Peak GH Response Research Articles

The prevalence of isolated growth hormone deficiency among children of short stature in Jordan and its relationship with consanguinity

The prevalence of isolated growth hormone deficiency (IGHD) among short-statured children in Jordan, where consanguineous marriage (CM) is common, is unknown. No studies have investigated the relationship between degrees of consanguinity and IGHD. This study aimed to determine the prevalence of IGHD among short-statured children referred to a university hospital in Jordan and its relationship with different degrees of consanguinity. We conducted a 24-month cross-sectional observational trial at an outpatient tertiary care center in Amman, Jordan. We obtained detailed family histories, medical evaluations and laboratory tests for 94 short-statured children (50 boys and 44 girls aged 6-16years). Complete and partial GHD were defined as peak GH responses of 5 and 7μg/l (15 and 21mIU/l) [IRMA/DiaSorin®], respectively, in both exercise and insulin tolerance tests. GHD was diagnosed in 69·1% of the short children, including 86% (43/50) of the children of consanguineous parents (83·3%, 93·8% and 81·8% of children of first cousins, first cousins once removed and second cousins, respectively) and 50% (20/44) of the children of nonconsanguineous parents (P=0·039, 0·002 and 0·013, respectively). However, there was no statistically significant difference in the prevalence of small pituitary MRI between GH-deficient children of consanguineous parents and those of nonconsanguineous parents (28·6% vs 13·6%, P=0·3). The prevalence of IGHD among referred short children in Jordan was exceptionally high and significantly higher in the children of CM. In countries where CM is common, preconception counselling and rigorous surveillance for GHD in short children may be indicated.

Evaluation of hypothalamic–pituitary function in children following acute bacterial meningitis

Previous studies in adults and case reports in children have shown increased frequency of hypothalamo-pituitary dysfunction after infectious diseases of the central nervous system. The aim of this study was to evaluate the function of hypothalamo-pituitary axis in children with a history of bacterial meningitis. Patients diagnosed with bacterial meningitis between April 2000 and June 2011 was included. Baseline and stimulated hormonal tests were performed as required for hormonal evaluations following a diagnosis of meningitis. Pituitary function was assessed following a period of 8-135 months (mean 53 months) after bacterial meningitis. Thirty-seven cases (27 male, 15 pubertal) with mean age of 11.1 ± 4.4 years were included. Mean height SDS was 0.01 ± 1.07 and mean BMI SDS was 0.54 ± 1.15 all patients had a SDS above -2 SD. Baseline cortisol and low dose ACTH stimulation revealed normal adrenal functions in all patients. Gonadotropin deficiency was not detected in any of the pubertal cases. Four cases (10.8%) had low IGF1 and IGFBP3 z-scores (<-2 SD) according to age, sex and Tanner stage, but peak GH response in clonidin test was >10 ng/ml in three of them suggesting neurosecretary dysfunction of GH in these cases. The fourth case has died before the test. No one had TSH deficiency and diabetes insipidus, only one case had mild hyperprolactinemia. Our findings suggest that hypothalamo-pituitary dysfunction is not as common in childhood as in adulthood. The most remarkable finding was neurosecretary dysfunction of GH in some cases.

Comparison of two growth hormone stimulation tests and their cut-off limits in healthy adults at an outpatient clinic

ObjectiveA peak GH less than 3μg/L to insulin tolerance test (ITT) is commonly used as a threshold indicating severe adult GH deficiency (GHD). This cut-off is based on results obtained by polyclonal radioimmunoassays preferably under standard conditions at hospital. Our aim was to evaluate the validity of this cut-off limit using two currently used immunometric GH assays and to compare GH responses in the ITT and the GH releasing hormone+arginine (GHRH+ARG) test in healthy adults at our outpatient endocrine unit. DesignITT was performed on 73 subjects and the GHRH+ARG test on those 28 who showed insufficient response to the ITT. MethodsGH was measured by an immunofluorometric and immunochemiluminometric assay. ResultsGH peak above 3μg/L was observed in 56% of the healthy volunteers with adequate hypoglycemia in the ITT. Among the 28 subjects with a peak GH below 3μg/L, only two overweight men had a GH peak response below the commonly used cut-off limit of 9.1μg/L in the GHRH+ARG test. ConclusionsLean healthy adults could erroneously be classified as GH deficient by the ITT while their results in the GHRH+ARG test were normal. The GH results are highly dependent on the immunoassay used, but false positive results in the ITT are often obtained even if lower cutoff limits determined on the basis on the calibration of the GH assay are used. Confounding factors seemed to blunt the GH response to the ITT more than to the GHRH+ARG test at our outpatient clinic.

The arginine and GHRP-2 tests as alternatives to the insulin tolerance test for the diagnosis of adult GH deficiency in Japanese patients: A comparison

The arginine + GHRH test has been established as an alternative to the insulin tolerance test (ITT) for the diagnosis of adult GH deficiency (AGHD). However, the glucagon, arginine, and GH releasing peptide-2 (GHRP-2) test are recommended as alternatives in Japan. The objective of this study was to evaluate the arginine and GHRP-2 tests as alternatives to the ITT for the diagnosis of AGHD in a Japanese population. Three stimulation tests (ITT, arginine test, and GHRP-2 test) were conducted in 71 pre-operative adult patients with pituitary tumors (age, 18-65 years). The peak GH responses to each test were examined. The peak GH responses were significantly lower with the ARG test (median 4.43 μg/L) (p < 0.0001) than with the ITT (median 9.38 μg/L), and the peak GH responses with the GHRP-2 test (median 28.88 μg/L) were higher (p < 0.0001). However, among the AGHD patients, there was no significant difference between the peak GH responses to the ARG test and the ITT. The sensitivities and specificities of the ARG / GHRP-2 tests compared to the ITT for the diagnosis of severe AGHD (peak GH responses to ITT ≤ 1.8 μg/L) were 93.8% / 81.3% and 85.5% / 94.5%, respectively. The arginine and GHRP-2 stimulation tests are acceptable alternatives to the ITT for the diagnosis of AGHD in Japanese patients. The method and criterion for the diagnosis of AGHD should be reconsidered and adjusted to each population.

Significance of insulin tolerance test in the diagnosis of adult growth hormone deficiency

Objective To assess the significance of insulin tolerance test(ITT) in clinical diagnosis of adult growth hormone deficiency(GHD).Methods Eighty-two patients with an established diagnosis of adult GHD [53males,29 females,mean age (30.9 ± 12.3) years (18-65 years)] were reviewed retrospectively for evaluating the GH response to ITT in the General Hospital of the People' s Liberation Army.Control data for peak GH after ITT were obtained in 15 healthy subjects [9 males,6 females,mean age (26.7 ± 5.6) years (22-41 years)].Receiver operating characteristic (ROC) curve analysis and the area under the curve (AUC) were used to evaluate the diagnostic cut-off point of peak GH and GH increment response to ITT.Results (1) Mean peak GH response to ITT was significantly higher in 15 controls compared with 82 patients (the median 14 μg/L vs 0.62 μg/L,P =0.001).The cut-off point of the peak GH(chemiluminescent immunoassay,CLIA) response to ITT in adult GHD was 4.935 μg/L (AUC 0.993).(2) Mean GH increment was significantly higher in 15 controls compared with 82 patients (the median 13.17 μg/L vs 0.19 ug/L,P＜0.001).The cut-off point of the GH increment was 4.088 μg/L(AUC 0.937),with a 91.5％ sensitivity and 100％ specificity.(3) The peak GH showed even higher diagnostic value than the GH increment after ITT.(4)The above mentioned cut-off points (peak GH less than 4.935 μg/L and 5 μg/L) had a coincidence with a 95.1％ sensitivity and 100％ specificity,respectively.Conclusion The current guidelines for the diagnosis of adult GHD based on the optimal cut-off point of the peak GH(CLIA) response to ITT less than 5 μg/L turned to be of reliable diagnostic value in our country. Key words: Insulin tolerance test; Cut-off point; Adult growth hormone deficiency; Growth hormone

Clinical characteristics, timing of peak responses and safety aspects of two dosing regimens of the glucagon stimulation test in evaluating growth hormone and cortisol secretion in adults

Weight-based (WB: 0.03mg/kg) and fixed dose (FD: 1-1.5mg) regimens of the glucagon stimulation test (GST) have been used to evaluate GH and cortisol secretion in children and adults, respectively. However, experience of the WB regimen in assessing GH and cortisol secretion in adults are limited. We describe a multicenter experience using WB and FD regimens in evaluating GH and cortisol secretion in adults suspected of GH deficiency and central adrenal insufficiency. Retrospective case series of GSTs (n=515) performed at five tertiary centers. Peak and nadir glucose, and peak GH and peak cortisol responses occurred later with WB (mean dose: 2.77mg) compared to FD (mean dose: 1.20mg) regimens. Main side-effects were nausea and vomiting, particularly in younger females. Nausea was comparable but vomiting was more frequent in the WB regimen (WB: 10.0% vs FD: 2.4%; P<0.05). Peak and nadir glucose, ΔGH, and peak and Δcortisol were higher in the WB regimen. In both regimens, age correlated negatively with peak cortisol levels, and body mass index (BMI), fasting, peak and nadir glucose correlated negatively with peak GH levels. WB and FD regimens can induce adult GH and cortisol secretion, but peak responses occur later in the WB regimen. Both regimens are relatively safe, and vomiting was more prevalent in the WB regimen. As age, BMI, and glucose tolerance negatively correlated with peak GH and cortisol levels, the WB regimen may be more effective than the FD regimen in older overweight glucose intolerant patients.

GH response to GHRH plus arginine is impaired in lipoatrophic women with human immunodeficiency virus compared with controls

GH secretion is impaired in lipodystrophic human immunodeficiency virus (HIV) patients and inversely related to lipodystrophy-related fat redistribution in men. Less is known about the underlying mechanisms involved in reduced GH secretion in HIV-infected women. A case-control, cross-sectional study comparing GH/IGF1 status, body composition, and metabolic parameters in 92 nonobese women with HIV-related lipodystrophy and 63 healthy controls matched for age, ethnicity, sex, and body mass index (BMI). GH, IGF1, IGF binding protein 3 (IGFBP3), GH after GHRH plus arginine (GHRH+Arg), several metabolic variables, and body composition were evaluated. GH response to GHRH+Arg was lower in HIV-infected females than in controls. Using a cutoff of peak GH ≤ 7.5 μg/l, 20.6% of HIV-infected females demonstrated reduced peak GH response after GHRH+Arg. In contrast, none of the control subjects demonstrated a peak GH response ≤ 7.5 μg/l. Bone mineral density (BMD), quality of life, IGF1, and IGFBP3 were lowest in the HIV-infected females with a GH peak ≤ 7.5 μg/l. BMI was the main predictive factor of GH peak in stepwise multiregression analysis followed by age, with a less significant effect of visceral fat in the HIV-infected females. This study establishes that i) GH response to GHRH+Arg is lower in lipoatrophic HIV-infected women than in healthy matched controls, ii) BMI more than visceral adipose tissue or trunk fat influences GH peak in this population, and iii) HIV-infected women with a GH peak below or equal to 7.5 μg/l demonstrate reduced IGF1, IGFBP3, BMD, and quality of life.

Growth Hormone (GH-1) Gene Deletions in Children with Isolated Growth Hormone Deficiency (IGHD)

To detect growth hormone GH-1 gene deletions (6.7 kb, 7.6 kb, 7 kb) in familial/nonfamilial isolated growth hormone deficiency (IGHD) and note their clinical and investigative profile. Thirty (M16,F14) prepubertal IGHD patients aged 0.25 to 14 y, from 25 families were screened. Duration of growth failure, relevant history, clinical phenotype, and height SDS were recorded. Peak GH response to Clonidine (0.15 mg/m(2)), IGF-1, IGFBP-3 and pituitary/target gland hormones were studied. Genomic DNA of patients and family was analysed by PCR and DNA fragments were visualized on agarose gel electrophoresis. This series was divided into deletion +ve, Group I (n=12,40%) inclusive of six familial/six nonfamilial patients, and deletion -ve Group II (n=18,60%), 5 familial/13 nonfamilial cases; in total 11/30 were familial. Onset of growth failure was earlier in Group I (p<0.001) mean 1.1 vs 4.7 y. Mean height SDS was -7 vs. -4.5 in Groups I/II (p<0.01), age at presentation 5.1 vs 8.6 y. Overhanging forehead, prominent eyes, hypoplastic facies characterized Group I with FBS <50 mg/dl in 50% and very low peak GH <0.04 vs 2.04 ng/ml (p<0.001) in Group II. In both groups IGF-1 and IGFBP3 were low, other hormones were normal and MRI showed hypoplastic adenohypophysis. 40% had GH-1 gene deletion (6.7 kb deletion in 83%, 7.6 kb and a compound heterozygote in 8% each). In this series of 30 IGHD patients, frequency of GH-1 gene deletions (12/30) was 40%, and 54% among familial patients, and 31% with height SDS>-4. 83% had 6.7 kb deletion. Height SDS>-4, clinical phenotype, peak GH<1 ng/ml and hypoglycemia characterised IGHD Type IA.

Complex regulation of GH autofeedback under dual-peptide drive: studies under a pharmacological GH and sex steroid clamp

To test the postulate that sex difference, sex steroids, and peptidyl secretagogues control GH autofeedback, 11 healthy postmenopausal women and 14 older men were each given 1) a single iv pulse of GH to enforce negative feedback and 2) continuous iv infusion of saline vs. combined GHRH/GHRP-2 to drive feedback escape during pharmacological estradiol (E(2); women) or testosterone (T; men) supplementation vs. placebo in a double-blind, prospectively randomized crossover design. By three-way ANCOVA, sex difference, sex hormone treatment, peptide stimulation, and placebo/saline responses (covariate) controlled total (integrated) GH recovery during feedback (each P < 0.001). Both sex steroid milieu (P = 0.019) and dual-peptide stimulation (P < 0.001) determined nadir (maximally feedback-suppressed) GH concentrations. E(2)/T exposure elevated nadir GH concentrations during saline infusion (P = 0.003), whereas dual-peptide infusion did so independently of T/E(2) and sex difference (P = 0.001). All three of sex difference (P = 0.001), sex steroid treatment (P = 0.005), and double-peptide stimulation (P < 0.001) augmented recovery of peak (maximally feedback-escaped) GH concentrations. Peak GH responses to dual-peptidyl agonists were greater in women than in men (P = 0.016). E(2)/T augmented peak GH recovery during saline infusion (P < 0.001). Approximate entropy analysis corroborated independent effects of sex steroid treatment (P = 0.012) and peptide infusion (P < 0.001) on GH regularity. In summary, sex difference, sex steroid supplementation, and combined peptide drive influence nadir, peak, and entropic measurements of GH release under controlled negative feedback. To the degree that the pharmacological sex steroid, GH, and dual-peptide clamps provide prephysiological regulatory insights, these outcomes suggest major determinants of pulsatile GH secretion in the feedback domain.

Comparative Validation of the Growth Hormone-Releasing Hormone and Arginine Test for the Diagnosis of Adult Growth Hormone Deficiency Using a Growth Hormone Assay Conforming to Recent International Recommendations

The GHRH plus arginine (GHRH+Arg) test is a promising alternative to the insulin tolerance test (ITT) for diagnosis of adult GH deficiency (AGHD). The objectives of the study were to validate the GHRH+Arg test for diagnosis of AGHD, using the ITT as comparator and a GH assay calibrated according to recent international recommendations, and to study the repeatability and tolerance of both tests. This was a multicenter, randomized, open-label, phase III study. The study was conducted at 10 French university hospitals. Sixty-nine subjects (38 and 15 with high and low probability of GH deficiency, respectively, and 16 healthy controls) were randomized: 35 to the GHRH+Arg-GHRH+Arg-ITT test sequence and 34 to the ITT-ITT-GHRH+Arg test sequence. Each subject underwent three tests of GH secretion separated by 24 h or more. The primary variable used for response assessments was serum peak GH response. Test results were compared with the final AGHD diagnosis. Peak GH responses in the two tests were strongly correlated. A cutoff value of 7.89 microg/liter for GHRH+Arg corresponding to 3 microg/liter for ITT was calculated. The cutoff value leading to 95% specificity with the GHRH+Arg test was measured at about 3.67 microg/liter (sensitivity 79.0%). Intermethod agreement and repeatability were high. Both tests were well tolerated. A preference for the GHRH+Arg test was expressed by 74% of subjects. The GHRH+Arg test demonstrated good accuracy and repeatability, was at least as sensitive as the ITT, and was associated with better subject acceptability. The GHRH+Arg test represents a good alternative to the ITT for the diagnosis of AGHD.

Body composition, endocrine and metabolic profiles in adults with Prader-Willi syndrome

Prader-Willi syndrome (PWS) is a complex genetic disease associated with hypothalamic-pituitary dysfunction and severe obesity. The aim of the present study was to describe the relationships between body composition, metabolic and hormonal profiles in PWS adults. Forty six adults with genetically verified PWS, 25 women and 21 men, median age 28 years were studied. Body composition was evaluated by standard anthropometric procedures and with computed tomography (CT) of the abdomen and at the mid-femur level. CT of abdomen was compared to 22 healthy, unmatched adults. Circulating lipids were measured and oral glucose tolerance test (OGTT) and hormonal screening including GH secretory capacity (GHRH/arginine test) was carried out. Median body mass index (BMI) was 27.2 kg/m(2), with women being more obese than men. Sixteen patients had dyslipidaemia, 10 impaired glucose tolerance and seven had diabetes. Fifty percent were hypogonadal and six fulfilled BMI related criteria for growth hormone deficiency (GHD). Visceral to subcutaneous abdominal fat ratio was reduced in PWS. Visceral abdominal fat fraction correlated with both subcutaneous fat, BMI and peak GH-response. Thigh muscle volume was about half of the thigh fat volume. Beneficial effects of sex-steroid replacement on body composition were not observed. Body fat was primarily located subcutaneously and metabolic consequences of obesity limited. The abnormal body composition similar to that in non-PWS GHD adults increases the interest of GH treatment in the prevention of obesity in adults with PWS.

The Glucagon Test in the Diagnosis of Growth Hormone Deficiency in Children With Short Stature Younger than 6 Years

Few studies have addressed the diagnostic role of the glucagon test in children with suspected GH deficiency (GHD). The objective of the study was to investigate the diagnostic value of the glucagon test as an alternative test to insulin tolerance test (ITT) and arginine in GHD children younger than 6 yr. This study was conducted in two pediatric endocrinology centers. Forty-eight children (median age 4.2 yr, median height -3.0 sd score) with GHD confirmed by a peak GH to ITT and arginine less than 10 microg/liter (median 4.7 and 3.4 microg/liter, respectively) underwent a glucagon stimulation test. Magnetic resonance imaging showed normal hypothalamic-pituitary anatomy in 24 children, isolated anterior pituitary hypoplasia in seven, and structural hypothalamic-pituitary abnormalities in 17. Median GH peak response to glucagon (13.5 microg/liter) was significantly higher than that observed after ITT and arginine (P < 0.0001). GH peak after glucagon was less than 10 microg/liter in 20 subjects (group 1) and greater than 10 microg/liter in 28 subjects (group 2) without significant clinical or biochemical differences between the two groups. Median GH peak after glucagon was similar between patients with multiple pituitary hormone deficiency and those with isolated GHD and between subjects with and without structural hypothalamic-pituitary abnormalities. The magnitude of the GH peak after glucagon was negatively correlated to age at diagnosis (rho = -0.636, P < 0.0001). This study shows that glucagon has an effective GH-releasing activity and can be used to evaluate somatotroph function in young children with short stature. Normative data for this test in young children need to be established before its use in clinical practice.

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

Some patients fail to achieve adequate hypoglycaemia following a standard dose of intravenous insulin during the insulin tolerance test (ITT). Persistent acromegaly or Cushing's disease may contribute to inadequate hypoglycaemia. Aim To identify factors that predict failure to achieve adequate hypoglycaemia during an ITT after pituitary surgery. We reviewed consecutive ITTs performed over a 10-year period in 76 patients following pituitary surgery. Analyses were performed to determine if body mass index (BMI), fasting blood glucose (FBG), cortisol, GH status or underlying diagnosis influenced the outcome. Adequate hypoglycaemia (blood glucose < 2.2 mmol/l) was not achieved in 33 patients (Group 1) following a standard dose of neutral insulin (0.1 units/kg); 43 patients (Group 2) achieved adequate hypoglycaemia. Group 1 had significantly higher BMI, FBG, baseline cortisol and peak cortisol concentrations than Group 2. Peak GH response was not different. Multiple regression analysis showed that FBG was the only independent predictor of adequate hypoglycaemia. An insulin dose of 0.2 units/kg achieved adequate hypoglycaemia in 80% of patients with FBG >or= 5.5 mmol/l. In patients with acromegaly or Cushing's disease, failure to achieve adequate hypoglycaemia was associated with persistent disease. FBG is an important determinant of the dose of insulin required to achieve adequate hypoglycaemia during an ITT in patients after pituitary surgery. A standard insulin dose of 0.1 U/kg is insufficient for adequate hypoglycaemia in patients with FBG > 5.5 mmol/l. Adequate response to a standard dose of insulin suggests a likelihood of cure of acromegaly or Cushing's disease after pituitary surgery.

Use of a GH receptor antagonist (GHRA) to explore the relationship between GH and IGF‐I in adults with severe GH deficiency (GHD)

At diagnosis, approximately 50% of adults with severe GH deficiency (GHD) have an IGF-I within the reference range. It is unclear whether in such patients serum IGF-I levels are regulated by factors other than GH. We performed a double-blind, randomized, placebo-controlled, cross-over study to investigate the effect of the GH receptor antagonist - pegvisomant (20 mg daily for 14 days) on GH and IGF-I levels in three cohorts: patients with GHD and a normal IGF-I (NORMS); patients with GHD and a low IGF-I (LOWS) and healthy volunteers (CONS). Pegvisomant decreased IGF-I in CONS and NORMS [158.5 (101-206) vs. 103 (77-125) microg/l, P < 0.01; 124 (81-136) vs. 95 (51-113) microg/l, P < 0.01 respectively], but not in LOWS [31 (< 31-32) vs. 34.5 (< 31-38) microg/l], and this was associated with an increase in mean 24 h GH in CONS [0.49 (0.12-0.89) to 1.38 (0.22-2.45) microg/l (P = 0.03)] and in NORMS [69 (0-320)% from 0.1 (< 0.1-0.13) to 0.17 (0.11-0.42) microg/l (P = 0.03)], but not in the LOWS. The peak GH response to arginine was increased by pegvisomant in CONS and NORMS [6.1 (0.8-9) vs. 20.4 (13.1-28.8) microg/l, P = 0.03; 0.4 (0.1-0.5) vs. 0.5 (0.3-0.6) microg/l, respectively], but not in LOWS. These data indicate that patients with severe GHD with a normal IGF-I are able to increase GH secretion in response to a pegvisomant-induced fall in IGF-I, whereas those with low IGF-I levels are unable to increase GH secretion. Therefore circulating IGF-I appears to be GH-independent in GHD patients with a low IGF-I, but remains partially GH-dependent in GHD patients with a normal IGF-I.

Cranially irradiated adult cancer survivors may have normal spontaneous GH secretion in the presence of discordant peak GH responses to stimulation tests (compensated GH deficiency)

We have previously demonstrated that spontaneous (physiological) GH secretion was entirely normal in cranially irradiated patients who had normal individual peak GH responses to the insulin tolerance test (ITT) but reduced maximal somatotroph reserve as indicated by substantially reduced group GH responses to the GHRH + arginine stimulation test (AST). The normality of spontaneous GH secretion was attributed to a compensatory increase in hypothalamic stimulatory input within a partially damaged hypothalamic-pituitary (h-p) axis. It is unknown, however, if such compensatory stimulation can also maintain normality of GH secretion in those who fail the ITT but pass the GHRH + AST. STUDY SUBJECTS AND DESIGN: We studied 24-h spontaneous GH secretion by 20-min sampling both in the fed state (n = 11) and in the last 24 h of a 33-h fast (n = 9) in adult cancer survivors with subnormal peak GH responses to the ITT but either normal or relatively less attenuated peak GH responses to the GHRH + AST. The study was conducted 8.3 +/- 1.8 (range 2-23) years after cranial irradiation for nonpituitary brain tumours (n = 9) or leukaemia/lymphoma (n = 2) in comparison with 30 normal controls (fasting, 14). Previously published diagnostic thresholds for the ITT, GHRH + AST and spontaneous GH secretion were used to characterize GH secretion. Four of the 11 patients with impaired stimulated responses to both tests showed only minor discordancies between stimulated and spontaneous GH secretion. Two of the remaining seven patients had subnormal spontaneous GH secretion. However, spontaneous GH secretion, both individually and as a group, was entirely normal in the remaining five patients who had impaired GH responses to the ITT but normal individual responses to the GHRH + AST; in these five patients, IGF-I standard deviation scores (SDS; -2.7 to -0.8) were significantly reduced to a moderate degree compared with normals. In cranially irradiated adult cancer survivors, it cannot be assumed that failure to pass the ITT in isolation reflects severe GH deficiency (GHD). It appears that in some patients near-maximal compensatory overdrive of the partially damaged somatotroph axis may result in near-normal quantitative restoration of spontaneous GH secretion, thus limiting further stimulation with the ITT to the extent that impaired GH responses can be seen even before spontaneous GH secretion starts to decline in adults. However, IGF-I status continues to provide useful information about the adequacy of the compensatory process and therefore the degree of normality of GH secretion.

Congenital Hypopituitarism: Clinico-Radiological Correlation

Non-tumoral causes constitute a major group of childhood hypopituitarism. The structural abnormalities of the stalk and the pituitary gland correlate with number and severity of concurrent hormone deficiencies. We describe clinico-radiological correlates in patients with non-tumoral hypopituitarism. Thirty-one children (23 boys) with congenital hypopituitarism, aged 1-17 years, with a peak GH levels of < 7 ng/ml after two pharmacological stimuli (insulin induced hypoglycemia [IIH] and clonidine) were included in the study. MRI tetrad of absent or hypoplastic pituitary, empty sella, redundant or absent stalk and absent/ectopic posterior pituitary bright spot (EPPBS) was considered as a radiological diagnostic criterion and these abnormalities were correlated with number of hormone deficiencies, severity of GH deficiency and mode of presentation at the time of delivery. Twenty (66%) children had vertex presentation, nine breech, and two children were delivered by lower segment Cesarean section (LSCS). Seven (78%) out of nine in the breech delivery group, 14 (70%) out of 20 in the vertex group and one out of two (50%) in the LSCS group had multiple pituitary hormone deficiencies (MPHD) (p = 0.665). Hypoplastic pituitary gland and posterior pituitary abnormalities were more frequent in patients with isolated growth hormone deficiency (IGHD) as opposed to MPHD (87.5% vs 65.2%, p = 0.08, 63% vs 47%, p = 0.64), whereas empty sella and stalk abnormalities were found more frequently in MPHD than in the IGHD group (76% vs 50%, p = 0.45 and 82.6% vs 37.5%, p = 0.01). Higher frequency of MR abnormalities was found in those with a peak GH response of < 3 ng/ml irrespective of the number of other pituitary hormone deficiencies (82.6% vs 37.5%, p = 0.02). Sixteen patients had MRI tetrad and it was more prevalent in the IGHD than in the MPHD group (75% and 44%, p = 0.01) and correlated with the severity of GH deficiency (r = 0.57, p = 0.01). The imaging abnormalities were also more prevalent in children with breech as compared to vertex presentation and correlated with severity of GH deficiency (100% vs 60%, p = 0.03, r = 0.52). Imaging abnormalities are frequent in patients with non-tumoral hypopituitarism and correlate best with severity of GH deficiency rather than number of hormone deficiencies and breech presentation.

Diagnosis of Growth Hormone Deficiency in Adults: Provocative Testing with GHRP6 in Comparison to the Insulin Tolerance Test

The aim of the study was to evaluate the clinical applicability of growth hormone releasing peptide 6 (GHRP6) for the diagnosis of GH deficiency in adults. Forty-nine patients with suspected hypothalamic or pituitary disease underwent both ITT and GHRP6 (1 microg/kg) testing. In addition, 20 healthy controls were tested by GHRP6 only. Blood samples were analyzed for GH levels. Thirty patients had a GH peak response of less than 3 microg/l during ITT and were considered growth hormone deficient (GHD). For the GHRP6 test, the GH mean peak was 3.0 microg/l (+/-0.8, 0.5-20.9) in the GHD group vs. 14.8 microg/l (+/-4.7, 1.8-95.3) in the growth hormone sufficient (GHS) group. Receiver operating characteristics (ROC) analysis suggested an optimal peak GH cut-point of 3.5 microg/l with 80% sensitivity and 95% specificity. Applying upper (11.3 microg/l) and lower (3.5 microg/l) cutoffs with high specificities established the diagnosis in nearly two third of the patients. During administration of GHRP6 no side effects were observed. GHRP6 alone as a provocative test is highly specific, but with limited sensitivity for the diagnosis of GH deficiency in adults. Using upper and lower cutoffs, further testing by ITT may be necessary in only one-third of patients.

Central Adiposity as an Important Confounder in the Diagnosis of Adult Growth Hormone Deficiency

When analyzed separately, subjects with a waist circumference less than 102 cm had a mean peak GH response of 26.9 g/ liter, and those with a waist circumference 102 cm or higher had a more than 3-fold lower mean response, 7.9 g/liter. This difference was much greater than the differences observed among

Retesting the childhood-onset GH-deficient patient

GH deficiency (GHD) in adults has to be shown by a single provocative test, provided that it is validated. Insulin tolerance test (ITT) has been indicated as the test of choice; now also glucagon test is validated and represents an alternative. The GHRH plus arginine (ARG) test and testing with GHRH plus a GH secretagogue are equally reliable diagnostic tools, and are now considered as 'golden' standards as ITT. Childhood-onset (CO) GHD needs retesting in late adolescence or young adulthood; this is a major clinical challenge and raises questions about the most appropriate method and cut-off value. Appropriate re-evaluation of GH status is represented by simple measurement of IGF1 concentration off rhGH treatment. Clearly, low IGF1 levels are evidence of persistent severe GHD in subjects with genetic GHD or panhypopituitarism. However, normal IGF1 levels never rule out severe GHD and CO-GHD with normal IGF1 levels must undergo a provocative test. The appropriate GH cut-off limit is specific for each provocative test. As shown by the ROC curve analysis, in late adolescents and young adults, the lowest normal GH peak response to ITT is 6.1 microg/l while that to GHRH+ARG test is 19.0 microg/l. These cut-off limits, however, are just indicative as being variable as a function of the assay used. No other test is validated for retesting. As GHRH+ARG test mostly explores the GH-releasable pool, normal GH response would be verified by a second ITT in order to rule out subtle hypothalamic defect.

Growth hormone and changes in energy balance in growth hormone deficient adults

Adults with growth hormone deficiency (AGHD) have an adverse body composition with an increased prevalence of obesity. It is not known whether growth hormone replacement (GHR) results in alterations in energy intake (EI) and/or energy expenditure (EE). The aim of the study was to investigate the effects of GHR on EI and EE. Nineteen hypopituitary adults (14 males, 5 females, mean age 46.2 years) with severe GHD (peak GH response to glucagon <or= 9 mU L(-1)) were studied. All patients self-injected recombinant human GH starting with 0.3 mg s.c. daily. The following were measured before and following 6 months of stable maintenance of GHR: food intake during a test meal, appetite ratings, resting EE (indirect calorimetry) and voluntary physical activity (accelerometry). GHR nearly doubled voluntary physical activity (mean activity units 3319 vs. 1881, P = 0.007) and improved quality of life score (mean score 9.1 vs. 16.5, P < 0.0001). Subjects reported higher fasting hunger ratings (mean 64.8 vs. 49.6, P = 0.02) but ad libitum energy intake remained unchanged. Eating behavioural traits were favourably altered with lower disinhibition (mean 6.0 vs. 7.2, P = 0.02) and lower susceptibility to hunger ratings (4.6 vs. 6.8, P = 0.001) after GHR. Additionally, GHR did not result in significant changes in resting EE, body weight and body mass index. GHR in AGHD significantly improves voluntary physical activity and quality of life. Following GHR, subjects experience greater 'state' (physiological) hunger, reductions in eating disinhibition and hunger susceptibility, but no effects on calorie intake or macronutrient choice were detected.