Clinical benefits of sex steroids given as a priming prior to GH provocative test or as a growth-promoting therapy in peripubertal growth delays: Results of a retrospective study among ENDO-ERN centres.

OBJECTIVES: Sex steroids, administered as a priming before GH stimulation tests (GHST) to differentiate between growth hormone deficiency (GHD) and constitutional delay of growth and puberty (CDGP) or as growth-promoting therapy using low-dose sex steroids (LDSS) in CDGP, are much debated. We aimed to compare auxological outcomes of CDGP or GHD children undergoing primed or unprimed GHST and to evaluate LDSS treatment in CDGP. DESIGN: Retrospective study among three paediatric University Hospitals in Italy and UK. METHODS: 184 children (72 females) aged 12.4 ± 2.08 years underwent primed (/P+ ) or unprimed (/P- ) GHST and were followed up until final height (FH). CDGP patients were untreated (CDG P- ) or received LDSS (CDGP+ ). The cohort included 34 CDG P- /P+ , 12 CDGP+ /P+ , 51 GHD/P+ , 29 CDG P- /P- , 2 CDGP+ /P- and 56 GHD/P- . FH standard deviation score (SDS), Δ SDS FH-target height (TH) and degree of success (-1 ≤ Δ SDS FH-SDS TH ≤ +1) were outcomes of interest. RESULTS: GHD/P+ had better FH-SDS (-0.87 vs -1.49; P = .023) and ΔSDS FH-TH (-0.35 vs -0.77; P = .002) than CDGP- /P+ . Overall, GHD/P+ showed the highest degree of success (90%, P = .006). Regardless of priming, both rhGH and LDSS improved degree of success compared to no treatment (89% and 86% vs 63%, P = .0009). GHD/P+ showed a trend towards a higher proportion of permanent GHD compared to GHD/P- (30.43% vs 15.09%; P = .067). CONCLUSION: In peripubertal children, priming before GHST improves diagnostic accuracy of GHST for idiopathic GHD. LDSS treatment improves auxological outcomes in CDGP.

Meta-analysis of metabolic changes in children with idiopathic growth hormone deficiency after recombinant human growth hormone replacement therapy.

PURPOSES: We aimed to assess the effects of recombinant human growth hormone (rhGH) replacement therapy on metabolic changes by synthesizing data from clinical trials involving children with idiopathic growth hormone deficiency (IGHD). METHODS: Two investigators independently completed literature search, quality assessment, and data extraction. Effect-size estimates are expressed as weighted mean difference (WMD) with 95% confidence interval (CI). RESULTS: A total of 16 clinical trials involving 1319 children were eligible for analysis. Overall analyses showed that total cholesterol was significantly decreased after rhGH replacement therapy (WMD: -0.20 mmol/l; 95% CI: -0.30 to -0.10; p < 0.001), and high-density lipoprotein was significantly increased (WMD: 0.29 mmol/l; 95% CI: 0.24 to 0.33; p < 0.001). Marginal increase was noted for low-density lipoprotein (WMD: -0.22 mmol/l; 95% CI: -0.47 to 0.22; p = 0.092). Subsidiary and meta-regression analyses revealed that length of intervention and sample size were possible causes of heterogeneity. There was a low probability of publication bias. CONCLUSIONS: Our findings indicate an obviously favorable role of rhGH replacement therapy in lipid metabolism in children with IGHD, and this role might be dependent on length of intervention.

Psychometric properties of the quality of life in short statured youth (QoLISSY) questionnaire within the course of growth hormone treatment.

BACKGROUND: The Quality of Life of Short Stature Youth (QoLISSY) questionnaire is a patient- and parent-reported outcome measure assessing health-related quality of life (HRQOL) in short stature youth. This study evaluates the psychometric properties of the QoLISSY questionnaire within a German prospective trial of short statured children treated with human growth hormone (hGH). METHOD: The instrument was administered to children with idiopathic growth hormone Deficiency (IGHD) and small for gestational age (SGA) before and after 12 month of hGH treatment. Children with idiopathic short stature (ISS) served as a reference group receiving no treatment. Psychometric testing included scale distribution characteristics, reliability (internal consistency), criterion-and convergent validity (correlations with the generic KIDSCREEN-Index, inter-correlations among QOLISSY subscales), known-group validity (treatment status, height SDS), and responsiveness analysis (ability to detect change). RESULTS: One hundred fifty-two parents and 66 children/adolescents completed both HRQOL assessments. The QoLISSY demonstrated good reliability with Cronbach's alpha > .70. Moderate significant correlations between QoLISSY domains and the KIDSCREEN-10 Index supported criterion validity. Statistically significant differences in HRQOL were observed between treatment groups at baseline with children who were about to start treatment reporting a significantly lower HRQOL compared to the children who will not receive treatment. No significant differences were found between the level of short stature based on height SDS scores (≤ - 2 SDS, > - 2 SDS). Furthermore, the instrument detected significant changes in HRQOL between the treated and the untreated group in patient-reports. CONCLUSIONS: In conclusion, the scales showed satisfactory reliability, adequate validity and ability to detect change in self-reported HRQOL within GH treatment. Findings support QoLISSY's further use in clinical trials, offering the opportunity to adequately assess HRQOL from the patients' and caregivers' perspective to improve patient-centered care.

Pituitary height at magnetic resonance imaging in pediatric isolated growth hormone deficiency.

BACKGROUND: Magnetic resonance imaging (MRI) is used for neuroradiologic evaluation of patients with idiopathic growth hormone deficiency (IGHD). OBJECTIVES: To compare pituitary height and morphology at MRI between patients with IGHD and controls. MATERIALS AND METHODS: This retrospective study was conducted in pediatric patients, 3 years-15 years old, who had had brain MRI with non-contrast-enhanced midsagittal T1-weighted images. These images were measured for pituitary height and morphology of the pituitary gland including shape, stalk and posterior pituitary bright spot was evaluated. RESULTS: One hundred and nineteen patients were included, with 49 and 70 patients assigned to the study and control groups, respectively. Mean pituitary height was significantly less in the IGHD group than in the control group (3.81 mm±1.38 vs. 4.92 mm±1.13, retrospectively; P<0.001). Subgroup analysis revealed a significant difference in the pituitary height between groups in the prepubertal (8-10 years) and pubertal (11-13 years) periods (P=0.039 and P=0.006, respectively) and a trend toward significance in the postpubertal period (P=0.053). There was a significant difference in pituitary shape between IGHD and controls when combining grades III, IV and V (P=0.007). Other abnormal MRI findings of the pituitary stalk and posterior bright spot were significantly more often observed in the IGHD group (P<0.05). CONCLUSION: Pituitary height was significantly smaller in patients with IGHD than in controls during prepuberty and puberty. Abnormal concave superior contour, hypoplastic stalk and absent/ectopic posterior bright spot were observed significantly more often among patients with IGHD.

Assessing the adrenal axis by the glucagon stimulation test in children with idiopathic growth hormone deficiency.

Approximately 30% of children with idiopathic growth hormone deficiency (IGHD) also suffer from other pituitary hormone deficien-cies. Of children with IGHD, approximately 10% are unable to generate appropriate ACTH levels in response to stress. This study was prospectively designed to test the integrity of the adrenal axis in patients with an established diagnosis of IGHD using the glucagon stimulation test (GST). The study population comprised 39 patients with established childhood-onset IGHD. The diagnosis of GHD was established on the basis of failure of GH to increase over 10 ng/ml after two stimulation tests. The GST was performed by intra-muscular injection of 1 mg glucagon. The criteria followed to define adrenal deficiency was cortisol less than 167 ng/l in response to GST. The mean peak blood glucose level was 8.64 ±1.71 mmol/l. Analysing the cohort using the cut-off of 167 ng/ml to define adrenal insufficiency under GST, there were 25.64% of children diagnosed: 20% among males and 35.7% among females. Subjects with GH and ACTH deficiency had a mean peak GH of 2.07 ±1.79 ng/ml - significantly lower than GH peak of children with IGHD alone (p < 0,001). The frequency of children with combined somatotroph and corticotroph deficiencies with a GH peak < 3 ng/ml was 21% (p < 0,001). The current study identified a prevalence of adrenal insufficiency of 25.64%, which could predict greater risk for children if untreated, especially because a substantial proportion of patients do not present clinical symptoms.

Using a spontaneous profile rather than stimulation test makes the KIGS idiopathic growth hormone deficiency model more accessible for clinicians.

AIM: Children treated with a growth hormone (GH) for idiopathic growth hormone deficiency (IGHD) may be monitored with the first-year prediction model from the Pfizer International Growth Database (KIGS) using auxology, age, GH dose and the maximum GH concentration from a stimulation test (GHmax stim). We tested the hypothesis that using a 12-hour spontaneous profile (GHmax 12h) would be as accurate. METHODS: We studied 98 prepubertal Swedish children (78 boys) aged 2-12 years enrolled in KIGS. The first-year growth was predicted using the GHmax from the GH profile and a stimulation test, and both of these were compared separately with the observed growth response. RESULTS: The increased height observed in the first year was 0.74 standard deviation scores (SDS), and the studentised residuals for the predicted and observed growth with GHmax stim (-0.16 SDS) and GHmax 12h (-0.22) were similar. Individual predictions calculated with stimulated or spontaneous GHmax showed a significant correlation (r = 0.80). CONCLUSION: We validated the KIGS IGHD prediction model and found that the stimulated GHmax peak can be reliably replaced by the GHmax 12h with similar accuracy. This makes the model more accessible for clinicians, who can then provide realistic expectations for the growth response during the first year of treatment.

Final Height in Children with Idiopathic Growth Hormone Deficiency treated with Growth Hormone: Albanian experience.

Objective- To evaluate the efficiency of recombinant growth hormone for increasing adult height in children treated for idiopathic growth hormone deficiency and to evaluate the prognostic factor for height at the end of treatment. Design- Observational follow up study. Setting- Population based registry. Participants- All Albanian children diagnosed with idiopathic growth hormone deficiency who had attained final height. Their treatment started between 2001 and 2011. Main outcome measures- Annual changes in height, and change in height between the start of treatment and adulthood; the importance of the factors that influence on final height. Results- Adult height was obtained for 83 (55%) patients. The mean dose of growth hormone at start of treatment was 0.21 IU/kg/week for 29 patients and 0.24 IU/week for 54 patients. Height gain was 2.41±1.19 z-scores, resulting in an adult height of -1.98±1.12 z-score (girls, -2.05±1.27 z-score; boys, -1.95±1.20 z-score). Patients who completed the treatment gained 2.40±1.13 z-score of height in 4.0±2.0 years. Most of the variation in height gain was explained by regression towards the mean, patients' characteristics, and delay in starting puberty. Conclusion- Nearly all our patients with idiopathic growth hormone deficiency treated with growth hormone were able to achieve their genetic height potential. Despite starting treatment late, they managed to gain 2.40±1.13 HAZ score in height and the final height for majority of them (61.5%) was within the target height range. It was found that the final height had good correlation with the prediction height, HAZ score at beginning of treatment, change of HAZ score during the puberty, duration of treatment with GH, and pubertal stage at the start of therapy.

Reassessment of Growth Hormone(GH) Status and Metabolic Disturbance in Young Adults with Childhood-onset GH Deficiency / 대한소아내분비학회지

PURPOSE: Adults with GH deficiency(GHD) have abnormal body composition, reduced physical performance, altered lipid metabolism, increased cardiovascular diseases, and reduced quality of life. Administration of GH to these patients reduce clinical abnormalities to normal ranges. Therefore, patients with childhood-onset GHD might need to continue GH replacement after the attainment of final height. Recently studies have shown that a high proportion of patients with childhood-onset GHD are no longer GHD when retested at young adult. METHODS: GH secretion was reevaluated with insulin and clonidine after completion of GH treatment in 29 young adult patients(21.3+/-2.8 yrs, 17 men, 12 women) with childhood-onset GHD diagnosed at a mean age of 11.4+/-3.5 yr. The mean duration of GH treatment was 3.7+/-3.0 yrs. Eleven(11 men) with idiopathic patients presented in 2(18%) isolated GHD and 9(82%) in multiple pituitary hormonal deficiencies. Eighteen(6 men, 12 women) with organic patients presented in 4(22%) isolated GHD and 14(88%) in multiple pituitary hormomal deficiencies, which was caused from craniopharyngioma, germinoma & other lesions. Blood sampling were done as usual method for checking LH, FSH and TSH concentration after injection of gonadotropin releasing hormone & thyrotropin releasing hormone. Serum cortisol levels were also checked after insulin injection and all hormonal concentrations were measured with radioimmunoassay method. Total cholesterol, high density lipoprotein (HDL)-cholesterol, low density lipoprotein(LDL)-cholesterol concentrations were measured by standard techniques. Bone density was measured in the level of lumbar spine and femur with DEXA. M-mode, two-dimensional and pulsed Doppler echocardiographic studies were performed. Quality of life was assessed from Beck depression inventory questionnaire with age-matched control. RESULTS: All patients with idiopathic and organic GHD were confirmed as GHD through combined pituitary function retesting at young adult. The additional pituitary hormonal deficiencies were increased in numbers. Their total cholesterol and triglyceride levels were increased especially in patients with organic GHD. There were no specific abnormal findings in echocardiographic findings compared to normal reference. Bone density with DEXA showed osteopenia(T score <-1) was found in 20/24(83%) and osteoporosis(T score <-2.5) in 8/24(33%) in young adult GHD. Quality of life was evaluated with BDI questionnaire and showed mild depression in 32% and moderate to severe depression in 11%. CONCLUSION: 82% of patients with idiopathic and 88% of organic GHD have additional pituitary hormonal deficiencies in childhood, showing multiple pituitary hormonal deficiencies rather than isolated GHD and has GHD permanently in all young adults with idiopathic and organic GHD and that is a little different findings from other foreign reports and needs to follow up in future.

Growth Response in Children with Idiopathic Growth Hormone Deficiency and Organic Growth Hormone Deficiency during Growth Hormone Treatment / 대한소아내분비학회지

PURPOSE: This study was undertaken to compare the growth promoting effect between patients with idiopathic growth hormone deficiency(IGHD) and those with organic growth hormone deficiency(OGHD). METHODS: Seventeen children with GH deficiency were divided into two groups: 7 IGHD and 10 OGHD including craniopharyngioma(5), sella germinoma(1), prolactinoma(1), Langerhans cell histiocytosis(1) and postirradiation(1). Diagnosis of GHD was made on the basis of two growth hormone provocative tests, serum IGF-1 & IGFBP 3 level, and bone age. Both groups were treated with recombinant human growth hormone(0.6-0.8IU/Kg/week) for 2 years and auxological parameters (height velocity, height SDS CA(standard deviation score for chronologic age)) were analyzed during 2 years of treatment by using KIGS 4.0 software program. RESULTS :The mean pretreatment height velocity in both groups did not differ statistically(2.6+/-.8cm/yr in IGHD vs 2.5+/-.9cm/yr in OGHD: p>0.05). However, height velocity after 2 years of growth hormone treatment was significantly greater in IGHD group than in OGHD group(9.0+/-.3cm/yr in IGHD vs 7.2+/-.8cm/yr in OGHD: P<0.05). The height SDS for CA has improved remakably during 2 years of growth hormone treatment; -3.46 SDS before treatment to -1.53 SDS in IGHD group, -2.3 SDS to -0.5 SDS in OGHD group. CONCLUSION: Growth hormone replacement therapy has remakably improved height velocity and height SDS for CA in both groups during the 2 years of the treatment. However, the height velocity in OGHD group was significantly less than in IGHD, indicating that additional factors such as malnutrition, associated multiple hormone deficiencies, spinal irradiation and sexual precocity might significantly hamper the growth promoting effect in OGHD group during growth hormone treatment.

EVALUATION OF ANTERIOR PITUITARY FUNCTION BY COMBINED ADMINISTRATION OF HYPOTHALAMIC RELEASING HORMONE IN PATIENTS WITH IDIOPATHIC GROWTH HORMONE DEFICIENCY / 中华内分泌代谢杂志

0.05), indicating that the functional reserve of PRL, TSH and ACTH cells were normal in IGHD patients. Except the ratio of peak and basal level, all the other five indices of the LH response to LHRH were significantly lower in IGHD patients than in normals of puberty. The functional reserve of LH cell was low in about 2/3 IGHD patients. These results might explain the delayed or no puberty in adult IGHD patients.