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PubMed1998

Corticosterone binding to tissues of adrenalectomized lean and obese Zucker rats.

The binding of corticosterone, dexamethasone and aldosterone was investigated in plasma and in homogenates of liver, kidney, brain, brown adipose tissue and visceral (periovaric) and subcutaneous white adipose tissues of Zucker lean and obese rats: intact controls, adrenalectomized and sham-operated. Corticosterone-binding globulin (CBG) accounted for most of the binding, whereas that of glucocorticoid and mineralocorticoid receptors was much lower. Plasma corticosterone levels increased in sham-operated and obviously decreased in the adrenalectomized animals. Sham-operated and adrenalectomized lean rats showed decreased plasma CBG; in the obese, CBG levels were lower than in controls and were not affected by either surgery. No variation with obesity or surgery was observed either in dexamethasone or aldosterone binding, the latter being practically zero in most samples. When expressed per unit of tissue protein, CBG activity was maximal in adipose tissues, with lowest values in brain and liver. In lean rats, tissue CBG activity decreased with either surgical treatment; no changes were observed in the obese, which also had lower CBG tissue levels. The relative lack of changes in CBG of obese rats suggests that they have lost -- at least in part -- the ability to counter-modulate the changes in glucocorticoid levels through CBG modulation, thus relying only on the control of corticosterone levels. This interpretation agrees with the postulated role of CBG modulating the availability of glucocorticoids to target cells.

Adipose Tissue↗
PubMed1997

Corticosteroid binding globulin, total serum cortisol, and stress in extremely low-birth-weight infants.

Our objective was to determine if low levels of corticosteroid binding globulin (CBG) might explain the low serum total cortisol levels found in some extremely low-birth-weight (ELBW) infants. In a prospective study, serum total cortisol and CBG were measured in single blood samples from 31 ELBW infants, with a gestational age less than 28 weeks, in the first 8 days of life. Severity of illness was assessed using the Score for Neonatal Acute Physiology Perinatal Extension (SNAP-PE). The mean serum total cortisol (mean +/- 1 SD) was 9.2 +/- 9.8 mcg/mL and the mean CBG level was 1.4 +/- 0.31 mg/dL. There was no significant correlation between serum total cortisol and CBG levels (r = -0.18), severity of illness as measured by the SNAP-PE (r = +0.12), or birth weight (r = -0.12). Five of 31 infants, having a mean SNAP-PE score of 41, had serum total cortisol levels < or = 3.0 mcg/dL. Estimated mean serum free cortisol concentrations in these five infants (0.76 mcg/dL) were comparable to estimated free cortisol levels diagnostic of adrenal insufficiency in sick adult patients. Our findings indicate that CBG levels are lower in ELBW infants than in term infants, but low CBG levels do not explain the low serum total cortisol levels found in some very sick infants. Low cortisol levels in small premature infants may be adequate to support growth if the infant is well, but may result in a syndrome of adrenal insufficiency in those with severe illnesses.

Adult↗
PubMed1978

Progesterone and corticosteroids in the initiation of lactation in the sow.

The concentration of lactose in the mammary secretion from individual glands of two sows increased significantly (P less than 0.01) between 0 and 24 h after parturition. In six sows studied during the perinatal period there was a negative correlation (r = -0.80; P less than 0.02) at parturition between the concentration of progesterone in the blood and the concentration of lactose in the mammary secretion. Furthermore, the increase in concentration of lactose in the mammary secretion after parturition was related to the timing of the decline of plasma progesterone to low levels. The results indicate that the initiation of lactation occurs within 24 h of parturition in most sows, and the results are consistent with the hypothesis that progesterone withdrawal acts as the 'trigger'. Neither the changes in corticosteroid binding globulin nor the changes in total corticosteroids were temporally related to the initiation of lactation. However, a circadian rhythm was observed for total corticosteroids in the blood of three out of nine lactating and pregnant sows, whereas no circadian rhythm was observed in progesterone of the four pregnant sows. The results are discussed in relation to the disease complex mastitis-metritis-agalactia.

Adrenal Cortex Hormones↗
PubMed1981

Progressive changes in plasma progesterone, prolactin and corticosteroid levels during late pregnancy and the initiation of lactose synthesis in the rat.

The relationship between progesterone, prolactin, corticosteroids and corticosteroid binding globulin (CBG) activity in plasma and the initiation of lactation were studied in normal parturient rats, and rats either ovariohysterectomized or Caesarean-sectioned on day 19 of gestation. In chronically cannulated rats the decline in plasma progesterone to low values (less than 10 micrograms/l) in normal parturient rats 20 h before term and in Caesarean-sectioned rats 10-14 h after surgery was closely related to an increase in plasma prolactin. However, in ovariohysterectomized rats the levels of progesterone declined abruptly to 20 micrograms/l within 30 min of surgery and prolactin remained low (5 micrograms/l) for 4-8 h and then gradually increased during the subsequent 16-18 h. Lactose concentrations in mammary tissue of rats killed at 0, 12, 18, 24, 36 and 48 h after surgery was low (less than 0.14 mg/g tissue) up to 12 h, and increased to reach maximum values at 36h and 48 h after surgery in ovariohysterectomized and Caesarean-sectioned rats respectively. The concentration of corticosteroids and CBG capacity in the plasma was 250-550 micrograms/l and 250-480 micrograms corticosterone bound per litre, respectively, in rats killed during the last 4 days of gestation. However, both the concentration of corticosteroids and the CBG capacity, within the individual cannulated rats, remained relatively constant during late gestation. These findings support the proposal that progesterone withdrawal is the lactogenic trigger and suggest the sequential involvement of prolactin. An increase in the concentration of free corticosteroids in late pregnancy and a related stimulatory role in the lactogenic mechanism were not established.

Adrenal Cortex Hormones↗
PubMed1981

Effects of photoperiod and feeding on plasma corticosteroid concentrations and maximum corticosteroid-binding capacity in pigs.

The effects of time of feeding and photoperiod on the circadian rhythm of total and free plasma corticosteroid concentrations and the maximum corticosteroid-binding capacity (MCBC) were measured in pigs. There were four photoperiod treatments: natural long and short daylengths (light:dark, 14:10; 101/2:131/2, respectively), artificial short daylength and reverse artificial short daylength (light:dark, 9:15). Photoperiod had a significant effect on corticosteroid concentrations. The corticosteroid concentrations on long daylength showed a major increase in the morning (from an average of 8 ng ml-1 at 0700 h to a peak level of 53.5 ng ml-1 at 0910 h). The amplitude of the morning peak was lower in the other treatments. Apart from this increase, corticosteroid levels at other times of day for pigs in all treatments were generally low. The MCBC varied greatly between animals (less than 25 - greater than 50 ng ml-1) but showed no circadian rhythm. There was no change in corticosteroid levels directly attributable to feeding. It was concluded that, in experiments where the effect of acute stressors on corticosteroid levels is examined, blood sampling should be performed in the afternoon-evening period because the between-animal variation in hormone levels is less and the hormonal levels are more stable, and also that time of feeding did not affect the rhythm of corticosteroids. A blood-sampling regime to define the circadian rhythm in corticosteroid concentration and to determine the MCBC is described.

Adrenal Cortex Hormones↗
PubMed2001

Lack of tissue glucocorticoid reactivation in 11beta -hydroxysteroid dehydrogenase type 1 knockout mice ameliorates age-related learning impairments.

11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD-1) intracellularly regenerates active corticosterone from circulating inert 11-dehydrocorticosterone (11-DHC) in specific tissues. The hippocampus is a brain structure particularly vulnerable to glucocorticoid neurotoxicity with aging. In intact hippocampal cells in culture, 11beta-HSD-1 acts as a functional 11beta-reductase reactivating inert 11-DHC to corticosterone, thereby potentiating kainate neurotoxicity. We examined the functional significance of 11beta-HSD-1 in the central nervous system by using knockout mice. Aged wild-type mice developed elevated plasma corticosterone levels that correlated with learning deficits in the watermaze. In contrast, despite elevated plasma corticosterone levels throughout life, this glucocorticoid-associated learning deficit was ameliorated in aged 11beta-HSD-1 knockout mice, implicating lower intraneuronal corticosterone levels through lack of 11-DHC reactivation. Indeed, aged knockout mice showed significantly lower hippocampal tissue corticosterone levels than wild-type controls. These findings demonstrate that tissue corticosterone levels do not merely reflect plasma levels and appear to play a more important role in hippocampal functions than circulating blood levels. The data emphasize the crucial importance of local enzymes in determining intracellular glucocorticoid activity. Selective 11beta-HSD-1 inhibitors may protect against hippocampal function decline with age.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1976

Photoaffinity site-specific covalent labeling of human corticosteroid-binding globulin.

A method was developed for the synthesis of high-specific-activity 21-diazo-21-[6,7-(3)H]deoxycorticosterone, an analog of corticosterone. This analog was used as a photoaffinity label of a high affinity steroid-binding protein, human corticosteroid-binding globulin. Based on direct binding studies and crosscompetition experiments, this diazo derivative exhibited the requisite affinity (within a factor of 1.5 times that of corticosterone) and site specificity to qualify as an affinity labeling legand. Irradiation of corticosteroid-binding globulin with the 21-diazo derivative resulted in irreversible binding to corticosteroid-binding globulin, identified by polyacrylamide gel electrophoresis. Specificity of covalent binding to corticosteroid-binding globulin was established by competition analysis with various steroids. Irreversibility of photodependent binding was shown by persistence of the complex on electrophoresis (in contrast to the noncovalently linked complex), and resistance to exchange with corticosterone or pregnanediol and to solvent extraction. Site specificity of covalent binding was inferred from the effects of a scavenger, Tris-HC1, and fluorescence quenching of a neighboring tryptophan.

Affinity Labels↗
PubMed1986

Specific binding of human corticosteroid-binding globulin to cell membranes.

Specific binding sites for corticosteroid-binding globulin were detected on membranes prepared from human prostates. The binding sites are typical of membrane receptors: they are saturable and specific and have high affinity. There was little specific binding at 4 degrees C and 23 degrees C. Maximal specific binding was obtained at 37 degrees C. Scatchard analysis revealed the presence of a single set of binding sites with an apparent dissociation constant of 8.7 X 10(-7) M and a binding capacity of 22 pmol/mg of membrane protein. The sites were specific for corticosteroid-binding globulin; binding was not inhibited by human testosterone/estradiol-binding globulin, by albumin, or by transferrin. The density of specific binding sites in membranes obtained from several organs from the rhesus monkey is consistent with the hypothesis that corticosteroid-binding globulin is involved in the transport of steroid hormones into target tissues.

Albumins↗
PubMed1987

Primary structure of human corticosteroid binding globulin, deduced from hepatic and pulmonary cDNAs, exhibits homology with serine protease inhibitors.

We have isolated and sequenced cDNAs for corticosteroid binding globulin (CBG) prepared from human liver and lung mRNAs. Our results indicate that CBG mRNA is relatively abundant in the liver but is also present in the lung, testis, and kidney. The liver CBG cDNA contains an open reading frame for a 405-amino acid (Mr 45,149) polypeptide. This includes a predominantly hydrophobic, leader sequence of 22 residues that precedes the known NH2-terminal sequence of human CBG. We, therefore, predict that the mature protein is composed of 383 amino acids and is a polypeptide of Mr 42,646. A second, in-frame, 72-base-pair cistron of unknown significance exists between the TAA termination codon for CBG and a possible polyadenylylation signal (AATAAA) located 16 nucleotides before the polyadenylylation site. The deduced amino acid sequence of mature CBG contains two cysteine residues and consensus sequences for the attachment of six possible N-linked oligosaccharide chains. The sequences of the human lung and liver CBG cDNAs differ by only one nucleotide within the proposed leader sequence, and we attribute this to a point mutation. No sequence homology was found between CBG and other steroid binding proteins, but there is a remarkable similarity between the amino acid sequences of CBG and of alpha 1-antitrypsin, and this extends to other members of the serpin (serine protease inhibitor) superfamily.

Amino Acid Sequence↗
PubMed1991

Expression of biologically active human corticosteroid binding globulin by insect cells: acquisition of function requires glycosylation and transport.

Human corticosteroid binding globulin (hCBG) is a 50- to 55-kDa serum glycoprotein that binds cortisol and progesterone with high affinity. To map the steroid-binding domain and to investigate the folding pathways of hCBG, we have established an expression system based on infection of insect cells with a recombinant baculovirus encoding hCBG. Infected Spodoptera frugiperda (Sf9) cells secrete immunoreactive hCBG at high levels (16-24 pmol per 10(6) cells per 40 h), and the recombinant protein binds cortisol with an affinity and specificity equivalent to that of human serum-derived hCBG. Thus, this system has the potential to provide large amounts of wild-type and mutant hCBGs for physical-chemical analysis. Cotranslational asparagine-linked glycosylation is essential for acquisition of steroid-binding capability, as shown by the lack of cortisol-binding activity of unglycosylated hCBG secreted in the presence of tunicamycin. Golgi-associated oligosaccharide processing, however, is not required for activity, as demonstrated by the endoglycosidase H susceptibility of the fully active, secreted glycoprotein. Comparison of the steroid-binding properties of intracellular and secreted hCBG with that synthesized in vitro in the rabbit reticulocyte lysate system suggests that this protein undergoes a maturation process during transport through the secretory pathway. This system will be useful for identifying the molecular determinants of biological function in hCBG.

Animals↗
PubMed2000

Identification of selective estrogen receptor modulators by their gene expression fingerprints.

Clinical studies have shown that estrogen replacement therapy (ERT) reduces the incidence and severity of osteoporosis and cardiovascular disease in postmenopausal women. However, long term estrogen treatment also increases the risk of endometrial and breast cancer. The selective estrogen receptor (ER) modulators (SERMs) tamoxifen and raloxifene, cause antagonistic and agonistic responses when bound to the ER. Their predominantly antagonistic actions in the mammary gland form the rationale for their therapeutic utility in estrogen-responsive breast cancer, while their agonistic estrogen-like effects in bone and the cardiovascular system make them candidates for ERT regimens. Of these two SERMs, raloxifene is preferred because it has markedly less uterine-stimulatory activity than either estrogen or tamoxifen. To identify additional SERMs, a method to classify compounds based on differential gene expression modulation was developed. By analysis of 24 different combinations of genes and cells, a selected set of assays that permitted discrimination between estrogen, tamoxifen, raloxifene, and the pure ER antagonist ICI164384 was generated. This assay panel was employed to measure the activity of 38 compounds, and the gene expression fingerprints (GEFs) obtained for each compound were used to classify all compounds into eight groups. The compound's GEF predicted its uterine-stimulatory activity. One group of compounds was evaluated for activity in attenuating bone loss in ovariectomized rats. Most compounds with similar GEFs had similar in vivo activities, thereby suggesting that GEF-based screens could be useful in predicting a compound's in vivo pharmacological profile.

Animals↗
PubMed2004

Circulating concentrations of hemostatic factors and two "steroid sensitive proteins" during oral hormone replacement therapy in women with coronary heart disease.

OBJECTIVE: To study a possible use of sex hormone-binding globulin (SHBG) and corticosteroid-binding globulin (CBG) as markers for changes in hemostatic factors during oral postmenopausal hormone replacement therapy (HRT). METHODS: Twenty-eight postmenopausal women were treated with oral conjugated equine estrogens+oral medroxyprogesterone acetate (CEE + MPA, n = 15) or with placebo (n = 13). Serum SHBG, CBG, testosterone, cortisol and plasma coagulation factors, coagulation inhibitors and markers of coagulation activation were measured before and after 6 and 12 months of treatment. RESULTS: Pretreatment plasminogen activator inhibitor 1 (PAI-1) levels correlated negatively to SHBG and antithrombin III (AT III) negatively to total and free cortisol. In the CEE + MPA group, CBG, SHBG and Factor VII increased, and PAI-1, AT III and free testosterone decreased during treatment. No significant changes were found in plasma von Willebrand factor antigen, thrombin-antithrombin complex, fibrin D-dimer and fibrinogen. A significant, negative correlation was found between changes in SHBG and PAI-1. No changes were found in the placebo group. CONCLUSION: The only correlation found between changes in "steroid sensitive" proteins and hemostatic factors was between increased SHBG and a possibly beneficial effect of estrogens, i.e. decreased PAI-1 values. SHBG or CBG could not be used as predictors of increased cardiovascular risk during postmenopausal oral HRT.

Administration, Oral↗
PubMed1984

Circadian fluctuations in plasma corticosterone, corticosterone-binding activity and total protein in male rats: possible disruption by serial blood sampling.

Male rats were bled serially every 6 h for 48 consecutive hours. Plasma so obtained was assayed for corticosterone (B), corticosterone-binding activity (CBA) and total plasma protein (TPP). Although the averaged data indicated a significant circadian rhythm in plasma B, inspection of the circadian changes in individual animals showed that 40% had irregular or aberrant patterns of plasma B. Additionally, circadian fluctuations in plasma CBA were approximately 3-fold lower in magnitude than previously reported, and there was no significant circadian change in TPP. Running wheel activity during the 48 h blood sampling period decreased by over 50% indicating that the serial sampling procedure caused disruption of the activity cycle. However, the majority of wheel-running activity occurred during the dark portion of the day-night cycle. Because circadian fluctuations in plasma proteins, including corticosteroid binding globulin (CBG), may be directly related to changes in locomotor activity, it is suggested that the attenuation of circadian changes in CBA and TPP were due to disruption of the daily cycle of locomotor activity. The abnormal circadian patterns in plasma B observed in some animals also may have been caused by disruption of the activity cycle in spite of the fact that the rats did not appear to be stressed as evidenced by concentrations of plasma B that were well within the normal range.

Animals↗
PubMed2002

Peripheral and central sex steroids have differential effects on the HPA axis of male and female rats.

Sex differences in hypothalamic-pituitary-adrenal (HPA) function were examined in gonadectomized male and female rats given equivalent sex hormone replacement regimens either using subcutaneous silastic implants (Experiment 1) or cannula implants in the medial preoptic area (MPOA) (Experiment 2) containing either dihydrotestosterone (DHT), testosterone propionate (TP), estradiol benzoate (EB), or left empty (control). Plasma was obtained before and after 20 min of restraint stress to determine plasma ACTH, corticosterone, and CBG levels as measures of HPA function. Consistent with the literature, androgens decreased, and estrogen increased these measures of HPA function, although peripheral implants were more effective than MPOA implants. Gonadectomy and sex hormone treatment did not eliminate sex differences; overall, females had higher levels than males on measures of HPA function. Analyses of variance (ANOVA) indicated interactions of sex and sex hormone treatment on CBG levels and post-stress corticosterone levels in Expt. 1. The results suggest that sexual dimorphisms influence HPA function even when males and females are given equivalent physiological doses of gonadal steroids, and that the relevant sexual dimorphisms involve both the periphery and the CNS.

Adrenocorticotropic Hormone↗
PubMed1975

[Relationship between the quality of dietary proteins and the functional status of the adrenal cortex. Variations in the content of transcortion, free corticosterone and total corticosterone in the blood plasma of rats fed with proteins of various quality].

Growing male Wistar rats were used to test in which way variations in the quality of dietary proteins (10% absorbable crude protein; casein supplemented with 4% methionine (K); casein/gelatine (1 : 3); maize gluten supplemented with 4 amino acids; and maize gluten) influenced the binding capacity of blood plasma for corticosterone, and the concentration of corticosteroid-binding globulin ("CBG"), total corticosterone, free corticosterone and albumin-bound corticosterone in blood plasma. The binding capacity of the blood plasma for corticosterone and the total concentration of corticosterone, CBG, free corticosterone and albumin-bound corticosterone were found to rise with the improving quality of the dietary proteins (r = 0.830). A close correlation was found to exist between the concentration of total corticosterone in the blood plasma and CBG. Increases in the total concentration of corticosterone in blood plasma are, in 84% of all cases, brought about by increases in CBG concentrations. In conclusion, reference is made to the significance which such results may have for the control of regulatory processes.

Adrenal Cortex↗