Impaired Growth Hormone Response Research Articles

Impaired Cortisol and Growth Hormone Counterregulatory Responses among Severe Hypoglycemic Patients with Type 2 Diabetes Mellitus

BackgroundElevated levels of cortisol and growth hormone are critical counterregulatory responses to severe hypoglycemia. However, the proportion and clinical characteristics of patients with type 2 diabetes mellitus (DM) who fail to show appropriate cortisol and/or growth hormone secretion in response to severe hypoglycemia have not been investigated.MethodsWe measured plasma cortisol and growth hormone levels in type 2 DM patients with severe hypoglycemia who visited the emergency department between 2006 and 2015.ResultsOf 112 hypoglycemic patients, 23 (20.5%) had an impaired cortisol response (<18 µg/dL) and 82 patients (73.2%) had an impaired growth hormone response (<5 ng/mL). Nineteen patients (17.0%) had impaired responses to both cortisol and growth hormone. The patients with impaired responses of cortisol, growth hormone, and both hormones were significantly older and more likely to be female, and had higher admission rates, lower growth hormone levels, and lower adrenocorticotropic hormone levels than the patients with a normal hormonal response. Multivariate logistic regression analysis indicated that an impaired growth hormone response was significantly associated with advanced age, shorter DM duration, a higher admission rate, and a higher body mass index (BMI). An impaired cortisol response was significantly associated with growth hormone levels. Patients with an impaired growth hormone response had higher admission rates than patients with a normal response.ConclusionA considerable number of type 2 DM patients had impaired cortisol and/or growth hormone responses to severe hypoglycemia. Advanced age, shorter DM duration, and higher BMI were independently associated with an abnormal growth hormone response.

Pituitary growth hormone (GH) secretion is partially rescued in HIV-infected patients with GH deficiency (GHD) compared to hypopituitary patients.

Biochemical growth hormone deficiency is prevalent among human immunodeficiency virus-infected patients, but if this condition is clinically relevant remains challenging. The aim is to prospectively compare the growth hormone deficiency/insulin-like growth factor-1 status of 71 human immunodeficiency virus-infected patients with impaired growth hormone response to growth hormone releasing hormone + Arginine with that of 65 hypopituitary patients affected by a true growth hormone deficiency secondary to pituitary disease. The main outcomes were: basal serum growth hormone, insulin-like growth factor-1, insulin-like growth factor binding protein 3, growth hormone peak and area under the curve after growth hormone response to growth hormone releasing hormone + Arginine test, body mass index, waist and hip circumference, and body composition by dual energy X-ray absorptiometry. Insulin-like growth factor-1 binding protein 3, basal growth hormone (p < 0.005), growth hormone peak and area under the curve after growth hormone response to growth hormone releasing hormone + Arginine, waist to hip ratio, insulin-like growth factor-1, fasting glucose, insulin, and triglycerides (p < 0.0001) were lower in hypopituitary than human immunodeficiency virus-infected patients. Total and trunk fat mass by dual energy X-ray absorptiometry were higher in hypopituitary than in human immunodeficiency virus-infected patients (p < 0.0001). In all the patients total body fat was associated with both growth hormone peak and area under the curve at stepwise linear regression analysis. The degree of growth hormone deficiency is more severe in hypopituitary than in human immunodeficiency virus-infected patients, suggesting that the function of growth hormone/insulin-like growth factor-1 axis is partially rescued in the latter thanks to a preserved pituitary secretory reserve. Data from the current study suggest that human immunodeficiency virus-infected patients with peak growth hormone < 9 mg/L may have partial growth hormone deficiency and clinicians should be cautious before prescribing recombinant human growth hormone replacement treatment to patients living with human immunodeficiency virus.

Effects of gender, body weight, and blood glucose dynamics on the growth hormone response to the glucagon stimulation test in patients with pituitary disease

ObjectiveBody weight blunts the growth hormone (GH) response to provocative stimuli. The appropriate GH cut-off to confirm GH deficiency in obese and overweight patients undergoing the glucagon stimulation test (GST) has recently been questioned. We hypothesized that the peak GH would be inversely related to the nadir blood glucose (BG) after glucagon and that this may be a mechanism influencing peak GH in overweight patients. This retrospective study examined effects of gender, body weight, and BG dynamics on GH response to GST in patients evaluated in our Pituitary Center. DesignAdult patients who underwent GST from September 2009–2014 were included. Continuous variable comparisons were analyzed using the Mann–Whitney U-test and categorical data by Fisher's Exact Test. Spearman correlation was used to determine associations between continuous variables. Results42 patients (N=28, 66.7% female) had sufficient data for analysis. Obese patients (N=26) had a reduced GH response, summarized as GH area under the curve (AUC) (p=0.03 vs. non-obese patients) and higher BG during GST, summarized as AUC (p<0.01 vs. non-obese patients). Obese women (N=19), in particular, stimulated lower (p=0.03 vs. non-obese women) and had a higher nadir BG (p=0.03 vs. non-obese women). While weight correlated with extent (rs=0.35; p=0.02) and timing (rs=0.31; p=0.05) of nadir BG reached, there was no significant correlation between BG dynamics and the GH response in the total population (N=42). Ten patients (7 with pan anterior hypopituitarism, defined as 3 anterior pituitary deficiencies) had a peak GH≤0.1ng/mL during GST. When these subjects with a negligible peak GH response were excluded from the analysis, weight was associated with GH AUC (rs=−0.45; p=0.01), peak GH response (rs=−0.42; p=0.02) and nadir BG (rs=0.48; p<0.01). Furthermore, the nadir BG achieved during GST was inversely related to GH AUC (rs=−0.38; p=0.03) and peak GH (rs=−0.37; p=0.04) such that patients (N=32) with higher nadir BG had lower peak GH in response to glucagon. ConclusionsObese patients, particularly women, do not respond as robustly to glucagon stimulation. These data suggest that there exists an altered BG profile during GST in obese individuals, and that a less robust hypoglycemic stimulus may contribute to an impaired GH response. We suggest measuring BG levels during glucagon stimulation testing to assist with clinical interpretation of GH dynamics. The diagnostic accuracy of the GST in patients with known disorders in glucose metabolism and those taking anti-diabetic medications deserves further study.

Classic Bartter syndrome complicated with profound growth hormone deficiency: a case report

IntroductionClassic Bartter syndrome is a salt-wasting tubulopathy caused by mutations in the CLCNKB (chloride channel Kb) gene. Although growth hormone deficiency has been suggested as a cause for persistent growth failure in patients with classic Bartter syndrome, in our opinion the diagnoses of growth hormone deficiency has been unconvincing in some reports. Moreover, Gitelman syndrome seems to have been confused with Bartter syndrome in some cases in the literature. In the present work, we describe a new case with CLCNKB gene mutations and review the reported cases of classic Bartter syndrome associated with growth hormone deficiency.Case presentationOur patient was a Japanese boy diagnosed as having classic Bartter syndrome at eight months of age. The diagnosis of Bartter syndrome was confirmed by CLCNKB gene analysis, which revealed compound heterozygous mutations with deletion of exons 1 to 3 (derived from his mother) and ΔL130 (derived from his father). His medical therapy consisted of potassium (K), sodium chloride, spironolactone, and anti-inflammatory agents; this regime was started at eight months of age. Our patient was very short (131.1cm, -4.9 standard deviation) at 14.3 years and showed profoundly impaired growth hormone responses to pharmacological stimulants: 0.15μg/L to insulin-induced hypoglycemia and 0.39μg/L to arginine. His growth response to growth hormone therapy was excellent.ConclusionsThe present case strengthens the association between classic Bartter syndrome and growth hormone deficiency. We propose that growth hormone status should be considered while treating children with classic Bartter syndrome.

Late Primary Autoimmune Hypothyroidism in a Patient with Postdelivery Autoimmune Hypopituitarism Associated with Antibodies to Growth Hormone and Prolactin-Secreting Cells

Pituitary and thyroid autoimmunity can be triggered by pregnancy. We report the first association of combined growth hormone (GH) and prolactin secretion deficiency due to autoimmune damage to GH- and prolactin-secreting cells in a patient with postdelivery lactation failure, presenting subsequently with primary autoimmune hypothyroidism. A 34-year-old woman presented with lactation failure following the delivery of her first child. She had a family history of hypothyroidism without a history of pituitary dysfunction. Physical examination did not show any abnormal findings. Laboratory investigations showed normal gonadotropin levels after the restoration of normal menstrual cycles following pregnancy, normal basal and stimulated cortisol levels, but an impaired GH response to insulin-induced hypoglycemia, and low basal prolactin and insulin-like growth factor-1 concentrations. Thyroid function was normal when initially investigated three months after delivery, but five months later, marked primary hypothyroidism (thyrotropin levels >100 mIU/L) occurred. Immunological investigation revealed the presence of antipituitary antibodies, identified by double immunofluorescence and targeting GH- and prolactin-secreting cells. Antithyroid antibodies, in the normal range three months postpartum, became significantly elevated when the hypothyroidism appeared. Autoimmune hypophysitis is responsible for selective or multiple pituitary-hormone deficiencies, sometimes involving thyrotropin secretion and causing secondary hypothyroidism, but usually associated with hyperprolactinemia. To our knowledge, this is the first observation of autoimmune hypopituitarism involving deficient growth hormone and prolactin secretion in a patient with lactation failure after delivery, subsequently followed by severe primary autoimmune hypothyroidism, thus falling into an unusual constellation of autoimmune polyendocrine syndrome type 3. Considering the well-known relationship between pregnancy and autoimmunity, an early postdelivery immunological and functional investigation in women presenting with disorders of lactation may be useful to detect potential pituitary and thyroid dysfunction even at a subclinical stage.

Changes in pain and insulin-like growth factor 1 in fibromyalgia during exercise: the involvement of cerebrospinal inflammatory factors and neuropeptides

IntroductionFibromyalgia (FM) is characterized by chronic pain. Impaired growth hormone responses and reduced serum insulin-like growth factor 1 (IGF-1) are common in FM. The aim was to examine changes in serum IGF-1, cerebrospinal fluid (CSF), neuropeptides, and cytokines during aerobic exercise in FM patients.MethodsIn total, 49 patients (median age, 52 years) with FM were included in the study. They were randomized to either the moderate- to high-intensity Nordic Walking (NW) program (n = 26) or the supervised low-intensity walking (LIW) program (n = 23). Patients participated in blood tests before and after 15 weeks of aerobic exercise. Changes in serum levels of free IGF-1, pain rating on a 0- to 100-mm scale, pain threshold, and 6-minute walk test (6MWT) were examined. CSF, neuropeptides, matrix metalloproteinase 3 (MMP-3), and inflammatory cytokines were determined. Nonparametric tests were used for group comparisons and correlation analyses.ResultsSerum free IGF-1 levels did not change during 15 weeks of exercise between the two groups, although the 6MWT significantly improved in the NW group (p = 0.033) when compared with LIW. Pain did not significantly change in any of the groups, but tended to decrease (p = 0.052) over time in the total group. A tendency toward a correlation was noted between baseline IGF-1 and a decrease of pain in response to exercise (r = 0.278; p = 0.059). When adjusted for age, this tendency disappeared. The change in serum free IGF-1 correlated positively with an alteration in CSF substance P (SP) levels (rs = 0.495; p = 0.072), neuropeptide Y (NPY) (rs = 0.802; p = 0.001), and pain threshold (rs = 0.276; p = 0.058). Differing CSF SP levels correlated positively to a change in pain threshold (rs = 0.600; p = 0.023), whereas the shift in CSF MMP-3 inversely correlated with an altered pain threshold (rs = -0.569; p = 0.034).ConclusionsThe baseline level of serum free IGF-1 did not change during high or low intensity of aerobic exercise. Changes in IGF-1 correlated positively with a variation in CSF SP, NPY, and pain threshold. These data indicate a beneficial role of IGF-1 during exercise in FM.Trial registration: ClinicalTrials.gov NCT00643006.

Pituitary Function and IGF-I Levels following Ischemic Stroke

Background: Pituitary dysfunction is a known complication of traumatic brain injury and subarachnoidal hemorrhage but there are few data about pituitary dysfunction as a complication of ischemic stroke. Methods: We prospectively studied patients 66–274 days after an ischemic stroke, evaluating the prevalence of pituitary dysfunction (by combined releasing hormone testing: GHRH, CRH), stroke severity, outcome and incidence of anxiety and depression. Results: Thirty-two patients (82%) presented with some degree of pituitary dysfunction with predominantly impaired growth hormone response (79.5%) and secondary adrenal failure (14.6%). Abnormal anxiety and/or depression was found in 28.3 and 32.7% of the patients. NIHSS (National Institute of Health Stroke Scale) varied between 1 and 15. Improvement in neurological deficit (ΔNIHSS) correlated significantly with NIHSS at baseline (p < 0.001) but not with pituitary function. Conclusions: Patients with ischemic stroke may suffer from pituitary dysfunction with predominantly impaired growth hormone response and secondary adrenal failure. We suggest that patients who suffer from stroke should undergo pituitary testing.

Impaired growth hormone response to clonidine in obesity.

Clonidine, an imidazoline derivative, is an antihypertensive agent which reduces sympathetic tone by acting in the central nervous system to stimulate alpha-2 adrenoceptors. There is evidence that dopamine and norepinephrine modulate the secretion of GH. Stimulation of GH release is a well-known effect of clonidine in man. Obesity is characterized by an impairment of GH release in response to various stimuli. The aim of this work is to study GH release in response to alpha-2 adrenoceptors stimulation by clonidine in obesity. 12 volunteer obese subjects were studied. 10 normal weight subjects, sex and age matched, were controls. The GH responsiveness was tested with a single oral dose of clonidine (0.15 mg). Blood was sampled for GH radioimmunoassay at 0', 30', 60', 90', 120', 150', 180'. Serum GH basal levels were not significant different in obese subjects compared to controls. In obese subjects, no significant changes occurred in blood GH concentration after clonidine. In normal weight controls, instead, a significant increase of GH values was reached at 90' (P less than 0.05) and at 120' (P less than 0.05) after clonidine. The impairment of GH release after clonidine in obese subjects might be in a reduced serotonin release or in a failure of the hypothalamic-pituitary system to stimulate plasma GH caused by a diminished GH releasing factor stimulatory effect or by an excessive endorphin or somatostatin secretion in obesity.

Growth hormone response to the GABA-B agonist baclofen in 3-week abstinent alcoholics

Gamma-aminobutyric acid (GABA) dysfunction is a known feature of alcoholism. We investigated GABA-B receptor activity in 3-week abstinent alcoholics using the growth hormone (GH) response to baclofen, a GABA-B receptor agonist. The study aimed to investigate the relationship between GABA-B receptor activity and alcohol withdrawal. GH response to baclofen was measured in alcohol-dependent males without depression ( n = 22) who were on day 21 of alcohol abstinence and in healthy control male subjects ( n = 23). After 20 mg baclofen was given orally to the subjects, blood samples for GH assay were obtained every 30 min for the subsequent 150 min. The patients were divided into two subgroups (continuing withdrawal and recovered withdrawal subgroups) according to their withdrawal symptom severity scores on day 21 of alcohol cessation. Baclofen administration significantly altered GH secretion in the controls, but not in the patients. When GH response to baclofen was assessed as ΔGH, it was lower in the patients with continuing withdrawal symptoms than in the controls and in the recovered withdrawal group. Impaired GH response to baclofen in all patients mainly pertained to the patients whose withdrawal symptoms partly continued. Our results suggest that reduced GABA-B receptor activity might be associated with longer-term alcohol withdrawal symptoms in alcoholic patients.

Growth hormone insufficiency and its impact on ovarian function.

Growth hormone (GH) and the insulin-like growth factor-I (IGF-I) play significant roles in pubertal development, menarche, the menstrual cycle, fertility, and reproduction. Growth hormone deficiency or insufficiency causes a delay in the onset of puberty and in its normal course unless treated with synthetic GH. It seems that GH affects the ovary during puberty both indirectly through the gonadotropins and IGF-I, and directly through its effect on steroidogenesis. The GH axis is activated by small increases in circulating estrogens, which initiate large increases in GH during puberty. The reproductive function of the female is also affected by GH. GH acts on the ovary affecting gametogenesis and steroidogenesis. GH receptor mRNA and protein have been found in ovarian cells, and this suggests that the direct action of GH provides an important modulatory effect on gonadotropin-dependent and -independent functions. It also affects the maturation of the follicle and gamete, and thereby plays a facilitatory role in fertility. The majority of women with GH-deficiency, but not all, require assisted reproductive technologies to induce ovulation. Many women with polycystic ovary syndrome (PCOS) have an impaired GH response to stimulation with Levo-Dopa and GH releasing hormone (GHRH). Hyperandrogenism in PCOS may contribute to the reduced GH secretion because testosterone directly stimulates somatostatin release. Reduction of the excessive androgens facilitates the dopaminergic control of GH. In conclusion, GH-insufficient states disrupt ovarian function, causing problems in sexual maturation, the menstrual cycle, and the reproductive ability of the female.

Metabolic regulation of growth hormone by free fatty acids, somatostatin, and ghrelin in HIV-lipodystrophy

Human immunodeficiency virus (HIV)-lipodystrophy is a syndrome characterized by changes in fat distribution and insulin resistance. Prior studies suggest markedly reduced growth hormone (GH) levels in association with excess visceral adiposity among patients with HIV-lipodystrophy. We investigated mechanisms of altered GH secretion in a population of 13 male HIV-infected patients with evidence of fat redistribution, compared with 10 HIV-nonlipodystrophic patients and 11 male healthy controls similar in age and body mass index (BMI). Although similar in BMI, the lipodystrophic group was characterized by increased visceral adiposity, free fatty acids (FFA), and insulin and reduced extremity fat. We investigated ghrelin and the effects of acute lowering of FFA by acipimox on GH responses to growth hormone-releasing hormone (GHRH). We also investigated somatostatin tone, comparing GH response to combined GHRH and arginine vs. GHRH alone with a subtraction algorithm. Our data demonstrate an equivalent number of GH pulses (4.1 +/- 0.6, 4.7 +/- 0.8, and 4.5 +/- 0.3 pulses/12 h in the HIV-lipodystrophic, HIV-nonlipodystrophic, and healthy control groups, respectively, P > 0.05) but markedly reduced GH secretion pulse area (1.14 +/- 0.27 vs. 4.67 +/- 1.24 ng.ml(-1).min, P < 0.05, HIV-lipodystrophic vs. HIV-nonlipodystrophic; 1.14 +/- 0.27 vs. 3.18 +/- 0.92 ng.ml(-1).min, P < 0.05 HIV-lipodystrophic vs. control), GH pulse area, and GH pulse width in the HIV-lipodystrophy patients compared with the control groups. Reduced ghrelin (418 +/- 46 vs. 514 +/- 37 pg/ml, P < 0.05, HIV-lipodystrophic vs. HIV-nonlipodystrophic; 418 +/- 46 vs. 546 +/- 45 pg/ml, P < 0.05, HIV-lipodystrophic vs. control), impaired GH response to GHRH by excess FFA, and increased somatostatin tone contribute to reduced GH secretion in patients with HIV-lipodystrophy. These data provide novel insight into the metabolic regulation of GH secretion in subjects with HIV-lipodystrophy.

Catecholamine and HPA Axis Dysfunction in Depression: Relationship with Suicidal Behavior

A large body of evidence suggests a potential role for catecholaminergic function as a possible biological factor in the control of suicidal behavior. Recently, we have used a neuroendocrine strategy to study dopaminergic and noradrenergic activities in depressed suicide attempters. However, some problems are associated with the use of growth hormone (GH) response to catecholaminergic challenge, because GH release could be decreased by a direct effect of corticosteroids at the pituitary level. Therefore, the purpose of the present study was to assess GH response to both apomorphine, a dopaminergic agonist, and clonidine, an α2-adrenergic agonist, according to the dexamethasone suppression test (DST) status in a sample of 20 major depressed inpatients with a history of suicide attempt compared with nonattempters. Our results tended to show that hypercortisolemia as assessed by post-DST cortisol values did not inhibit GH response to apomorphine or clonidine, suggesting that hypothalamo-pituitary-adrenal axis overactivity does not explain the impaired GH response to apomorphine in major depressed patients with a history of suicide attempt.

GH/IGF-I axis in anorexia nervosa

Patients with anorexia nervosa (AN) may develop multiple endocrine abnormalities, including amenorrhea, hyperactivity of the hypothalamus-pituitary-adrenal axis, hypothyroidism and particular changes in the activity of the growth hormone (GH)/insulin-like growth factor I (IGF-I) axis. Exaggerated GH secretion and reduced IGF-I levels are usually found in AN, as well as in conditions of malnutrition and malabsorption, insulin-dependent diabetes mellitus, liver cirrhosis and catabolic states. In AN, GH hypersecretion at least partially reflects malnutrition-induced peripheral GH resistance, which leads to reduced IGF-I synthesis and release; this implies an impairment of the negative IGF-I feedback action on GH secretion. On the other hand, primary alterations in the neural control of GH secretion cannot be ruled out. The neuroendocrine alterations include enhanced somatotroph responsiveness to growth hormone releasing hormone (GHRH) and impaired GH response to most central nervous system-mediated stimuli. Particular resistance to cholinergic manipulation has also been demonstrated, thus suggesting a somewhat specific alteration in the somatostatin (SS)-mediated cholinergic influence on GH secretion. Moreover, paradoxical GH responses to glucose load, thyrotropin releasing hormone (TRH) and luteinizing hormone releasing hormone (LHRH) have also been reported. The effect of reduced leptin levels on GH hypersecretion in AN is still unclear, but ghrelin (the gastric hormone that is a natural ligand of the GH secretagogue receptor and strongly stimulates somatotroph secretion) is thought to play a major role. Regardless of the supposed central and peripheral alterations, it has to be emphasised that the activity of the GH/IGF-I axis in AN is generally restored by nutritional and stable weight gain. It therefore reflects an impaired nutritional state and cannot be considered a primary hallmark of the disease.

Impaired growth hormone secretion in fibromyalgia patients: evidence for augmented hypothalamic somatostatin tone.

To determine whether female fibromyalgia (FM) patients exhibit a normal growth hormone (GH) response to an acute exercise stressor, and to assess the importance of somatostatin tone in the generation of this GH response. Twenty female FM patients were compared with 10 healthy female controls. All subjects exercised to volitional exhaustion on a treadmill. A standard metabolic cart was used to monitor pulse, blood pressure, electrocardiography, oxygen uptake, carbon dioxide output, anaerobic threshold, and maximal workload. Blood was drawn for GH and cortisol measurements 1 hour before exercise, immediately before exercise, immediately after exercise, and 1 hour after exercise. One month later, testing that was exactly similar was performed, except all subjects were given pyridostigmine bromide (Mestinon; 30 mg orally) 1 hour before exercise. Compared with controls, FM patients failed to exhibit a GH or cortisol response to acute exercise (P = 0.003). After administration of pyridostigmine, 1 hour before exercise, the GH levels of FM patients increased 8-fold (P = 0.001), to a value comparable with that of controls. Pyridostigmine did not increase the cortisol response to exercise in FM patients. Pyridostigmine alone did not stimulate GH secretion in FM patients, nor did it improve exercise-induced GH secretion in controls. FM patients with normal insulin-like growth factor 1 (IGF-1) levels had an impaired GH response to exercise. Three new findings are reported: 1) FM patients have a reduced GH response to exercise, 2) pyridostigmine reverses this impaired response, and 3) defective GH secretion in FM can occur in patients with normal IGF-1 levels. Because pyridostigmine is known to reduce somatostatin tone, it is surmised that the defective GH response to exercise in FM patients probably results from increased levels of somatostatin, a hypothalamic hormone that inhibits GH secretion.

Reduced dopamine function in depressed patients is related to suicidal behavior but not its lethality

Several lines of evidence suggest a role for dopamine in the control of suicidal behaviour. Previously, we suggested an involvement of D2-dopaminergic function in the biology of suicide by demonstrating a smaller growth hormone (GH) response to apomorphine, a dopaminergic agonist, in depressed patients who later died by suicide. The purpose of the present study was to assess GH response to apomorphine in major depressed in-patients with a history of highly lethal suicide attempt compared to depressed patients with a low lethal lifetime suicide attempt history and non-attempters. The study was performed in a sample of 26 male depressed in-patients with a history of suicide attempt compared to 26 male depressed non-attempters. We observed a significant difference between suicide attempters and non-attempters (for GH peak, 6.3+/-5.1 ng/ml vs 15.8+/-14.2 ng/ml, F=10.3, df=1, 50, P=0.002). Moreover, GH peak responses to apomorphine did not differ between depressed patients with a high lethal lifetime suicide attempt history and patients who made low lethal lifetime suicide attempt. In conclusion, the results of the present study support a role for dopamine in the biology of suicidal behaviour. More specifically, an impaired GH response to apomorphine could be a marker of suicide risk.

Effects of autonomic neuropathy on counterregulation and awareness of hypoglycemia in type 1 diabetic patients.

The recent EURODIAB Study has identified autonomic neuropathy as an independent risk factor for severe hypoglycemia in patients with type 1 diabetes. We tested the hypothesis that counterregulatory catecholamine responses and awareness of hypoglycemia are impaired to a greater extent in type 1 diabetic patients with autonomic neuropathy (AN+) than in those without autonomic neuropathy (AN-). We studied 22 type 1 diabetic patients (8 AN+, 14 AN-) matched for age, duration of diabetes, glycemic control, and history of hypoglycemic episodes. We also studied 33 nondiabetic control subjects using the stepped hypoglycemic clamp technique and determined glycemic thresholds and magnitudes of counterregulatory hormone responses and of hypoglycemia symptoms. Both groups of diabetic patients had reduced awareness of hypoglycemia as evidenced by an elevated glycemic threshold for autonomic symptoms > or =2 SD above normal but neither the magnitude nor thresholds for symptoms differed in AN+ patients and AN-patients. Both groups also had impaired glucagon, epinephrine, norepinephrine, growth hormone and cortisol responses to hypoglycemia. However, in AN+ patients compared with AN-patients, magnitudes of epinephrine and norepinephrine responses (194+/-49 vs. 784+/-206 pmol/l, P < 0.007, and 316+/-56 vs. 610+/-87 pmol/l, P < 0.02, respectively) and epinephrine and norepinephrine glycemic thresholds (2.33+/- 0.10 vs. 2.82+/-0.10 mmol/l, P < 0.009 and 2.34+/-0.06 vs. 2.79+/-0.10 mmol/l, P < 0.008, respectively) were impaired to a greater extent. This was associated with a 50% greater requirement of exogenous glucose to prevent more severe hypoglycemia during the 2.3 mmol/l glycemic plateau (P < 0.002). No differences were observed between other counterregulatory hormone responses in AN+ and AN- patients. We conclude that in patients with type 1 diabetes, autonomic neuropathy further reduces counterregulatory catecholamine responses. Since this should increase the risk for severe hypoglycemia, one might consider safer therapeutic goals in these patients.

Beta-thalassemia and normal growth: are they compatible?

The cause of growth retardation in the inherited blood disorder b-thalassemia major (b-thal) has long been a subject of debate. This has become an issue in the last few years since children with b-thal are undergoing hypertransfusion and iron chelation therapy, and now living well into their thirties and forties. Therefore, in addition to growth retardation, many of the endocrinopathies such as hypogonadism, hypothyroidism, hypoparathyroidism and diabetes mellitus, which were not apparent before, are now being diagnosed and treated. Despite the fact that much has been learned in the past few years about the etiology of growth retardation in children with b-thal, treatment is still difficult in many cases. Normal growth of b-thal children during the first 10 years of life depends upon the maintenance of hemoglobin levels above 8.5 g/dl. During this period of the child’s life hypoxia may be the main factor retarding growth, and the maintenance of hemoglobin levels above 10‐11 g/dl together with adequate iron chelation therapy makes the b-thal patients indistinguishable from their non-thalassemic peers (1). If deferoxamine, which is used for iron chelation therapy, is used before the age of 3 years it also produces marked stunted growth with a clinical and radiologic rickets-like syndrome (2). This is because, before there is iron overload from the blood transfusions, deferoxamine is thought to also chelate other essential minerals besides iron. After the age of 10 though, despite the fact that adequate levels of hemoglobin are maintained, many of the b-thal children start having decelerated growth. In the pubertal children there may be a reduced growth spurt with marked deceleration, for which iron overload may be responsible (3). In this age group truncal shortening, most likely due to hypogonadism secondary to iron deposition, may also be found. The hormonal cause of growth retardation in b-thal children is complex. Besides hypothyroidism and hypogonadism it has become apparent that growth hormone (GH) also plays a role in their abnormal growth. It still remains unclear, though, how the GH and insulin-like growth factor-I (IGF-I) axis may play a role. Several authors have reported reduced serum concentrations of IGF-I in the presence of a normal GH response to provocative studies (4, 5) and this led to the speculation that GH insensitivity is most likely the cause of the abnormal growth. Others have found, though, that classic GH deficiency and GH neurosecretory dysfunction (6) are the causes of the low IGF-I and short stature in many patients. The b-thal patients may have subnormal spontaneous GH secretion and an impaired GH response to GH-releasing hormone. Histologic examination at autopsy of the endocrine glands of b-thal patients has shown mild to moderate siderosis and a reduced number of cells in the pituitary gland together with fibrosis and siderosis of the thyroid gland and gonads (7). This is consistent with the view that many b-thal patients may have primary or secondary endocrine gland dysfunction. Undernutrition is also an important cause of low IGF-I and associated growth disturbances in this group. This may be compounded in certain cases of undernutrition by zinc deficiency. In the article by Soliman and coworkers (8), the authors studied the GH response to clonidine and glucagon, and the levels of IGF-I, insulin-like growth factor-binding protein-3 (IGFBP-3) and ferritin, and they also evaluated the levels of IGF-I after 1 day of GH administration. They also followed the growth velocity of three groups of children, b-thal patients, children with GH deficiency (GHD) and children with constitutional short stature (CSS), after 1 year of hGH therapy. They found that the b-thal children had a reduced IGF-I response after 1 day of GH administration, compared

Growth hormone response to growth hormone-releasing hormone varies with the hypothalamic-pituitary abnormalities

We determined growth hormone (GH) and insulin-like growth factor I (IGF-I) levels after a 3 h infusion of escalating doses of growth hormone-releasing hormone (GHRH(1-29)) followed by a bolus injection in hypopituitary patients with marked differences in pituitary features at magnetic resonance imaging (MRI) in order to evaluate further the contribution of MRI in the definition of pituitary GH reserve in GH-deficient patients. Twenty-nine patients (mean age 14.5 +/- 4.0 years) were studied. Group I comprised 13 patients: seven with isolated GH deficiency (IGHD) (group Ia) and six with multiple pituitary hormone deficiency (MPHD) (group Ib) who had anterior pituitary hypoplasia, unidentified pituitary stalk and ectopic posterior pituitary at MRI, Group II consisted of eight patients with IGHD and small anterior pituitary/empty sella, while in group III eight had IGHD and normal morphology of the pituitary gland. Growth hormone and IGF-I levels were measured during saline infusion at 08.30-09.00 h, as well as after infusion of GHRH (1-29) at escalating doses for 3h: 0.2 micrograms/kg at 09.00-10.00 h, 0.4 micrograms/kg at 10.00-11.00 h, 0.6 micrograms/kg at 11.00-12.00 h and an intravenous bolus of 2 micrograms/ kg at 12.00 h. In the group I patients, the peak GH response to GHRH(1-29) was delayed (135-180 min) and extremely low (median 2mU/l). In group II it was delayed (135-180 min), high (median 34.8 mU/l) and persistent (median 37.4 mU/l at 185-210 min). In group III the peak response was high (median 30.8 mU/l) and relatively early (75-120 min) but it declined rapidly (median 14.4 mU/l at 185-210 min). In one group I patient, GH response increased to 34.6 mU/l. The mean basal value of IGF-I levels was significantly lower in group I (0.23 +/- 0.05 U/ml) than in groups II (0.39 +/- 0.13U/ ml, p < 0.01) and III (1.54 +/- 0.46 U/ml, p < 0.001) and did not vary significantly during the GHRH(1-29) infusion. The present study demonstrates that the impaired GH response to 3 h of continuous infusion of escalating doses of GHRH(1-29) was strikingly indicative for pituitary stalk abnormality, strengthening the case for use of GHRH in the differential diagnosis of GH deficiency. The low GH response, more severe in MPHD patients, might be dependent on the residual somatotrope cells, while the better response (34.6 mU/l) in the group Ia patients might suggest that prolonged GHRH infusion could help in evaluating the amount of residual GH pituitary tissue. Pituitary GH reserve, given the GH response to GHRH infusion in GH-deficient patients with small anterior pituitary/empty sella, seems to be maintained.

Acipimox potentiates growth hormone response to growth hormone-releasing hormone by decreasing serum free fatty acid levels in hyperthyroidism

Hyperthyroidism is associated with an impairment of growth hormone (GH) responses to secretagogues. The aim of this study was to evaluate the effect of acipimox, an antilipolytic agent able to decrease free fatty acids (FFA), on GH response to GH-releasing hormone (GHRH) in hyperthyroid and normal control subjects. We studied six men with hyperthyroidism; seven normal men served as control subjects. Each subject underwent treatment with (1) 2 tablets of placebo orally or (2) 500 mg acipimox orally, 120 minutes before intravenous (IV) injection of 1 μg/kg GHRH-(1–29)NH 2. GH response to GHRH in hyperthyroid patients was markedly reduced; the mean peak GH response (9.6 ± 1.0 μg/L) and the area under the GH response curve (12.9 ± 1.3 μg/L × 2 h) were lower than those of control subjects (25.7 ± 1.8 μg/L, P < .05; 28.7 ± 2.1 μg/L × 2 h, P < .05). Hyperthyroid patients had higher baseline levels of plasma FFA than control subjects (998.0 ± 38.9 v 498.0 ± 36.0 μEq/L, P < .01). Acipimox decreased FFA levels in both hyperthyroid and control subjects; the lowest FFA levels of hyperthyroid subjects induced by acipimox were similar to those of control subjects. After acipimox pretreatment, GH responses to GHRH increased significantly ( P < .05); the mean peak plasma GH level (25.9 ± 4.6 μg/L) was similar to the peak GH levels of control subjects during the GHRH test, and the area under the GH response curve (41.1 ± 6.7 μg/L × 2 h) was even higher than that of control subjects with the GHRH test. However, the enhanced GH responses of hyperthyroid patients were still lower that those of control subjects during the acipimox plus GHRH test. We demonstrated that the decreased FFA levels induced by acipimox potentiate somatotrope responsiveness, likely acting at the pituitary level. Our results indicate that high FFA levels are responsible for impaired GH responses to GHRH in hyperthyroidism.

Chemotherapy‐induced growth hormone deficiency in children with cancer

Chemotherapy (CT) may produce growth impairment, however, the pathogenesis is still unclear. A series of 25 patients mean age 13.3 years (6.3-19.8), previously treated for malignant solid tumours with only CT and surgery were studied. Growth hormone (GH) reserve was assessed by two different provocative stimuli (Clonidine and L-Dopa). Mean time between completion of treatment and GH evaluation was 18.5 months (2-74 months). At that time, all patients were in complete remission. GH deficiency (GHD), defined by an impaired GH response to both provocative tests was observed in 11 out of 25 patients (44%). At diagnosis, mean standing height was +0.23 +/- 1.42 SDS in the GHD group (GHD-g) and +0.18 +/- 1.23 SDS in the non-GHD group (n-GHD-g). At the end of therapy, the mean standing height in the GHD-g was -0.31 +/- 1.22 SDS and -0.17 +/- 1.41 in the n-GHD-g, differing from the former group (P = 0.05). For a mean follow-up of 30 months from the end of treatment, the mean standing height was -0.48 +/- 1.23 SDS in the GHD-g and -0.24 +/- 1.51 SDS for the n-GHD-g (P = 0.03). Growth rate at the end of treatment was +0.13 +/- 1.54 in the GHD-g and +0.21 +/- 1.75 in the n-GHD-g. For a mean follow-up of 30 months from the end of treatment, the growth rate was different between GHD-g and n-GHD-g (-0.31 +/- 2.72 vs. -0.21 +/- 1.93, P < 0.05). 1) Growth impairment in children treated because of malignant diseases has a multifactorial etiology, but CT-induced GH deficiency is one potential adverse factor. 2) An endocrine follow-up should be introduced in order to detect and treat hormonal deficiencies as early as possible.