Ginevra Corneli

Cut-off limits of the GH response to GHRH plus arginine test and IGF-I levels for the diagnosis of GH deficiency in late adolescents and young adults

OBJECTIVEnTo define the appropriate diagnostic cut-off limits for the GH response to GHRH+arginine (ARG) test and IGF-I levels, using receiver operating characteristics (ROC) curve analysis, in late adolescents and young adults.nnnDESIGN AND METHODSnWe studied 152 patients with childhood-onset organic hypothalamic-pituitary disease (85 males, age (mean+/-s.e.m.): 19.2+/-0.2 years) and 201 normal adolescents as controls (96 males, age: 20.7+/-0.2 years). Patients were divided into three subgroups on the basis of the number of the other pituitary hormone deficits, excluding GH deficiency (GHD): subgroup A consisted of 35 panhypopituitary patients (17 males, age: 21.2+/-0.4 years), subgroup B consisted of 18 patients with only one or with no more than two pituitary hormone deficits (7 males, age: 20.2+/-0.9 years); and subgroup C consisted of 99 patients without any known hormonal pituitary deficits (60 males, age: 18.2+/-0.2 years). Both patients and controls were lean (body mass index, BMI<25 kg/m(2)). Patients in subgroup A were assumed to be GHD, whereas in patients belonging to subgroups B and C the presence of GHD had to be verified.nnnRESULTSnFor the GHRH+ARG test, the best pair of highest sensitivity (Se; 100%) and specificity (Sp; 97%) was found choosing a peak GH of 19.0 microg/l. For IGF-I levels, the best pair of highest Se (96.6%) and Sp (74.6%) was found using a cut-off point of 160 microg/l (SDS: -1.3). Assuming 19.0 microg/l to be the cut-off point established for GHRH+ARG test, 72.2% of patients in subgroup B and 39.4% in subgroup C were defined as GHD. In patients belonging to group B and C and with a peak GH response <19 microg/l to the test, IGF-I levels were lower than 160 microg/l (or less than 1.3 SDS) in 68.7 and 41.6% of patients respectively predicting severe GHD in 85.7% of panhypopituitary patients (subgroup A).nnnCONCLUSIONSnIn late adolescent and early adulthood patients, a GH cut-off limit using the GHRH+ARG test lower than 19.0 microg/l is able to discriminate patients with a suspicion of GHD and does not vary from infancy to early adulthood.

GH response to ghrelin in subjects with congenital GH deficiency: evidence that ghrelin action requires hypothalamic–pituitary connections

OBJECTIVESnEvaluation of GH response to ghrelin in patients with GH deficiency (GHD) may help to elucidate the site and mechanism of action of ghrelin. We aimed to investigate the GH-releasing effect of ghrelin in children and young adults with childhood-onset GHD.nnnDESIGNnAll subjects underwent ghrelin testing and neuro-imaging examination. Magnetic resonance imaging evidenced the presence of a vascular pituitary stalk (VPS) or its complete absence (PSA).nnnPATIENTS AND METHODSnSeventeen prepubertal children and nine adult patients with childhood-onset GHD were selected for the study. The children were enrolled at a median age of 5.8 years. The adult subjects were included at a median age of 23.3 years. The diagnosis of GHD in the adult patients had been established at a median age of 8.5 years. Ghrelin was administered at a dose of 1 microg/kg body weight, i.v. at time zero, and blood for GH determination was obtained at 0, 15, 30, 45, 60, 75, 90, 105 and 120 min.nnnRESULTSnMedian GH response after ghrelin was similar between children and adults. Median peak GH response to ghrelin (7.45 microg/l, IQR: 3.9-11.3 microg/l) was significantly higher in patients with VPS (10.9 microg/l, IQR: 2.4-15.1 mcirog/l) than in those with PSA (IQR: 2.3-6.7 microg/l; P=0.001). It was significantly higher in subjects with isolated GHD (12.5 microg/l, IQR: 10.8-15.5 microg/l) than in those with multiple pituitary hormone deficiencies (5.15 microg/l, IQR: 2.4-9.0 microg/l; P=0.003). No correlation was found between the GH peak after ghrelin and body mass index.nnnCONCLUSIONnThe GH response to ghrelin in patients with congenital hypopituitarism depends on the degree of the anatomical abnormalities and lends further support to the assumption that the main action of the peptide is exerted at the hypothalamic level and requires the integrity of hypothalamic-pituitary connections.

Managing patients with hypopituitarism after traumatic brain injury.

Purpose of reviewTo highlight how traumatic brain injury as well as subarachnoid hemorrhage and primary brain tumors of the central nervous system can induce hypopituitarism – an underdiagnosed clinical problem. Then, further information of the problem is likely to stimulate appropriate screening programs for patients with brain injuries, at high risk of developing an unrecognized hypopituitarism. Recent findingsRecent papers have alerted endocrinologists about brain injury-induced hypopituitarism. Both retrospective and prospective studies recommended that patients with more severe forms of head injury and, in particular, those with fractures of the base of the skull or early diabetes insipidus be closely monitored for signs and symptoms of endocrine dysfunction, and appropriate dynamic pituitary function tests performed. SummaryWe hope this review will stimulate further interest in the endocrine community about the pathophysiology and management (diagnosis and treatment) of different kinds and degrees of pituitary insufficiency due to traumatic brain injury. Further studies will be crucial to raise awareness and remind physicians of the prevalence of hypopituitarism in patients with traumatic brain injury, and elucidate any incremental benefits these patients may receive from hormone replacement.

Growth hormone levels in the diagnosis of growth hormone deficiency in adulthood

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 24xa0h 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 3xa0μg/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.

Traumatic Brain Injury-Induced Hypopituitarism in Adolescence

Childhood hypopituitarism may be present at birth or may be acquired. Young children and teenagers are particularly susceptible to TBI; in fact TBI is one of the first causes of death and disability in children older than one month of age since the most common cause of TBI is car crashes, including pedestrian-car and bicycle-car encounters, falls, child abuse, violence and sports injuries. Furthermore younger kids are more likely to have TBI due to falls while teenagers have more TBI than any other population from motor vehicle crashes. As reported for the adult patients hypopituitarism in adolescence should be suspected within an appropriate clinical context. In adolescents affected by TBI no experience about this condition has been reported but it is well known that treatment of hypopituitarism, in particular of GH deficiency, has multiple beneficial effects in addition to its promotion of linear growth and in particular in the transition phase. These include maintenance of normal body composition, structure function and metabolism through adult life. Therefore, the onset of TBI-induced GH deficiency in this particular phase of life should be strictly evaluated and corrected for the possible adult health consequences.

Ghrelin: A Molecular Target for Weight Regulation, Glucose and Lipid Metabolism

Ghrelin, a peptide predominantly produced by the stomach, was discovered as natural ligand of the Growth Hormone Secretagogue receptor type 1a (GHS-R1a) and was anticipated to play major role in the control of somatotroph function. Ghrelin progressively turned out to exert pleiotropic actions on several endocrine and non endocrine target tissues. Particular attention has focused on its central orexigenic effect and weight control, and more recently on its peripheral metabolic actions on insulin secretion and insulin sensitivity, glucose and lipid metabolism. Ghrelin circulates in two forms, acylated (AG) and unacylated (UAG). Interestingly, some metabolic actions of ghrelin are independent of its acylation, which is necessary for it to bind and activate the GHS-R1a, supporting the hypothesis of the existence of several ghrelin receptor subtypes involved in the control of metabolic functions and pancreatic cell survival. Recent data have introduced the hypothesis that the ghrelin system plays a role in polygenic obesity, type 2 diabetes, metabolic syndrome, atherogenesis, and β-cell survival in type 1 diabetes. Many experimental studies have recently tried to inhibit or amplify ghrelin secretion for the treatment of obesity and wasting syndromes, respectively. This review recapitulates what is known about ghrelin chemical structure, GHS-R1a and the putative unknown receptor subtypes, AG and UAG involvement in the control of feeding, weight, glucose and lipid metabolism, and the recently patented molecules that modulate the pleiotropic actions of the ghrelin system.