Efficacy and safety of a new ready-to-use recombinant human growth hormone solution.

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 (rh- GH, 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 endpoints 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 influence of prenatal dexamethasone treatment on urinary excretion of adrenocortical steroids in newborns.

UNLABELLED: Congenital adrenal hyperplasia due to 21-hydroxylase deficiency suspected in 14 newborns (5 F, 9 M), was treated prenatally with dexamethasone from weeks 7-9 of gestation. The 24 h urinary excretion of selected adrenocortical steroids derived from fetal and definitive adrenal zones was evaluated in these newborns at the age of 3 9 days. Among 11 babies born healthy, in one of six treated until confirmation of male karyotype in gestational weeks 12-17 and in four of five treated until delivery, suppression of fetal adrenal zone steroids was observed, accompanied additionally in three by a diminished excretion of tetrahydrocortisone. In three babies born affected (2 male, 1 female), excretion of 17alpha-hydroxyprogesterone and 21-deoxycortisol metabolites did not differ from 12 affected, age-matched controls, not treated prenatally. However, some influence on suppression of the fetal adrenal zone metabolite 16alpha-hydroxypregnenolone was observed in two newborns treated until delivery. CONCLUSIONS: Heterogeneity in the fetal adrenal response to maternal dexamethasone treatment was confirmed. Suppression of fetal adrenals, especially within the fetal adrenal zone, can be observed in some babies born healthy until at least 1 week after birth.

Molecular genetic diagnosis of von Hippel-Lindau disease in familial phaeochromocytoma.

Inherited predisposition to phaeochromocytoma is seen in multiple endocrine neoplasia type 2 syndromes, von Hippel-Lindau (VHL) disease, and neuro-fibromatosis type 1. In addition familial phaeochromocytoma alone has been reported. To investigate the genetic basis for familial phaeochromocytoma alone, we screened three affected kindreds for mutations in the RET proto-oncogene and the VHL tumour suppressor gene. We did not detect MEN 2 associated RET mutations in any family, but missense VHL gene mutations (V155L and R238W) were identified in two kindreds with no clinical evidence of VHL disease. Patients with familial, multiple, or early onset phaeochromocytoma should be investigated for germline VHL and RET gene mutations as the molecular diagnosis of multisystem familial cancer syndromes enables appropriate counselling and screening to be provided.

Heterogeneity of urinary steroid profiles in children with adrenocortical tumors.

The excretory patterns of urinary steroids determined by capillary gas chromatography in 11 children (aged 0.8-16.5 years) with adrenocortical tumors were established. In 8 patients the predominant clinical feature was virilization, in 3 others, Cushing's syndrome. In 5 patients (3 carcinoma, 2 adenoma) very high excretion of 3 beta-hydroxy-5-ene steroids was observed. In 2 others (adenomas) only moderately elevated excretion of 11 beta-hydroxyandrosterone was found. In 1 patient (adenoma) pregnanediol dominated in the steroid profile, accompanied by moderately elevated 3 beta-hydroxy-5-ene steroids. Out of 3 Cushingoid patients (1 carcinoma, 2 adenomas), 1 presented an atypical urinary steroid pattern for hypercortisolemia, without 5 alpha-reductase and 11 beta-hydroxysteroid dehydrogenase deficiencies. Neither the urinary steroid pattern nor tumor size alone were reliable indicators of tumor malignancy, as evaluated by a pathological examination and subsequent metastasis-free survival.

Neurological and adrenal dysfunction in the adrenal insufficiency/alacrima/achalasia (3A) syndrome.

Review of 20 patients with glucocorticoid deficiency (three cases also with salt loss) associated with absent tear secretion (19 cases) and achalasia of the cardia (15 cases) revealed neurological abnormalities in 17 including hyper-reflexia, muscle weakness, dysarthria, and ataxia together with impaired intelligence and abnormal autonomic function, particularly postural hypotension. These findings indicate that significant neurological problems are common in this multisystem disorder.

Prenatal brain development: effect of maternal growth hormone administration. Study in albino rats.

Growth hormone (GH) was administered to pregnant rats maintained on a standard diet, and fetal brain growth and placenta weight were examined. The results show that maternal GH administration resulted in an increase of placental weight and fetal brain cell number. A significant positive correlations of placental weight with elevated brain weight of fetus suggests that the maternal growth hormone treatment might influence fetal brain development and it may be mediated by the placenta.