Action Of Cortisol Research Articles

Association between a variant in the 11 beta-hydroxysteroid dehydrogenase type 2 gene and primary hypertension.

The enzyme 11 beta-hydroxysteroid dehydrogenase type 2 (11BHSD2) converts cortisol to cortisone in the kidney, thereby protecting the mineralocorticoid receptor from the mineralocorticoid actions of cortisol. The syndrome of Apparent Mineralocorticoid Excess (AME), a rare monogenic form of early onset hypertension with autosomal recessive inheritance, is caused by homozygous or compound heterozygous loss of function mutations in the 11BHSD2 gene. Association has been reported between a microsatellite marker flanking the 11BHSD2 gene (D16S496) and primary hypertension. The aim of this study was to identify variants in the 11BHSD2 gene and to test if such variants or the D16S496 are associated with primary hypertension, in Swedes. To address this, the coding sequences of the 11BHSD2 gene was screened for mutations in 20 patients with primary hypertension with single strand conformation polymorphism and direct DNA sequencing techniques. A polymorphism was identified in exon 3; G534A (Glu178Glu). This polymorphism and the D16S496 microsatellite were tested for association with primary hypertension in a population consisting of 292 patients with primary hypertension and 263 normotensive control subjects. The frequency of G534G homozygotes was higher in patients with primary hypertension than in normotensive control subjects (92.8% vs 87.8%; P < 0.05). The allele frequencies of the D16S496 microsatellite did not differ between the two groups (chi(2) = 11.0, df = 10; P = 0.36). In conclusion, over-representation of individuals homozygous for the G534 allele in hypertensive patients compared with control subjects suggests that a mutation in linkage disequilibrium with the G534A polymorphism could increase susceptibility to primary hypertension. Journal of Human Hypertension (2000) 14, 819-823

Functional adrenocorticotropic hormone receptor in cultured human vascular endothelial cells : possible role in control of blood pressure.

Hypertension is a prominent feature of patients with Cushing's disease and ectopic adrenocorticotropic hormone (ACTH) syndrome, who have elevated ACTH levels. Chronic administration of ACTH (1-24) also raises blood pressure in humans. This effect has been postulated to be due to ACTH-induced increases in cortisol secretion in the adrenal gland. It is well known that cortisol increases vascular tone by potentiating the vasoconstrictor action of a number of pressor hormones. In the present study, we show direct evidence that human aortic endothelial cells possess the ACTH receptor. 11beta-Dehydrogenation, converting cortisol to its inactive metabolite, cortisone, mediated by vascular 11beta-hydroxysteroid dehydrogenase type 2 is essential for the control of vascular tone, and the reduced activity may be relevant to the pathogenesis of hypertension. We found that ACTH (1-24) dose-dependently decreased the gene expression and enzyme activity of 11beta-hydroxysteroid dehydrogenase type 2 in these cells, and the decrease was partially abolished by a selective ACTH receptor antagonist. This may indicate that ACTH potentiates the action of cortisol through its direct effect on the vasculature. Therefore, the present study provides important information for understanding the mechanism of ACTH-induced hypertension.

Differential mRNA Expression of the Two Mineralocorticoid Receptor Splice Variants Within the Human Brain: Structure Analysis of their Different DNA Binding Domains

In human brain tissue, cortisol action, at basal concentrations, is mediated by the mineralocorticoid receptor (MR). An in-frame insertion of 12 bp in the MR-DNA-binding domain due to alternative splice site usage between exons 3 and 4 results in an MR mRNA splice variant (MR+4) encoding a receptor protein with four additional amino acids compared to the wild-type MR protein. To elucidate the questions of sex, age, and/or tissue dependent differences of the relative amount of the two mRNA subtypes, we examined 131 fresh human brain tissue samples from temporal and frontal lobe or hippocampus. One hundred and twenty samples were obtained from patients with epilepsy and 11 samples from patients with brain tumours. A small but significant difference of the MR+4 mRNA splice variant proportions in cortex (9.5 +/- 0.8%) and subcortical white matter (6.6 +/- 0.7%) of the temporal lobe could be detected, indicating differential MR splice variant expression within these brain areas. Moreover, the splice variant ratios in samples of the temporal lobe cortex collected from patients with epilepsy differed from samples of patients with brain tumours. These data point to an altered expression of the MR splice variants in epilepsy, and strengthen the supposition of a tissue specific alternative splicing of the MR mRNA. The frequent occurrence of the MR+4 transcript raises the question of its functional significance. For this reason, an MR+4 DNA-binding-domain structure model was generated by computer-based homology modelling based on the known glucocorticoid receptor structure. The data obtained revealed no distorting effect of the inserted four amino acids on the adjacent secondary structures, thereby suggesting that both zinc fingers retain their function. The resulting structure of the MR+4 model leads to the supposition that the receptor retains its function. Moreover, databank analysis with respect to this kind of steroid receptor variation and our own sequence data of the closely related progesterone receptor sustained the hypothesis that only corticosteroid receptors were affected by this alternative splicing event.

Transcriptional regulation of connective tissue growth factor by cortisol in osteoblasts.

Glucocorticoids have important effects on osteoblastic function. Connective tissue growth factor (CTGF)/insulin-like growth factor binding protein-related protein 2 (IGFBP-rP2) plays a role in cell adhesion and function. We examined the regulation of CTGF/IGFBP-rP2 synthesis in cultures of osteoblast-enriched cells from 22-day fetal rat calvariae (Ob cells). Cortisol caused a time- and dose-dependent increase in CTGF/IGFBP-rP2 mRNA levels in Ob cells. Cycloheximide did not preclude the effect, indicating that it was not protein synthesis dependent. Cortisol increased the rate of CTGF/IGFBP-rP2 transcription and, in transcriptionally arrested Ob cells, did not modify the decay of the transcript. Parathyroid hormone decreased, whereas transforming growth factor-beta and, to a lesser extent, bone morphogenetic protein 2 increased CTGF/IGFBP-rP2 mRNA levels, but other hormones and growth factors had no effect. In conclusion, cortisol stimulates CTGF/IGFBP-rP2 transcription in Ob cells. Because CTGF/IGFBP-rP2 binds IGFs, its increased expression could be relevant to the actions of cortisol in bone.

Stressful delivery influences circulating thrombopoietin (TPO) levels in newborns: possible role for cortisol in TPO-mpl binding.

The regulation mechanism of circulating thrombopoietin (TPO) level in human newborns remains unknown. In the present study, we examined whether the TPO concentrations in cord blood were influenced by the difference in the delivery method and the presence or absence of maternal/fetal complications. Cortisol levels were simultaneously measured to assess the adrenal response of fetuses. Both the TPO level and the cortisol level were substantially greater in the neonates delivered vaginally with and without the complications than in those delivered by cesarean section without the complications. The binding assay showed that the incubation of mpl(+)/BaF3 cells with cortisol gave rise to a significant decrease in the binding sites of TPO. These results suggest that the stress to the fetuses near the time of delivery affects the cord blood TPO levels, which may be mediated in part by the action of cortisol on the TPO-mpl binding system.

Evidence That Acute Stress Inhibits Ovarian Steroidogenesis in Rainbow Trout in Vivo, through the Action of Cortisol

Sexually mature (preovulatory) rainbow trout exposed to confinement stress showed a transitory increase in plasma cortisol levels that was accompanied by a similarly brief depression in plasma testosterone (T) levels. Plasma levels of maturational gonadotropin (GtH) and 17β-estradiol (E2) were unaffected by stress. A similar pattern was displayed by fish exposed to stress in midvitellogenesis. Treatment of vitellogenic fish with exogenous cortisol resulted in significant increases in plasma cortisol at 1 and 3 h postinjection (p.i.). This was associated with significant depression of plasma T levels at 1 and 3 h p.i. and plasma E2 levels at 3 and 6 h p.i. Plasma levels of GtH were unaffected by treatment with cortisol. Treatment of fish at an earlier stage of vitellogenesis with two different doses of cortisol resulted in very high elevations of plasma cortisol, but no effect on plasma levels of E2 or GtH. In contrast, plasma T levels showed a stepwise decline over time. These results suggest that the inhibitory effects of stress on reproduction are mediated by cortisol and that the effect does not involve inhibition of GtH secretion and possibly acts at the level of GtH signal-transduction.

Sarcopenia, hypermetabolism, and aging.

Sarcopenia is a constant in aging. Observed over long periods, it can reach 1% per year. But it is such a tenuous phenomenon that it cannot be observed over short periods at steady state. The aging phenomenon mainly hits fibers, Type II but on aged muscle thin, normal, and hypertrophic fibers cohabit with sclerosis and fat increases. Sarcopenia is difficult to study, due to the lack of simple clinical, biochemical, or imaging measures. Anthropometric data are largely dependent on water content. DEXA gives better information on appendicular muscle loss. Measures of strength analyze functional outcomes of sarcopenia. Sarcopenia appears largely multifactorial. Hormonal changes, e.g., drop in growth hormone, menopause, and andropause, explain impaired protein synthesis. Disuse (sedentary, bed rest) may explain chronical protein lysis. But the main factors for muscle lysis imply life events and occurring diseases. Cytokines (IL6, TNF alpha) and stress hormones (cortisol) induce quick protein lysis in muscle. Rapid and intensive successive aggressions during life cannot be compensated by slowed synthesis. Harmful consequences of sarcopenia explain many disabilities of old age: loss of strength, inducing itself loss of mobility, falls, equilibrium disorders, poor ADL: loss of nutritional reserves (protein and glycogen) impairing capacities of immune response. Muscle loss spoils vital functions as respiration. Treatment remains rather limited to resistance exercise. Although, these results are thin, they are the only ones to be validated in all the elderly even the frail or the old. However it is not efficient during the evolution of an inflammatory process. The powerful action of cytokine and cortisol on muscular hypermetabolism must be incited for early treatment of any infectious or inflammatory event. Nutritional supplementation has no efficiency in the absence of malnutrition and without exercise. Although mobility impairments mainly due to sarcopenia are the first cause of disablement in the elderly, we lack information on etiology, evolution, and measurement of sarcopenia. We also lack controlled therapeutical studies.

Severity of depression in abstinent alcoholics is associated with monoamine metabolites and dehydroepiandrosterone-sulfate concentrations

Depressed mood increases the relapse risk of abstinent alcoholics; its neurobiological correlates may include reduced serotonin and norepinephrine turnover rates and increased cortisol concentrations during detoxification stress. Neurosteroids such as dehydroepiandrosterone and its sulfate (DHEA and DHEA-S) may antagonize cortisol action and may have mood-elevating effects on their own. We measured severity of depression with Beck’s Depression Inventory (BDI) and Hamilton’s Depression Rating Scale (HDRS), plasma concentrations of cortisol, DHEA and DHEA-S, and CSF concentrations of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA), the norepinephrine metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) and the dopamine metabolite homovanillic acid (HVA) in 21 abstinent alcoholics after 4 weeks of abstinence and in 11 age-matched healthy control subjects. Only CSF MHPG concentrations were reduced in alcoholics compared to control subjects (41.4±6.6 vs. 53.3±8.6 pmol/ml). Self-rated depression was significantly correlated with CSF MHPG (Spearman’s R=+0.57, P<0.01), CSF 5-HIAA ( R=+0.51, P<0.05) and plasma cortisol concentrations ( R=+0.50, P<0.05). Negative correlations were found between DHEA-S concentrations and both self-rated depression ( R=−0.45, P<0.05) and observer-rated depression ( R=−0.55, P<0.05). The ratio of DHEA-S to cortisol serum concentrations was also negatively correlated with depression (BDI: R=−0.55, P<0.01; HDRS: R=−0.63, P<0.005). Anxiety (Spielberger’s State Anxiety Scale) was only associated with CSF MHPG concentrations ( R=+0.58, P<0.01). Our findings point to the importance of noradrenergic dysfunction in the pathogenesis of depression among abstinent alcoholics and indicate that their mood states may also be modulated by a low DHEA-S to cortisol ratio, hypothetically indicative of low stress protection capacities.

Syndrome of body fat redistribution in HIV-1-infected patients: relationships to cortisol and catecholamines.

Alterations of body fat distribution have been recently reported in HIV-infected patients. We aimed to investigate whether the hormones modulating adipose tissue metabolism could be implicated. We investigated twenty-eight HIV-infected patients who had developed abdominal fat, combined with peripheral lipodystrophy in 25 cases and 'buffalo hump' in 2 cases, but who had otherwise improved on antiretroviral therapies. Twelve patients with no change in body fat, matched for age, disease control and treatment, were studied as controls. Body composition was assessed by bioelectrical impedance analysis. Subcutaneous (SAT) and visceral (VAT) compartments of total abdominal adipose tissue (TAT) were measured by computed tomography. Resting metabolic rate (RMR) was assessed by indirect calorimetry. Endocrine investigations included plasma thyroid hormones, cortisol, testosterone, oestradiol and 24-hour urinary free cortisol (UFC) and catecholamines. Despite similar body mass index, the patients with body fat alterations showed significantly larger VAT and higher VAT:TAT ratio than controls (P = 0.002 and 0.0001, respectively). In these patients, RMR was significantly higher than estimated according to the Harris-Benedict formula (+ 19.7 +/- 11.6 %, P = 0.0001) and correlated with VAT (r = 0.58, P = 0.003) and 24-hour urinary output of catecholamines (r = 0.67, P = 0.002), that was significantly increased in comparison with controls (1737 +/- 1228 vs 476 +/- 292 nmol, P = 0.013). We also found a significant correlation between VAT and UFC (r = 0.41, P = 0.042) that was absent in controls, although levels of UFC were similar in the two groups. Our data suggest that body fat redistribution may involve cortisol and catecholamine actions. While high release of catecholamines may enhance RMR through increased lipolysis, cortisol may promote central fat storage. These effects might be related both to persistent hormonal responses to stress becoming inappropriate while disease control improved and to an increased sensitivity of visceral adipose tissue to cortisol in affected patients.

Cortisol enhances the expression of mac25/insulin-like growth factor-binding protein-related protein-1 in cultured osteoblasts.

Glucocorticoids inhibit the synthesis of insulin-like growth factor I (IGF-I) and regulate the expression of IGF-binding proteins (IGFBPs) in osteoblast cultures. IGFBP-related protein-1 (IGFBP-rP1), the product of the mac25 gene, binds IGF-I, IGF-II, and insulin, and we postulated that glucocorticoids regulate IGFBP-rP1 synthesis in osteoblasts. We tested the expression of mac25/IGFBP-rP1 in cultures of osteoblast-enriched cells from 22-day-old fetal rat calvariae (Ob cells). Cortisol treatment at 10 nM to 1 microM for 24-48 h caused a time- and dose-dependent increase in mac25/IGFBP-rP1 messenger RNA (mRNA) levels in Ob cells. Cycloheximide at 3.6 microM did not alter mac25/IGFBP-rP1 transcripts in control or cortisol-treated cells. Cortisol did not modify the decay of mac25/IGFBP-rP1 mRNA in transcriptionally arrested Ob cells and increased the rate of IGFBP-rP1 transcription as determined by nuclear run-on assays. Retinoic acid also increased mac25/IGFBP-rP1 mRNA levels, but 17beta-estradiol, testosterone, 5alpha-dihydrotestosterone, progesterone, and 1,25-dihydroxyvitamin D3 did not. In conclusion, cortisol stimulates mac25/IGFBP-rP1 expression in Ob cells by transcriptional mechanisms. As IGFBP-rP1 binds and possibly modifies the effects of IGFs and insulin, its increased expression could be relevant to the inhibitory actions of cortisol in bone.

Glucocorticoid modulation of Ca2+ homeostasis in human B lymphoblasts.

1. We determined the effect of cortisol (200 nM for 48 h) on the intracellular Ca2+ concentration ([Ca2+]i) and parameters of Ca2+i signalling in 19 lymphoblastoid cell lines (LCLs). 2. Using the fluorescent dye fura-2, the basal [Ca2+]i in Ca2+-containing medium was 63.5 +/- 2.4 nM in vehicle (ethanol)-treated LCLs and 55.7 +/- 2. 6 nM (mean +/- s.e.m.) in cortisol-treated LCLs. 3. Ca2+i signalling following platelet-activating factor (PAF, 100 nM) addition was enhanced by cortisol treatment, with LCLs having small PAF responses showing the largest percentage increase after cortisol treatment. Mean peak [Ca2+]i responses to PAF were enhanced 67.0% and 55.7% in Ca2+-free and Ca2+-containing medium, respectively. 4. The endoplasmic reticulum Ca2+-ATPase inhibitor thapsigargin (100 nM) caused a transient increase in [Ca2+]i in Ca2+-free medium in which the peak change was increased in cortisol-treated cells (98.5 +/- 5.8 vs. 79.8 +/- 4.5 nM). Peak changes in the freely exchangeable Ca2+ in response to 5 microM ionomycin were also enhanced in cortisol-treated cells (923.7 +/- 113.9 vs. 652.2 +/- 64.5 nM) and correlated to the PAF-evoked [Ca2+]i response. 5. Cortisol-treated LCLs exposed to thapsigargin to empty intracellular Ca2+ stores (10 min treatment in Ca2+-free medium) and exposed to CaCl2 or MnCl2 had a greater rate of Ca2+ entry (18.6 +/- 1.8 vs. 13.8 +/- 1.5 nM s-1) and higher rate constant for Mn2+ entry (0.0345 +/- 0.0029 vs. 0. 0217 +/- 0.0020) than vehicle-treated cells. Peak [Ca2+]i in cells exposed to CaCl2 was also enhanced (869.4 +/- 114.7 vs. 562.6 +/- 61.7 nM). Parameters of divalent cation influx were highly correlated to the peak [Ca2+]i elicited by thapsigargin or ionomycin. 6. Inclusion of RU 486 (a glucocorticoid antagonist) with cortisol prevented the decrease in basal [Ca2+]i and stimulatory actions of cortisol on all Ca2+i parameters. RU 486 alone had no apparent effects on basal [Ca2+]i or Ca2+i signalling. 7. Based on data obtained over a wide range of responses (in the presence and/or absence of cortisol or RU 486), the results show that cortisol stimulation of glucocorticoid receptors decreases basal [Ca2+]i and enhances PAF-evoked [Ca2+]i signalling, most probably through its effects on intracellular Ca2+ stores. In turn, the extent of Ca2+ entry via store-operated plasma membrane Ca2+ channels is closely linked to the size of the Ca2+ stores.

Cortisol and hypertension.

1. In humans, the hypertensive effects of adrenocorticotropic hormone (ACTH) infusion are reproduced by intravenous or oral cortisol. Oral cortisol increases blood pressure in a dose-dependent fashion. At a dose of 80-200 mg/day, the peak increases in systolic pressure are of the order of 15 mmHg. Increases in blood pressure are apparent within 24 h. 2. Cortisol-induced hypertension is accompanied by a significant sodium retention and volume expansion. Co-administration of the type I (mineralocorticoid) receptor antagonist spironolactone does not prevent the onset of cortisol-induced hypertension. Thus, sodium retention is not the primary mechanism of cortisol-induced hypertension. 3. Direct and indirect measures of sympathetic activity are unchanged or suppressed during cortisol administration, suggesting that cortisol-induced hypertension is not mediated by increased sympathetic tone. 4. Preliminary evidence in humans suggests that suppression of the nitric oxide system may play a role in cortisol-induced hypertension. 5. These potential mechanisms of cortisol action may be relevant in a number of clinical contexts, including Cushing's syndrome, apparent mineralocorticoid excess, the hypertension of liquorice abuse and chronic renal failure. There is also preliminary evidence suggesting a role for cortisol in essential hypertension.

Immune-endocrine interactions in agricultural species: chromium and its effect on health and performance

The purported performance-enhancing effects of supplemental Cr, as elaborated in studies focusing on beef and dairy cattle models of agricultural stress, affect both immune and endocrine pathways. Furthermore, interactions between the immune and endocrine systems, associated with the actions of insulin and cortisol, may be coordinated through the production of regulatory cytokines. Unlocking the mechanism of action of Cr as a useful farm animal management tool may provide further understanding of the health and performance ramifications of immune-endocrine interactions in agricultural species.

Glucocorticoids modulate human gonadotrophin releasing hormone upstream promoter activity in transfected human placental cells (JEG-3).

A human gonadotrophin releasing hormone (GnRH) upstream promoter/luciferase reporter gene construct (H2 construct) was generated by inserting a 1.7 kb XbaI/AflII fragment containing the human GnRH upstream promoter region only into a promoter-less luciferase reporter vector. When JEG-3 cells were transiently transfected with this construct and treated with cortisol or its synthetic analogue dexamethasone, a stimulatory effect on the upstream promoter activity was observed. This stimulation was dependent on the cotransfection of a glucocorticoid receptor (GR) cDNA expression vector due to the low level of GR in JEG-3 cells and could be completely abolished by RU486, a glucocorticoid antagonist. Moreover, the cortisol actions could be modulated to a different extent by oestradiol. Thus, since the human placenta contains GRs and the increase in cortisol metabolism near term is regulated by oestrogen, the current findings suggest that cortisol may be physiologically involved in the regulation of GnRH gene expression in the human placenta.

Human adrenocorticotropin-secreting pituitary adenomas show frequent loss of heterozygosity at the glucocorticoid receptor gene locus.

Corticotropinomas are characterized by a relative resistance to the negative feedback action of cortisol on ACTH secretion. In this respect there is a similarity with the clinical syndrome of cortisol resistance. As cortisol resistance can be caused by genetic abnormalities in the glucocorticoid receptor (GR) gene, we investigated whether the insensitivity of corticotropinomas to cortisol is also caused by de novo mutations in the GR gene. We screened for the GR gene in leukocyte and tumor DNA from 22 patients with Cushing's disease for mutations using PCR/single strand conformation polymorphism analysis. In a previous study, we identified 5 polymorphisms in the GR gene in a normal population. These polymorphisms were used as markers for the possible occurrence of loss of heterozygosity (LOH) at the GR gene locus. Except for 1 silent point mutation, we did not identify novel mutations in the GR gene in leukocytes or corticotropinomas from these patients. Of the 22 patients, 18 were heterozygous for at least 1 of the polymorphisms. In 6 of these patients, LOH had occurred in the tumor DNA. Of 21 patients examined for LOH on chromosome 11q13, only 1, with a corticotroph carcinoma, showed allelic deletion. As controls we studied 28 pituitary tumors of other subtypes (11 clinically nonfunctioning, 8 prolactinomas, and 9 GH-producing adenomas) and found evidence for LOH in only 1 prolactinoma. In six patients LOH was found at the GR gene locus (chromosome 5) in DNA derived from adenoma cells. Our observations indicate for the first time that LOH at the GR gene locus is a relatively frequent phenomenon in pituitary adenomas of patients with Cushing's disease. This might explain the relative resistance of the adenoma cells to the inhibitory feedback action of cortisol on ACTH secretion. The specificity of the GR LOH to corticotropinomas supports this concept. Somatic mutations of the GR are not a frequent cause of relative cortisol resistance in these cells.

Intrauterine cortisol, aldosterone, and corticosteroid binding globulin-like activity during early porcine pregnancy and the estrous cycle.

Studies were conducted to determine whether the corticosteroids cortisol and aldosterone, and corticosteroid-binding globulin (CBG) were present in the porcine early-embryonic environment. Cortisol was measured in uterine flushings from white crossbred gilts at Days 7, 10, 13, and 16 of the estrous cycle and pregnancy. Total content of cortisol increased (p < 0.01) between Days 13 and 16, and immunoreactive CBG (ir-CBG) increased (p < 0.01) between Days 10 and 13, in both cyclic and pregnant gilts. In a separate study with Chinese Meishan gilts, total cortisol and aldosterone content of uterine flushings increased (p < 0.02) between Days 10 and 15 of the estrous cycle and pregnancy. In another study with white crossbred gilts, CBG-like binding activity in uterine flushings was low at Day 10, then increased over 100-fold at Day 15 (p < 0.01). However, levels of CBG-like binding activity on Day 15 were 100-fold lower than those of ir-CBG measured in the previous study and could bind less than 4% of the uterine luminal cortisol. Differences between ir-CBG and CBG binding might be due to the ability of the CBG antibody to recognize either biologically inactive CBG or structurally similar molecules. CBG-like binding activity, which appeared unrelated to glucocorticoid receptors, was also present in the endometrial cytosol of white crossbred gilts. Concentrations (fmol/mg protein) of endometrial CBG-like activity decreased (p = 0.03) between Days 10 and 15 of the estrous cycle and pregnancy, did not differ with reproductive status, and on Day 15 were comparable to concentrations in uterine flushings but threefold lower (p < 0.01) than those in the serum. Equilibrium dissociation constants for CBG-like binding activities were comparable among the three locations. These studies indicate that corticosteroids are present-primarily in the free form-within the porcine uterine lumen and could influence early porcine conceptus development. Endometrial CBG-like binding activity could mediate actions of cortisol or progesterone on uterine function.

Distribution of glucocorticoid receptors in the brain of rainbow trout (Oncorhynchus mykiss): possible relationships with the neuroendocrine systems controlling reproduction

The distribution of the glucocorticoid receptor (GR)within the forebrain of rainbow trout has been studied by means of in situ hybridization (ISH) and immunohistochemistry (ICC) using probes and antibodies directed against the AB-domain of the rainbow trout GR (rtGR). Both rtGR mRNA and protein exhibited the same pattern of distribution. A strong labelling was observed in all subdivisions of the preoptic nucleus, in the thalamic region and in the mediobasal hypothalamus (nucleus recessus lateralis, nucleus lateralis tuberis).It was notably found that all magnocellular neurons of the nucleus preopticus pars magnocellularis (NPOmc) were positive with both ISH and ICC. Furthermore, numerous cells of the anterior lobe of the pituitary were positively stained. Double staining studies allowed to identify part of the rtGR expressing cells. At the telencephalic level, it was found that GnRH neurons frequently express rtGR in vitellogenic females. Virtually all tyrosine hydroxylase (TH) cells in the anteroventral part of the preoptic nucleus (NPOav) were rtGR-positive. In this same area, a colocalization between rainbow trout estradiol receptor (rtER) and TH has already been documented, indirectly demonstrating that rtER and rtGR are colocalized. The same holds true for the GTH-II cells of the anterior pituitary which express both types of receptors. These results provide information on the potential sites of cortisol action on the reproductive axis directly at the pituitary level or indirectly on neuroendocrine Systems controllingGTH-II secretion, possibly via GR-ER interactions.

Hypercalcemia and metastatic calcification.

Time for primary review 27 days. I grew up in Edinburgh, at the same latitude as Copenhagen, and then covered by a pall of coal smoke which gave it the sobriquet ‘auld reekie’. Many bandy-legged and dwarfed citizens carried the legacy of rickets contracted before the discovery of vitamin D, the fortification of food and the Clean Air Acts. However vitamin D, good in the right dose, is dangerous in overdose and there is no doubt that Gorm's Vikings miscalculated the dose–response curve of cod liver oil; a teaspoon would have been a better implement than their ladle or Mrs. T's tablespoon. In view of their formidable achievements, it is likely that the Vikings escaped the worst effects of vitamin D intoxication by irregular dosage and non-compliance. Their cavalier approach was repeated with more disastrous results after 1924 when high doses of tasteless ergocalciferol (vitamin D2) from irradiated ergosterol became available and were indiscriminately prescribed for rheumatoid arthritis, tuberculosis, Paget's disease and chilblains, in none of which it has been shown to produce benefit, and osteoporosis. The effects of overdosage were described within four years of high dose ergocalciferol being released for sale; the condition was reviewed in a cluster of papers in the early 1950's [1–3]. Diagnosis was often delayed because the commonest symptoms were the non-specific ones of hypercalcemia — nausea, vomiting, weight loss, colic, constipation, thirst, polyuria, headache, weakness, apathy and depression roughly in that order [1]. Once suspected, the diagnosis was confirmed by the presence of hypercalcemia and renal impairment. Although vitamin D stimulates phosphate absorption, serum phosphate was often normal, as in Mrs. T, unless the renal damage was severe. Reduction of serum calcium by administration of cortisol distinguished this cause of hypercalcemia from hyperparathyroidism; one action of cortisol is to inhibit … * Corresponding author.

Biochemical and physiological manifestations of acute insulin withdrawal.

When insulin is withdrawn acutely from a severely diabetic patient, a sequence of intricately interconnected events begins which, without intervention, can result in coma and death. These events involve not only carbohydrate metabolism, but protein and lipid metabolism, electrolyte and fluid balance as well. Acute insulin withdrawal permits the unopposed action of the counter-regulatory hormones (which are attempting to elevate the plasma glucose concentration), namely glucagon, cortisol, growth hormone, and epinephrine. This article details interrelationships existing between the many biochemical and physiological events that are occurring more or less simultaneously in the animal following acute insulin withdrawal.

Increase in urinary cortisol excretion and memory declines: MacArthur studies of successful aging.

Cortisol production is increased during stress, and the actions of cortisol on receptors in the brain and other body organs are involved in allostasis, the process of adaptation to stress, as well as in allostatic load, the wear and tear associated with excessive exposure to cortisol. Using data from a community-based longitudinal study of older men and women, aged 70-79 yr, we tested the hypothesis that exposure to increasing levels of cortisol is associated with declines in memory performance. Associations between 12-h urinary free cortisol excretion and performance on tests of memory (delayed verbal recall and spatial recognition), abstraction, and spatial ability were examined. Among the women, greater cortisol excretion was associated with poorer baseline memory performance, independent of socio-demographic, health status, health behavior, and psychosocial characteristics. Moreover, women who exhibited increases in cortisol excretion over a 2.5-yr follow-up period were more likely to show declines in memory performance. By contrast, women who experienced declines in cortisol exhibited improvements in memory performance. No significant associations were found among the men. The results for the women suggest that decrements in memory performance associated with increases in cortisol may not represent irreversible effects, as declines in cortisol were associated with improvements in memory.