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PubMed1980

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.

Animals↗
PubMed1986

Differences in oestrogen receptors in malignant and normal breast tissue as identified by the binding of a new synthetic progestogen.

Oestrogen receptor protein (ER) was detected in 9 of 11 samples of malignant breast tissue and 8 of 9 samples of normal breast tissue. Levels of cytosolic ER (ERc) in malignant breast were 21-1102 fmol mg-1 soluble protein (Kd 1.8 X 10(-9)-3.1 X 10(-8) mol l-1) and those of nucleosolic ER (ERn), 13-526 fmol mg-1 soluble protein (Kd 2.1 X 10(-9)-1.4 X 10(-8) mol l-1). In normal breast tissue ERc levels were 33-640 fmol mg-1 soluble protein (Kd 1.3 X 10(-10)-3.2 X 10(-9) mol l-1), ERn was detected in only 2 samples, 8 and 87 fmol mg-1 soluble protein with Kd 3.2 X 10(-9) and 1.4 X 10(-9) l mol-1 respectively. 17 alpha-ethinyl-13 beta-ethyl-17 beta-hydroxy-4,15-gonadiene-3-one (gestodene), a new synthetic progestogen displaced 3H-oestradiol (3H-E2) from both ERc and ERn in malignant tissue but not in normal breast, or these receptors from endometrial tissue. In competition studies gestodene was approximately 3 times more effective in displacing 3H-E2 from ERc and ERn in malignant breast tissue than the natural ligand. Quantitation of ER by gestodene were ERc, 12-1134 fmol gestodene bound mg-1 soluble protein (Kd 1 X 10(-9)-8.1 X 10(-9) mol l-1); ERn, 17-531 fmol gestodene bound mg-1 soluble protein (Kd 1.6 X 10(-9)-1.1 X 10(-8) mol l-1). L-13-ethyl-17 alpha-ethinyl, 17 beta-hydroxy-gonen-3-one (levonorgestrel) showed no binding to ER in malignant breast, normal breast or endometrial tissue. In circulation both gestodene and levonorgestrel displaced E2 from sex hormone binding globulin more than any of the androgens tested. These results suggest that gestodene is a progestogen with oestrogenic and/or antioestrogenic properties and provide strong evidence for differences in ER from malignant and normal breast tissue.

Binding, Competitive↗
PubMed2005

Corticosteroid binding globulin gene polymorphism influences cortisol driven fat distribution in obese women.

Hypothalamo-pituitary-adrenal axis has been reported to influence fat mass distribution in obesity. We investigated the hypothesis that corticosteroid-binding globulin (CBG) polymorphism could influence obesity, metabolic, or hypothalamo-pituitary adrenal (HPA) axis activity parameters. In 44 obese pre-menopausal women, a microsatellite located within the CBG gene was analyzed, providing three genotypes: 86/86 (n = 29), 86/90 (n = 14), and 90/90 (n = 1). No significant difference was found for obesity, metabolic, and HPA axis activity parameters between the genotypes 86/86 and 86/90. Looking for differences in correlations between HPA axis activity parameters and obesity or metabolic parameters between the two genotypes, genotype 86/90 showed a strong correlation between salivary cortisol after dexamethasone (0.25 mg) suppression test and waist-to-hip ratio (r = -0.84, p = 0.0007), whereas this correlation was weaker for genotype 86/86 (r = -0.34, p = 0.09). These data were completed with an analysis of the BclI polymorphism of the glucocorticoid receptor (GR) gene. There was an association between this GR polymorphism and both awakening salivary cortisol and postdexamethasone salivary cortisol but no association for obesity or metabolic parameters. We concluded that CBG gene polymorphisms might modulate the influence of the HPA axis on the fat mass distribution in this population.

Adult↗
PubMed1996

Pituitary adenylate cyclase-activating polypeptide induces expression of corticosteroid-binding globulin in cultured fetal hepatocytes: synergy with tri-iodothyronine.

The purpose of the present study was to determine whether functional receptors for pituitary adenylate cyclase-activating polypeptide (PACAP) are expressed in cultured rat fetal hepatocytes and eventually play a role in regulating gene expression of corticosteroid-binding globulin (CBG). We found PACAP38 and PACAP27 to elevate cAMP levels in hepatocytes in a dose-dependent manner, with a plateau being achieved at 10 nM and EC50 values of about 0.5-1 nM. PACAP failed to alter the turnover of inositol phosphates, whereas PACAP and VIP stimulated cAMP accumulation in an equipotent manner, suggesting the presence in these cells of type II receptor isoforms. As revealed by measurements of both CBG mRNA levels and concentrations of binding sites, long-term treatment of fetal cells with 10 nM PACAP, although resulting in partial desensitization of peptide-induced cAMP accumulation, caused a significant 3-fold elevation in CBG synthesis. This stimulatory influence of PACAP was mimicked by the cell permeant N6,2'-O-dibutyryladenosine 3',5'-phosphate (dbcAMP). Treatment of hepatocytes with tri-iodothyronine (T3) enhanced CBG expression and, most interestingly, appeared to synergize with PACAP to elicit a 2-3-fold amplification of CBG synthesis. This study thus provides first evidence for the up-regulation by PACAP and cAMP of CBG expression in fetal hepatocytes and for T3's playing a synergistic role in enhancing PACAP-induced synthesis of the binder.

Animals↗
PubMed1981

Effect of binding to plasma proteins on the interpretation of plasma cortisol concentrations after accidental injury.

1. The binding of cortisol to plasma proteins has been studied by multiple equilibrium dialysis of plasma samples taken from 14 patients before treatment after moderate or severe accidental injury and 2-5, 6-12 and 14-25 days later. 2. The total plasma cortisol concentration was initially high, but fell by 6-12 days to stable values probably near the upper limit of normal. 3. The plasma albumin and total protein concentrations fell during the first few days after the injury, but the fall in albumin was proportionally the greater. Both were rising again at the end of the study period. The albumin concentration was positively correlated with an index of its binding to cortisol calculable from the dialysis data. 4. The concentration of corticosteroid-binding globulin (CBG) rose between weeks 1 and 2 after trauma, with no statistically significant change before or afterwards. 5. The changes in binding proteins after injury were relatively small and did not greatly alter the relationship between free and total cortisol concentrations in plasma. It is concluded that in most trauma patients changes in free cortisol, generally considered to be the active fraction in plasma, can be followed adequately by measuring the total cortisol concentration.

Adolescent↗
PubMed1987

Corticosteroid binding globulin in normotensive and hypertensive human pregnancy.

Corticosteroid binding globulin (CBG) concentrations in maternal plasma have been measured throughout pregnancy in a series of 100 singleton pregnancies in 89 normotensive women. Plasma CBG concentrations were monitored also in 10 women with essential or renovascular hypertension. Plasma albumin, cortisol and oestriol were measured concurrently. Plasma CBG increased two and a half to three times during pregnancy. In those women who developed hypertension in pregnancy (mean arterial pressure greater than 107 mmHg), the plasma CBG concentrations were significantly lower than in those who remained normotensive. In women who developed hypertension, the CBG either failed to increase at the same rate as in normal pregnancies or the level fell before the appearance of hypertension. The earlier the onset of hypertension, the greater the decline in CBG. In all subjects, the CBG concentration at 34-36 weeks gestation was directly related to the birthweight of the infant. Plasma cortisol levels were depressed in hypertension relative to that in the normotensive women. Whilst plasma albumin levels decreased at least 30% in most women during pregnancy, the fall tended to be less in hypertensive women, but there was marked overlap between patient groups. Plasma oestriol concentrations were depressed only in the very severely affected cases. It is suggested the CBG concentration is a further reflection of the metabolic abnormalities associated with hypertension in pregnancy, and that it can be used as a marker to identify and monitor those patients at risk.

Adult↗
PubMed2002

Effects of moderate and intensive training on the hypothalamo-pituitary-adrenal axis in rats.

The influence of the two distinct training programmes, moderate (M) and intensive (I), on hypothalamo-pituitary-adrenal (HPA) axis was investigated, in rats. Changes in plasma concentrations of adrenocorticotropin hormone (ACTH) and corticosterone were followed in response to (i) a 60-min acute running session performed on 2nd, 4th and 6th of the seven training weeks (ii) an acute restraint stress of 40 min applied after the final training programme. After 2nd, 4th and 6th week of the two training programmes, a 60-min running resulted in an enhanced secretion of ACTH and corticosterone, compared with both the baseline values (i.e. before running) and to the sedentary (S) group. However, on 4th and 6th weeks compared with 2nd week, ACTH and corticosterone remained elevated in intensive group when they are significantly reduced in moderate group. We could suggest that a moderate training resulted in an adapted hormonal response whereas a deadapted process occurred for the intensive programme. The day after the last training session, basal ACTH, corticosterone and corticosteroid-binding globulin (CBG) capacity were not affected by training. Hypothalamic corticotropin-releasing factor tissue-content (CRF) was increased significantly in the two trained groups. When compared with the sedentary group, the body weight of the rats in the two trained groups was significantly decreased with a total adrenal mass increasing but only in intensive group. The surimposed restraint stress resulted in significant increases in plasma ACTH and corticosterone both in trained and in sedentary animals. This result suggests that the adapted HPA axis response induced by both a moderate and intensive training do not prevent against the effects of a novel stress such as restraint stress.

Adrenal Glands↗
PubMed2003

Cortisol and the metabolic syndrome in South Asians.

OBJECTIVE: The cardiovascular risk factors which comprise the metabolic syndrome are associated with increased hypothalamic-pituitary-adrenal axis (HPAA) activity in some Caucasian populations. South Asians have high rates of cardiovascular disease and its risk factors. We have investigated the relationships between HPAA activity, adiposity and the metabolic syndrome in a South Asian population. DESIGN: Cross-sectional cohort study. PARTICIPANTS: A total of 509 men and women born at the Holdsworth Memorial Hospital, Mysore, South India between 1934 and 1954 and still living in the area. MEASUREMENTS: Fasting 09.00 h cortisol and corticosteroid-binding globulin. The cohort had previously been investigated for features of the metabolic syndrome. RESULTS: At 09.00 h, cortisol concentration was strongly associated with systolic and diastolic blood pressure (r = 0.25 and r = 0.24, respectively; P < 0.001), fasting glucose concentration (r = 0.26; P < 0.001), insulin resistance (r = 0.20; P < 0.001) and fasting triglyceride concentration (r = 0.17; P < 0.001). In general, higher cortisol concentrations added to the effect of adiposity in increasing cardiovascular risk factors, but there was evidence of an interaction between cortisol and adiposity in determining fasting glucose concentration (P = 0.045) and insulin resistance (P = 0.006). CONCLUSIONS: Associations between 09.00 h cortisol concentration and cardiovascular risk factors in this South Asian cohort were stronger than those previously shown in Caucasian populations, despite similar mean cortisol concentrations, and were amplified by adiposity. This suggests that increased glucocorticoid action may contribute to ethnic differences in the prevalence of the metabolic syndrome, particularly among men and women with a higher body mass index.

Adult↗
PubMed2003

Hereditary corticosteroid-binding globulin deficiency due to a missense mutation (Asp367Asn, CBG Lyon) in a Brazilian kindred.

OBJECTIVE: Abnormal corticosteroid-binding globulin (CBG) is an extremely rare condition and only three mutations have been described in four families. The molecular basis of an abnormal CBG in a Brazilian family was studied and correlations between genotype and serum cortisol, cortisol binding capacity (CBC) and CBG levels were determined. SUBJECTS: All 10 family members, comprising three generations, and nine healthy volunteers were studied. MEASUREMENTS: Genomic DNA was extracted from white blood cells from all family members. The human cbg exons 2-5 were amplified by PCR, submitted to automatic sequencing. Cortisol and CBG levels in serum were measured by radioimmunoassay (RIA). CBC in serum was determined using tritiated cortisol and other cortisol binding parameters were calculated through Scatchard analysis. RESULTS: A missense mutation in exon 5 of cbg (1254G --> A; Asp367Asn), recently described as CBG Lyon, was found in all family members. The proband and one sister were homozygous whereas all other family members, including parents, were heterozygous for this mutation. Cortisol levels in the only two homozygotes were lower than in heterozygotes and both were significantly lower as compared to controls (69 and 182 nmol/l vs. 267 +/- 129 nmol/l vs. 459 +/- 195 nmol/l, respectively, P < 0.05). CBC was decreased in the two homozygotes as compared to heterozygotes and in both groups as compared to controls (< 90 and 114 nmol/l vs. 305.0 +/- 81.4 nmol/l vs. 594.8 +/- 59.5 nmol/l, respectively, P < 0.05). CBG levels were lower in homozygotes as compared to heterozygotes and in both as compared to controls (325 and 375 nmol/l vs. 496.75 +/- 50.75 nmol/l vs. 647.25 +/- 87.50 nmol/l, respectively, P < 0.05). CONCLUSIONS: An abnormal CBG resulting from a missense mutation and known as CBG Lyon was found in this Brazilian kindred. This abnormal CBG has decreased affinity for cortisol and results in low or low normal serum cortisol levels in homozygous and heterozygous subjects. Although relative hypotension and fatigue have recently been associated with CBG deficiency in a family with two CBG mutations (null and Lyon), the two homozygous subjects in this kindred were both normotensive and only the proband presented with fatigue.

Adult↗
PubMed2002

Visceral fat and psychosocial stress in identical twins discordant for obesity.

OBJECTIVES: Accumulation of intra-abdominal fat has been suggested, but not yet proved, to be basically as a result of chronic psychosocial stress causing arousal of hypothalamic-pituitary-adrenal cortex axis. Our objectives were to study the association between psychosocial stress, obesity and body fat distribution when genetic factors are identical. DESIGN: Monozygotic twins discordant for obesity were examined in an in-patient setting. SUBJECTS: Adult monozygotic twin pairs (12 female, 8 male) with an average intrapair difference of 17 kg in body weight. They were divided into two groups: in group A the visceral fat area of the obese cotwin was higher and, in group B, lower than the gender-specific median value. MAIN MEASURES: Hormonal, physiological and psychological distress indicators, and sleep measures. RESULTS: Daily urinary cortisol and noradrenaline excretion were higher in the obese cotwins when compared with the nonobese cotwins in group A but not in group B (P=0.026 and 0.020 when intrapair differences were compared between groups A and B, respectively). In serum cortisol, ACTH and CBG concentrations a similar trend was not statistically significant. In group A, the obese cotwins consumed almost 2.5 times as much alcohol as their lean cotwins, whilst in group B the situation was the opposite. The mean amount of active sleep was significantly higher and that of quiet sleep significantly lower in the obese than the lean cotwins only in group A. Intrapair differences in emotional reactions indicating distress and lack of subjective energy were seen only in group A. CONCLUSION: When genetic factors are identical, visceral fat accumulation, rather than obesity in general, is associated with increased psychosocial stress and concomitant hormonal changes.

Adipose Tissue↗
PubMed2000

Thyroxine modulates corticotropin-releasing factor but not arginine vasopressin gene expression in the hypothalamic paraventricular nucleus of the developing Rat.

Neonatal rats were daily injected with 100 microg/kg T4 and killed at 4, 8 or 15 days. Circulating corticosterone and corticosteroid binding globulin concentrations increased in 8- and 15-day-old rats after T4 treatment. Plasma adrenocorticotropic hormone (ACTH) concentrations, pituitary ACTH content and pro-opiomelanocortin mRNA expression were unaffected in T4-treated rats. T4 treatment induced an increase in corticotropin-releasing factor (CRF) mRNA expression in the whole population of CRF synthesizing cells of the paraventricular nucleus (PVN) that became significant at day 8 and disappeared at day 15. Double labelling in situ hybridization revealed that CRF gene expression in the CRF+/arginine vasopressin (AVP)+ subpopulation was increased at days 4 and 8 and decreased at day 15. CRF immunoreactivity in the zona externa of the median eminence increased with age but was not affected by the experimental hyperthyroidism. The degree of CRF and AVP colocalization, the concentration of AVP mRNA in the parvo and magnocellular cell bodies of the PVN and the density of immunoreactive AVP in the zona interna or zona externa of the median eminence did not change after T4 treatment. Our data demonstrate that experimental hyperthyroidism accelerates the maturation of hypothalamic CRF gene expression, including in particular in the CRF+/AVP+ subpopulation, during the stress hyporesponsive period. These observations suggest that the physiological peak of plasma thyroxine that occurs between days 8-12 may participate in the maturation of hypothalamic CRF cells.

Adrenocorticotropic Hormone↗
PubMed2000

Analysis of adrenocortical secretory responses during acute an prolonged immune stimulation in inflammation-susceptible and -resistant rat strains.

Endogenous corticosterone secreted during immune challenge restricts the inflammatory process and genetic variations in this neuroendocrine-immune dialogue have been suggested to influence an individuals sensitivity to develop chronic inflammatory disorders. We have tested inflammation-susceptible Dark Agouti (DA) rats and resistant, MHC-identical, PVG.1AV1 rats for their abilities to secrete corticosterone in response to acute challenge with bacterial lipopolysaccharide (LPS) or a prolonged activation of the nonspecific immune system with arthritogenic yeast beta-glucan. Intravenous injection of LPS triggered equipotent secretion of corticosterone in both rat strains. Interestingly, peak concentrations of corticosterone did not differ significantly between the strains. Intradermal injection of beta-glucan caused severe, monophasic, polyarthritis in DA rats while PVG.1AV1 responded with significantly milder joint inflammation. Importantly, serial sampling of plasma from glucan-injected DA and PVG.1AV1 rats did not reveal elevated concentrations of plasma corticosterone at any time from days 1-30 postinjection compared to preinjection values, in spite of the ongoing inflammatory process. Interestingly, adrenalectomized, beta-glucan-challenged DA rats responded with an aggravated arthritic process, indicating an anti-inflammatory role for the basal levels of corticosterone that were detected in intact DA rats challenged with beta-glucan. Moreover, substitution with subcutaneous corticosterone-secreting pellets, yielding moderate stress-levels, significantly attenuated the arthritic response. In contrast, adrenalectomized and glucan-challenged PVG.1AV1 rats did not respond with an elevated arthritic response, suggesting that these rats contain the arthritic process via corticosterone-independent mechanisms. In conclusion, the hypothalamic-pituitary-adrenal axis in both rat strains exhibited strong activation after challenge with LPS. This contrasted to the basal corticosterone levels observed strains during a prolonged arthritic process. No correlation between ability to secrete corticosterone and susceptibility to inflammation could be demonstrated. Basal levels of endogenous corticosterone appeared to restrain inflammation in beta-glucan-challenged DA rats whereas resistance to inflammation in PVG.1AV1 rats may be mediated via corticosterone-independent mechanisms.

Adrenal Cortex↗
PubMed2001

Seasonal regulation of membrane and intracellular corticosteroid receptors in the house sparrow brain.

A number of studies have demonstrated seasonal regulation of the adrenocortical response to stress, or of corticosteroid binding globulins, but very few studies have examined seasonal regulation of corticosteroid receptor levels. As a result, there have been few attempts to produce an integrated picture of seasonal plasticity of the stress response. We measured baseline and stress-induced corticosterone (CORT), corticosteroid binding globulin and neuronal cytosolic and membrane corticosteroid receptor levels in male and female, wild-caught house sparrows (Passer domesticus) during three different seasons over the annual cycle (nesting, molting and winter). We identified three neuronal corticosteroid receptors in the house sparrow brain: two intracellular receptors and one membrane-associated receptor. Little is known about corticosteroid receptors in neuronal membranes of avian and mammalian species, but we found that the levels of membrane corticosteroid receptors varied seasonally, being lowest during the nesting season. Cytosolic corticosteroid receptor numbers (both low and high affinity receptors) also varied seasonally. In contrast to the membrane bound receptors, however, the numbers of low and high affinity cytosolic receptors were lowest during winter. In addition, mean levels of total basal and stress-induced CORT in the plasma varied seasonally. Both basal and stress-induced levels of total CORT were significantly higher during nesting than during winter or molt. Finally, corticosteroid binding globulin levels in plasma were also seasonally regulated, in a pattern similar to total CORT, so that estimated free CORT levels did not vary between seasons. These data indicate that multiple components of the stress response are seasonally regulated in birds obtained from wild populations. Interactions between these regulated components provide a basis for seasonal differences in behavioural and physiological responses to stress.

Animals↗