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ABSTRACT
The occurrence and nature of corticosteroid inhibition of ACTH secretion at the rat anterior pituitary gland was investigated using three experimental models: animals bearing lesions of the basal hypothalamus, and two preparations of the gland incubated in vitro; these were tissue segments and collagenase-dispersed cells. Release of ACTH in the experiments was provoked using one of three distinct stimuli: acid extracts of whole hypothalami, corticotrophin releasing activity released by serotonin from hypothalami incubated in vitro and synthetic ovine corticotrophin releasing factor. Irrespective of whether ACTH was measured directly by radioimmunoassay (in the experiments in vitro) or indirectly in terms of corticosterone production (in the lesioned animals), its stimulated release from the anterior pituitary gland was inhibited by corticosterone. Two phases of inhibition were observed; these had some of the characteristics inferred previously from experiments with intact animals and designated fast feedback and delayed feedback.
However, the fast feedback demonstrable in lesioned animals did not show the rate-sensitivity shown previously in intact animals. 11-Deoxycortisol (or 11-deoxycorticosterone) and prednisolone proved to be agonists of corticosterone in provoking fast feed-back in lesioned animals, whereas they had been shown respectively to act as an antagonist or to have no effect in intact rats. Several steroids were able to cause delayed feedback in lesioned rats, but beclomethasone dipropionate (shown to be an agonist of corticosterone in intact rats) proved to have no inhibitory effect at the anterior pituitary gland of lesioned animals.
It is concluded that the dynamics of corticosteroid feedback mechanisms at the anterior pituitary gland, as indicated by experiments in lesioned animals, differ from those operative in the intact animals. Other work suggests that a more important site for such inhibitory mechanisms in vivo is the hypothalamus.
J. Endocr. (1984) 102, 33–42
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Corticosteroid control of distal nephron sodium handling, particularly through the amiloride-sensitive sodium channel (ENaC), has a key role in blood pressure regulation. The mechanisms regulating ENaC activity remain unclear. Despite the generation of useful mouse models of disorders of electrolyte balance and blood pressure, there has been little study of distal nephron sodium handling in this species. To investigate how corticosteroids regulate ENaC activity we isolated cDNA for the three mouse ENaC subunits (alpha, beta and gamma), enabling their quantitation by competitive PCR and in situ hybridisation. Kidneys were analysed from mice 6 days after adrenalectomy or placement of osmotic mini-pumps delivering aldosterone (50 microg/kg per day), dexamethasone (100 microg/kg per day), spironolactone (20 mg/kg per day) or vehicle alone (controls). In controls, renal ENaCalpha mRNA exceeded beta or gamma by approximately 1.75- to 2.8-fold. All subunit mRNAs were expressed in renal cortex and outer medulla, where the pattern of expression was fully consistent with localisation in collecting duct, whereas the distribution in cortex suggested expression extended beyond the collecting duct into adjacent distal tubule. Subunit mRNA expression decreased from cortex to outer medulla, with a gradual reduction in beta and gamma, and ENaCalpha decreased sharply ( approximately 50%) across the outer medulla. Expression of ENaCbeta and gamma (but not alpha) extended into inner medulla, suggesting the potential for inner medulla collecting duct cation channels in which at least ENaCbetagamma participate. Aldosterone significantly increased ENaC subunit expression; the other treatments had little effect. Aldosterone caused a 1.9- to 3.5-fold increase in ENaCalpha (particularly marked in outer medullary collecting duct), but changes for beta and gamma were minor and limited to the cortex. The results raise the possibility that medullary ENaCalpha upregulation by aldosterone will create more favourable subunit stoichiometry leading to a more substantial increase in ENaC activity. In cortex, such a mechanism is unlikely to have a major role.
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Disruptions in circadian rhythms have been associated with several diseases, including cardiovascular and metabolic disorders. Forced internal desynchronization induced by a period of T-cycles of 22 h (T22 protocol) reaches the lower limit of entrainment and dissociates the circadian rhythmicity of the locomotor activity into two components, driven by different outputs from the suprachiasmatic nucleus (SCN). The main goal of this study was to evaluate the cardiovascular and metabolic response in rats submitted to internal desynchronization by T22 protocol. Male Wistar rats were assigned to either a control group subjected to a usual T-cycles of 24 h (12 h–12 h) or an experimental group subjected to the T22 protocol involving a 22-h symmetric light–dark cycle (11 h–11 h). After 8 weeks, rats subjected to the T22 exhibited desynchrony in their locomotor activity. Although plasma glucose and insulin levels were similar in both groups, desynchronized rats demonstrated dyslipidemia, significant hypertrophy of the fasciculate zone of the adrenal gland, low IRB, IRS2, PI3K, AKT, SOD and CAT protein expression and an increased expression of phosphoenolpyruvate carboxykinase in the liver. Furthermore, though they maintained normal baseline heart rates and mean arterial pressure levels, they also presented reduced baroreflex sensitivity. The findings indicate that circadian timing desynchrony following the T22 protocol can induce cardiometabolic disruptions. Early hepatic metabolism dysfunction can trigger other disorders, though additional studies are needed to clarify the causes.
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Endocrine systems function as key mediators of adaptive responses to the external environment. As a reliable predictor of many salient variations in the external world, the light environment thus constitutes an influential source of control over neuroendocrine function. Accordingly, the vast majority of endocrine systems display 24-h variations in activity that are aligned to daily changes in external illumination. While the neural mechanisms responsible for driving these rhythms are still incompletely understood, circadian and light-dependent signals relayed via the suprachiasmatic nucleus of the hypothalamus (SCN) play a key role. Retinal projections to the SCN provide information from rods, cones and melanopsin, which, together, encode variations in the amount and spectral content of ambient light over the solar day. This sensory input, in turn, drives acute modulations in SCN cellular activity and aligns daily rhythms in the electrophysiological output of individual clock neurons. Neural outputs from the SCN can therefore convey both rapid and longer-term information about the light environment to other hypothalamic nuclei responsible for neuroendocrine control. In this review we summarise current understanding of the specific neural pathways by which the light environment influences key neuroendocrine axes, with a particular focus on the retinal and SCN-dependent circuits involved and their known sensory properties.
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Studies in vitro and in vivo have shown that corticosteroids play an important role in bone physiology and pathophysiology. It is now established that corticosteroid hormone action is regulated, in part, at the pre-receptor level through the expression of isozymes of 11beta-hydroxysteroid dehydrogenase (11beta-HSD), which are responsible for the interconversion of hormonally active cortisol to cortisone. In this report we demonstrate 11beta-HSD activity in human osteoblast (OB) cells. Osteosarcoma-derived OB cell lines TE-85, MG-63 and SaOS-2 and fibrosarcoma Hs913T cells express the type 2 isoform of 11beta-HSD, as determined by reverse transcription polymerase chain reaction (RT-PCR) and specific enzyme assays. Enzyme activity was shown to be strictly NAD dependent with a Km of approximately 71 nM; 11beta-HSD type 1 mRNA expression and enzyme activity were not detected. All four cell lines expressed mRNA for the glucocorticoid receptor (GR) and mineralocorticoid receptor, but specific binding was only detectable with radiolabelled dexamethasone (Kd=10 nM) and not aldosterone. MG-63 cells had two to three times more GR than the other OB cells, which correlated with the higher levels of 11beta-HSD 2 activity in these cells. In contrast to the osteosarcoma cell studies, RT-PCR analysis of primary cultures of human OB cells revealed the presence of mRNA for 11beta-HSD 1 as well as 11beta-HSD 2. However, enzyme activity in these cells remained predominantly oxidative, i.e. inactivation of cortisol to cortisone (147 pmol/h per mg protein at 500 nM cortisol) was greater than cortisone to cortisol (10.3 pmol/h per mg protein at 250 nM cortisone). Data from normal human OB and osteosarcoma cells demonstrate the presence of an endogenous mechanism for inactivation of glucocorticoids in OB cells. We postulate that expression of the type 1 and type 2 isoforms of 11beta-HSD in human bone plays an important role in normal bone homeostasis, and may be implicated in the pathogenesis of steroid-induced osteoporosis.
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SUMMARY
1. Plasma cortisol concentrations, and the urinary output of free and conjugated Porter-Silber reacting steroids, 17-ketosteroids (17-KS), 'total 17-OH CS', urinary cortisone and cortisol, free and conjugated tetrahydrocortisone and cortisol were measured before and after a 1 l. water load.
2. The plasma cortisol concentration fell within 30 min of water ingestion, and tended to increase as diuresis declined.
3. There was a simultaneous increase in the urinary output of 17-KS, total 17-OH CS, and free Porter-Silber reacting steroids. In contrast, urinary excretion of glucuronide-conjugated corticosteroids did not increase during diuresis.
4. The implications of these findings are discussed and it is concluded that (a) the enhanced corticosteroid output during water diuresis is renal in origin, suggesting that tubular factors play a part in the excretion of these hormones; and (b) the role of the adrenal in the excretion of a water load is permissive.
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ABSTRACT
The inhibition of γ-aminobutyric acid (GABA) synthesis did not interfere with the suppressive effect of dexamethasone on the stress-induced rise of plasma corticosterone levels in vasopressin-deficient homozygous Brattleboro rats. In dexamethasone-treated heterozygous rats corticosterone and vasopressin secretion increased after stress provided GABA synthesis was inhibited. The results indicate that inhibition of corticotrophin secretion by corticosteroids may in part be mediated by enhancement of GABA synthesis and a consequent inhibition of vasopressin release.
J. Endocr. (1985) 107, 303–307
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ABSTRACT
Milk yield declined significantly between days 22 and 28 of lactation in rats, when lactation was extended by frequent replacement of older litters with younger ones. Corticosterone implants but not cortisol injections or implants prevented this decline. Cortisol, however, appeared to inhibit milk ejection since the mammary glands became engorged with milk and milk yield was improved dramatically by oxytocin injections. In both cases corticosteroid concentrations increased approximately threefold above basal concentrations.
Both corticosteroids increased total mammary gland RNA content and lipoprotein lipase (LPL) activity of the mammary gland but were without effect on insulin binding. They also decreased LPL activity, lipogenesis and the number of insulin receptors on adipose tissue.
Serum prolactin and insulin concentrations were unaffected by any of the treatments.
The results suggest that corticosteroids (1) inhibit milk ejection under certain conditions, (2) may be circulating in lower concentrations, which thereby limit milk production, during prolonged lactation and (3) may improve milk yield during extended lactation in part by suppressing anabolic activity in adipose tissue.
J. Endocr. (1984) 103, 213–218
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SUMMARY
A corticosteroid 1α-hydroxylase was demonstrated in interrenal tissue of eleven species of elasmobranchs by the production in vitro of 1α-hydroxycorticosterone from corticosterone, and in seven of nine species examined from endogenous precursors. Interrenal tissue was collected from the following species: the skates and rays, Raja laevis, R. clavata, R. erinacea, and Dasyatis violacea; the dogfish, Squalus acanthias and Scyliorhinus stellaris; and the sharks, Isurus oxyrinchus, Prionace glauca, Sphyrna lewini, Carcharhinus falciformis and C. obscurus.
1α-Hydroxycorticosterone was identified in interrenal incubates by determination of a constant isotope ratio (3H:14C) through chromatography and preparation of sequential derivatives. [7α-3H] 1α-Hydroxycorticosterone was biosynthesized from [7α-3H]progesterone and its identity verified by demonstration of the homogeneity of its 1-dehydrated derivative with 11β,21-dihydroxypregna-1,4-diene-3,20-dione prepared by microbial dehydrogenation of corticosterone. 14C-Labelled 1α-hydroxycorticosterone was obtained from incubations of interrenal glands as a transformation product of [4-14C]corticosterone, or by acetylation of radioinert 1α-hydroxycorticosterone with [1-14C]acetic anhydride.
11-Deoxycorticosterone and corticosterone were isolated and identified as metabolites of endogenous precursors from an interrenal incubate of P. glauca. In all species, 11-dehydrocorticosterone was noted as a metabolite in vitro of corticosterone and its identity was confirmed in an interrenal incubate of S. lewini.
The results of this survey are discussed in relation to earlier studies of steroidogenesis in Elasmobranchii.
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ABSTRACT
The serum concentration of corticosteroid-binding globulin (CBG) is higher in female rats than in males. Combined hypophysectomy and gonadectomy of female rats reduced the serum concentration of CBG as measured by steady-state polyacrylamide gel electrophoresis, whereas hypophysectomy of male rats increased serum CBG. These effects were seen despite replacement therapy with thyroxine and glucocorticoids. Moreover, neither androgen nor oestrogen treatment affected the serum concentrations of CBG in hypophysectomized rats. Continuous infusions of human or bovine GH (1·4 U/kg per day), by means of osmotic minipumps for 1 week, increased serum concentrations of CBG in both hypophysectomized male and female rats. In contrast, intermittent GH replacement therapy by s.c. injections at 12-h intervals either had no effect or suppressed serum CBG levels. In male rats, neonatal (days 1–2) gonadectomy increased CBG levels more than did prepubertal (day 25) gonadectomy, and testosterone replacement therapy reversed these effects.
It is concluded that GH increases the serum CBG levels of hypophysectomized rats when it is given in a continuous manner, but not when given intermittently. The sex difference in serum CBG levels of normal rats may, therefore, be attributed to the more continuous secretory pattern of GH previously observed in female rats.
Journal of Endocrinology (1989) 122, 725–732
