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At least 1,063 records · Page 59Linked to original sources
PubMed2006

Hyporesponsiveness to glucocorticoids in mice genetically deficient for the corticosteroid binding globulin.

Corticosteroid binding globulin (CBG) is the carrier for glucocorticoids in plasma. The protein is believed to keep the steroids inactive and to regulate the amount of free hormone acting on target tissues (free hormone hypothesis). Here, we generated a mouse model genetically deficient for CBG to test the contribution of the carrier to glucocorticoid action and adrenocortical stress response. The absence of CBG resulted in a lack of corticosterone binding activity in serum and in an approximately 10-fold increase in free corticosterone levels in CBG-null mice, consistent with its role in regulation of circulating free hormone levels. Surprisingly, cbg(-/-) animals did not exhibit features seen in organisms with enhanced glucocorticoid signaling. Rather, the mice exhibited increased activity of the pituitary axis of hormonal control, normal levels of gluconeogenetic enzymes, and fatigue, as well as an aggravated response to septic shock, indicating an inability to appropriately respond to the excess free corticosterone in the absence of CBG. Thus, our data suggest an active role for CBG in bioavailability, local delivery, and/or cellular signal transduction of glucocorticoids that extends beyond a function as a mere cargo transporter.

Adrenocorticotropic Hormone↗
PubMed1971

Cortisol in the cerebrospinal fluid of patients suffering from affective disorders.

Cortisol concentration was estimated by a competitive protein-binding method in the lumbar cerebrospinal fluid (CSF) of patients suffering from depression or from mania, and compared with the CSF cortisol concentration of neurological control patients not suffering from an affective disorder. There were no significant differences between the groups.

Affective Symptoms↗
PubMed1995

Effects of incremental cortisol and adrenalectomy on plasma corticosteroid binding capacity in fetal sheep.

The effects of incremental cortisol infusion or fetal adrenalectomy on plasma corticosteroid-binding capacity (CBC) were examined in sheep fetuses during late gestation (term approximately 150 days). Cortisol, infused from day 120 at 1.5 mg/day for the first 3 days, 2.5 mg/day for the next 5 days, and 3.5 mg/day for the final 2 days, stimulated a significant rise in plasma CBC and immunoreactive corticosteroid binding globulin (CBG). There was a significant positive correlation between individual values for total plasma cortisol concentrations and CBC values. In contrast, fetal adrenalectomy at day 115 prevented the rise in plasma CBC found in intact fetuses at term. These experiments show that exogenous cortisol, given in a manner that mimics the prepartum rise in fetal plasma cortisol, stimulates CBG biosynthesis, whereas abolition of the cortisol rise prevents the increase in CBG. The study provides strong support for the proposal that the prepartum increase in CBG biosynthesis in fetal sheep occurs in response to the progressive rise in adrenal cortisol output by the fetus towards term.

Adrenal Cortex Hormones↗
PubMed2003

Greater replication and differentiation of preadipocytes in inherited corticosteroid-binding globulin deficiency.

Glucocorticoids are pivotal for adipose tissue development. Rodent studies suggest that corticosteroid-binding globulin (CBG) modulates glucocorticoid action in adipose tissue. In humans, both genetic CBG deficiency and suppressed CBG concentrations in hyperinsulinemic states are associated with obesity. We hypothesized that CBG deficiency in humans modulates the response of human preadipocytes to glucocorticoids, predisposing them to obesity. We compared normal preadipocytes with subcultured preadipocytes from an individual with the first ever described complete deficiency of CBG due to a homozygous null mutation. CBG-negative preadipocytes proliferated more rapidly and showed greater peroxisome proliferator-activated receptor-gamma-mediated differentiation than normal preadipocytes. CBG was not expressed in normal human preadipocytes. Glucocorticoid receptor number and binding characteristics and 11beta-hydroxysteroid dehydrogenase activity were similar for CBG-negative and normal preadipocytes. We propose that the increased proliferation and enhanced differentiation of CBG-negative preadipocytes may promote adipose tissue deposition and explain the obesity seen in individuals with genetic CBG deficiency. Furthermore, these observations may be relevant to obesity occurring with suppressed CBG concentrations associated with hyperinsulinemia.

11-beta-Hydroxysteroid Dehydrogenase Type 2↗
PubMed2004

Corticosterone binding globulin regulation and thymus changes after thermal injury in mice.

Thermal injury is extremely stressful, and data characterizing the systemic endocrine stress response to this injury are sparse. The objective of this study was to measure the effects of thermal injury on mice on corticosterone (Cort) levels in relation with corticosteroid-binding globulin (CBG) and thymus cell populations. The endocrine stress response was determined by measuring total Cort, free Cort, CBG binding capacity, liver CBG mRNA, and circulating CBG levels at 1, 2, 5, and 10 days postburn. Thymus cell populations were also analyzed. After thermal injury, a rapid increase of total Cort was observed in the first 48 h. This was associated with a decrease of hepatic CBG mRNA, protein levels, and binding capacity. Percentage of free Cort in the burn group peaked at day 2 postburn with a dramatic (+500%) increase. This correlated with a significant decrease of thymus cellularity (50% less). Phenotypic analyses showed that corticosensitive cells were significantly altered. After treatment (5 days), both endocrine and immune parameters returned to control levels. Our results demonstrate that, after a thermal injury, CBG is mainly responsible for Cort's action on corticosensitive immune cells.

Animals↗
PubMed1978

Alterations in steroid binding plasma proteins in Macaca nemestrina during pregnancy.

We measured the corticosterone and dihydrotestosterone steroid binding capacities of corticosteroid-binding globulin (CBG) and sex steroid plasma binding protein (SBP) throughout pregnancy in seven Macaca nemestrina. The nSBP binding capacity rises significantly by 28 days of pregnancy, remains elevated through 56 days, tends to fall through midpregnancy, and then decreases dramatically to very low values 130-153 days after conception. In contrast, nCBG rises slightly (1.2-fold) in early pregnancy, is elevated in midpregnancy, but is similar to nonpregnant values during the last trimester of pregnancy. Our data indicate that factors controlling the plasma concentration of nCBG and nSBP are not identical. The results are in sharp contrast to those observed in human pregnancies in which both hSBP and hCBG are increased severalfold during pregnancy, including at term. Because the changes of nCBG and nSBP during pregnancy do not paralle the changes observed in human beings even though their steroid binding characteristics are similar, the M. nemestrina may serve as a valuable model for defining the physiologic function of SBP and CBG and the mechanism(s) controlling their concentrations in blood.

Animals↗
PubMed1978

Plasma concentrations of total and free corticosterone during development in the rat.

A sensitive protein-binding assay has been used to measure plasma concentrations of total corticosterone during postnatal development in the rat. These concentrations were extremely low on days 6--12, showed a significant rise by day 14, and then continued to rise until peaking on day 24. Plasma titers of corticosteroid-binding globulin rose even more dramatically from day 12 onward. Consequently, the percentage of total plasma corticosterone, which was protein-bound, showed a gradual rise from 78% on day 12 to 98% on day 24. Despite this trend, when concentrations of free corticosterone were calculated, they were found to have a developmental profile very similar to that of total corticosterone. Assay of jejunal lactase and sucrase in the same animals that were used for the corticosterone studies showed that the ontogenic rise of both total and free corticosterone preceded the developmental changes in the activities of these enzymes by approximately 2 days. The data suggest that the rise in free corticosterone that begins on day 14 acts as a cue for enzymic changes in both liver and intestine.

Animals↗
PubMed1979

Glucocorticoid and estrogen regulation of corticosteroid-binding globulin production by rat liver.

We have recently demonstrated that rat liver can synthesize and secrete corticosteroid-binding globulin (CBG). The present study extends these observations and examines the hormonal regulation of hepatic CBG production. Male rats were pretreated by adrenalectomy and/or glucocorticoid or estrogen administration and the rate of CBG production was measured in vitro. The production rates were assessed by the generation of specific corticosterone binding sites in both a liver-slice preparation and in an isolated perfused liver. The two techniques showed qualitatively similar results. Adrenalectomy enhanced and glucorticoid administration inhibited the rate of CBG production and secretion. Pretreatment of male rats with estradiol stimulated the rate of CBG production. The production rates were 20- to 40-fold higher in the perfused liver demonstrating its superiority over the liver-slice system. The livers from intact rats secreted CBG binding sites at a rate of approximately 18 pmol/g liver per hours, generating an estimated 20% of the total CBG content of a rat each day. The possible clinical implications of the therapeutic use of glucocorticoids that bind to CBG, yet inhibit CBG production, are discussed.

Adrenalectomy↗
PubMed1981

Hormonal control of postnatal development of corticosteroid-binding globulin.

The hormonal regulation of the ontogenic rise in serum corticosteroid-binding globulin (CBG) has been studied in the rat. Pups received daily injections of estrogens (either estradiol, estrone, or diethylstilbesterol, each at 0.05 microgram/g body wt) or thyroxine (0.1 microgram/g body wt) on postnatal days 2-7. When CBG binding capacity was determined on day 8, only the thyroxine-injected pups were found to have elevated CBG. This effect of thyroxine on CBG binding capacity was further studied by daily administration of the hormone (0.1 microgram.g body wt-1.day-1) between postnatal days 5-12. This caused a precocious rise in serum CBG, with CBG values 6- to 38-fold higher than euthyroid controls on days 8, 10, and 12. Conversely, in pups made hypothyroid by administration of propylthiouracil, the normal ontogenic increase in CBG was suppressed. Thyroxine replacement resulted in the reappearance of the CBG rise. These results suggest that the developmental rise in the binding capacity of CBG is independent of estradiol and estrone and instead is elicited by the rising concentrations of circulating thyroxine that normally occur in the early postnatal period.

Animals↗
PubMed1982

Role of thyroxine in coordinate control of corticosterone and CBG in postnatal development.

The role of thyroxine (T4) in the ontogeny of serum corticosteroid-binding globulin (CBG) and corticosterone has been studied in the rat. Daily injection of T4 (0.1 micrograms/g body wt) resulted in the precocious appearance of both CBG and corticosterone. A dose-response study revealed an increase in both CBG and corticosterone at thyroxine doses greater than 0.02 micrograms/g body wt. In propylthiouracil-induced hypothyroid pups, the developmental rise of both CBG and corticosterone was suppressed. To determine whether T4 elevation of CBG was mediated by corticosterone, serum CBG was measured in corticosterone-injected pups (10 micrograms/g body wt). No increase in CBG was detected on days 8 and 10. A slight increase, only one-eighth that elicited by T4, occurred on day 12. There was also no synergistic effect between T4 and corticosterone. We conclude that the postnatal increase in serum T4 concentrations cues the developmental rise of both CBG and corticosterone in the rat.

Aging↗
PubMed1986

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.

Animals↗
PubMed1987

Plasma protein-mediated transport of steroid and thyroid hormones.

The free hormone or free drug hypotheses have traditionally assumed that the concentration of cellular exchangeable hormone (i.e., the pool that drives cellular hormone or drug receptor occupancy) can be reliably estimated by in vitro measurements of unbound hormone concentrations. The corollary of this view is that the large reservoir of bound hormone in blood is passively transported by plasma proteins and is physiologically inactive. However, when these assumptions are subjected to direct empiric testing with either in vivo or perfused organ techniques, it is found that the large pool of bound hormone in blood is operationally available for transport across microcirculatory barriers without the plasma protein, per se, significantly exiting the plasma compartment. This process is believed to involve a mechanism of enhanced dissociation of hormone or drug from the plasma protein caused by transient conformational changes about the ligand binding site within the microcirculation: The biochemical mechanism of the interaction of the plasma protein with the surface of the microcirculation may involve receptor, charged selectivity, or local inhibitor mechanisms.

Adrenal Cortex Hormones↗
PubMed1987

Mineralocorticoid specificity of renal type I receptors: in vivo binding studies.

We have injected rats with [3H]aldosterone or [3H]corticosterone, plus 100-fold excess of the highly specific glucocorticoid RU 28362, with or without excess unlabeled aldosterone or corticosterone and compared type I receptor occupancy in kidney and hippocampus. Thirty minutes after subcutaneous injection [3H]aldosterone was well retained in renal papilla-inner medulla, renal cortex-outer medulla, and hippocampus; in contrast, [3H]corticosterone was well retained only in hippocampus. Competition studies for [3H]aldosterone binding sites showed corticosterone to be a poor competitor in the kidney compared with hippocampus. Time-course studies, with rats killed 10-180 min after tracer administration, showed very low uptake/retention of [3H]corticosterone by kidney; in hippocampus [3H]corticosterone retention was similar to that of [3H]aldosterone in kidney, and retention of [3H]aldosterone by hippocampus was much more prolonged than of either tracer in any other tissue. Studies in 10-day-old rats, with very low levels of corticosteroid binding globulin (CBG), showed a high degree of aldosterone selectivity in both zones of the kidney, whereas [3H]aldosterone and [3H]corticosterone were equivalently bound in hippocampus. We interpret these data as evidence for a mechanism unrelated to extravascular CBG conferring mineralocorticoid specificity on renal type I receptors and propose two models derived from our findings consistent with such differential selectivity.

Aldosterone↗
PubMed1988

TeBG- and CBG-bound steroid hormones in rabbits are available for influx into uterus in vivo.

The metabolic clearance rate (MCR) of gonadal or adrenal steroid hormones in rabbits often does not bear the expected inverse relationship with hormone binding to testosterone-binding globulin (TeBG) or corticosteroid-binding globulin (CBG). This suggests TeBG or CBG may not impede steroid hormone delivery to tissues. The effects of rabbit plasma proteins on the influxes of 3H-labeled steroids from the circulation into the rabbit uterus were measured in vivo using a tissue sampling single-injection technique. In the absence of plasma proteins, estradiol (E2) and testosterone (T) were freely diffusible through the uterine microvasculature (i.e., extraction greater than 80%). The extractions of dihydrotestosterone (DHT) and corticosterone (B) ranged from 60 to 72%, while that of cortisol (F) was reduced at 40%. Rabbit serum exerted no inhibition of the influxes of the steroids tested. The influxes of T and B greatly exceeded the rates that would be expected if only the free and albumin-bound fractions estimated in vitro were diffusible in vivo. However, the extraction of [3H]corticosteroid-binding globulin or bovine [3H]albumin were low, consistent with little, if any, extravascular uptake of the plasma proteins. The results indicate both albumin-bound and globulin-bound steroid hormone are available for transport into the uterus in the rabbit in vivo without significant exodus of the plasma protein, per se.

Animals↗
PubMed1995

Postprandial free fatty acids stimulate activity of human corticosteroid binding globulin.

The effect of postprandial variation of free fatty acids (FFA) on serum corticosteroid binding globulin (CBG) properties and cortisol (hydrocortisone) concentrations were explored in 11 women (20-30 yr) during 8 h after an oral load of tallow (26% C16:0, 18% C18:0, and 43% C18:1), oleic-sunflower (oleic-SF; 73% C18:1), sunflower (SF; 67% C18:2), and mixed oil (MO; 39% C18:1 and 48% C18:2). Serum FFA increased little after SF and MO but more than doubled in the late postprandial period (6 and 8 h) after oleic-SF (due to monounsaturated FFA) or tallow (due to saturated and monounsaturated FFA). CBG concentrations remained unchanged, but in relation with the postprandial elevation of serum FFA, CBG binding activity was increased after tallow or oleic-SF as a result of a combined two- to threefold increase in affinity constant and a 50% reduction in binding sites. Immunological and in vitro binding studies showed the changes in CBG behavior to be conformational and to be mediated mainly by monounsaturated FFA, especially C18:1. The modifications of CBG properties were associated with sustained high concentrations of cortisol (suppression of midday decrease) 6 and 8 h after tallow or oleic-SF. Thus dietary FFA may have an impact on bioavailability of glucocorticoids.

Adult↗