Changes In Adrenocortical Function Research Articles

Characterization of Cortisol Secretion Rate in Secondary Adrenal Insufficiency.

Context:In secondary adrenal insufficiency (SAI), chronic deficiency of adrenocorticotropin (ACTH) is believed to result in secondary changes in adrenocortical function, causing an altered dose-response relationship between ACTH concentration and cortisol secretion rate (CSR).Objective:We sought to characterize maximal cortisol secretion rate (CSRmax) and free cortisol half-life in patients with SAI, compare results with those of age-matched healthy controls, and examine the influence of predictor variables on ACTH-stimulated cortisol concentrations.Design:CSRmax was estimated from ACTH1-24 (250 μg)–stimulated cortisol time-concentration data. Estimates for CSRmax and free cortisol half-life were obtained for both dexamethasone (DEX) and placebo pretreatment conditions for all subjects.Setting:Single academic medical center.Patients:Patients with SAI (n = 10) compared with age-matched healthy controls (n = 21).Interventions:The order of DEX vs placebo pretreatment was randomized and double-blind. Cortisol concentrations were obtained at baseline and at intervals for 120 minutes after ACTH1-24.Main Outcome Measures:CSRmax and free cortisol half-life were obtained by numerical modeling analysis. Predictors of stimulated cortisol concentrations were evaluated using a multivariate model.Results:CSRmax was significantly (P < 0.001) reduced in patients with SAI compared with controls for both placebo (0.17 ± 0.09 vs 0.46 ± 0.14 nM/s) and DEX (0.18 ± 0.13 vs 0.43 ± 0.13 nM/s) conditions. Significant predictors of ACTH1-24–stimulated total cortisol concentrations included CSRmax, free cortisol half-life, and baseline total cortisol, corticosteroid-binding globulin, and albumin concentrations (all P < 0.05).Conclusions:Our finding of significantly decreased CSRmax confirms that SAI is associated with alterations in the CSR-ACTH dose-response curve. Decreased CSRmax contributes importantly to the laboratory diagnosis of SAI.

El ejercicio físico moderado evita la aparición de insulinorresistencia y de alteraciones morfofuncionales adrenocorticales en ratas tratadas con una dieta rica en sacarosa

Introducción: niveles elevados de glucocorticoides se asocian a las alteraciones somáticas y bioquímicas presentes en pacientes y en animales con insulinorresistencia (IR). Hemos demostrado previamente que la IR inducida por una dieta rica en sacarosa (DRS) induce cambios morfológicos y funcionales a nivel adrenocortical y que estas alteraciones pueden evitarse mediante la administración simultánea de un agonista PPAR-γ.Objetivo: evaluar el impacto de un protocolo de ejercicio moderado sobre las alteraciones morfológicas y funcionales adrenocorticales asociadas con el desarrollo de IR inducida por una DRS administrada durante siete semanas.Metodología: Resultados: los animales (ratas Wistar macho adultas) tratados con la DRS (agregado de sacarosa al 30% en el agua de bebida) mostraron un incremento del peso corporal y de los panículos adiposos, así como de los niveles séricos de glucosa, insulina y triglicéridos. La respuesta glucémica a la administración de insulina i.p. se vio claramente menoscabada. Se observó una infiltración lipídica de la corteza adrenal, con aumento de la expresión de proteínas esteroidogénicas y marcadores de inflamación (IL-1β, TNF-α, iNOS, COX-2) y un incremento marcado de la corticosteronemia basal. El protocolo de ejercicio consistió en correr en una cinta continua adaptada especialmente durante un máximo de 7 min/día. Este ejercicio moderado previno la aparición de los cambios somáticos y bioquímicos característicos del estado de IR y la infiltración lipídica adrenocortical, revirtiendo además los cambios inflamatorios y normalizando la corticosteronemia.Conclusiones: nuestros resultados subrayan el rol deletéreo del consumo exagerado de carbohidratos simples conteniendo fructosa y sugieren que el ejercicio moderado podría tener efectos adicionales cuando se emplea en el tratamiento de la IR.

Primary aldosteronism and impaired natriuresis in mice underexpressing TGFβ1

To uncover the potential cardiovascular effects of human polymorphisms influencing transforming growth factor β1 (TGFβ1) expression, we generated mice with Tgfb1 mRNA expression graded in five steps from 10% to 300% normal. Adrenal expression of the genes for mineralocorticoid-producing enzymes ranged from 50% normal in the hypermorphs at age 12 wk to 400% normal in the hypomorphs accompanied with proportionate changes in plasma aldosterone levels, whereas plasma volumes ranged from 50% to 150% normal accompanied by marked compensatory changes in plasma angiotensin II and renin levels. The aldosterone/renin ratio ranged from 0.3 times normal in the 300% hypermorphs to six times in the 10% hypomorphs, which have elevated blood pressure. Urinary output of water and electrolytes are markedly decreased in the 10% hypomorphs without significant change in the glomerular filtration rate. Renal activities for the Na(+), K(+)-ATPase, and epithelial sodium channel are markedly increased in the 10% hypomorphs. The hypertension in the 10% hypomorphs is corrected by spironolactone or amiloride at doses that do not change blood pressure in wild-type mice. Thus, changes in Tgfb1 expression cause marked progressive changes in multiple systems that regulate blood pressure and fluid homeostasis, with the major effects being mediated by changes in adrenocortical function.

Nature of changes in adrenocortical function in chronic hyperleptinemic female rats.

Neonatal treatment of rats with monosodium L-glutamate, which destroys hypothalamic arcuate nucleus neuronal bodies, induces several metabolic abnormalities; as a result, rats develop a phenotype of pseudoobesity. This study was designed to explore, in the monosodium L-glutamate-treated female rat, the influence of chronic hyperleptinemia on adrenal cortex functionality. For this purpose, we evaluated in control and hypothalamic-damaged rats: (a) in vivo and in vitro adrenocortical function, (b) adrenal leptin receptor immunodistribution and mRNA expression, and (c) whether the inhibitory effect of leptin on adrenal function remains. Our results indicate that, compared to normal counterparts, pseudoobese animals displayed (1) hyperadiposity, despite being hypophagic and of lower body weight, (2) in vivo and in vitro enhanced adrenocortical response to ACTH stimulation, (3) an in vitro adrenal fasciculata-reticularis cell hyper-sensitivity to ACTH stimulus, (4) hyperplasia of their adrenal zona fasciculata cells, and (5) adrenal fasciculata-reticularis cell refractoriness to the inhibitory effect of leptin on ACTH-stimulated glucocorticoid production due, at least in part, to decreased adrenal leptin receptor expression. These data further support that increased hypothalamo-pituitary-adrenal axis function, in the adult neurotoxin-lesioned female rat, is mainly dependent on the development of both hyperplasia of adrenal zona fasciculata and adrenal gland refractoriness to leptin inhibitory effect. Our study supports that adrenal leptin resistance could be responsible, at least in part, for enhanced glucocorticoid circulating levels in this phenotype of obesity.

Changes in Adrenocortical Function with Aging and Therapeutic Implications

Throughout life, the adrenal cortex exhibits dramatic morphogenic and steroidogenic changes. While there is subtle senescent decline in aldosterone, and a similarly subtle increase in cortisol, the adrenal androgens dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) decline with age in a situation similar to menopause, and this decline is considered by some to aggravate some age-related diseases. This decline is associated with an almost complete loss of the inner zone of the adrenal cortex, known as the zona reticularis. This review addresses these adrenal cortical changes, and explores their clinical significance. In particular, the clinical data on DHEA replacement in aging is addressed.

Changes in Adrenocortical Function with Aging and Therapeutic Implications

Changes in Adrenocortical Function with Aging and Therapeutic Implications

Intra‐ and Interindividual Variation in Urine Osmolality and Urine Specific Gravity in Healthy Pet Dogs of Various Ages

Urine specific gravity (Usg) and urine osmolality (Uosm) are used routinely to assess renal concentrating ability, but limited data on these variables are available for healthy dogs. Consequently, we studied the intra- and interindividual variations in Usg and Uosm in healthy dogs as well as the influence of age and gender on these variables. Dogs were selected for health and anestrus in female dogs through the use of a detailed questionnaire. Eighty-nine owners collected morning and evening urine samples from their dogs on 2 consecutive days. In 8 dogs in which the Uosm of different samples varied more than 50%, owners collected urine for 24 hours at 2-hour intervals during the day and at 4-hour intervals at night. The possible effect of changes in adrenocortical function with age was assessed by measurements of urinary corticoid/creatinine (C/C) ratios. Among all samples, Uosm ranged from 161 to 2,830 mOsm/kg and Usg from 1.006 to > 1.050. In the morning, Uosm (1,541 +/- 527 mOsm/kg, range 273-2,620 mOsm/kg) and Usg (1.035 +/- 0.010, range 1.009-->1.050) were higher than in the evening (Uosm 1,400 +/- 586 mOsm/kg, range 161-2,830 mOsm/kg; Usg 1.031 +/- 0.012, range 1.006-->1.050). The interindividual coefficient of variation in Uosm was 34.2% for morning urine samples and 41.9% for evening samples. In 8 dogs with large differences in urine concentration, there were 2- to 3-fold increases or decreases in Uosm during the day, and the intraindividual coefficient of variation was 33.0%. There was no relation between gender and urine concentration. Urine concentration in both the morning and evening samples decreased with age. Urinary corticoid/ creatinine ratios did not change with age. It can be concluded that Uosm and Usg vary widely among healthy dogs. Urine concentration is generally lower in the evening than in the morning and is not related to gender. Urine concentration decreases with age, and this cannot be ascribed to an associated increase in endogenous corticoids. In some dogs, Uosm varies widely during the day, with an intraindividual coefficient of variation approaching the interindividual coefficient of variation. This may be regarded as a biologic variation but also could represent an early undiagnosed clinical abnormality.

Safety of high-dose inhaled corticosteroids

Inhaled corticosteroids are being given to more patients, at increasing doses and for longer periods of time. This has led to renewed concern about side-effects, particularly when higher doses (> 1 mg day-1) are used. The side-effects of particular concern are adrenocortical suppression, bone resorption, decreased growth in children, skin thinning and cataract formation. Changes in adrenocortical function are seen in a small proportion of patients given doses of 1-2 mg day-1. Long-term studies of the effect of inhaled corticosteroids on bone density are not available. Cross-sectional studies of bone density have been performed, but confounding variables, such as previous courses of oral corticosteroids and poor matching of control groups, make the studies difficult to interpret. Short-term effects on markers of bone turnover have been demonstrated, but their relevance to the long-term risk of osteoporosis is unclear. Studies reporting an increased incidence of skin changes and cataract formation are difficult to interpret because of confounding variables and inadequate control groups. Further studies of the long-term side-effects of inhaled corticosteroids are now required to enable prescribers to judge better the relative benefits and risks of this important asthma therapy.

A comparative study of the effects of intranasal triamcinolone acetonide aerosol (ITAA) and prednisone on adrenocortical function

A comparison of adrenocortical function before and after treatment with either intranasal triamcinolone acetonide aerosol (ITAA), prednisone, or placebo was done. Sixty-two male subjects with allergic rhinitis were treated for 6 weeks with either ITAA (220 or 440 μg/day), oral prednisone (10 mg /day), or placebo in double-blind, parallel-group fashion. Adrenoeortical function was assessed by 6-hour cosyntropin stimulation before and at the end of the treatment period. The placebo-treated and two ITAA-treated groups produced no changes in adrenocortical function with treatment, and the ITAA-treated groups were not different from the placebo-treated group with mean ± SEM changes in stimulated plasma cortisol (micrograms per deciliter) as follows: placebo, −2.68 ± 1.77; ITAA 220 μg, −2.69 ± 1.18; ITAA 440 μg, −2.96 ± 1.81. The prednisone-treated group had a mean reduction in adrenocortical function (mean ± SEM change in stimulated plasma cortisol of −19.8 ± 1.77 μg/dl) that was significant (p < 0.0001) compared with that of the placebo-treated group. The results of this study indicate that 6 weeks of treatment with 220 14g1 day or 440 pg/day of ITAA has no effect on adrenocortical function, but prednisone, at a dosage of 10 mg /day for 6 weeks, produces partial adrenocortical suppression.

Effect of alcohol on the interaction of cortisol with plasma proteins, glucocorticoid receptors and erythrocytes

Alcohol ingestion stimulates glucocorticoid secretion in animals and normal men. It is generally believed that this effect is mediated through the pituitary-adrenal axis. To investigate its mechanism, we focussed on the effects of ethanol on cortisol binding to plasma proteins and to glucocorticoid receptors, and on cortisol uptake by erythrocytes. Addition of ethanol (up to 800 mg/dl) decreased cortisol binding to albumin and corticosteroid-binding globulin (CBG), causing an increase in the plasma unbound component. Ethanol also decreased cortisol binding to glucocorticoid receptors in normal human peripheral lymphocytes. The uptake of cortisol by erythrocytes was not affected at ethanol concentrations as high as 2000 mg/dl. These results provide new insight to ethanol effects in vivo. The stimulatory effect of ethanol on the pituitary-adrenal axis appears to be attributable in part to a relative ineffectiveness of cortisol in cortisol-responsive cells consequent to ethanol's ability to diminish cortisol binding, to glucocorticoid receptors. A compensatory increase in ACTH secretion in response to the relative hypoglucocorticoid state perceived by corticotrophs would result in maintenance of elevated plasma unbound cortisol and cytosol cortisol levels. We conclude that altered interactions of cortisol with its receptors and transport proteins could be pathophysiological components of the changes in adrenocortical function induced by ethanol ingestion.

Effect of alcohol on the interaction of cortisol with plasma proteins, glucocorticoid receptors, and erythrocytes

Abstract Alcohol ingestion stimulates glucocorticoid secretion in animals and normal men. It is generally believed that this effect is mediated through the pituitary-adrenal axis. To investigate its mechanism, we focussed on the effects of ethanol on cortisol binding to plasma proteins and to glucocorticoid receptors, and on cortisol uptake by erythrocytes. Addition of ethanol (up to 800 mg/dl) decreased cortisol binding to albumin and corticosteroid-binding globulin (CBG), causing an increase in the plasma unbound component. Ethanol also decreased cortisol binding to glucocorticoid receptors in normal human peripheral lymphocytes. The uptake of cortisol by erythrocytes was not affected at ethanol concentrations as high as 2000 mg/dl. These results provide new insight to ethanol effects in vivo . The stimulatory effect of ethanol on the pituitary-adrenal axis appears to be attributable in part to a relative ineffectiveness of cortisol in cortisol-responsive cells consequent to ethanol's ability to diminish cortisol binding, to glucocorticoid receptors. A compensatory increase in ACTH secretion in response to the relative hypoglucocorticoid state perceived by corticotrophs would result in maintenance of elevated plasma unbound cortisol and cytosol cortisol levels. We conclude that altered interactions of cortisol with its receptors and transport proteins could be pathophysiological components of the changes in adrenocortical function induced by ethanol ingestion.

Variable adrenocortical function in acute medical illness.

Acute medical illness may produce dramatic changes in endocrine function. Although cortisol levels rise in acute medical illness, changes in adrenocortical function and reserve have not been well documented in medical ICU patients. We evaluated plasma ACTH and cortisol levels, and cortisol response to intravenous ACTH in 40 acutely ill patients and 20 anxious but nonacutely ill controls. A wide range of plasma cortisol values (212 to 8430 nmol/L) was observed. More severely ill patients did not necessarily have higher plasma cortisol values. Patients who survived hospitalization had lower mean initial and post-ACTH cortisol levels than patients who succumbed. ACTH levels varied widely and correlated poorly with levels of plasma cortisol. There was no evidence of occult adrenocortical insufficiency. We conclude that plasma cortisol elevations are common in acute medical illness.

Seasonal changes in plasma and adrenal concentrations of cortisol, corticosterone, aldosterone, and electrolytes in the adult male sand rat ( Psammomys obesus)

Seasonal changes in adrenocortical function were studied in the adult male sand rat ( Psammomys obesus) live-trapped in the region of Béni-Abbès in the Algerian Sahara Desert. Cortisol was found to be the primary corticosteroid secreted in the sand rat. Plasma and adrenal concentrations of cortisol, corticosterone, and aldosterone exhibited marked significant annual variations mainly characterized by a decline during spring, a minimum in early summer, and an increase in autumn. In spite of the high sodium intake of this animal in the field, the aldosterone levels seemed similar to those of other mammals. Plasma sodium and potassium concentrations were relatively high in Psammomys obesus (respectively, about 150 and 8 m M) and, except for a slight increase in early summer, varied little throughout the year.

Changes in adrenocortical function and lipid metabolism during peripheral electrical nociceptive stimulation as a means of studying the antistress action of diazepam and activation of the positive reinforcement system

Experiments on rats showed that the self-stimulation (SS) response reduces the increase in the 11-hydroxycorticosteroid (11-HCS) concentration in blood after electrical nociceptive stimulation (ENS) of the limbs. Diazepam (1 mg/kg) reduced the liberation of 11-HCS and the β-lipoprotein concentration in response to SS and ENS and raised the phospholipid concentration. Diazepam and preliminary ENS evoked activation of SS. It is concluded that diazepam and activation of the positive reinforcement system act in the same direction with respect to 11-HCS excretion and the changes in lipid metabolism during ENS.

Opposing effects of deoxycorticosterone and spironolactone on isoprenaline-induced myocardial infarction.

Adult, male Sprague-Dawley rats were subjected to massive myocardial infarction with isoprenaline. Some of the animals were treated with the potent mineralocorticoid, deoxycorticosterone, or the anti-mineralocorticoid, spironolactone. Autopsies spaced at sequential time intervals demonstrated that circulating levels of enzymes, eg, CPK, SGOT, SGPT and LDH, lipids, eg, triglycerides, free fatty acids, and cholesterol, glucose, Bun, and corticosterone rose in conjunction with on-going necrosis and became lowered in conjunction with myocardial repair. Body and organ weights, ie, adrenal, thymus, heart, and kidney, underwent dynamic changes commensurate with necrosis and repair. Animals given isoprenaline alone died (52% survival) during the height of their massive infarct and congestive heart failure (Days 3 and 4). Animals treated with DOC showed the most severe congestion but died (36% survival) during the late repair phase (Days 7 and 8). Animals treated with spironoloactone showed the most effective clearance of thoracic fluid and also dies (18% survival) during the late repair phase (Days 7 and 8). These spironolactone-treated animals had large, left ventricular aneurysms with organised, adherent thrombi. It is believed that alterations in electrolyte balance induced by DOC or spironolactone caused changes in adrenocortical function which greatly modified the usual pathophysiological response to myocardial infarction.

Changes in adrenocortical function precede the onset of persistent estrus in rats exposed to constant light before puberty.

The purpose of this study was to determine whether changes in adrenal function precede the onset of persistent estrus in rats undergoing exposure to constant light either from birth (LL) or after weaning age (S-LL-shift to LL from a 14 h light, 10 h dark photoperiod). Serum corticosterone shifts in response to a two minute ether stress administered at 0800 h at 25, 50 or 100 days of age were compared in LL, S-LL and LD (reared from birth in 14:10) rats. The patterns of serum corticosterone were comparable in all three groups at 25 days of age. At 50 days of age, the S-LL rats had higher basal corticosterone and showed an earlier stress response which persisted for 2 h while the other two groups showed a slower response that peaked at the 30 mm sample period and then fell to baseline by 60 mm. At 100 days of age, the LD rats continued to show a slower rise and more rapid fall while both LL exposed groups had higher basal levels, a more rapid response and persistent elevation past 60 mm. This difference in the appearance of a deviant stress pattern was associated with the onset of persistent estrus which began at 100 days of age in the S-LL rats and at 150 days in the LL rats. It therefore appears that changes in adrenocortical function precede the loss of ovulatory cycles in both LL-reared groups and that these changes (elevated basal corticosterone and a prolonged stress response) emerge earlier in the S-LL groups which developed persistent estrus earlier.

Ovarian and adrenal steroids during pregnancy and the oestrous cycle in the rat.

Changes in adrenocortical function of the rat during the 4-day oestrous cycle and pregnancy were studied in vivo and in vitro. Regulation of adrenal production of progesterone and corticosterone was of particular interest. Morning (09.00 h) plasma concentrations of corticosterone were similar at each phase of the cycle, but a higher concentration was found in the afternoon (15.00 h pro-oestrus). However, the rate of progesterone utilization for corticosterone production by adrenal homogenates was essentially unchanged at all periods of the cycle. Therefore, the activities of the 21- and 11β-hydroxylating systems appeared not to be important determinants of plasma corticosterone levels (coefficient of determination (r2) = 0·06). These results indicate that adrenal secretion of progesterone is not specifically regulated during the cycle. On the other hand, resting plasma levels of corticosterone declined by 80–85% from the value on the morning of pro-oestrus between days 5 and 12 of pregnancy and then increased on day 22 and after parturition. These fluctuations did not result from alterations in the rate of metabolic clearance but rather, were closely coupled to the capacity of adrenal tissue to convert progesterone to corticosterone (r2 = 0·87). These findings suggest that progesterone utilization may be specifically curtailed at the expense of corticosterone production at days 5 and 12 of pregnancy. Concurrent measurements of adrenal venous progesterone and ovarian venous progesterone (under stressful conditions) showed that the adrenal gland secretes 2–10 times more progesterone than the ovary at all stages of the oestrous cycle, on day 22 of pregnancy, and on the first day of lactation. Thus, the adrenal gland is capable of secreting large amounts of progesterone which, if present at the appropriate time, may inhibit, delay or facilitate ovulation and onset of mating behaviour as described by other workers. Under such circumstances, however, progesterone secretion appears not to be specifically regulated but seems instead to be due to precursor spillover, since the proportionate secretion of corticosterone does not change.

Cortisol secretion in acidotic and nonacidotic diabetes mellitus.

Acute changes in adrenocortical function were assessed by a method which permits simultaneous determination of cortisol and short-term cortisol secretion rates from specific activities in serum. Four children were studied during the first two hours of their initial hospitalization for impending ketoacidosis. Three were acidotic (plasma bicarbonate [unk] 19 mEq/liter); two of these were restudied one week later following stabilization of their disease. In all six studies cortisol secretion rate was directly correlated to the degree of acidosis ( r =.96), being high in the presence of, but normal in the absence or following correction of, acidosis. These studies document the magnitude of adrenal response to the stress of diabetic ketoacidosis. The consistent presence of normal cortisol secretion rate in diabetic children without acidosis argues against the contention that increased cortisol secretion is a factor in the pathogenesis of juvenile diabetes mellitus.

Pituitary-Adrenal Activity During Psychosis and Depression

Publisher Summary This chapter focuses on pituitary–adrenal activity during psychosis and depression. The most common reaction is a depressive reaction and the psychiatric symptoms almost always remit with successful treatment of the condition. In Addison's disease, psychiatric symptoms are also prominent; depression, apathy, and irritability are among the most common symptoms. These symptoms also improve with adequate therapy. There is evidence of a small increase in adrenocortical activity in depressive illness but not in mania, and usually, the increase is of the same order as the increase occasioned by admission to a psychiatric hospital. Some patients show little change during recovery from a depressive illness and a marked increase in adrenocortical activity is by no means an invariable accompaniment of a depressive illness. There are also reports that adrenalectomized patients on fixed doses of steroids may suffer depression that will respond to electroconvulsive treatment or antidepressant medication. Changes in adrenocortical function have a primary place in the etiology of most cases of affective disorders.

Correlation of anxiety and hostility with adrenocortical function.

DURING THE COURSE of their disease, patients with bronchogenic carcinoma manifest adrenocortical hyperfunction as measured by several parameters. One of the most notable indices of this hyperactivity appears to be the concentration of morning plasma unconjugated 17-hydroxycorticosteroids (17-OHCS) which increase as the disease progresses and the interval to death shortens. Although several metabolic aspects might be suspected of influencing the adrenocortical status of these seriously ill patients, a possible factor to be considered is their emotional state, as numerous studies of patients with cancer have indicated a wide range of emotional response. Of the many emotional factors to be considered, anxiety has been most closely associated with changes in adrenocortical function, 1, 2 probably through neuroendocrine pathways affecting corticotrophin release. The purpose of the present study has been to explore this possible relationship by correlating plasma 17-OHCS levels with anxiety in patients with and without lung cancer. The factor