Provocative Tests Of GH Secretion Research Articles

Reliability of clonidine testing for the diagnosis of growth hormone deficiency in children and adolescents.

The diagnosis of growth hormone deficiency (GHD) is currently based on clinical, auxological, biochemical and neuro-radiological investigation. Provocative tests of GH secretion using physiological/pharmacological stimuli are required to confirm GHD. The clonidine test (CT) is widely used to assess GH secretory status. In this retrospective study, we analyzed the reliability of CT and the effect of puberty in a large number of children with short stature who had been evaluated for suspected GHD. Data were collected retrospectively from 327 children and adolescents with short stature (204 boys and 123 girls, median age 10.5years (IQR 7.90-12.40) followed in four Italian Paediatric Endocrine Units (Cagliari, Genova, Napoli and Roma) between 2005 and 2013. All children underwent CT as the first GH stimulation test after exclusion of other known cause of their short stature. In 73 prepubertal children and 25 pubertal children, the GH peak after CT was <7μg/L. GHD was confirmed in 87 (37 organic, 50 idiopathic). Six prepubertal and five pubertal patients showed false positive responses. The median BMI-SDS in these children was similar to that of children with GH peak ≥7μg/L, and none were obese. Overall, the prevalence of false-positive responses was 3.3%. The median (IQR) peak GH after CT was similar between prepubertal and pubertal GHD (3.80μg/L [1.7-6.00] vs 3.51μg/L [0.76-5.74]) and non-GHD (13.70μg/L [10.70-18.40] vs 12.40μg/L [9.90-19.25]) children. Our results show that CT is a reliable and safe GH-releasing agent in both prepubertal and pubertal children.

Growth Hormone Secretion After Conformal Radiation Therapy in Pediatric Patients With Localized Brain Tumors

Growth hormone deficiency (GHD) after radiation therapy negatively affects growth and development and quality of life in children with brain tumors. Between 1997 and 2008, 192 pediatric patients with localized primary brain tumors (ependymoma, n = 88; low-grade glioma, n = 51; craniopharyngioma, n = 28; high-grade glioma, n = 23; and other tumor types, n = 2) underwent provocative testing of GH secretion by using the secretogogues arginine and L-dopa before and after (6, 12, 36, and 60 months) conformal radiation therapy (CRT). A total of 664 arginine/l-dopa test procedures were performed. Baseline testing revealed preirradiation GHD in 22.9% of tested patients. On the basis of data from 118 patients, peak GH was modeled as an exponential function of time after CRT and mean radiation dose to the hypothalamus. The average patient was predicted to develop GHD with the following combinations of the time after CRT and mean dose to the hypothalamus: 12 months and more than 60 Gy; 36 months and 25 to 30 Gy; and 60 months and 15 to 20 Gy. A cumulative dose of 16.1 Gy to the hypothalamus would be considered the mean radiation dose required to achieve a 50% risk of GHD at 5 years (TD(50/5)). GH secretion after CRT can be predicted on the basis of dose and time after irradiation in pediatric patients with localized brain tumors. These findings provide an objective radiation dose constraint for the hypothalamus.

Deficiência de GH na vida adulta: como diagnosticar e quando tratar?

Adult growth hormone deficiency (AGHD) is a well-established clinical entity with heterogeneous characteristics, in which the main causes are hypothalamus-pituitary tumors and/or their treatment. The diagnosis of ADGH should be considered in patients with a prior history of childhood-onset GH deficiency or a history of organic hypothalamus-pituitary disease. In these patients diagnosis is performed biochemically by provocative tests of GH secretion, once the measurement of the biological markers for GH action:IGF-l and IGFBP-3 levels, can be in the normal range in an important percentage of AGHD patients. The current treatment using an initial low dose of hrGH followed by individualised dose titration adjusted according to serum IGF-1 levels, leads to similar beneficial effects with less incidence of side effects, improved tolerance to treatment and a lower stable GH dose as compared to hrGH replacement therapy based on body weight or body surface area. As some patients might not profit from hrGH therapy, the potential beneficial effects of hrGH replacement therapy should be analyzed on individualized basis. Alternative available therapies with similar efficacy should be taken into consideration. Physical activity may improve body compostion, cardiovascular perfomance and well being in ADGH subjects not submitted to hrGH treatment. An important target of hrGH replacement therapy is its impact on quality of life, leading to social and professional improvement. Epidemiological evidence points to a decreasing life expectancy in ADGH patients but data regarding the impact of hrGH replacement on life expectancy are still lacking.

Diagnosis of adult GH deficiency

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

Diagnostic reliability of a single IGF-I measurement in 237 adults with total anterior hypopituitarism and severe GH deficiency.

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. 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). 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. 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.

Update on the diagnosis of GH deficiency in adults.

GH deficiency (GHD) in adults is associated with considerable morbidity and mortality. The diagnosis of GHD is generally straightforward in children as growth retardation is present; however, in adults, diagnosis of GHD is often challenging. Other markers are therefore needed to identify adults who have GHD and could potentially benefit from GH replacement therapy. Consensus guidelines for the diagnosis and treatment of adult GHD recommend provocative testing of GH secretion for patients who have evidence of hypothalamic-pituitary disease, patients with childhood-onset GHD, and patients who have undergone cranial irradiation or have a history of head trauma. Suspicion of GHD is also heightened in the presence of other pituitary hormone deficits. Tests for GHD include measurement of the hormone in urine or serum or measurement of stimulated GH levels after administration of various provocative agents. The results of several studies indicate that non-stimulated serum or urine measurements of GH levels cannot reliably predict deficiency in adults. Although glucagon and arginine tests produce a pronounced GH response with few false positives, the insulin tolerance test (ITT) is currently considered to be the gold standard of the GH stimulation tests available. Unfortunately, the ITT has some disadvantages and questionable reproducibility, which have prompted the development of several new tests for GHD that are based on pharmacological stimuli. Of these, GH-releasing hormone (GHRH) plus arginine and GHRH plus GH-releasing peptide (GHRP) appear to be reliable and practical. Thus, in cases where ITT is contraindicated or inconclusive, the combination of arginine and GHRH is an effective alternative. As experience with this test as well as with GHRH/GHRP-6 accumulates, they may supplant ITT as the diagnostic test of choice.

The prevalence of severe growth hormone deficiency in adults who received growth hormone replacement in childhood

The few previous studies in which reassessment of GH status has been carried out in young adults treated with GH therapy for childhood GH deficiency concentrated on determining the incidence of 'transient GH deficiency'. As the benefits of GH replacement therapy in adults become increasingly appreciated, it is likely that GH therapy started in childhood for GH deficiency will be continued into adult life in many of those with severe GH deficiency. The aim of this study is to determine how many patients who received GH replacement therapy in childhood until completion of growth have GH deficiency severe enough to be considered for GH replacement therapy in adult life. Retrospective analysis of the peak GH responses to provocative stimuli performed at the time of diagnosis of GH deficiency in childhood and at the completion of growth after GH replacement therapy had been stopped. Eighty-eight adults (49 male, 39 female) who had received GH therapy in childhood for a diagnosis of GH deficiency. The aetiology of the GH deficiency included craniopharyngioma, radiation induced associated with either a cerebral tumour or acute lymphoblastic leukaemia, histiocytosis-X and idiopathic. In childhood the original diagnosis of GH deficiency was based biochemically on the failure of the peak GH response to reach 20 mU/l during two provocative tests in 59 of the 88 patients and to a single test in the remaining 29. A total of 147 tests were performed, the most common being an insulin tolerance test (ITT, n = 72) and an arginine stimulation test (AST, n = 53). At reassessment in young adult life 146 tests were performed (74 ITT, 64 AST). Severe GH deficiency was defined arbitrarily as a peak GH response of less than 9 mU/l to a single (n = 33) or to two (n = 55) pharmacological stimuli. By definition all patients were considered GH deficient at the time of initial diagnosis. A peak GH response of less than 9 mU/l was seen in 64.8% at initial assessment and 60.2% at reassessment. Analysis in aetiological terms, however, showed that between assessments the incidence of severe GH deficiency increased in the group of radiation induced (48.8 vs. 55.8%) but decreased in the idiopathic group (78.1 vs. 53.1%). Out of the 55 patients who underwent two tests at reassessment, 47.3% of those with a GH peak less than 9 mU/l at one test had a GH peak greater than 9 mU/l at the second test. Fifteen of the 55 patients had additional pituitary hormone deficiencies and all 15 had a GH peak below 9 mU/l in both tests. Our study suggests that all children who have received GH replacement therapy in childhood should undergo reassessment of GH status in young adult life. Between 40 and 60% of such patients merit consideration for GH therapy in adult life depending on the definition of severe GH deficiency in use. Patients with isolated GH deficiency should undergo two provocative tests of GH secretion, but those with additional anterior pituitary hormone deficiencies require only one test at reassessment.

Measurement of spontaneous, 12-hour sleep-associated GH secretion in prepubertal children with short stature: clinical relevance and practicability?

We have asked whether or not sleep-associated 12-hour GH profiles were a clinically relevant and practicable tool to identify short children with low spontaneous GH secretion. In 67 prepubertal patients (19 girls and 48 boys, mean age 9.34 years, range 1.99-14.5) sleep-associated 12-hour GH profiles were obtained by drawing peripheral venous blood every 30 min over a 12-hour night period. The diagnosis of GH deficiency (GHD, n = 26), constitutional delay of puberty and growth (CDPG, n = 19), familial short stature (FSS, n = 8), GH neurosecretory dysfunction (GHND, n = 5), and constitutional delay of puberty and growth plus familial short stature (CDPGFSS, n = 9) was made by clinical parameters (SDS height range:-0.69 to -5.59, SDS growth velocity:-4.6 to -2.4) and provocative testing of GH secretion. Integrated GH secretion (area above baseline = AOB, area above zero line = AOOL), peak frequency, area under the peaks, peak amplitude length, peak amplitude height, maximal peak values, and median peak values were calculated using the PULSAR program. Significant differences of GH secretion between patient groups in regard to mean values for area over baseline, area over zero line, amplitude height, maximal peak values, and median peak values of secretion were found. However, there was a large interindividual variation of integrated GH secretion within each patient group and, most importantly, a large overlap between the different patient groups. We conclude that the assessment of pulsatile GH secretion during sleep, even if it can contribute to distinguish between different groups of short children, is not helpful to distinguish between different causes of short stature in an individual child. We suggest that measurement of sleep-associated spontaneous GH secretion needs to be restricted to research facilities.

1 - 1 Disorders of prolactin and growth hormone secretion

A large range of tests is now available to help us understand, diagnose and manage GH-related growth disorders. The traditional provocative tests of GH secretion will identify short children with severe GH deficiency. However, evidence is emerging that these pharmacological tests may not be sufficiently sensitive to identify some subjects with GH deficiency arising from neurosecretory disturbance of GH release. There is a need for a simple sensitive test that will detect subtle GH secretion of this type. hGRF administration is a reliable test of GH reserve and, when used in combination with conventional tests, may help to identify GH-deficient children with hypothalamic GRF deficiency. Whether the GH responses following GRF administration reflects physiological GH secretory activity needs to be established. The diagnosis of acromegaly is made on clinical grounds. The abnormal GH responses to glucose and TRH support the diagnosis, but by themselves should not be considered to be diagnostic of acromegaly. An elevated Sm C level also helps to establish the diagnosis, although Sm C concentrations may be elevated to the same degree in pregnancy and during puberty. The use of Sm C to monitor disease activity remains to be established. Circulating GRF levels should be measured in patients with acromegaly so that ectopic production of GRF can be identified.

385 ABNORMALITIES IN GROWTH HORMONE SECRETION AFTER CRANIAL IRRADIATION IN PRIMATES

Abnormalities of GH secretion have previously been reported in children given cranial irradiation for CNS prophylaxis in acute lymphocytic leukemia or for brain tumors. To better define these neuroendocrine abnormalities, prospective longitudinal studies of GH secretion were performed in young adult male rhesus monkeys (N=4 in each group). Two doses of cranial irradiation were given (2400 or 4000 rad in 10 fractions over 2 weeks). Three consecutive provocative tests of GH secretion were used (arginine infusion, insulin induced hypoglycemia and L-Dopa stimulation) prior to radiation and 10, 30 and 50 weeks after radiation. The 2400 rad group at 10 weeks had an excessive and prolonged GH response to arginine (GH at 30, 60 and 90 min was 15±15, 37±11 and 30±11 ng/ml vs 22±4, 15±4 and 6±1 ng/ml for 13 controls, mean ± SE) and insulin (GH at 30 and 60 min was 46±13 and 49±7 ng/ml vs 40±9 and 8±1.5 ng/ml for 9 controls). In subsequent studies, GH responses to arginine and L-Dopa were normal, but GH response to insulin was blunted. In the 4000 rad group the arginine and L-Dopa tests were normal throughout, but the response to insulin was consistently blunted. In conclusion, there are abnormalities of GH secretion after cranial irradiation with doses frequently used in clinical practice, but their clinical significance is not yet clear. This may be a useful model for the study of neuroendocrine regulation of GH secretion.