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Evaluation of the Integrity of the Hypothalamic-Pituitary-Adrenal Axis by Insulin Hypoglycemia Test1
Abstract
We retrospectively reviewed dynamic ACTH and cortisol responses to insulin hypoglycemia in 193 subjects with suspected ACTH deficiency to ascertain the predictive values of various diagnostic criteria. Based on the achievement of a peak cortisol level of 18 micrograms/dL or above, 133 subjects were classified as having an intact hypothalamic-pituitary-adrenal (HPA) axis, and 60 subjects were determined to have ACTH deficiency. Baseline and peak cortisol concentrations were strongly correlated (r = 0.63; P < 0.0001). Peak cortisol increased in parallel to ACTH increments, but plateaued at approximately 22 micrograms/dL at peak ACTH levels above approximately 75 pg/mL (r = 0.61; P < 0.0001). Basal cortisol values above 17 micrograms/dL or below 4 micrograms/dL were highly predictive of an intact or impaired HPA axis, respectively, but intermediate values had only limited sensitivity and specificity. The criteria of HPA axis integrity, defined as an increment in plasma cortisol of more than 7 micrograms/dL above the baseline or as a doubling of the baseline cortisol value, were associated with high false positive and false negative rates. We conclude that 1) the baseline morning serum cortisol concentration has very limited predictive power in differentiating between normal and impaired HPA function; 2) the use of criteria based on incremental changes in serum cortisol from baseline leads to unacceptably high false positive and false negative rates; and 3) insulin hypoglycemia i…
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Most primary reports detailing the 140 nmol/L cutoff value are not based on subjects with PAI.
“Unfortunately, most of the primary reports detailing this cutoff value are not based on subjects with PAI (23,24,(61)(62)(63)(64).”
From Diagnosis and Treatment of Primary Adrenal Insufficiency: An Endocrine Society Clinical Practice Guideline (2016) · cites this paper as [62]
The choice of morning cortisol concentration to rule out adrenal insufficiency is controversial, with studies arguing levels from >285 nmol/L to >480 nmol/L.
“It should be noted that the choice of what morning cortisol concentration to utilize to rule out adrenal insufficiency (100% sensitivity) is controversial, with studies arguing levels from Ͼ285 nmol/L (10.3 g/dL) (23) to Ͼ480 nmol/L (17 g/dL) (62).”
From Diagnosis and Treatment of Primary Adrenal Insufficiency: An Endocrine Society Clinical Practice Guideline (2016) · cites this paper as [62]
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“Oelkers et al. ( 14 ) found a very similar dose-response relation using exogenous ACTH.”
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“Itshouldbenotedthatthechoiceofwhatmorningcortisol concentration to utilize to rule out adrenal insufficiency (100% sensitivity) is controversial, with studies arguing lev-elsfrom (cid:4) 285nmol/L(10.3 (cid:2) g/dL)(23)to (cid:4) 480nmol/L(17 (cid:2) g/dL) (62).”
BackgroundInfluentialDiagnosis of Adrenal Insufficiency
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Metadata
- Authors
- Erturk, E., Jaffe, C. A., & Barkan, A. L.
- Affiliations
- University of Michigan (US)
- ORCID
- Barkan, Ariel L.
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 1998-07
- Volume
- 83
- Issue
- 7
- Pages
- 2350-2354
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- OpenAlex
- W2073360576
- Cited by
- 204
- References
- 2
- Citations by year
- 2026: 5 · 2025: 2 · 2024: 8 · 2023: 7 · 2022: 6 · 2021: 9 · 2020: 12 · 2019: 9 · 2018: 11 · 2017: 9 · 2016: 13 · 2015: 10 · 2014: 9 · 2013: 10 · 2012: 2
- FWCI
- 1.67
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Public Health Service (R01-38449)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pituitary Gland Disorders and Treatments
- Keywords
- hypothalamic-pituitary-adrenal axis, ACTH deficiency, insulin hypoglycemia test, ACTH stimulation test, cortisol response, diagnostic criteria, false positive and false negative rates, stress response
- MeSH terms
- Adolescent, Adult, Aged, Aged, 80 and over, Evaluation Studies as Topic, Female, Humans, Hypoglycemic Agents, Hypothalamo-Hypophyseal System, Insulin, Male, Middle Aged, Pituitary-Adrenal System, Predictive Value of Tests, Retrospective Studies, Reproducibility of Results, Linear Models
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