Combined treatment with corticosteroids and moclobemide favors normalization of hypothalamo-pituitary-adrenal axis dysregulation in relapsing-remitting multiple sclerosis: a randomized, double blind trial

Hyperresponsiveness of the hypothalamo-pituitary-adrenal (HPA) axis in multiple sclerosis (MS), an autoimmune inflammatory disease of the central nervous system, is presumably due to diminished corticosteroid receptor function. It probably influences the immune response, but its clinical significance is not clear. Similar HPA dysregulation occurs in depression and is reversible with successful antidepressant treatment. We conducted a double blind, placebo-controlled trial to evaluate the neuroendocrine effect of cotreatment with the antidepressant moclobemide as an adjunct to oral corticosteroids in MS. Twenty-one patients with definite relapsing-remitting MS (11 females, aged 33.9 +/- 2.0 yr; Expanded Disability Status Scale score of neurological impairment, 2.0--6.5) in acute relapse were treated with placebo (n = 13) or 300 mg moclobemide (reversible monoamine oxidase A inhibitor; n = 8) for 75 days. All received oral fluocortolone from day 7 on, and the dose was tapered until day 29. Effects were evaluated using the combined dexamethasone-CRH test and clinically on days 1, 30, and 75. At baseline, the HPA axis was mildly activated, comparably for treatment groups [area under the curve for cortisol (AUC-Cort), 213.8 +/- 76.8 arbitrary units in the moclobemide group vs. 225.8 +/- 65.1 in the steroid alone group; mean +/- SEM]. In a group of healthy controls with comparable demographic characteristics, the AUC-Cort was 107.4 +/- 14.1. Moclobemide cotreatment resulted in normalization of the HPA axis response, whereas the HPA system hyperresponse was maintained with steroids alone (AUC-Cort on day 30, 85.9 +/- 22.8 vs.177.1 +/- 68.5; on day 75, 111.0 +/- 46.0 vs. 199.2 +/- 64.6). The change in Expanded Disability Status Scale was comparable for both groups. Although corticosteroids alone had no effect on the HPA response using the dexamethasone-CRH test, treatment with moclobemide combined with corticosteroids favors normalization of the HPA response in relapsing-remitting MS.     

Effect of periconceptional undernutrition and gender on hypothalamic-pituitary-adrenal axis function in young adult sheep

Glucocorticoids are proposed to act as intermediary factors that transcribe the developmental programming sequelae of maternal nutrient restriction (NR). Periconceptional under-nutrition of sheep markedly activates fetal hypothalamic-pituitary-adrenal (HPA) axis activity leading to preterm birth, while transient undernutrition during late gestation in sheep programs adult HPA axis function. To date, no study has examined resting or stimulated HPA axis function in young adult offspring following a periconceptional nutritional challenge. In the present study, 20 ewes were either periconceptionally undernourished (50% metabolisable energy requirements from days 1 to 30 gestation; NR, n = 8) or fed to control levels (100% requirement; controls, n = 12) to term (147 days gestation). Ewes were blood sampled remotely at 2 and 30 days using automated blood sampling equipment. Thereafter, offspring (controls, n = 6/6 males/females; NR, n = 4/4 males/females) were reared to 1 year of age and on separate days received either an i.v. corticotrophin-releasing hormone (CRH; 0.5 microg/kg) and vasopressin (AVP; 0.1 microg/kg) challenge or a synthetic ACTH i.v. bolus (Synacthen; 1.25 microg/kg), and blood samples were taken (manually and remotely) at appropriate intervals for measurement of plasma ACTH and cortisol accordingly. Resting plasma cortisol, assessed remotely, was similar in ewes during undernutrition (control 18.3 +/- 1.4 vs NR 23.4 +/- 1.9 nmol/l) and in offspring at 4 months of age (control male 17.6 +/- 2.9; control female 17.2 +/- 0.4, NR male 16.5 +/- 3.1, NR female 21.7 +/- 4.0 nmol/l). At 12 months of age, however, resting plasma cortisol was significantly increased in NR females (control male 28.0 +/- 1.5, control female 32.9 +/- 9, NR male 32 +/- 7, NR female 53 +/- 10 nmol/l, F 5.7, P = 0.02) despite no difference in plasma ACTH concentration. There was an interaction between nutritional group and gender for both the pituitary and adrenal responses to CRH and AVP, i.e. for controls, females exhibited increased plasma ACTH or cortisol relative to males but for NR this trend was either not present or reversed. The adrenocortical response to synthetic ACTH was gender-dependent only, being greater in female offspring. Combined CRH and AVP provoked a transient hypertension and marked bradycardia in all animals, irrespective of dietary group or gender and could be effectively reproduced by an AVP bolus alone. In conclusion, the present study has shown that periconceptional undernutrition of sheep has only a minor influence on HPA axis function in their young adult offspring when considered alongside the effect of gender per se.     

Cortisol-binding globulin is important in the interpretation of dynamic tests of the hypothalamic--pituitary--adrenal axis

OBJECTIVE: Assessment of the hypothalamic--pituitary--adrenal (HPA) axis relies on the interpretation of serum (total) cortisol in response to dynamic tests of the HPA axis. Most cortisol is bound to cortisol-binding globulin (CBG) and serum total cortisol levels are significantly affected by variation in CBG. We hypothesised that CBG variation significantly affects interpretation of dynamic tests of the HPA axis. DESIGN: We investigated the effect of CBG variation on the outcome of the 250 microg short Synacthen test (SST) in 30 healthy adults. METHODS: Blood was sampled at time -30, 0 (at which point Synacthen was given) and +30 min. CBG and total cortisol were measured at each time-point. Integrity of the HPA axis was confirmed by measurement of urine cortisol. RESULTS: We found that CBG varied significantly within individuals, falling from 51+/-3.4 to 43 +/-3.2 microg/ml (P<0.0001) on changing from standing to lying. Total cortisol levels strongly correlated with CBG (r=0.88, P<0.0001). Thirteen subjects had a +30 min total cortisol <550 nmol/l. In these subjects, the CBG levels at each time-point were significantly lower compared with subjects who had a +30 min total cortisol of >550 nmol/l (P<0.05). To correct for variation in CBG we calculated the total cortisol:CBG ratio and found no significant difference in the +30 min ratio between these two groups. CONCLUSION: CBG varies significantly within and between individuals. This is accompanied by changes in serum total cortisol large enough to affect the outcome of an SST and, by implication, other tests of the HPA axis.     

Abnormalities of uterine cervix in women with inflammatory bowel disease

INTRODUCTION Cervical cancer is responsible for almost 4000 deaths annually in the United States[1]. Due in large part to mass screening protocols with papanicolaou (Pap) smears, mortality from cervical cancer has declined by over 70% in the past 50 years…     

Free fatty acids exert an inhibitory effect on adrenocorticotropin and cortisol secretion in humans

Free fatty acid (FFA) administration stimulates the hypothalamic-pituitary-adrenal (HPA) axis in rats, suggesting that the HPA axis and lipolysis may be linked by a positive-feedback loop. To clarify the influence of FFA on the HPA axis in humans, we studied the effect of lipid load on both basal and stimulated ACTH and cortisol secretion in normal subjects. In six young female volunteers [(mean +/- SEM) age, 24.4 +/- 2.1 yr; body mass index, 23.1 +/- 1.2 kg/m(2)), ACTH, cortisol, FFA, glucose, and insulin levels were measured every 30 min for 330 min during the following procedures: 1) i.v. saline infusion (from 0 to 330 min); 2) i.v. FFA infusion (Intralipid 10%, from 0 to 210 min) followed by saline infusion (from 210 to 330 min); 3) human CRH (hCRH) administration (2 microg/kg i.v. at 90 min) during saline infusion (from 0 to 330 min); and 4) hCRH administration during FFA infusion (Intralipid 10%, from 0 to 210 min, followed by saline infusion from 210 to 330 min). During saline infusion, ACTH and cortisol levels progressively declined. Lipid-heparin emulsion (LHE) infusion strikingly increased circulating FFA levels and, simultaneously, amplified the ACTH and cortisol decrease (P < 0.05). After LHE withdrawal, FFA decrease was associated with an increase (P < 0.05) in ACTH and cortisol levels (restored to baseline values within 60 min). The ACTH and cortisol responses to hCRH, however, were unaffected by LHE that, concomitantly, induced an increase (P < 0.05) in glucose but not in insulin levels. This study shows that an LHE-induced increase in FFA levels has an inhibitory effect on spontaneous ACTH and cortisol secretion in humans. Lipid load, however, does not affect the ACTH and cortisol responses to hCRH; this evidence would indicate that the negative influence of FFA on the HPA axis in humans takes place at the suprapituitary level.     

Long-term basal and dynamic evaluation of hypothalamic-pituitary-adrenal (HPA) axis in acromegalic patients

Objective Long‐term effects of trans‐naso‐sphenoidal surgery (TNS) or long‐acting somatostatin analogs (SSA) on the function of hypothalamic–pituitary–adrenal (HPA) axis have been poorly investigated. Aim of this study was to evaluate HPA axis integrity during the follow‐up in patients with GH‐secreting pituitary adenomas and preserved HPA function post‐TNS or prior SSA. Design and patients This retrospective study investigated 36 acromegalic patients (16M and 20F, age: 47 ± 13 years), 20 of whom cured by TNS and 16 controlled by SSA therapy (12 previously operated and 4 in primary medical therapy), before and after long‐term follow‐up (median: 72 months, range: 12–240). No patient previously underwent radiotherapy. Measurements HPA function was studied by morning circulating cortisol and ACTH levels, 24‐h urinary free cortisol (UFC) and cortisol response to low‐dose short Synacthen test (LDSST, 1 µg) with a peak > 500 nmol/l as cut‐off for normal function. Results Serum basal cortisol, ACTH and UFC levels were in the normal range and did not significantly change over time. As far as the cortisol peak after LDSST is concerned, 12 patients (32%, 8 TNS and 4 SSA) developed biochemical hypoadrenalism. None of the patients in primary medical therapy showed cortisol peak < 500 nmol/l. No significant correlations between HPA axis deterioration and follow‐up duration, serum GH/IGF‐I levels, occurrence of other pituitary deficiencies, presence of secondary empty sella, changes in tumour or residual volume were observed. Conclusions The HPA axis function must be carefully monitored over the time by dynamic testing in all acromegalic patients, independently from the type of treatment.     

Regional blood flow correlates of ST segment depression in tachycardia-induced myocardial ischemia

Tachycardia produces subendocardial ischemia and ST segment abnormalities after coronary obstruction. To determine whether a quantitative relationship exists between these ST shifts and transmural blood flow, 19 dogs were studied. Coronary obstruction was produced by ameroid constriction of the left circumflex artery, and tachycardia was generated by atrial pacing at 90 to 210 beats/min. ST shifts were studied by body surface isopotential mapping with an 84-electrode torso grid, and blood flow was quantitated by serial radiolabeled microsphere injections. Isopotential maps at each paced rate, 40 msec into the ST segment, were classified as normal or ischemic based on spatial patterns of voltages. Pacing after 3 weeks of ameroid constriction reduced endocardial/epicardial flow ratios in 11 dogs from 1.16 +/- 0.22 at rest to 0.41 +/- 0.18 at 210 beats/min. Abnormal ST depression developed in these dogs at a rate of 184.0 +/- 16.5 beats/min. Endocardial/epicardial ratios with ST depression (0.45 +/- 0.15) were lower than at those without ST depression (1.05 +/- 0.19; p less than .01). Logistic regression analysis demonstrated that ST depression corresponded to an endocardial/epicardial ratio of 0.67 or less (p less than .01). With this model, 95.5% of data sets were correctly classified. Neither heart rate nor perfusion bed size were significant independent predictors of an ischemic electrocardiographic response. The magnitude of abnormal ST segment shift was significantly correlated (r = .87) with the transmural flow ratio. Thus development of electrocardiographic changes indicative of ischemia corresponds to a predictable degree of flow redistribution and the magnitude of the ST shift is correlated with the intensity of the flow abnormality.     

Effects of twinning and periconceptional undernutrition on late-gestation hypothalamic-pituitary-adrenal axis function in ovine pregnancy

The relationships between reduced size at birth, increased activity of the hypothalamic-pituitary-adrenal (HPA) axis, and increased risk of disease in adulthood are well described in singletons but are much less clear in twins. This may be because the physiological processes underlying reduced size at birth are different in singletons and twins. Periconceptional undernutrition can cause altered activity of the fetal and postnatal HPA axis without altering size at birth. However, the independent effects of periconceptional undernutrition and twinning on activity of the maternal and fetal HPA axes are not well described. We therefore studied maternal and fetal HPA axis function during late gestation in twin and singleton sheep pregnancies, either undernourished around conception or fed ad libitum. We found that twinning led to suppressed baseline HPA axis function and decreased adrenal sensitivity to ACTH stimulation but increased fetal pituitary ACTH response both to direct stimulation by CRH (ACTH area under the curve response: 29.7 +/- 2.2 vs. 17.1 +/- 1.6 ng/min x ml, P < 0.01) and to decreased cortisol negative feedback. In contrast, periconceptional undernutrition resulted in a decreased pituitary response (ACTH area under the curve response: 19.4 +/- 1.6 vs. 26.1 +/- 2.2 ng/min x ml, P = 0.02) but no difference in adrenal response. Thus, the HPA axis function of twin sheep fetuses in late gestation is very different from that of control and undernourished singletons. If the HPA axis is an important mediator between fetal adaptations and adult disease, these data may help explain why the relationship between fetal growth and postnatal physiology and disease risk is inconsistent in twins.     

Bronchial hyperreactivity and allergic status in inflammatory bowel disease

BACKGROUND: Despite the known systemic manifestations of inflammatory bowel disease (IBD) and a large number of reports associating lung disease and IBD, the frequency of atopy and bronchial hyperreactivity (BHR) in IBD remains obscure. OBJECTIVES: The aim of this study was to investigate the prevalence of abnormal pulmonary function tests, BHR and the atopic status in patients with IBD. METHODS: Thirty patients with IBD (19 with ulcerative colitis and 11 with Crohn's disease; 19 male, 11 female) and 16 controls without any gastrointestinal disease (9 female, 7 male) were included. Patients were questioned with respect to pulmonary and allergic symptoms; subsequently, lung function tests, BHR, skin prick test positivity, peripheral eosinophilia and serum IgE levels were evaluated and compared with those of control subjects. RESULTS: The mean duration of IBD was 5.3 +/- 4.8 years. IBD patients had significantly more often respiratory symptoms in comparison with controls (odds ratio, OR: 9.0, p < 0.04). A previous diagnosis of asthma and antiasthmatic drug treatment were noted in 3/30 (10%) IBD patients. Allergic symptoms were more prevalent in IBD patients in comparison with the controls (OR: 13, p < 0.007), particularly in patients with ulcerative colitis (OR: 16, p < 0.004). The mean FEV(1 )was 3.1 +/- 0.9 liters (96 +/- 18% predicted), mean methacholine PD(20): 14.7 +/- 3.6 mg/ml, mean IgE: 190.5 +/- 305.6 IU/ml (normal value <94 IU/ml) and the percentage of peripheral eosinophils was 3.1 +/- 3.3% in the IBD patients. These values did not result in statistically significant differences in comparison with controls. Furthermore, abnormal lung function and BHR were observed in 8/30 (27%) and 5/30 (17%) IBD patients, respectively. Abnormal lung function tests were more prevalent in the IBD patients than in the controls (OR: 12, p < 0.04). Skin prick tests were positive in 15/30 (50%) IBD patients. The risk of a positive skin prick test increased in the IBD patients in comparison with the controls (OR: 7.0, p < 0.02). Duration and activity of IBD did not influence the prevalence of BHR, allergic and respiratory symptoms, abnormal lung function, high serum IgE levels and skin test positivity. CONCLUSIONS: Allergic symptoms, respiratory symptoms, abnormal lung function tests and skin prick test positivity were more common among the IBD patients in comparison with the controls.     

Hypothalamic-pituitary-adrenal axis and sympathetic nervous system activities in Pima Indians and Caucasians

It has been proposed that both hypercortisolism and low sympathetic nervous system (SNS) activity contribute to obesity. Because glucocorticoids inhibit SNS activity, we hypothesized that hypercortisolism and low SNS activity may be found in association in Pima Indians, a population with a high prevalence of obesity. We therefore measured indices of hypothalamic-pituitary-adrenal (HPA) axis and SNS activities in 39 nondiabetic men, 20 Pimas (age, 30+/-5 years; weight, 94+/-26 kg; 35%+/-8% body fat [mean +/- SD]) and 19 Caucasians (33+/-9 years, 91+/-23 kg, 28%+/-11% body fat). HPA axis activity was assessed by measurements of morning fasting plasma corticotropin (ACTH) and cortisol concentrations and 24-hour urinary free cortisol (UFC) excretion. SNS activity was assessed as muscle sympathetic nerve activity (MSNA) by microneurography and by measurement of catecholamines (fasting plasma concentration and 24-hour urinary excretion). Plasma ACTH and cortisol and UFC were similar in Pimas and Caucasians. MSNA was positively correlated with percent body fat (r = .49, P = .002) and was lower in Pimas compared with Caucasians after adjustment for percent body fat (24+/-9 v 31+/-10 bursts/min, P = .04). We conclude that Pima Indians, a population with a high prevalence of obesity, have lower SNS activity but normal HPA axis activity compared with Caucasians.     

Screening for hypothalamo-pituitary-adrenal axis suppression in asthmatics taking high dose inhaled corticosteroids

High dose inhaled corticosteroids may cause suppression of the hypothalamo-pituitary-adrenal (HPA) axis. Several tests are available to screen for this suppression but it is not clear which is the most useful. HPA function was assessed in 78 adult asthmatics inhaling long-term, high dose (median 1600 micrograms; range 1200-2650 micrograms) beclomethasone dipropionate (n = 69) or budesonide (n = 9). Screening tests performed in all patients were 9 am serum cortisol, short tetracosactrin test and 24-h urine free cortisol excretion. Eleven patients also underwent insulin stress tests. Subnormal results were: 9 am cortisol less than 190 nmol l-1; urine free cortisol less than 80 nmol 24 h-1; rise in cortisol in response to tetracosactrin or hypoglycaemia less than 200 nmol l-1 and/or achieved cortisol less than 500 nmol l-1. HPA suppression (defined as subnormal results of at least two of the three initial tests and/or subnormal response to hypoglycaemia), was found in 16 patients. In the 11 patients who underwent insulin stress tests, results of all initial tests were normal in three, one test was abnormal in three and two tests were abnormal in four patients. All three tests were abnormal in the remaining patient. The response to hypoglycaemia was normal in the three patients whose screening tests were all normal; HPA suppression was present in seven patients and one patient had a borderline result. Close correlation was observed between the maximum cortisol during hypoglycaemia and both urine free cortisol (rs = 0.84; P = 0.001) and post-tetracosactrin cortisol (r = 0.75; P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

Evaluation of the hypothalamic-pituitary-adrenal axis immediately after pituitary adenomectomy: is perioperative steroid therapy necessary?

Patients undergoing pituitary adenomectomy are usually given glucocorticoid therapy, although there are no data to document the need for such therapy. We prospectively studied hypothalamic-pituitary-adrenal axis (HPA) function in 88 consecutive pituitary adenoma patients before and after selective adenomectomy, excluding those with corticotroph adenomas. Preoperatively, 5 patients had adrenal insufficiency (AI); they were treated with glucocorticoids and excluded from the analysis. The remaining 83 patients had normal HPA function preoperatively and were not given glucocorticoids before, during, or immediately after surgery, but were closely monitored, and their serum cortisol levels were measured in the immediate postoperative period. Two patients were clinically suspected to have AI postoperatively and were treated accordingly. The remaining 81 patients had no clinical manifestations of AI and received no glucocorticoid therapy. Their serum cortisol levels in the immediate postoperative period were appropriately elevated. The mean serum cortisol level was 40.5 +/- 11.1 (+/- SD) micrograms/dL (1117 +/- 306 nmol/L) 6 h after surgery; serum cortisol levels decreased gradually thereafter. Morning serum cortisol levels were within the normal range on the fourth, fifth, and sixth days after surgery: day 4, 15.1 +/- 7.0 micrograms/dL (417 +/- 193 nmol/L); day 5, 16.4 +/- 5.6 micrograms/dL (453 +/- 155 nmol/L); and day 6, 16.3 +/- 5.7 micrograms/dL (450 +/- 157 nmol/L). When tested 3 months after surgery, all 81 patients had normal HPA function. We conclude that HPA function is rarely compromised after selective pituitary adenomectomy. Close observation and serum cortisol measurements in the immediate postoperative period can reliably predict the integrity of the HPA after surgery. Routine glucocorticoid therapy is not needed in patients undergoing selective adenomectomy whose preoperative adrenal function is normal.     

Effect of recombinant human growth hormone (GH) replacement on the hypothalamic-pituitary-adrenal axis in adult GH-deficient patients

The aim of the study was to evaluate the hypothalamus-pituitary-adrenal (HPA) axis in patients (nine males, three females; mean age +/- sem 51 +/- 2 yr) with adult-onset GH deficiency (GHD) due to surgically treated pituitary tumors with preserved HPA function and without evidence of tumor recurrence before and during recombinant human (rh) GH replacement therapy (duration 31 +/- 6 months). HPA function was assessed by urinary free cortisol and morning serum cortisol levels as well as cortisol responses to 1 mug ACTH test (n = 7 patients) or insulin tolerance test (n = 5 patients) before and during rhGH therapy, the cut-off for the diagnosis of hypoadrenalism being a cortisol peak less than 18 microg/dl (<500 nmol/liter) after stimulatory tests. Serum cortisol and urinary free cortisol levels were significantly lower on therapy than before [7.6 +/- 0.8 vs. 11.5 +/- 0.9 microg/dl (208 +/- 22 vs. 317 +/- 24 nmol/liter), P < 0.01, and 19.6 +/- 2.5 vs. 32.2 +/- 3.2 microg per 24 h (54 +/- 7 vs. 89 +/- 9 nmol per 24 h), P < 0.05, respectively], whereas no change in cortisol-binding globulin levels was observed. Cortisol peak after either ACTH test or insulin tolerance test was lower on rhGH therapy than before [15.9 +/- 1.5 vs. 20.2 +/- 1.1 microg/dl (437 +/- 43 vs. 557 +/- 31), P = 0.01, and 13.1 +/- 2.6 vs. 20.4 +/- 1.4 microg/dl (362 +/- 71 vs. 564 +/- 37 nmol/liter), P = 0.03, respectively]. Accordingly, central hypoadrenalism was detected in nine of 11 patients. In conclusion, low GH and IGF-I levels, likely enhancing the conversion of cortisone to cortisol, may mask a condition of central hypoadrenalism. Therefore, the reassessment of HPA function in GHD patients during rhGH therapy is mandatory.     

Hypothalamo-pituitary-adrenal axis suppression in asthmatics inhaling high dose corticosteroids

The frequency of hypothalamo-pituitary-adrenal (HPA) axis suppression in asthmatics taking high dose (greater than 1000 micrograms daily) inhaled corticosteroids is unknown. HPA function was studied in 78 adult asthmatics taking long-term inhaled corticosteroids (median dose 1600 micrograms, range 1200-2650 micrograms daily). All patients except one were using metered dose aerosols; 15 were using large volume spacer devices. Median duration of high dose therapy was 13 months (range 1-54). Sixty-nine patients were taking beclomethasone dipropionate (1500 micrograms, n = 36; 2000 micrograms, n = 26, greater than 2000 micrograms, n = 7) and nine budesonide (1200 micrograms, n = 2; 1600 micrograms, n = 6; 1800 micrograms, n = 1). Four patients, all of whom were taking greater than 2000 micrograms beclomethasone dipropionate, were taking 200-400 micrograms of their total dose intranasally. Twenty-six patients had discontinued long term systemic corticosteroid treatment (at least 5 mg prednisolone daily, or equivalent, for a minimum of 6 months) between 7 months and 22 years prior to assessment. All patients had measurements of 9 am serum cortisol and 24-h urine free cortisol excretion and a short tetracosactrin test. Subnormal results were: 9 am cortisol less than 190 nmol l-1; rise in serum cortisol in response to tetracosactrin less than 200 nmol l-1 and/or achieved cortisol less than 500 nmol l-1; urine free cortisol less than 80 nmol 24 h-1. Hypothalamo-pituitary-adrenal suppression was defined as subnormal results in at least two of the three tests. Tests were performed at least 2 weeks after completion of any short course prednisolone treatments. Suppression was found in 16 (20.5%) patients (1500 micrograms, n = 6; 1600 micrograms, n = 1; 2000 micrograms, n = 7; 2400 micrograms, n = 2). Risk factors identified for this suppression were: (a) previous requirement for long-term systemic corticosteroids (10/26, chi 2 = 6.1, P less than 0.02); and (b) increasing duration of high dose inhaled therapy (median 28.5 months in suppressed vs. 12 months in normal, P less than 0.05). No clear relationship was identified between HPA function and dose, even when corrected for body surface area and there was no relationship between suppression and number of short courses of prednisolone in the preceding 12 months. Screening tests of HPA function should be performed in all asthmatics taking greater than or equal to 1500 micrograms inhaled corticosteroid daily. Unless function has been shown to be normal, all patients taking these doses should carry steroid cards.     

Hypothalamic-pituitary-adrenal activity in type 2 diabetes mellitus: role of autonomic imbalance

Symptomatic diabetic neuropathy has been found to be associated with hypothalamus-pituitary-adrenal (HPA) axis hyperfunction, but no data are available about HPA activity in diabetic patients with asymptomatic autonomic imbalance. To evaluate HPA axis activity in patients with type 2 diabetes mellitus (T2DM) in relation to the presence or the absence of subclinical parasympathetic or sympathetic neuronal dysfunction, we performed an observational study on 59 consecutive type 2 diabetic patients without chronic complications and/or symptoms of neuropathy or hypercortisolism. The following were measured: serum cortisol at 08:00 am and at midnight (F8 and F24, respectively), post-dexamethasone suppression cortisol, 24-hour urinary free cortisol (UFC), and morning corticotropin (ACTH). Deep-breathing (DB) and LS (LS) autonomic tests were performed to assess the parasympathetic function; postural hypotension test was performed to evaluate sympathetic activity. Patients were subdivided into 4 groups: subjects with parasympathetic failure (group A), sympathetic failure (group B), both para- and sympathetic failure (group C), and without autonomic failure (group D). Hypothalamus-pituitary-adrenal activity was increased in group A compared with group D (UFC, 48.6 +/- 21.4 vs 21.6 +/- 9.8 microg/24 h, P < .0001; ACTH, 27.0 +/- 8.6 vs 15.7 +/- 5.7 pg/dL, P < .01; F8, 20.4 +/- 4.5 vs 13.6 +/- 3.8 microg/dL, P < .05; post-dexamethasone suppression cortisol, 1.2 +/- 0.4 vs 0.8 +/- 0.6 microg/dL, P < .05, respectively) and group B (UFC, 26.3 +/- 11.0 microg/24 h, P < .0001; ACTH, 19.9 +/- 8.0 pg/dL, P < .05). Regression analysis showed that UFC levels were significantly associated with the deep-breathing test (beta = -0.40, P = .004) and tended to be associated with the lying-to-standing test (beta = -0.26, P = .065), whereas body mass index, glycated hemoglobin, and duration of disease were not. Type 2 diabetic patients with asymptomatic parasympathetic derangement have increased activity of HPA axis, related to the degree of the neuronal dysfunction.     

Assessment of elastic properties of the descending thoracic aorta by transesophageal echocardiography with acoustic quantification in patients with a stroke

Previous studies have described the use of transesophageal echocardiography (TEE) with acoustic quantification (AQ) in assessing aortic elastic properties. We hypothesized that patients with a prior history of stroke (ST) may have a higher risk of atherosclerotic change in great vessels compared to nonstroke subjects (NST) and thus have decreased elastic properties. We assessed the elastic properties of the descending thoracic aorta (DTA) by TEE in ST patients and compared them with data in NST patients. Subjects included 31 with ST without any evidence of emboli originating from the heart (age 51 +/- 10 years, M:F = 20:11) and 25 age-matched NST (M:F = 8:17). Patients with significant valvular heart disease including aortic and mitral regurgitation, left ventricular dysfunction (ejection fraction < 55%), and congenital heart disease were excluded. Compliance (C), distensibility (D), and stiffness index (SI) were measured using AQ and M-mode measurement at a level of the left atrium. We scored atherosclerotic risk factors (ARF) such as a history of diabetes, hypertension, smoking, hypercholesterolemia, and the presence of atheroma of DTA. There was no evidence of atheroma of DTA in NST. There were no significant differences in heart rate and systolic and diastolic blood pressure between ST and NST patients. Fractional area change (FAC) of DTA was significantly lower in ST than in NST patients (3.2 +/- 1.6 vs 5.4 +/- 2.5%, P = 0.000). ST patients had significantly lower C (1.2 +/- 0.4 vs 1.5 +/- 0.7 x 10(-3) cm2 mmHg(-1), P = 0.039), lower D (0.8 +/- 0.3 vs 1.5 +/- 0.8 x 10(-3) mmHg(-1), P = 0.000), and higher SI (10.3 +/- 8.8 vs 5.3 +/- 2.9, P = 0.006) than NST patients. ST patients without atheroma of DTA (n = 21) also had significantly lower C (1.1 +/- 0.4 vs 1.5 +/- 0.7 x 10(-3) cm2 mmHg(-1), P = 0.038) and lower D (3.5 +/- 1.4 vs 4.8 +/- 2.4 x 10(-3) mmHg(-1), P = 0.021) than NST patients. There was a significant positive correlation between SI and the score of ARF (r = 0.51, P = 0.000). The regional elastic properties of DTA measured by TEE with AQ and M-mode method were abnormal in ST. Therefore, TEE with AQ technique may have a possible clinical application for the detection of early atherosclerotic changes such as alteration of elastic properties in morphological normal DTA.     

Evidence for a positive correlation between serum cortisol levels and IL-1beta production by peripheral mononuclear cells in anorexia nervosa

A hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis has been reported in anorexia nervosa (AN), together with some immunological abnormalities, involving citokine - and particularly Tumor Necrosis-Factor-alpha (TNF-alpha) - production by polymorphonuclear cells. The ability of pro-inflammatory cytokines to activate the HPA axis is well known; however, there are no data demonstrating an interdependence between immunological and endocrine response in AN. To investigate the presence of a correlation between immune response and pituitary-adrenal function, plasma ACTH and serum cortisol concentrations were measured in 13 AN patients and in the same number of controls. TNF-alpha and interleukin (IL)-1beta production by ex-vivo unstimulated and LPS-stimulated peripheral mononuclear cells was also assessed. Circulating cortisol concentrations were higher (p<0.01) in AN (156.7 +/- 45.1 microg/l, mean +/- SD) than in controls (105.9 +/- 25.7 microg/l). Unstimulated IL-1beta release in supernatants of mononuclear cell cultures was slightly but not significantly higher in AN than in controls, while TNF-alpha release was similar in the two groups. A positive correlation was found between IL-1beta concentrations in unstimulated culture supranatants and serum cortisol levels in AN (r=0.782, p=0.002), while in normal subjects there was a trend toward a negative correlation; a slight positive correlation, while not significant, between IL-1beta and plasma ACTH, as well as between TNF-alpha and serum cortisol was also found in AN. These data suggest that the normal relationship between pro-inflammatory cytokines release, particularly IL-1beta, and cortisol secretion is deranged in AN.     

Visual versus computerized analysis of upsloping ST segment depression in the exercise electrocardiogram

A slowly upsloping ST segment depression is an abnormal, and a rapidly upsloping ST segment depression is a normal exercise ECG response. We investigated the agreement of expert physicians on the visual classification of the ST segment depression, and compared the (majority) vote with the computer-generated ST slope. A total of 206 exercise ECG leads with an amplitude of the ST segment depression > or = 0.15 mV and a ST segment slope > or = 0.5 mVs(-1) were evaluated. All three interpreters agreed in 68 cases, two agreed in 123 cases, and all disagreed in 15 cases. Intraobserver agreement was 61%. The ST segment slope was significantly (p < 0.001) greater in leads generally interpreted as rapidly upsloping (n = 38; 2.1 +/- 0.8 mVs(-1)), than in those interpreted as slowly upsloping (n 121; 1.3 +/- 0.6 mVs(-1)) or horizontal (n = 32; 1.1 +/- 0.4 mVs(-1)), although there was some overlap. Thus, standardization of the computer-assisted exercise ECG interpretation should be continued.     

The midnight-to-morning urinary cortisol increment method is not reliable for the assessment of hypothalamic-pituitary-adrenal insufficiency in patients with end-stage kidney disease

A previous study reported that the midnight-to-morning urinary cortisol increment method could be used to reliably assess the insufficiency of the hypothalamic-pituitary-adrenal (HPA) axis. The principal aim of the present study is to verify whether the midnight-to-morning urinary cortisol increment is a reliable method for the assessment of the HPA axis in patients with various degrees of impaired kidney function. Fifty-six clinically stable patients with chronic kidney disease (CKD) and 14 healthy subjects were enrolled in the present study. Patients with CKD were divided on the basis of glomerular filtration rate (GFR) into the following arbitrary groups: mild (GFR: 60-89 ml/min/1.73 m2, no.=15), moderate (GFR: 30-59 ml/min/1.73 m2, no.=12) and severe kidney insufficiency (GFR: 15-29 ml/min/1.73 m2, no.=13), and hemodialysis patients. Plasma cortisol and ACTH levels were measured. The HPA axis was assessed by short Synacthen test and overnight dexamethasone suppression test. Double voided urine samples were collected at midnight and waking in the patients and the controls. Urinary free cortisol (UFC) and creatinine levels were measured and the UFC/creatinine ratio (Cort/Cr) was calculated. Then, the Cort/Cr increment was calculated as the morning Cort/Cr minus the midnight Cort/Cr. Baseline plasma cortisol levels were not significantly different between two groups. However, we found that CKD patients had significantly greater plasma ACTH levels than controls. The patients with CKD had also significantly lower morning UFC levels than controls and there was a progressive fall in morning UFC levels with decreasing GFR. The assessment of the HPA axis in patients with GFR lower than 29 ml/min was hampered by falsely abnormal responses to the midnight-to-morning urinary cortisol increment method. Plasma cortisol responded normally to exogenously administered ACTH, while plasma cortisol was suppressed by overnight dexamethasone administration in all patients with CKD. In conclusion, this method is not a reliable test for assessment of the HPA insufficiency in patients with GFR lower than 29 ml/min.     

The adrenal steroid status in relation to inflammatory cytokines (interleukin-6 and tumour necrosis factor) in polymyalgia rheumatica

OBJECTIVES: To determine the correlation between inflammatory cytokines and adrenal hormones in patients with polymyalgia rheumatica (PMR) and to compare the ratio of serum cortisol and androstenedione (ASD) or dehydroepiandrosterone sulphate (DHEAS) in normal subjects with PMR patients. METHODS: In 102 patients with PMR (32 beginning and 70 chronic disease) and 31 age-matched and sex-matched healthy subjects, ASD, cortisol, DHEAS, interleukin-6 (IL-6), and tumour necrosis factor (TNF) were measured by immunometric assays. RESULTS: Serum levels of IL-6 were elevated in patients with PMR as compared with normal subjects (10.0 +/- 1.6 vs 2.1 +/- 0.1 pg/ml, P = 0.01), which was not found for TNF. In PMR patients, serum levels of IL-6 were positively correlated with serum levels of ASD (P < 0.001), cortisol (P < 0.001), and DHEAS (P = 0. 038) irrespective of corticosteroid treatment. Serum levels of cortisol in relation to IL-6 were significantly lower in patients with chronic disease and long-standing corticosteroid administration as compared with patients with recent onset of the disease and without corticosteroid therapy (P < 0.01). CONCLUSIONS: In PMR, as expected, there was an increase in IL-6 serum levels that was associated with elevated serum levels of ASD, DHEAS, and cortisol which was more marked in patients with recent-onset disease and without corticosteroids. However, serum levels of cortisol in patients with and without corticosteroids were lower than expected by considering the inflammatory status (increased IL-6). This may indicate a change in the hypothalamic-pituitary-adrenal (HPA) axis responsiveness to inflammatory stimuli such as IL-6 during chronic disease. Furthermore, there seems to be a shift of biosynthesis to cortisol in relation to DHEAS or ASD in chronic disease.