Growth hormone (GH) provocation tests and the response to GH treatment in GH deficiency.

OBJECTIVE: To identify factors, particularly the growth hormone (GH) provocation test result, affecting growth response to GH treatment in children with GH deficiency (GHD). SUBJECTS: A total of 337 prepubertal GHD patients aged <10 years from the UK Pharmacia KIGS database (GH response to provocation test <20 mU/l). OUTCOME MEASURE: Annual change in height standard deviation score (SDS) (revised UK reference) in the first and second years of treatment. RESULTS: Height increased by 0.74 SDS units (SD 0.39) in the first year of treatment and 0.37 units (SD 0.27) in the second. Adjusting for age, height, weight, midparent height, and injection frequency, the strongest predictor of first year growth response was the GH provocation test result; halving the result predicted an extra height increment of 0.09 units (p<0.0001). It predicted the second year response less well (p<0.0002) and after adjusting for the first year response was not predictive at all. CONCLUSIONS: Among patients referred for possible GHD, the GH provocation test, though not a gold standard for diagnosis, is a valuable predictor of growth response in the first year of treatment. A year's treatment is recommended for cases with a marginal provocation test result, with the option to continue treatment if the response is adequate. The value of unified protocols for single or repeated provocation tests needs to be assessed.     

Usefulness of growth hormone (GH) stimulation tests and IGF-I concentration measurement in GH deficiency diagnosis

The diagnosis of growth hormone (GH) deficiency (GHD) is still problematic for the clinician. There is no gold standard for estimating GH secretion. The aim of this study was to compare the diagnostic usefulness of spontaneous GH secretion test, pharmacological tests with insulin, clonidine, L-dopa, and glucagon, and IGF-I measurement in GHD. We studied 180 prepubertal, short children. Predictive values were calculated for different GH cutoff levels for each diagnostic test. ROC curves were used to estimate the diagnostic usefulness of the tests. The results show that sleep is the strongest stimulatory agent for GH secretion. The estimation of GH secretion after onset of sleep can be used as a screening test in GHD diagnosis. The insulin test has the highest discrimination. A combination of insulin test with another provocative test allows high discrimination and accuracy for standard cut-off GH level. Measurement of IGF-I is characterized by low predictive values. IGF-I level below the mean according to age indicates high probability of GHD. Auxological parameters should be the most important factor in diagnosing GHD.     

Adult height after growth hormone (GH) treatment for GH deficiency due to cranial irradiation

BACKGROUND: The indications and factors affecting the growth in response to treatment with growth hormone (GH) of patients with cranial irradiation-induced GH deficiency remain unclear. PROCEDURE: The adult heights of 56 patients treated with GH (0.4-0.6 U/kg/week) as daily sc injections were analysed. They had been given 18 or 24 Grays (Gy) cranial irradiation for leukemia (group 1, 26 cases), 50 +/- 1 Gy for various tumors (group 2, 13 cases), 46 +/- 1 Gy for retinoblastoma (group 3, 8 cases), or 34 +/- 2 Gy with spinal irradiation for medulloblastoma (group 4, 9 cases). Twenty- five of these 56 patients had early puberty and were also treated with gonadotropin-releasing hormone (GnRH) analog. RESULTS: The standing (-1.0 +/- 0.2 in group 1, -0.7 +/- 0.3 in group 2, -1.1 +/- 0.3 in group 3, and -2.0 +/- 0.4 SD in group 4) and sitting (-1.8 +/- 0.2 in group 1, -0.4 +/- 0.4 in group 2, -1.2 +/- 0.4 in group 3, and -3. 4 +/-0.4 SD in group 4) adult heights were shor ter (P < 0.05 for standing and P < 0.001 for sitting heights) for group 4 than for each of the other groups. Of the 47 patients given cranial (and not craniospinal) irradiation, sitting adult height was shorter (P = 0. 02) and the difference between standing adult and target heights greater (P = 0.03) in those patients in whom puberty occurred at a normal age than in those treated with GnRH analog. Conclusion. The incomplete catch-up of growth seems to be mainly due to the reduction in sitting height of patients given spinal irradiation and in whom puberty occurred at a normal age. This suggests that GnRH analog treatment should be more widely used to treat children with early and/or rapidly progressing puberty after cranial irradiation.     

Reevaluation of growth hormone deficiency during and after growth hormone (GH) treatment: diagnostic value of GH tests and IGF-I and IGFBP-3 measurements

Retesting of patients with growth hormone (GH) deficiency (GHD), especially those with idiopathic GHD, has yielded normalization of the results in several studies. The aim of this study was to reevaluate patients diagnosed as GHD at completion or reconfirm the diagnosis before completion of GH treatment by retesting with provocative tests, and to evaluate the value of IGF-I and IGFBP-3 levels in the diagnosis of GHD. Fifty (33 M, 17 F) patients with GHD (peak GH level <0.46 pmol/l (10 ng/ml]) in two pharmacological tests were retested and IGF-I and IGFBP-3 levels measured. The age of the patients at retest was 15.2+/-5.0 yr. Thirteen of 50 patients (26%) normalized their GH secretion. According to the initial diagnosis, 69% of those with partial GHD (peak GH level 0.32-0.46 pmol/l [7-10 ng/ml]), 43% with isolated GHD, 33% idiopathic and 11% of those with complete GHD (peak GH level <0.32 pmol/l [7 ng/ml]) normalized their GH level at retesting. None of the patients with multiple hormone deficiency and none with small pituitary on MRI normalized GH levels at retest. The sensitivities of IGF-I and of IGFBP-3 were 70% and 67%, respectively, and the specificities were 100%, when peak GH cutoff is taken as 0.46 pmol/l (10 ng/ml) for the diagnosis of GHD. The sensitivities of IGF-I and IGFBP-3 increased to 76.5% and 73.5% when the cutoff level for GHD is taken as 0.32 pmol/l (7 ng/ml). Those patients who normalized their GH levels at retest showed a satisfactory height velocity when GH therapy was discontinued. In conclusion, reevaluation of GH status may also be undertaken while patients are still on treatment as well as at completion of treatment, especially in patients with idiopathic, partial and isolated GHD, by retesting and by IGF-I and IGFBP-3 measurements. Lowering the cutoff level of GH peak at pharmacological tests to 0.32 pmol/l (7 ng/ml) will lower the number of false positive results in the diagnosis of GHD.     

Growth hormone (GH) profiles in response to continuous subcutaneous infusion of GH-releasing hormone(1— 29)-NH2 in children with GH deficiency

Six children presenting with partial growth hormone (GH) deficiency (mean GH peak in two different tests, 8.0 k1.3 μ g/l ) aged 8–10.3 years (mean, 2.7 ± 0.9 years) were treated for 6 months by continuous subcutaneous infusion of GH-releasing hormone(1–29)-NH, (GHRH(1–29)-NH₂); 24-hour GH profiles and height velocity were measured. A biphasic effect of GHRH(1–29)-NH₂ infusion was observed. After an early substantial increase in the 24-hour integrated concentration of GH, from 1.6 ± 0.1 to 3.5 ± 0.7 μg/l/minute, a subsequent consistent decrease occurred by 3 months, which was more pronounced after 6 months (mean 24-hour integrated concentration of GH, 1.9± 0.9 μg/l/minute). This effect reflects modification of both pulse amplitude and frequency of GH secretion. At the end of the study, one child had complete suppression of GH secretion and two others showed only one peak above 5 μg/1 during a 24-hour period. No correlation was found between these changes and height velocity. Three children did not grow significantly; the other three children who had a growth response to GHRH(1–29)-NH₂ were those with the lowest 24-hour integrated GH concentration at the end of the study. The possible mechanisms involved in this biphasic effect, including GHRH antibodies, changes in somatostatin levels and/or desensitization of pituitary GHRH receptors, have been investigated.     

Dual growth hormone (GH) response to repeated GH releasing hormone stimulus in children and adults

Several authors have demonstrated that plasma growth hormone (GH) levels as response to acute GH releasing hormone (GHRH) stimulation in adults are decreased by a previous GHRH injection whereas they are maintained in children. Probably the most accepted hypothesis for this finding is the increase in the somatostatinergic tone. The aim of the present study was to evaluate the dual GH response to repeated GHRH stimuli to clarify the possible influence of somatostatinergic activity in the type of response. Eighteen healthy prepubertal children, mean age 9.2 years (range: 6.0-12.9 years) and 19 healthy adult volunteers, mean age 25.5 years (range: 17-35 years) were studied with the GHRH test. An additional group of 10 normal adults with similar characteristics (mean age 31 years, range 25-35 years) were also recruited as a control group for somatostatinergic assessment. The GH response to the first GHRH bolus was similar in both children and adults. However, while children showed a preserved response to the second stimulus, it was diminished in adults. As expected, thyroid stimulating hormone (TSH) was within the normal range in all subjects. When the evolution of TSH was compared between the group of non-responders and the control group, no significant differences were found either at basal time or at 120 min, showing a similar decreasing trend for serum TSH level. The variation of TSH levels were also expressed as the proportion of TSH response after 2 hours compared to the basal level (TSH-120/TSH-0) but no significant differences were found (GHRH non-responders group mean: 73.6%, range: 51.3-93.7; control group mean: 70.7%, range: 62.9-92.5). In conclusion, the results confirm that in adults but not in children, the somatotrope responsiveness to GHRH is inhibited by a previous bolus of GHRH. The finding that the plasma TSH level diminishes in a similar manner in both non-responders and the control group is in agreement with the rejection of the hypothesis of the influence of somatostatin.     

Growth response to human growth hormone treatment in children with partial and total growth hormone deficiency

The growth response during the first and second years of human growth hormone (hGH) treatment was studied in 14 prepubertal children with so-called "partial" GH deficiency (peak GH between 8 and 15 mU/l) and compared to 28 prepubertal children with "total" GH deficiency (peak GH less than 8 mU/l). There was no difference in growth acceleration between children with partial and total GH deficiency, when initial covariables were taken into account. In a stepwise multiple regression analysis initial stature, pre-treatment growth velocity and skinfold thickness were shown to be most related to growth response, but after exclusion of 3 children with a genetic form of total GH deficiency and partial TSH deficiency this relationship was lost. GH levels during provocation tests and auxological criteria have a poor predictive value for growth response to hGH therapy.     

Growth response, pubertal growth and final height in Greek children with growth hormone (GH) deficiency on long-term GH therapy and factors affecting outcome

The growth data of 156 children (100 boys, 56 girls) with growth hormone deficiency (GHD), treated with human growth hormone (GH) for 5.7+/-3.7 years, from 1970-1997, were retrospectively analyzed to assess the efficacy of GH treatment and the factors involved. 62.2% of the studied population had idiopathic GHD (IGHD) and 35.2% had organic GHD (OGHD). At initiation of treatment, chronological age (CA) was 10.1+/-4.0 years in children with IGHD and 9.7+/-4.0 years in those with OGHD, while bone age (BA) was 7.0+/-3.7 and 7.7+/-3.2 years, respectively. The SDS of the growth velocity during the first year of therapy (GV1) was negatively related to CA at start of therapy (r = -0.53, p = 0.01). 109 children have reached final height (FH): 67 boys (FH = 165.3+/-6.3 cm) and 42 girls (FH = 153.9+/-5.4 cm). FH SDS was not significantly different from target height (TH) SDS. In the total group, FH SDS was positively related to height SDS for CA and BA at start of therapy (p = 0.01, p = 0.001, respectively), to TH SDS (r = 0.40, p = 0.001), and to GV1 (r = 0.33, p = 0.001). TH SDS was not different between the IGHD and OGHD groups (-1.02+/-0.8 vs. -0.94+/-6.9). The height gain at puberty did not differ between the groups with induced or spontaneous puberty in boys (23.7+/-8.6 vs. 25.4+/-6.9, not significant), while in girls it was higher in the group with spontaneous puberty (12.7+/-7.3 vs. 20.0+/-9.0, p = 0.008). The age and height at start of puberty was higher in girls and boys with induced puberty. In the total group, the FH SDS of children with induced puberty was higher in comparison with those with spontaneous puberty (-1.0+/-0.8 vs. -1.7+/-0.9, p = 0.001) and it was positively related to the height at start of puberty. When the two sexes were analyzed separately, the difference reached significance only in boys. In conclusion, children with GHD on GH treatment achieved a final height which was comparable to their genetic potential. The FH of children with OGHD was not different from those with IGHD. The age and height at start of puberty were the most significant determining factors for FH. Hence, a better FH might be expected by delaying or arresting puberty.     

Physical repercussions of childhood-onset growth hormone (GH) deficiency and hGH treatment in adulthood

The aim of this study was to evaluate the physical condition of young adults with childhood-onset growth hormone deficiency (GHD) before and after 6 months of hGH therapy. Ten men and three women, aged 22.3 +/- 3.3 years, previously treated with hGH for 8.6 +/- 4.07 years at a dose of 0.5 IU/kg/week with a minimun of 2.5 years without treatment at the time of study, were studied. Nine patients presented isolated GHD and four patients had combined pituitary hormone deficiencies; they were treated with hGH at a dosage of 0.125 IU/kg/week for the first month and 0.25 IU/kg/week for the following 5 months. The tests performed were: exercise test, heart rate, rating of perceived exertion, blood lactate analysis, jump test and hand grip. Body composition was also analyzed using Holtain Body Analysis. Skinfold thickness was measured at four sites (triceps, biceps, subscapular and suprailiac). After 6 months of treatment a significant increase in lean body mass (42.0 +/- 7.72 to 46.2 +/- 8.01 kg, p = 0.004) and decrease in fat mass (19.6 +/- 10.01 to 16.1 +/- 10.79 kg, p = 0.01) were observed. The initial physical condition of these patients was lower than expected, and improved after treatment with an increase in maximum oxygen consumption from 2.0 +/- 1.2 to 2.33 +/- 0.68 l x min(-1) (p = 0.01). Maximum heart rate increased significantly from 189 +/- 14.8 to 193 +/- 11.7 beats x min(-1) (p = 0.03). No modifications were observed in anaerobic threshold (4 mmol x l(-1)). Only slight, non-significant increases were observed in jump and strength tests. We conclude that a) adults with childhood-onset growth hormone deficiency present a deficient physical condition and lower than expected for age and sex; b) this condition improves after 6 months of treatment, particularly in the aerobic aspect; c) changes observed in strength tests were discrete and of little significance; and d) the increase observed in lean body mass plays an important role in these changes. Further studies investigating GH action on maximum oxygen consumption are required, once its basic mechanism of action has been determined, either in the heart or peripheral factors.     

Plasma growth hormone (GH) responses to growth hormone releasing factor (hp GRF 1-44) in familial GH deficiency

In four children with familial GH deficiency peak and integrated GH responses to an acute intravenous bolus of hp GRF 1-44 were lower than in 18 children with non-familial idiopathic GH deficiency and in 5 children with structural hypothalamic abnormalities. It is possible that the familial forms of GH deficiency described may be due to absence or biological inactivity of endogenous GRF or possibly GRF receptor or post receptor abnormalities.     

Administration of arginine plus growth hormone releasing hormone to evaluate growth hormone (GH) secretory status in children with GH deficiency

BACKGROUND: Diagnosis of growth hormone deficiency (GHD) in childhood is usually based on growth hormone (GH) response to at least two provocative stimuli. The aim of this study was to determine whether sequential administration of arginine (Arg) plus GH releasing hormone (GHRH) could be a useful tool in evaluating GHD in children. METHODS: Thirty patients with short stature (mean age 9.0 years) with decreased growth rate were tested for GHD with Arg and the insulin tolerance test (ITT). Patients with confirmed GHD (peak GH <8 ng/ml) were subsequently tested with Arg + GHRH. RESULTS: Maximum GH stimulation for Arg and ITT was 6.3 (1.0-7.8) and 6.7 (0.5-7.7) ng/ml, respectively. Peak GH for the Arg + GHRH test was 36.3 (4.3-84.5) ng/ml and significantly different from the other provocative tests. Peak GH values for the three tests were not significantly correlated between tests or with clinical parameters. There were no significant differences in Arg + GHRH results between children with or without abnormal hypothalamic-pituitary MRI scans. CONCLUSION: Arg + GHRH gave higher GH levels than insulin or Arg alone. Because of the different causes of childhood GHD (hypothalamic and/or pituitary dysfunction), the Arg + GHRH test is unsuitable .for evaluating GHD and deciding whether GH replacement therapy is indicated.     

Growth hormone treatment of Turner syndrome patients with insufficient growth hormone response to pharmacological stimulation tests

Growth before and during treatment with biosynthetic human growth hormone (hGH) was studied in 13 patients with Turner syndrome (TS) and a growth hormone (GH) response of less than 10 g/l to two standard provocative tests. During 1 year of treatment with hGH (0.15 IU/kg per day) height velocity (mean±SD) increased significantly (P<0.001) from 3.7±1.8 cm/year to 7.6±1.5 cm/year. The auxological data in these girls before and during treatment with hGH were similar to those observed in TS patients with a normal response of GH to pharmacological stimuli. It is concluded that in girls with Turner syndrome GH testing should only be performed when height velocity is below the Turner norm. In TS patients with residual growth potential a clinically significant growth acceleration can be obtained with a higher-than-replacement dose of hGH, i.e. 0.15 IU/kg per day, regardless of GH testing.     

Predicting the growth response to growth hormone (GH) treatment in prepubertal and pubertal children with isolated GH deficiency--model validation in an observational setting (GeNeSIS)

AIM: Validation of a preexisting mathematical model for predicting height velocity in the first year of growth hormone (GH) treatment, using an independent cohort of pediatric patients with confirmed GH deficiency (GHD). DESIGN: 210 prepubertal and pubertal patients with isolated GHD were enrolled within the 'growth prediction module' of a prospective international postmarketing research program (GeNeSIS). METHODS: The patients were grouped as 'prepubertal', at 'start of puberty' and 'pubertal', and the performance of the model was validated by comparing predicted and observed height velocity (HV) in the first treatment year for each group. The operational characteristics of the model, when used as a screening method to predict poor and good growth response to GH, were calculated using the first year change in height standard deviation score as a cut-off for treatment response. RESULTS: Depending on pubertal stage, the growth prediction model explained 53-72% of the variability of the first year HV. The model fulfilled the statistical prerequisites to identify patients with poor and good responses to GH with sufficient reliability in individual patients. CONCLUSIONS: The growth prediction model was successfully validated in a large cohort of prepubertal and pubertal pediatric patients under field conditions.     

The relationship between clinical severity of Noonan's syndrome and growth, growth hormone (GH) secretion and response to GH treatment

Short stature is one of the major features of Noonan's syndrome (NS). In a multicentre trial of growth hormone (GH) therapy in 25 children with NS, we observed a large inter-individual variation in first-year response to GH treatment. This suggested that subgroups might exist in NS that differ in either endogenous GH status or responsiveness to GH therapy. We therefore related growth, GH secretion and 2 years response to GH treatment to subtypes of phenotypic expression of NS. Twelve patients were moderately affected and 13 had a severe clinical phenotype of NS. The variability in phenotype did not correlate with significant differences in intra-uterine growth, infancy growth or childhood growth, and response to GH treatment. However, the variability in phenotype severity did account for striking differences in endogenous GH secretion.     

Diagnosis of growth hormone (GH) deficiency: comparison of pituitary stalk interruption syndrome and transient GH deficiency

Background  

Most patients with childhood non-organic growth hormone (GH) deficiency (GHD) produce a normal GH peak as young adults. Our objectives were to better define this transient GHD and evaluate the factors influencing the growth response of patients with pituitary stalk interruption syndrome (PSIS).     

A practical approach to the diagnosis of growth hormone (GH) deficiency in patients transitioning to adulthood using GH stimulation testing

To establish the diagnosis of adult growth hormone deficiency (GHD), GH-deficient children transitioning to adulthood are evaluated by two separate stimuli 2 or more weeks after ceasing GH therapy. While 20-88% of children diagnosed with idiopathic GHD retest with normal values, those with proven genetic defects in GH production/secretion/bioactivity and patients with panhypopituitarism consistently test deficient. The US Food and Drug Administration (FDA) defines GHD in adults by stimulated peak serum GH concentrations <5 ng/ml if measured by polyclonal radioimmunoassays (RIA) or lower if measured by monoclonal assays. Some investigators define severe GHD by a peak GH concentration <3 ng/ml. Adult responses to arginine and glucagon testing are similar to the responses to insulin tolerance testing; clonidine, pyridostigmine, and galanin cause lesser peaks of GH. Growth hormone-releasing hormone (GHRH) combined with arginine, GH releasing peptide-6 (GHRP-6), or hexarelin leads to higher peak responses than GHRH alone. Thus the choice of testing methods impacts the diagnosis of GHD in transition patients.