patients with low and moderate pre-test probability for SAI. CST can erroneously exclude patients with SAI. Thus, OMT should be considered in selected patients with normal CST.
Keywords: Diagnosis, cortisol, cosyntropin stimulation, accuracy, adverse event
Introduction
Inadequate production of cortisol from the adrenal cortex leads to adrenal insufficiency (AI)1. AI can be classified as primary (loss of adrenal gland function) or secondary (dysfunctioning of the hypothalamic-pituitary-adrenal axis)1, 2. The diagnosis of AI is based on history, clinical examination, and biochemical workup that includes baseline adrenal hormonal testing and dynamic testing1. Diagnosing secondary AI (SAI) can be especially challenging due to non-specific clinical presentation and occasionally borderline and normal baseline hormonal testing. Cosyntropin stimulation test (CST) is the most widely used among the dynamic tests used to diagnose SAI. However, as CST tests for adrenal cortex atrophy, the sensitivity of this test to diagnose SAI is suboptimal, reported at 64%3, 4. The insulin tolerance test (ITT) is considered the gold standard for diagnosing SAI, but it is expensive, laborious, and associated with potential risks related to hypoglycemia, and as such, is rarely performed5–9.
The overnight metyrapone test (OMT) is a dynamic test that can diagnose SAI by testing the hypothalamic-pituitary response to cortisol deficiency9, 10, Figure 1. Several studies have reported a high concordance of OMT with the insulin tolerance test9, 11–14. However, OMT has not been used extensively due to a lack of test set-up in most endocrine practices, concern for potential adverse events when used in the outpatient setting, and limited availability of 11-deoxycortisol assays9. In addition, various 11-deoxycortisol cutoffs have been used in diagnosing SAI without a uniform standardized approach, complicating interpretation. Studies on post-OMT cutoffs varied in protocols and assays and included small sample sizes and heterogeneous patient populations15–17. The safety of OMT in an outpatient setting is incompletely characterized, and hospitalization was previously recommended in patients at high risk for adrenal crisis8, 9.
Figure 1. Overnight metyrapone test.
Footnote: Metyrapone is administered at midnight at 2500 mg or 30 mg/kg. Metyrapone blocks the conversion of 11-deoxycortisol to cortisol by 11-beta-hydroxylase, the last step in the synthesis of cortisol, and induces a rapid decrease of cortisol and an increase of its immediate precursor 11-deoxycortisol. In healthy individuals, the decrease in serum cortisol leads sequentially to decreased negative feedback at the hypothalamic and anterior pituitary, which increases corticotropin-releasing hormone (CRH) and corticotropin (ACTH) secretion, as well as adrenal steroidogenesis before the blockade. The resultant increase in serum 11-deoxycortisol concentrations indicates the increase in ACTH release. Failure for 11-deoxycortisol (and ACTH) to increase post-metyrapone is consistent with secondary adrenal insufficiency.
In this study, we aimed to characterize the population of patients undergoing OMT, describe indications for OMT, and determine the prevalence and factors associated with adverse events in patients undergoing OMT. In addition, we aimed to determine the performance of the cosyntropin stimulation test (CST) compared to OMT.
Materials and Methods
Study Design
This retrospective cohort study was approved by the Institutional Review Board. Included patients were adults ≥ 18 years old who provided research authorization for the use of medical records and who had undergone OMT at our institution between April 1, 2018, and January 27th, 2023. Medical records were reviewed for clinical presentation, suspected etiology of SAI, other concomitant pituitary deficiencies, metyrapone dose, clinician’s pre-test probability of SAI (low, medium, or high), oral contraceptive use, exposure to exogenous glucocorticoids, and final clinician-made diagnosis of SAI. The clinician’s pre-test probability was abstracted from the endocrine consult note before OMT within the plan and counseling section of the note. Hormonal data were collected and included baseline adrenal function testing, OMT testing, and results from other dynamic tests.
Overnight Metyrapone Test Procedure
OMT was performed in the outpatient Endocrine Testing Center per protocol. In brief, patients were advised to take metyrapone (single dose) at midnight with a snack. Prescribing clinicians had two options for metyrapone dosing: a standard 2500 mg dose or a dose calculated based on weight (30 mg/kg), with a maximum dose of 3000 mg. Following the overnight metyrapone administration, patients were instructed to present to the Endocrine Testing Center in the morning (8 a.m.). Trained nursing staff confirmed the accuracy of metyrapone administration, assessed for adverse events, and collected blood for cortisol and 11-deoxycortisol. As a part of the protocol, corticotropin (ACTH) measurement was optional and required an active order by the clinician. As a part of the standard annual review and to minimize potential adverse events, the OMT protocol was reviewed and adapted on April 17th, 2022, to include the administration of hydrocortisone 20 mg immediately after the morning blood collection.
Interpretation of OMT
Post-OMT morning cortisol is expected to be < 7 mcg/dL following the overnight metyrapone administration. Three diagnostic cutoffs for SAI based on the OMT results are suggested in the protocol: 1) post-OMT 11-deoxycortisol of 7 mcg/dL, 2) post-OMT 11-deoxycortisol of 10 mcg/dL, and 3) sum of post-OMT 11-deoxycortisol and cortisol of 15 mcg/dL. After confirming appropriate metyrapone administration, diagnosis of SAI is confirmed if post-OMT 11-deoxycortisol is < 7 mcg/dL, excluded if post-OMT 11-deoxycortisol is > 10 mg/dL, and depends on the clinician’s pre-test probability if post-OMT 11-deoxycortisol is between 7 and 10 mcg/dL. Depending on the post-OMT morning cortisol and OCP use, criteria for case selection in the analysis of post-OMT 11-deoxycortisol cutoffs applied, Appendix 1.
Cosyntropin Stimulation Test
CST was performed as an outpatient procedure at the Endocrine Testing Center. An intravenous catheter was inserted into the antecubital vein for blood sample collection and Cosyntropin administration. Cosyntropin 250 mcg (Mylan Institutional, Amsterdam, Netherlands) was reconstituted with 2 mL 0.9% and administered once over 2 minutes. Blood samples at baseline, 30, and 60 minutes were obtained and analyzed for total cortisol. Per our institutional protocol, post-CST peak cortisol < 18 mcg/dL was considered diagnostic of SAI.
Assays
Baseline serum cortisol (normal range: 7–22 mcg/dL) was measured using a competitive binding immunoenzymatic assay (Beckman Coulter, Brea, CA). Baseline ACTH (normal range 7.2–63 pg/mL) was measured using Roche Elecsys ACTH assay (Los Angeles, CA). Baseline dehydroepiandrosterone sulfate (DHEAS) (μg/dL, normal range varies based on sex and age) was analyzed using automated chemiluminescent competitive immunoassay on the IMMULITE® 2000 platform (Siemens Diagnostics, Tarrytown, NY). 11-deoxycortisol was measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS) using an Applied Biosystems Tandem Mass Spectrometer with Atmospheric Pressure Chemical Ionization Source.
Adverse Events
A detailed description of adverse events was recorded by the nurses performing OMT and by the clinicians who ordered the OMT. The overall prevalence of adverse events was calculated.
Statistics
Statistical analysis was conducted using JMP software, Version 16.1.0 (SAS Institute Inc., Carey, NC, USA). For descriptive analysis, categorical variables are reported as numbers and percentages, and the continuous variables as medians and interquartile ranges (IQR). Subgroup analyses were performed using chi-squared tests for categorical variables and the Kruskal-Wallis test for continuous variables. Diagnostic accuracy parameters were calculated using the online calculator (www.medcalc.org). Statistical significance was defined as p-value < 0.05.
Results
Patients
OMT was performed in 114 patients (81, 71% women) at a median age of 48 (IQR 37–58). The etiologies for suspected SAI included pituitary-related pathology or treatment, chronic glucocorticoid use, opioid therapy, or idiopathic SAI, Table 1. Concomitant pituitary deficiencies were seen in 21 (18%) patients, including those with multiple pituitary deficiencies in 5 (28%) patients, Table 1. The pre-test probability for SAI was low in 52 (46%) patients, moderate in 48 (42%) patients, and high in 14 (12%) patients undergoing OMT.
Table 1.
Concomitant pituitary deficiencies in patients based on suspected etiology of adrenal insufficiency
| Etiology of suspected adrenal insufficiency | n (%) | Concomitant pituitary deficiencies | n (%) |
|---|---|---|---|
| Idiopathic | 39 (34%) | 0 | 0 |
| Pituitary surgery | 8 (7%) | Secondary hypogonadism and secondary hypothyroidism (n=2) Secondary hypogonadism (n=1) Growth hormone deficiency and secondary hypogonadism (n=1) |
5 (62.5%) |
| Pituitary adenoma | 5 (4%) | Secondary hypogonadism (n=1) Growth hormone deficiency (n=1) |
2 (40%) |
| Traumatic brain injury | 6 (5%) | Secondary hypogonadism (n=1) Growth hormone deficiency (n=1) Diabetes insipidus, GH deficiency and Secondary hypogonadism (n=1) |
3 (50%) |
| Empty sella syndrome | 5 (4%) | 0 | 0 |
| Radiotherapy | 2 (2%) | Secondary hypogonadism (n=1) Secondary hypogonadism and secondary hypothyroidism (n=1) |
2 (100%) |
| Granulomatous disease | 1 (1%) | Diabetes insipidus (n=1) | 1 (100%) |
| Sheehan syndrome | 1 (1%) | Panhypopituitarism (n=1) | 1 (100%) |
| Chronic opioid use | 26 (23%) | Secondary hypogonadism (n=4) Growth hormone deficiency (n=1) |
5 (19%) |
| Exogenous glucocorticoid therapy | 10 (9%) | 0 | 0 |
| Multiple or other risk factors | 11 (10%) | Secondary hypogonadism (n=2) | 2 (18%) |
Hormonal Workup Before OMT
Baseline median cortisol was 9 mcg/dL (IQR, 6.3–11.8), median ACTH was 19 pg/dL (IQR, 13–26.5), and median DHEAS was 55.5 mcg/dL (IQR 26.8–93), Table 2. Of 114 patients, 53 (46.5%) underwent CST with median peak cortisol of 22 mcg/dL (IQR 17.8–24.5), and 13 (24.5%) patients demonstrated abnormal results (peak cortisol < 18 mcg/L).
Table 2.
Diagnosis and testing for adrenal insufficiency based on the three diagnostic cutoffs for the overnight metyrapone test
| Variables | All patients | Cutoffs for diagnosis of adrenal insufficiency based on the overnight metyrapone test | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| 11-deoxycortisol 7 mcg/dL | 11-deoxycortisol 10 mcg/dL | (11-deoxycortisol + cortisol) 15 mcg/dL | |||||||||
| <7 | ≥7 | P value | <10 | ≥10 | P value | <15 | ≥15 | P value | |||
| Variable | n | 114 | 26 | 85 | 47 | 56 | 50 | 59 | |||
| Baseline testing | |||||||||||
| Cortisol, mcg/dL# Median (IQR) |
112 | 9 (6.3–11.8) |
8.4 (6.3–9.6) |
9 (6.3–11) |
0.5455 | 8.4 (6.3–10) |
8.8 (6–11) |
0.6698 | 8.2 (6.2–9.9) |
9.5 (6.5–12.9) |
0.0477 |
| ACTH, pg/mL Median (IQR) |
105 | 19.0 (13–26.5) |
25.0 (16.5–33) |
17.0 (10.7–23.3) |
0.0060 | 22.0 (14–32.0) |
16.0 (9.1–22.5) |
0.0040 | 20.98 (14.8–30.5) |
17.0 (11–24.3) |
0.0490 |
| DHEAS, mcg/dL Median (IQR) |
86 | 55.5 (26.8–93) |
34 (18–68) |
67.0 (33–106) |
0.0336 | 39.0 (21.0–92) |
62.0 (36.5–94.5) |
0.119 | 46.0 (21.75–87.5) |
57 (28.5–157.4) |
0.2647 |
| Testing following the overnight metyrapone administration | |||||||||||
| Cortisol, mcg/dL Median (IQR) |
113 | 4.3 (2.4–6.8) |
1.6 (1–2.7) |
5.1 (3.4–7.2) |
<0.001 | 2.3 (1.4–4) |
5.2 (3.8–7.3) |
<0.001 | 2.3 (1.4–3.3) |
5.9 (4.4–7.9) |
<0.001 |
| ACTH, pg/dL Median (IQR) |
78 | 179 (97.5–294) |
65 (30.5–90.6) |
215 (149–359) |
<0.001 | 99 (50.5–175.5) |
236 (177.5–361.5) |
<0.001 | 112 (50.8–180.5) |
235 (178.5–361.5) |
<0.001 |
| 11-deoxycortisol, mcg/dL Median (IQR) |
114 | 9.8 (6.9–13.4) |
3.3 (1.7–5.9) |
11.8 (9.3–14.4) |
- | 6.6 (2.7–8.8) |
13.4 (11.8–15.1) |
- | 6.5 (2.91–8.9) |
13.2 (10.5–14.9) |
- |
| (cortisol + 11-deoxycortisol), mcg/dL Median (IQR) |
113 | 15.8 (10.1–19.2) |
5.9 (3.2–7.5) |
17.1 (13.8–20.4) |
<0.001 | 9.2 (5.6–11.7) |
19.2 (16.6–22) |
<0.001 | 9.2 (5.5–12.02) |
19.1 (16.6–21.6) |
<0.001 |
| Cosyntropin stimulation test | |||||||||||
| Peak cortisol, mcg/dL Median (IQR) |
53 | 22 (17.8–24.5) |
17.3 (13.5–21) |
23 (18–25) |
0.0047 | 17.6 (14–21) |
24 (21.8–25.3) |
<0.0001 | 17.8 (14.5–20.9) |
24 (22.5–26) |
<0.001 |
| <14 mcg/dL | 5 (9.4%) | 3 (30%) | 2 (5%) | 0.0316 | 4 (17.4%) | 0 (%) | 0.0258 | 4 (16.7%) | 1 (3.7%) | 0.1202 | |
| Pre-test probability and final adrenal insufficiency diagnosis | |||||||||||
| Low | 52 (45.6%) | 4 (15.4%) | 46 (54.1%) | 8 (17.02%) | 39 (69.6%) | 12 (24%) | 38 (64.4%) | ||||
| Final diagnosis of AI, n (%) | 114 | 42 (36.8%) | 26 (100%) | 15 (17.7%) | - | 36 (76.6%) | 3 (5.4%) | - | 37 (74%) | 4 (6.8%) | - |
Abbreviations: AI: adrenal insufficiency; ACTH: corticotropin; DHEAS: dehydroepiandrosterone sulfate
OMT Procedure and Adverse Events
Patients were prescribed a median metyrapone dose of 2500 mg (IQR 2188–3000), corresponding to a median of 30.2 mg/kg (IQR 28.2–33.0). Few patients (22, 19.3%) were advised to take 20 mg hydrocortisone immediately after the morning blood collection following the overnight metyrapone administration. Seven (6.1%) patients reported adverse events related to OMT, including nausea, vomiting, chills, fatigue, lightheadedness, drowsiness, bad taste, feeling of warmth, and nocturnal disorientation, Table 3. One patient required admission to the hospital for severe vomiting and nausea without signs of hemodynamic instability. Notably, this patient’s testing excluded SAI. Among the patients who experienced adverse events, all patients had post-OMT 11-deoxycortisol > 7 mg/dL, with four patients demonstrating post-OMT 11-deoxycortisol between 7 and 10 mg/dL, and five patients with the sum of post-OMT cortisol and 11-deoxycortisol of > 15 mcg/dL, Table 3. We found no factors associated with the development of adverse events, Table 4.
Table 3.
Adverse events associated with administration of overnight metyrapone.
| n | Age | Sex | Baseline hormonal testing | Post-CST cortisol, mcg/dL | Metyrapone dose | Post-OMT 11-deoxycortisol, mcg/dL | Post-OMT cortisol, mcg/dL | Adverse event | Post-OMT hydrocortisone |
|---|---|---|---|---|---|---|---|---|---|
| 1 | 42 | F | Cortisol: 9.5 mcg/dL ACTH: 16 pg/dL DHEAS: 78 mcg/dL |
24 | 2250 mg 31.2 mg/kg |
13.7 | 4.2 | hypotension fatigue drowsiness |
Planned: no Reactive: no |
| 2 | 42 | F | Cortisol: 12 mcg/dL ACTH: 11 pg/dL |
25 | 3000 mg 29.4 mg/kg |
12.3 | 3.8 | severe nausea vomiting hospitalization (no hemodynamic instability) |
Planned: no Reactive: yes, intravenous |
| 3 | 23 | M | Cortisol: 4.8 mcg/dL ACTH: 37 pg/dL DHEAS: 107 mcg/dL |
9.9 | 2000 mg 39.9 mg/kg |
8.1 | 1.1 | lightheadedness feeling of warmth shakiness |
Planned: no Reactive: no |
| 4 | 38 | F | Cortisol: 15.3 mcg/dL ACTH: 21 pg/dL |
- | 2500 mg 33.9 mg/kg |
9.46 | 7 | fatigue nausea vomiting |
Planned: no Reactive: no |
| 5 | 43 | F | Cortisol: 21 mcg/dL ACTH: 26 pg/dL |
19 | 2500 mg 31.6 mg/kg |
7.67 | 9, on oral estrogen | nausea lightheadedness feeling of warmth |
Planned: yes, oral Reactive: no |
| 6 | 40 | F | Cortisol: 8.7 mcg/dL ACTH: 19 pg/dL |
18 | 2000 mg 29.4 mg/kg |
11.9 | 3.2 | nausea bad mouth taste lightheadedness nocturnal disorientation |
Planned: no Reactive: no |
| 7 | 44 | F | Cortisol: 10 mcg/dL DHEAS: 92 mcg/dL |
- | 2000 mg 36.7 mg/kg |
8.85 | 1.7 | chills severe nausea vomiting lightheadedness |
Planned: yes, oral Reactive: no |
Abbreviations: ACTH: corticotropin; AI: adrenal insufficiency; CST: Cosyntropin stimulation test; DHEAS: dehydroepiandrosterone sulfate; OMT: overnight metyrapone test; SAI: secondary adrenal insufficiency
Reference ranges: ACTH: 7.2–63 pg/dL, morning cortisol 7–25 mcg/dL, DHEAS: sex and age-based reference ranges (mayocliniclabs.com).
Table 4:
Factors potentially associated with development of adverse events after overnight administration of metyrapone
| Variable | Adverse event | No adverse event | P value |
|---|---|---|---|
| n | 7 | 107 | |
| Women, n (%) | 6 (5.3%) | 75 (65.8%) | 0.6712 |
| Age, years Median (IQR) |
42 (38–43) |
49 (37–59) |
0.1122 |
| Metyrapone dose, mg/kg Median (IQR) |
31.6 (29.4–39.9) |
30 (28.1–32.9) |
0.1097 |
| Metyrapone total dose, mg Median (IQR) |
2250 (2000–2500) |
2500 (2250–3000) |
0.1264 |
| Advised to take hydrocortisone post overnight metyrapone testing, n (%) | 1 (14.3%) | 21 (19.6%) | 1.000 |
| Baseline testing | |||
| Cortisol, mcg/dL Median (IQR) |
10 (8.7–15.3) |
8.9 (6.3–11) |
0.1859 |
| ACTH, pg/mL Median (IQR) |
20 (14.75–28.75) |
19 (13–27) |
0.6585 |
| DHEAS, mcg/dL Median (IQR) |
92 (78–107) |
54 (26–90) |
0.1649 |
| Testing following the overnight metyrapone administration | |||
| Cortisol, mcg/dL Median (IQR) |
3.8 (1.7–7) |
4.3 (2.4–6.8) |
0.6507 |
| ACTH, pg/dL Median (IQR) |
263 (115–407) |
178 (93–290) |
0.1869 |
| 11-deoxycortisol, mcg/dL Median (IQR) |
9.46 (8.07–12.3) |
9.82 (6.62–13.5) |
0.9295 |
| Cosyntropin stimulation test | |||
| Peak cortisol, mcg/dL Median (IQR) |
19 (13.95–24.5) |
22 (17.7–24.75) |
0.5522 |
Abbreviations: ACTH: corticotropin; DHEAS: dehydroepiandrosterone sulfate; OMT: overnight metyrapone test
Reference ranges: ACTH: 7.2–63 pg/dL, morning cortisol 7–25 mcg/dL, DHEAS: sex and age-based reference ranges (mayocliniclabs.com).
OMT-Based Diagnosis of Adrenal Insufficiency
Median post-OMT cortisol was 4.3 mcg/dL (IQR, 2.4–6.8), median post-OMT ACTH was 179 pg/mL (IQR, 97.5–294), and median post-OMT 11-deoxycortisol was 9.8 mcg/dL (IQR, 6.9–13.4), Table 2. Prevalence of the OMT-based SAI diagnosis was 26 (23%), 47 (46%), and 50 (46%) using 11-deoxycortisol cutoff < 7 mcg/dL, < 10 mcg/dL and sum of post-OMT cortisol and 11-deoxycortisol of < 15 mcg/dL, respectively.
Pre-test probability was associated with the OMT-based diagnosis, with results varying based on the post-OMT 11-deoxycortisol cutoff used and being abnormal in 71–86% of patients with high pre-test probability, 26–65% of those with moderate pre-test probability, and 8–23% of those with low pre-test probability, Table 5.
Table 5.
Diagnosis of adrenal insufficiency based on the overnight metyrapone test in relation to pre-test probability
| Pre-test probability | N | Diagnosis of adrenal insufficiency based on the overnight metyrapone test | Final diagnosis of adrenal insufficiency | ||
|---|---|---|---|---|---|
| 11-deoxycortisol <7 mcg/dL | 11-deoxycortisol <10 mcg/dL | (11-deoxycortisol + cortisol) <15 mcg/dL | |||
| High pre-test probability | 14 | 10 (71%) | 12 (86%) | 12 (86%) | 12 |
| Moderate pre-test probability | 48 | 12 (26%) | 27 (65%) | 26 (54%) | 24 |
| Low pre-test probability | 52 | 4 (8%) | 8 (17%) | 12 (23%) | 6 |
| Total | 114 | 26 (23%) | 47 (46%) | 50 (46%) | 42 |
Both baseline and post-OMT ACTH were lower in patients with the OMT-based diagnosis of SAI regardless of the definition used, Table 2. Post-OMT ACTH weakly correlated with post-OMT 11-deoxycortisol (r2=0.246, p<0.0001). Post-OMT ACTH cutoff of 150 pg/mL had an overall accuracy of 74% when a post-OMT 11-deoxycortisol cutoff of 10 mcg/dL was used, Appendix 2.
When compared to the OMT-based diagnosis of SAI, the overall accuracy of CST was suboptimal at 78% with a low sensitivity of 52% but a high specificity of 100% when post-OMT 11-deoxycortisol of 10 mcg/dL was used, Appendix 2.
Follow-up
A total of 42 (36.8%) patients were diagnosed with SAI by the clinician after considering biochemical testing and pre-test probability. Of 33 patients started on daily glucocorticoid therapy, symptomatic improvement was noted in 22 (66.7%) patients, no change in symptoms in 5 (15.2%) patients, and unknown due to lack of follow-up in 6 (18.2%) patients.
Discussion
In this study, we found that outpatient single-dose OMT is a safe procedure, with a prevalence of mostly mild adverse events in 6.1% of patients. We found no factors associated with the development of adverse events. Our results show that clinicians order OMT mostly in patients with a low or medium pre-test probability of SAI and that the post-OMT 11-deoxycortisol cutoff of less than 10 mcg/dL is most used to diagnose SAI. Post-OMT ACTH was associated with the post-OMT 11-deoxycortisol concentrations. In a subset of patients who underwent both OMT and CST, we show suboptimal performance of CST compared to the OMT-based diagnosis of SAI.
We showed that adverse events were recorded in 6.1% of patients and occurred in patients with SAI and those in whom SAI was excluded. Reported symptoms included fatigue, nausea, vomiting, and lightheadedness. One patient was hospitalized after OMT due to vomiting and concern about adrenal crisis; however, no hemodynamic instability was noted, and several baseline and dynamic testing results excluded SAI. Notably, as uniform hydrocortisone administration was introduced only in the latter part of the study, most patients undergoing OMT did not receive hydrocortisone in the morning following metyrapone administration. However, we have not found that the prevalence of adverse events was lower in patients who received hydrocortisone immediately after the morning blood collection. In addition, we have not found that the baseline adrenal function, post-OMT diagnosis of SAI, overall metyrapone dose, or metyrapone mg/kg dose were associated with the development of adverse events. Several previous studies commented on adverse events during outpatient OMT, with discrepant results. Two studies12, 16 with 63 patients reported no adverse events during OMT, while three studies11, 18, 19 with 186 patients reported mild adverse events with prevalence ranging from 2–28%. These symptoms included dizziness, nausea, sweating, vomiting, headaches, and loose stools, Appendix 3. Additionally, three other studies17, 20, 21 reported similar adverse events to metyrapone, including nausea, slight headache, and dizziness. However, the exact number of patients experiencing these adverse events to metyrapone was not specified, Appendix 3. No studies investigated factors associated with the development of adverse events.
Clinicians diagnosed SAI in 100% of patients with post-OMT 11-deoxycortisol < 7mcg/dL, but also an additional 16 patients with post-OMT 11-deoxycortisol between 7 and 10 mcg/dL, more often when the pre-test probability was moderate and high. Notably, we found that a quarter of all patients (23%) demonstrated post-OMT cortisol > 7 mcg/dL. Despite the nonsuppressed cortisol, most patients in this category demonstrated post-OMT 11-deoxycortisol concentrations > 7–10 mcg/dL, allowing the exclusion of SAI diagnosis. Two previous studies reported on post-OMT ACTH measurement in diagnosing SAI. One study reported that a post-OMT ACTH cutoff of 147 pg/mL had a sensitivity of 73.2% and specificity of 83.9% compared to the post-OMT 11-deoxycortisol of 7 mcg/dL (chosen reference standard)18. In the only small study of 31 patients that compared post-OMT ACTH to ITT, a cutoff of 150 pg/mL demonstrated a sensitivity of 78.6% and specificity of 47.1%16. Our study found that post-OMT ACTH of 150 pg/mL has a sensitivity of 88% and specificity of 71% when using the post-OMT 11-deoxycortisol of less than 7 mcg/dL. Post-OMT ACTH measurement may bring additional value when interpreting post-OMT borderline 11-deoxycortisol results.
The overall accuracy of CST in our study was suboptimal at 78%, with a low sensitivity of 52%, indicating that CST can incorrectly exclude patients with SAI. We found that CST was abnormal in only half of the patients diagnosed with SAI. These findings are consistent with the systematic review and meta-analysis by Singh-Ospina et al., which reported an overall sensitivity of high-dose CST of 64% in diagnosing SAI4. Low-dose CST was reported to have a sensitivity of 83% in diagnosing SAI, higher than the high-dose CST4. We could not distinguish between the two tests as all patients in our study underwent a high-dose CST. Based on our data and data previously reported4, we conclude that patients with normal CST results but suspected to have SAI may need another test, such as OMT, to make a confident diagnosis.
Strengths of our study include relatively large sample size, a consecutive cohort of patients, consideration of the pre-test probability, the inclusion of patients with low and moderate pre-test probability, and a standardized assessment of adverse events. Another strength is the use of the liquid chromatography-tandem mass spectrometry assay for the measurement of 11-deoxycortisol. Limitations include information bias, selection bias, and heterogeneity in the OMT procedure (within the protocol limits). As all clinicians ordering OMT were adrenal experts, it is possible that pre-test probability estimates are not generalizable to clinicians with a smaller proportion of adrenal practice. As this study was based on routine clinical practice, not all patients had CST and post-OMT ACTH concentrations.
In conclusion, OMT is a safe and well-tolerated procedure when performed in an outpatient setting. The pre-test probability was associated with abnormal OMT results. Clinicians ordered OMT in patients with low and moderate pre-test probability for SAI, and most used the post-OMT 11-deoxycortisol cutoff of 10 mcg/dL to exclude SAI. CST has low sensitivity, thus erroneously excluding patients with SAI.
Supplementary Material
Funding Statement:
This study was partially supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health (NIH) USA under awards K23DK121888 and R03DK132121. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Footnotes
Conflict of interest statement: Dr. Bancos reports advisory board participation/consulting (fees to institution) with HRA Pharma, Corcept, Recordati, Sparrow Pharmaceutics, Neurocrine, Spruce, Diurnal outside the submitted work, data monitoring and safety board participation for Adrenas, and funding from Recordati unrelated to this work. The remainder of the authors have nothing to disclose.
Data availability statement
Some or all datasets generated during or analyzed during the current study are not publicly available but are available from the corresponding author on reasonable request.
References
- 1.Bancos I, Hahner S, Tomlinson J, Arlt W. Diagnosis and management of adrenal insufficiency. Lancet Diabetes Endocrinol. Mar 2015;3(3):216–26. doi: 10.1016/s2213-8587(14)70142-1 [DOI] [PubMed] [Google Scholar]
- 2.Charmandari E, Nicolaides NC, Chrousos GP. Adrenal insufficiency. Lancet. Jun 21 2014;383(9935):2152–67. doi: 10.1016/S0140-6736(13)61684-0 [DOI] [PubMed] [Google Scholar]
- 3.Dorin RI, Qualls CR, Crapo LM. Diagnosis of adrenal insufficiency. Ann Intern Med. Aug 5 2003;139(3):194–204. doi: 10.7326/0003-4819-139-3-200308050-00009 [DOI] [PubMed] [Google Scholar]
- 4.Ospina NS, Al Nofal A, Bancos I, et al. ACTH Stimulation Tests for the Diagnosis of Adrenal Insufficiency: Systematic Review and Meta-Analysis. J Clin Endocrinol Metab. Feb 2016;101(2):427–34. doi: 10.1210/jc.2015-1700 [DOI] [PubMed] [Google Scholar]
- 5.Erturk E, Jaffe CA, Barkan AL. Evaluation of the integrity of the hypothalamic-pituitary-adrenal axis by insulin hypoglycemia test. J Clin Endocrinol Metab. Jul 1998;83(7):2350–4. doi: 10.1210/jcem.83.7.4980 [DOI] [PubMed] [Google Scholar]
- 6.Grinspoon SK, Biller BM. Clinical review 62: Laboratory assessment of adrenal insufficiency. J Clin Endocrinol Metab. Oct 1994;79(4):923–31. doi: 10.1210/jcem.79.4.7962298 [DOI] [PubMed] [Google Scholar]
- 7.Fish HR, Chernow B, O’Brian JT. Endocrine and neurophysiologic responses of the pituitary to insulin-induced hypoglycemia: a review. Metabolism. Aug 1986;35(8):763–80. doi: 10.1016/0026-0495(86)90245-3 [DOI] [PubMed] [Google Scholar]
- 8.Streeten DH, Anderson GH Jr., Dalakos TG, et al. Normal and abnormal function of the hypothalamic-pituitary-adrenocortical system in man. Endocr Rev. Summer 1984;5(3):371–94. doi: 10.1210/edrv-5-3-371 [DOI] [PubMed] [Google Scholar]
- 9.Fiad TM, Kirby JM, Cunningham SK, McKenna TJ. The overnight single-dose metyrapone test is a simple and reliable index of the hypothalamic-pituitary-adrenal axis. Clin Endocrinol (Oxf). May 1994;40(5):603–9. doi: 10.1111/j.1365-2265.1994.tb03011.x [DOI] [PubMed] [Google Scholar]
- 10.Steiner H, Bahr V, Exner P, Oelkers PW. Pituitary function tests: comparison of ACTH and 11-deoxy-cortisol responses in the metyrapone test and with the insulin hypoglycemia test. Exp Clin Endocrinol. 1994;102(1):33–8. doi: 10.1055/s-0029-1211262 [DOI] [PubMed] [Google Scholar]
- 11.Suliman AM, Smith TP, Labib M, Fiad TM, McKenna TJ. The low-dose ACTH test does not provide a useful assessment of the hypothalamic-pituitary-adrenal axis in secondary adrenal insufficiency. Clin Endocrinol (Oxf). Apr 2002;56(4):533–9. doi: 10.1046/j.1365-2265.2002.01509.x [DOI] [PubMed] [Google Scholar]
- 12.Courtney CH, McAllister AS, McCance DR, et al. The insulin hypoglycaemia and overnight metyrapone tests in the assessment of the hypothalamic-pituitary-adrenal axis following pituitary surgery. Clin Endocrinol (Oxf). Sep 2000;53(3):309–12. doi: 10.1046/j.1365-2265.2000.01093.x [DOI] [PubMed] [Google Scholar]
- 13.Gibney J, Healy ML, Smith TP, McKenna TJ. A simple and cost-effective approach to assessment of pituitary adrenocorticotropin and growth hormone reserve: combined use of the overnight metyrapone test and insulin-like growth factor-I standard deviation scores. J Clin Endocrinol Metab. Oct 2008;93(10):3763–8. doi: 10.1210/jc.2008-0154 [DOI] [PubMed] [Google Scholar]
- 14.Cunningham SK, Moore A, McKenna TJ. Normal cortisol response to corticotropin in patients with secondary adrenal failure. Arch Intern Med. Dec 1983;143(12):2276–9. [PubMed] [Google Scholar]
- 15.Jubiz W, Meikle AW, West CD, Tyler FH. Single-dose metyrapone test. Arch Intern Med. Mar 1970;125(3):472–4. [PubMed] [Google Scholar]
- 16.Giordano R, Picu A, Bonelli L, et al. Hypothalamus-pituitary-adrenal axis evaluation in patients with hypothalamo-pituitary disorders: comparison of different provocative tests. Clin Endocrinol (Oxf). Jun 2008;68(6):935–41. doi: 10.1111/j.1365-2265.2007.03141.x [DOI] [PubMed] [Google Scholar]
- 17.Berneis K, Staub JJ, Gessler A, Meier C, Girard J, Muller B. Combined stimulation of adrenocorticotropin and compound-S by single dose metyrapone test as an outpatient procedure to assess hypothalamic-pituitary-adrenal function. J Clin Endocrinol Metab. Dec 2002;87(12):5470–5. doi: 10.1210/jc.2001-011959 [DOI] [PubMed] [Google Scholar]
- 18.Papierska L, Rabijewski M, Migda B, et al. Evaluation of plasma ACTH in the metyrapone test is insufficient for the diagnosis of secondary adrenal insufficiency. Front Endocrinol (Lausanne). 2022;13:1004129. doi: 10.3389/fendo.2022.1004129 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.English K, Inder WJ, Weedon Z, et al. Prospective evaluation of a week one overnight metyrapone test with subsequent dynamic assessments of hypothalamic-pituitary-adrenal axis function after pituitary surgery. Journal Article. Clin Endocrinol (Oxf) Jul 2017;87(1):35–43. doi: 10.1111/cen.13334 [DOI] [PubMed] [Google Scholar]
- 20.Endert E, Ouwehand A, Fliers E, Prummel MF, Wiersinga WM. Establishment of reference values for endocrine tests. Part IV: Adrenal insufficiency. Journal Article. Neth J Med Dec 2005;63(11):435–43. [PubMed] [Google Scholar]
- 21.Calis M, Gokce C, Ates F, et al. Investigation of the hypothalamo-pituitary-adrenal axis (HPA) by 1 microg ACTH test and metyrapone test in patients with primary fibromyalgia syndrome. Clinical Trial Controlled Clinical Trial Journal Article. J Endocrinol Invest Jan 2004;27(1):42–6. doi: 10.1007/BF03350909 [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
Some or all datasets generated during or analyzed during the current study are not publicly available but are available from the corresponding author on reasonable request.