GH-deficient Subjects Research Articles

Diagnostic value of a ghrelin test for the diagnosis of GH deficiency after subarachnoid hemorrhage

ObjectiveTo determine the diagnostic value of a ghrelin test in the diagnosis of GH deficiency (GHD) shortly after aneurysmal subarachnoid hemorrhage (SAH).DesignProspective single-center observational cohort study.MethodsA ghrelin test was assessed after the acute phase of SAH and a GH-releasing hormone (GHRH)–arginine test 6 months post SAH. Primary outcome was the diagnostic value of a ghrelin test compared with the GHRH–arginine test in the diagnosis of GHD. The secondary outcome was to assess the safety of the ghrelin test, including patients' comfort, adverse events, and idiosyncratic reactions.ResultsForty-three survivors of SAH were included (15 males, 35%, mean age 56.6±11.7). Six out of 43 (14%) SAH survivors were diagnosed with GHD by GHRH–arginine test. In GHD subjects, median GH peak during ghrelin test was significantly lower than that of non-GHD subjects (5.4 vs 16.6, P=0.002). Receiver operating characteristics analysis showed an area under the curve of 0.869. A cutoff limit of a GH peak of 15 μg/l corresponded with a sensitivity of 100% and a false-positive rate of 40%. No adverse events or idiosyncratic reactions were observed in subjects undergoing a ghrelin test, except for one subject who reported flushing shortly after ghrelin infusion.ConclusionOwing to its convenience, validity, and safety, the ghrelin test might be a valuable GH provocative test, especially in the early phase of SAH.

Growth Hormone and Muscle Strength in Children

When I was asked to write an editorial to comment on the article by Simon et al (1) in this issue of the Journal, I felt it would be a real challenge. The use of GH therapy in children has provoked more discussion in the last few years from a legal, journalistic, economical, and even political point of view than from medical and scientific perspectives. I decided to take the challenge and to comment on the facts as I perceive them. An impact of recombinant human GH (rhGH) on muscle strength is controversial. As physicians, we are essentially warned about rhGH doping in professional and Olympic athletics, with the presumption that it has a beneficial effect on muscle strength. This is despite the fact that there appears to be no evidence that rhGH enhances muscle strength, power, or aerobic capacity in trained adult athletes. However, rhGH does increase modestly anaerobic exercise capacity when administered alone and to a greater extent when combined with testosterone (2). Thus, despite the abuse of rhGH by athletes, there is little support of performance benefit except for an effect on anaerobic exercise capacity (2). In GH-deficient patients, replacement of rhGH improves aerobic exercise capacity, although it remains to be elucidated whether this is due to the direct effect on muscle function or on other factors influencing cardiovascular function, well-being, and motivation. Long-term rhGH replacement in excess of 12 months seems to be required for improved muscle strength to take place in GH-deficient adult subjects (2). It has been reported that 10 years of rhGH replacement therapy in GH-deficient adults increased muscle strength during the first half of the study and then protected partly against the normal decline withage inmusclestrength,resulting inapproximatelynormalized muscle strength after 10 years (3). Even fewerdataareavailable inchildren,with theexception of data gathered from children affected with Prader-Willi syndrome(PWS),araregenetic formofobesitywithhypothalamic involvement that leads to GH deficiency. One group assessed the impact of rhGH therapy begun early in life on the natural history of PWS and compared height, body composition, and strength in similar-age children with PWS naive to rhGH with those treated with hGH for 6 years (4). Motor strength testing included broad jump, agility run, sit-ups, and upper arm strength assessments. The evaluator of motor strength testing was blinded to the treatment status of each child. PWS children treated with rhGH demonstrated greater motor strength (increased standing broad jump 22.9 2.1 vs 14.6 1.9 inches (P .001) and sit-ups 12.4 0.9 vs 7.1 0.7 repetitions in 30 seconds; P .001). Clear trends were seen in the 2 other areas of the testing, including improved agility run and weight-lift repetitions, although these did not reach statistical significance. Thus, thisnonrandomizedstudysuggestedabeneficialeffecton muscle strength in children affected by PWS. However, these few reports on young active adults, on GH-deficient adults, and on children affected by PWS may not be relevant to the chronically ill and less active children included in the study of Simon et al (1). In this study, the authors evaluated the effects of rhGH on muscle strength in children receiving long-term glucocorticoid therapy. Expected effects of growth hormone on height and body composition were assessed and confirmed, but those will not be commented upon here. This was a pilot study, randomized and controlled, with a delayed-start of rhGH for 12 months. rhGH was started after randomization (month 0) or 6 months later (month 6). A total of 30 children with various diagnoses, on glucocorticoid therapy for a chronic disease, startedat least1year earlierwithheight1SDorat2SDscore (SDS) below and bone age 15 years in boys and 13 years in girls. rhGH was administered at a dose of 0.065 mg/kg/d for 6monthsandtheninthedosagemaintainingserumIGF-1levels

Urine metabonomic profiling of a female adolescent with PIT-1 mutation before and during growth hormone therapy: Insights into the metabolic effects of growth hormone

ObjectiveGrowth hormone (GH) is a protein hormone with important roles in growth and metabolism. The objective of this study was to investigate the metabolism of a human subject with severe GH deficiency (GHD) due to a PIT-1 gene mutation and the metabolic effects of GH therapy using Nuclear Magnetic Resonance (NMR)-based metabonomics. NMR-based metabonomics is a platform that allows the metabolic profile of biological fluids such as urine to be recorded, and any alterations in the profile modulated by GH can potentially be detected. DesignUrine samples were collected from a female subject with severe GHD before, during and after GH therapy, and from healthy age- and sex-matched controls and analysed with NMR-based metabonomics. SettingThe samples were collected at a hospital and the study was performed at a research facility. ParticipantsWe studied a 17year old female adolescent with severe GHD secondary to PIT-1 gene mutation who had reached final adult height and who had ceased GH therapy for over 3years. The subject was subsequently followed for 5years with and without GH therapy. Twelve healthy age-matched female subjects acted as control subjects. InterventionThe GH-deficient subject re-commenced GH therapy at a dose of 1mg/day to normalise serum IGF-1 levels. Main outcome measuresUrine metabolic profiles were recorded using NMR spectroscopy and analysed with multivariate statistics to distinguish the profiles at different time points and identify significant metabolites affected by GH therapy. ResultsNMR-based metabonomics revealed that the metabolic profile of the GH-deficient subject altered with GH therapy and that her profile was different from healthy controls before, and during withdrawal of GH therapy. ConclusionThis study illustrates the potential use of NMR-based metabonomics for monitoring the effects of GH therapy on metabolism by profiling the urine of GH-deficient subjects. Further controlled studies in larger numbers of GH-deficient subjects are required to determine the clinical benefits of NMR-based metabonomics in subjects receiving GH therapy.

Acylated ghrelin as a provocative test for the diagnosis of GH deficiency in adults

Insulin tolerance test (ITT) is the test of reference for the diagnosis of adult GH deficiency (GHD), although GHRH in combination with arginine (ARG) or GH secretagogues are considered equally reliable tests. Testing with GH secretagogue alone is, anyway, a potent stimulus exploring the integrity of hypothalamic pathways controlling somatotropic function. We therefore aimed to determine the diagnostic reliability of testing with ghrelin, the natural GH secretagogue. We studied the GH response (every 15 MIN from 15 TO +120 MIN) to acylated ghrelin (1G/KG I.V. AT 0MIN) IN 78 patients with a history of pituitary disease (49 male, 29 female; age (MEANS.D.): 52.1±18.7 years; BMI: 26.7±5.3 kg/m(2)). The lack of GH response to GHRH+ARG and/or ITT was considered the gold standard for the diagnosis of GHD. The best GH cut-off to ghrelin test, defined as the one with the best sensitivity (SE) and specificity (SP), was identified using the receiver-operating characteristic curve analysis. The best GH cut-off to ghrelin test was 7.3 μg/l in lean subjects (SE 88.2%, SP 90.9%), 2.9 μg/l in overweight subjects (SE 92.6%, SP 100%) and 0.6 μg/l in obese subjects (SE 50%, SP 100%). The diagnostic accuracy was 89.3, 94.1 and 62.5% respectively. Our data show that testing with acylated ghrelin represents a reliable diagnostic tool for the diagnosis of adult GHD, in lean and overweight subjects, if appropriate cut-off limits are assumed. Obesity strongly reduces GH response to ghrelin, GH weight-related cut-off limit and diagnostic reliability of the test.

IGF-1 and IGFBP 3 in Growth Hormone Deficiency Role of Insulin Like Growth Factor-1 (IGF-1) and IGF Binding Protein 3 in the Diagnosis of Growth Hormone Deficiency: Changing Paradigm

GH stimulation tests are widely used in the diagnosis of GH deficiency (GHD), although they are associated with a high false positive rate. Serum IGF-I levels are monitored during GH replacement treatment in subjects with GH deficiency (GHD) to guide GH dose adjustment and to minimize occurrence of GHrelated side-effects. The need for reliance on provocative testing is based on evidence that the evaluation of spontaneous growth hormone (GH) secretion over 24 hours and the measurement of IGF-I and IGFBP-3 levels do not distinguish between normal and GHD subjects. Regarding IGF-I, it has been demonstrated that very low levels in patients highly suspected for GHD (i.e., patients with childhood-onset, severe GHD, or with multiple hypopituitarism acquired in adulthood) may be considered definitive evidence for severe GHD obviating the need for provocative tests. However, normal IGF-I levels do not rule out severe GHD and therefore adults suspected for GHD and with normal IGF-I levels must undergo a provocative test of GH secretion. We hereby review the various literatures at disposal justifying the use of IGF-1 and IGBP3 for diagnosis of growth hormone deficiency.Data Source: We searched PUBMED and MEDLINE database for relevant articles including key words. References of each article were further reviewed for final synthesis of the manuscript.J Nepal Paediatr Soc 2012;32(2):154-162 doi: http://dx.doi.org/10.3126/jnps.v32i2.5342

GH Replacement Improves Quality of Life and Metabolic Parameters in Cured Acromegalic Patients with Growth Hormone Deficiency

Effects of GH replacement in patients with GH deficiency (GHD) after a cure for acromegaly so far have been poorly studied, although its prevalence among acromegalic patients may reach the 60%. The aim of the study was to evaluate whether metabolic parameters and quality of life are improved by GH replacement in patients with prior acromegaly and severe GHD. This was a prospective study on 42 GHD subjects [22 men, mean age (sd): 48 ± 10]: 10 acromegalics treated with recombinant human GH (group A), 12 acromegalics who refused treatment (group B), and 20 subjects operated for nonfunctioning pituitary adenoma on recombinant human GH (group C). Serum IGF-I levels, lipid profile, glucose levels (fasting and after an oral glucose tolerance test), glycosylated hemoglobin, insulin resistance (homeostasis model assessment insulin resistance index), anthropometric parameters (body mass index, waist circumference, body composition), and quality of life (Questions on Life Satisfaction-Hypopituitarism Z-scores) were evaluated at baseline and after 12 and 36 months. At baseline, group B showed higher IGF sd score than group A and C, as well as better quality of life and higher post-oral glucose tolerance test glucose levels than group A. After 12-months, similarly in group A and C, the IGF-I sd score significantly increased, and body composition and lipid profile improved, without deterioration of glucose tolerance. Quality of life significantly improved too, and the baseline difference between group A and B disappeared. Results were confirmed after 36 months. In GHD acromegalic patients, GH therapy improved body composition, lipid profile, and quality of life as in patients with GHD due to nonfunctioning pituitary adenoma, without negative effects on glucose metabolism. GH replacement therapy should be considered in these patients, as in patients with GHD from other causes.

Effects of replacement therapy on sleep architecture in children with growth hormone deficiency

Children with GH deficiency (GHD) show a general decrease in electroencephalographic (EEG) arousability represented by a significant global decrease in Cyclic Alternating Pattern (CAP). The aim of the present study was to evaluate if sleep structure is influenced by GH substitutive therapy by analyzing the classical sleep architecture parameters and sleep microstructure by means of CAP. Laboratory polysomnographic sleep recordings were obtained from five children affected by GHD (two girls and three boys; mean age: 4.6 ± 3.1 years), at baseline and after GH therapy, and from 10 normal healthy children (four girls and six boys, mean age: 5.6 ± 2.2 years). Compared to controls, GHD subjects showed a reduced total sleep time with increased wakefulness and a consequent decrease in sleep efficiency; GH therapy was associated with an increase of the awakenings/hour and a large effect size was evident for sleep latency, sleep efficiency, and stage N3, which were decreased, and for stage W, which was increased. CAP appeared to be globally reduced and all phase A subtypes and CAP cycle showed a longer duration in GHD children vs. controls. GH substitutive treatment was followed by an increase in CAP rate (total, in N2, and in N3); additionally, A1 index was also significantly increased, especially during stage N3, with a very large effect size. On the other hand, A2 and A3 index and CAP cycle mean duration were reduced. Sleep stage architecture seems to be influenced by the GH status, but the analysis of sleep microstructure by means of CAP reveals an enhancement of EEG slow oscillations in GHD patients (demonstrated by an increase in CAP rate and A1 index during N3) after the start of GH replacement therapy. These findings deserve to be verified in a larger trial.

Effect of Arginine Infusion on Ghrelin Secretion in Growth Hormone-Sufficient and GH-Deficient Children

BackgroundThe physiological link between ghrelin and growth hormone (GH) has not yet been fully clarified. Furthermore, the existence of a negative feedback mechanism between growth hormone–insulin-like growth factor (GH–IGF)-I axis and ghrelin and the influence of amino acids on ghrelin secretion in children remain matters of debate.ObjectivesTo understand the regulation of ghrelin secretion and clarify the relationship between ghrelin and GH secretion in GH-deficient (GHD) and GH-sufficient (GHS) children.Patients and MethodsTen GHD (male/female [M/F], 6/4; age [mean ± SEM], 10.7 ± 0.9 years) and 10 GHS prepubertal children (M/F, 6/4; age [mean ± SEM], 10.3 ± 0.6 years), underwent an arginine (ARG) test (infusion, 0.5 g/kg, iv). Levels of GH, total ghrelin, and acylated ghrelin (AG) were assayed every 30 min from 0 to +120 min.ResultsPeak GH values were lower in GHD subjects than in GHS subjects (P < 0.0001). The baseline levels, peak levels, or area under the curves (AUC) for total ghrelin and AG were similar between GHD and GHS children. ARG infusion was followed by a slight to significant decrease in total ghrelin levels, but not AG levels, both in GHD and GHS subjects with a nadir at +30 min. No correlation was seen between GH, total ghrelin, or AG response and ARG infusion.ConclusionsTotal ghrelin and AG levels seemed unaffected by GH status in prepubertal children. ARG infusion was unable to blunt ghrelin secretion irrespective of GH status in childhood. Moreover, since ARG influences GH secretion via modulation of somatostatin release, ghrelin secretion seems to be partially refractory to somatostatin action.

Unreplaced Sex Steroid Deficiency, Corticotropin Deficiency, and Lower IGF-I Are Associated with Lower Bone Mineral Density in Adults with Growth Hormone Deficiency: A KIMS Database Analysis

GH deficiency (GHD) is associated with low bone mineral density (BMD). Risk factors for lower BMD in this GHD population have not been fully elucidated. In particular, there are limited published data in GH-naïve subjects. The objective of the study was to identify endocrine correlates of low BMD in treatment-naïve adult GHD subjects. This was a retrospective analysis of data extracted from the (Pfizer International Metabolic Study) KIMS database. The study was an international epidemiological survey of more than 15,000 adult GHD patients from 31 countries. A total of 1218 subjects with stringently defined GHD of adult onset (641 women and 577 men) who were GH naïve and had BMD measured in the posterior anterior lumbar spine and femoral neck by dual-energy X-ray absorptiometry. Variables associated with standardized BMD (sBMD) in adult-onset GHD were examined. In the LS, body mass index (r = 0.13, P < 0.01), unreplaced sex steroid deficiency (r = -0.17, P < 0.0001), and corticotropin deficiency (r = -0.11, P < 0.01) were independently associated with sBMD. In the FN, age (r = -0.19, P < 0.0001), female gender (r = -0.18, P < 0.0001), body mass index (r = 0.21, P < 0.0001), and decreased IGF-I SD scores (r = 0.10, P < 0.001) were independently associated with sBMD. Hormone variables associated with lower sBMD in patients with adult-onset GHD include unreplaced sex steroid deficiency and corticotropin deficiency in the LS and lower IGF-I SDS in the FN.

Metabolic, Cardiovascular, and Cerebrovascular Outcomes in Growth Hormone-Deficient Subjects with Previous Cushing's Disease or Non-Functioning Pituitary Adenoma

Metabolic, Cardiovascular, and Cerebrovascular Outcomes in Growth Hormone-Deficient Subjects with Previous Cushing's Disease or Non-Functioning Pituitary Adenoma

P01-287 - Psychiatric and neuropsychologic changes in growth hormone deficient subjects after traumatic brain injury and response to growth hormone replacement therapy

ObjectiveTraumatic brain injury (TBI) is recently recognized as a risk factor for hypopituitarism, presented most frequently with growth hormone deficiency (GHD). GHD is associated not only with changes in body composition, but also with impaired quality of life, cognitive dysfunctions and some psychiatric sequelae, usually classified as “depression” or “atypical depression”. The impact of GH therapy on mental status is still unknown.DesignPsychiatric and cognitive functions were tested in six adult GHD subjects at baseline (minimum three years after TBI), reassessed after six months of GH replacement therapy as well as twelve months after discontinuation of GH therapy. Psychiatric and cognitive examinations included semi-structured interviews and three instruments: Symptom-checklist (SCL-90-R), Zung Depression Inventory and standard composite neuropsychological battery.ResultsSix months of GH therapy in GHD TBI patients improved cognitive abilities (particularly verbal and nonverbal memory) and improved psychiatric functioning. Severity of depression decreased, as well as intensity of interpersonal sensitivity, hostility, paranoid ideation, anxiety and psychoticism. In three GHD patients who stopped GH therapy for twelve months we registered worsening of the verbal and nonverbal memory, as well as increase in Zung score and three SCL dimensions: inter-personal sensitivity, anxiety and paranoid ideation.ConclusionThis preliminary data suggest that GH therapy induced reduction of depression, social dysfunction and improvement in certain cognitive domains in GHD patients after TBI. Our data support the necessity of conducting randomized placebo-controlled trials on the effects of GH therapy on neuropsychological and psychiatric status in GHD TBI patients.

Metabolic, Cardiovascular, and Cerebrovascular Outcomes in Growth Hormone-Deficient Subjects with Previous Cushing’s Disease or Non-Functioning Pituitary Adenoma

Previous exposure to hypercortisolism due to Cushing's disease (CD) may adversely affect long-term metabolic and cardiovascular outcomes. In particular, metabolic and cardiovascular outcomes of patients with previous CD who require GH replacement have not been fully established. The aim of the study was to compare the prevalence and incidence of metabolic syndrome (Adult Treatment Panel III criteria), diabetes mellitus, cardiovascular disease, and cerebrovascular disease in GH-treated subjects with previous CD with GH-treated subjects with previous nonfunctioning pituitary adenoma (NFPA). We conducted post hoc analysis of the observational Hypopituitary Control and Complications Study conducted at 362 international centers (1995-2006). We studied adult-onset GH-deficient subjects with previous CD (n = 160) or NFPA (n = 879). All subjects received GH replacement therapy and were GH naive at enrollment. Multiple pituitary deficits were prevalent in both groups. We measured the prevalence and incidence of metabolic syndrome, diabetes mellitus, cardiovascular disease, and cerebrovascular disease at baseline and at 3 yr, standardized for age and sex differences between groups. Compared with subjects with previous NFPA, subjects with previous CD had a significantly greater 3-yr incidence of metabolic syndrome (CD, 23.4%; NFPA, 9.2%; P = 0.01), baseline (CD, 6.3%; NFPA, 2.2%; P < 0.01) and 3-yr (CD, 7.6%; NFPA, 3.9%; P = 0.04) prevalence of cardiovascular disease, and baseline (CD, 6.4%; NFPA, 1.8%; P = 0.03) and 3-yr (CD, 10.2%; NFPA, 2.9%; P = 0.01) prevalence of cerebrovascular disease. Previous hypercortisolism may predispose GH-treated, GH-deficient subjects with prior CD to an increased risk of metabolic syndrome, cardiovascular disease, and cerebrovascular disease.

Reduced Growth Hormone Secretion Is Associated with Increased Carotid Intima-Media Thickness in Obesity

Obesity is associated with reduced GH. The aim of the study was to determine whether reduced GH is associated with increased carotid intima-media thickness (cIMT) in obesity. A total of 102 normal-weight and obese men and women without known hypopituitarism were studied. Subjects underwent GH stimulation testing with GHRH-arginine. Lipid profile, inflammatory markers, oral glucose tolerance test, abdominal computed tomography, dual-energy x-ray absorptiometry, and cIMT were measured. Relative GH deficiency was defined as peak GH of 4.2 microg/liter or less. Subjects were separated based on BMI and GH testing into three groups: normal weight, obese GH sufficient (GHS), and obese relative GH deficient (GHD). Age, gender, and race were similar between the groups. BMI, percentage body fat, and visceral adiposity did not differ between obese GHS and relative GHD. Peak GH was associated with cIMT, IGF-I, high-density lipoprotein, low-density lipoprotein, triglycerides, adiponectin, C-reactive protein, and TNF-alpha (all P < 0.05). Obese GHS subjects had similar cIMT compared to normal-weight subjects (P = not significant), whereas obese GHD subjects had higher cIMT compared to normal-weight subjects (P < 0.05) (normal weight, 0.645 +/- 0.023, vs. obese GHS, 0.719 +/- 0.021, vs. obese GHD, 0.795 +/- 0.063 mm; P = 0.01 by ANOVA). Similar results were seen in sensitivity analyses with less stringent cutoffs (< 5, < or = 8, < 9 microg/liter) to define GHD. In multivariate modeling, peak GH remained significantly associated with cIMT after controlling for age, gender, race, tobacco, blood pressure, cholesterol, and fasting glucose (R(2) for model, 0.35; P < 0.0001). These results suggest that reduced GH secretion is associated with a more abnormal metabolic phenotype in obesity, characterized by increased cIMT, dyslipidemia, insulin resistance, and inflammation.

Serum ghrelin levels in growth hormone-sufficient and growth hormone-deficient patients during growth hormone-releasing hormone plus arginine test

Ghrelin is an orexigenic hormone produced in the stomach and in other organs, exerting a wide range of metabolic functions, including stimulation of GH secretion. Ghrelin secretion is decreased by iv or oral glucose load as well as during euglycemic-hyperinsulinemic clamp and hypoglycemia. We evaluated the circulating ghrelin levels in GH-deficient (GHD) and in GH-sufficient (GHS) patients during GHRH plus arginine test. The study group comprised 35 patients, including 20 with pituitary tumors, 12 with empty sella, 2 with short stature, and 1 with post-traumatic isolated GH deficiency. According to the results of GHRH plus arginine test, 14 patients were defined as GHD and 21 as GHS. Patients with central hypothyroidism, hypocorticism, and hypogonadism had been on replacement therapy for at least 3 months at the moment of the study. Blood samples were collected every 20 min up to 60 min after GHRH and arginine administration. By definition, GH response to GHRH plus arginine was higher in GHS than GHD group (p<0.0001). Basal serum ghrelin levels were not different in the two groups and did not correlate with body mass index, GH, IGFI and insulin concentrations. After GHRH plus arginine, serum ghrelin decreased significantly in both groups, with percent decreases ranging 13.3-66.6% in GHD patients (p=0.001) and 7.2-42.2% in GHS patients (p=0.004), with no significant difference in the two groups (p=0.12). Our results show that ghrelin secretion is not modulated by acute GH increase observed in GHS subjects during GHRH plus arginine infusion. The similar decrease of serum ghrelin after GHRH plus arginine stimulation in both GHS and GHD subjects demonstrated that there is no negative feedback of GH on ghrelin secretion.

Circulating Levels of High-Sensitivity C-Reactive Protein and Soluble Markers of Vascular Endothelial Cell Activation in Growth Hormone-Deficient Adolescents

Background/Aims: Significant endothelial dysfunction as determined by lower flow-mediated vasodilation of the brachial artery was recently reported by us in growth hormone-deficient (GHD) adolescents. The circulating concentrations of markers of vascular endothelial cell and platelet activation and their relationship to inflammatory markers have not been previously evaluated in this group of patients. Objective: To assess the relationship between circulating levels of high-sensitivity C-reactive protein (CRP) and soluble markers of vascular endothelial cell activation in GHD adolescents. Design/Methods: Twenty-eight GHD children on GH treatment with a chronological age of 15.7 ± 2.6 years and 16 untreated GHD adolescents with a chronological age of 16.6 ± 3.3 years were studied. Concentrations of CRP, as an inflammatory marker, were measured in all patients and the association between CRP and the fasting soluble markers of vascular endothelial cell activation intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), E-selectin and P-selectin levels was evaluated. Sixteen healthy adolescents with a mean chronological age of 15.1 ± 2.2 years served as controls. Results: CRP and P-selectin levels were significantly higher in untreated GHD adolescents than in treated GHD subjects or in healthy controls (p < 0.02), while VCAM-1 concentrations were increased in both untreated and treated GHD adolescents when compared to controls (p < 0.007). E-selectin and ICAM-1 levels were similar in all three groups. CRP was found to be associated with BMI (r: 0.62; p < 0.001), P-selectin (r: 0.43; p < 0.01), E-selectin (r: 0.27; p < 0.03), ICAM-1 (r: 0.23; p < 0.05) and VCAM-1 (r: 0.40; p < 0.001) concentrations in untreated GHD adolescents and with P-selectin (r: 0.88; p < 0.001) and E-selectin (r: 0.29; p < 0.01) in treated GHD subjects. A weak inverse association was observed in a subgroup of patients between brachial artery endothelium-dependent dilation and P-selectin (r: –0.56; p < 0.07). Conclusions: Low-grade inflammation as manifested by increased circulating levels of CRP seems to be associated with the early activation of vascular endothelial cells in GHD adolescents

Advantages and disadvantages of GH/IGF-I combination treatment

Growth hormone (GH) is the primary regulator of insulin-like growth factor-I (IGF-I) production in a wide variety of tissues. There is much overlap in the endocrine, metabolic and anabolic effects of GH and IGF-I but both hormones have divergent effects on glucose metabolism, insulin sensitivity and differentiation of prechondrocytes. Theoretically combined administration of GH and IGF-I may be more effective than GH alone or IGF-I alone. Arguments in favor for this are: 1] Clearance of IGF-I may be markedly altered by the co-administration of GH and this will provide sustained actions of IGF-I. 2] Higher serum IGF-I levels are achieved with a combination treatment of GH and IGF-I than with GH treatment alone or IGF-I alone. In addition, combination therapy may have additive or synergistic effects. 3] The combination GH and IGF-I counteracts disadvantageous effects on glucose metabolism of either GH alone or IGF-I alone. 4] GH may exert direct actions on tissues independently from IGF-I. 5] Combination of GH and IGF-I may be more effective in improving tissue IGF-I levels. The combination therapy of GH and IGF-I might be beneficial in growth retardation, in certain specific subgroups of critically ill or catabolic patients and in the treatment of GH-deficient subjects with the metabolic syndrome and/or manifest diabetes. It is at present unknown whether an optimal balance between safety and efficacy can be achieved with the combination therapy of GH and IGF-I, since this combination has been evaluated in only a small number of patient populations and in studies of a relatively short duration. In addition, a disadvantage may be the financial costs of combination therapy of GH and IGF-I. In conclusion, there are many reasons for believing that administration of the combination therapy of GH and IGF-I could have advantages above GH alone or IGF-I alone. However, determination of whether co-administration of GH and IGF-I indeed is superior to either agent alone awaits further study.

Diagnosis of adult GH deficiency

Based on previous consensus statements, it has been widely accepted that the diagnosis of adult growth hormone deficiency (GHD) must be shown biochemically by provocative tests of GH secretion; in fact, the measurement of IGF-I as well as of other markers was considered unable to distinguish between normal and GHD subjects. The Insulin Tolerance Test (ITT) was indicated as that of choice and severe GHD defined by a GH peak lower than 3 microg/l. It is now recognized that, although normal IGF-I levels do not rule out severe GHD, very low IGF-I levels in patients highly suspected for GHD (i.e. patients with childhood-onset severe GHD or with multiple hypopituitarism acquired in adulthood) can be considered as definite evidence for severe GHD. However, patients suspected for adult GHD with normal IGF-I levels must be investigated by provocative tests. ITT remains a test of reference but it should be recognized that other tests are as reliable as ITT. Glucagon as classical test and, particularly, new maximal tests such as GHRH in combination with arginine or GH secretagogues (GHS) (i.e. GHRP-6) have well defined cut-off limits, are reproducible, able to distinguish between normal and GHD subjects. Overweight and obesity have confounding effect on the interpretation of the GH response to provocative tests. In adults cut-off levels of GH response below which severe GHD is demonstrated must be appropriate to lean, overweight and obese subjects to avoid false positive diagnosis in obese adults and false negative diagnosis in lean GHD patients.

Traumatic Brain Injury is a Rarely Reported Cause of Growth Hormone Deficiency

We determined the frequency of traumatic brain injury (TBI)-related growth hormone deficiency (GHD) from a large registry of growth hormone-deficient subjects and compared these subjects' clinical characteristics with those of children with idiopathic growth hormone deficiency (IGHD). A surprisingly small number of subjects with TBI-induced GHD (n = 141) were registered compared with those with IGHD (n = 23,722). At onset of treatment, the subjects with TBI-induced GHD were older (P = .045), had lower height velocity (P < .001), had a greater number of other pituitary hormone deficiencies (P < .001) and, after a year of recombinant human GH treatment, demonstrated a greater change in height velocity (P = .016). We speculate that TBI-induced GHD may be a neglected phenomenon in childhood, and recommend prospective longitudinal studies to explore its natural history and frequency.

The Neuroendocrine Effects of Traumatic Brain Injury

The Neuroendocrine Effects of Traumatic Brain Injury

The Neuroendocrine Effects of Traumatic Brain Injury

Neuroendocrine dysfunction after traumatic brain injury (TBI) is under-diagnosed, under-treated, and may adversely affect the rate of recovery. Single or multiple pituitary-target hormone disruption occurs in up to two-thirds of persons with TBI, most commonly affecting the gonadal and growth hormone axes. The time course of decline in and recovery of pituitary function in relation to cognitive dysfunction and rehabilitation progress are not well described. This article reviews the clinical spectrum of neuroendocrine deficits after TBI and their underlying mechanisms. Future studies of the effects of hormonal replacement on recovery are recommended.