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Differentiating hypothalamic from pituitary adrenal insufficiency: underlying causes and diagnostic utility of the corticotropin-releasing hormone and growth hormone-releasing peptide-2 stimulation tests
Open accessAbstract
In Japan, the Corticotropin-releasing hormone (CRH) stimulation test is widely used to evaluate secondary adrenal insufficiency (SAI); however, the insulin tolerance test (ITT) is sometimes required to assess hypothalamic dysfunction. This study aimed to identify the clinical conditions in which the ITT is necessary in addition to CRH testing. We retrospectively analyzed 69 patients who underwent both tests between August 2015 and December 2024. Forty-three patients with insufficient cortisol responses during the ITT were diagnosed with SAI and the others with non-SAI. Among SAI cases, cortisol level ≥18 μg/dL during CRH testing defined hypothalamic SAI and <18 μg/dL defined pituitary SAI. Clinical profiles and ACTH responses were compared. Pituitary SAI was associated with tumors, immune-related adverse events, glucocorticoids, COVID-19, hypophysitis and empty sella. Hypothalamic SAI was mainly associated with tumors, opioids, and COVID-19. During CRH testing, ACTH responses alone poorly distinguished hypothalamic SAI from non-adrenal insufficiency among patients with normal cortisol responses to CRH; however, a specific pattern of low basal level combined with a high peak of ACTH after CRH stimulation suggested hypothalamic SAI. In addition, a peak cortisol level <12 μg/dL in the growth hormone-releasing peptide-2 (GHRP-2) stimulation test was also specific to hypothalamic SAI among patients with normal cortisol responses to CRH. In conclusion, even when cortisol responses to CRH appear adequate, the ITT remains necessary for patients with clinical or etiological features suggestive of hypothalamic dysfunction. When the ITT is contraindicated, analyzing ACTH values during the CRH stimulation test and peak cortisol levels during the GHRP-2 test would effectively support hypothalamic SAI diagnosis.
Overview
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TL;DR
In a retrospective single-center cohort, 43 of 64 patients who underwent both insulin tolerance testing (ITT) and CRH testing were diagnosed with secondary adrenal insufficiency (SAI); among them, 9 had preserved cortisol responses to CRH and were classified as hypothalamic SAI. CRH cortisol responses alone could not reliably identify hypothalamic SAI, but ACTH patterns during CRH testing and GHRP-2 peak cortisol levels may support diagnosis when ITT is contraindicated, while ITT remains necessary for definitive diagnosis.
Key findings
- Among 43 SAI patients, 34 (79.1%) had pituitary SAI and 9 (20.9%) had hypothalamic SAI based on CRH peak cortisol. Pituitary SAI etiologies included irAEs (7/34, 20.6%), iatrogenic causes (7/34, 20.6%), tumors (6/34, 17.6%), COVID-19-related SAI (3/34, 8.8%), and hypophysitis (1/34, 2.9%); hypothalamic SAI was predominantly tumor-related (5/9, 55.6%), followed by COVID-19-related SAI (2/9, 22.2%) and one opioid-induced case.
- During CRH testing, peak ACTH was higher in hypothalamic than pituitary SAI (median 71.7 [53.2–127] vs. 33.1 [22.4–58.6] pg/mL, p = 0.01; AUC 0.77; cutoff 37.1 pg/mL, sensitivity 0.62, specificity 0.89). Among patients with a normal cortisol response to CRH, peak ACTH alone discriminated poorly from non-SAI (AUC 0.63; cutoff 81.4 pg/mL, sensitivity 0.90, specificity 0.44), but basal ACTH <25 pg/mL plus peak ACTH >83 pg/mL was exclusively observed in hypothalamic SAI (PPV 100%, sensitivity 44%).
- GHRP-2 peak cortisol correlated with ITT peak cortisol (ρ = 0.85) and CRH peak cortisol (ρ = 0.69). A GHRP-2 peak cortisol cutoff of 14.7 μg/dL differentiated SAI from non-SAI (AUC 0.91; sensitivity 0.78; specificity 0.92); 17.0 μg/dL differentiated hypothalamic SAI from non-SAI (AUC 0.80; sensitivity 0.75; specificity 0.83); and <12.0 μg/dL in patients with normal CRH cortisol responses identified hypothalamic SAI with PPV 100% and sensitivity 50%.
Methods
- Retrospective study at St. Marianna University Hospital, August 2015–December 2024. Of 69 patients who underwent both ITT and CRH testing, 4 were excluded for inadequate hypoglycemia and 1 was judged not to have SAI; 43 were classified as SAI by ITT peak cortisol <18 μg/dL and 21 as non-SAI by peak cortisol ≥18 μg/dL. SAI was subclassified by CRH peak cortisol: ≥18 μg/dL as hypothalamic SAI (n = 9) and <18 μg/dL as pituitary SAI (n = 34).
- ITT: overnight fast, IV regular insulin; adequate hypoglycemia defined as plasma glucose ≤50 mg/dL or ≤50% of baseline at 30 min; cortisol and ACTH measured at baseline and 30, 60, 90, and 120 min. CRH test: 100 μg human CRH IV after overnight fasting and bed rest; samples at baseline and 30, 60, 90, and 120 min. GHRP-2 test: 100 μg IV bolus; samples at baseline and 15, 30, 45, and 60 min.
- Analyses used median [IQR] or proportions, Mann-Whitney U or Fisher’s exact tests, p < 0.05, ROC curve analysis with Youden-index cutoffs, and Spearman correlations. Cortisol was measured using four different assay systems during the study period.
Limitations
- Paper-stated: selection bias because ITT was performed by clinical judgment; the non-SAI group may not represent the healthy general population; COVID-19-related SAI lacks established diagnostic criteria and misclassification is possible; the hypothalamic SAI group was small, external validation was not performed, and proposed cutoffs are exploratory; heterogeneous etiologies may confound ACTH/cortisol responses without statistical adjustment; no positive controls with clearly established hypothalamic or pituitary structural lesions were included; and this was a single-center study limiting generalizability.
- Text-evident: the retrospective design and use of four different cortisol assays over the study period may affect comparability; the proposed ACTH and GHRP-2 criteria had high PPV but limited sensitivity; and longitudinal endocrine data were unavailable for three excluded iatrogenic cases suspected to be in recovery from glucocorticoid-induced suppression.
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In the paper
“Tumor-related lesions were more common in the hypothalamic group (5/9, 55.6%) than in the pituitary group (6/34, 17.6%).”
§ Differentiating hypothalamic from pituitary adrenal insufficiency: underlying causes and diagnostic utility of the corticotropin-releasing hormone and growth hormone-releasing peptide-2 stimulation tests > Endocrine Journal Advance Publication
plainstates an association- Asserted: passes — The authors put it forward as true.
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In the paper
“Similarly, the peak-to-basal ACTH ratio demonstrated an improved AUC of 0.75, yielding a sensitivity of 0.58 and a specificity of 0.89 at an updated cutoff value of 2.57 (Supplementary Fig. 1D).”
§ Differentiating hypothalamic from pituitary adrenal insufficiency: underlying causes and diagnostic utility of the corticotropin-releasing hormone and growth hormone-releasing peptide-2 stimulation tests > Endocrine Journal Advance Publication
boostedstates an association- Asserted: passes — The authors put it forward as true.
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In the paper
“Peak cortisol levels were significantly lower in both the hypothalamic and pituitary SAI groups than in the non-SAI group (overall SAI vs. non-SAI, p < 0.01; hypothalamic SAI vs. non-SAI, p < 0.05; pituitary SAI vs. non-SAI, p < 0.01; Table 3).”
§ Differentiating hypothalamic from pituitary adrenal insufficiency: underlying causes and diagnostic utility of the corticotropin-releasing hormone and growth hormone-releasing peptide-2 stimulation tests > Diagnostic utility of the growth hormone-releasing peptide-2 (GHRP-2) stimulation test and correlations with the ITT and CRH stimulation test
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In the paper
“The peak ACTH levels in the non-SAI group were equivalent to those in the hypothalamic group (median peak, 71.7 [53.2-127] vs. 63.6 [47.1-72.8]pg/mL; p = 0.31).”
§ Differentiating hypothalamic from pituitary adrenal insufficiency: underlying causes and diagnostic utility of the corticotropin-releasing hormone and growth hormone-releasing peptide-2 stimulation tests > Discrimination between hypothalamic SAI and nonadrenal insufficiency in patients with a normal cortisol response to CRH
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“SAI following COVID-19 was identified in both groups (two hypothalamic and three pituitary cases).”
§ Differentiating hypothalamic from pituitary adrenal insufficiency: underlying causes and diagnostic utility of the corticotropin-releasing hormone and growth hormone-releasing peptide-2 stimulation tests > Endocrine Journal Advance Publication
plainn = 3- Asserted: passes — The authors put it forward as true.
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In the paper
§ Differentiating hypothalamic from pituitary adrenal insufficiency: underlying causes and diagnostic utility of the corticotropin-releasing hormone and growth hormone-releasing peptide-2 stimulation tests > Diagnostic utility of the growth hormone-releasing peptide-2 (GHRP-2) stimulation test and correlations with the ITT and CRH stimulation test
“In addi-tion, the optimal cutoff value for differentiating hypothalamic SAI from non-SAI was 17.0 μg/dL (AUC, 0.80; sensitivity, 0.75; specificity, 0.83; Fig. 4F).”
§ Differentiating hypothalamic from pituitary adrenal insufficiency: underlying causes and diagnostic utility of the corticotropin-releasing hormone and growth hormone-releasing peptide-2 stimulation tests > Diagnostic utility of the growth hormone-releasing peptide-2 (GHRP-2) stimulation test and correlations with the ITT and CRH stimulation test
“Among the included patients, the GHRP-2 stimulation test was performed in 27 patients with SAI (21 with pituitary SAI and 6 with hypothalamic SAI) and 12 individuals without SAI.”
Rated major: it would touch a result — a value a result rests on, reported and recomputed p-values on opposite sides of the significance level, two passages that conflict with no sign which is right, or a cited work retracted before this paper was published.
In the paper
§ Differentiating hypothalamic from pituitary adrenal insufficiency: underlying causes and diagnostic utility of the corticotropin-releasing hormone and growth hormone-releasing peptide-2 stimulation tests > Discrimination between hypothalamic SAI and nonadrenal insufficiency in patients with a normal cortisol response to CRH
“A cutoff value of 81.4 pg/mL yielded high sensitivity (0.90) but low specificity (0.44) for identifying hypothalamic SAI.”
§ Differentiating hypothalamic from pituitary adrenal insufficiency: underlying causes and diagnostic utility of the corticotropin-releasing hormone and growth hormone-releasing peptide-2 stimulation tests > Study population and classification
“Among the 43 patients diagnosed with SAI, 9 (20.9%)patients showed an adequate cortisol response in the CRH stimulation test that had been performed previously and were classified as having hypothalamic dysfunction, whereas the remaining 34 (79.1%)patients showed an insufficient cortisol response and were classified as having pituitary dysfunction (Fig. 1).”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Differentiating hypothalamic from pituitary adrenal insufficiency: underlying causes and diagnostic utility of the corticotropin-releasing hormone and growth hormone-releasing peptide-2 stimulation tests > Abstract
“We retrospectively analyzed 69 patients who underwent both tests between August 2015 and December 2024.Forty-three patients with insufficient cortisol responses during the ITT were diagnosed with SAI and the others with non-SAI.”
§ Differentiating hypothalamic from pituitary adrenal insufficiency: underlying causes and diagnostic utility of the corticotropin-releasing hormone and growth hormone-releasing peptide-2 stimulation tests > Study population and classification
“Among them, four patients in whom adequate hypoglycemic stimulation was not achieved during the ITT and one patient who was comprehensively judged not to have SAI were excluded.Based on the ITT results, 43 patients with a blunted or absent cortisol response were diagnosed with SAI, whereas 21 patients with a normal cortisol response were classified into the non-SAI group.”
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Metadata
- Authors
- Okada, N., Nakagawa, T., Murahashi, N., Kurosu, T., Kusuda, S., Kaneko, C., Hishida, Y., Nakamura, Y., Asai, S., Yokota, K., & Sone, M.
- Affiliations
- St. Marianna University School of Medicine (JP)
- ORCID
- Venue
- Endocrine Journal
- Publisher
- Japan Endocrine Society
- Published
- 2026
- ISSN
- 0918-8959 (ISSN-L)
- 1348-4540
- OpenAlex
- W7212132032
- Semantic Scholar
- db7bd2ae9edb3dbdbd9f1a816b1f17cf7bfe7b66
- Cited by
- 0
- References
- 0
- FWCI
- 0.00
- Type
- journal article
- Language
- en
- Open access
- diamond
- doi.org
- Licence
- cc-by-nc-nd
- Locations
- Endocrine Journal (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- Ministry of Health, Labour and Welfare (26FC1042)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pituitary Gland Disorders and Treatments
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Keywords
- secondary adrenal insufficiency, corticotropin-releasing hormone stimulation test, insulin tolerance test, ACTH response, cortisol response, hypophysitis, empty sella, COVID-19 pandemic, differential diagnosis
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- Okada, N., Nakagawa, T., Murahashi, N., Kurosu, T., Kusuda, S., Kaneko, C., Hishida, Y., Nakamura, Y., Asai, S., Yokota, K., & Sone, M. (2026). Differentiating hypothalamic from pituitary adrenal insufficiency: underlying causes and diagnostic utility of the corticotropin-releasing hormone and growth hormone-releasing peptide-2 stimulation tests. Endocrine Journal. https://doi.org/10.1507/endocrj.ej26-0192
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