U. Heinrich

Growth-stimulating effects of recombinant human growth hormone in children with end-stage renal disease

Because patients with uremia have evidence for growth hormone resistance, we investigated whether this resistance can be overcome by administration of recombinant human growth hormone in supraphysiologic doses in children with severe uremia. Nine stunted children with end-stage renal disease (median age 5.8 years, median bone age 2.7 years) were treated with recombinant human growth hormone, 4 IU/m2/day subcutaneously, for a period of 1 year. Median height velocity was increased from 4.4 cm/yr before therapy to 8.0 cm/yr during treatment. Negative values for height velocity standard deviation scores for chronologic age were improved from a median of -2.6 to +1.5 without advancing bone age more than chronologic age. The growth hormone-insulin-like growth factor I resistance may be explained in part by the increased serum concentration of the high molecular weight insulin-like growth factor binding protein despite normal insulin-like growth factor I serum concentration. Treatment with recombinant human growth hormone improved the ratio between the serum concentrations of insulin-like growth factor I and its binding protein, and normalized the somatomedin bioactivity in the growth cartilage bioassay.

Growth hormone treatment in children with preterminal chronic renal failure: no adverse effect on glomerular filtration rate.

Impaired growth and stunting remains a major therapeutic problem in children with chronic renal failure (CRF). Recombinant human growth hormone (rhGH) treatment may be beneficial, but concern has been raised about possible side-effects, i.e. deterioration of renal function and glucose intolerance. We have treated 10 prepubertal children with CRF (median age 7.5 [1.7–10.0] years) with 4 IU rhGH/m2 per day s.c. over a period of 1 year. Height velocity increased significantly (P<0.03) from basal 4.6 (2.0–14.0) cm/year to 9.7 (6.8–17.6) cm/year. Height velocity SDS for chronological age and for bone age increased in all children from basal median −2.3 to +3.8 (P<0.005). Median glomerular filtration rate (GFR) measured by single injection inulin clearance at onset was 18 (11–66) ml/min per 1.73 m2 and did not change significantly during the treatment year. The loss of GFR as estimated by creatinine clearance was similar during the treatment year (median loss 1.3 ml/min per 1.73 m2) compared to the year before treatment (median loss 3.7 ml/min per 1.73 m2). Serum glucose levels during an oral glucose tolerance test did not change, but fasting as well as stimulated insulin levels increased significantly with time during the study period. It is concluded that the rhGH regimen employed was remarkably effective in improving growth velocity in children with CRF without adversely affecting GFR. Glucose homeostasis remained stable, but at the expense of increased serum insulin levels.

Growth Hormone and Insulin‐Like Growth Factor I in Chronic Renal Failure—Pathophysiology and Rationale for Growth Hormone Treatment

For many years, the problem of how to overcome growth disturbance and short stature in children with chronic renal failure (CRF) remained unsolved. It was originally assumed that the growth hormone (GH) and insulin-like growth factor I (IGF-I) system was not involved in the pathogenesis of uraemic growth failure. Recent investigations have produced new insights which bring us closer to understanding how CRF disrupts the normal growth process. This review emphasizes these recent investigations and gives a rationale for treating children with CRF with recombinant human growth hormone (rhGH).

How safe is the treatment of uraemic children with recombinant human growth hormone

Exogenous growth hormone (GH) treatment for growth failure in uraemic children is effective over a period of up to 3 years. The safety of this new treatment modality is remarkably high, at least for this short period of time. Despite a reduced renal metabolic clearance rate of GH in uraemia, exogenous GH does not accumulate in the serum. In a dose range of 28 units/m2 per week, GH does not impair glucose tolerance but increases serum insulin levels, indicating that euglycaemia is maintained at the expense of increased insulin secretion. No alterations of lipid metabolism, mineral metabolism, pituitary-thyroid axis and blood pressure were observed. The GH-induced glomerular hyperfiltration in healthy subjects seems to be obliterated in chronic renal failure. Accordingly, no accelerated progression of renal disease was observed under GH treatment. However, potential side effects during long-term treatment, especially regarding carbohydrate metabolism and malignancy in children under immunosuppression, are not yet excluded.

Effects of Dehydroepiandrosterone Therapy on Pubic Hair Growth and Psychological Well-Being in Adolescent Girls and Young Women with Central Adrenal Insufficiency : A Double-Blind, Randomized, Placebo-Controlled Phase III Trial

CONTEXT AND OBJECTIVE The efficacy of oral dehydroepiandrosterone (DHEA) in the treatment of atrichia pubis and psychological distress in young females with central adrenal insufficiency is unknown. Our study aimed to evaluate this therapy. DESIGN AND PATIENTS A total of 23 young females (mean age 18 yr, range 13-25) was enrolled in a double-blind randomized placebo-controlled trial. Inclusion criteria were ACTH deficiency plus two or more additional pituitary deficiencies, serum DHEA less than 400 ng/ml, and pubertal stage more than B2. Exclusion criteria were cerebral radiation with more than 30 Gy, tumor remission less than 1 yr, amaurosis, hypothalamic obesity, psychiatric disorders, and unstable hormone medication. INTERVENTION Patients were randomized to placebo (n = 12) or 25 mg HPLC-purified DHEA/d (n = 11) orally for 12 months after stratification into a nontumor (n = 7) and a tumor group (n = 16). MAIN OUTCOME MEASURES Clinical scoring of pubic hair stage was performed at 0, 6, and 12 months (primary endpoint), and psychometrical evaluation (Symptom Check-List-90-R and the Centre for Epidemiological Studies-Depression Scale) at 0 and 12 months (secondary endpoint). Androgen levels and safety parameters were measured at 0, 6, and 12 months; 24-h androgen urinary excretion rates were calculated at 0 and 12 months. RESULTS In the placebo group, four patients dropped out because of recurrence of craniopharyngioma, manifestation of type 1 diabetes, and change of residence (n = 2); in the DHEA group, one patient dropped out because of recurrent anxiety attacks. DHEA substitution resulted in normalization of DHEA sulfate and androstanediol glucuronide morning serum levels 2 h after drug intake (P < 0.006), and of its 24 h urinary metabolite levels (P < 0.0001), placebo had no effect. Morning serum levels of androstenedione increased in the DHEA group (P < 0.02) but did not normalize. The DHEA group exhibited significant progress in pubic hair growth from Tanner stage I-III to II-V (mean: +1.5 stages), whereas the placebo group did not (relative risk 0.138; 95% confidence interval 0.021-0.914; P = 0.0046). Importantly, eight of the 10 Symptom Check-List-90-R scores, including those for depression, anxiety, and interpersonal sensitivity, and the global severity index improved in the DHEA group in comparison to the placebo group (P < 0.048). DHEA was well tolerated. CONCLUSIONS In adolescent girls with central adrenal insufficiency, daily replacement with 25 mg DHEA orally is beneficial: atrichia pubis vanishes, and psychological well-being improves significantly.

Effect of iodine supply on neonatal thyroid volume and TSH.

A cross‐sectional study was performed to prove the correlation between iodine intake and neonatal thyroid volume in a randomized group of 100 mother/newborn pairs. Thyroid volume and iodine excretion were measured by ultrasound and urinary iodine excretion, respectively. Iodine intake and, nutritional and smoking habits were estimated by questionnaire. In 89 mother/child‐pairs the data were complete for all parameters and have been analyzed: 32 mothers substituted with iodine tablets, average dose 175 |ig K‐Iodide/day. Iodine excretion of prenatally iodine‐subsituted newborns increased by 62% whereas neonatal thyroid volume was reduced by 18% compared with the non‐iodine‐supplemented group. Smokers newborns (n = 8) had a thyroid volume 20% larger than that of newborns of non‐smokers. Neonatal TSH‐screening values remained within normal limits.

Ligand Blot Analysis of Insulin-Like Growth Factor-Binding Proteins using Biotinylated Insulin-Like Growth Factor-I

A nonradioactive method for the detection of insulin-like growth factor-binding proteins (IGFBPs) was developed utilizing human recombinant insulin-like growth factor-I (IGF-I) biotinylated with N-hydroxysuccinimido-biotin. Human plasma samples were separated by 15% SDS polyacrylamide gel electrophoresis, and proteins were transferred to nitrocellulose by Western blotting. The nitrocellulose sheets were incubated overnight with IGF-I-biotin at 4°C. The next day streptavidin-peroxidase was added for 1 h, and IGFBPs were visualized by an enhanced chemiluminescence system. Five characteristic bands with molecular weights of 41 and 39 (IGFBP-3), 34 (IGFBP-2), 30 (IGFBP-1) and 24 kD (IGFBP-4) were detected. Binding was specific for IGFs, since unlabeled IGF-I inhibited IGF-I-biotin binding. IGFBP ligand blots with biotinylated IGF-I and 125I-IGF-I yielded comparable results. The suitability of the new assay for clinical purposes was demonstrated by several clinical examples. In summary, a rapid, reliable, nonradioactive assay for qualitative analysis of IGFBPs has been developed.

MRI findings and genotype analysis in patients with childhood onset growth hormone deficiency : Correlation with severity of hypopituitarism

AIM To evaluate the relationship between pituitary size, PIT1 and PROP1 genotype, and the severity of childhood onset growth hormone deficiency (coGHD). PATIENTS Forty-four patients with coGHD (34 M; 9.7 +/- 4.1 years): severe isolated (SI) GHD (n = 14); partial isolated (PI) GHD (n=13); multiple pituitary hormone deficiencies (MPHD) (n=17). RESULTS Pituitary abnormalities were found in 7/14 patients with SIGHD (50%), 16/17 patients with MPHD (94.1%), and no patient with PIGHD. Mean pituitary height (PHT SDS) was significantly lower in MPHD than in SIGHD and PIGHD. Pituitary height SDS and pituitary volume (PV) SDS correlated with IGF-I SDS and stimulated GH peaks in the SIGHD and MPHD groups. No PIT1 mutation was identified. The PROP1 AG deletion (301-302) was present in five related patients with MPHD and more severe phenotype than the other patients with MPHD. CONCLUSIONS Pituitary abnormalities corresponded to the severity of coGHD. Genetic alterations were identified in five related patients with MPHD.

Growth Hormone as a New Treatment Modality for Short Children with Chronic Renal Failure

Recombinant human growth hormone (rhGH) has become a new treatment modality for short children with chronic renal failure (CRF) and after renal transplantation. The rationale for high-dose rhGH treatment is the insensitivity of the uremic organism to GH. As the insensitivity to GH is expressed more in end-stage renal failure than in earlier stages of CRF, patients on dialysis respond less to rhGH. In transplanted children, rhGH can counterbalance the growth-depressing effects of corticosteroids. In prepubertal children, rhGH improves the height standard deviation score by a mean of +2 within 5 years. The effect of rhGH treatment on final height remains to be studied.

Mutational Analysis and Genotype-Phenotype Correlation in Patients with Classic 21-Hydroxylase Deficiency from Transylvania (North-West Romania)

The regional incidence of 21-hydroxylase deficiency, its mutational spectrum and the correlation of genotype and phenotype has been studied by European, American and Latin-American groups. However, little information is known about the molecular background of the disease in patients from Central-Eastern Europe. The present study aimed to genotype a group of patients from Transylvania, the north-western part of Romania, in order to gain some insight into the molecular pattern and the genotype-phenotype correlation of congenital adrenal hyperplasia (CAH) in this region. We genotyped 17 patients with classic 21-hydroxylase deficiency and, whenever available, their parents in order to verify mutational segregation. The patients came from 13 unrelated families. DNA was prepared from peripheral blood leucocytes and four gene fragments were amplified by PCR. The 21-hydroxylase gene (CYP21B) was completely sequenced and analyzed for point mutations or deletions. Percentage distribution of mutations was as follows: 12G--34.6%, deletions and large conversions (del)--19.2%, P30L--15.4%, 1172N--15.4%, P30L+I2G+del8bp (triple mutation)--11.5%, and R356W--3.8%. Mutational percentage distribution compared to other Latin populations is higher for I2G and I172N and lower for deletions, while the P30L mutation was found at a higher rate than in any other analyzed population. Some differences may arise from the low patient number and from ethnic particularities. The incidence of compound heterozygotes in our group was 76.5%. The genotype seemed to correlate fairly well to phenotype, with a general concordance rate of 82.35%. Clear divergence was found in two patients with the simple virilizing form, exhibiting a homozygous status for I2G and del, respectively. This study offers the first information about the molecular pathology of CAH in Romania and should help to improve management and clinical outcome for patients with CAH in Transylvania. Hopefully, it might also be the first step towards exact and accurate prenatal diagnosis in our country.