Search

Current guidelines for the diagnosis of adult growth hormone deficiency (GHD) state that the diagnosis must be proven biochemically by provocative testing that is done within the appropriate clinical context. The need for reliance on provocative testing is based on evidence that the evaluation of spontaneous growth hormone (GH) secretion over 24 h 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. The insulin tolerance test (ITT) is the test of choice, with severe GHD being defined by a GH peak less than 3 microg/l, the cut-off that distinguishes normal from GHD adults. The ITT is contraindicated in the presence of ischemic heart disease, seizure disorders, and in the elderly. Other tests are as reliable as the ITT, provided they are used with appropriate cut-off limits. Glucagon stimulation, a classical test, and especially new maximal tests such as GHRH in combination with arginine or GHS (i.e., GHRP-6) have well-defined cut-off limits, are reproducible, are independent of age and gender, and are able to distinguish between normal and GHD subjects. The confounding effect of overweight or obesity on the interpretation of the GH response to provocative tests needs to be considered as the somatotropic response to all stimuli is negatively correlated with body mass index. Appropriate cut-offs for lean, overweight, and obese subjects must be used in order to avoid false-positive diagnoses of severe GHD in obese adults.

Objective: Hypopituitarism frequently follows pituitary neurosurgery (NS) and/or irradiation. However, the frequency of hypothalamic-pituitary dysfunction after NS of non-pituitary intracranial tumors is unclear. The aim of this study was to assess the presence of endocrine alterations in patients operated on for intracranial tumors., Design: This is a retrospective study., Methods: We studied 68 consecutive adult patients (28 female, 40 male, age 45.0 +/- 1.8 years; body mass index (BMI): 26.5 +/- 0.6) with intracranial tumors who underwent NS only (n = 17) or in combination with radiotherapy (RT) and/or chemotherapy (CT) (n = 51). In all subjects, basal endocrine parameters and the GH response to GHRH + arginine test (using BMI-dependent cut offs) were evaluated., Results: In 20.6% of the patients, peripheral endocrinopathy related to CT and/or RT was present. Hypopituitarism was found in 38.2% of the patients. Total pituitary hormone, multiple pituitary hormone, and isolated pituitary hormone deficits were present in 16.2, 5.8, and 16.2% respectively. The most common pituitary deficits were, in decreasing order: LH/FSH 29.4%, GH 27.9%, ACTH 19.1%, TSH 17.7%, and diabetes insipidus 4.4%. Hyperprolactinemia was present in 13.2%. The prevalence of hypopituitarism was higher in patients who underwent NS only and with tumors located closely to the sella turcica, but a substantial proportion of patients with tumors not directly neighboring the sella also showed hypopituitarism., Conclusions: Hypopituitarism frequently occurs after NS for intracranial tumors. Also, exposure of these patients to CT and/or RT is frequently associated with peripheral endocrinopathies. Thus, endocrine evaluation and follow-up of patients treated for intracranial tumors should be performed on a regular basis.

Hypopituitarism represents the consequence of many conditions, in both the adult and child population. It may occur after neurosurgical treatment of brain tumors arising near sella turcica. Much more attention has been focused on lesions far from the hypothalamic-pituitary region as possible causes of pituitary impairment, validating the concept of the particular fragility of these structures. The aim of this study was to evaluate pituitary function in particular GH deficiency (GHD) in patients submitted to neurosurgery for benign tumors of the central nervous system (CNS) not involving hypothalamic-pituitary region. We observed 37 patients with benign brain tumors [13 males, 24 females, age: 54.6+/-13.9 yr; body mass index (BMI): 25.1+/-4.0 kg/m2] performing a basic evaluation of the pituitary function and a dynamic test of the GH/IGF-I axis [GHRH (1 microg/kg iv)+arginine (0.5 g/kg iv) test] for 3 and 12 months after the neurosurgical treatment. Some degree of hypopituitarism was shown in 16 patients (43.2%) at the 3-months follow-up. Hypogonadism was present in 4 patients, hypoadrenalism in another 4 and hypothyroidism in 2. Two patients showed mild hyperprolactinemia and no patients had diabetes insipidus. Seven patients (18.9%) were GH deficient (peak GH <16.5 microg/dl). At 12 months retesting, some degree of hypopituitarism was confirmed in 8 patients, hypogonadism in 2 and hypothyroidism in one; no patients showed hypoadrenalism and GHD was present in 5. This data suggests that hypopituitarism of various degree may develop in patients who are submitted to neurosurgery for primary brain tumors, even far from hypothalamic-pituitary region.

Objective: The aim of this study is to estimate the annual incidence and prevalence rate of the GH treatment exposure in patients under the age of 18 treated for hypopituitarism or isolated GH deficiency (GHD) in Piedmont, during the period January 1, 2002 to December 31, 2004., Methods: The selection criteria for recombinant human GH (rhGH) treatment in childhood were approved by the Ministry of Health in Italy in the yr 1998. The present analysis is based on data from the Registry of subjects receiving GH therapy (GH Registry) made up of the 918 pediatric patients (age <18 yr) with a diagnosis of GHD (excluding Prader-Willi and Turner syndromes and other conditions), diagnosed in the period January 1, 2002 - December 31, 2004. The case series has been described as regards the number of cases per year of diagnosis; the prevalence and incidence rates, calculated per 10,000 (per ten thousand) inhabitants, are given for each year of the study period., Results: The prevalence rate increases slightly from 8.62 per thousand in 2002 to 9.44 per thousand in 2004 and the incidence rates estimated were 2.49 per ten thousand, 1.86 per ten thousand and 1.97 per ten thousand in the yr 2002, 2003 and 2004, respectively., Conclusion: The Piedmont GH Registry represents the first database available in Italy and could set an example for the other Italian regions as well.

Background/aims: The aim of the present study was to investigate whether short children with normal growth hormone (GH) immunoreactivity, but reduced bioactivity (bioinactive GH) could benefit from rhGH treatment as GH deficient (GHD) patients., Methods: We evaluated 12 pre-pubertal children (8 M, 4 F), with GH deficiency-like phenotype showing normal serum GH peak levels (>10 ng/ml), measured by immunofluorimetric assay (IFMA-GH), in contrast with a reduced GH bioactivity (bio-GH), evaluated using the Nb(2) cells. We also evaluated 15 age-matched GHD pre-pubertal children (11 M, 4 F) with serum GH peak <5 ng/ml. Both groups were treated with rhGH therapy at the dose of 0.23 mg/kg/week s.c., Results: Serum bio-GH/IFMA-GH ratio at peak time for each patient during the provocative test was significantly lower in bioinactive GH than in GHD children (0.29 vs. 2.05, p = 0.00001). Recombinant human GH therapy induced a significant (p < 0.001) increase in growth rate in both groups during the first 2 years. In the third year of treatment, while growth rate in GHD children is maintained, in bioinactive GH patients it decreases remaining, however higher compared to the pre-treatment one., Conclusions: Short rhGH therapy given to selected bioinactive GH children improve growth rate and might result in greater final adult height., (Copyright (c) 2006 S. Karger AG, Basel.)

Traumatic brain injury (TBI) has been associated with hypopituitarism in general and GH deficiency (GHD) in particular; the consequences of this on growth and development are likely to be critical in children and adolescents in the so-called "transition phase". In order to verify the consequences of TBI on pituitary function in the transition phase, we studied a population of adolescents and young adults 3 and 12 months after brain injury [no. = 23, 9 females, 14 males; age: 16-25 yr; body mass index (BMI): 21.9 +/- 0.6 kg/m2]. At 3 months, hypopituitarism was present in 34.6%. Total, multiple and isolated deficits were present in 8.6, 4.3 and 21.7%, respectively. Diabetes insipidus (DI) was present in 8.6% patients and mild hyperprolactinemia in 4.3%. At 12 months, hypopituitarism was present in 30.3%. Total, multiple and isolated deficits were present in 8.6, 4.3 and 17.4%, respectively. DI was present in 4.3% of patients and mild hyperprolactinemia in 4.3%. Total hypopituitarism was always confirmed at retesting. Multiple and isolated hypopituitarism were confirmed in 0/1 and 2/5, respectively. Two/23 patients showed isolated hypopituitarism at 12 months only; 1 patient with isolated at 3 months showed multiple hypopituitarism at retesting. GHD and secondary hypogonadism were the most common acquired pituitary deficits. These results show the high risk of TBI-induced hypopituitarism also in the transition age. Thus it is recommended that pediatric endocrinologists follow-up pituitary function of children and adolescents after brain injuries.

Context: Traumatic brain injury (TBI) and subarachnoid hemorrhage (SAH) are conditions at high risk for the development of hypopituitarism., Objective: The objective of the study was to clarify whether pituitary deficiencies and normal pituitary function recorded at 3 months would improve or worsen at 12 months after the brain injury., Design and Patients: Pituitary function was tested at 3 and 12 months in patients who had TBI (n = 70) or SAH (n = 32)., Results: In TBI, the 3-month evaluation had shown hypopituitarism (H) in 32.8%. Panhypopituitarism (PH), multiple (MH), and isolated (IH) hypopituitarism had been demonstrated in 5.7, 5.7, and 21.4%, respectively. The retesting demonstrated some degree of H in 22.7%. PH, MH, and IH were present in 5.7, 4.2, and 12.8%, respectively. PH was always confirmed at 12 months, whereas MH and IH were confirmed in 25% only. In 5.5% of TBI with no deficit at 3 months, IH was recorded at retesting. In 13.3% of TBI with IH at 3 months, MH was demonstrated at 12-month retesting. In SAH, the 3-month evaluation had shown H in 46.8%. MH and IH had been demonstrated in 6.2 and 40.6%, respectively. The retesting demonstrated H in 37.5%. MH and IH were present in 6.2 and 31.3%, respectively. Although no MH was confirmed at 12 months, two patients with IH at 3 months showed MH at retesting; 30.7% of SAH with IH at 3 months displayed normal pituitary function at retesting. In SAH, normal pituitary function was always confirmed. In TBI and SAH, the most common deficit was always severe GH deficiency., Conclusion: There is high risk for H in TBI and SAH patients. Early diagnosis of PH is always confirmed in the long term. Pituitary function in brain-injured patients may improve over time but, although rarely, may also worsen. Thus, brain-injured patients must undergo neuroendocrine follow-up over time.

Context: Poor sensitivity of IGF binding protein (IGFBP)-3 assessment in the work-up of GH deficiency (GHD) has been ascribed to the equal affinity of IGFBP-3 for IGF-I and IGF-II and to IGFBP-3 proteolysis., Objective: The objective of this study was to determine the IGF-II GH dependency and IGFBP-3 proteolysis in patients with GHD from childhood to young adulthood., Design: This study was cross-sectional., Setting: This was a national multicenter study performed in university hospitals., Patients: One hundred thirty-one subjects (chronological age, 1.3-25 yr), 72 patients with GHD and 59 subjects with idiopathic short stature, were studied., Interventions: IGF-I, IGF-II, and IGFBP-3 serum concentrations were measured by immunoradiometric assay. IGFBP-3 circulating forms were assessed by Western immunoblot (WIB) analysis., Main Outcome Measures: Main outcome measures were sensitivity and specificity of IGF-I, IGF-II, and IGFBP-3 measurements., Results: Sensitivity and specificity of IGFBP-3 measurement were 27 and 100%, respectively. IGFBP-3 sensitivity was 46% in young adulthood. Sensitivity and specificity of IGF-I were 69 and 81%, respectively. Sensitivity and specificity of IGF-II assessment were 23 and 97%, respectively. IGFBP-3 WIB revealed the presence of the intact form and the major 29-kDa fragment in both GHD and subjects with idiopathic short stature. In patients with GHD, WIB showed the presence of an additional smaller IGFBP-3 fragment migrating at approximately 18 kDa., Conclusions: Our results suggest that in children and young adults with GHD, the low GH dependency of IGF-II together with IGFBP-3 proteolytic activity yielding the 18-kDa fragment concur to reduce the sensitivity of IGFBP-3 assessment, ultimately making it too inaccurate as a screening test in the work-up of GHD.

Results of recent and ongoing studies have made it clear that brain injuries like traumatic brain injury (TBI) pose substantial risk to pituitary function, perhaps even greater risk than previously believed. Patients with TBI should be screened both prospectively and retrospectively for isolated, multiple and even total pituitary deficits. It is well known that, patients with "classical" hypopituitarism (due to primary hypothalamic-pituitary pathologies) do benefit from hormonal replacement therapy. It has been suggested that patients with TBI-induced hypopituitarism may benefit with appropriate hormonal replacement receiving replacement therapy such as anti-diuretic hormone (ADH), glucocorticoid and thyroid hormones when needed. Gonadal and recombinant human growth hormone (rhGH) replacement therapy should also be introduced if there are deficiencies demonstrated and even reconfirmed in a second step. The signs and symptoms of post-TBI hypopituitarism may be masked by what has been assumed to be merely the post-traumatic syndrome. By increasing awareness among physicians of the risks of brain injuries-induced endocrinopathies and the need for appropriate endocrinological testing, it may be possible to improve the quality of life and enhance the rehabilitation prospects for these patients. In most instances, these patients are first seen and treated by trauma surgeons and neurosurgeons, and subsequently by rehabilitation physicians; they must be knowledgeable about the risks of hypopituitarism so that they can determine which patients are candidates for screening for hypopituitarism. In addition, endocrinologists and internists must be educated about TBI-induced hypopituitarism and encouraged to actively share their expertise with other physicians.

Primary Objective: The goal of this consensus statement is to increase awareness among endocrinologists and physicians treating patients with traumatic brain injury (TBI) of the incidence and risks of hypopituitarism among patients with TBI., Rationale: TBI poses significant risk to the pituitary gland, leading to elevated risks of diabetes, hypopituitarism and other endocrinopathies. Signs and symptoms associated with hypopituitarism often mimic the sequellae of TBI, although the severity of symptoms is not necessarily related to the severity of the injury. Patients with TBI-induced hypopituitarism may benefit both physically and psychologically from appropriate hormone replacement therapy (HRT). Participants at this unique consensus meeting attempted to define and spearhead an approach to increase awareness of the risks of TBI-induced endocrinopathies, in particular growth hormone deficiency (GHD), and to outline necessary and practical objectives for managing this condition., Recommendations: Systematic screening of pituitary function is recommended for all patients with moderate-to-severe TBI at risk of developing pituitary deficits. Patients with hypopituitarism benefit from appropriate hormonal replacement and prospects for rehabilitation of patients with TBI-induced hypopituitarism may be enhanced by appropriate HRT. Further exploration of this possibility requires: (1) active collaboration between divisions of endocrinology and rehabilitation at the local level to perform a screening of pituitary function in patients after TBI, (2) creation of a consultancy service by endocrine societies for use by rehabilitation centres, (3) development of continuing medical education (CME) programmes that can be offered as crossover training to the physicians who manage the care of patients with TBIs, (4) targeting of patient organizations with educational information for dissemination to patients and their families, (5) continued efforts to more clearly define the population at greatest risk of TBI-induced hypopituitarism and (6) monitor results of efficacy studies as they become available to evaluate whether and how much replacement therapy can improve the symptoms of individuals with TBI-induced hypopituitarism.

Recent studies have demonstrated that hypopituitarism, and in particular growth hormone (GH) deficiency, is common among survivors of traumatic brain injury (TBI) tested several months or years following head trauma. In addition, it has been shown that post-traumatic neuroendocrine abnormalities occur early and with high frequency. These findings may have significant implications for the recovery and rehabilitation of patients with TBI. Although data emerging after 2000 demonstrate the relevance of the problem, in general there is a lack of awareness in the medical community about the incidence and clinical repercussions of the pathology. Most, but not all, head trauma associated with hypopituitarism is the result of motor accidents. The subjects at risk are those who have suffered moderate-to severe head trauma although mild intensity trauma may precede hypopituitarism also. Particular attention should be paid to this problem in children and adolescents. Onset of pituitary deficits can evolve over years following injury. For the assessment of the GH-IGF axis in TBI patients, plasma IGF-I concentrations, plus dynamic GH testing is indicated. Some degree of hypopituitarism is found in 35-40% of TBI patients. Among multiple pituitary deficits, the most common ones were GHD and gonadotrophin deficiency. In most series 10-15% presented with severe GHD and 15% with partial GHD after stimulating GH secretion confirming that the most common isolated deficit is GHD. Psychometric evaluation together with neurocognitive testing shows variability of disability and the possibility that untreated TBI induced hypopituitarism contributes to the chronic neurobehavioral problems seen in many head-injured patients warrants consideration. Preliminary data, from small pilot, open-label studies show that subjects treated with GH experience significant improvements in concentration, memory, depression, anxiety and fatigue. In conclusion, pituitary failure can occur even in minor head injuries and is poorly recognized.

Objective: A consensus exists that severe growth hormone deficiency (GHD) in adults is defined by a peak GH response to insulin-induced hypoglycemia (insulin tolerance test, ITT) of less than 3 microg/l based on a cohort of subjects with a mean age of 45 years., Design and Methods: By considering one of the following two criteria for the diagnosis of probable permanent GHD, i.e. the severity of GHD (suggested by the presence of multiple pituitary hormone deficiencies (MPHD)) or the magnetic resonance (MR) imaging identification of structural hypothalamic-pituitary abnormalities, 26 patients (17 males, 9 females, mean age 20.8 +/- 2.3 years, range 17-25 years) were selected for re-evaluation of the GH response to ITT and their IGF-I concentration. Eight subjects had isolated GHD (IGHD) and 18 had MPHD. Normative data for peak GH were obtained after ITT in 39 healthy subjects (mean age 21.2 +/- 4.4 years, range 15.1-30.0 years) and the reference range for IGF-I was calculated using normative data from 117 healthy individuals., Results: Mean peak GH response to ITT was significantly lower in the 26 patients (1.8+/-2.0 microg/l, range 0.1-6.1 microg/l) compared with the 39 controls (18.5 +/- 15.5 microg/l, range 6.1-84.0 microg/l; P < 0.0001). One subject with septo-optic dysplasia had a peak GH response of 6.1 microg/l that overlapped the lowest peak GH response obtained in normal subjects. There was an overlap for IGF-I SDS between subjects with IGHD and MPHD, as well as with normal controls. The diagnostic accuracy of a peak GH response of 6.1 microg/l showed a 96% sensitivity with 100% specificity. The maximum diagnostic accuracy with IGF-I SDS was obtained with a cut-off of -1.7 SDS (sensitivity 77%, specificity 100%) while an IGF-I < or = - 2.0 SDS showed a sensitivity of 62%., Conclusion: Our data show that the cut-off value of the peak GH response to ITT of less than 3 microg/l or 5 microg/l and of IGF-I of less than -2.0 SDS are too restrictive for the diagnosis of permanent GH deficiency in the transition period. We suggest that permanent GHD could be investigated more accurately by means of an integrated analysis of clinical history, the presence of MPHD, IGF-I concentration and the MR imaging findings of structural hypothalamic-pituitary abnormalities.

To verify if the entity of the peak GH responses to the GHRH+arginine (ARG) test is able to show different degree forms of GH deficiency (GHD), we linked these responses with the number of other anterior pituitary deficits. These anterior pituitary deficits were also related with IGF-I levels. To this purpose, we studied a large cohort of lean patients with pituitary disease of different etiologies [86 males and 68 females; age: mean +/- SEM 41.5 +/- 1.2 yr, body mass index (BMI) <25 kg/m2]. The patients were subdivided into 4 groups according to the increasing number of hormone deficiencies: isolated GHD (HYPO1, no.=28) or GHD plus one, two or three additional hormones (gonadotrophin, ACTH, and TSH) deficiencies (HYPO2, no.=20; HYPO3, no.=15; HYPO4, no.=91). Peak GH responses to the GHRH+ARG test and IGF-I levels showed a clear difference among the groups (p < 0.01 and p < 0.001, respectively). A significant difference was found between HYPO1 and HYPO4 for IGF-I levels (p < 0.05), and between HYPO1 and HYPO4 and between HYPO2 and HYPO4 for the GHRH+ARG test (p < 0.005). Considering only the patients who underwent both GHRH+ARG test and insulin tolerance test (ITT) (no.=70), the pattern of the peak GH responses to the GHRH+ARG test was the same of the whole group of patients, while no statistical difference was found with ITT. Our data show that the peak GH responses to the GHRH+ARG test and the IGF-I levels are linked to the severity of hypopituitarism, expressed by the number of increasing anterior pituitary deficits. This association is lost if the evaluation of the GH status is performed by the ITT. In all, the GHRH+ARG test and measurement of IGF-I are able to evidence different degrees of GHD in adult patients with pituitary disease.

GH deficient (GHD) adult patients, either from child- or adulthood onset, have impaired health (impairment in body composition and structure functions as well as derangement in lipoprotein and in carbohydrate metabolism leading to increased cardiovascular morbidity), which improves with GH replacement. For patients with childhood-onset GHD, the so called "transition phase", defined as the period between reaching the final height and the completion of the development of such organs, can be considered as the most important phase of life for the development of important target organs: heart, bones and muscles. Particularly, children with GHD may not attain the peak bone mass (PBM) at the time of discontinuation of GH therapy, as the complete achievement of PBM is likely reached later on, during the transition phase to adulthood. In addition, patients with GHD generally have a delayed timing of PBM compared to normal individuals. GH treatment should be continued until the attainment of PBM, independently of the final height achieved. Individual titration of the recombinant human GH (rhGH) dose is recommended, and measurement of IGF-I levels is needed for monitoring the adequacy of replacement. The GH dose for replacement in the transition adolescent is still higher than in adulthood; after puberty, the rhGH dose should be progressively decreased in the following years (probably up to 25 yr of age) in order to obtain the achievement of optimal PBM.

Traumatic Brain Injury (TBI) and Subarachnoid Haemorrhage (SAH) are conditions at high risk to develop hypopituitarism as pointed out by many papers in scientific literature. But most of the papers were referred to retrospective evaluations, not considering the possible evolution of the pituitary function over time. Aim of our studies was to clarify whether pituitary deficiencies and normal pituitary function recorded at short term follow-up (3 months), would improve or worsen, respectively, at long term (12 months after the brain injury). In a multicenter study protocol, in patients who suffered TBI (n = 70; 50 Males, 20 Females; age 39.31 +/- 2.4 years; BMI 23.8 +/- 0.4 kg/m(2)) or SAH (n = 32; 12M, 20F; age: 51.9 +/- 2.2 year; BMI: 24.7 +/- 0.6 kg/m(2)) we tested 3 and 12 months after the pathological events the pituitary function. In TBI patients, the 3 month evaluation had shown some degree of hypopituitarism in 32.8% and the 12 months retesting demonstrated some degree of hypopituitarism in 22.7%. Total hypopituitarism was always confirmed at 12 months while Multiple and Isolated deficits recorded at 3 months was confirmed in nearly 25% only of the patients. On the other hand, in 5.5% of TBI with normal pituitary function at 3 months Isolated deficits were recorded at 12 months testing. Moreover, in 13.3% of TBI with Isolated deficit at 3 months Multiple hypopituitarism was demonstrated at 12 months retesting. In SAH patients, the 3 months evaluation had shown some degree of hypopituitarism in 46.8% and the 12 month retesting demonstrated some degree of hypopituitarism in 37.5%. No multiple hypopituitarism recorded at 3 months was confirmed at 12 months, but 2 patients with isolated deficits at 3 months showed multiple hypopituitarism at 12 month retesting. At 12 as well as at 3 months, both in TBI and SAH patients, the most common deficit was severe GHD (>20%) followed by secondary hypogonadism and then hypoadrenalism and hypothyroidism. In all, in patients who experienced TBI or SAH the risk to develop hypopituitarism is very high; early diagnosis of total hypopituitarism is always confirmed at the long term follow-up; however pituitary function in brain injured patients may improve over time, because, isolated and even multiple pituitary insufficiencies recorded at short term can be transient; on the other hand normal pituitary function recorder at short term may, become impaired 12 months after the injury. Thus, brain injured patients must undergo neuroendocrine follow-up over time in order to monitoring pituitary function and eventually providing appropriate placement.

In the current guidelines for the diagnosis of adult GH deficiency (GHD) it is stated that, within the appropriate clinical context, it has to be shown by provocative tests only. But the diagnostic value of measuring IGF-I levels has been recently revisited. It has been confirmed that normal IGF-I levels do not rule out severe GHD in adults. However, it has also been emphasized that very low IGF-I levels in patients highly suspected for GHD (and without malnutrition, liver disease or hypothyroidism) could be considered definite evidence for severe GHD. This assumption particularly applies to patients with childhood-onset, severe GHD or with multiple hypopituitarism acquired in adulthood. The value of measuring IGF-I levels for monitoring the efficacy and the adequacy of rhGH replacement remains definitely accepted.

Recent studies have demonstrated that hypopituitarism, in particular GH deficiency, is common among survivors of traumatic brain injury (TBI) years tested several months or following head trauma. In addition, it has been shown that post-traumatic neuroendocrine abnormalities occur early and with high frequency. These findings may have significant implications for the recovery and rehabilitation of patients with TBI. Although data emerging after year 2000 demonstrate the relevance of the problem, in general there is a lack of awareness in the medical community about the incidence and clinical repercussions of the pathology. Most, but not all, head trauma associated with hypopituitarism is the result of motor vechicle accidents. The subjects at risk are those who have suffered moderate-to-severe head trauma, although mild intensity trauma may also precede hypopituitarism. Particular attention should be paid to this problem in children and adolescents; onset of pituitary deficits can evolve over years following injury. Plasma IGF-I concentrations, plus dynamic GH testing, are indicated for the assessment of the GH-IGF axis in TBI patients. Some degree of hypopituitarism is found in 35-40% of TBI patients. Among mulitple pituitary deficits, the most common ones were GH deficiency (GHD) and gonadotrophin deficiency. In most series, 12-15% presented with severe GHD and 14% with partial GHD after stimulating GH secretion, confirming that the most common isolated deficit is GHD. Psychometric evaluation and neurocognitive testing show variability of disability, and these measures are needed and important to support hormonal replacement. Preliminary data, from small pilot, open-label studies show that subjects treated with GH experience significant improvements in concentration, memory, depression, anxiety and fatigue. In conclusion, pituitary failure can occur even in minor head injuries and is poorly recognized.

The diagnosis and treatment of growth hormone deficiency (GHD), as well as the possibility of counteracting somatopause and age-related changes in body composition, structural functions, and metabolism, prompted interest in potential clinical uses of GH-releasing hormone (GHRH) and GH secretagogues (GHS). GHD often reflects hypothalamic GHRH deficiency and it has been clearly demonstrated that the age-related decline in the function of the GH/IGF-I axis reflects a reduction in hypothalamic function as evidenced by the preservation of the releasable pool of pituitary GH in aged subjects. The effectiveness of recombinant human GH (rhGH) is well established, but it is also recognized that GH replacement does not mimic physiological GH secretion which theoretically would be restored by GHRH and/or GHS. At present, it has been clearly demonstrated that GHRH and/or GHS represent reliable tools for the diagnosis of GHD. On the other hand, neither GHRH nor GHS has been shown to provide effective alternatives to rhGH for the treatment of GHD. Although GHRH and/or GHS represent the most logical approaches for the restoration of the GH/IGF-I axis to a youthful level of activity and for counteracting the somatopause, this hypothesis has never been proven definitively. Conceptually, GHRH replacement would be the most physiological approach and its safety is guaranteed, provided an appropriate dose is used, in order to avoid hyperactivity of the GH/IGF-I axis. However, a long-acting preparation is needed. On the other hand, GHS, e.g., ghrelin analogues, could be considered as a function of their selectivity of action. However, ghrelin has a wide spectrum of endocrine and non-endocrine actions at both central and peripheral levels. Thus, non-selective GHS, although available in orally active forms, could elicit unforeseen side effects. Previous studies with GHRH and/or GHS in aging patients provided encouraging results. However, it still remains to be definitively demonstrated that aged subjects would benefit from chronic treatment with these molecules.

Objective: In adults, excessive GH secretion may lead to secondary diabetes mellitus, while prolonged GH treatment may accelerate the onset of type 2 diabetes mellitus in predisposed children. The aim of the study was to evaluate insulin sensitivity (IS) and glucose tolerance (GT) in a group of GH-deficient children treated with GH for a period of 6 years., Patients and Design: One hundred and twenty-eight children (40 females, 88 males) were included in the study. At the beginning of treatment chronological age was 8.9 +/- 3.2 years, height standard deviation score (SDS) -2.43 +/- 0.90 and body mass index (BMI) SDS 0.18 +/- 1.60. At the end of the study chronological age was 13.0 +/- 2.9 years, height SDS -1.24 +/- 1.27 and BMI SDS 0.23 +/- 1.54. GH was administered at a mean weekly dosage of 0.3 mg/kg, injected subcutaneously over 6-7 days. GT was assessed according to the criteria of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. IS was evaluated with the quantitative insulin sensitivity check index (QUICKI)., Results: No cases of impaired GT or diabetes were recorded during the follow-up period. IS, already lower than in controls before starting treatment with GH, decreased significantly during the first year of therapy (QUICKI: 0.346 +/- 0.033 vs. 0.355 +/- 0.044, P < 0.05), with no further decrease in the following years. No correlation was found between QUICKI, BMI, years of treatment and onset of puberty., Conclusions: GH treatment in GH-deficient children does not lead to an impaired GT or type 2 diabetes mellitus, although it does significantly decrease IS.

Objective: Acquired hypopituitarism in adults is obviously suspected in patients with primary hypothalamic-pituitary diseases, particularly after neurosurgery and/or radiotherapy. That brain injuries (BI) can cause hypopituitarism is commonly stated and has been recently emphasized but the management of BI patients does not routinely include neuroendocrine evaluations., Aim: To clarify the occurrence of hypopituitarism in patients after traumatic brain injury (TBI) or subarachnoid haemorrhage (SAH) 3 months after the BI., Subjects and Methods: The occurrence of hypopituitarism in conscious patients after traumatic brain injury [TBI, n = 100, 31 women, 69 men; age 37.1 +/- 1.8 years; body mass index (BMI) 23.7 +/- 0.4 kg/m(2); Glasgow Coma Scale (GCS) 3-15] or subarachnoid haemorrhage [SAH, n = 40, 14 men, 26 wpmen, 51.0 +/- 2.0 years; 25.0 +/- 0.6 kg/m(2); Fisher's scale 1-4] was studied in a multicentre study 3 months after the BI. All patients underwent wide basal hormonal evaluation; the GH/IGF-I axis was evaluated by GHRH + arginine test and IGF-I measurement., Results: In TBI patients, some degree of hypopituitarism was shown in 35%. Total, multiple and isolated deficits were present in 4, 6 and 25%, respectively. Diabetes insipidus was present in 4%. Secondary adrenal, thyroid and gonadal deficit was present in 8, 5 and 17%, respectively. Severe GH deficiency (GHD) was the most frequent pituitary defect (25%). In SAH patients, some degree of hypopituitarism was shown in 37.5%. Despite no total hypopituitarism, multiple and isolated deficits were present in 10 and 27.5%, respectively. Diabetes insipidus was present in 7.5%. Secondary adrenal, thyroid and gonadal deficit was present in 2.5, 7.5 and 12.5%, respectively. Severe GHD was the most frequent defect (25%)., Conclusions: TBI and SAH are conditions associated with high risk of acquired hypopituitarism. The pituitary defect is often multiple and severe GHD is the most frequent defect. Thus neuroendocrine evaluations are always mandatory in patients after brain injuries.

Objective: Excessive GH secretion may lead to secondary diabetes mellitus, while prolonged GH treatment may accelerate the onset of type 2 diabetes mellitus in predisposed individuals. Turner's syndrome (TS) patients are a population at risk since they have reduced glucose tolerance (GT) spontaneously and because they are usually treated with high doses of GH., Design and Methods: The aim of the study was to evaluate insulin sensitivity (IS) and glucose tolerance (GT) in a group of TS patients treated with GH for a period of 6 years. Forty-seven TS girls were included in the study. GH was administered at a mean weekly dosage of 0.35 mg/kg, injected subcutaneously over 6-7 days. GT was assessed according to the criteria of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. IS was evaluated with the quantitative insulin sensitivity check index (QUICK-I)., Results: No significant increase of impaired GT was observed in the patients during the follow-up period, while a reduced IS was detected. IS in TS patients was already lower than in prepubertal controls (P<0.001) before starting treatment and further decreased during the first year of therapy (P<0.05), and then remained stable over the following years. No correlation was found between QUICK-I, body mass index, years of treatment, onset and duration of puberty. One patient became diabetic during the course of treatment., Conclusions: GH treatment in TS girls does not significantly increase the prevalence of impaired GT or type 2 diabetes mellitus, while it does, however, decrease IS.

Background: Previous investigations on the ghrelin gene reported three common polymorphisms (Arg51Gln, Leu72Met, and Gln90Leu), but their role in overweight and obese individuals remains to be clarified., Objective: To ascertain whether these genetic variants could influence ghrelin secretion and play a part in predisposing to earlier onset of obesity or in modulating the overweight phenotype in childhood., Design and Methods: Mutational analysis of the entire ghrelin gene and total and acylated plasma determinations were performed in 81 obese or overweight children and adolescents (46 were obese and 35 overweight: Ob/Ow). We also recruited 168 normal-weight healthy controls (72 young adults and 96 children) for mutational or plasma ghrelin analysis., Results: Median total and acylated plasma ghrelin concentrations were significantly lower in Ob/Ow individuals than in controls (175 pg/ml compared with 345 pg/ml, P<0.0001, and 95 pg/ml compared with 114 pg/ml, P<0.0001, respectively). The ghrelin gene variants showed similar allele frequencies in the Ob/Ow individuals and in controls; in the former, they were not associated with any change in total and acylated circulating ghrelin concentrations or anthropometric data. The Leu72Met status was associated with a positive family history for obesity (75% for Leu72Met compared with 39% for Leu72Leu, P=0.03) and with a greater percentage of newborns born 'large for gestational age' (33% for Leu72Met compared with 5% for Leu72Leu, P=0.03), but in the control group it was related to a lower mean body mass index z-score (-0.03 for Leu72Met and -0.47 for Leu72Leu, P=0.04)., Conclusion: Our present findings do not support the hypothesis that the ghrelin gene polymorphisms have a relevant impact in the secretion of total and acylated ghrelin.

In adults, hypopituitarism and growth hormone deficiency (GHD) should be suspected and diagnosed within an appropriate clinical context. It has been demonstrated that all patients with primary hypothalamic-pituitary diseases before and after any medical intervention (defined as neurosurgery, radiotherapy and medical therapy) are at obvious risk - more than just at high risk - for hypopituitarism (greater than 80% had severe GHD). The same obvious risk applies to patients diagnosed as having congenital or acquired GHD in childhood (between 30% and 50% of patients with severe GHD after retesting). Taking into account the fragility of the infundibular-hypothalamic structure, patients with other common pathological conditions of the central nervous system (CNS), such as traumatic brain injury (TBI), subarachnoid haemorrhage (SAH) or primary brain tumours (BT) with related medical intervention could be at risk for developing hypopituitarism, including GHD. GHD is the first and most common sign of pituitary impairment. Despite the risk of pituitary dysfunction and the results of some studies that these risks are greater than previously believed, neuroendocrine evaluations are still not routinely included as part of the clinical management plan for patients with TBI and SAH. Preliminary results of a multicenter study performed under the auspices of the Italian Society of Endocrinology underscore the high risk of hypopituitarism and GHD under these clinical conditions. Thus, careful screening of pituitary function should always be performed in patients following TBI and SAH.

The current guidelines state that, within the appropriate clinical context, the diagnosis of adult growth hormone (GH) deficiency must be made biochemically using provocative tests. Measurement of insulin-like growth factor I (IGF-I) and binding protein 3 (IGFBP-3) levels cannot always distinguish between healthy and GH-deficient individuals. In particular, IGFBP-3 as a marker of GH status is clearly less sensitive than IGF-I and there is general agreement that its measurement does not provide useful diagnostic information. However, the diagnostic value of measuring IGF-I levels has been revisited recently. It has been confirmed that normal IGF-I levels do not rule out severe GH deficiency (GHD) in adults, in whom the diagnosis has therefore to be based on the demonstration of severe impairment of the peak GH response to provocative tests. It has also been emphasized that very low IGF-I levels in patients with high suspicion of GHD could be considered to be definite evidence for severe GHD. This assumption particularly applies to patients with childhood-onset, severe GHD or with multiple hypopituitary deficiencies acquired in adulthood. In addition, the use of IGF-I levels to monitor the efficacy and adequacy of recombinant human GH replacement remains widely accepted., (Copyright 2004 S. Karger AG, Basel.)

Objective: The objective of this study is to investigate the performance of two novel tests in diagnosing growth hormone deficiency in adults., Patients: Fifty patients presenting with long-standing hypopituitarism and two control groups consisting of 50 healthy subjects in each group [age-, sex- and body mass index (BMI)-matched] participated in a multicentre study. All underwent two provocative tests on different days within 3 months apart: (i) a combined GHRH + GHRP-6 test and (ii) arginine + GHRH test. Main outcome measures were sensitivity, specificity and areas under receiver operating characteristic curves (ROC) for GHRH + GHRP-6 and arginine + GHRH tests in the diagnosis of GH deficiency in adults., Results: A peak GH level after GHRH + GHRP-6, under 15.0 microg/l had a sensitivity of 94.4% and specificity of 98.8% for diagnosing GHD and area under the ROC curve was 0.99 (95% confidence interval 0.95-0.99). For peak GH levels after arginine + GHRH, a level under 9.6 microg/l had a sensitivity of 88.4% and specificity of 95% and area under the ROC curve of 0.96 (95% confidence interval 0.91-0.98). The relationship between the increment in serum GH following GHRH + GHRP-6 and arginine + GHRH test was positive, i.e. r = 0.749, P = 0.001.Thus, there was high concordance between both tests., Conclusion: Both GHRH + GHRP-6 and/or arginine + GHRH test may serve as an alternative to the ITT in diagnosing GHD in adults.

Objective: Within an appropriate clinical context, GH deficiency (GHD) in adults must be demonstrated biochemically by a single provocative test. Insulin-induced hypoglycaemia (ITT) and GH-releasing hormone (GHRH) + arginine (ARG) are indicated as the tests of choice, provided that appropriate cut-off limits are defined. Although IGF-I is the best marker of GH secretory status, its measurement is not considered a reliable diagnostic tool. In fact, considerable overlap between GHD and normal subjects is present, at least when patients with suspected GHD are considered independently of the existence of other anterior pituitary defects. Considering the time and cost associated with provocative testing procedures, we aimed to re-evaluate the diagnostic power of IGF-I measurement., Design: To this goal, in a large population [n = 237, 139 men, 98 women, age range 20-80 years, body mass index (BMI) range 26.4 +/- 4.3 kg/m2] of well-nourished adults with total anterior pituitary deficit including severe GHD (as shown by a GH peak below the 1st centile limit of normal response to GHRH + ARG tests and/or ITT) we evaluated the diagnostic value of a single total IGF-I measurement. IGF-I levels in hypopituitary patients were evaluated based on age-related normative values in a large population of normal subjects (423 ns, 144 men and 279 women, age range 20-80 years, BMI range 18.2-24.9 kg/m2)., Results: Mean IGF-I levels in GHD were lower than those in normal subjects in each decade, but not the oldest one (74.4 +/- 48.9 vs. 243.9 +/- 86.7 micro g/l for 20-30 years; 81.8 +/- 46.5 vs. 217.2 +/- 56.9 micro g/l for 31-40 years; 85.8 +/- 42.1 vs. 168.5 +/- 69.9 micro g/l for 41-50 years; 82.3 +/- 39.3 vs. 164.3 +/- 60.3 micro g/l for 51-60 years; 67.5 +/- 31.8 vs. 123.9 +/- 50.0 micro g/l for 61-70 years; P < 0.0001; 54.3 +/- 33.6 vs. 91.6 +/- 53.5 micro g/l for 71-80 years, P = ns). Individual IGF-I levels in GHD were below the age-related 3rd and 25th centile limits in 70.6% and 97.63% of patients below 40 years and in 34.9% and 77.8% of the remaining patients up to the 8th decade, respectively., Conclusions: Total IGF-I levels are often normal even in patients with total anterior hypopituitarism but this does not rule out severe GHD that therefore ought to be verified by provocative testing of GH secretion. However, despite the low diagnostic sensitivity of this parameter, very low levels of total IGF-I can be considered definitive evidence of severe GHD in a remarkable percentage of total anterior hypopituitary patients who could therefore skip provocative testing of GH secretion.

Hypothalamus-pituitary tumours and their treatments (neurosurgery and/or radiotherapy) are major causes of acquired hypopituitarism. Scientific and clinical evidences show the positive effect of GH replacement therapy in severe adult GH deficiency (GHD) pointed toward the need of diagnostic screening of conditions at high risk for GHD. We screened 152 adults (82 males, 70 females; age: 52.3+/-1.2 years, age-range: 20-80 years, BMI: 26.4+/-0.8 kg/m(2)) in order to disclose the presence of GHD after neurosurgery for hypothalamus-pituitary tumours. The whole group (studied at least 3 months after neurosurgery) included: 111 non-functioning pituitary adenomas and 41 peri-pituitary tumours (24 craniopharyngiomas, 7 meningiomas, 5 cysts, 2 chondrosarcomas, 1 colesteatoma, 1 germinoma and 1 hemangiopericitoma). In 14 patients who underwent both neurosurgery and radiotherapy due to a tumour remnant, the somatotroph function was evaluated again 6 months after the end of radiotherapy. GHD was assumed to be shown by GH peak <5 microg/L (severe <3 microg/L) after Insulin Tolerance Test (ITT) or <16.5 microg/L (severe <9 microg/L) after GH-releasing hormone+arginine test (GHRH+ARG) (3rd and 1st centile limits of normality, respectively), two widely accepted provocative tests. Before neurosurgery GHD was present in 97/152 (63.8%) and resulted severe in 66/152 (43.4%) patients. After neurosurgery GHD was present in 122/152 (80.2%) and severe in 106/152 (69.7%). While 26 patients developed severe GHD (GHD) as consequence of neurosurgery, only one patient who had been classified as GHD before neurosurgery showed normal GH response after surgery. After neurosurgery, 91.0% (81/89) of the pan-hypopituitaric patients showed severe GHD. Considering the 14 patients who underwent also radiotherapy after neurosurgery, 7/14 had GHD before neurosurgery while 12/14 became severe GHD after radiotherapy in a context of pan-hypopituitarism. IGF-I levels below the 3rd age-related normal limits were present in 39.0% of patients in whom severe GHD was showed by provocative tests. In conclusion, this study shows that the occurrence of acquired severe GHD is extremely common in adult patients bearing non-functioning tumour masses in the hypothalamus-pituitary area and further increases after neurosurgery. All patients bearing non-functioning hypothalamus-pituitary tumours should undergo evaluation of their somatotroph function before and after neurosurgery that represents a condition at obvious more than high risk for hypopituitarism.

Background: Simple obesity and Cushing's syndrome (CS) are two clinical models of leptin hypersecretion coupled with GH hyposecretion. Fasting inhibits leptin while stimulating GH secretion in normal human subjects., Objectives: To clarify the effect of fasting on leptin and GH secretion in obesity and CS. PATIENTS AND PROTOCOL: We studied six women with CS [age 17-66 years; body mass index (BMI) 28.6 kg/m2], seven women with visceral obesity (OB; 20-41 years; BMI 42.9 kg/m2) and seven normal women (NS; 25-31 years; BMI 19.3 kg/m2). The effects of 36-h fasting on 8-h diurnal mean leptin, GH, insulin and glucose concentrations (mLEPTc, mGHc, mINSc and mGLUc) as well as on the IGF/IGFBP system were studied., Results: Before fasting, mLEPTc in OB and in CS were similar and both were higher (P < 0.01) than in NS. OB and CS showed similar mGHc, which were lower (P < 0.05) than in NS. Fasting induced a reduction in mLEPTc that was significant in NS and CS (P < 0.04) but not in OB. The mLEPTc in OB and CS after fasting remained higher (P < 0.05) than in NS. After fasting, OB and CS showed no increase in mGHc, although this clearly increased (P < 0.02) in NS. IGF-I but not IGFBP-3 levels decreased in all groups (P < 0.05). Fasting reduced mINSc and mGLUc while increasing IGFBP-1 in all groups. After fasting, mINSc in OB and CS remained higher (P < 0.03) than in NS., Conclusions: Short-term fasting has less inhibitory effect on leptin and no stimulatory effect on GH secretion in patients with Cushing's syndrome as well as simple obesity. After fasting, insulin levels in hypercortisolaemic and also in obese patients remained higher than in normal subjects suggesting that hyperinsulinism could play a role in the altered response of leptin and GH to starvation in these conditions.

It is widely accepted that the classical dose of 250.0 microg ACTH (1-24) (tetracosactin) is clearly supra-maximal while 1.0 and 0.03 microg have been shown as the maximal and the lowest stimulatory ACTH doses for cortisol (F) secretion in normal young subjects. Testing with low ACTH dose would better evaluate adrenal sensitivity to corticotropin. The aims of the present study were: a) to clarify the adrenal sensitivity to ACTH in patients with different duration of corticotroph insufficiency by testing with low and very low tetracosactin doses; and b) to evaluate diagnostic implication regarding the ability of ACTH tests to distinguish patients with corticotroph insufficiency from normal subjects. In 24 hypopituitaric patients (HYPOPIT, 15 male and 9 female, age 22-50 yr, BMI: 22-26 kg/m2) with corticotrophin deficiency we studied the F, DHEA and aldosterone (A) responses to challenges with low ACTH doses (0.06 or 0.5 microg iv at 0 min) followed by 250 microg iv (at +60 min). The results in HYPOPIT were compared with those recorded in 12 normal controls (NS, 6 male and 6 female, age 22-34 yr, BMI: 20-25 kg/m2). Basal F and DHEA levels in HYPOPIT were lower than in NS, while A levels were similar in both groups. The F responses to ACTH in HYPOPIT were dose-independent and markedly lower (p < 0.0001) than in NS. After the 0.06 and 0.5 microg ACTH dose, 16% of HYPOPIT patients showed AF peak within the range of normal response. No HYPOPIT showed AF peak within the normal range after 250 microg ACTH. The DHEA responses to ACTH in HYPOPIT were dose-independent and markedly lower than in NS (p < 0.0001). Overlap between individual DHEA responses in HYPOPIT and NS was present after 0.06 microg and 0.5 microg but not after 250 microg tetracosactin. The A responses in HYPOPIT were dose-dependent and overlapped with those in NS. The adrenal responses to ACTH in HYPOPIT were not associated with the duration of the disease. In conclusion, the present study shows that the mean F and DHEA but not the A responses to ACTH (1-24) are markedly impaired in hypopituitaric patients with corticotroph insufficiency independently of the duration of the disease. The impaired F and DHEA response to ACTH is also independent of the dose, suggesting the existence of relatively enhanced sensitivity of the fasciculata and reticularis adrenal zone to ACTH but meantime remarkable impairment of the adrenal function due to corticotrophin deficiency. In the present study, testing with submaximal ACTH doses did not distinguish patients with secondary adrenal insufficiency from normal subjects.

Ghrelin, a 28 amino acid-acylated peptide predominantly produced by the stomach, displays strong growth hormone (GH)-releasing activity. It is mediated by the hypothalamic-pituitary GH secretagogue (GHS) receptors, which are specific to a family of synthetic, orally active molecules known as GHSs. However, despite their potent and reproducible GH-releasing activity, the potential clinical use of GHSs as orally active growth-promoting agents or anabolic anti-aging drugs has not been confirmed. Ghrelin and GHSs also exert other actions mediated through central and peripheral receptors, including stimulation of adrenocorticotrophic hormone and prolactin secretion, influence on insulin secretion and glucose metabolism, orexigenic effects and modulatory activity on the neuroendocrine and metabolic response to starvation, influence on exocrine gastro-entero-pancreatic functions, cardiovascular effects and modulation of cell proliferation and apoptosis. The discovery of ghrelin and the characterization of these GH-independent biological activities has widened the knowledge of some critical aspects of neuroendocrinology and suggests possible roles for GHSs and ghrelin in the treatment of pathophysiological conditions, including those unrelated to disorders of GH secretion.

The diagnostic usefulness of the insulin tolerance test (ITT) in patients with radiation-induced GH deficiency (GHD) is well established, whereas that of the combined GHRH plus arginine stimulation test (AST) is unproven. Both tests were undertaken in 49 adult survivors (aged 16-53.7 yr), who were previously irradiated for non-pituitary brain tumors or leukemia, and 33 age-, gender-, and BMI-matched controls. The aims of the study were to examine the impact of the time interval after irradiation on the pattern of GH responsiveness to the two provocative tests and to establish the role of the GHRH + AST in the diagnosis of radiation-induced GHD. The median (range) peak GH responses to either test were significantly lower (P < 0.0001) in the patients [GHRH + AST, 19.9 (range, 2.7-103.5) microg/liter; ITT, 5 (0.2-34.8) microg/liter] than in normals [GHRH + AST, 55 (5.7-173.5) microg/liter; ITT, 23.8 (4.2-80) microg/liter]. In patients and normal controls, the median peak GH response to the GHRH + AST was significantly greater (P < 0.0001) than the response to the ITT. However, the ratio of the peak GH response to the GHRH + AST over that achieved with the ITT (discordancy ratio) was significantly higher (P = 0.007) in the patients (median, 3.45; range, 0.8-53.5) compared with normals (median, 2; range, 0.34-18.6), consistent with dominant hypothalamic damage and relatively preserved somatotroph responsiveness. The peak GH response to the ITT fell significantly within 5 yr of irradiation with little further change over the subsequent 10 yr. In contrast, the peak GH response to the GHRH + AST barely changed within 5 yr of irradiation but subsequently declined significantly over the next 10 yr. Thus, the evolution of change in GH responsiveness to the two different stimuli over time was markedly different, resulting in a significantly raised discordancy ratio of 6 within the first 5 postirradiation years, which then normalized over the next 10 yr. The peak GH responses to the GHRH + AST and the discordancy ratio were negatively correlated with the time interval after irradiation (r = -0.40, P = 0.0037; and r = -0.4, P = 0.0046, respectively). On a practical clinical level, the discordancy between the GH test results was important; 50% of those classified as severely GHD patients by the ITT were judged normal or only GH insufficient by the GHRH + AST. In conclusion, these findings suggest that hypothalamic dysfunction occurs early and somatotroph dysfunction occurs late, following radiation damage to the hypothalamic-pituitary axis. This time dependency of somatotroph dysfunction may reflect either secondary somatotroph atrophy due to hypothalamic GHRH deficiency or delayed direct radiation-induced damage to the pituitary gland. The high false negative diagnosis rate for severe GHD makes the GHRH + AST an unreliable test in clinical practice when GH status is explored in the early years after cranial irradiation with the intention to treat.

The aim of this study was to evaluate the relationship between GH and leptin in a group of short children and adolescents. Leptin and GH serum levels were measured before and during pharmacological stimulation tests (arginine and insulin) in a group of 45 children (30 male, 15 female), mean age 8.6+/-3.9 yr, affected by idiopathic isolated GH deficiency (GHD), and in a group of 27 children (15 male, 12 female), age 10.9+/-3.3 yr, with constitutional growth delay. Results showed that basal and peak leptin levels as well as the AUC were significantly higher in GHD patients compared to controls (p<0.05) and correlated with BMI SDS (p<0.0001) in GHD patients. No change in leptin serum levels was observed during either stimulation test. No correlation was found, however, between basal leptin serum levels and basal, peak and the AUC of GH during the tests. Moreover, no correlation was found between the acute changes of serum GH concentration during both stimulation tests and leptin serum levels. The results suggest that leptin and GH secretion is not correlated and that leptin serum levels mainly reflect the amount of fat tissue, which is higher in GHD patients.

Ghrelin, a 28-amino-acid acylated peptide, produced mainly by the stomach, displays strong growth hormone-(GH)-releasing activity mediated by the hypothalamus-pituitary growth hormone potential secretagogue (GHS) receptor which had been shown to be specific for a family of synthetic, orally active GHS. GHS are reliable provocative tests for the diagnosis of GH deficiency but, as orally active growth-promoting agents, they are not comparable with human recombinant GH in terms of efficacy. The usefulness of GHS in anabolic, anti-ageing drug intervention in the somatopause is still unclear. GHS also act on central and peripheral receptors and show other actions, including an orexigenic effect, an influence on gastroentero-pancreatic functions, and cardiovascular and anti-proliferative effects. Ghrelin mediates the neuroendocrine and metabolic response to starvation. Taking into account its orexigenic effect, GHS analogues acting as agonists or antagonists on appetite could represent a new drug intervention for eating disorders.

We evaluated the GH-releasing effect of GHRH plus arginine (ARG) in 36 patients (22 males and 14 females) with acquired GH deficiency including idiopathic inflammatory pituitary stalk thickness (n = 15), Langerhans cell histiocytosis (LCH) affecting the hypothalamic-pituitary area (n = 11), and craniopharyngioma (n = 10). All of the patients (mean age, 9.6 +/- 3.1 yr; range, 5.6-20.8) showed GH response less than 10 microg/liter after 2 pharmacological stimuli and were tested with GHRH plus ARG at a mean age of 11.2 +/- 4.1 yr. Twenty-nine patients had vasopressin deficiency, 10 had TSH deficiency, 8 had gonadotropin deficiency, and 4 had ACTH deficiency. The median peak GH response to insulin test was 2.1 microg/liter (range, 1.1-2.9), whereas it was 1.5 microg/liter (range, 1.3-2.4) after ARG. The median peak GH response to insulin was significantly lower in the patients with craniopharyngioma (1.4 microg/liter; range, 0.8-1.7) than in the patients with idiopathic pituitary stalk thickness (2.2 microg/liter; range, 1.0-2.4) or with LCH (2.6 microg/liter; range 2.0-4.3, P = 0.02). The median peak GH response to ARG was significantly lower in the patients with idiopathic inflammatory pituitary stalk thickness (1.3 microg/liter; range, 0.8-1.8) than in those with craniopharyngioma (1.5 microg/liter; range, 1.1-1.6) or with LCH (2.8 microg/liter; range, 1.9-3.2, P = 0.00007). The median peak GH response after GHRH plus ARG was significantly lower in the overall patient population (8.3 microg/liter; range, 4.4-28.4) than in the age-matched controls (49.8 microg/liter; range, 39.9-81.6, P < 0.00001). The median peak GH response was significantly lower in the patients with craniopharyngioma (4.6 microg/liter; range, 3.6-6.3) than in those with LCH (8.9 microg/liter; range, 4.4-28.4) or with idiopathic pituitary stalk thickness (12.6 microg/liter, range, 6.4-24, P = 0.07). Ten patients had a GH response of more than 20 microg/liter after GHRH plus ARG. There was a trend toward a decrease in peak GH response to GHRH plus ARG (r = -0.57, P = 0.06) as patient age increased. For cut-off values of 20 microg/liter, the sensitivity of GHRH plus ARG was 75% (95% CI, 57.8-87.9%) and the specificity was 96.4% (95% CI, 89.9-99.2%); whereas, for cut-off values of 24.2 microg/liter, sensitivity was 86.1% (95% CI, 70.5-95.3%), and specificity was 95.2% (95% CI, 88.2-98.7%). The median IGF-I level did not differ between the children with idiopathic pituitary stalk thickness (57 microg/liter; range, 46-68), those with LCH (55 microg/liter; range, 34-63), and those with craniopharyngioma (41 microg/liter; range, 39-49). The present study confirmed the diagnostic potential of the GHRH-plus-ARG test in children with acquired GH deficiency caused by hypothalamic-pituitary lesion. It stimulates GH secretion to a greater extent in those patients with GH deficiency with primary involvement of the hypothalamic area, e.g. patients with idiopathic pituitary stalk thickness or LCH, than in those with both hypothalamic and pituitary lesion, as in craniopharyngioma. In some patients, the GHRH-plus-ARG test stimulates GH response to a so-called: normal value, suggesting that pituitary responsiveness to GHRH plus ARG may fail to recognize acquired GHD. Finally, the number of pituitary hormone deficits and the patient's age affect the GH response to GHRH plus ARG.

Objective: Ghrelin, a 28 amino acid acylated peptide, is a natural ligand of the GH secretagogues (GHS) receptor (GHS-R), which is specific for synthetic GHS. Similar to synthetic GHS, ghrelin strongly stimulates GH secretion but also displays significant stimulatory effects on lactotroph and corticotroph secretion. It has been hypothesized that isolated GH deficiency (GHD) could reflect hypothalamic impairment that would theoretically involve defect in ghrelin activity., Patients: In the present study, we verified the effects of ghrelin (1 microg/kg i.v.) on GH, PRL, ACTH and cortisol levels in adult patients with isolated severe GHD [five males and one female, age (mean +/- SEM) 24.7 +/- 2.6 years, BMI 25.7 +/- 2.7 kg/m2]. In all patients, the GH response to insulin-induced hypoglycaemia (ITT, 0.1 IU regular insulin i.v.) and GH releasing hormone (GHRH) (1 microg/kg i.v.) + arginine (ARG, 0.5 g/kg i.v.) was also studied. The hormonal responses in GHD were compared with those in age-matched normal subjects (NS, seven males, age 28.6 +/- 2.9 years, BMI 22.1 +/- 0.8 kg/m2)., Results: IGF-I levels in GHD were markedly lower than in NS (69.8 +/- 11.3 vs. 167.9 +/- 19.2 microg/l, P < 0.003). Ghrelin administration induced significant increase in GH, PRL, ACTH and cortisol levels in all GHD. In GHD, the GH response to ghrelin was higher (P < 0.05) than that to GHRH + ARG, which, in turn, was higher (P < 0.05) than that to ITT (9.2 +/- 4.1 vs. 5.3 +/- 1.7 vs. 1.4 +/- 0.4 microg/l). These GH (1 microg/l = 2 mU/l) responses in GHD were markedly lower (P < 0.0001) than those in NS (ghrelin vs. GHRH + ARG vs. ITT 92.1 +/- 16.7 vs. 65.3 +/- 8.9 vs. 17.7 +/- 3.5 microg/l). In GHD, the highest individual peak GH response to ghrelin was markedly lower than the lowest peak GH response in NS (28.5 vs. 42.9 microg/l). GHD and NS showed overlapping PRL (1 microg/l = 32 mU/l) (10.0 +/- 1.4 vs. 14.9 +/- 2.2 microg/l), ACTH (22.3 +/- 5.3 vs. 18.7 +/- 4.6 pmol/l) and cortisol responses (598.1 +/- 52.4 vs. 486.9 +/- 38.9 nmol/l)., Conclusions: This study shows that ghrelin is one of the most powerful provocative stimuli of GH secretion, even in those patients with isolated severe GHD. In this condition, however, the somatotroph response is markedly reduced while the lactotroph and corticotroph responsiveness to ghrelin is fully preserved, indicating that this endocrine activity is fully independent of mechanisms underlying the GH-releasing effect. These results do not support the hypothesis that ghrelin deficiency is a major cause of isolated GH deficiency but suggest that ghrelin might represent a reliable provocative test to evaluate the maximal GH secretory capacity provided that appropriate cut-off limits are assumed.

The activity of the GH/IGF-I axis as a function of parathyroid activity and calcium metabolism in humans has never been assessed. To address this issue, we studied 18 patients (5 men, 13 women; age range, 23-76 yr; mean, 61 yr) with primary hyperparathyroidism (PHP) due to solitary parathyroid adenoma. GH secretion was evaluated by serum IGF-I levels, spontaneous mean GH secretion over two morning hours, and GH response to arginine (ARG) alone or combined with GHRH. In five patients, serum GH concentrations were measured every 20 min for 24 h, and deconvolution analysis was performed. A group of 35 age- and sex-matched normal subjects served as controls. Mean serum IGF-I levels in PHP were lower than in normal controls, and in six PHP patients individual serum IGF-I levels were below the age-related normal range. The mean (+/-SE) peak GH response to ARG alone in PHP patients was significantly lower than in normal subjects (4.0 +/- 1.0 vs. 22.0 +/- 1.3 microg/liter; P < 0.001). Likewise, the mean (+/-SE) peak GH response to ARG plus GHRH was reduced in PHP patients (9.9 +/- 0.9 vs. 38.0 +/- 3.5 microg/liter; P < 0.001). The mean GH concentration over two morning hours in PHP was lower (0.20 +/- 0.05 vs. 1.34 +/- 0.31 microg/liter; P < 0.001). The mean GH concentration over 24 h in five PHP patients was lower than in six normal controls (0.3 +/- 0.1 vs. 0.7+/- 0.1 microg/liter; P < 0.05); the deconvolution analysis showed that 24-h GH production rate (3.0 +/- 1.7 vs. 28.2 +/- 4.7 microg/liter.d; P < 0.05) and mean secretory burst mass (1.2 +/- 0.7 vs. 10.5 +/- 2.6 microg/liter; P < 0.05), but not pulse frequency, were lower in PHP patients than in normal controls. GH half-life and approximate entropy values of 24-h GH profiles were similar in PHP patients and normal controls. No correlation was found between serum-ionized calcium or PTH levels and spontaneous or stimulated GH levels in PHP patients. In conclusion, this study demonstrates that PHP patients have a reduction in both spontaneous and stimulated GH secretion. Accordingly, PHP should be mentioned as a further example of a metabolic condition in which GH secretion in adults is reduced.

The aim of the present study was to evaluate the GH status in children with familial, idiopathic short stature (FSS). To this goal we evaluated the GH response to GHRH (1 microg/kg iv) + arginine (ARG) (0.5 g/kg iv) test which is one of the most potent and reproducible provocative tests of somatotroph secretion, in 67 children with FSS [50 boys and 17 girls, age 10.8+/-0.4 yr, pubertal stages I-III, height between -3.6 and -1.6 standard deviation score (SDS), target height <10 degrees centile, normality of both spontaneous and stimulated GH secretion as well as of IGF-I levels]. The results in FSS were compared with those in groups of children of normal height (NHC) (42 NHC, 35 boys and 7 girls, age 12.0+/-0.5 yr, pubertal stages I-III, height between -1.3 and 1.4 SDS, height velocity standard deviation score (HVSDS)>25 degrees centile, GH peak >20 microg/l after GHRH+ARG test, mean GH concentration [mGHc]>3 microg/l) and children with organic GH deficiency (GHD) (38 GHD, 29 boys and 9 girls, age 11.2+/-3.7 yr, pubertal stages I-III, height between -5.7 and -1.3 SDS, GH peak <20 microg/l after GHRH +ARG test, mGHc <3 mg/l). Basal IGF-I levels and mGHc were also evaluated in each group over 8 nocturnal hours. IGF-I levels in FSS (209.2+/-15.6 microg/l) were similar to those in NHC (237.2+/-17.2 microg/l) and both were higher (p<0.0001) than those in GHD (72.0+/-4.0 microg/l). The GH response to GHRH +ARG test in FSS (peak: 66.4+/-5.6 microg/l) was very marked and higher (p<0.01) than that in NHC (53.3+/-4.5 microg/l) which, in turn, was higher (p<0.01) than in GHD (8.2+/-0.8 microg/l). Similarly, the mGHc in FSS was higher than in NHC (6.7+/-0.5 microg/l vs 5.1+/-0.7 microg/l, p<0.05) which, in turn, was higher than in GHD (1.5+/-0.2 microg/l, p<0.0001). In conclusion, our present study demonstrates that short children with FSS show enhancement of both basal and stimulated GH secretion but normal IGF-I levels. These findings suggest that increased somatotroph function would be devoted to maintain normal IGF-I levels thus reflecting a slight impairment of peripheral GH sensitivity in FSS.

Primary empty sella (PES) is generally not associated with overt endocrine abnormalities, although mild hyperprolactinemia and, in children, deficient GH secretion have been reported. The aim of this multi-center collaborative study was to evaluate basal and stimulated GH secretion in a large series of adult PES patients. The study group consisted of 51 patients [41 women and 10 men, age range: 20-78 yr; (mean+/-SD) 47+/-11 yr]; results were compared with those in normal subjects (Ns) (Ns: no.=110, 55 women, age: 20-50 yr, 37+/-14 yr), and in hypopituitaric patients (HYP) with GH deficiency (HYP: no.=44,17 women, age: 20-72, 49+/-16 yr). Baseline IGF-I levels and GH responses to insulin-induced hypoglycemia (insulin tolerance test, ITT) and/or GHRH+arginine (ARG) stimulation tests were evaluated. PES patients were also subdivided according to BMI in lean (BMI <28 kg/M2 no.=22) or obese (BMI >28 kg/m2 no.=29). PES patients had serum total IGF-I concentrations (mean+/-SE: 142.2+/-9.6 ng/ml) higher than HYP patients (77.4+/-6.4 ng/ml, p<0.001), but lower than Ns (213.3+/-17.2 ng/ml, p<0.005), with no differences between lean and obese PES subjects. The increase in serum GH concentrations following ITT and/or GHRH+ARG stimulation tests, although higher than that observed in HYP patients, was markedly reduced with respect to Ns. No difference was observed in the GH response to provocative tests between lean and obese PES patients. When individual GH responses to ITT or GHRH+ARG were taken into account, a large proportion of PES patients (52% after ITT, 61% after GHRH+ARG) showed a GH peak increase below the 1st centile of normal limits. Serum IGF-I levels in PES patients with blunted GH responses to provocative tests were significantly (p<0.001) lower in PES patients with normal GH responses, and a positive correlation was observed between IGF-I levels and serum GH peak concentrations after GHRH+ARG. In conclusion, the results of the present study provide evidence that adult PES patients often have an impairment of GH secretion, as indicated by the blunted GH response to ITT and GHRH+ARG provocative tests, and by the reduction in serum IGF-I levels. These changes are independent of body mass.

We have recently reported that GH secretion is impaired in primary hyperparathyroidism (PHP). No systematic assessment of the whole anterior pituitary function in PHP is available. In this study, anterior pituitary function was evaluated in basal and stimulated conditions in a series of 12 consecutive women with PHP. Serum GH secretion was decreased in 9 of 12 PHP patients (75%) confirming our previous results in different series of PHP patients. Instead, at variance, secretion of all the other anterior pituitary hormones was normal. Thus, PHP is associated with an impaired secretion of GH, but not of the other anterior pituitary hormones. The reason why only GH secretion is affected in PHP is unknown.

The aim of this study was to clarify the activity of GH/IGF-1 axis as well as the variations of nutritional parameters following a thermal injury in man. To this goal, in 22 patients with burn [BURN, age (mean+/-SE): 46.5+/-3.4 yr, BMI: 25.0+/-0.8 kg/m2, % burn surface area: 26.0+/-3.0%, ROI score: 0.22+/-0.1] we evaluated IGF-1, IGF binding protein (IGFBP-3), GH, GH binding protein (GHBP), pre-albumin (pre-A), albumin (A) and transferrin (TRA) levels on days 1, 3, 7, 14 and 28 after intensive care unit (ICU) admission. IGF-1, IGFBP-3, GH and GHBP levels were also assayed basally in 29 normal subjects (Ns) (Ns, age: 47.5+/-2.8 yr, BMI: 22.0+/-1.4 kg/m2) and in 34 panhypopituitary patients with severe GH deficiency (GHD, age: 42.7+/-2.5 yr, BMI: 25.6+/-0.8 kg/m2). On ICU day 1, IGF-1 and IGFBP-3 in BURN were higher than those in GHD (p<0.05 for both, respectively) and lower than those in Ns (p<0.05) while GH levels in BURN did not differ from those in Ns and higher than GHD (p<0.01). In BURN, IGF-I and IGFBP-3 levels showed a progressive decline (p<0.05) with nadir on day 14, when they overlapped those in GHD, and then an increase on day 28, though persisting lower than in Ns, while GH levels did not vary during ICU stay. IGF-I levels were associated neither to burn extension nor to ROI score. On ICU day 1 pre-A, A and TRA levels were similar to those in Ns, but underwent a progressive decrease with nadir on day 7 (p<0.001) for pre-A and TRA, and later, on day 14 (p<0.05) for A; pre-A and TRA but not A showed a rebound increase (p<0.01) on day 14, though persistingly lower than in Ns. In conclusion, our present data firstly show the time course variation of IGF-I levels in burn patients as function of nutritional and hormonal variables. It has to be emphasized that in the most critical phase after burn injuries, IGF-1 levels are as low as in hypopituitary patients with severe GHD. The physiological basis which leads to the impairment of this endogenous anabolic drive in this phase is, however, not clear yet.

Objective: Adults with severe GH deficiency (GHD) need recombinant human growth hormone (rhGH) replacement to restore body composition, structure functions and metabolic abnormalities. The optimal rhGH dose for replacement has been progressively reduced to avoid side effects. The aim of the present study was to define the minimal rhGH dose able to increase both IGF-I and IGF binding protein (BP)-3 levels in GHD and to verify the possible change in GH sensitivity., Design and Patients: To this goal, we studied the effect of 4-day treatment with 3 rhGH doses (1.25, 2.5 and 5.0 microg/kg/day) on IGF-I and IGFBP-3 levels in 25 panhypopituitary adults with severe GHD (12 males and 13 females, age: 44.5+/-3.0 years, body mass index (BMI): 27.0+/-0.9 kg/m(2)) and 21 normal young adult volunteers (NV, 12 males and 9 females, age: 30.5+/-2.0 years, BMI: 20.8+/-0.5 kg/m(2))., Results: Basal IGF-I and IGFBP-3 levels in GHD were lower (P<0.001) than in NV. In NV the 1.25 microg/kg dose of rhGH did not modify IGF-I levels. The dose of 2.5 microg/kg rhGH significantly increased IGF-I levels in men (P<0.001) but not in women, while the 5.0 microg/kg dose increased IGF-I levels in both sexes (P<0.001). IGFBP-3 levels were not modified by any of the administered rhGH doses. In GHD patients, all rhGH doses increased IGF-I levels 12 h after both the first (P<0.01) and the fourth rhGH dose (P<0.001). At the end of treatment percentage increases in IGF-I were higher (P<0.001) in GHD patients than in NV. In contrast with NV, in GHD patients the IGF-I response to short-term stimulation with rhGH was independent of gender. Moreover, GHD patients showed increases in IGFBP-3 after the fourth administration of both 2.5 and 5.0 microg/kg rhGH., Conclusion: The results of the present study demonstrate that the minimal rhGH dose able to increase IGF-I and IGFBP-3 levels in GHD patients is lower than in normal subjects, at least after a very short treatment. This evidence suggests an enhanced peripheral GH sensitivity in GH deprivation.

Either in children or in adults, arginine (ARG) alone and combined with GHRH (GHRH+ARG) are reliable tests for the diagnosis of GH deficiency. The procedures of these tests generally include GH measurement every 15 min from baseline up to 90-120 min. Aim of our study was to verify if the procedure of these tests could be usefully shortened in clinical practice. To this goal we have studied 173 normally growing children and adolescents (C, 117 M and 56 F, age: 11.3 +/- 0.4 yr.) and 125 young and middle aged normal adults (A, 68 M and 57 F, age: 30.0 +/- 0.6 yr.). ARG alone test was performed by 81 C and 33 A (0.5 g/kg arginine, i.v., from 0 to +30 min, up to a maximum of 30 g) while GHRH (1 microg/kg i.v. bolus at 0 min) + ARG test was performed by 92 C and 92 A. After ARG alone, taking into account data from +15 to +105 min, GH values above the 3rd centile limit of arbitrary cut-off (7 or 10 microg/l in C and 5 microg/l in A) occurred in 85% or 64% and 94% subjects, respectively. After GHRH+ARG test, taking into account only data at +30, +45, +60 min GH values above the 3rd centile limit (20 microg/l in C and 16.5 microg/l in A) occurred in 99% of subjects in both groups. Taking into account only these 3 timing points, the percentage of GH peak above the third centile limits after ARG alone was never higher than 60% in C and 85% in A. In conclusion, this study shows that single GHRH+arginine test can be reliably performed in a shortened procedure which makes easier the clinical practice and further reduces costs.

Objective: Reduction of growth hormone (GH) secretion in obesity probably reflects neuroendocrine and metabolic abnormalities. Even short-term fasting stimulates GH secretion and distinguishes normal from hypopituitary subjects with growth hormone deficiency (GHD). Marked weight loss improves GH secretion in obesity but the effect of fasting is controversial. We studied the effects of a 36 h fasting on the GH/IGF-I axis and metabolic parameters in obesity., Subjects: We studied nine obese patients (OB; three male and six female; age, 29.2+/-4.8; range, 18-59 y; body mass index (BMI), 43.4+/-2.7 kg/m(2); WHR, 0.9+/-0.1). Fifteen normal subjects (NS; eight male and seven female 28.9+/-0.6, 25-35 y; 21.6+/-0.4 kg/m(2)) and 10 adult hypopituitary patients with severe GH deficiency (GHD; seven male and three female; 37.6+/-2.3, 29-50 y; 24.5+/-1.0 kg/m(2); GH peak<3 microg/l after ITT and/or<9 microg/l after GHRH+arginine) served as control groups., Study Design: We studied the effects of 36 h fasting on 8 h diurnal mean GH, insulin and glucose concentrations (mGHc, mINSc and mGLUc; assay every 30 min from 8.00 am to 4.00 pm) as well as on IGF-I, IGFBP-3, ALS, IGFBP-1, GHBP and free fatty acid (FFA) levels., Results: Before fasting, basal IGF-I and ALS levels in OB were similar to those in NS and both were higher (P<0.001) than those in GHD. IGFBP-3 levels in OB were lower (P<0.01) than in NS but higher (P<0.02) than in GHD. GHBP levels in OB and GHD were similar and both were higher (P<0.01) than in NS. Glucose levels were similar in all groups. FFA levels in OB were higher (P<0.01) than in NS but similar to those in GHD. IGFBP-1 in OB were lower (P<0.05) than in NS and GHD which, in turn, were similar. On the other hand, mINSc in OB was higher (P<0.01) than that in NS and GHD which, in turn, were similar. The mGHc in OB was similar to that in NS but only the latter was higher (P<0.05) than in GHD. The individual mGHc in the three groups overlapped. After fasting, IGF-I levels in GHD were unchanged while they decreased in OB (P=NS) as well as in NS (P<0.01). IGFBP-3 and ALS levels did not change. GHBP levels in OB and GHD were unchanged while they increased in NS (P<0.01). Glucose and FFA levels were reduced and increased, respectively, in all groups (P<0.02 and P<0.01). IGFBP-1 increased while mINSc decreased in all groups (P<0.02 and P<0.01); in OB they persisted lower and higher (P<0.01) respectively, than in NS and GHD. Fasting significantly increased mGHc in NS (P<0.001) but not in OB as well as in GHD. Individual mGHc in OB showed persistent overlap with GHD., Conclusions: Short-term fasting does not increase GH secretion in obesity and does not distinguish somatotroph function in obese from that in severe GHD adults. Short-term fasting in obesity has attenuated effects on insulin and IGFBP-1 secretion while it normally increases free fatty acids in spite of any change in GH secretion.

Insulin-induced hypoglycemia (ITT) is currently the "gold-standard" test for the diagnosis of adult growth hormone deficiency (GHD). ITT is often contraindicated, however, particularly in conditions that are also common in patients with suspected GHD. Used alone, GH-releasing hormone (GHRH) has no diagnostic value owing to within-subject variability and the inability to distinguish GHD from normal subjects. When combined with arginine, however, GHRH becomes a potent and reproducible test, which is unaffected by gender and aging, showing excellent specificity. The GHRH+ arginine (ARG) test distinguishes GHD patients from normal subjects and is at least as sensitive as ITT, provided that appropriate cutoff limits are considered. Its reliability for retesting GHD has also been demonstrated. The GHRH+ARG test can also be performed in a shorter procedure, resulting in potential for cost reduction. Synthetic GH secretagogues (GHSs) possess a strong and reproducible GH-releasing effect and synergize with GHRH. The combination of GHRH and a peptidyl GHS, such as hexarelin or GH-releasing peptide-6, has recently been shown as another reliable test for the diagnosis of adult GHD, again provided that the cutoff limit is appropriate to the potency of the test. Thus, GHRH combined with either arginine or GHS is a potential tool for the diagnosis of adult GHD.

The relationship between the hypothalamus-pituitary morphology and the somatotroph responsiveness to maximal provocative tests exploring the GH releasable pool is still unclear. We evaluated the GH-releasing effect of GHRH plus arginine (GHRH plus Arg) in 36 patients with congenital GH deficiency (GHD) according to their pituitary magnetic resonance imaging findings, consisting of anterior pituitary hypoplasia, stalk agenesis (neural and or vascular component), and posterior pituitary ectopia. Seventeen children (12 boys and 5 girls, aged 1--5.2 yr) were evaluated at the time of diagnosis of GHD (mean age, 3.6 +/- 1.4 yr), and 19 adults (13 males and 6 females, aged 15.9-28.6 yr) with childhood-onset GHD were reevaluated after completion of GH treatment (at least 6 months of withdrawal) at a mean age of 20.5 +/- 3.5 yr. Eleven children had isolated GHD, and 6 had multiple pituitary hormone deficiency (MPHD) whereas 7 adults had isolated GHD, and 12 had MPHD. A residual vascular component of the pituitary stalk was visualized in 7 children and 7 adults with isolated GHD, whereas magnetic resonance imaging showed complete pituitary stalk agenesis (both vascular and neural components) in 10 children and 10 adults, including 16 with MPHD (6 children) and 4 children with isolated GHD. In the children, the median peak GH response to GHRH plus Arg (7.6 microg/L; range, 2.4--40.2 microg/L) was significantly higher than that in the adults (1.8 microg/L; range, 0.8--37.4 microg/L; P = 0.0039); it was also significantly higher in the isolated GHD patients (18 microg/L; range, 3.3--40.2 microg/L) than in those with MPHD (1.9 microg/L; range, 0.8--7.6 microg/L; P = 0.00004). In the patients with residual vascular component of the pituitary stalk the median peak GH responses to GHRH plus Arg (19.1 microg/L; range, 1.6--40.2 microg/L) was significantly higher than that in patients with complete pituitary stalk agenesis (2.2 microg/L; range, 0.8--8.8 microg/L; P = 0.00005). There was a trend toward a decrease with age in peak GH response to GHRH plus ARG: Mean serum insulin-like growth factor I (IGF-I) levels were 36 +/- 7.1 microg/L in the children and 63.5 +/- 22.6 microg/L in the adults (P = 0.0001). The mean IGF-I level did not differ between the children with (35.7 +/- 4.8 microg/L) and those without (36.3 +/- 8.7 microg/L) the pituitary stalk; it was much higher in the adults with residual vascular pituitary stalk (81.1 +/- 17.7 microg/L) than in those with complete pituitary stalk agenesis (47.7 +/- 12.5 microg/L; P = 0.0002). The IGF-I level was 36.1 +/- 6.7 microg/L in the isolated GHD children and 36 +/- 8.6 microg/L in those with MPHD; levels were 82.1 +/- 19.4 and 52.7 +/- 16.8 microg/L respectively, in the adults (P = 0.003). In this study we have confirmed that the partial integrity of the hypothalamic pituitary connections is essential for GHRH plus Arg to express its GH-releasing activity and have shown that this provocative test is able to stimulate GH secretion to a greater extent in those patients with GHD, but with a residual vascular component of the pituitary stalk. This test is reliable in the diagnosis of congenital hypopituitarism in both children and adults when associated with complete pituitary stalk agenesis and MPHD. In younger children with congenital GHD but less severe impairment of the pituitary stalk the GH response to GHRH plus Arg may be within the normal range; deterioration of pituitary GH reserve with a GH response of less than 10 microg/L after 20 yr of age makes this test very sensitive in the diagnosis of adult GHD.

Objective: To verify the hypothesis of an increased sensitivity to GH in obesity (OB) and Cushing's syndrome (CS)., Design: We studied the effects of short-term administration of low-dose rhGH on circulating IGF-I levels in patients with simple OB or CS and in normal subjects (NS)., Methods: Nineteen women with abdominal OB aged (mean +/- s.e.m.) 38.2+/-3.1 years, body mass index 40.7+/-2.5 kg/m(2), waist to hip ratio 0.86+/-0.02, ten with CS (50.4+/-4.2 years, 29.7 +/- 3.3 kg/m(2)) and 11 NS (35.0+/-3.6 years, 20.5+/-0.5 kg/m(2)) underwent s.c. administration of 5 microg/kg per day rhGH at 2200 h for four days. Serum IGF-I, IGF-binding protein-3 (IGFBP-3), GH-binding protein (GHBP), insulin and glucose levels were determined at baseline and 12 h after the first and the last rhGH administration., Results: Basal IGF-I levels in NS (239.3+/-22.9 microg/l) were similar to those in OB (181.5+/-13.7 microg/l) and CS (229.0+/-29.1 microg/l). Basal IGFBP-3, GHBP and glucose levels in NS, OB and CS were similar while insulin levels in NS were lower (P<0.01) than those in OB and CS. In NS, the low rhGH dose induced a sustained rise of IGF-I levels (279.0+/-19.5 microg/l, P<0.001), a non-significant IGFBP-3 increase and no change in GHBP, insulin and glucose levels. In OB and CS, the IGF-I response to rhGH showed progressive increase (246.2+/-17.2 and 311.0+/-30.4 microg/l respectively, P<0.01 vs baseline). Adjusting by ANCOVA for basal values, rhGH-induced IGF-I levels in CS (299.4 microg/l) were higher than in OB (279.1 microg/l, P<0.01), which, in turn, were higher (P<0.05) than in NS (257.7 microg/l). In OB, but not in CS, IGFBP-3 and insulin levels showed slight but significant (P<0.05) increases during rhGH treatment, which did not modify glucose levels in any group; thus, in the OB patient group a significant fall in glucose/insulin ratio was observed., Conclusions: Short-term treatment with low-dose rhGH has enhanced stimulatory effect on IGF-I levels in OB and, particularly, in hypercortisolemic patients. These findings support the hypothesis that hyperinsulinism and hypercortisolism enhance the sensitivity to GH in humans.