Role Of Corticosteroid-binding Globulin Research Articles

Cortisol, Stress, and Disease-Bidirectional Associations; Role for Corticosteroid-Binding Globulin?

Selye described stress as a unified neurohormonal mechanism maintaining homeostasis. Acute stress system activation is adaptive through neurocognitive, catecholaminergic, and immunomodulation mechanisms, followed by a reset via cortisol. Stress system components, the sympathoadrenomedullary system, hypothalamic-pituitary-adrenal axis, and limbic structures are implicated in many chronic diseases by establishing an altered homeostatic state, allostasis. Consequent "primary stress system disorders" were popularly accepted, with phenotypes based on conditions such as Cushing syndrome, pheochromocytoma, and adrenal insufficiency. Cardiometabolic and major depressive disorders are candidates for hypercortisolemic etiology, contrasting the "hypocortisolemic symptom triad" of stress sensitivity, chronic fatigue, and pain. However, acceptance of chronic stress etiology requires cause-and-effect associations, and practical utility such as therapeutics altering stress system function. Inherent predispositions to stress system perturbations may be relevant. Glucocorticoid receptor (GR) variants have been associated with metabolic/neuropsychological states. The SERPINA6 gene encoding corticosteroid-binding globulin (CBG), was the sole genetic factor in a single-nucleotide variation-genome-wide association study linkage study of morning plasma cortisol, a risk factor for cardiovascular disease, with alterations in tissue-specific GR-related gene expression. Studies showed genetically predicted high cortisol concentrations are associated with hypertension and anxiety, and low CBG concentrations/binding affinity, with the hypocortisolemic triad. Acquired CBG deficiency in septic shock results in 3-fold higher mortality when hydrocortisone administration produces equivocal results, consistent with CBG's role in spatiotemporal cortisol delivery. We propose some stress system disorders result from constitutional stress system variants rather than stressors themselves. Altered CBG:cortisol buffering may influence interstitial cortisol ultradian surges leading to pathological tissue effects, an example of stress system variants contributing to stress-related disorders.

Central role for corticosteroid-binding globulin in rat HPA axis sexual dimorphism

Central role for corticosteroid-binding globulin in rat HPA axis sexual dimorphism

Corticosteroid-Binding Globulin is expressed in the adrenal gland and its absence impairs corticosterone synthesis and secretion in a sex-dependent manner

Corticosteroid-binding globulin (CBG) is synthesized by the liver and secreted into the bloodstream where binds to glucocorticoids. Thus CBG has the role of glucocorticoid transport and free hormone control. In addition, CBG has been detected in some extrahepatic tissues without a known role. CBG-deficient mice show decreased total corticosterone levels with missing of classical sexual dimorphism, increased free corticosterone, higher adrenal gland size and altered HPA axis response to stress. Our aim was to ascertain whether CBG deficiency could affect the endocrine synthetic activity of adrenal gland and if the adrenal gland produces CBG. We determined the expression in adrenal gland of proteins involved in the cholesterol uptake and its transport to mitochondria and the main enzymes involved in the corticosterone, aldosterone and catecholamine synthesis. The results showed that CBG is synthesized in the adrenal gland. CBG-deficiency reduced the expression of ACTH receptor, SRB1 and the main genes involved in the adrenal hormones synthesis, stronger in females resulting in the loss of sexual dimorphism in corticosteroid adrenal synthesis, despite corticosterone content in adrenal glands from CBG-deficient females was similar to wildtype ones. In conclusion, these results point to an unexplored and relevant role of CBG in the adrenal gland functionality related to corticosterone production and release.

The role of corticosteroid-binding globulin in the evaluation of adrenal insufficiency.

Cortisol is a hydrophobic molecule that is largely bound to corticosteroid-binding globulin (CBG) in the circulation. In the assessment of adrenal insufficiency, many clinicians measure a total serum cortisol level, which assumes that CBG is present in normal concentrations and with a normal binding affinity for cortisol. CBG concentration and affinity are affected by a number of common factors including oral contraceptive pills (OCPs), fever and infection, as well as rare mutations in the serine protease inhibitor A6 (SERPINA6) gene, and as such, total cortisol levels might not be the ideal way to assess adrenal function in all clinical circumstances. This paper reviews the limitations of immunoassay and liquid chromatography-tandem mass spectrometry (LC-MS/MS) in the measurement of total cortisol, the challenges of measuring free serum cortisol directly as well as the difficulties in calculating an estimated free cortisol from total cortisol, CBG and albumin concentrations. Newer approaches to the evaluation of adrenal insufficiency, including the measurement of cortisol and cortisone in the saliva, are discussed and a possible future role for these tests is proposed.

Bridging the Gap: The Potential Role of Corticosteroid Binding Globulin in Cardiac Steroid Facilitation.

Corticosteroid (glucocorticoids [GCs] and mineralcorticoids [MCs]) interact directly with cells of the cardiovascular system. Their signaling affects genomic and non-genomic receptors and comprises a multitude of alternative and interfering levels of interaction, which influence the physiological response. This review describes genomic and non-genomic pathways of steroid facilitation and portrays the current body of knowledge regarding corticosteroid-binding globulin (CBG). The latter is a carrier protein facilitating corticosteroid availability in the circulation and has recently been discovered intrinsically in cardiomyocytes. Thought experiments highlight potential areas of clinical research and hypotheses are presented for steroid- carrier interaction. Furthermore, this review comprises a conclusive overview of disease conditions and substances that influence CBG levels and summarizes the potential of CBG as a potential future biomarker.

Role of corticosteroid binding globulin in emotional reactivity sex differences in mice.

Sex differences exist for stress reactivity as well as for the prevalence of depression, which is more frequent in women of reproductive age and often precipitated by stressful events. In animals, the differential effect of stress on male's and female's emotional behavior has been well documented. Crosstalk between the gonadal and stress hormones, in particular between estrogens and glucocorticoids, underlie these sex differences on stress vulnerability. We have previously shown that corticosteroid binding globulin (CBG) deficiency in a mouse model (Cbg k.o.) leads, in males, to an increased despair-like behavior caused by suboptimal corticosterone stress response. Because CBG displays a sexual dimorphism and is regulated by estrogens, we have now investigated whether it plays a role in the sex differences observed for emotional reactivity in mice. By analyzing Cbg k.o. and wild-type (WT) animals of both sexes, we detected sex differences in despair-like behavior in WT mice but not in Cbg k.o. animals. We showed through ovariectomy and estradiol (E2) replacement that E2 levels explain the sex differences found in WT animals. However, the manipulation of E2 levels did not affect the emotional behavior of Cbg k.o. females. As Cbg k.o. males, Cbg k.o. females have markedly reduced corticosterone levels across the circadian cycle and also after stress. Plasma free corticosterone levels in Cbg k.o. mice measured immediately after stress were blunted in both sexes compared to WT mice. A trend for higher mean levels of ACTH in Cbg k.o. mice was found for both sexes. The turnover of a corticosterone bolus was increased in Cbg k.o. Finally, the glucocorticoid-regulated immediate early gene early growth response 1 (Egr1) showed a blunted mRNA expression in the hippocampus of Cbg k.o. mutants while mineralocorticoid and glucocorticoid receptors presented sex differences but equivalent mRNA expression between genotypes. Thus, in our experimental conditions, sex differences for despair-like behavior in WT mice are explained by estrogens levels. Also, in both sexes, the presence of CBG is required to attain optimal glucocorticoid concentrations and normal emotional reactivity, although in females this is apparent only under low E2 concentrations. These findings suggest a complex interaction of CBG and E2 on emotional reactivity in females.

A role for corticosteroid-binding globulin variants in stress-related disorders

Primary stress-related diseases such as chronic fatigue syndrome, fibromyalgia or chronic widespread pain have been associated with altered activity of the hypothalamic–pituitary–adrenal axis due to measured relative hyper- or hypo-cortisolism in basal or experimentally stimulated states. A hereditary risk to development of these diseases has been proposed. Corticosteroid-binding globulin (CBG), a plasma transport vehicle for cortisol, may play a more active role in the hypothalamic–pituitary–adrenal axis. Chronically altered hypothalamic–pituitary–adrenal axis has been associated with common medical problems. Hypocortisolism has been observed in kindred studies of rare mutations of the SERPIN A6 (CBG) gene and more common SERPIN A6 polymorphisms associated with reduced CBG levels or CBG:cortisol-binding affinity. Over the last decade, studies of five different CBG gene mutations in humans, human genetic associations and transgenic mouse models have suggested that CBG may have hitherto unexpected roles in modulation of the stress response. Naturally occurring CBG variants may alter susceptibility to disorders associated with chronic stress and relative hypocortisolism. On the other hand, hypercortisolism has been linked with Cushing's disease and metabolic syndrome and CBG gene polymorphisms have been linked to obesity in animal models. In this article, we look at the evidence suggesting a role for CBG in stress-related disorders, focusing particularly on CBG gene polymorphisms and chronic pain/fatigue syndromes.

Characterization and quantification of corticosteroid-binding globulin in a southern toad, Bufo terrestris, exposed to coal-combustion-waste

Corticosteroid-binding globulin (CBG) is a plasma protein that binds corticosterone and may regulate access of hormone to tissues. The role of CBG during a stress response is not clear. At least two hypotheses have been proposed: 1) CBG levels may increase in response to a stressor, thereby decreasing the amount of circulating free corticosterone, or 2) CBG levels may decline, making corticosterone available for its role in increased metabolic needs during stress. In this study, southern toads, Bufo terrestris, were exposed to a chronic pollutant (coal-combustion-waste), to determine changes in CBG and free corticosterone levels. Since toads exposed to chronic pollutants in previous studies did not exhibit the predicted changes in metabolic rate and mass, but did experience a significant elevation in total corticosterone, we hypothesized that CBG would likewise increase and thus, mitigate the effects of a chronic (i.e. 2 months) pollutant stressor. To conduct this study, we first characterized the properties of CBG in southern toads. Toad CBG has a K d = 20.6 ± 1.0 nM and a B max = 332.2 ± 5.1 nmol/L plasma. The rank order potencies for steroid inhibition of tritiated corticosterone are: dihydrotestosterone > corticosterone ≫ progesterone = testosterone ⋙ estrogen = dexamethasone. After characterization, we monitored the changes in CBG, total corticosterone, and free corticosterone in male toads that were exposed to either coal-combustion-waste or control conditions. CBG increased in all groups throughout the experiment. Total corticosterone, on the other hand, was only significantly elevated at four weeks of exposure to coal-combustion-waste. The increase in CBG did not parallel the increase in total corticosterone; as a result, free corticosterone levels were not buffered by CBG, but showed a peak at four weeks similar to total corticosterone. This finding indicates that, in this species, CBG may not provide a protective mechanism during long-term pollution exposure.

Regulation factors of corticosteroid-binding globulin: lesson from ontogenesis.

This short review summarizes recent data on corticosteroid-binding globulin (CBG), especially enlightening results on regulation factors of CBG gene expression during ontogenesis. The role of CBG as a specific steroid carrier, a structurally conserved glycoprotein of 50-60 kD in vertebrate species, is well documented, but this knowledge has often been limited to the young or adult life since CBG levels are low in the neonate. However, CBG and CBG mRNA have been recently detected, sometimes, in relatively high amounts, in various fetal tissues of mammals including liver, lung, pancreas, adrenal and kidney. CBG can thus participate in glucocorticoid-inducible events crucial for maturation. Moreover, its original molecular cloning, followed by its chromosomal localization, has shed a new light on the CBG role, as a member of the serine protease inhibitors and substrates (SERPINS) superfamily. This evidenced a special and unexpected way of steroid hormones delivery to their sites of action. Additionally, two classes of CBG receptors have been characterized, and an adenylate cyclase activity has been measured when the CBG-glucocorticoid complex binds to cell membranes.

Interspecies variations of corticosteroid-binding globulin parameters

In mammalian plasma, cortisol binds to a specific α 1-glycoprotein: corticosteroid-binding globulin (CBG). In this study, we measured the protein binding of cortisol by equilibrium dialysis in seven species in which plasma cortisol concentrations varied from 0.02 to 0.05 (ewe, dog, cow) to 0.1 to 0.6 (horse, human, cynomolgus monkey) to reach 1.6 μM (squirrel monkey). No binding of cortisol to CBG was discernible in plasma from squirrel monkey. In all other species examined, we showed that the CBG maximal capacity ( B max) was 3 (1.7 to 5.2) times more than the plasma cortisol levels, with cow, dog, ewe exhibiting the lowest and cynomolgus monkey exhibiting the highest values. We also noted the existence of a linear relationship between B max and the corresponding dissociation constant ( K d ), B max being systematically 10 (8.5 to 11.8) times more than K d . The low binding affinity of cortisol assigned to albumin did not differ between species. The free (6 to 14%), CBG-bound (67 to 87%), and albumin-bound (7 to 19%) cortisol fractions calculated from the estimated binding parameters and measured plasma cortisol concentrations were similar within species, except for squirrel monkey, in which half of the cortisol was albumin bound, and the other half remained protein free. Our most appealing finding was that in most species, as much as 68% of plasma CBG remained free of cortisol under physiologic conditions. These results are discussed with respect to the theories concerning the role of CBG in plasma transport and the local delivery of cortisol and free CBG as a proper hormone.

On the role of corticosteroid-binding globulin (CBG) in modulating activity of glucocorticoids: developmental patterns for CBG, corticosterone, and a-fetoprotein levels in the rat serum.

The levels of corticosterone, corticosteroid-binding globulin (CBG), and a-fetoprotein (AFP) were measured in the serum of developing rats. It has been shown that the dramatic increase in CBG concentration and the decrease in AFP concentration of the same degree occur in males and females during the third postnatal week. The considerable rise in corticosterone level was observed only during 4th postnatal week. The data obtained in the study suggest that CBG may be responsible for the essential contribution to the developmental rise in glucocorticoid activity.

A Role for Corticosteroid-Binding Globulin in Delivery of Cortisol to Activated Neutrophils*

In human blood, cortisol is transported by a plasma protein known as corticosteroid-binding globulin (CBG). As anticipated from primary structure comparisons of CBG and alpha 1-proteinase inhibitor (A1-PI), CBG acts as a substrate for neutrophil elastase. However, unlike A1-PI, CBG does not alter the activity of this enzyme, but is cleaved by it at a single location close to its carboxy-terminus, and this reduces its molecular size by 5 kDa with the concomitant release of more than 80% of CBG-bound cortisol. Three small molecular size fragments are detected after elastase cleavage, and carbohydrate analysis of these fragments suggests that they represent the same polypeptide fragment which has been differentially glycosylated. To assess the biological significance of these observations, CBG was incubated with either mononuclear cells or granulocytes obtained from patients with acute inflammation (sepsis) and from a normal volunteer. Only granulocytes from septic patients reduced the mol wt of CBG by about 5 kDa and destroyed its steroid-binding activity. Preincubation with A1-PI prevented this, which demonstrates that neutrophil elastase plays a key role in this event. These results suggest a physiological role for CBG in the delivery of cortisol to sites of inflammation.

Hamster Uterine Tissues Accumulate Corticosteroid-Binding Globulin during Decidualization1

Although corticosteroid-binding globulin (CBG) is known to be a serum steroid-binding protein, its function outside of the vascular space is not well understood. To prove an extravascular role for CBG, it must first be established that CBG occurs in steroid target tissues. We sought information on the occurrence of CBG in the cytosol, nuclear, and membrane fractions of 6 tissues during decidualization in the hamster. Our objectives were to determine if CBG is distributed in a tissue-specific manner, and to investigate the relationship between serum CBG and tissue CBG. Hamsters were given progesterone pellets s.c. on cycle Day 1 and decidualization was induced on Day 4. A 3H-cortisol-binding assay, which distinguished between CBG and glucocorticoid receptor, was used to determine CGB levels in the serum and in the cytosol, nuclear, and membrane fractions of deciduoma, myometrium, liver, kidney, muscle, and small intestine. Cytosol CBG accounted for greater than 97% of the total CBG detected in all tissues except liver, where nuclei contained 11% of the measurable CBG. For all cell fractions, CBG levels showed consistent tissue-specific differences. Cytosol CBG was highest in deciduoma and myometrium, 2-fold less in liver and kidney, and 5-fold less in muscle and small intestine. Nuclear CBG concentration was greatest in liver and approximately 10-fold less in other tissues, except for small intestine, where nuclear CBG was undetectable. Membrane CBG was highest in liver, 5-fold less in deciduoma, 10-fold less in myometrium, and about 20-fold less in other tissues. Serum CBG increased 7-fold from Day 4 to Day 9 in decidualized hamsters, but not in nondecidualized sham-operated hamsters. In all tissues, serum CBG was correlated with cytosol CBG. The high levels of CBG in uterine tissues were not the result of serum contamination because whole-body perfusion with buffered saline failed to remove the majority of cytosol CBG under conditions where over 70% of 51Cr-labeled red blood cells were removed. The identity of uterine cytosol CBG with serum CBG was established by ion-exchange chromatography (O-(diethylaminoethyl)-cellulose) and by immunoprecipitation with an antibody generated against serum CBG. These data demonstrate that uterine tissues accumulate substantial amounts of CBG during decidualization, thus raising the possibility of a functional role of CBG in uterine tissues during early pregnancy.

CBG does not restrict blood-brain barrier corticosterone transport in rabbits.

The metabolic clearance rate of corticosterone in rabbits is unrelated to the physiological concentration of corticosteroid binding globulin (CBG) in rabbit plasma. This suggests that corticosterone is available for transport into peripheral tissues in rabbits from the circulating CBG-bound pool, similar to what is known to occur in rat liver. This hypothesis was tested in the present studies, which investigate the transport of corticosterone into rabbit brain from the circulating rabbit or human CBG-bound pool. Corticosterone was readily exchangeable in brain capillaries in vivo from the circulating albumin-bound and rabbit or human CBG-bound pools. The involvement of specific CBG receptors on brain capillary endothelia in this process was investigated with [3H]-labeled human CBG prepared by reductive methylation. The transport of [3H]CBG across rabbit brain capillaries in vivo was immeasurably low, and no specific binding of this radiolabeled plasma protein to isolated brain capillaries in vitro was observed at 37 degrees C during incubations up to 120 min. These studies indicate that the rabbit is a novel system for assessing the role of CBG in delivering corticosterone to peripheral tissues in vivo and that specific endothelial CBG receptors may not participate in the transport process.

Role of corticosteroid-binding globulin in interaction of corticosterone with uterine and brain progesterone receptors.

The central actions of the steroid hormone progesterone remain an enigma. However, there is no doubt that this hormone has a vital role in the control of sexual function and behaviour in many species, including man. Furthermore, progesterone may be involved in the premenstrual and postpartum syndromes. It would therefore be very useful to know the role and mechanism of action of progesterone in the brain. We now show that there are differences between progesterone receptors in brain and uterus, and possibly in the distribution of the serum progesterone-binding protein, corticosteroid-binding globulin (CBG), which may enter uterine but not brain cells.

The steroid induction of glutamine synthetase in chick embryo retinas in culture a possible role of corticosteroid-binding globulin

The relationship between the induction of retinal glutamine synthetase in tissue culture and changes in the corticosteroid-binding capacity of serum in the culture medium was investigated. As measured by equilibrium dialysis, corticosteroid-binding capacity was consistently higher in the medium after the culture period indicating a removal of corticosteroid from the medium during this time. The effect of heat inactivation of serum corticosteroid-binding globulin and the effect of steroid depleted (stripped) serum in the medium on the induction were studied. The uptake of [1,2− 3H 2]-cortisol by retinal tissue in the presence of varying concentrations of stripped serum was found to parallel glutamine synthetase induction. These studies demonstrate: (1) the uptake of endogenous glucocorticoid of the serum-containing culture medium during glutamine synthetase induction; (2) the identity of steroid with a previously reported inducing factor in serum; and (3) an influence of corticosteroid-binding globulin in mediating the effects of the hormone.