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Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom
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Introduction Corticosteroid-binding globulin (CBG) transports glucocorticoids and progesterone in human blood and regulates their access to target tissues ( Hammond 2016 a ). Human CBG is also known as SERPINA6 because it shares structural
Department of Obstetrics and Gynaecology, University of British Columbia, Vancouver, British Columbia, Canada
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Department of Obstetrics and Gynaecology, University of British Columbia, Vancouver, British Columbia, Canada
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Introduction Produced primarily by the liver, corticosteroid-binding globulin (CBG) is a plasma glycoprotein that binds ~90% of circulating glucocorticoids, and regulates their bioavailability in target tissues ( Lin et al. 2010 ). Plasma
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Max Planck Institute of Psychiatry, Institut National de la Recherche Agronomique (INRA), University of Bordeaux, Research Group of Psychoneuroendocrinology, Kraepelinstrasse 2-10, 80804 Munich, Germany
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Max Planck Institute of Psychiatry, Institut National de la Recherche Agronomique (INRA), University of Bordeaux, Research Group of Psychoneuroendocrinology, Kraepelinstrasse 2-10, 80804 Munich, Germany
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Max Planck Institute of Psychiatry, Institut National de la Recherche Agronomique (INRA), University of Bordeaux, Research Group of Psychoneuroendocrinology, Kraepelinstrasse 2-10, 80804 Munich, Germany
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, sex hormone-, and corticosteroid-binding globulin (CBG, also called transcortin). CBG is a monomeric glycoprotein synthesized and stored mainly by the liver ( Rothschild et al . 1972 , Weiser et al . 1979 , Kuhn et al . 1986 , Hammond et al
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ABSTRACT
Previous studies utilizing steroid-binding assays have suggested that corticosteroid-binding globulin (CBG)-like glucocorticoid binding sites are present in various tissues of the rat. It is not known, however, whether such binding reflects the intracellular presence of CBG derived from serum or a special class (type III) of receptors. In order to elucidate this problem, immunocytochemical localization of rat CBG was carried out using a specific antiserum prepared against rat serum CBG and the peroxidase-antiperoxidase technique. Positive staining was found in certain cells of the liver, the distal and/or convoluted tubules of the kidney, the uterus, the follicular cells of the thyroid, and some cells of the anterior pituitary. Other tissues including heart, muscle, thymus, hypothalamus, supraoptic and paraventricular nuclei, and diaphragm were negative. The presence of immunoreactive CBG in specific cells of some glucocorticoid-responsive tissues and not others raises interesting questions concerning the transport of glucocorticoids and their mechanism of action.
J. Endocr. (1986) 108, 31–36
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ABSTRACT
A radioimmunoassay (RIA) for human corticosteroid binding globulin (CBG) has been developed using 125I-labelled CBG and a monospecific solid-phase CBG-antiserum (CBG-Ab-cellulose). In an RIA of serum CBG concentrations, pure CBG standards (1–100 ng protein) or samples (1 : 200) were incubated (16 h at 20 °C) with 125I-labelled CBG and CBG-Ab-cellulose. After addition of 2 ml 0·9% NaCl, the tubes were centrifuged, supernatants were aspirated and the 125I-labelled CBG bound to the CBG-Ab-cellulose pellet was counted. The specificity of the RIA was confirmed by parallel displacement curves for serial dilutions of male, female and pregnancy sera, as well as pure CBG standards. The mean ± s.d. recovery (99±8%) of pure CBG (1·6–25·0 ng) added to a diluted serum sample verified the accuracy of the method, and a good correlation (r = 0·97; n = 43) existed between serum CBG cortisol binding capacity (nmol/l) measurements and CBG concentrations (mg protein/l) measured by RIA. Intra- and interassay precisions (C.V.) at low to high serum CBG concentrations were <5% and <9% respectively. The mean ± s.d. serum CBG concentrations (mg protein/l) measured by the RIA were: 21·8±4·6 in boys (n = 12), 20·0±4·2 in girls (n = 9), 20·7±2·7 in men (n = 6), 20·5±2·9 in women (n = 6) and 47·1 ±10·5 in pregnant women (n = 5). The sensitivity of the standard curve used in the routine RIA of serum CBG was 1·0 ng CBG/assay tube, but this could be increased to 0·2 ng/assay tube by reducing the amount of CBG-Ab-cellulose used. The RIA is suitable for both clinical and research purposes, and will aid the identification of abnormal forms of CBG and facilitate studies of the regulation of CBG production in vitro.
J. Endocr. (1985) 104, 259–267
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ABSTRACT
The serum concentration of corticosteroid-binding globulin (CBG) is higher in female rats than in males. Combined hypophysectomy and gonadectomy of female rats reduced the serum concentration of CBG as measured by steady-state polyacrylamide gel electrophoresis, whereas hypophysectomy of male rats increased serum CBG. These effects were seen despite replacement therapy with thyroxine and glucocorticoids. Moreover, neither androgen nor oestrogen treatment affected the serum concentrations of CBG in hypophysectomized rats. Continuous infusions of human or bovine GH (1·4 U/kg per day), by means of osmotic minipumps for 1 week, increased serum concentrations of CBG in both hypophysectomized male and female rats. In contrast, intermittent GH replacement therapy by s.c. injections at 12-h intervals either had no effect or suppressed serum CBG levels. In male rats, neonatal (days 1–2) gonadectomy increased CBG levels more than did prepubertal (day 25) gonadectomy, and testosterone replacement therapy reversed these effects.
It is concluded that GH increases the serum CBG levels of hypophysectomized rats when it is given in a continuous manner, but not when given intermittently. The sex difference in serum CBG levels of normal rats may, therefore, be attributed to the more continuous secretory pattern of GH previously observed in female rats.
Journal of Endocrinology (1989) 122, 725–732
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ABSTRACT
A monospecific antiserum against human corticosteroid binding globulin (hCBG) has been used to identify structural similarities between hCBG and CBG in the blood of other primates and representative species of different vertebrate classes. Double immunodiffusion analysis indicated that only CBG in Old World monkeys and apes cross-react with the hCBG antiserum. This was confirmed by a solid-phase radioimmunoassay for hCBG which also demonstrated that CBG in apes is immunologically identical to hCBG and that Old World monkey CBG comprises most, but not all, of the hCBG epitopes. The electrophoretic mobilities of human, gorilla and gibbon CBG were similar (R F 0·50–0·51), but differed from Old World monkey CBG (R F 0·44–0·49) and chimpanzee CBG (R F 0·47). Although serum/plasma cortisol binding capacities were similar in Old World primates, the dissociation half-times (t ½) of cortisol were higher from human and ape CBG (18–25 min) than from Old World monkey CBG (14–18 min). The steroid binding specificities of human and ape (CBG corticosterone > cortisol > progesterone ≥ testosterone) were also different from those of Old World monkey CBG (corticosterone >> cortisol ≃ progesterone > testosterone). Lemur plasma cortisol binding capacity and CBG dissociation t ½ of cortisol were similar to hCBG, but its steroid binding specificity was different (cortisol > corticosterone > progesterone ≥ testosterone) and it did not cross-react with the hCBG antiserum. We could not detect high affinity cortisol binding activity in blood samples from New World monkeys, and they did not cross-react with the hCBG antiserum. These results suggest that considerable modification in the steroid binding activity and structure of CBG has occurred since the evolutionary appearance of the primates, but that the rate of change decreased after the cladogenesis of Catarrhine primates.
J. Endocr. (1985) 104, 251–257
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ABSTRACT
A corticosteroid binding globulin variant (CBGv) has been identified in a serum sample taken from an apparently healthy woman during late pregnancy. Identification was based on the observation that it exhibited approximately half the cortisol binding capacity expected when compared to its concentration measured by radioimmunoassay (RIA). Affinity purification of CBGv excluded the possibility that this anomaly was caused by assay interference, and demonstrated that immunoreactive CBGv was capable of binding cortisol. The CBGv had a molecular weight (63 800) similar to normal CBG, and no evidence of molecular aggregation was found by gel filtration. Although the electrophoretic mobility, isoelectric profile and immunochemical identity of CBGv appeared to be similar to normal CBG, it focussed as two distinct bands (pI 5·48 and pI 5·53) after desialylation with neuraminidase, unlike normal CBG which focusses only at pI 5·48. Investigation of the steroid binding characteristics of CBGv revealed a reduced association-rate constant (K a = 1·05 × 109 1/mol) and dissociation half-time (12·5 min) when compared with normal CBG (K a = 1·39 × 109l/mol and 25 min at 0 °C) but an apparently normal steroid binding specificity. Although the physiological significance of this variant is not known, the cortisol concentration in the variant serum was within the normal range of women during late pregnancy. No other CBG variants were identified among other normal controls (n = 66) or nine patients with Cushing's syndrome. It is suggested that comparisons between cortisol binding capacity and RIA will reveal other variants of CBG, and lead to greater understanding of their physiological significance.
J. Endocr. (1985) 104, 269–277
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Hypothalamic-pituitary-adrenal (HPA) activity is governed by glucocorticoid negative feedback and the magnitude of this signal is determined, in part, by variations in plasma corticosteroid-binding globulin (CBG) capacity. Here, in gonadectomized male rats we examine the extent to which different testosterone replacement levels impact on CBG and HPA function. Compared with gonadectomized rats with low testosterone replacement ( approximately 2 ng/ml), plasma adrenocorticotropin and beta-endorphin/beta-lipotropin responses to restraint stress were reduced in gonadectomized rats with high testosterone replacement ( approximately 5 ng/ml). Plasma CBG levels also varied negatively as a function of testosterone concentration. Moreover, glucocorticoid receptor binding in the liver was elevated by higher testosterone replacement, suggesting that testosterone acts to enhance glucocorticoid suppression of CBG synthesis. Since pituitary intracellular CBG (or transcortin) is derived from plasma, this prompted us to examine whether transcortin binding was similarly responsive to different testosterone replacement levels. Transcortin binding was lower in gonadectomized rats with high plasma testosterone replacement ( approximately 7 ng/ml) than in gonadectomized rats with low testosterone replacement ( approximately 2 ng/ml). This testosterone-dependent decrease in pituitary transcortin was associated, in vitro, with an enhanced nuclear uptake of corticosterone. These findings indicate that the inhibitory effects of testosterone on corticotrope responses to stress may be linked to decrements in plasma and intrapituitary CBG. This could permit greater access of corticosterone to its receptors and enhance glucocorticoid feedback regulation of ACTH release and/or proopiomelanocortin processing.
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Plasma cortisol is largely bound to corticosteroid-binding globulin (CBG), which regulates its bioavailability by restricting exit from capillaries. Levels of CBG may be altered by several factors including stress and this can influence the amount of cortisol reaching cells. This study investigated the effect of social instability on plasma concentrations of CBG, total and free (not protein bound) cortisol in horses. Horses new to our research herd ('newcomers') were confined in a small yard with four dominant resident horses for 3-4 h daily for 3-4 (n = 5) or 9-14 (n = 3) days. Jugular blood was collected in the mornings from newcomers before the period of stress began ('pre-stress'), and then before each day's stress. Residents were bled before stress on the first and thirteenth day. Residents always behaved aggressively towards newcomers. By the end of the stress period, all newcomers were subordinate to residents. In newcomers (n = 8) after 3-4 days of social stress, CBG binding capacity had fallen (P = 0.0025), while free cortisol concentrations had risen (P = 0.0016) from pre-stress values. In contrast, total cortisol did not change. In residents, CBG had decreased slightly but significantly (P = 0.0162) after 12 days of stress. Residents and newcomers did not differ in pre-stress CBG binding capacity, total or free cortisol concentrations. However, by the second week of stress, CBG binding capacity was lower (P = 0.015) and free cortisol higher (P = 0.030) in newcomers (n = 3) than in residents. Total cortisol did not differ between the groups. In conclusion social stress clearly affected the adrenal axis of subordinate newcomer horses, lowering the binding capacity of CBG and raising free cortisol concentrations. However, no effect of stress could be detected when only total cortisol was measured. Therefore, to assess adrenal axis status accurately in horses, it is essential to monitor the binding capacity of CBG and free cortisol concentrations in addition to total cortisol levels.
