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Revised GH and cortisol cut-points for the glucagon stimulation test in the evaluation of GH and hypothalamic–pituitary–adrenal axes in adults: results from a prospective randomized multicenter study

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Abstract

Context

Recent studies suggest using lower GH cut-points for the glucagon stimulation test (GST) in diagnosing adult GH deficiency (GHD), especially in obese patients. There are limited data on evaluating GH and hypothalamic–pituitary–adrenal (HPA) axes using weight-based dosing for the GST.

Objective

To define GH and cortisol cut-points to diagnose adult GHD and secondary adrenal insufficiency (SAI) using the GST, and to compare fixed-dose (FD: 1 or 1.5 mg in patients >90 kg) with weight-based dosing (WB: 0.03 mg/kg). Response to the insulin tolerance test (ITT) was considered the gold standard, using GH and cortisol cut-points of ≥3 ng/ml and ≥18 µg/dL, respectively.

Design

28 Patients with hypothalamic-pituitary disease and 1–2 (n = 14) or ≥3 (n = 14) pituitary hormone deficiencies, and 14 control subjects matched for age, sex, estrogen status and body mass index (BMI) underwent the ITT, FD- and WB-GST in random order.

Results

Age, sex ratio and BMI were comparable between the three groups. The best GH cut-point for diagnosis of GHD was 1.0 (92 % sensitivity, 100 % specificity) and 2.0 ng/mL (96 % sensitivity and 100 % specificity) for FD- and WB-GST, respectively. Age negatively correlated with peak GH during FD-GST (r = −0.32, P = 0.04), but not WB-GST. The best cortisol cut-point for diagnosis of SAI was 8.8 µg/dL (92 % sensitivity, 100 % specificity) and 11.2 µg/dL (92 % sensitivity and 100 % specificity) for FD-GST and WB-GST, respectively. Nausea was the most common side effect, and one patient had a seizure during the FD-GST.

Conclusion

The GST correctly classified GHD using GH cut-points of 1 ng/ml for FD-GST and 2 ng/ml for WB-GST, hence using 3 ng/ml as the GH cut-point will misclassify some GH-sufficient adults. The GST may also be an acceptable alternative to the ITT for evaluating the HPA axis utilizing cortisol cut-points of 9 µg/dL for FD-GST and 11 µg/dL for WB-GST.

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Acknowledgments

We are grateful to Dr. Manjula Gupta for her assistance with running hormonal assays at Cleveland Clinic. We thank Robert Weil, Stacy Leg, Kellie Spiller and Ann Minnock for their assistance with dynamic tests. We acknowledge the partial support by the Clinical Research Center and its staff at Cleveland Clinic through the Case Western Reserve University/Cleveland Clinic CTSA Grant Number UL1TR000439 from the National Center for Advancing Translational Sciences (NCATS), a component of the National Institutes of Health. The contents of this manuscript are solely the responsibility of the authors and do not necessarily represent the official view of NCATS or NIH.

Funding

This study was partially supported by a Grant from Novo Nordisk.

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Authors and Affiliations

  1. Department of Endocrinology, Diabetes and Metabolism, Cleveland Clinic, Cleveland, OH, 44022, USA

    Amir H. Hamrahian

  2. Department of Endocrinology, Medical Subspecialty Institute, Cleveland Clinic Abu Dhabi, 7th Floor, Swing Wing, Al Maryah Island, PO Box 112412, Abu Dhabi, UAE

    Amir H. Hamrahian

  3. Swedish Pituitary Center, Swedish Neuroscience Institute, Seattle, WA, 98122, USA

    Kevin C. J. Yuen

  4. Department of Medicine and Neurosurgery, Allegheny Neuroendocrinology Center, Allegheny General Hospital, Pittsburgh, PA, 15212, USA

    Murray B. Gordon

  5. Neuroendocrine Unit, Massachusetts General Hospital, Boston, MA, 02114, USA

    Karen J. Pulaski-Liebert & Beverly M. K. Biller

  6. Quantitatve Health Sciences, Lerner Research Institute, Cleveland, OH, 44195, USA

    James Bena

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Correspondence to Amir H. Hamrahian.

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Conflict of interest

JB has nothing to declare. AHH received research Grant from Novo Nordisk and had received consulting honoraria from Versartis. KJP-H has received consulting honoraria from Novo Nordisk. KCJY and BMKB had received research Grants from Novo Nordisk, OPKO and Versartis and consulting honoraria from Novo Nordisk, Pfizer and Versartis. MBG has received research Grants from OPKO, Novo Nordisk, Teva and Pfizer and consulting honoraria from Novo Nordisk.

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Hamrahian, A.H., Yuen, K.C.J., Gordon, M.B. et al. Revised GH and cortisol cut-points for the glucagon stimulation test in the evaluation of GH and hypothalamic–pituitary–adrenal axes in adults: results from a prospective randomized multicenter study. Pituitary 19, 332–341 (2016). https://doi.org/10.1007/s11102-016-0712-7

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