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Corticosteroid-Binding Globulin: A Review of Basic and Clinical Advances
Abstract
Corticosteroid-binding globulin (CBG, transcortin) is the primary cortisol binding protein. It is a non-inhibitory serine protease inhibitor, capable of conformational change from a high cortisol-binding affinity form to a low affinity form upon cleavage of its reactive centre loop by various proteases, such as neutrophil elastase. The burgeoning inflammatory role of CBG applies to acute, severe inflammation where depletion is associated with mortality, and to chronic inflammation where defects in cortisol delivery may perpetuate inflammation. Naturally occurring human mutations influence a wide range of CBG properties and point toward a role in hitherto unexplained chronic musculoskeletal pain and fatigue disorders as well as potentially affecting fertility outcomes including offspring gender. In vitro and knock-out animal models of CBG propose a role for CBG in cortisol transport to the brain, providing a foundation for understanding the human observations in those with CBG mutations and sex differences in stress-related mood and behaviour. Finally, CBG measurement has a practical role in the estimation of free cortisol, useful in clinical circumstances where CBG levels or cortisol binding affinity is reduced. Taken together, novel data suggest a role for cortisol in targeted cortisol delivery, with implications in acute and chronic inflammation, as well as roles in metabolism and neurocognitive function, implying that CBG is a multifaceted component in the mechanisms of hypothalamic-pituitary-adrenal axis related homeostasis.
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“This interaction regulates bioavailability during high CORT secretion”
From Hypothalamic–pituitary–adrenal and hypothalamic–pituitary–gonadal axes: sex differences in regulation of stress responsivity (2017) · cites this paper as Meyer, Nenke, Rankin, Lewis, & Torpy, 2016
In the citing paper
“This study does not evaluate whether variations in cortisol binding globulin (CBG) concentration or genetic variations affecting CBG-cortisol affinity may influence salivary cortisol and cortisone concentrations [50].”
From Salivary cortisol and cortisone in diagnosis of Cushing's syndrome: a comparison of six different analytical methods (2023) · cites this paper as [50]
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“Inflammatory reaction and immunity are influenced by serum albumin and globulin; hypoalbuminemia [10] and hyperglobulinemia are considered indicators of chronic inflammation in oncologic patients [11].”
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“Furthermore, it has roles in metabolism and neurocognitive function, implying that CBG is a multifaceted component in the mechanisms of hypothalamic‐ pituitary‐adrenal axis related homeostasis [191].”
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“Recently, based on the CBG knock‐out mice models, CBG and cortisol have been reported to be associated with neurocognitive functions (Meyer et al., 2016).”
MethodGulfo, J., Castel, R., Ledda, A., Romero, M. D. M., Esteve, M., & Grasa, M. (2019) · Scientific Reports · doi:10.1038/s41598-019-50355-1 · Cited by 23
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“Globulin, as one of the main cortisol-binding proteins, can participate in immune and inflammatory responses (10).”
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“In humans it is encoded by the SERPINA6 gene and an alpha globulin [35,36].”
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“CBG, a 383 amino acid glycoprotein, transports cortisol in a 1:1 stoichiometric ratio increasing the solubility of cortisol in serum, buffering fluctuating cortisol levels and, critically, allowing tissue-specific delivery.(2,3) One well characterized mechanism that facilitates the delivery of cortisol at target sites…”
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“Based on these findings, it is tempting to speculate that CBG functions in the nuclear trafficking of proteins other than cortisol [57].”
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“Globulin, as one of the main cortisol-binding proteins, can participate in immune and inflammatory responses [11].”
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“Although it has been confrmed that globulin plays an important role in the immune microenvironment [28, 29], it was still confused whether it could afect tumor immunotherapy or not.”
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Are serum cortisol measurements by immunoassays reliable?
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“In addition to a handful of rare CBG-gene mutations, common illnesses such as preeclampsia, diabetes, renal and hepatic failure decrease CBG levels.(15) Increases in CBG concentrations can occur during pregnancy and oral estrogen administration.”
BackgroundYang, S. H., Tey, M. L., Zhou, S., et al. (2024) · Journal of Breast Cancer · doi:10.4048/jbc.2023.0242 · Cited by 6
“Globulin, the primary cortisol binding protein, holds a crucial role in immunity and inflammation [41,42].”
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“In humans, several CBG mutations in the gene encoding CBG (SERPINA6) have been identified that affect the expression of CBG or its affinity for glucocorticoids, and some mutations knockout CBG entirely [25].”
BackgroundMiura, N., Mori, K., Laukhtina, E., Schuettfort, V. M., Abufaraj, M., Teoh, J. Y., Luzzago, S., Stolzenbach, L. F., Deuker, M., Karakiewicz, P. I., et al. (2021) · Japanese Journal of Clinical Oncology · doi:10.1093/jjco/hyab023 · Cited by 6
Landscape condition influences energetics, reproduction, and stress biomarkers in grizzly bears
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Short treatment with antalarmin alters adrenal gland receptors in the rat model of endometriosis
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“About 78% of corticosterone in plasma is bound to CBG rendering it inactive [29].”
BackgroundImpaired SERPIN–Protease Balance in the Peripheral Lungs of Stable COPD Patients
Stefano, A. D., Nucera, F., Rosani, U., et al. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26072832 · Cited by 4
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“The role of extrahepatic CBG is discussed in the literature (Sivukhina and Jirikowski, 2014; Meyer et al., 2016).”
BackgroundWilson, A. E., Michaud, S. A., Jackson, A., Stenhouse, G. B., McClelland, C. J. R., Coops, N. C., & Janz, D. M. (2021) · Conservation Physiology · doi:10.1093/conphys/coab091 · Cited by 3
“…expression of CBG. CBG has been used as a biomarker of stress in several species, including brown bears (Chow et al., 2010; Wilson et al., 2020b), as it is the protein primarily responsible for binding and transporting cortisol, a key hormone in the mammalian stress response (Meyer et al., 2016).”
BackgroundPrognostic Value of Inflammatory and Nutritional Indicators in Non-Metastatic Soft Tissue Sarcomas
Yuan, Y., Zhang, Y., Chen, Y., et al. (2025) · Journal of Inflammation Research · doi:10.2147/jir.s501079 · Cited by 3
Karakaya, S., Karadağ, İ., Doğan, M., et al. (2021) · Acta Oncologica Turcica · doi:10.5505/aot.2021.58815 · Cited by 3
Plasma Steroids are Not Associated with Resting and Exercise Blood Pressure
He, Z., Rankinen, T., Leon, A. S., Skinner, J. S., Tchernof, A., & Bouchard, C. (2018) · International Journal of Sports Medicine · doi:10.1055/a-0660-0121 · Cited by 3
Gudmand‐Hoeyer, J., & Ottesen, J. T. (2018) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2018.04.003 · Cited by 3
“The affinity of human CBG for progesterone is of a considerable strength [81] with dissociation constants reported in the range of 11.”
BackgroundDisorders of the adrenal gland
Bertholf, R. L. (2020) · Elsevier eBooks · doi:10.1016/b978-0-12-818277-2.00004-2 · Cited by 3
Moon, A. L., Mawson, E. R., Gasalla, P., Wilkinson, L. S., Dwyer, D. M., Thomas, K. L., & Hall, J. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26125547 · Cited by 4
Binding for life: corticosteroid binding globulin from vertebrate physiology to human diseases
Rouzic, P. L., & Rousseau, K. (2025) · Frontiers in Endocrinology · doi:10.3389/fendo.2025.1647096 · Cited by 4
Prognostic significance of serum globulin in patients with acute ischemic stroke
Han, Q., Sun, X., Chen, D., et al. (2023) · Journal of Stroke and Cerebrovascular Diseases · doi:10.1016/j.jstrokecerebrovasdis.2023.107342 · Cited by 2
Influence of age and seasonality on boar seminal plasma steroids quantification: A preliminary study
Aniballi, C., Elmi, A., Govoni, N., Bulla, T., Canelli, E., Casalini, A., Bacci, M. L., & Ventrella, D. (2023) · Veterinary World · doi:10.14202/vetworld.2023.2150-2157 · Cited by 2
“Corticosteroid-binding globulin is the primary CORT-binding protein and represents an eclectic component in the mechanisms of hypothalamic–pituitary–adrenal axis–related homeostasis [33].”
BackgroundDorin, R. I., & Qualls, C. (2024) · IntechOpen eBooks · doi:10.5772/intechopen.1003598 · Cited by 2
Gao, S., Li, S., Wu, B., et al. (2025) · BMC Urology · doi:10.1186/s12894-024-01687-2 · Cited by 2
Hemmatzadeh, S., Ahmadpour, P., Kamrani, S., et al. (2022) · Journal of Obstetrics and Gynaecology · doi:10.1080/01443615.2022.2069001 · Cited by 2
“…dexamethasone use (Jenssen and Wright 1977) and two others were excluded because they were written in Bulgarian and their data were not available (Penev 1985; Grudev 1990); However according to Kavanagh et al. about one of these two Bulgarian studies, they used before and after method for…”
MethodA Proteomic Analysis of Human Follicular Fluid: Proteomic Profile Associated with Embryo Quality
Ji, J., Zhu, X., Zhang, Y., et al. (2023) · Reproductive Sciences · doi:10.1007/s43032-023-01293-x · Cited by 2
Moon, A. L., Mawson, E., Gasalla, P., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.08.08.607145 · Cited by 2
Wu, R., Hamden, J. E., Salehzadeh, M., Li, M. X., Poudel, A., Schmidt, K. L., Kobor, M. S., & Soma, K. K. (2024) · PLoS ONE · doi:10.1371/journal.pone.0309478 · Cited by 2
Zhu, J.-Y., Zhou, S.-J., Jiang, M., Wang, W.-Y., & Yan, J. (2025) · Medicine · doi:10.1097/md.0000000000044153 · Cited by 2
“[40] Leveraging genetic variants as robust IVs and controlling for the influence of other hormones, our study offers novel insights, suggesting that MCE is a significant potential factor in promoting OP progression in the FN.”
Highab, S. M., Ya’u, J., Magaji, M. G., et al. (2023) · Oriental Pharmacy and Experimental Medicine · doi:10.1007/s13596-023-00688-0 · Cited by 1
“…studies have shown elevated serum globulin levels and decreased albumin to globulin (A/G) ratio in patients with infection and advanced malignancy, suggesting their important role in the immune and inflammatory system (Hill et al. 2016; Lv et al. 2018; Meyer et al. 2016; Yoshino et al. 2019).”
Wu, M., Zheng, K., Cao, Y., Yin, Q., Hu, Y., Ren, Q., Zhu, H., Lan, X., & Zhu, W. (2024) · The Aging Male · doi:10.1080/13685538.2024.2388529 · Cited by 1
Zhang, Y., Liu, L., Yang, C., Xie, W., & Wang, J. (2024) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2024.110158 · Cited by 1
Metadata
- Authors
- Meyer, E., Nenke, M., Rankin, W., Lewis, J., & Torpy, D.
- Affiliations
- Royal Adelaide Hospital (AU)
- South Australia Pathology (AU)
- Canterbury Health Laboratories (NZ)
- Corresponding author
- Meyer, E.
- Venue
- Hormone and Metabolic Research
- Publisher
- Georg Thieme Verlag KG
- Published
- 2016-05-23
- Volume
- 48
- Issue
- 06
- Pages
- 359-371
- ISSN
- 0018-5043 (ISSN-L)
- 1439-4286
- OpenAlex
- W2408046298
- Cited by
- 139
- References
- 0
- Citations by year
- 2026: 6 · 2025: 17 · 2024: 12 · 2023: 20 · 2022: 9 · 2021: 29 · 2020: 17 · 2019: 6 · 2018: 11 · 2017: 9 · 2016: 3
- FWCI
- 9.68
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Hormone and Metabolic Research (publishedVersion)
- PubMed (publishedVersion)
- Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Interaction Studies and Fluorescence Analysis
- Keywords
- corticosteroid-binding globulin, cortisol binding, serine protease inhibitors, reactive center loop, neutrophil elastase, chronic inflammation, acute inflammation, hypothalamic-pituitary-adrenal axis, chronic musculoskeletal pain, fertility, sex differences in stress, neurocognitive function
- MeSH terms
- Animals, Disease, Disease Models, Animal, Humans, Models, Biological, Mutation, Transcortin, Drug Delivery Systems
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