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Free Cortisol Index Is Better Than Serum Total Cortisol in Determining Hypothalamic-Pituitary-Adrenal Status in Patients Undergoing Surgery
Abstract
Serum total cortisol has traditionally been used for the interpretation of tests of the hypothalamic-pituitary-adrenal axis. Approximately 80% of total cortisol is bound to cortisol-binding globulin (CBG), and variation in CBG significantly affects serum total cortisol levels. Reliable assessment of hypothalamic-pituitary-adrenal axis reserve is difficult in severely ill patients, because CBG falls substantially during the acute phase response. The free cortisol index (FCI), defined as the ratio of total cortisol/CBG, correlates well with serum free cortisol. We evaluated the FCI in the context of severe stress and the acute phase response by measuring total cortisol and CBG pre- and postoperatively in 31 patients undergoing major elective surgery. Serum total cortisol increased by 55% from 453 +/- 35.2 (mean +/- SEM) nmol/liter (range, 88-882) to 700 +/- 47.2 (range, 294-1631) nmol/liter. Serum CBG decreased by 30% from 45 +/- 1.7 (range, 26.6-64.1) to 31.4 +/- 1.62 (range, 16.1-51.9) mg/liter, but FCI increased by 130% from 10 +/- 0.8 (range, 2-18) to 23 +/- 1.7 (range, 13-58) nmol/mg. In seven patients (23%), postoperative serum total cortisol was less than 500 nmol/liter, but their postoperative CBG levels were significantly lower than levels in the rest of the group (P < 0.01). However, there was no difference in the FCI between this subgroup and the rest of the group. This study demonstrates the importance of CBG measurement and the calculation of FCI for the interpretation of serum total cortisol in situations where CBG changes significantly.
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“For instance, activation and reserve capacity of the hypothalamic–pituitary–adrenal (HPA) axis in critically ill patients undergoing surgery was found to correlate better with serum free than total cortisol concentrations. The use of serum total cortisol alone could lead to a misdiagnosis of HPA axis insufficiency in up to 23% of these patients [241, 242].”
From Role of sex hormone-binding globulin in the free hormone hypothesis and the relevance of free testosterone in androgen physiology (2022) · cites this paper as [242]
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“Patients with diseases such as nephrotic syndrome (43) and liver disease (50) as well as those who are in the immediate postoperative period (51) or who require intensive care (52) may have lower CBG and albumin and hence, lower cortisol measurements.”
From Diagnosis and Treatment of Primary Adrenal Insufficiency: An Endocrine Society Clinical Practice Guideline (2016) · cites this paper as [51]
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“Measurement of free cortisol is the best indicator of adrenal glucocorticoid secretion [9] because cortisol is more than 80% bound to cortisol binding globulins (CBG) in the circulation and therefore measurements of plasma cortisol can be compromised by conditions that alter CBG levels [10,11].”
BackgroundYener, S., Tuna, G., Kant, M., Akış, M., Kara, Ö., Kalas, B., BARIŞ, M. M., & İşlekel, H. (2021) · Hormone and Metabolic Research · doi:10.1055/a-1661-4126 · Cited by 3
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“FCI has been previously reported to correlate well with serum free cortisol, the biologically active component, in healthy volunteers [29] as well as in patients undergoing major elective surgery [30].”
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“CBG levels have been documented to fall during critical illness [4, 11, 12], and these changes are postulated to increase the amount of circulating free cortisol.”
BackgroundActivation of Hypothalamic Pituitary Axis in Critically Ill Patients
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Kim, H. I., Koo, B. K., Lee, Y. J., Lee, E. J., Kwak, S. H., Cho, S. W., Choi, H. J., Cho, Y. M., & Kim, S. Y. (2005) · Journal of Korean Endocrine Society · doi:10.3803/jkes.2005.20.1.90
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“L’impiego di misure indirette è stato proposto ampiamente negli ultimi anni, soprattutto nei pazienti affetti da malattie severe (shock settico, traumi multipli, interventi chirurgici, cirrosi epatica) [11, 20, 37, 38]: la soluzione più utilizzata è il calcolo dell’indice di cortisolo libero (ICL), che richiede solo l…”
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“No less important is the ability of cortisol to suppress the secretion of corticoliberin and, accordingly, ACTH, protecting the body from overload (Le Roux et al., 2003; Handrahian et al., 2004; Kozlov and Kozlova, 2014; Michailidou et al., 2022).”
Wang, X., Wang, M., Zhang, W., Yan, D., Kong, L., & Wang, G. (2026) · Talanta · doi:10.1016/j.talanta.2026.130164
Cortisol Dynamics at High Temporal Resolution For Wearable Biosensor Research
Ferdoushi, M., Billings, T., Cai, W., & Khan, Y. (2026) · Advanced Sensor Research · doi:10.1002/adsr.70212
Metadata
- Authors
- le Roux, C. W., Chapman, G. A., Kong, W. M., Dhillo, W. S., Jones, J., & Alaghband-Zadeh, J.
- Affiliations
- Hammersmith Hospital (GB)
- Bradford Royal Infirmary (GB)
- Corresponding author
- le Roux, C. W.
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2003-05
- Volume
- 88
- Issue
- 5
- Pages
- 2045-2048
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- OpenAlex
- W2023342988
- Cited by
- 146
- References
- 19
- Citations by year
- 2026: 4 · 2025: 7 · 2024: 2 · 2023: 2 · 2022: 3 · 2021: 7 · 2020: 3 · 2019: 7 · 2018: 6 · 2017: 7 · 2016: 4 · 2015: 7 · 2014: 6 · 2013: 6 · 2012: 5
- FWCI
- 3.41
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- 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 › Hyperglycemia and glycemic control in critically ill and hospitalized patients
- Keywords
- corticosteroid-binding globulin, hypothalamic-pituitary-adrenal axis, acute phase response, surgical stress, elective major surgery, postoperative cortisol, adrenal reserve
- MeSH terms
- Adrenal Glands, Adult, Carrier Proteins, Female, Humans, Hydrocortisone, Hypothalamus, Male, Middle Aged, Pituitary Gland, Protein Binding, Reference Values, Sensitivity and Specificity, Stress, Physiological, Surgical Procedures, Operative, Time Factors
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