Heat-shock protein peptide DiaPep277 treatment in children with newly diagnosed type 1 diabetes: a randomised, double-blind phase II study.

BACKGROUND: Type 1 diabetes mellitus (T1DM) is a T-cell-mediated autoimmune disease that leads to the destruction of insulin-producing beta cells. Treatment with DiaPep277, a peptide derived from heat-shock protein 60 (hsp60), has been found to slow the deterioration of beta-cell function after clinical onset of diabetes in NOD mice and human adults. Our aim was to evaluate the efficacy and safety of DiaPep277 treatment in attenuating beta-cell destruction in children with recent-onset T1DM. METHODS: A prospective, randomized, double-blind, phase II design was used. The sample included 30 children (19 males) aged 7-14 years who had been diagnosed with T1DM from 53 to 116 days previously, and had basal C-peptide concentrations above 0.1 nmol/L. The children were randomized to receive subcutaneous injections of 1 mg DiaPep277 (15 patients) or 40 mg mannitol (placebo) at entry and at 1, 6, and 12 months. The duration of follow-up was 18 months. The groups were compared for stimulated C-peptide level, exogenous insulin dose, and HbA1c concentration. RESULTS: C-peptide levels similarly decreased over time in the DiaPep277- and placebo-treated patients. There was no significant difference in insulin dose or HbA1c concentration between the groups at any time point. No serious drug-related adverse effects were recorded throughout the study period. CONCLUSIONS: One-year treatment with DiaPep277 at a dosage of 1 mg is safe for use and well tolerated in children with recent-onset T1DM. However, it appears to have no beneficial effect in preserving beta-cell function or improving metabolic control.

Adrenal hypoplasia congenita with multiple pituitary hormone deficiency without documented mutation in DAX1 or SF1 gene.

A boy with adrenal hypoplasia congenita (AHC) and multiple pituitary hormone deficiency (MPHD), without mutations in the DAX1 or SF1 genes, is described. The association of AHC and MPHD has not been previously reported.

Type 1 diabetes environmental factors and correspondence analysis of HLA class II genes in the Yemenite Jewish community in Israel.

OBJECTIVE: The Israeli Yemenite Jewish community has displayed an exceptionally rapid increase in the frequency of type 1 diabetes, having the highest rate of all Israeli ethnic groups. We studied the role of the environment, in relation to the nature and frequency of HLA class II genes, to evaluate its possible involvement in the development of diabetes. RESEARCH DESIGN AND METHODS: We interviewed 196 elderly Yemenite women, who had immigrated to Israel as adults, in programmed encounters about signs and symptoms of type 1 diabetes, infant feeding customs, and infectious diseases in Yemen. We also performed HLA oligotyping of DRB1, DQA1, and DQB1 genes in 120 unrelated Yemenite Jews, including 44 type 1 diabetic patients and 76 healthy control subjects, and used these data in correspondence analysis comparing Yemenites with different Israeli ethnic groups. RESULTS: Interviews indicated that early exposure to cow's milk was very common in Yemen. However, none of the women could recall classical presentations of diabetes. HLA oligotyping showed that gene frequencies of non-Asp-57 (of the HLA-DQB chain) in the patients (0.94) and control subjects (0.6) were similar to those of other populations with a known high incidence of type 1 diabetes. Correspondence analysis revealed that Yemenite Jews are genetically distinct from other ethnic groups in Israel. CONCLUSIONS: The genetic distinctiveness of Yemenite Jews may explain their unusually high incidence of type 1 diabetes in Israel. Despite the presence of highly susceptible diabetogenic HL4 class II genes in this community, early exposure to cow's milk did not cause phenotypic expression of diabetes in Yemen. This finding suggests that in this population, either cow's milk does not play a crucial role in triggering diabetes, or environmentally conferred protection, such as frequent infectious disease in Yemen, was dominant.

Thyrotoxicosis in prepubertal children compared with pubertal and postpubertal patients.

The course of Graves' thyrotoxicosis in 7 prepubertal children (6.4+/-2.4 yr) was compared with that in 21 pubertal (12.5+/-1.1 yr) and 12 postpubertal (16.2+/-0.84 yr) patients. In the prepubertal group the main complaints were weight loss and frequent bowel movements (86%), whereas typical symptoms (irritability, palpitations, heat intolerance, and neck lump) occurred significantly less often (P < 0.01). The most prominent manifestation at diagnosis was accelerated growth and bone maturation: their height SD score was significantly greater than that of the pubertal and postpubertal patients (2.6+/-0.7 us. 0.15+/-0.65 and 0.15+/-0.9, respectively, P < 0.001), and their bone age to chronological age ratio was 1.39+/-0.35 compared with 0.98+/-0.06 in the pubertal children (P = 0.02). T3 levels were also significantly higher than in the other two groups (9.9+/-2.9 nmol/L vs. 6.32+/-1.9 nmol/L and 6.02+/-2.0 nmol/L, P = 0.01). All patients were initially prescribed antithyroid drugs (ATDs). Overall, adverse reactions to ATDs occurred in 35%, with a higher rate among the prepubertal children (71%) than the pubertal (28%) and postpubertal (25%) patients (P = 0.08). Major adverse reactions were noted in two children, both prepubertal. Remission was achieved in 10 patients (28%). Although the rate of remission did not differ among the three groups, time to remission tended to be longer in the prepubertal children (P = 0.09). In conclusion, thyrotoxicosis has an atypical presentation and more severe course in prepubertal children. Considering their adverse reactions to ATD, overall low remission rate, and long period to remission, definitive treatment should be considered earlier in this age group.

Genotype-phenotype associations in non-classical steroid 21-hydroxylase deficiency.

OBJECTIVE: To evaluate whether genotype differences can explain the clinical variability of non-classical steroid 21-hydroxylase deficiency (NC21-OHD) and to determine if genotype is related to ethnic origin. DESIGN: Genotyping for mutations in the steroid 21-hydroxylase (CYP21) gene was performed in 45 unrelated Israeli Jewish patients (nine males) with NC21-OHD (60min 17-hydroxyprogesterone (17-OHP), 45-386nmol/l) who were referred for evaluation of postnatal virilization or true precocious/early puberty. Eleven siblings diagnosed through family screening were genotyped as well. METHODS: Patients were divided by genotype into three groups: (A) homozygous or compound heterozygous for the mild mutations (V281L or P30L) (n=29; eight males); (B) compound heterozygous for one mild and one severe mutation (Q318X, I2 splice, I172N) (n=12; no males); (C) mild mutation detected on one allele only (n=4; one male; peak 17-OHP 58-151nmol/l). We then related the genotype to the ethnic origin, clinical phenotype and hormone level. Since group C was very small, comparisons were made between groups A and B only. RESULTS: At diagnosis, group B tended to be younger (5. 8+/-3.0 vs 8.1+/-4.3 years, P=0.09), had greater height SDS adjusted for mid-parental height SDS (1.6+/-1.1 vs 0.7+/-1.4, P=0.034), tended to have more advanced bone age SDS (2.9+/-1.5 vs 1.7+/-2.1, P=0.10) and had a higher peak 17-OHP level in response to ACTH stimulation (226+/-92 vs 126+/-62nmol/l, P<0.01). Group B also had pubarche and gonadarche at an earlier age (5.1+/-2.4 vs 7.4+/-2.2 years, P<0.01 and 7.4+/-1.8 vs 9.9+/-1.4 years, P<0.001, respectively) and a higher rate of precocious puberty (50 vs 17%, P=0.04). Stepwise logistic regression analysis (excluding males) yielded age at gonadarche as the most significant variable differentiating the two groups, with a positive predictive value of 86% for a cut-off of 7.5 years. CONCLUSIONS: The findings suggest that genotype might explain some of the variability in the phenotypic expression of NC21-OHD. Compound heterozygotes for one mild and one severe mutation have a higher peak 17-OHP associated with pubarche and gonadarche at an earlier age and more frequent precocious puberty. Hence, the severity of the enzymatic defect might determine the timing and pattern of puberty.

Combined clonidine-short-ACTH test for the simultaneous assessment of growth hormone reserve and hypothalamic-pituitary-adrenal axis integrity in children.

OBJECTIVE: To determine the feasibility of using the combined oral clonidine and the short-ACTH test instead of the sometimes dangerous insulin-induced hypoglycemia test as a screening procedure, for the simultaneous assessment of growth hormone reserve and hypothalamic-pituitary-adrenal axis integrity in children with growth retardation. DESIGN: Evaluative study. METHOD: Seventy-three children (52 males) aged 11+/-3 years with attenuated growth (group 1) were tested by combined clonidine (150 microg/m(2)) and short-ACTH test (either the standard 250 microg or the low-dose 1 microg/1. 73 m(2)). Thirty-one children received no pretreatment (nonprimed) (subgroup 1NP), and 42 were primed with ethynylestradiol 40 microg/m(2)/day two days before testing (subgroup 1P). The control group for the short-ACTH test (group 2) consisted of 42 children and adolescents (13 males) aged 12+/-3 years with early or accelerated puberty or premature closure of epiphyses, who received ACTH only (21 standard, 21 low-dose) with no evidence of adrenal or pituitary pathology. The peak GH response was compared between the primed and the nonprimed group 1 subjects, and the cortisol levels were compared between the combined test subgroups and the controls. The peak pass level for growth hormone was 10 ng/ml; the peak pass level for cortisol was 520 nmol/l. RESULTS: Sixty-four of the 73 children in group 1 (87.7%) showed a growth hormone level of >/=10 ng/ml on the first stimulation test, including 26/31 (84%) nonprimed and 38/42 (90.5%) primed. Of the 9 patients who failed the first clonidine test, 4 also failed the second, primed test, including 1/5 nonprimed patients (20%) and 3/4 primed patients (75%). This yielded a GH deficiency/insufficiency rate of 5.5% and a rather low false-positive rate of 13.3% (4/30) for the nonprimed subjects and 2. 6% (1/39) for the primed subjects. Peak 30-min cortisol in response to ACTH stimulation was similar in the patients who underwent the 250 microg or the 1 microg test within each group (subgroup 1NP, subgroup 1P and group 2); therefore, the results for the two tests were considered together. Compared with group 2, subgroup 1NP patients had a similar 30-min cortisol response (P=NS), and subgroup 1P patients had a much higher response (P<0.05) (group 2=690+/-145 nmol/l, subgroup 1NP=772+/-195 nmol/l, subgroup 1P=934+/-209 nmol/l). However, there was no significant difference in the increment in cortisol response between the three groups. CONCLUSIONS: Our results suggest that the combined clonidine-short-ACTH test is a reliable and safe tool for the simultaneous assessment of growth hormone reserve and hypothalamic-pituitary-adrenal axis integrity in children.

Neonatal pig islets induce a lower T-cell response than adult pig islets in IDDM patients.

BACKGROUND: Pancreatic pig islets may provide a substitute in the future for difficult to obtain human islets for transplantation in insulin-dependent diabetes millitus (IDDM) patients. However, the immune response to xenografts may significantly hamper this approach. Because neonatal tissue is believed to be less immunogenic, we examined whether the T-cell response to neonatal pig islets differs from the response to adult islets. METHODS: The T-cell proliferative response to different concentrations of sonicated neonatal and adult pig islets, as well as to insulin and mitogens, was tested in 21 recent onset IDDM patients and 21 healthy controls. We determined the presence of various circulating islet autoantibodies and their association with the T-cell response in IDDM patients. RESULTS: In the IDDM patients, sonicated adult pig islets (at 1 microg protein/ml) induced a significantly higher frequency (12 of 21 vs. 1 of 21, p<0.001) and magnitude (2.58+/-0.44 vs. 1.38+/-0.13, p<0.02) of positive T-cell responses than neonatal islets at the same concentration. Similar results were obtained with a 10-fold higher concentration of islet sonicate. There was no significant association between the individual T-cell responses and the presence of circulating autoantibodies in IDDM patients. CONCLUSION: These results indicate that neonatal pig islets induce a lower T-cell reactivity than adult islets, suggesting that the neonatal tissue may be immunologically more suitable for future islet xenotransplantation.

Parenteral selenium supplementation in extremely low birth weight infants: inadequate dosage but no correlation with hypothyroidism.

OBJECTIVE: Selenium is an essential trace element, known to be important in thyroid metabolism. We speculated that parenteral selenium supplementation is inadequate in preterm infants and may contribute to the development of hypothyroidism. STUDY DESIGN: Serum selenium and thyroid function were evaluated on day 10 of life in extremely low birth weight infants. Selenium intake provided by parenteral nutrition was prospectively evaluated. RESULTS: Selenium intake was close to the recommended 2 micrograms/kg per day. Serum selenium values were 0.54 +/- 0.13 microM (mean +/- SD, n = 29). Selenium serum levels were low in 26 of 29 infants. In infants with subnormal serum selenium levels, free T4 was transiently low in 10 of 26 infants but was normal in 16 of 26 infants. No significant correlation was found between serum selenium levels and hypothyroidism. CONCLUSION: Current selenium supplementation guidelines may be inadequate in extremely low birth weight infants. However, selenium deficiency does not seem to play a major role in neonatal hypothyroidism.

Standard and low-dose short adrenocorticotropin test compared with insulin-induced hypoglycemia for assessment of the hypothalamic-pituitary-adrenal axis in children with idiopathic multiple pituitary hormone deficiencies.

Insulin-induced hypoglycemia (IIH) is the gold standard test for assessment of the integrity of the hypothalamic-pituitary-adrenal (HPA) axis, but it may be hazardous. We sought to determine whether the standard (250 micrograms) or low-dose (1 microgram/1.73 m2) short ACTH test can replace IIH in patients with idiopathic multiple pituitary hormone deficiencies (MPHD). Three groups of subjects were studied: 1) control group, children with early or accelerated puberty and no other evidence of adrenal or pituitary pathology (n = 13, age 10.1 +/- 2.2 yr, 3 males); 2) patients with idiopathic hypothalamic pituitary insufficiency and either isolated GH deficiency or MPHD and preserved HPA function (n = 20, age 13.7 +/- 4.4 yr, 13 males); and 3) MPHD patients with impaired HPA axis function (n = 10, age 16.8 +/- 4.8 yr, 9 males). IIH and the 250 micrograms and 1 microgram/1.73 m2 ACTH tests were performed in groups 2 and 3; group 1 underwent only the ACTH tests. Pass peak cortisol level was defined as 520 nmol/L. No significant difference was noted between the standard and low-dose tests in the 30-min cortisol response to ACTH. Basal and peak cortisol levels attained on both ACTH tests were similar in groups 1 and 2 and significantly lower in group 3 (P < 0.0001). Both the 250 and 1 microgram ACTH tests were highly correlated with IIH (r = 0.71, P < 0.0001 for the 250 micrograms, r = 0.7, P < 0.0001 for the 1 microgram, n = 30), and both demonstrated high sensitivity (90% each) and specificity (100% and 90%, respectively) compared with IIH. We conclude that in idiopathic MPHD patients, both the standard and low-dose ACTH tests are equivalent to IIH in detecting HPA insufficiency. We suggest that they can replace IIH as a screening test for the integrity of the HPA axis in children with suspected MPHD.

MR findings in hereditary isolated growth hormone deficiency.

PURPOSE: To describe the MR characteristics by which patients with hereditary isolated growth hormone deficiency (GHD) can be distinguished from patients with other types of GHD. METHODS: A total of 51 patients with GHD were examined prospectively with MR imaging. On the basis of familial occurrence of GHD and genetic analysis, 10 patients met the criteria for hereditary deficiency. In each case, the height of the pituitary gland, the presence and location of the posterior neurohypophysis, and the completeness of the stalk were recorded. The findings in the hereditary group were compared with those in the rest of the patients. RESULTS: In all 10 patients with hereditary GHD, the adenohypophysis, the neurohypophysis, and the stalk were normal. Of the other 41 patients, the height of the gland was normal in three (7%), the neurohypophysis was abnormal in all, and the stalk was truncated in all but two patients (95%). CONCLUSIONS: The subgroup of patients with hereditary GHD exhibited an anatomically normal pituitary-hypothalamic region. This is in contrast to the majority of patients with idiopathic GHD. MR imaging can contribute to the classification of patients with GHD.

Normal proinsulin processing despite beta-cell dysfunction in persistent hyperinsulinaemic hypoglycaemia of infancy (nesidioblastosis).

Persistent hyperinsulinaemic hypoglycaemia of infancy (PHHI) is a genetic disorder which causes severe hypoglycaemia in the neonate. The beta cells fail to respond to changes in blood glucose levels in all the stages of the disease, which often ends with NIDDM. Fasting insulin, intact proinsulin and des 31,32 split proinsulin levels were measured in PHHI patients with active disease, patients after partial pancreatectomy, and those in clinical remission. All but one of the pancreatectomized patients developed diabetes and were hyperglycaemic on evaluation. Fasting insulin was comparable in pancreatectomized and medically treated patients. Des 31,32 split proinsulin levels were much higher in pancreatectomized compared to non-pancreatectomized patients (10.7 +/- 2.5 vs 3.4 +/- 0.8 pmol/l, p = 0.001) and age-matched control subjects (3.8 +/- 1.4 pmol/l, p = 0.018). Also the ratio of des 31,32 split proinsulin to total insulin plus proinsulin-like peptides was higher in pancreatectomized patients (18.7 +/- 2.8 vs 7.2 +/- 0.8% in non-pancreatectomized patients, p = 0.001, and 6.8 +/- 2.1% in normal control subjects, p = 0.004). Furthermore, des 31,32 split proinsulin was the dominating species of proinsulin-like molecules in the pancreatectomized patients (62.7 +/- 1.6% vs 45.5 +/- 3.8%, and 49.0 +/- 3.2% in non-pancreatectomized patients and control subjects, respectively, p = 0.001 and p = 0.0002). Intact proinsulin levels, and the proinsulin percentage, tended to be higher in pancreatectomized patients; however, the differences did not reach statistical significance. All parameters were similar in non-pancreatectomized patients and age-matched control subjects. Subgroup analysis showed comparable proinsulin-like peptide levels in patients with active disease and those in apparent clinical remission. Fasting levels of insulin and proinsulin-like peptides were also measured in a larger group of healthy children and young adults. Insulin and des 31,32 split proinsulin increased with age, the differences being most prominent when the young age group (0-8 years) was compared to the older groups (8-16 and > 16 years). The fasting levels of plasma insulin were correlated with those of intact proinsulin and des 31,32 split proinsulin (r = 0.82 and 0.81, respectively). Fasting insulin, intact proinsulin and des 31,32 split proinsulin were correlated with BMI (r = 0.55, 0.56 and 0.53, respectively). In summary, relative hyperproinsulinaemia was noted only in PHHI patients with increased secretory demand following pancreatectomy, but not in patients with active disease or those in spontaneous clinical remission. These findings suggest that abnormal proinsulin processing is not an intrinsic feature of PHHI despite the severe beta-cell dysfunction.

Effects of enalapril and nitrendipine on the excretion of epidermal growth factor and albumin in hypertensive NIDDM patients.

OBJECTIVE: To compare the effect of the antihypertensive drugs nitrendipine and enalapril on the excretion of epidermal growth factor (EGF) and albumin in hypertensive non-insulin-dependent diabetes mellitus (NIDDM) subjects. RESEARCH DESIGN AND METHODS: After a 4-week washout period, mildly hypertensive (systolic blood pressure [sBP] > or = 140 mmHg and/or diastolic blood pressure [dBP] > or = 90 mmHg) NIDDM patients with albuminuria (15-200 micrograms/min) were randomized into an 8-month-long therapy with either nitrendipine (n = 11) or enalapril (n = 10). Blood pressure, EGF, and microalbumin excretion were measured at baseline and throughout the treatment period. RESULTS: A significant fall in sBP was noticed in the enalapril group and in dBP in the nitrendipine group. In the enalapril group, EGF excretion progressively increased from 188 to 214 nmol/mmol creatinine after 6 weeks and to 274 after 8 months of therapy (P = 0.03). There was a significant fall in albumin excretion while patients were on enalapril, but in the nitrendipine group, neither albuminuria nor EGF excretion changed significantly. There was no correlation of improved EGF excretion with a decrease in albuminuria or BP. CONCLUSIONS: The angiotensin-converting enzyme inhibitor enalapril has been effective in decreasing albumin and increasing EGF excretion. Measurement of urinary EGF may provide a new valuable index of renal function.

Excretion of epidermal growth factor (EGF) in diabetes.

Excretion of epidermal growth factor (EGF) is decreased in renal failure. We assayed it in diabetes mellitus in an attempt to relate it to clinical parameters, esp. those of diabetic nephropathy. EGF excretion declined with age but in all age groups of diabetic patients was below the first percentile for controls. In 26 control and 34 prepubertal diabetic children excretion was correspondingly 1126 +/- 442 and 932 +/- 489 pmol/mmol creatinine (P = 0.087); in 26 control and 42 diabetic adolescents below age 18, 778 +/- 222 and 676 +/- 335 (P = 0.023) and in 81 control and 83 diabetic adults, 371 +/- 153 and 235 +/- 140 (P less than 0.0001). Decreased excretion of EGF was seen in some patients without any diabetic complications. Excretion of EGF was independently and inversely correlated with age and duration of diabetes but not with type of diabetes, treatment, body built, C-peptide, plasma glucose, glycohemoglobin or retinopathy. A positive correlation was seen with creatinine clearance and a negative correlation, with albuminuria, but the strongest and the only independent correlation found by stepwise multiple variable selection was with serum creatinine (r -0.711, P less than 0.0001). EGF excretion was not elevated in patients with hyperfiltration. We conclude that EGF excretion is abnormal in many patients with diabetes and that this abnormality reflects a kidney function different from glomerular filtration or glomerular permeability.

Congenital hereditary hypothyroidism--prenatal diagnosis and treatment.

Intrauterine diagnosis of congenital hypothyroidism was established on the basis of TSH concentration in amniotic fluid in the 22nd week of gestation for the offspring of a couple both known to have an iodide organification defect. Prenatal treatment consisted of intramniotic injections of 500 mcg Na-1-thyroxine, which was administered from the first amniocentesis until one week before delivery. Following delivery, the diagnosis was confirmed by the elevated level of TSH, 60.5 uU/ml, and a gradual decrease of fT4 to 0.8 ng/ml. Regular substitution therapy was commenced on the third day of life. The normal shape and location of the thyroid gland was demonstrated by Technetium scintiscan. At 18 months the infant revealed no significant deviation from normalcy in growth or mental capacity. This experience indicates that testing of amniotic fluid for TSH in the 22nd week of gestation can be diagnostic for congenital primary hypothyroidism. Furthermore, it is suggested that the treatment approach described is warranted in all cases in which there is a high risk of congenital primary hypothyroidism.

Effect of oral clonidine, insulin-induced hypoglycemia and exercise on plasma GHRH levels in short-stature children.

Human growth hormone release is affected by a variety of pharmacological and physiological stimuli. We have studied the effect of oral clonidine, insulin hypoglycemia, and exercise on plasma hGH and GHRH levels in 31 healthy short-stature children. Thirteen underwent an oral clonidine test (0.15 mg/m2), 12 an iv. insulin test (0.1 U/kg), and 6 performed exercise (running for 10 min in a defined route). GHRH-1-44 was extracted from plasma on silica columns and determined by RIA. Although all three stimuli induced a marked increase in plasma hGH levels, only clonidine induced a significant increase in plasma GHRH levels. Maximal increment in GHRH during clonidine was 6.82 +/- 1.05 pmol/l (mean +/- SEM) as compared with 0.51 +/- 0.28 and 0.53 +/- 0.62 during hypoglycemia and exercise (p less than 0.0005 and p less than 0.005), respectively. An additional 24 subjects received TRH 0.2 mg/kg iv: 8 TRH alone, 8 TRH and insulin, and 8 TRH and clonidine. Only insulin potentiated the TRH-induced TSH response with a peak of 22.0 +/- 3.2 vs 16.0 +/- 0.8 and 15.3 +/- 1.5 mU/l (p less than 0.025) for TRH alone and TRH and clonidine, respectively. It is suggested that clonidine stimulates hGH secretion mainly through an enhancement of GHRH release, whereas stress stimuli such as hypoglycemia and exercise achieve hGH release by a different mechanism, possibly inhibition of somatostatin.

When should hydrocortisone therapy be instituted in children with hypopituitarism?

The records of 72 pediatric and adolescent patients with multiple hypothalamic and/or pituitary hormone deficiencies of nontumoral origin who were followed up for years and receiving somatotropin, thyroxine, and sex hormones at the appropriate age have been reviewed. According to their corticotropin-releasing factor-corticotropin-cortisol (CAC) axis function as evaluated by basal plasma cortisol levels and the response of cortisol to insulin hypoglycemia and to corticotropin-releasing factor, the patients were divided into three groups: group 1 (n = 25), patients with multiple hypothalamic and/or pituitary hormone deficiencies with normal CAC axis; group 2 (n = 38), patients with partial CAC deficiency without cortisol replacement therapy (hydrocortisone); and group 3 (n = 9), patients with CAC deficiency receiving hydrocortisone therapy (5 to 10 mg/d). Repeated CAC axis evaluation in patients of group 2 over years revealed a progressive decrease in the basal and stimulated cortisol levels with age and pubertal advancement. Despite the low cortisol levels and the low cortisol response to insulin hypoglycemia, these patients did not have clinical symptoms until the end of puberty when nine of 24 patients complained of abdominal pain, weakness, or anorexia. Linear growth, which was followed up in all patients at regular intervals, showed a lower growth velocity and irregular growth in response to somatotropin treatment in the patients receiving low doses of hydrocortisone (group 3 patients when compared with group 2 patients not receiving hydrocortisone).

Discrimination between growth hormone (GH) deficiency of hypothalamic or pituitary origin: an aid in selecting patients for GH-releasing hormone (RH) prolonged therapy.

Eleven patients with GH deficiency (GHD) underwent i.v. GH-RH tests (1 mu/kg); 7 had idiopathic GH deficiency (IGHD) and 4 had multiple pituitary hormone deficiencies (MPHD)--diagnosed on the basis of the insulin hypoglycemia, clonidine and sleep tests. One test was done before and the other after five s.c. injections of 1 microgram/kg GH-RH given in the evening. There were three types of response: four patients in whom there was an increase of human GH (hGH) to twice the former level, from 11.6 +/- 4.9 to 22.8 +/- 7.3 ng/ml following priming (a partial hypothalamic lesion); five patients in whom there was no response to the pharmacological tests but the same rise of approximately 13 ng/ml in hGH in response in both acute GH-RH tests (partial pituitary lesion); and two patients with no response to the pharmacological and acute GH-RH tests (pituitary lesion). In all except one patient there was no change in the serum IGF-I values after 5 days priming with GH-RH. It is suggested that patients with a partial GHD due to a hypothalamic lesion might benefit from long-term therapy with GH-RH.