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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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“The consensus is that the free cortisol, rather than the protein-bound fraction, is responsible for the physiologic function of the hormone at the cellular level (6, 50, 86).”
BackgroundMeasurements of Serum Free Cortisol in Critically Ill Patients
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“However, free cortisol is the only biologically active fraction (Le Roux et al., 2003) and is responsible for all cortisol-related activities in the body.”
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Prete, A., Yan, Q., Al‐Tarrah, K., Akturk, H. K., Prokop, L. J., Alahdab, F., Foster, M. A., Lord, J. M., Karavitaki, N., Wass, J. A., et al. (2018) · Clinical Endocrinology · doi:10.1111/cen.13820 · Cited by 192
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MethodCortisol Response in Relation to the Severity of Stress and Illness
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Review—Towards Wearable Sensor Platforms for the Electrochemical Detection of Cortisol
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Label-Free Optical Detection of Multiple Biomarkers in Sweat, Plasma, Urine, and Saliva
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Increased Cortisol in the Cerebrospinal Fluid of Women with Functional Hypothalamic Amenorrhea
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“The free cortisol index has been shown to be a robust and reliable estimate of the unbound fraction of cortisol (12).”
Immunosensor with fluid control mechanism for salivary cortisol analysis
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“The free cortisol index (serum total cortisol/cortisol-binding globlin; FCI) might be better index for hypothalamic-pituitaryadrenal (HPA) status than the serum total cortisol (le Roux et al., 2003).”
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“Because of the variability in CBG concentrations, though, particularly in severely ill patients”
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Fede, G., Spadaro, L., Tomaselli, T., Privitera, G., Piro, S., Rabuazzo, A. M., Sigalas, A., Xirouchakis, E., O’Beirne, J. P., Garcovich, M., et al. (2010) · Journal of Hepatology · doi:10.1016/j.jhep.2010.06.034 · Cited by 90
“However, due to the fact that we did not directly measure the free cortisol, but it was indirectly calculated using the Coolens formula [26], we cannot draw a valid conclusion on this issue, and further studies are needed.”
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Karuppaiah, G., Lee, M., Bhansali, S., & Manickam, P. (2023) · Biosensors and Bioelectronics · doi:10.1016/j.bios.2023.115600 · Cited by 87
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“The FCI (measured in nmol/mg) was calculated by dividing the total cortisol (nmol/L) by the pCBG (mg/L; le Roux et al., 2003).”
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Measurement of Serum Free Cortisol Shows Discordant Responsivity to Stress and Dynamic Evaluation
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Redefining the stress cortisol response to surgery
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“This has been shown to be due to changed levels of corticosteroid-binding globulin levels during these situations (27, 28), which in turn affects the serum cortisol concentrations (29).”
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Langer, M., Modi, B. P., & Agus, M. S. D. (2006) · Current Opinion in Pediatrics · doi:10.1097/01.mop.0000236397.79580.85 · Cited by 61
Clinical and Technical Aspects in Free Cortisol Measurement
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“FCI could be a better tool in evaluating the HPA status than total cortisol levels in serum, in conditions where CBG changes significantly under acute-phase stress [25].”
MethodProven infection-related sepsis induces a differential stress response early after ICU admission
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“Free cortisol index (FCI) has been advocated as a better determinant of the HPA status than cortisol in stressed patients [32], although not recommended for routine use by a recent international task force [4].”
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Verbeeten, K. C., & Ahmet, A. H. (2018) · Journal of Pediatric Endocrinology and Metabolism · doi:10.1515/jpem-2017-0270 · Cited by 51
Diagnosis and Treatment of Adrenal Insufficiency in the Critically Ill Patient
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“The effect of a decrease in serum proteins (corticosteroid-binding globulin and albumin) on measured total cortisol has been realized by studies in patients with trauma or sepsis(18) and those undergoing major surgery.(67) These studies recommend the use of a correction factor known as the free-cortisol index (defined…”
BackgroundTrevisi, E., Bertoni, G., Lombardelli, R., & Minuti, A. (2013) · Journal of Dairy Science · doi:10.3168/jds.2012-6375 · Cited by 50
Serum Free Cortisol Fraction in Healthy and Septic Neonatal Foals
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Cortisol: Biosensing and detection strategies
Balasamy, S., Atchudan, R., Arya, S. K., Gunasekaran, B. M., Nesakumar, N., & Sundramoorthy, A. K. (2024) · Clinica Chimica Acta · doi:10.1016/j.cca.2024.119888 · Cited by 51
Jeon, J., Uthaman, S., Lee, J., Hwang, H., Kim, G. B., Yoo, P. J., Hammock, B. D., Kim, C. S. K., Park, Y.-S., & Park, I. (2018) · Sensors and Actuators B Chemical · doi:10.1016/j.snb.2018.03.167 · Cited by 47
Cortisol as a marker of stress
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Evaluation and Management of Adrenal Insufficiency in Critically ill Patients: Disease State Review
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Molenaar, N., Groeneveld, A. B. J., Dijstelbloem, H. M., de Jong, M. F. C., Girbes, A. R. J., Heijboer, A. C., & Beishuizen, A. (2011) · Intensive Care Medicine · doi:10.1007/s00134-011-2342-x · Cited by 45
“Nevertheless, total cortisol somewhat underestimated a higher free cortisol, as observed before [ 14 , 15, 17], in sepsis as compared to non-sepsis.”
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“In a recent study, postoperative patients exhibiting significant differences in total serum cortisol levels were found to have a similar FCI when CBG concentrations were considered (le Roux et al., 2003).”
Salzmann, S., Euteneuer, F., Laferton, J. A. C., Auer, C. J., Mora, M. C. S., Schedlowski, M., Moosdorf, R., & Rief, W. (2017) · Psychosomatic Medicine · doi:10.1097/psy.0000000000000483 · Cited by 41
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“Modification of the free/bound GC ratio is important because only free GC actively regulates metabolism and immunity (Le Roux et al., 2003; Torpy & Ho, 2007; Schwinn et al., 2018).”
BackgroundHyponatraemia and hypernatraemia: Disorders of Water Balance in Neurosurgery
Castle‐Kirszbaum, M., Kyi, M., Wright, C. A., Goldschlager, T., Danks, R. A., & Parkin, W. G. (2021) · Neurosurgical Review · doi:10.1007/s10143-020-01450-9 · Cited by 37
“However, as cortisol is highly protein bound, simultaneous “negative acute-phase” changes in carrier protein concentration may dictate that free cortisol levels are actually normal [47, 68].”
BackgroundUncoupling of sympathetic nervous system and hypothalamic‐pituitary‐adrenal axis in cirrhosis
Wiest, R., Moleda, L., Zietz, B., Hellerbrand, C., Schölmerich, J., & Straub, R. H. (2008) · Journal of Gastroenterology and Hepatology · doi:10.1111/j.1440-1746.2008.05456.x · Cited by 37
The effect of cardiopulmonary bypass on the hypothalamic-pituitary-adrenal axis in children*
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Ghrelin Levels After a Cold Pressor Stress Test in Obese Women With Binge Eating Disorder
Gluck, M. E., Yahav, E., Hashim, S. A., & Geliebter, A. (2013) · Psychosomatic Medicine · doi:10.1097/psy.0000000000000018 · Cited by 35
“Saliva-based (free) cortisol measurements might be more accurate in situations where acute changes are present (53), such as the ones examined in the current study, and our results might have differed had we used a free cortisol measurement.”
MethodHarbeck, B., Kropp, P. A., & Mönig, H. (2009) · Applied Psychophysiology and Biofeedback · doi:10.1007/s10484-009-9082-5 · Cited by 34
Correlation of salivary cortisol level with obstructive sleep apnea syndrome in pediatric subjects
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“Because total cortisol levels show an increase similar to that of free cortisol levels in response to stress, serum total cortisol has traditionally been used as an indicator of HPA axis activity [13,14].”
BackgroundRelative adrenal insufficiency in cirrhotic patients with ascites (hepatoadrenal syndrome)
Singh, R. R., Walia, R., Sachdeva, N. K., Bhalla, A., Singh, A. K., & Singh, V. (2018) · Digestive and Liver Disease · doi:10.1016/j.dld.2018.05.011 · Cited by 34
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McAfee, J. M., Kattesh, H. G., Lindemann, M. D., Voy, B. H., Kojima, C. J., Sanchez, N. C. B., Carroll, J. A., Gillespie, B. E., & Saxton, A. M. (2019) · Journal of Animal Science · doi:10.1093/jas/skz300 · Cited by 30
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“The CBG and free cortisol levels were not directly measured, and we might have underestimated baseline free cortisol levels and rises upon ACTH stimulation, as pointed out previously [6,14,16,19,27-29].”
BackgroundMethodAlexandraki, K., Kaltsas, G., le Roux, C. W., Faßnacht, M., Ajodha, S. J., Christ‐Crain, M., Akker, S. A., Drake, W. M., Edwards, R., Allolio, B., et al. (2009) · Clinical Endocrinology · doi:10.1111/j.1365-2265.2009.03631.x · Cited by 29
Adrenal insufficiency in patients with decompensated cirrhosis
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Pituitary-adrenal responses following major abdominal surgery
Dimopoulou, I., Tzanela, M., Vassiliadi, D. A., Mavrou, I., Kopterides, P., Orfanos, S. E., Kotanidou, A. N., Kontogiannopoulou, S., Vasdekis, S. N., Tsangaris, I., et al. (2008) · HORMONES · doi:10.14310/horm.2002.1203 · Cited by 27
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“At the same time the importance of measuring free, not total, cortisol in ACTH stimulation tests is also gaining recognition (10, 26, 27).”
BackgroundNon-enzymatic electrochemical determination of salivary cortisol using ZnO-graphene nanocomposites
Rison, S., Rajeev, R., Bhat, V. S., Mathews, A. T., Varghese, A., & Hegde, G. (2021) · RSC Advances · doi:10.1039/d1ra07366d · Cited by 27
Salivary and free serum cortisol evaluation.
Duplessis, C., Rascona, D. A., Cullum, M., & Yeung, E. (2010) · Military Medicine · doi:10.7205/milmed-d-09-00166 · Cited by 26
Endocrine Assessments During Critical Illness
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“Interpretation of plasma total cortisol concentrations, in situations where CBG changes significantly, does not address the free cortisol fraction and thus may not provide a true representation of its biological impact (le Roux et al. 2003).”
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“Free cortisol, which is technically demanding to measure, mirrors better cortisol availability [43] and may be important in understanding the lack of changes in GCR isoforms over time and the changes in downstream targets in PBMCs and PMNs. Neverthe-less, in critical illness, tissue cortisol levels…”
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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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