A comparison between the 1-microg adrenocorticotropin (ACTH) test, the short ACTH (250 microg) test, and the insulin tolerance test in the assessment of hypothalamo-pituitary-adrenal axis immediately after pituitary surgery

The short ACTH stimulation test is an easy, reliable, and extensively used test in the assessment of the hypothalamo-pituitary-adrenal (HPA) axis. However, its use immediately after pituitary surgery is a matter of debate. The insulin tolerance test (ITT) is the gold standard in the evaluation of the HPA axis, but it is not always without side effects and may be unpleasant early after pituitary surgery. Our aim was to investigate the value of the 1-microg ACTH test in the assessment of the HPA axis early after pituitary surgery. We also aimed to determine the value of the 1-microg and 250-microg ACTH tests and the ITT in the estimation of HPA axis status after 3 months postoperatively. Nineteen patients subjected to pituitary tumor surgery were included in the study, and the ITT and the 1-microg and 250-microg ACTH tests were performed between the 4th and 11th days of surgery. The tests were repeated at the first month in 3 patients with subnormal peak cortisol responses (454, 125, and 301 nmol/L) and in 18 patients at the third month postoperatively. ACTH stimulation tests were performed by using 1 microg and 250 microg ACTH iv as a bolus injection, and blood samples were drawn at 0, 30, and 60 min for measurement of serum cortisol levels. The ITT was performed by using iv regular insulin, and serum glucose and cortisol levels were measured. The 1-microg and 250-microg ACTH stimulation tests and the ITT were performed consecutively. At least 48 h were allowed between each test. A peak serum cortisol level of 550 nmol/L or greater was considered as a normal response for both the ITT and the ACTH tests. The serum cortisol level was measured by RIA using commercial kits. Serum glucose was determined by glucose oxidase method. There were correlations between the peak cortisol response to the ITT and the 1-microg ACTH test (r = 0.39, P < 0.05) in the early postoperative period. No correlation was found between the ITT and the 250-microg ACTH test responses. In the early postoperative period, two patients showed normal cortisol responses (> or =550 nmol/L) to the 1-microg ACTH test and five patients showed normal cortisol responses to the 250-microg ACTH test among the six patients with subnormal cortisol responses to the ITT. Three patients with subnormal cortisol responses to ITT and baseline cortisol values less than 240 nmol/L showed normal HPA axis at the end of the first month. In the late postoperative period, at the third month, all the patients showed normal HPA axis. In the early postoperative period of pituitary surgery, the 1-microg ACTH test results are more concordant than the 250-microg ACTH test in comparison with the ITT. Our results also indicate that HPA axis dysfunction shown by ACTH stimulation tests and the ITT in early postoperative period may be normalized 1-3 months after surgery. For this reason, we think that dynamic tests including the ITT may not be useful early after pituitary surgery.     

Reproducibility of the insulin tolerance test (ITT) for assessment of growth hormone and cortisol secretion in normal and hypopituitary adult men

OBJECTIVE: The within subject variability of the insulin tolerance test (ITT) for assessment of growth hormone (GH) status and cortisol reserve has rarely been examined, particularly in patients with hypopituitarism. This becomes important when biochemical criteria are used to determine which adults with hypopituitarism should receive GH and/or cortisol replacement. In the present study we assessed the reproducibility of GH and cortisol responses in repeated ITTs. Baseline insulin-like growth factor 1 (IGF-1) levels were also assessed for reproducibility on each occasion. DESIGN AND PATIENTS: Three consecutive ITTs were performed in seven normal adult men (ages 22-27 years) and two ITTs in 11 men with hypopituitarism and suspected GH deficiency (ages 23-48 years). MEASUREMENTS: Serum GH and IGF-1 were measured by immunoradiometric and cortisol by immunofluorimetric assays. RESULTS: In normal men group peak GH responses did not differ between the three tests. There was no correlation between individual peak values. The within subject peak GH variability was between 4.6 and 59.3%, and the overall variability in 21 tests was 35%. The lowest peak GH concentration was 70 mU/l (27 microg/l). All hypopituitary men had severe GH deficiency (all peak GH concentrations < 4 mU/l (1.5 microg/l) in both tests). There was a highly significant correlation between individual peak GH values (r = 0.95, P < 0.0001). Basal IGF-1-values in normal and hypopituitary men were highly correlated between tests (r = 0.98, P < 0.0001). The overall within subject variability of IGF-1-values was 11.9% in normal and 22.7% in hypopituitary men. In normal men group peak cortisol responses were not different between the three tests. There was a good correlation between individual peak cortisol responses in the three ITTs. The within subject peak cortisol variability (median 8.3%; range 0.7-21.5%) was significantly less than that of GH (P < 0.03) in two of three test comparisons. In hypopituitary men the within subject peak cortisol variability (median 41.6%; range 3.5-92.7%) was significantly greater (P < 0.001) than in normal men. All patients were correctly classified as cortisol deficient or normal in both ITTs. CONCLUSION: The cortisol response to repeated hypoglycaemia is very reproducible in normal men but the GH response is less so. In hypopituitary men the reproducibility of the GH response is good while that of the cortisol response is poor. However, a single ITT did not misclassify hypopituitary patients who are severely GH and/or ACTH deficient and was therefore adequate for clinical decisions regarding GH and/or cortisol replacement. Nevertheless, it remains possible that a single ITT could misclassify some hypopituitary patients with partial GH or ACTH deficiency.     

Establishment of reference values for standard dose short synacthen test (250 microgram), low dose short synacthen test (1 microgram) and insulin tolerance test for assessment of the hypothalamo-pituitary-adrenal axis in normal subjects

OBJECTIVE: To assess the integrity of the hypothalamo-pituitary-adrenal(HPA) axis, many authors have proposed the short synacthen test (ACTH1-24, Tetracosactrin) as a replacement for the insulin tolerance test (ITT). The aim of this study was to compare the plasma cortisol response obtained with both short synacthen tests (high dose (HDT, 250 microgram) and low dose (LDT, 1 microgram)) with the peak reached during the ITT in healthy volunteers, and to establish the plasma cortisol cut-off level in each test. SUBJECTS AND METHODS: Thirty healthy subjects (16 F, 14 M), mean age 34 years, underwent both short synacthen tests. Twenty healthy subjects, 15 of whom (11 F, nine M) belonged to the above group, mean age 30 years, underwent an ITT. Plasma cortisol was measured using a chemiluminiscence immunoassay. RESULTS: There were no differences between plasma cortisol 30 minutes after both short synacthen tests (HDT: 684 +/- 123, LDT: 669 +/- 119 nmol/l) and the peaks reached with the LDT (691 +/- 123 nmol/l) and the ITT (673 +/- 99 nmol/l).The only difference (P < 0.001) was found in the comparison of plasma cortisol peak reached with the HDT (802 +/- 142 nmol/l) with the other tests. Plasma cortisol levels obtained in the 5th percentile in each test were: at + 30 minutes: (HDT: 537, LDT: 489 nmol/l), peak: (HDT 649, LDT 498, ITT: 539 nmol/l). CONCLUSIONS: Comparison of the plasma cortisol response at + 30 minutes with both short ACTH tests and the peak in the insulin tolerance test did not reveal differences. Each test, for each time point and for each biochemical method, requires its own minimum threshold of normality to assess the hypothalamo-pituitary-adrenal axis.     

The low dose (1 microg) ACTH stimulation test for assessment of the hypothalamo-pituitary-adrenal axis

Traditional testing of the hypothalamo-pituitary-adrenal axis function has relied essentially upon the insulin tolerance test or the metyrapone challenge: both tests are not only uncomfortable, but carry also real dangers. The standard ACTH stimulation test uses an extremely hyperphysiological amount (250 microg) of ACTH to evaluate a physiologic response, which may result in false normal responses. The proposed low dose (1 microg) ACTH test is more physiological and more sensitive, especially in cases of mild adrenal insufficiency and allows also to assess pituitary-adrenal suppression after long-term treatment with glucocorticoids. According to the rules of evidence-based medicine, the low dose ACTH test should replace the conventional 250 microg test when evaluating for central adrenal insufficiency.     

Comparison of the low dose short synacthen test (1 microg), the conventional dose short synacthen test (250 microg), and the insulin tolerance test for assessment of the hypothalamo-pituitary-adrenal axis in patients with pituitary disease

There is still uncertainty about what is the most appropriate test for assessment of the integrity of the hypothalamo-pituitary-adrenal (HPA) axis. Many advocate the insulin tolerance test (ITT), but this is unpleasant and resource intensive, and may occasionally give misleading results. The conventional [250 microg tetracosactrin, ACTH-(1-24)] short synacthen test (SST) has been used as a simple alternative to the ITT, but it has produced some falsely reassuring results with potentially serious consequences. A low dose [1 microg tetracosactrin, ACTH-(1-24)] short synacthen test (LDSST) has recently been advocated as a more reliable and safer alternative to ITT. Some studies, however, have failed to demonstrate any difference between SST and LDSST. The purpose of this study was to assess the clinical usefulness of LDSST compared to SST and ITT in patients with pituitary disease. We studied 64 patients with suspected or proven pituitary disease. All patients underwent SST and LDSST. Forty-two patients underwent ITT. There was a high correlation between the ITT and LDSST peak cortisol responses (r = 0.89; P < 0.0001), the ITT and SST 30 min cortisol levels (r = 0.83; P < 0.0001), and the LDSST peak cortisol response and the SST 30 min cortisol level (r = 0.85; P < 0.0001). In the LDSST, all but six patients achieved maximal cortisol response by 30 min. A plasma cortisol cut-off of 600 nmol/L is more helpful than 500 nmol/L for clinical decision-making using either the SST 30 min cortisol level or the LDSST peak cortisol response. The sensitivity of the LDSST was 100% (cortisol response of >600 nmol/L indicates intact HPA axis), with no falsely reassuring results. SST (pass cortisol level, >600 nmol/L) was less sensitive than LDSST, it produced 2 of 64 (3%) falsely reassuring results. Even the ITT (pass cortisol level, >500 nmol/L) failed to identify one patient with clinically evident cortisol deficiency. The results of this study indicate that both SST and LDSST, at a cortisol cut-off of 600 nmol/L, are safe for the purpose of clinical decision-making with regard to steroid replacement therapy in patients with pituitary disease. As the LDSST produced no falsely reassuring decisions, we suggest that this could replace the SST and ITT for initial evaluation of the HPA axis in patients with pituitary disease. We suggest administering 1 microg tetracosactrin, i.v., with sampling at 0, 20, and 30 min.     

Endotoxin and the hypothalamo-pituitary-adrenal (HPA) axis

Endotoxin is considered to be a systemic (immunological) stressor eliciting a prolonged activation of the hypothalamo-pituitary-adrenal (HPA) axis. The HPA-axis response after an endotoxin challenge is mainly due to released cytokines (IL-1, IL-6 and TNF-alpha) from stimulated peripheral immune cells, which in turn stimulate different levels of the HPA axis. Controversy exists regarding the main locus of action of endotoxin on glucocorticoid secretion, since the effect of endotoxin on this neuro-endocrine axis has been observed in intact animals and after ablation of the hypothalamus; however, a lack of LPS effect has been described at both pituitary and adrenocortical levels. The resulting increase in adrenal glucocorticoids has well-documented inhibitory effects on the inflammatory process and on inflammatory cytokine release. Therefore, immune activation of the adrenal gland by endotoxin is thought to occur by cytokine stimulation of corticosteroid-releasing hormone (CRH) production in the median eminence of the hypothalamus, which, in turn stimulates the secretion of ACTH from the pituitary. Acute administration of endotoxin stimulates ACTH and cortisol secretion and the release of CRH and vasopressin (AVP) in the hypophysial portal blood. During repeated endotoxemia, tolerance of both immune and HPA function develops, with a crucial role for glucocorticoids in the modulation of the HPA axis. A single exposure to a high dose of LPS can induce a long-lasting state of tolerance to a second exposure of LPS, affecting the response of plasma TNF-alpha and HPA hormones. Although there are gender differences in the HPA response to endotoxin and IL-1, these responses are enhanced by castration and attenuated by androgen and estrogen replacement. Estrogens attenuate the endotoxin-induced stimulation of IL-6, TNF-alpha and IL-1ra release and subsequent activation in postmenopausal women. There appears to be a temporal and functional relation between the HPA-axis response to endotoxin and nitric oxide formation in the neuro-endocrine hypothalamus, suggesting a stimulatory role for nitric oxide in modulating the HPA response to immune challenges.     

Diabetes and the hypothalamo-pituitary-adrenal (HPA) axis

Patients and animals with poorly controlled or uncontrolled diabetes present with diurnal hypersecretion of glucocorticoids and altered regulation of the hypothalamo-pituitary-adrenocortical (HPA) axis. Although some of these changes are reversed with insulin replacement therapy, neuroendocrine function is not always restored to normal, even with rigorous glycemic control. In addition, stress responsiveness is also impaired in diabetes and this has important implications in the way patients with diabetes cope with many stress challenges, including the metabolic challenge of insulin-induced hypoglycemia. HPA dysregulation in diabetes appears to involve complex interactions between impaired glucocorticoid negative feedback sensitivity and factors such as hypoinsulinemia, hyperglycemia and/or hypoleptinemia, that may increase central drive of the axis. This review examines some of the evidence indicating hyperactivation of the HPA axis in patients with diabetes. Using the streptozotocin-diabetic rat as a model of type-1 diabetes, we will focus on elucidating some of the mechanisms underlying HPA dysregulation in diabetes. Hyperactivation of the HPA axis in diabetes is associated with increased expression of hypothalamic corticotrophin-releasing hormone (CRH) mRNA and hippocampal mineralocorticoid receptor (MR) mRNA. Although insulin replacement restores ACTH and corticosterone levels to normal, likely through glucocorticoid-mediated suppression of ACTH secretion, CRH and MR mRNA expression remain elevated. A better understanding of these mechanisms may be important in developing new treatment modalities for patients with diabetes mellitus.     

Circadian rhythms in the hypothalamo-pituitary-adrenal (HPA) axis

The pronounced daily variation in the release of adrenal hormones has been at the heart of the deciphering and understanding of the circadian timing system. Indeed, the first demonstration of an endocrine day/night rhythm was provided by Pincus (1943), by showing a daily pattern of 17-keto-steroid excretion in the urine of 7 healthy males. Twenty years later the adrenal gland was one of the very first organs to show, in vitro, that circadian rhythmicity was maintained. In the seventies, experimental manipulation of the daily corticosterone rhythm served as evidence for the identification of respectively the light- and food-entrainable oscillator. Another 20 years later the hypothalamo-pituitary-adrenal (HPA)-axis was key in furthering our understanding of the way in which rhythmic signals generated by the central pacemaker in the hypothalamic suprachiasmatic nuclei (SCN) are forwarded to the rest of the brain and to the organism as a whole. To date, the adrenal gland is still of prime importance for understanding how the oscillations of clock genes in peripheral tissues result in functional rhythms of these tissues, whereas it has become even more evident that adrenal glucocorticoids are key in the resetting of the circadian system after a phase-shift. The HPA-axis thus still is an excellent model for studying the transmission of circadian information in the body.     

Factors determining inadequate hypoglycaemia during insulin tolerance testing (ITT) after pituitary surgery

Background  Some patients fail to achieve adequate hypoglycaemia following a standard dose of intravenous insulin during the insulin tolerance test (ITT). Persistent acromegaly or Cushing's disease may contribute to inadequate hypoglycaemia.
Aim  To identify factors that predict failure to achieve adequate hypoglycaemia during an ITT after pituitary surgery.
Methods  We reviewed consecutive ITTs performed over a 10-year period in 76 patients following pituitary surgery. Analyses were performed to determine if body mass index (BMI), fasting blood glucose (FBG), cortisol, GH status or underlying diagnosis influenced the outcome.
Results  Adequate hypoglycaemia (blood glucose < 2·2 mmol/l) was not achieved in 33 patients (Group 1) following a standard dose of neutral insulin (0·1 units/kg); 43 patients (Group 2) achieved adequate hypoglycaemia. Group 1 had significantly higher BMI, FBG, baseline cortisol and peak cortisol concentrations than Group 2. Peak GH response was not different. Multiple regression analysis showed that FBG was the only independent predictor of adequate hypoglycaemia. An insulin dose of 0·2 units/kg achieved adequate hypoglycaemia in 80% of patients with FBG ≥ 5·5 mmol/l. In patients with acromegaly or Cushing's disease, failure to achieve adequate hypoglycaemia was associated with persistent disease.
Conclusion  FBG is an important determinant of the dose of insulin required to achieve adequate hypoglycaemia during an ITT in patients after pituitary surgery. A standard insulin dose of 0·1 U/kg is insufficient for adequate hypoglycaemia in patients with FBG > 5·5 mmol/l. Adequate response to a standard dose of insulin suggests a likelihood of cure of acromegaly or Cushing's disease after pituitary surgery.     

Investigation of the hypothalamo-pituitary-adrenal axis (HPA) by 1 microg ACTH test and metyrapone test in patients with primary fibromyalgia syndrome

Primary fibromyalgia syndrome (PFS) is characterized by widespread chronic pain that affects the musculoskeletal system, fatigue, anxiety, sleep disturbance, headache and postural hypotension. The pathophysiology of PFS is unknown. The hypothalamic-pituitary-adrenal (HPA) axis seems to play an important role in PFS. Both hyperactivity and hypoactivity of the HPA axis have been reported in patients with PFS. In this study we assessed the HPA axis by 1 microg ACTH stimulation test and metyrapone test in 22 patients with PFS and in 15 age-, sex-, and body mass index (BMI)- matched controls. Metyrapone (30 mg/kg) was administered orally at 23:00 h and blood was sampled at 08:30 h the following morning for 11-deoxycortisol. ACTH stimulation test was carried out by using 1 microg (iv) ACTH as a bolus injection after an overnight fast, and blood samples were drawn at 0, 30 and 60 min. Peak cortisol level (659.4 +/- 207.2 nmol/l) was lower in the patients with PFS than peak cortisol level (838.7 +/- 129.6 nmol/l) in the control subjects (p < 0.05). Ten patients (45%) with PFS had peak cortisol responses to 1 microg ACTH test lower than the lowest peak cortisol detected in healthy controls. After metyrapone test 11-deoxycortisol level was 123.7 +/- 26 nmol/l in patients with PFS and 184.2 +/- 17.3 nmol/l in the controls (p < 0.05). Ninety five percent of the patients with PFS had lower 11-deoxycortisol level after metyrapone than the lowest 11-deoxycortisol level after metyrapone detected in healthy controls. We also compared the adrenal size of the patients with that of the healthy subjects and we found that the adrenal size between the groups was similar. This study clearly shows that HPA axis is underactivated in PFS, rather than overactivated.     

Molecular regulation of the hypothalamo-pituitary-adrenal axis in streptozotocin-induced diabetes: effects of insulin treatment

Increased hypothalamo-pituitary-adrenocortical (HPA) activity in diabetes is likely important in the development of some pathologies associated with the disorder. We hypothesized that central regulation of HPA activity differs among normal, streptozotocin (STZ)-diabetic, and insulin-treated diabetic rats. Blood glucose, ACTH, and corticosterone were elevated, 8 d after inducing diabetes. Insulin treatment normalized these parameters. Plasma norepinephrine was similar in all groups, but epinephrine was lower in STZ-diabetic and higher in insulin-treated rats vs. normals. Increased ACTH with diabetes corresponded with increased hypothalamic CRH mRNA, but no change in pituitary POMC mRNA. With insulin-treatment, CRH mRNA remained elevated, and POMC mRNA was unaltered. Hippocampal MR mRNA expression was dramatically increased with diabetes and, moreover, was not normalized by insulin. No differences in GR mRNA were detected between normal and STZ-diabetic rats. However, insulin treatment increased GR mRNA levels in the paraventricular nucleus and pituitary. We postulate that, in STZ-diabetes: 1) increased HPA activity is caused by increased central drive at and/or above the level of the paraventricular nucleus and is associated with decreased epinephrine; and 2) normalized pituitary-adrenal activity with insulin may be caused by the compensatory increase in GR mRNA allowing glucocorticoid-mediated suppression of ACTH secretion despite the residual increase in central HPA activity. Thus, insulin apparently restored HPA activity at and below the pituitary but, surprisingly, not above it.     

Endomorphins and activation of the hypothalamo-pituitary-adrenal axis

Endomorphin (EM)-1 and EM-2 are opioid tetrapeptides recently located in the central nervous system and immune tissues with high selectivity and affinity for the mu-opioid receptor. Intracerebroventricular (i.c.v.) administration of morphine stimulates the hypothalamo-pituitary-adrenal (HPA) axis. The present study investigated the effect of centrally administered EM-1 and EM-2 on HPA axis activation. Rats received a single i.c.v. injection of either EM-1 (0.1, 1.0, 10 microg), EM-2 (10 microg), morphine (10 microg), or vehicle (0.9% saline). Blood samples for plasma corticosterone determinations were taken immediately prior to i.c.v. administration and at various time points up to 4 h post-injection. Trunk blood, brains and pituitaries were collected at 4 h. Intracerebroventricular morphine increased plasma corticosterone levels within 30 min, whereas EM-1 and EM-2 were without effect. In addition, pre-treatment of i.c.v. EM-1 did not block the rise in corticosterone after morphine. Corticotrophin-releasing factor (CRF) mRNA and arginine vasopressin (AVP) mRNA in the paraventricular nucleus (PVN) and POMC mRNA in the anterior pituitary were found to be unaffected by either morphine or endomorphins. Since release of other opioids are elevated in response to acute stress, we exposed rats to a range of stressors to determine whether plasma EM-1 and EM-2 can be stimulated by HPA axis activation. Plasma corticosterone, ACTH and beta-endorphin were elevated following acute restraint stress, but concentrations of plasma EM-1-immunoreactivity (ir) and EM-2-ir did not change significantly. Corticosterone, ACTH and beta-endorphin were further elevated in adjuvant-induced arthritis (AA) rats by a single injection of lipopolysaccharide (LPS), but not by restraint stress. In conclusion, neither EM-1 or EM-2 appear to influence the regulation of the HPA axis. These data suggest that endomorphins may be acting on a different subset of the mu-opioid receptor than morphine. The failure to induce changes in plasma EM-ir in response to the chronic inflammatory stress of AA, the acute immunological stress of LPS, or the psychological stress of restraint, argues against an important role for endomorphins in mediating HPA axis activity.     

Low dose (1 microg) adrenocorticotropin stimulation test in the evaluation of hypothalamo-pituitary-adrenal axis in patients with active pulmonary tuberculosis

Adrenocortical function in patients with active pulmonary tuberculosis is a debate of matter. Previous studies related to adrenocortical function in patients with active pulmonary tuberculosis demonstrated a high rate of suboptimal cortisol response to standard dose ACTH (250 microg) stimulation test. The aim of this study was to assess the hypothalamo-pituitary-adrenal (HPA) axis in low dose (1 microg) and standard dose ACTH (250 microg) stimulation tests in the patients with active pulmonary tuberculosis. Twenty-seven patients and 21 healthy subjects were included in the study. Cortisol levels were measured before, 30 and 60 min after ACTH (1 microg or 250 microg iv) injection. Cortisol responses to 1 microg ACTH at 30 and 60 min were significantly higher in the patient group than in the control group (p<0.05). Peak cortisol levels were significantly higher in the patient group than in the control group after both 1 microg and 250 microg ACTH administration (p<0.05). Cortisol responses to 250 microg ACTH at 30 and (at 30 and 60) 60 min were significantly higher in the patient group than in the control group (p<0.05). Peak cortisol levels obtained after 250 microg ACTH and after 1 microg ACTH were similar in the patient group (p>0.05). This study shows that 1 microg ACTH iv gives an equivalent peak cortisol value to 250 microg ACTH in patients with activated HPA axis. The cortisol levels obtained at 08:00, 11:00, 17:00 and 24:00 h were significantly higher in the patients than in the controls. This study clearly shows that HPA axis is activated in active pulmonary tuberculosis rather than underactivated.     

Clinical utility of insulin and insulin analogs

Diabetes is a pandemic disease characterized by autoimmune, genetic and metabolic abnormalities. While insulin deficiency manifested as hyperglycemia is a common sequel of both Type-1 and Type-2 diabetes (T1DM and T2DM), it does not result from a single genetic defect—rather insulin deficiency results from the functional loss of pancreatic β cells due to multifactorial mechanisms. Since pancreatic β cells of patients with T1DM are destroyed by autoimmune reaction, these patients require daily insulin injections. Insulin resistance followed by β cell dysfunction and β cell loss is the characteristics of T2DM. Therefore, most patients with T2DM will require insulin treatment due to eventual loss of insulin secretion. Despite the evidence of early insulin treatment lowering macrovascular (coronary artery disease, peripheral arterial disease and stroke) and microvascular (diabetic nephropathy, neuropathy and retinopathy) complications of T2DM, controversy exists among physicians on how to initiate and intensify insulin therapy. The slow acting nature of regular human insulin makes its use ineffective in counteracting postprandial hyperglycemia. Instead, recombinant insulin analogs have been generated with a variable degree of specificity and action. Due to the metabolic variability among individuals, optimum blood glucose management is a formidable task to accomplish despite the presence of novel insulin analogs. In this article, we present a recent update on insulin analog structure and function with an overview of the evidence on the various insulin regimens clinically used to treat diabetes.     

Dysregulation of the hypothalamo-pituitary-adrenal axis and duration of diabetes

We compared insulin-dependent diabetic outpatients with and without retinopathy for plasma indices of hypothalamo-pituitary-adrenal (HPA) axis activity. Diabetic patients with moderate-to-severe retinopathy had significantly higher postdexamethasone plasma levels of adrenocorticotropic hormone than patients with minimal or no retinopathy. However, when duration of diabetes was taken into account this difference was no longer significant. These data suggest that dysregulation of the HPA axis and retinal microvascular complications found in diabetic patients may both be a function of duration of diabetes.     

Canadian multi-institutional survey of immune tolerance therapy (ITT) – experience with the use of recombinant factor VIII for ITT

Immune tolerance therapy (ITT) is currently the most effective approach to eradicate inhibitors in patients with haemophilia A. Limited evidence suggests that the use of plasma-derived factor VIII (pdFVIII) for ITT may be associated with a greater success rate than recombinant factor VIII (rFVIII). Analysis of ITT cases in Canada offered the opportunity to examine the success rate of using rFVIII for ITT, as rFVIII has been used almost exclusively for Canadian haemophilia A patients since 1994. The results of 32 patients from five haemophilia treatment centres were collated. Three patients continue on ITT. Of the 29 patients who completed ITT, 25 (86.2%) used rFVIII exclusively, and four used pdFVIII exclusively or pdFVIII followed by rFVIII. The initial FVIII dosing frequency was once per day in 72.4% of patients at an average dose of 98 U kg(-1) (range 50-200). Eight patients (25%) received one or more adjuvant therapies. The median duration of ITT was 1.1 years (mean 1.5 years, range 9 days to 6 years). The overall success rate of the 29 patients who completed ITT was 79.3% (23/29), which is comparable with the results of immune tolerance registries. Our results suggest that the success rate of ITT using rFVIII is not inferior to the results with pdFVIII.