Aviva Silbergeld

Lack of effect of methylphenidate on serum growth hormone (GH), GH-binding protein, and insulin-like growth factor I

The aim of this study was to assess the growth hormone (GH) axis in methylphenidate (MPH)-treated and untreated boys with attention-deficit and hyperactivity disorder (ADHD), by evaluating serum GH, GH-binding protein (GHBP) activity, and insulin-like growth factor I (IGF-I) levels as compared to age-matched normal controls. Blood samples were taken from 42 boys (aged 6-16 years) diagnosed as having ADHD according to DSM-III-R criteria and confirmed by using the Schedule for Affective Disorder and Schizophrenia for school-age children (K[Kiddle]-SADS). A total of 21 patients were treated with MPH (5-20 mg/day; 0.15-0.77 mg/kg/day), on a drug holiday protocol, for 1-36 months, and 21 were drug naive. A total of 46 age-matched normal boys at height and weight within normal range served as controls. No significant differences were detected between the MPH-treated ADHD children, the untreated ADHD children, and the control children on fasting serum GH levels, GHBP activity, or IGF-I levels. Active treatment with MPH, in ADHD children on a drug holiday protocol, does not cause changes in GH axis as manifested by normal values of GH, GHBP, and IGF-I.

GROWTH HORMONE TREATMENT INCREASES CIRCULATING LIPOPROTEIN(A) IN CHILDREN WITH CHRONIC RENAL FAILURE

Cardiovascular disease is the major cause of death in chronic renal failure (CRF) patients managed by dialysis or kidney transplantation. Whilst the use of human growth hormone (hGH) is of established benefit in CRF children particularly in those with short stature, in the present study we assessed in CRF children the effect of hGH treatment on circulating lipoprotein(a) [Lp(a)], a genetically determined cardiovascular risk factor. We studied 15 CRF children treated by dialysis or conventional therapy and after kidney transplantation. Overnight fasting blood samples were collected immediately before and after 6 months hGH treatment. In all but one of the children there was a significant increase in serum Lp(a) over the 6 month treatment period -(+)66.7% over the basal levels (range 14 to 180%). After the hGH treatment, in six children Lp(a) levels were elevated to above 300 mg/l, the cut-off level for increased coronary artery disease (CAD) risk. Concomitantly/children also had an increase in serum levels of IGF-I (+96.4%) and insulin (+85.8%). All children had an accelerated growth velocity during the treatment; there was no effect on serum creatinine. Our study shows that hGH treatment in CRF children, though beneficial in its growth promoting effects, increases the already characteristically high levels of serum Lp(a), a risk factor for CAD, and that serum Lp(a) monitoring during treatment with hGH may be useful in evaluating future cardiovascular risk.

Foot Length Before and During Insulin-like Growth Factor-I Treatment of Children with Laron Syndrome Compared to Human Growth Hormone Treatment of Children with Isolated Growth Hormone Deficiency

OBJECTIVE To compare foot length deficits between patients with Laron syndrome (LS) (primary growth hormone [GH] insensitivity) and congenital isolated GH deficiency (IGHD) and their response to replacement therapy with insulin-like growth factor-I (IGF-I) and hGH, respectively. DESIGN Data for the study were collected from the records of nine children with LS (3 M, 6 F) 7.8 +/- 4.8 years old (mean +/- SD), and nine children with IGHD (3 M, 6 F), 3.8 +/- 3.3 years old. Fifteen non-treated adult patients with LS were also included in the study. METHODS Measurements of foot length were recorded without treatment and monitored during 9 years of treatment in the children and in the untreated adult patients. For statistical analysis the non-parametric Mann-Whitney U test was used. RESULTS With almost similar basal values in growth deficit and pre-treatment growth velocities, the achievements towards norms after 9 years of treatment were greater in the patients with IGHD than in the patients with LS: foot length reached -1.4 +/- 0.8 vs. -3.3 +/- 1.0 SDS (mean +/- SD), and body height -2.2 +/- 1.0 vs. -3.9 +/- 0.5 SDS. The difference between the two groups could be due to the initiation of replacement therapy in the patients with IGHD at a younger age. Adult foot size of untreated patients with LS is small but less retarded than the height deficit. CONCLUSIONS Both IGF-I and hGH are potent growth stimulating hormones of linear growth and acrae as exemplified by foot growth.

Serum insulin-like growth factor-I (IGF-I) levels during long-term IGF-I treatment of children and adults with primary GH resistance (Laron syndrome).

Serum IGF-I levels were measured in 14 patients (9 children and 5 adults) with Laron syndrome (LS) during long-term treatment by IGF-I. Recombinant IGF-I (FK-780, Fujisawa Pharmaceutical Co. Ltd., Japan) was administered once daily subcutaneously before breakfast for 3-5 years to the children and for 9 months to the adults. The initial daily dose was 150 micrograms/kg for children and 120 micrograms/kg for adults. Before initiation of treatment the mean overnight fasting levels of serum IGF-I in the children was 3.2 +/- 0.8 nmol/l (mean +/- SEM), rising to 10 +/- 1.7 nmol/l during long-term treatment even on a dose of 120 micrograms/kg/day. The serum IGF-I levels 4 hours after injection rose from 31.2 +/- 3.5 to 48 +/- 2 nmol/l. In the adult patients, the initial basal IGF-I was 4.1 +/- 0.7 nmol/l, rising to 16.1 +/- 3.84 nmol/l after 8-9 months treatment. Serum IGF-I levels at 4 hours after injection rose in the adult patients from 24.1 +/- 5.8 up to 66.8 +/- 15.4 nmol/l. A progressively increasing half-life during long term exogenous administration of IGF-I to patients with Laron syndrome was demonstrated by following serum IGF-I dynamics after injection. Based on the fact that no antibodies to IGF-I were detected and on findings in previous studies, it is speculated that the increasing serum IGF-I levels during long-term IGF-I treatment are caused by an increase in serum IGFBP-3 induced by chronic IGF-I administration. It is concluded that treatment with IGF-I necessitates regular monitoring of serum IGF-I levels; in patients in whom the age adjusted maximal levels are exceeded, a reduction of the daily IGF-I dose is indicated to avoid undesirable effects.

Serum leptin in obese patients with Laron syndrome before and during IGF-I treatment.

Fifteen patients with primary GH resistance (Laron syndrome, LS) were studied before and during 6 months of daily replacement treatment with IGF-I. The main findings were that patients with LS and normal or high serum GH binding protein (GHBP) were less obese than those with a negative GHBP, and that serum leptin levels varied with body mass as in other types of obesity.

Effect of different serum concentrations of growth hormone-binding protein (GHBP) on the regulation of GH receptor/GHBP gene transcription in a human hepatoma cell line.

Although high-affinity growth hormone (GH)-binding protein (GHBP) seems to mirror tissue GH receptor (GH-R) status and effects GH kinetics, the physiological importance and ultimate biological role of GHBP remain largely unknown and obscure. Therefore, the aims of this study were, first, to test the hypothesis that different serum concentrations of GHBP may regulate GH-R/GHBP gene transcription and, second, to define a new nonradioactive polymerase chain reaction (PCR) method to quantify GH-R/GHBP mRNA levels which was to compare with the RNase protection assay. Sera from patients with Laron-type dwarfism (n = 10) and adult obese patients (n = 7) containing distinct GH and GHBP concentrations were added to human hepatoma cells (HuH 7) cultured in a hormonally-adapted medium. GH-R/GHBP gene expression was studied 3 h after the addition of the sera. The results of the regulated GH-R/GHBP mRNA levels imply a direct impact of GHBP on GH-R/GHBP gene transcription under these circumstances. In conclusion, we set up a nonradioactive quantitative PCR method which enables the measurement and quantification of GH-R/GHBP mRNA. The results were identical with the data obtained using RNase protection assay. In addition, these results provide evidence that GHBP may have some effect on the regulation of the GH-R/GHBP transcription and that it is more than simply a shed or secreted product with extracellular destinations and functions. Our personal view, therefore, is that GHBP is rather an active player than an erratic extracellular domain of a receptor.

Short Term Effect of Intranasal Administration of Hexarelin — A Synthetic Growth Hormone-Releasing Peptide. Preliminary Communication

Twice or three times daily intranasal administration of the hexapeptide hexarelin for 7 days to children with short stature and normal growth hormone (GH) secretion evoked a significant rise in serum levels of insulin-like growth factor-1 (IGF-1) and alkaline phosphatase. There was also a significant, within normal limits, rise of thyroid stimulating hormone (TSH) without evidence of thyroxine suppression.

Girls with Laron syndrome having positive growth hormone binding protein (GHBP) are less retarded in height than those lacking GHBP.

The cloning of the growth hormone receptor (GHR) and the finding that its extracellular domain (ECD) is identical in structure to the high-affinity serum GHBP /l/, a molecule derived from membrane-bound proteins 111, justified the assessment of serum GHBP activity as a means of identifying patients having a molecular defect in the gene for the GHR 131. Laron syndrome (LS) is characterized by GH resistance due to defects in the GHR or post-receptor pathways, leading to a deficiency in insulin-like growth factor I (IGF-I) 14,51. In the majority of affected individuals, exon deletions or point mutations are confined to the ECD of the GHR 161, a finding consistent with the lack of serum GHBP activity found in these patients /7/. Recently, an increasing number of patients with LS who have normal /8,9/ GHBP levels have been described. In our cohort, three GHBP-positive siblings had a defect in the post receptor pathway /10/, and elevated GHBP activity was found in two cousins with a splice site mutation affecting the intracellular domain of the GHR / l l / . Extremely high GHBP levels (30-fold that of an adult) in a girl with LS I Ml appear to be caused by a point mutation on intron 7, leading to skipping of exon 8, a region encoding the transmembranal domain. Despite the great variety of mutations of the GHR in LS (genotype), the clinical and biochemical abnormalities (phenotype) seem remarkably similar /5,13/. Nevertheless, when comparing GHBP-

Hand size and growth in untreated and IGF-I treated patients with Laron syndrome.

UNLABELLED We have previously reported on the linear growth, growth of the head circumference and foot length in untreated and IGF-I treated patients with Laron syndrome (LS) (primary GH insensitivity). AIM To assess the size and growth of the hands in patients with LS from early childhood to adult age. PATIENTS Ten IGF-I treated children with LS (4 M, 6 F) and 24 untreated patients (10 M, 14 F) were studied. METHODS Measurements of palm length were made on available standardized hand X-rays from infancy to adult age. The measurements were compared to normal references and SD values were calculated for each measurement. The growth of the hand was compared to the concomitant height of the body. RESULTS Hand SDS in untreated patients with LS decreased with age, from a mean of -2.8 +/- 0.7 (age 1-3 years) to -7.3 +/- 0.8 (age 13-15 years) and to -9.0 +/- 3.9 (age 40-50 years). During 9 years of IGF-I treatment the hand size deficit SDS did not improve in contradistinction to the height SDS which decreased from -6.2 +/- 1.2 to -3.9 +/- 0.5. CONCLUSION Congenital IGF-I deficiency, as in Laron syndrome, profoundly affects the size and growth of the hand as part of its growth retardation characteristics, resulting in acromicria.

OPPOSING EFFECTS OF GROWTH HORMONE AND INSULIN-LIKE GROWTH FACTOR I ON SERUM LIPOPROTEIN(A)

Lipoprotein(a) [Lp(a)] is an atherogenic lowdensity lipoprotein (LDL)-like cholesterol ester-rich plasma lipoprotein particle /1,2/. In addition to an apo(B) molecule, it also contains apo(A) an immunochemically unique apolipoprotein on which most quantification methods are based 111. Although the physiological function of Lp(a) remains unclear, its pathophysiological significance has become increasingly evident. A large body of epidemiological data has shown that elevated Lp(a) levels are associated with increased risk for coronary artery, cerebrovascular and peripheral vascular disease /1-5/. This Lp(a)-related elevated vascular risk is evident in the general population and also in special groups of patients, such as those with diabetes or end-stage renal disease /l/.