Impaired Adrenal Response Research Articles

CIRMI—a new term for a concept worthy of further exploration: a narrative review

Background and ObjectiveCritical illness-related corticosteroid insufficiency (CIRCI) describes hypothalamic-pituitary-axis impairment during critical illness associated with three major pathophysiological events; dysregulation of the hypothalamic-pituitary-axis, altered cortisol metabolism, and tissue corticosteroid resistance. Similar changes are evident with regard to mineralocorticoid dysfunction in critical illness. Hyperreninemic hypoaldosteronism describes a sub-population of critically ill patients with an impaired adrenal aldosterone response to increased levels of renin. In the light of the recent demonstration of significant mortality improvements associated with adjunctive glucocorticoid treatment in combination with fludrocortisone in septic shock, and the suggestion that angiotensin II is effective in treating vasodilatory shock, the clinical relevance of mineralocorticoid dysfunction in critical illness requires further exploration. This interpretative review considers hyperreninemic hypoaldosteronism, a concept worth re-examining in the light of the potential mortality benefit of mineralocorticoid supplementation in critical illness. We compare the pathophysiological and clinical characteristics of CIRCI and hyperreninemic hypoaldosteronism, two syndromes that represent corticosteroid and mineralocorticoid dysfunction in critical illness. We highlight gaps in the literature and give novel insights into the limitations of assessment, diagnosis and treatment.MethodsEnglish language abstracts and articles published before June 2021 were identified through PubMed and Google Scholar. Randomized trials, observational studies, basic sciences studies, systematic and narrative reviews were considered. Reference lists of articles were searched for further relevant material.Key Content and FindingsDifficulties are encountered in interpreting measures of gluco- and mineralo-corticoid activity in critical illness. Aldosterone levels, like cortisol, have been shown to be increased in sepsis and hemorrhagic shock. The finding of hyperreninemia and hyperaldosteronism with an aldosterone/plasma renin activity ratio below 2 should prompt consideration of hyperreninemic hypoaldosteronism, a finding, which likely signifies the loss of negative feedback control of the renin-angiotensin-aldosterone system.ConclusionsAs there is evidence to suggest that in acute critical illness, hyperreninemic hypoaldosteronism, is associated with poor outcomes, co-administration of hydrocortisone with fludrocortisone in patients with septic shock should be considered. In keeping with the concept of CIRCI, we suggest the term critical illness-related mineralocorticoid insufficiency as a more appropriate description of the impaired aldosterone response to increased levels of renin seen in this group of patients.

Mineralocorticoid Dysfunction during Critical Illness: A Review of the Evidence.

The recent demonstration of the significant reduction in mortality in patients with septic shock treated with adjunctive glucocorticoids combined with fludrocortisone and the effectiveness of angiotensin II in treating vasodilatory shock have renewed interest in the role of the mineralocorticoid axis in critical illness. Glucocorticoids have variable interactions at the mineralocorticoid receptor. Similarly, mineralocorticoid receptor-aldosterone interactions differ from mineralocorticoid receptor-glucocorticoid interactions and predicate receptor-ligand interactions that differ with respect to cellular effects. Hyperreninemic hypoaldosteronism or selective hypoaldosteronism, an impaired adrenal response to increasing renin levels, occurs in a subgroup of hemodynamically unstable critically ill patients. The suggestion is that there is a defect at the level of the adrenal zona glomerulosa associated with a high mortality rate that may represent an adaptive response aimed at increasing cortisol levels. Furthermore, cross-talk exists between angiotensin II and aldosterone, which needs to be considered when employing therapeutic strategies.

Hypotension following Patent Ductus Arteriosus Ligation: The Role of Adrenal Hormones

To test the hypothesis that an impaired adrenal response to stress might play a role in the hypotension that follows patent ductus arteriosus (PDA) ligation. We performed a multicenter study of infants born at <32weeks' gestation who were about to undergo PDA ligation. Serum adrenal steroids were measured 3 times: before and after a cosyntropin (1.0μg/kg) stimulation test (performed before the ligation), and at 10-12hours after the ligation. A standardized approach for diagnosis and treatment of postoperative hypotension was followed at each site. A modified inotrope score (1×dopamine [μg/kg/min]+1×dobutamine) was used to monitor the catecholamine support an infant received. Infants were considered to have catecholamine-resistant hypotension if their greatest inotrope score was >15. Of 95 infants enrolled, 43 (45%) developed hypotension and 14 (15%) developed catecholamine-resistant hypotension. Low postoperative cortisol levels were not associated with the overall incidence of hypotension after ligation. However, low cortisol levels were associated with the refractoriness of the hypotension to catecholamine treatment. In a multivariate analysis: the OR for developing catecholamine-resistant hypotension was OR 36.6, 95% CI 2.8-476, P=.006. Low cortisol levels (in infants with catecholamine-resistant hypotension) were not attributable to adrenal immaturity or impairment; their cortisol precursor concentrations were either low or unchanged, and their response to cosyntropin was similar to infants without catecholamine-resistant hypotension. Infants with low cortisol concentrations after PDA ligation are likely to develop postoperative catecholamine-resistant hypotension. We speculate that decreased adrenal stimulation, rather than an impaired adrenal response to stimulation, may account for the decreased production.

Impaired Glucocorticoid Production and Response to Stress in Arntl-Deficient Male Mice

The basic helix-loop-helix transcription factor Aryl Hydrocarbon Receptor Nuclear Translocator-Like (ARNTL, also known as BMAL1 or MOP3) is a core component of the circadian timing system in mammals, which orchestrates 24-hour rhythms of physiology and behavior. Genetic ablation of Arntl in mice leads to behavioral and physiological arrhythmicity, including loss of circadian baseline regulation of glucocorticoids (GCs). GCs are important downstream regulators of circadian tissue clocks and have essential functions in the physiological adaptation to stress. The role of the clock machinery in the regulation of stress-induced GC release, however, is not well understood. Here we show that already under unstressed conditions Arntl-deficient mice suffer from hypocortisolism with impaired adrenal responsiveness to ACTH and down-regulated transcription of genes involved in cholesterol transport in adrenocortical cells. Under stress they show diminished GC and behavioral responses and develop behavioral resistance to acute and subchronic stressors, as shown using forced swim, tail suspension, and sucrose preference tests. These data suggest that the clock gene Arntl regulates circadian and acute secretion of GCs by the adrenal gland. Arntl disruption, probably via its effect on adrenal clock function, modulates stress axis activity and, thus, may promote resistance to both acute and repeated stress.

Hydrocortisone Reduces the Beneficial Effects of Toll-Like Receptor 2 Deficiency on Survival in a Mouse Model of Polymicrobial Sepsis

Toll-like receptors (TLRs) play a crucial role in early host defense against microorganisms. Toll-like receptor 2 (TLR2) polymorphisms have a prevalence of 10%; functional defects of TLR2 are associated with higher susceptibility toward gram-positive bacteria, and TLR2 deficiency has been associated with an impaired adrenal stress response. In the present study, we compared endogenous corticosterone production of wild-type (WT) and TLR2-deficient (TLR2) mice and analyzed survival after hydrocortisone therapy during sepsis induced by cecal ligation and puncture (CLP). Male C57BL/6J (WT); and B6.129-Tlr2tm1Kir/J (TLR2) mice were subjected to CLP or sham operation and randomly assigned to postoperative treatment with either hydrocortisone (5 mg/kg) or vehicle (n = 10 mice/group). Survival was documented for an observation period of 48 h. Endogenous corticosterone production following hydrocortisone treatment and lipoteichoic acid (LTA) exposure, interleukin 6 (IL-6) and IL-1β plasma levels, and blood counts were determined following sham operation or CLP using another n = 5 mice/group. Statistical analysis was performed using analysis of variance/Bonferroni. TLR2 mice exhibited a lack of suppression and an attenuated increase in endogenous corticosterone production following hydrocortisone or LTA treatment, respectively. After CLP, TLR2 mice exhibited an uncompromised adrenal stress response, higher IL-6 levels, and increased survival compared with WT controls (75 vs. 35%; P < 0.05). Hydrocortisone therapy of TLR2 mice completely abolished this advantage (decrease in survival to 45%, P < 0.05 vs. vehicle-treated TLR2 mice) and was associated with decreased IL-1β plasma concentrations. Toll-like receptor 2 deficiency is associated with an uncompromised adrenal stress response and increased survival rates during polymicrobial sepsis. Hydrocortisone treatment increases mortality of septic TLR2 mice, suggesting that hydrocortisone therapy might be harmful for individuals with functional TLR2 polymorphisms.

Adrenal suppression in bronchiectasis and the impact of inhaled corticosteroids

The present study identified three patients with bronchiectasis receiving inhaled corticosteroids (ICSs) who had symptomatic adrenal suppression secondary to ICS. The prevalence of adrenal suppression is unknown in bronchiectasis. The frequency of adrenal suppression and the impact of ICS use in bronchiectasis patients were examined. In total, 50 outpatients (33 receiving ICSs) underwent a short Synacthen test and completed a St George's Respiratory Questionnaire (SGRQ). Symptoms of adrenal suppression, steroid use and lung function were compared between subjects who were suppressed and those who were not. Adrenal suppression was evident in 23.5% of subjects who did not receive ICSs and 48.5% of those who did. Basal cortisol and the increments by which cortisol increased 30 min after Synacthen were lower in suppressed than in nonsuppressed subjects. The incremental cortisol rise was negatively correlated with SGRQ impacts and total score, suggesting a worse quality of life in those who had an impaired adrenal response. The greatest frequency of generalised symptoms was seen in the suppressed group. A significant proportion of subjects with bronchiectasis have evidence of adrenal suppression, and this is increased when inhaled corticosteroids are also used. Impairment of the cortisol response to stimulation is associated with poorer health status.

Impairment in insulin sensitivity after early androgenization in the post-pubertal female rat

A link is known to exist between hyperandrogenicity and insulin resistance in mammals. We explored whether androgenization, early in reproductive life, in the female rat has any impact on later peripheral insulin sensitivity and parametrial (PM) fat function. Female, 60 day-old, rats were injected (i.m.) with 100 μl of sterile corn oil either alone (CT) or containing 2 mg of testosterone propionate (TP); rats were then used for experimentation at age 120 days. Daily food intake and body weight were recorded. Different groups of CT and TP rats were subjected to a high glucose load test or 24 h fasting for evaluation of changes in circulating levels of several metabolites and body composition. In vitro experiments were run to study the impact of androgenization on isolated PM adipocyte response to insulin. Finally, the direct effect of testosterone on insulin-induced leptin secretion by normal PM adipocytes was also evaluated. Androgenization induced a significant increase in daily food intake and body weight for the first 20 days after treatment. In vivo experiments indicate that TP rats released more ( P < 0.05) insulin than CT animals after high glucose load in order to maintain similar circulating glucose levels, a characteristic accompanied by decreased ( P < 0.05) overall corticoadrenal response in TP rats. Several metabolic responses to fasting were similar in both groups, although impaired adrenal response and changes in body composition were observed only in TP rats. Interestingly, cultured PM adipocytes from TP rats were less ( P < 0.05) sensitive than CT cells to insulin-induced leptin secretion. Also, we found that 48 h exposure of normal PM adipocytes to high testosterone concentration also impaired adipocyte endocrine function. Our study strongly supports that development of insulin resistance, in the female gender, can be established after an early, even transient, hyperandrogenemia.

Toll-like receptor 4 plays a crucial role in the immune–adrenal response to systemic inflammatory response syndrome

Sepsis and septic shock are leading killers in the noncoronary intensive care unit, and they remain worldwide health concerns. The initial host defense against bacterial infections involves Toll-like receptors (TLRs), which detect and respond to microbial ligands. In addition, a coordinated response of the adrenal and immune systems is crucial for survival during severe inflammation. Previously, we demonstrated a link between the innate immune system and the endocrine stress response involving TLR-2. Like TLR-2, TLR-4 is also expressed in human and mouse adrenals. In the present work, by using a low dose of LPS to mimic systemic inflammatory response syndrome, we have revealed marked cellular alterations in adrenocortical tissue and an impaired adrenal corticosterone response in TLR-4-/- mice. Our findings demonstrate that TLR-4 is a key mediator in the crosstalks between the innate immune system and the endocrine stress response. Furthermore, TLR polymorphisms could contribute to the underlying mechanisms of impaired adrenal stress response in patients with bacterial sepsis.

Toll-like receptor 4 plays a crucial role in the immune-adrenal response to endotoxemia

Sepsis and septic shock are leading killers in the non-coronary intensive care unit and still remain worldwide health concerns. The initial host' defense to bacterial infections involves Toll-like receptors (TLRs), which detect and respond to microbial ligands. In addition, a coordinated response of the adrenal and immune system is crucial for survival during severe inflammation. Previously, we have demonstrated a novel link between the innate immune system and the endocrine stress response involving TLR-2. Like TLR-2, TLR-4 is also expressed in human and mice adrenals. In the present study following LPS-induced stress, we have revealed marked cellular alterations in adrenocortical tissue and an impaired adrenal corticosterone response in TLR-4-/- mice. Our findings demonstrate that TLR-4 is a key mediator in the cross-talk between the innate immune system and the endocrine stress response. Furthermore, TLR polymorphisms could contribute to the underlying mechanisms of impaired adrenal stress response in patients with bacterial spepsis.

Impaired adrenal stress response in Toll-like receptor 2-deficient mice

Septicemia is one of the major health concerns worldwide, and rapid activation of adrenal steroid release is a key event in the organism's first line of defense during this form of severe illness. The family of Toll-like receptors (TLRs) is critical in the early immune response upon bacterial infection, and TLR polymorphisms are frequent in humans. Here, we demonstrate that TLR-2 deficiency in mice is associated with reduced plasma corticosterone levels and marked cellular alterations in adrenocortical tissue. TLR-2-deficient mice have an impaired adrenal corticosterone release after inflammatory stress induced by bacterial cell wall compounds. This defect appears to be mediated by a decrease in systemic and intraadrenal cytokine expression, including IL-1, tumor necrosis factor alpha, and IL-6. Our data demonstrate a link between the innate immune system and the endocrine stress response. The critical role of TLR-2 in adrenal glucocorticoid regulation needs to be considered in patients with inflammatory disease.

Adrenal function during coronary artery bypass grafting.

To assess adrenal function in patients undergoing coronary artery bypass grafting (CABG) by means of the low-dose (1 microg) ACTH test, and to correlate the adrenal function with clinical outcome. During a 5-Month period we prospectively included 45 patients undergoing elective CABG with cardiopulmonary bypass and without symptoms of endocrine disease. Low-dose (1 microg) ACTH tests were performed on the day before surgery (day -1), immediately after the operation (day 0), on the two subsequent days in the intensive care unit (day 1 and day 2), and on the day of discharge from the hospital. A number of clinical, hemodynamic and laboratory parameters were monitored throughout. On day -1, 75% of the study patients had normal stimulated plasma cortisol concentrations. Eleven patients (25%) had an impaired adrenal response to 1 microg ACTH. The stimulated plasma cortisol concentrations in patients who had an inadequate adrenal response on day -1 remained significantly reduced on day 1 (756+/-205 vs 949+/-259 nmol/l, P=0.03) (mean+/-s.d.), day 2 (644 (580-793) vs 885 (713-1087), P=0.03) (median (interquartile range)), and on the day of discharge (698+/-201 vs 854+/-186, P=0.05). In patients with a normal adrenal response in the preoperative setting peak cortisol concentrations were reached on day 1, in patients with a blunted adrenal response they were reached on day 2. There were significant correlations between the stimulated plasma cortisol concentrations and the blood loss (r=-0.50, P=0.002) and Volume balance (r=0.41, P=0.015). Occult (partial) adrenal insufficiency is common in patients undergoing CABG who are otherwise asymptomatic as regards endocrine disease. The adrenal function in these patients differs both in the magnitude of cortisol response to ACTH and in the time course, with significantly delayed peak cortisol concentrations. Adequate regulation of Volume balance and the amount of blood loss seem to correlate with adequacy of adrenal function.

The expression of the ACTH receptor.

Adrenal glucocorticoid secretion is regulated by adrenocorticotropic hormone (ACTH) acting through a specific cell membrane receptor (ACTH-R). The ACTH-R is a member of the G protein superfamily-coupled receptors and belongs to the subfamily of melanocortin receptors. The ACTH-R is mainly expressed in the adrenocortical cells showing a restricted tissue specificity, although ACTH is recognized by the other four melanocortin receptors. The cloning of the ACTH-R was followed by the study of this gene in human diseases such as familial glucocorticoid deficiency (FGD) and adrenocortical tumors. FGD is a rare autosomal recessive disease characterized by glucocorticoid deficiency, elevated plasma ACTH levels and preserved renin/aldosterone secretion. This disorder has been ascribed to an impaired adrenal responsiveness to ACTH due to a defective ACTH-R, a defect in intracellular signal transduction or an abnormality in adrenal cortical development. Mutations of the ACTH-R have been described in patients with FGD in segregation with the disease. The functional characterization of these mutations has been prevented by difficulties in expressing human ACTH-R in cells that lack endogenous melanocortin receptor activity. To overcome these difficulties we used Y6 cells, a mutant variant of the Y1 cell line, which possesses a non-expressed ACTH-R gene allowing the functional study without any background activity. Our results demonstrated that the several mutations of the ACTH-R found in FGD result in an impaired cAMP response or loss of sensitivity to ACTH stimulation. An ACTH-binding study showed an impairment of ligand binding with loss of the high affinity site in most of the mutations studied.

Hypothalamo–Pituitary–Adrenal Axis Responses to Lipopolysaccharide in Male and Female Rats with Adjuvant-Induced Arthritis

We have previously demonstrated that rats with adjuvant-induced arthritis (AA) are unable to mount a hypothalamo–pituitary–adrenal (HPA) axis response to either psychological or physical stress. In the present study we have taken male and female rats with AA and injected these with lipopolysaccharide (LPS) as an acute immune challenge and assessed the effects of this challenge at all levels of the HPA axis. We have demonstrated that, in contrast to acute stress, there is an activation of the HPA axis in male AA rats in response to acute immune challenge which occurs at all levels of the HPA axis. The hypothalamic and pituitary response to LPS is intact in the female AA rat. However, there appears to be an impaired adrenal responsiveness in the AA female given LPS. The non-AA female is able to respond to LPS suggesting that this defect is not inherent but is a reaction to the development of inflammation. This hyporesponsiveness has major implications for the ability of the organism to survive infections or immune challenges which are potentially life threatening in the absence of release of anti-inflammatory glucocorticoids from the adrenal cortex. The implications of these changes in the female on the subsequent development of the disease and the mechanisms mediating these effects may provide a better understanding of the gender differences underlying susceptibility to autoimmune diseases.

Differential effects of psychological and immunological challenge on the hypothalamo-pituitary-adrenal axis function in adjuvant-induced arthritis.

Inability to mount a suitable glucocorticoid response to a stressor can be life-threatening. Rats with hind-paw inflammation, associated with the development of adjuvant-induced arthritis (AA), are unable to mount a hypothalamo-pituitary-adrenal (HPA) axis response to acute stress. In the present study we have compared the effects of acute psychological stress (noise) and acute immunological challenge (lipopolysaccharide [LPS] injection), on the activation of the HPA axis in rats with the chronic inflammatory stress of AA. We conclude that the increase in HPA axis activity in AA is principally due to an increase in corticosterone pulse frequency and not to any alteration in pulse magnitude. The lack of response to acute stress can be accounted for by the increase in pulse frequency and the associated refractory period following each pulse, producing dramatic but specific changes in basal HPA function. These changes may account for the loss of responsiveness to acute stress, but not to acute immunological challenge, because the HPA axis is able to respond to LPS in male rats with AA. However, there appears to be an impaired adrenal responsiveness in female rats with AA that is not inherent, but occurs as a consequence of the development of inflammation.

Plasma 18-hydroxycorticosterone and aldosterone responses to angiotensin II and corticotropin in diabetic patients with hyporeninemic and normoreninemic hypoaldosteronism

To examine the nature of adrenal abnormalities in diabetic patients with hyporeninemic and normoreninemic hypoaldosteronism, responses of plasma 18-hydroxycorticosterone and plasma aldosterone to angiotension II infusions and ACTH injection were investigated in 8 diabetic patients with hyporeninemic hypoaldosteronism and 9 diabetic patients with normoreninemic hypoaldosteronism compared to 11 control subjects. In both the patients with hyporeninemic and normoreninemic hypoaldosteronism, plasma 18-hydroxycorticosterone and plasma aldosterone were low, whereas plasma cortisol and plasma corticosterone were within normal ranges. Percent increments of plasma 18-hydroxycorticosterone and plasma aldosterone above their baseline levels after angiotensin II infusions were low or somewhat low in the patients with hyporeninemic hypoaldosteronism and low in the patients with normoreninemic hypoaldosteronism. Percent increments of plasma 18-hydroxycorticosterone and plasma aldosterone above their baseline levels after ACTH injection were similar in three groups. These results suggest that in diabetic patients with isolated hypoaldosteronism, the adrenal abnormality, regardless of whether it is primary or secondary, is mainly due to impaired adrenal responsiveness to angiotension II and atrophy and the zona glomerulosa.

The cortisol response to corticotrophin-releasing factor is blunted in obesity.

Abnormalities of the adrenal cortex may be associated with extreme obesity but there is little information about hypothalamic-pituitary function. We have investigated this by measuring plasma ACTH and cortisol responses to ovine corticotrophin releasing factor (CRF-41), 0.5 microgram/kg/body weight, in 10 obese women and seven age-matched normal weight women. The cortisol response to insulin-induced hypoglycaemia and intravenous synacthen (2.5 ng/kg/body weight) were also measured on different occasions in some of the subjects. The peak ACTH response to CRF was less in the obese but this was not significant (obese ACTH +/- SEM, 31 +/- 4 ng/l, controls 39 +/- 4 ng/l) whereas the peak cortisol was significantly reduced in the obese (obese cortisol, 456 +/- 21 nmol/l, controls 638 +/- 50 nmol/l). Doubling the dose of CRF did not significantly alter either ACTH or cortisol responses in six of the obese patients. The peak cortisol response to symptomatic hypoglycaemia and following i.v. low dose synacthen stimulation was similar in the obese and normal weight women. We conclude that obese women have a normal cortisol response to hypothalamic-pituitary stimulation by hypoglycaemia and direct adrenal stimulation by synacthen but an impaired adrenal response to pituitary stimulation with CRF. Although the explanation for these findings is uncertain, our study underlines the importance of considering an individual's body weight when assessing the cortisol response to CRF stimulation.

Impaired adrenal vascular response to hemorrhagic hypotension by an adreno-femoral venous shunt

We studied the influence of an adreno-femoral venous shunt on the regional blood flow in the dog adrenal gland during hemorrhagic hypotension. An adreno-femoral venous shunt was placed transperitoneally in the left adrenal gland while the animal was under pentobarbital anesthesia. The right adrenal gland was left intact. Hemorrhagic hypotension was induced at 50 mm Hg mean arterial blood pressure for 1 hr in six dogs and the other six dogs served as normotensive controls. Nonradioactive microspheres (2 × 10 6, 15 ± 2 μm) were injected into the ventricle. The adrenal cortical and medullary blood flows were estimated by microscopic counting of the microspheres in the serially sectioned adrenal gland. The total adrenal blood flow (sum of the cortical and medullary blood flows) of two methods was compared; the microsphere method vs timed venous sampling through the shunt. In the intact right adrenal gland, the cortical blood flow was significantly decreased, but the medullary blood flow remained unchanged during hemorrhagic hypotension. Subsequently the total adrenal blood flow was not significantly decreased. In the cannulated left adrenal gland, both the cortical and medullary blood flows were significantly decreased and adrenal vascular autoregulation was inhibited. The total adrenal blood flow calculated by the microsphere method showed a significant correlation with that by timed venous sampling through the shunt. These results indicate that the adrenal medullary vasculature autoregulates during hemorrhagic hypotension and that an adreno-femoral venous shunt abolishes this vascular response.

Corticotropin versus hydrocortisone in the intravenous treatment of ulcerative colitis: A prospective, randomized, double-blind clinical trial

Sixty-six patients hospitalized for ulcerative colitis were treated in a prospective, double-blind, clinical trial. They received either 120 U/day of intravenous corticotropin or 300 mg/day of intravenous hydrocortisone. Patients were randomized within strata defined by whether they had received oral corticosteroids continuously for at least 30 days before the study (group A, 35 patients), or whether they had received no such prior treatment (group B, 31 patients). Twenty-eight of the 66 patients (42%) achieved remission. In group B, the proportion of patients entering remission was greater with corticotropin than with hydrocortisone (63% vs. 27%, 0.025 < p < 0.05). The opposite trend was observed within group A, for whom hydrocortisone appeared more effective (53% vs. 25%, 0.05 < p < 0.10). Impaired adrenal responsiveness, as measured by serum cortisol and dehydroepiandosterone-sulfate levels, did not explain the different responses to therapy within the two study groups. Twenty of 28 patients whose acute therapy was successful were still in remission 1 yr after study. These data suggest that, at the doses used, intravenous corticotropin therapy of severe ulcerative colitis is the more effective choice for those patients not previously treated with corticosteroids, while intravenous hydrocortisone seems preferable for patients already receiving steroid treatment.

Effect of alternate-day steroid administration on adrenal function in allergic children

Twenty-four allergic children were given equivalent high and low doses of dexamethasone and prednisone on an alternate-day schedule, and adrenal function was determined by adrenocorticotropic hormone (ACTH) response tests before and at the end of each treatment period. Adrenal suppression was not demonstrated in prednisone-treated patients but did occur in those taking the larger dose of dexamethasone. Adrenal response tests with synthetic ACTH were done in another group of 24 asthmatic children who had required alternate-day prednisone for periods of 6 to 42 months. Only one patient of the group had impaired adrenal responsiveness. It is concluded that, in equivalent doses, prednisone has less adrenal suppressive activity than does dexamethasone and that long-term alternate-day prednisone administration in the doses used does not ordinarily produce an impaired adrenal response to exogenous ACTH.

A fundamental defect of adrenocortical control in Cushing's disease.

SUMMARY The plasma sugar, 11-hydroxycorticosteroid, and growth hormone responses to insulin have been studied in patients with Cushing's disease. They showed an impaired or absent plasma 11-hydroxycorticosteroid and growth hormone rise during the test, as compared with control subjects, despite the injection of amounts of insulin which produced a similar degree of hypoglycaemia. This test proved of value in differentiating between these patients and those with 'simple ' obesity since the latter usually showed a normal growth hormone and adrenal response provided an adequate amount of insulin was administered. The patients with Cushing's disease also had an impaired adrenal response to pyrogen and to dexamethasone administration and failed to show a normal plasma 11-hydroxycorticosteroid circadian rhythm. Their response to corticotrophin, lysine vasopressin, and metyrapone, however, was normal or enhanced. It is suggested that these findings imply an abnormality of hypothalamic or cerebral control and not a primary defect of pituitary function as proposed originally by Harvey Cushing. The growth hormone response to insulin remained impaired in four out of six patients totally adrenalectomized for Cushing's disease but was normal in three patients adrenalectomized for other reasons. It is suggested that the defect which impairs the adrenal response to insulin may, on occasions, also impair the mechanism normally operative for growth hormone secretion.