Aim: This phase III clinical study in growth hormone deficiency (GHD) children with growth retardation was designed to compare efficacy and safety of Omnitrope® with Genotropin® and assess the long-term safety and efficacy of Omnitrope®. The results of 7 years of treatment with Omnitrope® are presented. Patients and Methods: Eighty-nine treatment-naïve, prepubertal children with GHD were randomized (part 1) to Omnitrope® lyophilisate (group A, n = 44) or Genotropin® (group B, n = 45) for 9 months and received a subcutaneous dose of 0.03 mg/kg/day. In part 2, patients receiving Omnitrope® lyophilisate continued the same treatment for a further 6 months, while patients on Genotropin® were switched to Omnitrope® liquid for the subsequent 6 months. In part 3, patients in both groups received Omnitrope®liquid for a period up to 69 months. Results: The development of the 4 auxological parameters (height, height SD score, height velocity and height velocity SD score) and IGF-1 and IGFBP-3 levels were comparable between both groups of patients and confirmed the well-known growth response of GHD children to recombinant human GH treatment. Omnitrope® was well tolerated and safe over 7 years of treatment. Conclusion: The clinical comparability between Omnitrope® and Genotropin® was demonstrated within 9 months of treatment. Long-term safety and efficacy of 7 years of treatment with Omnitrope® was proven.

BACKGROUND:The Pfizer International Metabolic Database (KIMS), a large pharmacoepidemiologic database for adults with growth hormone deficiency (GHD), was recently analyzed to determine which tests are in use to assess GHD and how well they correlate. At the time of this analysis, a total of 15,724 tests had been reported to KIMS. The most frequently used is the insulin tolerance test (ITT), followed in order by the arginine stimulation test (AST), the glucagon stimulation test (GST) and the GH-releasing hormone+arginine (GHRH+arg) test. The ITT correlated with both the AST and the GST, but not with the GHRH+arg.CONCLUSIONS:For the AST and GST, use of a diagnostic threshold of 3 mug/l does not attenuate the effects of severe GHD.

We report 24-month interim results of two multicenter phase III studies in previously untreated children with growth failure secondary to GH deficiency (GHD) that were paramount to the development of a new recombinant human GH (rhGH, somatropin), approved as the first ‘biosimilar’ in Europe. Study 1 consisted of 3 parts performed in 89 children. The objective was to compare efficacy and safety of the lyophilized formulation of the new somatropin [Somatropin Powder (Sandoz)] with a licensed reference rhGH preparation and the liquid formulation of the new somatropin [Somatropin Solution (Sandoz)] and to assess long-term efficacy and safety of this ready-to-use Somatropin Solution. Study 2 was performed in 51 children and designed to demonstrate efficacy and safety of Somatropin Powder and to confirm its low immunogenic potential; rhGH was given sc at a daily dose of 0.03 mg/kg. Primary [body height, height SD score (HSDS), height velocity, and height velocity (HV) SD score (HVSDS)] and secondary [IGF-I and IGF binding protein 3 (IGFBP-3)] efficacy end-points and safety parameters were assessed regularly. In study 1, all treatments showed comparable increases in growth. The baseline-adjusted difference between Somatropin Powder and the reference rhGH product in mean HV was −0.20 cm/yr (95% confidence interval (CI) [−1.34;0.94]) and in mean HVSDS was 0.76 (95% CI [−0.57;2.10]) after 9 months. These very small differences demonstrate comparable therapeutic efficacy between the two treatments. The results of study 2 were consistent with those seen in study 1. Equivalent therapeutic efficacy and clinical comparability in terms of safety and immunogenicity between Somatropin Powder and the reference rhGH product and between Somatropin Powder and Somatropin Solution was demonstrated. The safety and immunogenicity profiles were similar and as expected from experience with rhGH preparations.

The main aim of sex steroid replacement during induction of puberty is to obtain a balance between healthy psychological and somatic development and optimal final height and peak bone mass (PBM). At present, the age at which it is considered appropriate to begin inducing puberty is younger than it was in the past. This trend aims for optimisation of prepubertal and pubertal growth through earlier onset of growth hormone (GH) therapy and administration of higher doses during puberty as necessary. Adequate initiation of puberty should ensure not only optimal final height and psychological balance, but also normal body proportions, appropriate bone formation and preservation of fertility for children with GH and gonadotropin deficiencies.

Authors made a comparison between 167 suffers from Scheuermann's disease (SD), 70 adolescence idiopathic scoliosis (AIS) and 132 age, sex, height, weight, pubertal developmental stages (Tanner stages) matched controls. The height percentile in 130 cases was also determined. The bone mineral density (BMD) was measured by pQCT on the non dominate sided radial bone. The alkaline phosphatase (AP) level increased at the beginning of puberty and in the puberty in SD. In SD the trabecular Z-score of BMD was significantly decreased in Tanner stage 1 to 4 in both boys and girls. It was not found any significance difference, however, in Tanner stage 5, while in AIS girl no significance decrease of BMD was found. In SD good correlation could be demonstrated between increase in AP and decrease in trabecular Z score r = 0.2, while did not correlate with height percentile. The AP level's increase, and radiomorphometric data of SD severity (intervertebral space narrowing and antero-posterior diameter increase of vertebral body) shows a significant correlation with decreased trabecular Z-score in the period of prepuberty.

There are many publications about the relationship between bone mineralization and effects of thyroid hormones, especially in adults, and they have fairly conflicting conclusions. The authors present their BMD results obtained from 105 children and adolescents with thyroid diseases. In general, normal values were measured in the 46 patients with congenital hypothyroidism replaced with L-thyroxine for a number of years. Every Z-score value was found within the normal range in the 18 cases with juvenile chronic lymphocytic thyroiditis, and the 12 patients with simple goitre treated with L-thyroxine. However, definite osteopenia was detected in a few patients with Graves' disease, and the BMD values were in the negative zone in the overwhelming majority of cases. This deficiency proved to be reversible during the antithyroid therapy, but in general the tempo of the improvement is slow and the influencing main factors are not known.

The authors' original observation on the elevated osteocalcin level in Scheurmann's disease (SD) was presented at the first workshop on pediatric osteology. The aim of this work is to reexamine Willner's results (1976) on "growth hormone and somatomedine A in girls with adolescent idiopathic scoliosis (AIS)" the results suggest higher GH secretion in these patients compared to healthy females. Forty-four children and adolescents (average age 13.5 years, between 5 and 17 years) were recruited for hormone studies (24 children in AIS, 20 in SD). Their height, weight, bone age, Tanner staging (for puberty development), Cobb degree (Cd) (for progression of scoliosis), basal GH and IGF-I (44 children) were measured. Normal height was found in Tanner stage 5 but height was accelerated in Tanner stage 1-3 according to an average of the 80th percentile, Bone age was also advanced in 64% of AIS patients, but retarded by 1 year in 76% of SD cases. All the basal GH and/or IGF-I levels increased in 10 out of the 44 patients. Significant correlation was found between the Cd progression per month [1] and rise of hormone levels (1.5 vs. 0.5 Cd). The authors' results confirm the importance of the GH-IGF-I axis in AIS and SD, with AIS suggesting that these parameters may indicate the progressive trend of scoliosis.

A pituitary adenoma was transsphenoidally removed from a 4.5-year-old girl suffering from gigantism. Prior to the operation both the growth hormone (GH) and the prolactin (PRL) levels in the serum were elevated. By light microscopy the tumor appeared to be an acidophilic adenoma. Two distinct cell types, the densely granulated and the sparsely granulated cells, could be distinguished by electron microscopy. Double immunolabeling revealed the presence of GH alone in some densely granulated cells and PRL alone in some sparsely granulated cells, as well as GH and PRL co-localized in both of the morphologically distinguished cell types. Both cell types were identified in the monolayer and the suspension cultures by electron microscopy. GH and PRL concentrations in the culture media were measured by radioimmunoassay. The basal secretion of growth hormone was almost uniform during the 3-week cell culture period. GH and PRL release was significantly inhibited by bromocriptine. Our studies revealed a bimorphous and bihormonal mixed adenoma in childhood.

Serum C-peptide and Immunoreactive Insulin (IRI) level was measured during per os glucose tolerance test as well as fasting specific insulin binding percentage and capacity of erythrocytes in hypothalamic obesity and in obese children due to hypercalorization, and was compared with ideal-weight controls. Integral values of curves (sigma) and sigma C-peptide/sigma IRI ratios were calculated. In 4 cases fasting C-peptide content was substantially increased as compared to the other groups. The data suggest that hyperinsulinism in diencephalic obesity is primary. The ratio of the two peptides was normal or increased: insulin binding % of erythrocytes corresponded to that of the control group, which explains in these cases normal or favourable glucose metabolism. It is thought that in obese children high fasting C-peptide levels with an adequate clinical picture can indicate the functional examination of the hypothalamic-pituitary system. Sigma C-peptide/sigma IRI ratio differing from normal indirectly shows the changes of receptor function.

The experience obtained in one of two Hungarian screening centers for congenital hypothyroidism (CH) is reported which is based on the examinations of dried blood samples tested with the aid of TSH-RIA developed in this laboratory. During the past six years (1982-88) and CH was diagnosed in 54 cases out of a total of 306,265 newborns (prevalence: 1:5470). The recall rate because of increased TSH values was 0.28-0.29% within the last two years. The triple of this had to repeat for technical reasons (imperfect samples, borderline results). Within the last year the treatment of diagnosed infants with L-thyroxine was started at the average age of 13 days. The history of three missed cases is briefly reported. Four out of 54 patients (7.4%) died in infancy. Since the pituitary sensitivity for TSH suppression by replacement doses of L-thyroxine appeared to be decreased in several cases, the control of free thyroxine levels is preferred to avoid the clinical hypo- or hyperthyroidism. The shortening of the present three days TSH RIA method, the extension of systematic examination of TSH binding antibodies and psychological studies are in progress.