Adrenal Glucocorticoid Hormones Research Articles

Paraventricular hypothalamic obesity in rats: Role of corticosterone

The role of adrenal glucocorticoid hormones in the weight gain produced by lesions of the paraventricular nuclei was explored in two experiments. In the first experiment, female rats with PVN lesions were found to have normal a.m. plasma corticosterone concentrations and blunted, albeit still elevated, p.m. concentrations. Nighttime corticosterone levels were moderately correlated with plasma insulin levels. In the second experiment, adrenalectomy markedly suppressed weight gain in animals with very large PVN lesions (mean weight gain of 33.0 g/20 days compared to 137.6 g/20 days for PVN rats with sham adrenalectomies). In the ADX-PVN group, there was a +0.90 correlation between plasma corticosterone levels and weight gain. Administration of corticosterone restored the abnormal weight gain in ADX-PVN animals. It is concluded that the steroid receptors mediating this effect of corticosterone lie outside the hypothalamus.

Glucocorticoid inhibition of stimulus-evoked adrenocorticotrophin release caused by suppression of intracellular calcium signals.

Stress provokes a cohort of homeostatic reflexes by the central nervous, the immune as well as the metabolic control systems of the body. These powerful adaptive responses, which can cause a collapse of body homeostasis in the absence of feedback inhibition, are suppressed by adrenal glucocorticoid hormones. A prominent and physiologically significant early action of glucocorticoids that requires the induction of newly synthesized messenger RNA and protein is the suppression of ACTH release by anterior pituitary corticotroph cells. It is demonstrated here that glucocorticoids inhibit stimulated ACTH secretion in pituitary corticotroph tumour (AtT-20) cells by reducing stimulus-evoked intracellular free calcium transients. Thus, the data show for the first time that intracellular calcium signals may be modified by rapidly induced proteins. It is proposed that this is a general mechanism that underlies the early inhibitory effects of glucocorticoids during stress in various types of cell.

Glucocorticoids and hypothalamic obesity

Recent studies have demonstrated a role for adrenal glucocorticoid hormones in the hyperphagia and obesity which follow lesions of the ventromedial hypothalamus (VMH). Although VMH lesions elevate morning plasma corticosterone levels, it is concluded that this contributes little to the development of obesity. More importantly, animals with VMH lesions appear to be hyperresponsive to very low levels of circulating glucocorticoids. The overeating and obesity are both prevented and reversed by either complete adrenalectomy or complete hypophysectomy (i.e., resulting in plasma corticosterone levels of less than 1.0 microgram/dl) and restored by dosages of glucocorticoids that have no effect on feeding behavior and weight gain in nonlesioned adrenalectomized animals. Mineralocorticoid hormones have no effect on hypothalamic obesity. Judging by the time course of effects on feeding behavior in VMH-damaged mice of a single intracerebroventricular injection of a low dose of glucocorticoid, which has no effect when administered intraperitoneally, it is concluded that glucocorticoids exert their effect centrally in a permissive, rather than a regulatory, manner. Stimulation of the neighboring paraventricular nuclei (PVN) with norepinephrine or neuropeptide Y produces a rapid feeding response which is also abolished by adrenalectomy and restored with administration of glucocorticoids. However, it is unlikely that the PVN is the site at which glucocorticoids exert their effect in animals with VMH lesions, for PVN lesions or knife-cuts, or combination VMH-PVN lesions, also result in hyperphagia and obesity. It is concluded that adrenal glucocorticoid hormones exert their permissive effects on feeding behavior at brain sites other than the medial hypothalamus. The septo-hippocampal complex is suggested as a possible site.

Adrenocortical steroids and the brain.

In summary, a wide variety of effects of adrenal steroids on the brain have been reported and have been recently and exhaustively reviewed. From the viewpoint of endocrine physiology, however, what is often forgotten is the extraordinary difference in signal level between the two unique products of the adrenal cortex, the mineralocorticoid and glucocorticoid hormones. Levels of cortisol or corticosterone are 2-3 orders of magnitude higher than those of aldosterone, a difference that is tempered by perhaps one order of magnitude by the much higher binding of glucocorticoids to plasma protein. The signal-detecting mechanisms for the lower-intensity signal, i.e. the mineralocorticoid receptor, must therefore have powerful specificity-conferring mechanisms to enable it to recognize, bind, and respond to aldosterone. In vitro studies from a number of laboratories have shown that Type I receptors, in both classic mineralocorticoid target tissues (kidney, parotid, gut) and nontarget tissues (pituitary, hippocampus), cannot distinguish between aldosterone and corticosterone. This finding highlights the problem of aldosterone-selectivity in the kidney (Na+ transport) or the brain (Na+ appetite). In vivo studies, in contrast, show that corticosterone is very poorly taken up and/or retained in kidney, colon, parotid, and pituitary (but not in hippocampus) in mature and 10-day-old (minimal transcortin) rats, whereas aldosterone is well taken up and/or retained by all tissues, evidence for tissue-specific aldosterone selectivity in vivo. Two nonexclusive (i.e. possibly additive) models for such aldosterone selectivity are proposed, one "prebinding" and the other "postbinding". Both models accommodate the experimental findings of the nonselectivity of cytosol preparations in vitro and the stringent specificity seen in in vivo receptor and effector studies. In any real sense, the action of adrenal steroids on the brain is still largely an area of unconnected phenomenology, despite the efforts of a number of talented individuals and groups over the past two decades. Without descriptions of phenomena, even of the most basic ablation and replacement type, we have no chance of making physiological statements. It is equally important, in the attempt to make a coherent physiology, to erect a scaffolding of hypothesis that can be tested against the existing experimental findings and that can serve to suggest further studies in a logical sequence. These hypotheses themselves, and the models used to reify them, may be validated, altered, or rejected by the studies over the next few years.(ABSTRACT TRUNCATED AT 400 WORDS)

Effects of hydrocortisone, oestradiol and progesterone on A23187-stimulated prostaglandin output from the guinea-pig uterus superfused in vitro

Hydrocortisone (10 μg/ml) had no effect on the basal outputs and A23187-stimulated outputs of PGF 2α, PGE 2 and 6-keto-PGF 1α from the Day 15 guinea-pig uterus superfused in vitro . These findings indicate that the high output of PGF 2α from the guinea-pig uterus during the last one-third of the oestrous cycle is not modulated by the adrenal glucocorticoid hormones. Progesterone (10 gmg/ml) had no effect on the A23187-induced increases in PG output from the Day 15 guinea-pig uterus. However, oestradiol (10 gmg/ml but not 1 μg/ml) significantly reduced the increases in outputs of PGF 2α, PGE 2 and 6-keto-PGF 1α induced by A23187 from the Day 15 guinea-pig uterus, without affecting basal PG outputs. The increase in uterine tone induced by A23187 in the Day 15 guinea-pig uterus was reduced by 20–50% by oestradiol (10 μg/ml). The addition of oestradiol (10 μg/ml) and progesterone together (10 gmg/ml) produced the same effects on the Day 15 guinea-pig uterus as oestradiol alone. Oestradiol (10 μg/ml) also reduced the A23187-induced increases in PG output from the Day 7 guinea-pig uterus, but did not reduce the increase in uterine tone. Oestradiol (10 gmg/ml) reduced the increases in outputs of PGF 2α, PGE 2 and 6-keto-PGF 1α induced by exogenous arachidonic acid from the Day 7 and Day 15 guinea-pig uterus. Previous studies have shown that oestradiol is not a cyclo-oxygenase inhibitor. The present findings suggest that oestradiol, at a relatively high concentration, may interfere with the access of arachidonic acid to the cyclo-oxygenase enzyme. This action of oestradiol may explain its anti-luteolytic action when administered to guinea-pigs in large doses after Day 9 of the cycle.

Glucocorticoid Hormones in Stress: Physiological and Pharmacological Actions

What are the normal functions of the adrenal glucocorticoid hormones? This seemingly simple question has not yet any simple agreed-on answer. In the half-century since the glucocorticoids were distinguished from other cortical steroids, the question of their physiological functions has generated much inconclusive debate. Likewise, questions of their role in disease and therapy lack definitive answers. The authors propose that there is no fundamental distinction between the physiological and pharmacological effects of glucocorticoids and that their inhibitory actions on inflammatory and immune responses are concerned with modulating the body's defense mechanisms.

Hypothalamic obesity after hypophysectomy or adrenalectomy: dependence on corticosterone.

Recent studies have found that the hyperphagia and obesity resulting from lesions of the ventromedial hypothalamus (VMH) are both reversed and prevented by complete adrenalectomy. Several previous experiments, however, reported little or no suppression of VMH weight gain in hypophysectomized (HYPOX) rats. This study directly compared the effects of hypophysectomy and adrenalectomy on hypothalamic obesity in adult female rats. Complete adrenalectomy (i.e, stress-induced plasma corticosterone less than 1.0 micrograms/dl) totally suppressed abnormal weight gain in the first 20 days after VMH lesions but did not affect intracranial self-stimulation. Hypophysectomy also resulted in suppression of weight gain, but the HYPOX-VMH rats nevertheless gained significantly more weight than HYPOX rats with sham lesions. However, the HYPOX-VMH animals had very low levels of plasma corticosterone and adrenocorticotropin (ACTH) (from residual pituitary tissue or of diencephalic origin), and incompletely adrenalectomized rats with similar low levels of plasma corticosterone gained an equal amount of weight after VMH lesions. It was concluded that adrenal glucocorticoid hormones play a largely permissive role in the VMH syndrome, with only very small levels required for the manifestation of obesity.

Cellular and Biochemical Actions of Adrenal Glucocorticoid Hormones on Rat Thymic Lymphocytes

The molecular, biochemical, and cellular effects of adrenal glucocorticoid hormones on thymic lymphocytes are reviewed, with emphasis on their relationship to the growth suppressive and lethal actions that occur in lymphoid tissues when glucocorticoids are administered to the whole animal. The data support the hypothesis that the hormonal inhibition of growth and development is a consequence of its ability to suppress cellular energy production, causing the cells to behave as though they were in a more stringent environment. Slight changes in ratios of adenine and guanine nucleotides appear to account for the reordering of metabolic priorities that occurs, with processes related to growth and development curtailed in favor of those more essential to immediate cell survival. The lethal glucocorticoid actions appear to be the result of the operation of separate mechanisms (unrelated to energy metabolism) that lead to lethal attack at the level of the nuclear membrane. Resistance to the lethal effects appears to occur via the selection (in the case of cancer cells where the animal or patient is undergoing chemotherapy with glucocorticoids) or the normal development (in the case of immunologically noncommitted thymocytes progressing to immunologically committed ones) of cells with hardier membranes. This progression is associated with a change in a few cellular proteins. One such protein appears identical in both kinds of cells, offering itself as a candidate for an intracellular mechanism conferring resistance. Evidence is also presented for the appearance of hormone-induced proteins that could be metabolic regulators that mediate the individual cellular and biochemical actions of glucocorticoids. It is proposed that toxins could alter cellular metabolism through mechanisms similar to those utilized by steroid hormones, or possibly alter the sensitivity of cells to steroids, or vice versa.

Cellular and biochemical actions of adrenal glucocorticoid hormones on rat thymic lymphocytes.

The molecular, biochemical, and cellular effects of adrenal glucocorticoid hormones on thymic lymphocytes are reviewed, with emphasis on their relationship to the growth suppressive and lethal actions that occur in lymphoid tissues when glucocorticoids are administered to the whole animal. The data support the hypothesis that the hormonal inhibition of growth and development is a consequence of its ability to suppress cellular energy production, causing the cells to behave as though they were in a more stringent environment. Slight changes in ratios of adenine and guanine nucleotides appear to account for the reordering of metabolic priorities that occurs, with processes related to growth and development curtailed in favor of those more essential to immediate cell survival. The lethal glucocorticoid actions appear to be the result of the operation of separate mechanisms (unrelated to energy metabolism) that lead to lethal attack at the level of the nuclear membrane. Resistance to the lethal effects appears to occur via the selection (in the case of cancer cells where the animal or patient is undergoing chemotherapy with glucocorticoids) or the normal development (in the case of immunologically noncommitted thymocytes progressing to immunologically committed ones) of cells with hardier membranes. This progression is associated with a change in a few cellular proteins. One such protein appears identical in both kinds of cells, offering itself as a candidate for an intracellular mechanism conferring resistance. Evidence is also presented for the appearance of hormone-induced proteins that could be metabolic regulators that mediate the individual cellular and biochemical actions of glucocorticoids. It is proposed that toxins could alter cellular metabolism through mechanisms similar to those utilized by steroid hormones, or possibly alter the sensitivity of cells to steroids, or vice versa.

Distribution of Dexamethasone between Mother and Fetus after Maternal Administration

FUNKHOUSER, J. D.; PEEVY, K. J.; MOCKRIDGE, P. B. and; HUGHES, E. R. Author Information

Distribution of dexamethasone between mother and fetus after maternal administration.

Summary: The adrenal glucocorticoid hormones are believed to have an important role in the definitive biochemical differentiation of a number of fetal organs. This paper presents data for dexamethasone transfer and distribution between mother and fetus using 20-21 days pregnant rats. This synthetic glucocorticoid is rapidly transferred to the fetus and reaches a plateau by 90 min after administration to the mother. Pregnant rats receiving either a high dose (20 mg) or a low dose (2.2 µg) had almost identical concentration distribution ratios with a mean of 0.311 (± 0.013) and 0.332 (± 0.019) between fetal and maternal plasmas, respectively. In vitro binding measured by equilibrium dialysis showed that maternal plasma bound only 4-5% more than the fetal plasma. Essentially no radioactivity remained bound to protein after Sephadex G-50 chromatography, indicating no high affinity sites for dexamethasone in either maternal or fetal plasma. Acetylation of ethyl acetate extracts of fetal and maternal plasma followed by paper chromatograph revealed two identical peaks for both the dexamethasone standard and the plasma radioactivity. This study demonstrates a rapid transfer of administered dexamethasone from the mother to the fetus with a concentration difference between the two plasma pools. The difference in concentration does not appear to be the result of differential protein binding or metabolism. Speculation: The rat placenta would appear to maintain an appreciable concentration difference between maternal and fetal plasma for the glucocorticoid hormones. The nature of the process which accounts for this phenomenon needs further investigation.

Substrate specificities of base-level and induced forms of oncofetal alkaline phosphatase in HeLa cells.

HeLa65 cells contain an oncofetal form of alkaline phosphatase that exhibits an increase in catalytic activity when cultures are grown in medium containing adrenal glucocorticoid hormones such as hydrocortisone or its analogue prednisolone. The increase in alkaline phosphatase specific activity in cells grown with hormone is apparently the result of a reduced phosphate content of the enzyme which alters the transition state of the enzyme-substrate complex with an increase in catlytic efficiency. Fourteen different substrates possessing aliphatic, aromatic and heterocyclic configurations were studied with respect to the initial velocities of hydrolysis catalyzed by the base-level and induced forms of the enzyme. The magnitude of increase in catalytic activity was not substantially influenced by the structure of the nonphosphoryl moiety of substrates.

The effects of adrenal glucocorticoid hormones on transformation by polyoma virus

Treatment of polyoma virus-infected hamster embryo fibroblasts with physiological concentrations of glucocorticoids enhances focus formation between three- and fivefold. The transformed state is stable. The cytoplasmic receptors which mediate the physiological actions of the steroid hormones appear to be involved in the present effect.

Isolation of lymphoma cell variants resistant to killing by glucocorticoids

Pseudo-diploid (2s) and pseudo-tetraploid (4s) cultured mouse lymphoma cells are killed by physiological concentrations of adrenal glucocorticoid hormones. A method is described for the single-step isolation of 2s and 4s variants resistant to dexamethasone, a synthetic adrenal hormone. The transition from steroid sensitivity to resistance is stochastic and occurs at a rate of 3.5 × 10 −6/cell/generation. Several types of mutagens significantly increase this rate. The chromosome number, growth rate, gross morphology, and cloning efficiency of the steroid-resistant variants are not detectably different from those of their steroid-sensitive parents.

Interrelated changes in host metabolism during generalized infectious illness

The metabolic effects of acute infectious illness in man involve virtually every biochemical pathway studied. For a number of years investigators in our Institute have worked systematically to define and provide a mechanistic explanation for the changes in host metabolism that accompany infection. Many such metabolic changes occur during only certain stages of a generalized infectious process. Some begin during the incubation period, others during the febrile period, and still others during convalescence. Some changes exhibit biphasic patterns in the course of their progression. For these reasons, serial measurements must be obtained throughout the course of an infection in order to understand the sequential process. Our initial studies in man (1-6) employed metabolic balance methods and were designed to describe infection-related changes in protein, electrolyte, and mineral metabolism as well as changes in endocrine functions. Tularemia, 0 fever, and sandfly fever were included in these studies as was an evaluation, in ancillary investigations, of the role of single pertinent variables such as fever, impaired dietary intake, increased secretion of adrenal glucocorticoid hormones, specific immunity, and antibiotic therapy.

Hormonal induction of increased zinc uptake in mammalian cell cultures: requirement for RNA and protein synthesis.

The zinc content of HeLa S(3) cells is markedly increased after growth in medium containing adrenal glucocorticoid hormones. Studies with inhibitors indicate that the synthesis of RNA and protein is required for enhanced zinc uptake. When protein synthesis is blocked in the presence of the steroid, an intermediate, presumably messenger RNA, which specifies enhanced zinc uptake accumulates and is expressed when the inhibition of protein synthesis is removed.

Effect of variations in protein intake on enzymes of amino acid metabolism.

Changes in the protein intake of animals result in changes in the activities of many enzymes of nitrogen metabolism. Effects of starvation on enzymes of amino acid metabolism are frequently quite different from effects of ingestion of a protein-free diet. The nature of the changes is such as to suggest that the lability of body proteins depends not on protein intake as such but on the metabolic requirements of the organism. Many of the enzymes of nitrogen metabolism are elevated in starved animals, animals fed a high protein diet, and animals injected with adrenal glucocorticoid hormones. These changes appear to be associated with increasing dependence of the organism on protein metabolism. Many of these enzyme responses to dietary changes can be interpreted as adaptations contributing to the maintenance of homeostasis in the face of alterations in the external environment—alterations that might otherwise affect the internal environment of the organism detrimentally.

EFFECT OF ADRENOCORTICOTROPHIC HORMONE AND CORTISONE ON THE UPTAKE OF TRITIATED THYMIDINE BY REGENERATING LIVER TISSUE IN THE WHITE RAT.

THERE have been many reports concerning the relations between nucleic acid metabolism and adrenocortical hormones. But there are only a few data concerning the mechanism by which the adrenal glucocorticoid hormones (and ACTH) influence mitosis1. Cortisone has been found to lessen hepatic regeneration2, probably through an antimitotic action on regenerating liver3. It has also been demonstrated that ACTH, cortisone and dehydrocortisone inhibit the formation of granulation tissue4,5. However, the mechanism by which corticoids influence the metabolism of proteins4 and that of the nucleic acids is not yet known.