The functional role and properties of transcortin in the human body

Steroid hormones take an active part in a whole complex of physiological processes that are fundamental for the normal development and functioning of the human body. In the bloodstream steroid hormones are bind with specific transport proteins, in particular with transcortin. The matter of changes in hormone-protein complex in various conditions were actively studied in the second half of the twentieth century, but currently this issue has been taken a back seat by the development of high-precision diagnostic methods of steroid hormones determining. This literature review presents accumulated data on the physicochemical properties of transcortin, genetic factors affecting its synthesis and secretion. Published data on its physiological significance in the human body are analyzed in detail within the framework of not only the “free hormone” hypothesis, but also the reservoir hypothesis. Research results have shown that the synthesis of transcortin has been detected in some extrahepatic tissues, including the adrenal glands, however, its role is unknown.

1. Bae YJ, Kratzsch J. Corticosteroid-binding globulin: modulating mechanisms of bioavailability of cortisol and its clinical implications. Best Pract Res Clin Endocrinol Metab. 2015;29(5):761-772. doi: https://doi.org/10.1016/j.beem.2015.09.001

2. Daughaday WH. Binding of corticosteroids by plasma proteins. I. Dialysis equilibrium and renal clearance studies. J Clin Invest. 1956;35(12):1428-1433. doi: https://doi.org/10.1172/JCI103400

3. Westphal U, Devenuto F. Steroid-protein interactions. XI. Electrophoretic characterization of corticosteroidbinding proteins in serum of rat, man and other species. Biochim Biophys Acta. 1966;115(1):187-196. doi: https://doi.org/10.1016/0304-4165(66)90063-8

4. Hammond GL. Molecular properties of corticosteroid binding globulin and the sex-steroid binding proteins. Endocr Rev. 1990;11(1):65-79. doi: https://doi.org/10.1210/edrv-11-1-65

5. Torpy DJ, Ho JT. Corticosteroid-binding globulin gene polymorphisms: clinical implications and links to idiopathic chronic fatigue disorders. Clin Endocrinol (Oxf ). 2007;67(2):161-167. doi: https://doi.org/10.1111/j.1365-2265.2007.02890.x

6. Hammond GL, Smith CL, Paterson NA, et al. A role for corticosteroid-binding globulin in delivery of cortisol to activated neutrophils. J Clin Endocrinol Metab. 1990;71(1):34-39. doi: https://doi.org/10.1210/jcem-71-1-34

7. Hunt LT, Dayhoff MO. A surprising new protein superfamily containing ovalbumin, antithrombin-III, and alpha 1-proteinase inhibitor. Biochem Biophys Res Commun. 1980;95(2):864-871. doi: https://doi.org/10.1016/0006-291x(80)90867-0

8. Huntington JA, Read RJ, Carrell RW. Structure of a serpinprotease complex shows inhibition by deformation. Nature. 2000;407(6806):923-926. doi: https://doi.org/10.1038/35038119

9. Cohen M, Davydov O, Fluhr R. Plant serpin protease inhibitors: specificity and duality of function. J Exp Bot. 2019;70(7):2077-2085. doi: https://doi.org/10.1093/jxb/ery460

10. Pemberton PA, Stein PE, Pepys MB, et al. Hormone binding globulins undergo serpin conformational change in inflammation. Nature. 1988;336(6196):257-258. doi: https://doi.org/10.1038/336257a0

11. Underhill DA, Hammond GL. Organization of the human corticosteroid binding globulin gene and analysis of its 5’-flanking region. Mol Endocrinol. 1989;3(9):1448-1454. doi: https://doi.org/10.1210/mend-3-9-1448

12. Hammond GL, Smith CL, Goping IS, et al. Primary structure of human corticosteroid binding globulin, deduced from hepatic and pulmonary cDNAs, exhibits homology with serine protease inhibitors. Proc Natl Acad Sci USA. 1987;84(15):5153-5157. doi: https://doi.org/10.1073/pnas.84.15.5153

13. Deviche P, Breuner C, Orchinik M. Testosterone, corticosterone, and photoperiod interact to regulate plasma levels of binding globulin and free steroid hormone in dark-eyed juncos, Junco hyemalis. Gen Comp Endocrinol. 2001;122(1):67-77. doi: https://doi.org/10.1006/gcen.2001.7613

14. Malisch JL, Breuner CW. Steroid-binding proteins and free steroids in birds. Mol Cell Endocrinol. 2010;316(1):42-52. doi: https://doi.org/10.1016/j.mce.2009.09.019

15. Vergara RC, Torres-Araneda A, Villagra DA, et al. Erratum: Are eavesdroppers multimodal? Sensory exploitation of floral signals by a non-native cockroach. Blatta orientalis. Curr Zool. 2017;67(3):353. doi: https://doi.org/10.1093/cz/zox050

16. Henley DE, Lightman SL. New insights into corticosteroid-binding globulin and glucocorticoid delivery. Neuroscience. 2011;180:1-8. doi: https://doi.org/10.1016/j.neuroscience.2011.02.053

17. Cizza G, Rother KI. Cortisol binding globulin: more than just a carrier? J Clin Endocrinol Metab. 2012;97(1):77-80. doi: https://doi.org/10.1210/jc.2011-3090

18. Mickelson KE, Forsthoefel J, Westphal U. Steroidprotein interactions. Human corticosteroid binding globulin: some physicochemical properties and binding specificity. Biochemistry. 1981;20(21):6211-6218. doi: https://doi.org/10.1021/bi00524a047

19. Hammond GL, Smith CL, Underhill DA. Molecular studies of corticosteroid binding globulin structure, biosynthesis and function. J Steroid Biochem Mol Biol. 1991;40(4-6):755-762. doi: https://doi.org/10.1016/0960-0760(91)90300-t

20. Breuner CW, Beyl HE, Malisch JL. Corticosteroid-binding globulins: Lessons from biomedical research. Mol Cell Endocrinol. 2020;514:110857. doi: https://doi.org/10.1016/j.mce.2020.110857

21. Bolton JL, Hayward C, Direk N, et al. Genome wide association identifies common variants at the SERPINA6/SERPINA1 locus influencing plasma cortisol and corticosteroid binding globulin. PLoS Genet. 2014;10(7):e1004474. doi: https://doi.org/10.1371/journal.pgen.1004474

22. Van Baelen H, Power SG, Hammond GL. Decreased cortisolbinding affinity of transcortin Leuven is associated with an amino acid substitution at residue-93. Steroids. 1993;58(6):275-277. doi: https://doi.org/10.1016/0039-128x(93)90072-u

23. Perogamvros I, Kayahara M, Trainer PJ, et al. Serum regulates cortisol bioactivity by corticosteroid-binding globulin-dependent and independent mechanisms, as revealed by combined bioassay and physicochemical assay approaches. Clin Endocrinol (Oxf ). 2011;75(1):31-38. doi: https://doi.org/10.1111/j.1365-2265.2011.04003.x

24. Qian X, Droste SK, Gutièrrez-Mecinas M, et al. A rapid release of corticosteroid-binding globulin from the liver restrains the glucocorticoid hormone response to acute stress. Endocrinology. 2011;152(10):3738-3748. doi: https://doi.org/10.1210/en.2011-1008

25. Weiser JN, Do YS, Feldman D. Synthesis and secretion of corticosteroid-binding globulin by rat liver. A source of heterogeneity of hepatic corticosteroid-binders. J Clin Invest. 1979;63(3):461-467. doi: https://doi.org/10.1172/JCI109323

26. Perrot-Applanat M, Milgrom E. Messenger ribonucleic acid for corticosteroid-binding globulin. Translation and preliminary characterization. Biochemistry. 1979;18(25):5732-5737. doi: https://doi.org/10.1021/bi00592a033

27. Wolf G, Armstrong EG, Rosner W. Synthesis in vitro of corticosteroid-binding globulin from rat liver messenger ribonucleic acid. Endocrinology. 1981;108(3):805-811. doi: https://doi.org/10.1210/endo-108-3-805

28. Doe RP, Fernandez R, Seal US. Measurement of corticosteroidbinding globulin in man. J Clin Endocrinol Metab. 1964;24:1029-1039. doi: https://doi.org/10.1210/jcem-24-10-1029

29. Sueda K, Seo H, Matsui N. Human transcortin synthesis by a cell-free translation of hepatic mRNA. Endocrinol Jpn. 1985;32(2):295-303. doi: https://doi.org/10.1507/endocrj1954.32.295

30. Khan MS, Aden D, Rosner W. Human corticosteroid binding globulin is secreted by a hepatoma-derived cell line. J Steroid Biochem. 1984;20(2):677-678. doi: https://doi.org/10.1016/0022-4731(84)90142-0

31. Gulfo J, Castel R, Ledda A, et al. Corticosteroid-Binding Globulin is expressed in the adrenal gland and its absence impairs corticosterone synthesis and secretion in a sex-dependent manner. Sci Rep. 2019;9(1):14018. doi: https://doi.org/10.1038/s41598-019-50355-1

32. Schäfer HH, Gebhart VM, Hertel K, et al. Expression of corticosteroidbinding globulin CBG in the human heart. Horm Metab Res. 2015;47(8):596-599. doi: https://doi.org/10.1055/s-0034-1389957

33. Sivukhina EV, Jirikowski GF. Adrenal steroids in the brain: role of the intrinsic expression of corticosteroid-binding globulin (CBG) in the stress response. Steroids. 2014;81:70-73. doi: https://doi.org/10.1016/j.steroids.2013.11.001

34. Kvetnansky R, Sabban EL, Palkovits M. Catecholaminergic systems in stress: structural and molecular genetic approaches. Physiol Rev. 2009;89(2):535-606. doi: https://doi.org/10.1152/physrev.00042.2006

35. Predine J, Brailly S, Delaporte P, et al. Protein binding of cortisol in human cerebrospinal fluid. J Clin Endocrinol Metab. 1984;58(1):6-11. doi: https://doi.org/10.1210/jcem-58-1-6

36. Schwarz S, Pohl P. Steroid hormones and steroid hormone binding globulins in cerebrospinal fluid studied in individuals with intact and with disturbed blood-cerebrospinal fluid barrier. Neuroendocrinology. 1992;55(2):174-182. doi: https://doi.org/10.1159/000126112

37. Sivukhina EV, Jirikowski GF, Bernstein HG, et al. Expression of corticosteroid-binding protein in the human hypothalamus, co-localization with oxytocin and vasopressin. Horm Metab Res. 2006;38(4):253-259. doi: https://doi.org/10.1055/s-2006-925346

38. Caldwell JD, Jirikowski GF. An active role for steroid-binding globulins: an update. Horm Metab Res. 2013;45(7):477-484. doi: https://doi.org/10.1055/s-0033-1334945

39. Lazzarino AI, Hamer M, Gaze D, et al. The association between cortisol response to mental stress and high-sensitivity cardiac troponin T plasma concentration in healthy adults. J Am Coll Cardiol. 2013;62(18):1694-1701. doi: https://doi.org/10.1016/j.jacc.2013.05.070

40. Yamaji M, Tsutamoto T, Kawahara C, et al. Serum cortisol as a useful predictor of cardiac events in patients with chronic heart failure: the impact of oxidative stress. Circ Heart Fail. 2009;2(6):608-615. doi: https://doi.org/10.1161/CIRCHEARTFAILURE.109.868513

41. Misao R, Nakanishi Y, Fujimoto J, et al. Levels of sex hormonebinding globulin and corticosteroid-binding globulin mRNAs in corpus luteum of human subjects: correlation with serum steroid hormone levels. Gynecol Endocrinol. 1999;13(2):82-88. doi: https://doi.org/10.3109/09513599909167537

42. Misao R, Iwagaki S, Sun WS, et al. Evidence for the synthesis of corticosteroid-binding globulin in human placenta. Horm Res. 1999;51(4):162-167. doi: https://doi.org/10.1159/000023351

43. Atkinson G, Campbell DJ, Cawood ML, et al. Steroids in human intrauterine fluids of early pregnancy. Clin Endocrinol (Oxf ). 1996;44(4):435-440. doi: https://doi.org/10.1046/j.1365-2265.1996.710532.x

44. Shams M, Kilby MD, Somerset DA, et al. 11Beta-hydroxysteroid dehydrogenase type 2 in human pregnancy and reduced expression in intrauterine growth restriction. Hum Reprod. 1998;13(4):799-804. doi: https://doi.org/10.1093/humrep/13.4.799

45. Sun K, Yang K, Challis JR. Differential expression of 11 betahydroxysteroid dehydrogenase types 1 and 2 in human placenta and fetal membranes. J Clin Endocrinol Metab. 1997;82(1):300-305. doi: https://doi.org/10.1210/jcem.82.1.3681

46. Gibb W. The role of prostaglandins in human parturition. Ann Med. 1998;30(3):235-241. doi: https://doi.org/10.3109/07853899809005850

47. Ng PC. The fetal and neonatal hypothalamic-pituitary-adrenal axis. Arch Dis Child Fetal Neonatal Ed. 2000;82(3):F250-F254. doi: https://doi.org/10.1136/fn.82.3.f250

48. Dölz W, Eitner A, Caldwell JD, et al. Expression of corticosteroid binding globulin in the rat olfactory system. Acta Histochem. 2013;115(4):376-381. doi: https://doi.org/10.1016/j.acthis.2012.09.012

49. Trotier D, Eloit C, Wassef M, et al. The vomeronasal cavity in adult humans. Chem Senses. 2000;25(4):369-380. doi: https://doi.org/10.1093/chemse/25.4.369

50. Bhatnagar KP, Smith TD. The human vomeronasal organ. III. Postnatal development from infancy to the ninth decade. J Anat. 2001;199(Pt 3):289-302. doi: https://doi.org/10.1046/j.1469-7580.2001.19930289.x

51. D’Aniello B, Semin GR, Scandurra A, et al. The Vomeronasal Organ: A Neglected Organ. Front Neuroanat. 2017;11:70. doi: https://doi.org/10.3389/fnana.2017.00070

52. Khaustov SA, Dubynin VA. Human pheromones: An analysis of misconceptions, problems and study perspectives (review). Sci Educ Today. 2022;12(2):172-192. doi: https://doi.org/10.15293/2658-6762.2202.09

53. Robinson AM, Kern RC, Foster JD, Fong KJ, Pitovski DZ. Expression of glucocorticoid receptor mRNA and protein in the olfactory mucosa: Physiologic and pathophysiologic implications. Laryngoscope. 1998;108(8):1238-1242. doi: https://doi.org/10.1097/00005537-199808000-00026