Classical Growth Hormone Deficiency Research Articles

Long-term effects of GH therapy in adult patients with Prader-Willi syndrome: a longitudinal study.

Prader-Willi syndrome (PWS) is a complex disorder resulting from the failure of expression of paternal alleles in the PWS region of chromosome 15. The PWS phenotype resembles that observed in the classic non-PWS GH deficiency (GHD), including short stature, excessive fat mass, and reduced muscle mass. To date, a small number of studies on the long-term effects of GH treatment are available in adult subjects with PWS. In this longitudinal study, 12 obese subjects with PWS (GHD/non-GHD 6/6) were treated for a median of 17 years, with a median GH dose of 0.35 mg/day. The median age was 27.1 years. Anthropometric, body composition, hormonal, biochemical, and blood pressure variables were analyzed in all subjects. Waist circumference was significantly lower at the end of the treatment period (p-value=0.0449), while body mass index (BMI) did not differ significantly. Compared to the baseline, a highly significant reduction of Fat Mass % (FM%) was observed (p-value=0.0005). IGF-I SDS values significantly increased during GH therapy (p-value=0.0005). A slight impairment of glucose homeostasis was observed after GH therapy, with an increase in the median fasting glucose levels, while insulin, HOMA-IR, and HbA1c values remained unchanged. Considering GH secretory status, both subjects with and without GHD showed a significant increase in IGF-I SDS and a reduction of FM% after GH therapy (p-value= 0.0313 for all). Our results indicate that long-term GH treatment has beneficial effects on body composition and body fat distribution in adults with PWS associated with obesity. However, the increase in glucose values during GH therapy should be considered, and continuous surveillance of glucose metabolism is mandatory during long-term GH therapy, especially in subjects with obesity.

Counseling for Growth Hormone Therapy.

Growth hormone (GH) therapy is an integral part of the treatment of short stature. Over the period of the last few decades, due to the better availability of recombinant human growth hormone (rHGH), we have more clinical data on the uses of GH in various diseases. The list of approved uses of the GH apart from the classical growth hormone deficiency (GHD) is increasing and is much longer than before but still, adherence to therapy is poor as seen in other chronic diseases also. In this review, we plan to discuss the means of better communication and counseling of the patient to ensure adequate adherence to therapy for optimal clinical outcome.

Dilemmas of growth hormone treatment for GH deficiency and idiopathic short stature: defining, distinguishing, and deciding.

Worrisome growth can be a sign of underlying pathology but usually reflects healthy variation. It is often recognized through short stature, which is defined by arbitrarily separating height, a physical trait on a continuum, into "normal" and "abnormal." In some cases of worrisome growth, recombinant human growth hormone (rhGH) treatment is indicated to hasten growth/increase height. This review addresses the two most frequently treated indications for rhGH, growth hormone deficiency (GHD) and idiopathic short stature (ISS). A review of worrisome growth itself, of the history of GH treatment, of the blurry line between partial GHD and ISS, of the GH stakeholders, and of the outside pressures involved in these cases demonstrates the ambiguous platform upon which treatment decisions are made. The rhGH treatment decision process can be examined further by considering the three most impactful factors on parental height-related medical decision-making: treatment characteristics, child health, and psychosocial function. While it is important to note that treatment for classical GHD is uncontroversial and supported, treatment decisions for partial GHD and ISS are more complicated and require careful evaluation of both patient needs and the supporting evidence. As the rhGH community grows, physicians, parents, and patients are encouraged to engage in a shared decision-making process to navigate the many challenges facing the GH field. Although this review addresses GHD and ISS specifically, the issues discussed are often applicable to pediatrics as a whole.

GROWTH HORMONE THERAPY;

Objective: To detect growth hormone deficiency in short stature children and to observe the response of growth hormonereplacement therapy in isolated GH deficient. Design: An interventional descriptive study. Place and Duration of Study: The study wascarried out in the Department of Pediatrics at Military Hospital Rawalpindi in collaboration with Armed Forces Institute of PathologyRawalpindi over a period of two years from Jan 2007 to Dec 2008. Patients and Methods: Thirty short children between three to fourteenyears of age having isolated growth hormone deficiency confirmed by laboratory investigation were included in the study prospectivelyand retrospectively. Growth hormone replacement therapy with recombinant GH was given to all children at the dose of 0.14iu/kg, sixdays a week subcutaneously. Each patient was assessed and evaluated after every three months. Results: The mean chronologic agewas 8.05 +/- 2.74 years with a height age of 4.02 years. The male to female ratio was 1.72:1. They were treated with recombinant GH in adose of 0.14iu/kg, six days a week, subcutaneously at evening. Response to GH was excellent and the mean growth speed had gone upfrom 2.53 +/- 0.87 cm per year before the treatment to 8.94 +/- 3.18 cm / year in the first twelve months of treatment and 6.8 +/- 1.6cm / year during the second year of treatment. During the first twenty four months of treatment, height standard deviation score increasedby 1.0 +/- 0.4 SD (p < 0.0001) The height velocity increased, the bone age / chronological age ratio and height SDS for chronologicalage decreased, while height SDS for bone age increased. There were no adverse reactions. Conclusion: Short stature with classic growthhormone deficiency is not uncommon. Early diagnosis and prompt treatment with growth hormone replacement has a very goodoutcome and the child attains a reasonable height.

Partial Loss of Function of the GHRH Receptor Leads to Mild Growth Hormone Deficiency.

Recessive mutations in GHRHR are associated with severe isolated growth hormone deficiency (IGHD), with a final height in untreated patients of 130 cm ± 10 cm (-7.2 ± 1.6 SDS; males) and 114 ± 0.7 cm (-8.3 ± 0.1 SDS; females). We hypothesized that a consanguineous Pakistani family with IGHD in three siblings (two males, one female) would have mutations in GH1 or GHRHR. Two novel homozygous missense variants [c.11G>A (p.R4Q), c.236C>T (p.P79L)] at conserved residues were identified in all three siblings. Both were absent from control databases, aside from pR4Q appearing once in heterozygous form in the Exome Aggregation Consortium Browser. The brothers were diagnosed with GH deficiency at 9.8 and 6.0 years (height SDS: -2.24 and -1.23, respectively), with a peak GH of 2.9 μg/liter with low IGF-1/IGF binding protein 3. Their sister presented at 16 years with classic GH deficiency (peak GH <0.1 μg/liter, IGF-1 <3.3 mmol/liter) and attained an untreated near-adult height of 144 cm (-3.0 SDS); the tallest untreated patient with GHRHR mutations reported. An unrelated Pakistani female IGHD patient was also compound homozygous. All patients had a small anterior pituitary on magnetic resonance imaging. Functional analysis revealed a 50% reduction in maximal cAMP response to stimulation with GHRH by the p.R4Q/p.P79L double mutant receptor, with a 100-fold increase in EC50. We report the first coexistence of two novel compound homozygous GHRHR variants in two unrelated pedigrees associated with a partial loss of function. Surprisingly, the patients have a relatively mild IGHD phenotype. Analysis revealed that the pP79L mutation is associated with the compromise in function, with the residual partial activity explaining the mild phenotype.

Growth hormone therapy for Prader-willi syndrome: challenges and solutions.

Prader–Willi syndrome (PWS) is characterized by a dysregulation of growth hormone (GH)/insulin-like growth factor I axis, as the consequence of a complex hypothalamic involvement. PWS’ clinical picture seems to resemble the classic non-PWS GH deficiency (GHD), including short stature, excessive body fat, decreased muscle mass, and impaired quality of life. GH therapy is able to ameliorate the phenotypic appearance of the syndrome, as well as to improve body composition, physical strength, and cognitive level. In this regard, however, some pathophysiologic and clinical questions still remain, representing a challenge to give the most appropriate care to PWS patients. Data about the prevalence of GHD in PWS children are not unequivocal, ranging from 40% to 100%. In this context, to establish whether the presence (or not) of GHD may have a different effect on clinical course during GH therapy may be helpful. In addition, the comparison of GH effects in PWS children diagnosed as small for gestational age with those obtained in subjects born appropriate for gestational age is of potential interest for future trials. Emerging information seems to demonstrate the maintenance of beneficial effects of GH therapy in PWS subjects after adolescent years. Thus, GH retesting after achievement of final height should be taken into consideration for all PWS patients. However, it is noteworthy that GH administration exerts positive effects both in PWS adults with and without GHD. Another critical issue is to clarify whether the genotype–phenotype correlations may be relevant to specific outcome measures related to GH therapy. Moreover, progress of our understanding of the role of GH replacement and concomitant therapies on bone characteristics of PWS is required. Finally, a long-term surveillance of benefits and risks of GH therapy is strongly recommended for PWS population, since most of the current studies are uncontrolled and of short duration.

Decreased GH dose after the catch‐up growth period maintains metabolic outcome in short prepubertal children with and without classic GH deficiency

Few studies have evaluated metabolic outcomes following growth hormone (GH) treatment in short prepubertal children during different periods of growth. Previously, we found that individualized GH dosing in the catch-up period reduced the variation in fasting insulin levels by 34% compared with those receiving a standard GH dose. We hypothesized that the GH dose required to maintain beneficial metabolic effects is lower during the prepubertal growth phase after an earlier catch-up growth period. Short prepubertal children with isolated GH deficiency or idiopathic short stature were randomized to individualized GH treatment (range, 17-100μg/kg/day) or a standard dose in a preceding 2-year study. After achieving near mid-parental height(SDS) , children receiving an individualized dose were randomized to either a 50% reduced individualized dose (RID, n=28) or an unchanged individualized dose (UID, n=37) for 2years. The dose remained unchanged in 33 children initially randomized to receive a standard dose (FIX, 43μg/kg/day).We evaluated whether the variations in metabolic parameters measured during maintenance growth diminished in RID compared with UID or FIX. We observed less variation in fasting insulin levels (-50%), insulin sensitivity as assessed by homoeostasis model assessment (-55·1%), lean soft tissue (-27·8%) and bone mineral content (-31·3%) in RID compared with UID (all P<0·05), but no differences compared with FIX. Continued reduced individualized GH treatment after the catch-up growth period is safe and reduces hyperinsulinism. Individualized GH dose can be reduced once the desired height(SDS) is achieved to avoid overtreatment in terms of metabolic outcome.

ORIGINAL ARTICLE: Metabolic outcome of GH treatment in prepubertal short children with and without classical GH deficiency

SummaryContext Few studies have evaluated the metabolic outcomes of growth hormone (GH) treatment in idiopathic short stature (ISS). Moreover, children with ISS appear to need higher GH doses than children with GH deficiency (GHD) to achieve the same amount of growth and may therefore be at increased risk of adverse events during treatment. The individualized approach using prediction models for estimation of GH responsiveness, on the other hand, has the advantage of narrowing the range of growth response, avoiding too low or high GH doses.Design Short prepubertal children with either isolated GHD (39) or ISS (89) participated in a 2‐year randomized trial of either individualized GH treatment with six different GH doses (range, 17–100 μg/kg/day) or a standard dose (43 μg/kg/day).Objective To evaluate if individualized GH treatment reduced the variance of the metabolic measures as shown for growth response and to compare changes in metabolic variables in children with ISS and GHD.Hypothesis Individualized GH dose reduces the range of metabolic outcomes, and metabolic outcomes are similar in children with ISS and GHD.Results We observed a narrower variation for fasting insulin (−34·2%) and for homoeostasis model assessment (HOMA) (−38·9%) after 2 years of individualized GH treatment in comparison with standard GH dose treatment. Similar metabolic changes were seen in ISS and GHD. Delta (Δ) height SDS correlated with Δinsulin‐like growth factor I (IGF‐I), Δleptin and Δbody composition. Principal component analysis identified an anabolic and a lipolytic component. Anabolic variables [Δlean body mass (LBM) SDS and ΔIGF‐I SDS] clustered together and correlated strongly with Δheight SDS and GH dose, whereas lipolytic variables [Δfat mass (FM) SDS and Δleptin] were clustered separately from anabolic variables. Regression analysis showed GH dose dependency in ISS, and to a lesser degree in GHD, for ΔLBM SDS and Δheight SDS, but not for changes in FM.Conclusions Individualized GH dosing during catch‐up growth reduces the variance in insulin and HOMA and results in equal metabolic responses irrespective of the diagnosis of GHD or ISS.

Facial and pituitary morphology are related in Dutch patients with GH deficiency

Classical GH deficiency (GHD) is associated with typical phenotypic features. We have analysed standardized photographs of 137 Caucasian patients with GHD, in order to examine the relations between auxological, biochemical, pituitary and facial morphometric features. We analysed pictures of 137 patients: 73 (55 Males/18 Females) with Isolated GHD and 64 (48 M/16 F) with multiple pituitary hormone deficiency (MPHD). Of each patient, standardized frontal and lateral digital pictures were taken and analysed using Adobe Photoshop 5.0. Canthal index (CI), the relative distance between the eyes, was related to pituitary morphology. Patients with an ectopic posterior pituitary (EPP) had significantly higher CI values than patients without EPP. We found CI > 39 to be a good cut-off value to select children with highest probability of having EPP. The combination of CI > 39 with the presence of hormonal deficiencies additional to GHD strongly predicted EPP: 93% of the patients with a CI > 39 and additional hormonal deficiencies had EPP, in contrast to 77% of the patients with additional hormonal deficiencies but a CI < 39, and 29% of the patients with none of these criteria (P = 0.0001). CI, measured on digital pictures, is associated with ectopia of the posterior pituitary and this might be caused by an altered midline development, affecting both the pituitary and the facial structures of GHD patients.

GH secretory pattern in young adults who discontinued GH treatment for GH deficiency and decreased longitudinal growth in childhood

Some adolescents who discontinue GH treatment due to GH deficiency (GHD) and short stature in childhood do not have classical GHD at retesting in adult life. It is unknown whether there is a neuroendocrine disturbance in the spontaneous pattern of GH release in these patients. DESIGN/PATIENTS/METHODS: Thirty-seven adolescents, who had received treatment with GH due to impaired longitudinal growth, were included. The adolescents were divided into two groups; one (GHD; n = 19) with classical GHD in adult life and another (GH sufficient (GHS); n = 18) without classical adult GHD. One year after GH discontinuation, 24-h GH profiles were performed with blood sampling every 30 min. Sixteen matched healthy controls were also studied. All blood samples were analysed using an ultrasensitive GH assay and then, approximate entropy (ApEn) and deconvolution analysis were performed. The GHD group had higher mean ApEn level than the healthy controls (P < 0.05). As measured by deconvolution analysis, they had lower basal GH secretion (P < 0.01), increased number of GH peaks (P < 0.001), but lower burst mass (P < 0.001), lower percentage pulsatile GH secretion (P < 0.001) and lower total GH secretion (P < 0.001), compared with control subjects. Adolescents in the GHS group had a pattern of 24-h GH release similar to that in healthy controls. Young adults with childhood-onset severe GHD have a high-frequency, low-amplitude GH secretion with decreased orderliness. The adolescents without classical GHD in adult life maintain a pattern of spontaneous GH release that is not statistically different from that in the healthy controls.

Growth hormone deficiency in a patient with lysinuric protein intolerance

Lysinuric protein intolerance (LPI; MIM 222700) is a rare, autosomal recessive metabolic disorder caused by mutations in the SLC7A7 gene, which encodes the light chain of the cationic amino acids (CAA) transporter y+. The clinical presentation of LPI includes gastrointestinal symptoms, failure to thrive, episodes of coma, hepatosplenomegaly and osteoporosis. However, other findings have also been reported, and these suggest a multisystem involvement. We report a girl with confirmed LPI who presented with severe short stature that was unresponsive to adequate LPI treatment. The girl was found to have a classic growth hormone deficiency (GHD) and responded well to growth hormone (GH) replacement therapy. While it is not known whether the mechanisms involved in the GHD of our patient are related to LPI, this case suggests that GH/IGF-I axis should be investigated in LPI children with persistent growth failure.

Role of ghrelin in growth hormone-deficient patients

Ghrelin is the endogenous ligand for the growth hormone (GH) secretagog receptor and exogenous ghrelin is a strong stimulator of GH secretion. Whether endogenous ghrelin is a major regulator of GH release remains dubious, but there is increasing evidence to suggest that ghrelin exhibits direct effects on appetite regulation. Systemic ghrelin levels in patients with GH deficiency (GHD) are normal, whereas GH substitution moderately suppresses ghrelin. Certain subgroups of GHD do respond to ghrelin with significant GH release, but the clinical implications are uncertain. Administration of ghrelin or a synthetic GH secretagog in other conditions with low GH levels, such as obesity and aging, has also been performed in controlled trials and has been shown to translate into insulin-like growth factor-I stimulation and changes in body composition; however, long-term data are not available. Even though ghrelin does not seem to be abnormal in patients with classic GHD, these patients constitute an interesting model for studying GH- and adrenocorticotropic hormone-independent effects of ghrelin.

Effects of gastric bypass on the GH/IGF-I axis in severe obesity – and a comparison with GH deficiency

Overfeeding suppresses GH secretion and makes evaluation of a suspected GH deficiency (GHD) difficult. In normal weight subjects, gender is known to influence GH concentrations, which is most apparent in the ambulatory, morning-fasted state. In this study, we examined the GH/IGF-I axis in obese men and women and the effect of surgically induced weight loss. Sixty-three subjects (body mass index (BMI) 45 +/- 6 kg/m2; 54 women, 9 men) were studied prior to, and 6 and 12 months following Roux-en-Y gastric bypass (RYGBP) surgery. Fifty-four patients with classic GHD (BMI 27 +/- 6 kg/m2; 35 men, 19 women) were included for comparison. Hormones were analysed in fasting morning serum samples. RYGBP resulted in a decreased BMI to 35 +/- kg/m2 at 6 months and 32 +/- 6 kg/m2 at 12 months. GH and IGF-I increased at 6 months in the women and at 12 months in both sexes by > or = 300 and 11% respectively. Prior to RYGBP, GH concentrations were low in the obese men and similar to those of GHD men (mean 0.09 mU/l). Obese women had tenfold higher values than obese men and sevenfold higher than GHD women. IGF-I levels were in the low reference range in the obese and below -2 S.D. for age in 13%. Surgically induced weight loss partially restores GH secretion. Despite a marked suppression of GH values, a gender influence is maintained in severe obesity. In obese women, single morning GH and IGF-I values seem sufficient to exclude a suspicion of classic GHD.

Physiological and Pathological Growth Hormone Secretion

Growth hormone (GH) secretion is normally episodic, with discrete bursts of GH super-imposed on a minimal basal level of production. This pattern of GH production yields a dynamic state between a low baseline and intervening peaks, posing a challenge for the clinician attempting to understand the 'true GH status' in a specific patient. This pulsatile pattern is maintained throughout the day, but there are clear differences between different segments of the day, with approximately two-thirds of the total daily secretion produced at night. The dynamic nature of GH production has led many investigators to suggest that when evaluating short stature, parameters of spontaneous GH production be applied rather than the GH response to artificial stimulation. GH secretory patterns in healthy control populations are compared to those in patients with several conditions seen by the pediatric endocrinologist (classical GH deficiency, GH neurosecretory dysfunction, acute lymphoblastic leukemia, hypothyroidism, small for gestational age, Russell-Silver syndrome, constitutional delay of growth and puberty and Fanconi's anemia) and variables used for analysis of these patterns are described. Inferences made from comprehensive evaluations of the GH axis in Fanconi's anemia provide unique insight into general GH pathophysiology.

Growth hormone therapy and quality of life in adults and children.

A fundamental goal of growth hormone (GH) treatment for both adults and children is improvement in quality of life (QOL). Assessments of the therapeutic role of GH depend on its effectiveness in meeting this and other goals (including improved metabolic status in adults and improved growth in children) in relation to economic parameters. However, there are difficulties in interpreting data on GH treatment and QOL. These include controversy about appropriate definitions and measures for assessing QOL, disease adaptation, comorbid conditions, and potential patient selection bias. In GH-deficient adults who have completed linear growth, there is considerable evidence that GH exerts effects on body composition, serum lipids, and bone and mineral density. Several controlled trials have also examined the effect of GH treatment on QOL in GH-deficient adults. They generally indicate improvement in QOL with GH treatment, although there are inconsistencies in the data. Caveats include differing outcome measures and instruments, instruments that are not disease specific, variation in characteristics of patient samples and treatment protocols, evidence of a placebo effect, and some inconsistency among results. Open-label trials in adults also suggest improvement in QOL with GH treatment, although interpretation is limited by potential placebo effects and patient self-selection. Studies in children have generally addressed psychological status, and relatively few specifically focus on QOL. In children with classical GH deficiency, it is intuitive that GH treatment will improve QOL, although hard data are lacking. In children with idiopathic short stature, evidence for improved QOL as a result of GH treatment is not well developed. Translating changes in QOL, together with physiological and metabolic benefits, into economic cost-benefit or cost-effectiveness analyses are needed. In doing so, it will be important to consider subgroups of patients who may derive differential benefit from GH treatment. These analyses are central to the development of a framework for research, decision making, and policy for GH treatment.

Growth and growth hormone in children born small for gestational age

Growth hormone has an important role in childhood growth, but growth hormone is also detectable from early gestation, suggesting a role in fetal development and metabolism. In early postnatal life, infants who have been growth restricted in utero have abnormal patterns of growth hormone secretion with what appears to be evidence of growth hormone resistance, whereas in later childhood, growth hormone deficiency is often observed. Recent studies using high doses of growth hormone in short small for gestational age children have demonstrated increases in growth rate whether or not these children have classical growth hormone deficiency. The benefits are in terms not only of height but also of body composition and psychosocial function. However, the risk of side effects and long-term complications, such as increased insulin resistance, need to be assessed carefully, especially in people who have a family history of type 2 diabetes or the metabolic syndrome in later life.

Increased prevalence of growth hormone deficiency in patients with vernal keratoconjuntivitis; an interesting new association.

Vernal keratoconjunctivitis (VKC) is a chronic conjunctivitis that mainly affects children living in temperate areas. The notable difference between genders and VKC's resolution with puberty have persistently suggested a role of hormonal factors in VKC development. To describe six cases of males with VKC and growth hormone deficiency (GHD) reported as a long-term follow-up during rhGH treatment. Six consecutive male patients (median age at GHD diagnosis 9.7, range 7.9 to 13.1 years) with VKC, were recruited from July 2005 to July 2013 at the Paediatric Endocrinology Unit of Anna Meyer Children's Hospital in Florence, Italy. In these patients, anthropometric data were collected periodically. In three of these patients, data were collected to near-adult or adult height. Familial history was uneventful for all patients. The target height was normal, ranging from 0.65 standard deviation scores (SDS) to 2.01 SDS. The patients showed a normal birth-weight (from -1.21 to 1.35 SDS) and birth-length (from -0.93 to 1.21 SDS). At GHD diagnosis, all of the patients exhibited demonstrated important growth retardation (from -2.05 to -2.78 SDS). Plasmatic concentrations of IGF-1 and IGFBP-3 were low (from -1.85 to -3 SDS and from -1.81 to -2.76 SDS, respectively). GH stimulation tests showed classic GHD symptoms in all of the patients. Pubertal onset was normal. All of the patients treated with rhGH responded well to rhGH treatment. Adult height, evaluated in three patients, was in accordance with their target height. To our current knowledge, we have described for the first time six patients affected by VKC with GH deficiency, in some of whom we performed a long-term follow-up to adult height. Further studies will be needed to establish whether GHD may be a common feature of VKC patients. Nevertheless, it appears to be useful to carefully follow statural growth of VKC patients, while the possibility of a GH deficiency must to be taken into account in the presence of growth failure.

The Use of Somatropin (Recombinant Growth Hormone) in Children of Short Stature

The availability of somatropin [recombinant human growth hormone (GH)] has revolutionized the treatment of short stature resulting from GH deficiency. It is also widely used as an adjunct in the treatment of other disorders which do not fit the definition of classic GH deficiency, such as intrauterine growth restriction, Turner syndrome, healthy children with short stature and skeletal dysplasias. The widespread use and ready availability of GH treatment has prompted questions about its tolerability, rationality, and the psychological effects of long-term treatment, leading to several trials. Early treatment of GH deficiency will allow the child to reach his or her genetic potential, although there continues to be marked variability in the criteria used to diagnose the deficiency, and in the treatment schedule, especially during puberty. Treatment has also been shown to have a beneficial effect on growth in children with chronic renal failure, with no adverse effects on the renal function. There are, however, no long-term data to determine final height, or randomized controlled studies to justify routine use of GH in conditions such as intrauterine growth restriction. It remains controversial in conditions such as Turner syndrome and achondroplasia, where the response to treatment is only moderate. Healthy children with short stature have not been shown to have a psychological disadvantage, again proving difficult to justify prolonged GH treatment for idiopathic short stature. Meticulous monitoring, long-term follow-up to adult or near-adult final height, and well-defined endpoints of treatment need to be better clarified. The metabolic effects of treatment on the patient's lipid profile, bone mineral density, and muscle mass need careful documentation, especially with the high doses used in an already susceptible population such as low birthweight children and those with Turner syndrome. Lastly, the psychosocial impact of GH treatment, financial implications, and cost efficacy of treatment in an ever-increasing list of indications should be taken into consideration for rationalizing its use in future.

Novel application of IGF-I and IGFBP-3 generation tests in the diagnosis of growth hormone axis disturbances in children with beta-thalassaemia.

Children with beta-thalassaemia major (beta-thal) frequently have growth retardation in the presence of low serum IGF-I and a normal GH response to pharmacological stimulation suggesting that they have GH insensitivity (GHIS). This study was carried out to study the cause of their growth retardation. We studied IGF-I and IGFBP-3 generation after exogenous GH administration for four days, in 15 prepubertal controls (C) and 41 prepubertal beta-thal patients divided into three groups according to their growth status: (Group 1) 15 with normal growth (N-thal) (Group 2) 16 with decelerated growth (D-thal) and (Group 3) 10 with short stature (S-thal), in order to determine whether GHIS is the cause of their growth retardation. IGF-I and IGFBP-3 were measured daily, before and for 4 days after daily administration of 0.1 IU/kg hGH, in 3 groups of prepubertal beta-thal patients and normal controls. N-thal and C had similar basal serum IGF-I (142 +/- 52 and 196 +/- 56 ng/ml, respectively) and IGFBP-3 concentrations (2.07 +/- 0.49 and 2.66 +/- 0.41 mg/l, respectively) as well as a similar percent increase of IGF-I (101 +/- 23% and 104 +/- 37%, respectively) and IGFBP-3 (52 +/- 36%, and 38 +/- 14%, respectively) during the generation tests. S-thal and D-thal had significantly lower basal IGF-I and IGFBP-3 concentrations (85 +/- 42 and 101 +/- 36 ng/ml; and 1.60 +/- 0.49 and 1.79 +/- 0.52 mg/l, respectively) as compared to N-thal and C (P < 0.001 and P < 0.005, respectively), and a significantly higher percent increase of IGF-I and IGFBP-3 during the generation tests (249 +/- 43 and 161 +/- 76%; and 121 +/- 99 and 73 +/- 35%, respectively) as compared to N-thal and C (P < 0.0001 and P < 0.01, respectively). Twenty-five percent of the growth retarded patients had classic GH deficiency (GHD) and percent increases of IGF-I and IGFBP-3 in the generation tests (164 +/- 86% and 80 +/- 49%, respectively) which were similar to those of the remaining growth-retarded children. The greater percent increases of IGF-I and IGFBP-3 in the generation tests of the growth retarded beta-thal patients, both with and without GHD, strongly suggest impaired GH secretion rather than GHIS as the cause of their growth retardation. We conclude that the IGF-I and IGFBP-3 generation tests are useful tools for the study not only of GHIS but also of GH secretory disorders in patients with beta-thal and short stature that can easily be performed in an outpatient setting as an initial test to identify the patients that may benefit from GH therapy.

Short-Term Tools to Measure Responsiveness to Growth Hormone Replacement

Growth hormone (GH) replacement is a prolonged and expensive treatment modality which involves daily subcutaneous injections in children and adults. Efforts have been made, therefore, to develop short-term tests to predict long-term clinical response. The so-called insulin-like growth factor I (IGF-I) generation test was originally introduced in order to select responders to GH among short children without classical GH deficiency. A positive correlation between short-term increase in serum IGF-I and linear growth has, however, only been reported in a minority of studies. There is no single outcome measure available in GH-deficient adults, and no evidence of a correlation between IGF-I and the effects of GH replacement on factors such as body composition or physical fitness. In conclusion, no reliable short-term test to predict long-term response to GH replacement is available in either children or adults. For safety reasons, however, measurement of serum IGF-I concentrations in GH-deficient patients remains an important means of monitoring during GH replacement.