Final height in patients with idiopathic short stature and high growth hormone responses to stimulation tests

Children with idiopathic short stature (ISS) may have normal or increased growth hormone (GH) responses to provocation tests and achieve a final height (FH) below -2.0 standard deviation score (SDS) if untreated. FH of subjects with high stimulated GH levels has not been studied in detail. AIM: It was the aim of this study to analyse FH in ISS patients with high GH peak responses to the provocation test. PATIENTS AND METHODS: We studied 16 patients (9 pre-pubertal) with ISS and a GH peak >or=40 mU/l to insulin-induced hypoglycaemia. The patients were recalled at age 19.7 +/- 2.5 years for measurement of FH when blood samples were obtained for serum insulin-like growth factor (IGF)-I, IGF binding protein 3, acid-labile subunit and GH binding protein measurements. GH bioactivity was determined using the Nb2 bioassay. RESULTS: FH was -3.1 +/- 1.0 SDS, being significantly lower than target height (TH). At FH, IGF-I levels were within -1.5 and +1.5 SDS for age and sex in 10 patients and higher than +1.5 SDS in 6 patients. IGF binding protein 3, acid-labile subunit, GH binding protein levels and GH bioactivity values were normal. SUMMARY: These data suggest that patients with ISS and high GH levels during a GH stimulation test may have a more compromised FH. The association of severe ISS with a peak GH >40 mU/l might suggest a degree of insensitivity for the GH-IGF-I axis.     

Growth hormone response to a growth hormone-releasing hormone stimulation test in a population-based study following cranial irradiation of childhood brain tumors

Children with brain tumors are at high risk of developing growth hormone deficiency (GHD) after cranial irradiation (CI) if the hypothalamus/pituitary (HP) axis falls within the fields of irradiation. The biological effective dose (BED) of irradiation to the HP region was determined, since BED gives a means of expressing the biological effect of various irradiation treatment schedules in a uniform way. Hypothalamic versus pituitary damage as cause of GHD was distinguished in 62 patients by comparing the growth hormone (GH) peak response to an insulin tolerance test (ITT)/arginine stimulation test and the GH response to a growth hormone-releasing hormone (GHRH) stimulation test. Peak GH response to a GHRH test was significantly higher (median 7.3 mU/l; range: 0.5--79.0 mU/l) than that of an ITT/arginine test (median 4.7 mU/l; range: 0.01--75.0 mU/l) (p = 0.017). Peak GH after a GHRH test was significantly inversely correlated to follow-up time (r(s) = -0.46, p < 0.0001) and to BED (R(s) = -0.28, p = 0.03), and both were found to be of significance in a multivariante regression analysis. We speculate that a significant number of patients developed hypothalamic radiation-induced damage to the GHRH secreting neurons, and secondary to this the pituitary gland developed decreased responsiveness to GHRH following CI in childhood.     

Plasma levels of insulin-like binding protein-2 in prepubertal short children and its diagnostic value in the evaluation of growth hormone deficiency

AIM: This study was designed to investigate whether determination of plasma insulin-like growth factor (IGF)-binding protein-2 (IGFBP-2) levels could be of benefit in the evaluation of childhood growth hormone (GH) deficiency (GHD). METHOD: A retrospective analysis was performed on 91 prepubertal children referred for investigation of short stature. Maximal GH levels in plasma after provocative stimuli were between 1.0 and 93.0 mU/l, 6 subjects exhibiting peak values of <5 mU/l. Initially a GH peak of 20 mU/l was used as a cutoff limit to define GHD and idiopathic short stature (ISS) patients. The results of GH provocative tests were compared to age- and gender-based standard deviation scores (SDS) of plasma IGFBP-2, IGF-I, IGFBP-3 and the molar ratios of the latter two to IGFBP-2. The respective normative range values for these parameters were determined in plasma samples from 353 healthy children (i.e. 171 girls, 182 boys). RESULTS: Circulating IGFBP-2 levels did not correlate with height SDS, height velocity SDS or the peak GH levels after provocative stimuli. A weak negative relationship was found between IGFBP-2 and IGF-I. Plasma levels of IGFBP-2 in GHD patients were higher than those of ISS children, who had normal levels. Although at the optimal cutoff point of -0.71 SDS 91.5% of the GHD patients were identified correctly, a substantial proportion (71.9%) of the ISS subjects also had IGFBP-2 levels above this limit. The use of various combinations of IGFBP-2, IGF-I, IGFBP-3 and the derived ratios only slightly improved the diagnostic efficiency as compared to the results of the individual tests. Neither IGFBP-2 nor the IGFBP-3/IGFBP-2 and IGF-I/IGFBP-2 ratios were found to be related to the short- (1 year) or long-term (3 years) growth response to GH therapy. CONCLUSION: It is concluded that none of the tests investigated, either alone or in various combinations, are reliable in either predicting the peak GH level after provocative stimuli in prepubertal short children or in predicting their growth response to GH.     

Interpretative difficulties with growth hormone provocative retesting in childhood-onset growth hormone deficiency

A review of literature demonstrates that there are many ill-understood factors that determine the results of GH provocative (re)testing, so that these results should be interpreted with extreme caution when used for diagnosis or confirmation of diagnosis of GHD. GH provocation tests are probably of no value at all for what has been called 'partial GHD'. The phenomenon of 'normalization' of test results after long-term treatment with GH needs no 'transient GHD' hypothesis as it can be largely explained by the very low reproducibility of the tests and by a regression to the mean effect. Moreover, it is possible that 'normal values' increase with age. Other determinants of normal peak values may also change from childhood to adulthood and contribute to 'normalization'.     

Oral clonidine provocative test in the diagnosis of growth hormone deficiency in childhood: should we make the timing uniform?

INTRODUCTION: Oral clonidine is one of the most frequent drugs used for the diagnosis of growth hormone deficiency (GHD), but the duration of the test, depending on which European centres use it, is not uniform and can vary from 120 to 150 min or even 180 min. SUBJECTS AND METHODS: To standardize this test, evaluating the possibility to shorten it to 90 min, we investigated the response of GH to the oral clonidine test in 291 children evaluated for short stature (height <-2 SD). Of these, 164 were diagnosed as idiopathic short stature (ISS) and 127 as GHD. In these patients, we calculated: (1) the frequency distribution of the GH peaks to clonidine in GHD and in ISS at various times; (2) the percentage of GH peaks to clonidine before and after 90 min in all and in ISS children; (3) the percentage of the first GH value >or=10 ng/ml before 90 min and after 90 min in ISS. RESULTS: GH peak distribution varied between 30 and 180 min, even though the vast majority of peaks occurred between 30 and 60 min. There was no significant difference (p > 0.05) in the peak distribution between ISS and GHD children. The percentages of GH peaks within 90 min were 92.1% in all children and 95.7% in ISS. If considering the first value of GH >or=10 ng/ml this last percentage reaches 96.3%. CONCLUSION: Our study suggests that the oral clonidine test can be administered for only 90 min without significantly changing its validity. This test should be standardized at 90 min in European protocols just as in those currently used in the USA in order to reduce the discomfort of patients and the cost of this diagnostic procedure.     

Partial growth hormone deficiency (GHD) in children has more similarities to idiopathic short stature than to severe GHD

INTRODUCTION: Assessment of growth hormone (GH) secretion is based on stimulation tests. Low GH peaks in stimulation tests, together with decreased insulin-like growth factor-I (IGF-I) secretion, confirm a diagnosis of GH deficiency (GHD). However, limitations in interpreting the test results and discrepancies between GH and IGF-I secretion in particular patients have both been reported. GH therapy should improve the prognosis of adult height (PAH). The aim of the study was to compare the deficit of height at diagnosis, IGF-I secretion and PAH in children with either decreased (in varying degrees of severity) or normal GH secretion in stimulation tests. MATERIAL AND METHODS: The analysis comprised 540 short children (373 boys, 167 girls), aged 11.7 +/- 3.2 years. In all the patients two GH stimulation tests were performed, IGF-I serum concentration was measured, bone age was assessed and PAH was calculated. According to the GH peak in the two stimulation tests, the patients were classified into the following groups: severe GHD (sGHD)--GH peak < 5 ng/mL (n = 44), partial GHD (pGHD)--GH peak 5-10 ng/mL (n = 190), idiopathic short stature (ISS)--GH peak at least 10 ng/mL (n = 306). RESULTS: A significantly greater deficit of height, lower IGF-I secretion and worse PAH were observed in sGHD than in both remaining groups, while all the differences between pGHD and ISS in the parameters analysed were insignificant. CONCLUSION: The results obtained indicate the necessity of applying another methods of qualifying short children for GH therapy other than GH stimulation tests with a cut-off value at a level of 10 ng/mL.     

Growth hormone (GH) secretion in patients with childhood-onset GH deficiency: retesting after one year of therapy and at final height

BACKGROUND: Recent studies have shown that many patients treated with growth hormone (GH) during childhood because of idiopathic GH deficiency (GHD) are no longer GH deficient when retested after cessation of GH therapy when final height is achieved. These patients are labelled as transient GHD. We hypothesized that normalization of GH secretion in transient GHD could occur earlier during the course of GH treatment, which could allow earlier cessation of GH treatment. METHODS: In a retrospective study, GH secretion was re-evaluated after cessation of GH treatment at final height in 43 patients diagnosed during childhood as idiopathic GHD (10 with multiple pituitary hormonal deficiencies (MPHD) and 33 with isolated GHD (IsGHD)). In a prospective study, GH secretion was re-assessed after interruption of GH treatment given for 1 year in 18 children with idiopathic GHD (2 MPHD, 16 IsGHD). GH secretion was evaluated by glucagon or insulin stimulation tests. RESULTS: In the retrospective study, all the 10 patients with MPHD and 64% of the 33 patients with IsGHD were still deficient at re-evaluation using the paediatric criteria to define GHD (GH peak <10 ng/ml at provocative test). The proportion of persisting deficiency was greater in patients with complete IsGHD (86%, 12/14 patients) than in patients with partial IsGHD (47%, 9/19 patients). With the criteria proposed in adulthood (GH peak <3 ng/ml), all the 10 patients with MPHD were still considered to be deficient. In contrast, only 15% (5/33 patients) with IsGHD had a maximal GH value <3 ng/ml (36% of the 14 patients with complete IsGHD and none of the 19 patients with partial IsGHD). In the prospective study, after interruption of GH therapy given for 1 year, the 2 patients with MPHD were still GHD at re-evaluation and they resumed GH treatment. Among the 16 patients with IsGHD, 13 (81%) were still deficient (peak response <10 ng/ml) after 1 year. Two of the 3 patients in whom GHD was not confirmed at retesting after 1 year GH showed again a deficient response at second retesting. CONCLUSIONS: Although many patients diagnosed with IsGHD during childhood have a normalized GH secretory capacity when retested during adulthood, early retesting after interruption of GH treatment given for 1 year during childhood does not enable to determine if GH therapy has to be discontinued before cessation of growth.     

Proteins related to lipoprotein profile were identified using a pharmaco-proteomic approach as markers for growth response to growth hormone (GH) treatment in short prepubertal children

Background  

The broad range in growth observed in response to growth hormone (GH) treatment is mainly caused by individual variations in both GH secretion and GH sensitivity. Individual GH responsiveness can be estimated using evidence-based models that predict the response to GH treatment; however, these models can be improved. High-throughput proteomics techniques can be used to identify proteins that may potentially be used as variables in such models in order to improve their predictive ability. Previously we have reported that proteomic analyses can identify biomarkers that discriminate between short prepubertal children with idiopathic short stature (ISS) who show good or poor growth in response to GH treatment. In this study we used a pharmaco-proteomic approach to identify novel factors that correlate with the growth response to GH treatment in prepubertal children who are short due to GH deficiency or ISS. The study included 128 short prepubertal children receiving GH treatment, of whom 39 were GH-deficient and 89 had ISS. Serum protein expression profiles at study start and after 1 year of GH treatment were analyzed using SELDI-TOF. Cross-validated regression and random permutation analyses were performed to identify significant correlations between protein expression patterns and the 2-year growth response to GH treatment.     

Spontaneous prolactin secretion in growth hormone-deficient children.

OBJECTIVE: To establish the spontaneous nocturnal prolactin (PRL) release in relation to growth hormone (GH)-deficient children and idiopathic short-stature children (ISS). METHODS: A total of 32 prepubertal children (11 girls, 21 boys) aged between 3 and 12 years were studied retrospectively and sorted according to diagnosis: idiopathic GH deficiency (GHD, n = 9), neurosecretory deficiency of GH secretion (NSD, n = 10) and ISS (n = 13). Nocturnal spontaneous hormone secretion was studied by intermittent venous sampling. Secretion profiles and copulsatility were analyzed using Pulsar and AnCoPuls software. RESULTS: (median, range in mug/l): Children with GHD and NSD had significantly lower GH and area-under-the-curve (AUC) levels than normal children (p < 0.001), whereas ISS children showed normal values. In contrast, prolactin levels were significantly higher (p < 0. 05) in children with GHD and NSD (11.1, 4.9 - 13.0 and 10.3, 8. 8 - 19. 6, respectively) compared to the ISS children (8.0, 4.9 - 13.0). In addition, prolactin AUC and peak height were higher (p < 0.05) in GH-deficient patients, whereas all other secretion parameters were the same. Correlation and copulsatility analysis revealed no evidence for a direct relation between PRL and GH secretion. CONCLUSIONS: PRL secretion is significantly higher in children with GHD and NSD compared to ISS children but PRL and GH show no copulsatile secretion pattern.     

Chronic growth hormone administration does not suppress endogenous growth hormone secretion in patients with neurosecretory growth hormone dysfunction.

Short children who respond normally to growth hormone (GH) stimulation, but have a subnormal spontaneous secretion of GH (neurosecretory GH dysfunction, NSD) are treated with exogenous GH which might suppress their endogenous GH secretion. The effect of chronic administration of GH (8-24 months) on plasma GH responses to GHRH, clonidine and spontaneous GH secretion were studied in 17 NSD patients. The diagnosis of NSD was based on a normal GH response to clonidine (greater than 10 micrograms/l) and an integrated concentration of (IC-GH) GH less than 3.2 micrograms/l. The GH dose used in this study was 0.25 IU/kg three times a week in 10 patients and 0.05 IU/kg daily in 7 patients. Insulin-like growth factor I levels (nmol) increased significantly on therapy from 9.3 +/- 3.8 to 24.4 +/- 22.4 (p less than 0.001). The GH response (microgram/l) to GHRH was 20.4 +/- 5.5 before treatment and 22.4 +/- 6.2 on GH. Peak GH after clonidine was 22.4 +/- 8.9 and 22.8 +/- 8.1, respectively. There was no significant decrease in the number of GH spontaneous peaks (1.8 +/- 0.7 vs. 2.0 +/- 0.7, respectively) or in the area under the curve. A subcutaneous GH bolus of 0.25 IU/kg in 4 patients resulted in a GH peak of 55-82 micrograms/l at 3-5 h and a gradual return to basal levels at 15-20 h after GH administration. The first spontaneous GH peak appeared 26-28 h after GH injection, peak amplitude was 10-15 micrograms/l.(ABSTRACT TRUNCATED AT 250 WORDS)     

Physiological growth hormone secretion in children with short stature and intra-uterine growth retardation

31 prepubertal children with short stature [mean height standard deviation score (SDS) -2.84] and low birth weight (mean -2.82 SDS) were studied. Mean age was 6.0 years and mean height velocity SDS was -0.76. Patients were classified as having either the clinical characteristics of Russell-Silver syndrome (RSS) (4 F, 13 M) or not (4 F, 10 M). All children had an overnight profile of spontaneous growth hormone (GH) secretion. 4 children achieved a maximum GH concentration of less than 20 mU/l. 9 children with RSS secreted only one large GH peak during the night. Most of the non-RSS group had normal GH pulse frequency but 3 boys had a fast-frequency pattern. Abnormal GH secretion may contribute towards growth failure in children with low birth weight/RSS.     

Effects of acute intravenous injection of two growth hormone-releasing hormones (GHRH 1-40 and 1-29) on serum growth hormone and other pituitary hormones in short children with pulsatile growth hormone secretion

We administered two different growth hormone-releasing hormones (GHRH) to 20 short, prepubertal children who had spontaneous secretion of growth hormone (GH), assessed from 24-hour GH secretion profiles (72 sampling periods of 20 min). We compared one i.v. injection of 1 microgram/kg of GHRH 1-40 with that of GHRH 1-29 regarding serum concentrations of GH, prolactin, luteinizing hormone, follicle-stimulating hormone and IGF-I. The children were allocated to two groups without statistical randomization. Both groups were given both peptides, with at least 1 week in between. The first group started with GHRH 1-40, the other with GHRH 1-29. The peptides both induced an increased serum concentration of GH of the same magnitude: mean maximal peak of 89 +/- 12 mU/l after GHRH 1-40 and 94 +/- 10 mU/l after GHRH 1-29 (n.s.). The mean difference in maximum serum GH concentration in each child after injection was 52 +/- 9 mU/l, range 1-153 mU/l. GHRH 1-29 also induced a short-term, small increase in the concentrations of prolactin (p less than 0.05), luteinizing hormone (p less than 0.01) and follicle-stimulating hormone (p less than 0.05). We conclude that the shorter sequence GHRH 1-29, when given in a dose of 1 microgram/kg, gives a rise in serum concentration of GH similar to that after the native form GHRH 1-40.     

Response to long-term growth hormone therapy in short children with reduced GH bioactivity

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.     

Acipimox enhances spontaneous growth hormone secretion in obese women

We hypothesized that a high circulating free fatty acid (FFA) concentration is involved in the pathogenesis of hyposomatotropism associated with obesity. To evaluate this hypothesis, 10 healthy premenopausal women (body mass index 33.8 +/- 1.0 kg/m(2)) were studied in the follicular phase of their menstrual cycle at two occasions with a time interval of at least 8 wk, where body weight remained stable. Subjects were randomly assigned to treatment with either acipimox (an inhibitor of lipolysis, 250 mg orally 4 times daily) or placebo in a double-blind crossover design, starting 1 day before admission until the end of the blood sampling period. Blood samples were taken during 24 h with a sampling interval of 10 min for assessment of growth hormone (GH) concentrations, and GH secretion was estimated by deconvolution analysis. Identical methodology was used to study GH secretion in a historical control group of age-matched normal weight women. GH secretion was clearly blunted in obese women (total daily release 66 +/- 10 vs. lean controls: 201 +/- 23 mU x l(Vd)(-1) x 24 h(-1), P = 0.005, where l(Vd) is lite of distribution volume). Acipimox considerably enhanced total (113 +/- 50 vs. 66 +/- 10 mU x l(Vd)(-1) x 24 h(-1), P = 0.02) and pulsatile GH secretion (109 +/- 49 vs. 62 +/- 30 mU x l(Vd)(-1) x 24 h(-1), P = 0.02), but GH output remained lower compared with lean controls. Further analysis did not show any relationship between the effects of acipimox on GH secretion and regional body fat distribution. In conclusion, acipimox unleashes spontaneous GH secretion in obese women. It specifically enhances GH secretory burst mass. This might mean that lowering of systemic FFA concentrations by acipimox modulates neuroendocrine mechanisms that orchestrate the activity of the somatotropic ensemble.     

Timing of GH Peak in Both Glucagon and Clonidine Tests is of Major Clinical Importance

Objective: To detect a possible correlation between timing of the peak value of growth hormone (GH) during stimulatory tests (STs) and the effectiveness of treatment with recombinant human growth hormone (rhGH) in children with idiopathic GH deficiency (iGHD).Methods: We retrospectively studied 92 patients with iGHD (57 boys; mean age at diagnosis: 9.93 years). Diagnosis was confirmed by 2 different STs, glucagon stimulation test (GST), and clonidine stimulation test (CST). Auxologic parameters were recorded, while observed and predicted (according to KIGS Prediction Model) height velocity during the first year of treatment and the index of responsiveness (IoR) were calculated for the prepubertal children (n = 65).Results: Atypical GST was defined as that with peak GH value at time 0 minutes, 30 minutes, 60 minutes, or 180 minutes, whereas atypical CST was defined as that with peak timing at 0 minutes, 30 minutes, or 120 minutes. Atypical GST was detected in 18 patients (19.57%). IoR was lower in the prepubertal children with atypical GST (-1.81 ± 0.67 versus -1.34 ± 0.85; P = .051). In the CST, the 18 children who had atypical timing, had significantly lower IoR (-1.86 ± 0.66 versus -1.35 ± 0.84; P = .047). When the patients were categorized according to the number of atypical tests, significant differences in the IoR were detected (-2.09 ± 0.68 with 2 atypical STs &lsqb;n = 6], -1.64 ± 0.61 with 1 atypical ST &lsqb;n = 16], and -1.29 ± 0.87 with no atypical ST &lsqb;n = 43], P = .045).Conclusion: The presence of atypical peak GH timing during ST may be a factor that predicts lower growth hormone velocity during the first year of rhGH treatment in prepubertal children with iGHD.Abbreviations: CST = clonidine stimulation test; GH = growth hormone; GHD = growth hormone deficiency; GST = glucagon stimulation test; iGHD = idiopathic growth hormone deficiency; IoR = index of responsiveness; rhGH = recombinant human growth hormone; SDS = standard deviation scores; ST = stimulatory test     

Growth and growth hormone in children after bone marrow transplantation

Growth and growth hormone (GH) were investigated every year in 24 children after allogeneic bone marrow transplantation (BMT) for severe aplastic anemia (SAA) or leukemia. Conditioning included total body irradiation (TBI) in all cases of leukemia. The young leukemic children grew poorly. At 4 years after BMT, the mean standard deviation score for attained height had decreased from 0 to -1.73. GH deficiency was diagnosed with provocation tests. Three years after BMT, 10/18 children had a subnormal response. Ten children were further investigated with 24-hour GH profiles. Children with SAA had normal growth and GH levels. TBI seemed to be the major factor responsible for impaired growth.     

Challenges of Securing Growth Hormone Coverage for Idiopathic Short Stature: Review of the 7-Year Experience at one Institution

Objective: Despite U.S. Food & Drug Administration (FDA) approval of growth hormone (GH) for idiopathic short stature (ISS), many providers face challenges obtaining insurance coverage. We reviewed the insurance coverage experience for ISS at our hospital to identify factors predictive of approval or denial.Methods: We reviewed charts of patients who underwent GH stimulation testing from July 1, 2009, to April 30, 2017, to identify ISS patients (height <-2.25 SD, subnormal predicted adult height (PAH) and peak GH >10 ng/mL).Results: Eighty-seven patients met ISS criteria, of whom 47 (29 male/18 female) had a GH request submitted to insurance. Mean age, height, and growth velocity were 8.6 ± 2.7 years, 2.83 ± 0.4 SD, and 4.4 ± 1.7 cm/year, respectively. Mean PAH based on bone age was -2.50 ± 0.9 SD, equaling 62 inches for males and 58 inches for females. Most had private managed care insurance (74%). Overall, 17/47 (36%) received treatment approval, 7 immediately and 10 more on appeal. There were no differences in age, height SD, growth rate, insurance type, or PAH between the 17 who were approved and the 30 denied. For 21 patients who were treated, a mean increase in 0.6 SD in height was seen after 1 year.Conclusion: At our institution, GH coverage requests for ISS included very short children mostly ages 6 to 11, with heights well below -2.25 SD and poor PAH. Only 36% were approved even after appeal. This highlights the challenge in our area to secure GH treatment for a FDA-approved indication. Collaboration between pediatric endocrinologists and insurers focusing on height SD and PAH, may improve cost-effective coverage to deserving short children who meet FDA guidelines for ISS treatment.Abbreviations: FDA = Food and Drug Administration; GH = growth hormone; IGF-1 = insulin-like growth factor 1; ISS = idiopathic short stature; PAH = predicted adult height     

Effect of arginine on the GHRH-stimulated GH secretion in patients with hyperthyroidism.

Patients with hyperthyroidism have reduced GH responses to pharmacological stimuli and reduced spontaneous nocturnal GH secretion. The stimulatory effect of arginine on GH secretion has been suggested to depend on a decrease in hypothalamic somatostatin tone. The aim of our study was to evaluate the effects of arginine on the GH-releasing hormone (GHRH)-stimulated GH secretion in patients with hyperthyroidism. Six hyperthyroid patients with recent diagnosis of Graves' disease [mean age +/- SEM, 39.2 +/- 1.4 years; body mass index (BMI) 22 +/- 0.4 kg/m2] and 6 healthy nonobese volunteers (4 males, 2 females; mean age +/- SEM, 35 +/- 3.5 years) underwent two experimental trials at no less than 7-day intervals: GHRH (100 micrograms, i.v.)-induced GH secretion was evaluated after 30 min i.v. infusion of saline (100 ml) or arginine (30 g) in 100 ml of saline. Hyperthyroid patients showed blunted GH peaks after GHRH (13.2 +/- 2.9 micrograms/l) as compared with normal subjects (23.8 +/- 3.9 micrograms/l, p < 0.05). GH peaks after GHRH were only slightly enhanced by arginine in hyperthyroid subjects (17.6 +/- 2.9 micrograms/l), whereas, in normal subjects, the enhancement was clear cut (36.6 +/- 4.4 micrograms/l; p < 0.05). GH values after arginine + GHRH were still lower in hyperthyroid patients with respect to normal subjects. Our data demonstrate that arginine enhances but does not normalize the GH response to GHRH in patients with hyperthyroidism when compared with normal subjects. We hypothesize that hyperthyroxinemia may decrease GH secretion, both increasing somatostatin tone and acting directly at the pituitary level.     

Influence of estrogen administration on the growth response to growth hormone (GH) in GH-deficient mice

In women who are growth hormone (GH) deficient, exogenous estrogens increase the dosage of GH that is needed to normalize circulating levels of insulin-like growth factor (IGF-1). Serum IGF-1 derives mostly from the liver, and it is unknown whether the peripheral effects of GH are also impaired by estrogens. Because the ultimate effect of GH is longitudinal growth, we have investigated the influence of estrogen administration on the growth response to recombinant mouse GH therapy in prepubertal GH-deficient (GHD) GHRH knockout (GHRHKO) female mice. Twenty-four GHRHKO female mice (4 animals/group) were treated for 4 weeks (from the second to sixth week of age) with the following schedules: Group I, GH only (25 microg/day); Group II, subcutaneous (sc) ethynil estradiol (EE) (0.035 ES01247g/day); Group III, GH + scEE; Group IV, oral (po) EE (0.035 microg/day); Group V, GH + poEE; Group VI, placebo. At the end of the treatment period, we measured uterine weight, total body weight (TBW), body length (nose-anus, N-A), and femur length. In addition, serum IGF-1 levels were measured. Uteri of mice treated with oral or scEE showed similar increases in weight. There was no difference in the increase in longitudinal growth parameters between mice treated with GH alone or with GH in association with oral or scEE. Serum IGF-1 decreased in animals treated with GH + scEE, compared with GH group, but no group was significantly different from placebo. These results show that subcutaneous or oral EE does not reduce the growth response to GH in female GHD mice.     

Growth hormone responses to sleep, insulin hypoglycaemia and arginine infusion

This study compares the peak serum growth hormone (GH) concentration during slow wave sleep with the serum GH responses to insulin-induced hypoglycaemia and intravenous arginine infusion in 23 children referred because of short stature (20) or precocious puberty (3). Peak serum GH concentration during sleep correlated significantly with peak GH response to insulin hypoglycaemia (r = 0.64, p less than 0.01) and arginine infusion (r = 0.57, p less than 0.01). 3 children had subnormal (less than 15 mU/l) peak serum GH concentrations during sleep but normal responses to either insulin-induced hypoglycaemia or intravenous arginine infusion. 1 child had a normal peak serum GH response to sleep but subnormal responses to insulin and arginine. Sleep studies of GH secretion may be indicated when the GH responses to pharmacological stimuli are inconsistent with the observed growth pattern.