J. Paul Frindik

Effects of Recombinant Human Growth Hormone on Height and Skeletal Maturation in Growth Hormone-Deficient Children with and without Severe Pretreatment Bone Age Delay

The relative effects of growth hormone (GH) on GH-deficient (GHD) children with and without severely delayed skeletal maturation prior to treatment are unclear. Methods: Pre-pubertal GHD children enrolled in the National Cooperative Growth Study were divided into two groups: severe pretreatment BA delay (BA Z-score ≤–2, group 1) and mild to moderate delay (BA Z-score between –2 and 0, group 2). BA Z-scores (BAZ), height Z-scores and predicted adult height (PAH) Z-scores at pubertal onset were determined after initiation of recombinant human GH (rhGH) therapy. Results: Height Z-scores increased from baseline to the start of puberty in both groups (group 1: mean difference of +0.99, males and +1.02, females; group 2: +0.68, males and +0.75, females). Mean BAZ also increased in all group 1 children (+1.62, males and +1.08, females) with no corresponding change in mean BAZ in group 2. PAH Z-scores increased in both groups. There was no evidence of undue advance in BA since mean BAZ remained well below zero in group 1 and was unchanged in group 2. Conclusion: rhGH has a beneficial effect on growth in prepubertal GHD children at all levels of pretreatment BA delay.

Insulin Pump Therapy Started at the Time of Diagnosis: Effects on Glycemic Control and Pancreatic β-Cell Function in Type 1 Diabetes

BACKGROUND In the interest of preserving residual insulin secretory capacity present at the time of diagnosis with type 1 diabetes (T1D), we compared the efficacy of starting insulin pump therapy at diagnosis with standard multiple daily insulin injections (MDIs). METHODS We conducted a prospective, randomized, pilot trial comparing MDI therapy with continuous subcutaneous insulin therapy (pump therapy) in 24 patients, 8-18 years old, with newly diagnosed T1D. Subjects were evaluated at enrollment and 1, 3, 6, 9, and 12 months after initial diagnosis of T1D. Preservation of insulin secretion, measured by mixed-meal-stimulated C-peptide secretion, was compared after 6 and 12 months of treatment. Between-group differences in glycosylated hemoglobin (HbA1c), continuous glucose sensor data, insulin utilization, anthropometric measures, and patient satisfaction with therapy were also compared at multiple time points. RESULTS Initiation of pump therapy within 1 month of diagnosis resulted in consistently higher mixed-meal tolerance test-stimulated C-peptide values at all time points, although these differences were not statistically significant. Nonetheless, improved glycemic control was observed in insulin pump-treated subjects (more time spent with normoglycemia, better mean HbA1c), and pump-treated subjects reported comparatively greater satisfaction with route of treatment administration. CONCLUSIONS Initiation of insulin pump therapy at diagnosis improved glycemic control, was well tolerated, and contributed to improved patient satisfaction with treatment. This study also suggests that earlier use of pump therapy might help to preserve residual β-cell function, although a larger clinical trial would be required to confirm this.

Effect of Metabolic Control on Serum Protein Concentrations in Diabetes

ABSTRACT. Serum albumin, transferrin, transthyretin (prealbumin), and retinol binding protein concentrations were determined in 74 children with insulin‐dependent diabetes mellitus before and after a 10‐day camp session during which blood glucose concentrations were controlled. Initial concentrations of albumin and transferrin in the subjects were not different from those in 21 children and adults without diabetes, and did not change during the study period. Transthyretin and retinol binding protein concentrations were lower in subjects with diabetes than in the control population, and increased from 182±49 mg/l and 42.5±13.4 mg/l to 232±71 mg/l and 47.2±13.5 mg/l, respectively. We observed correlations between the changes in transferrin, transthyretin, and retinol binding protein. Although reductions in glycated albumin and transferrin indicated improvement in blood glucose control, there was no correlation between changes in the glycated markers and the concentrations of serum transport proteins. Thus, serum protein concentrations were influenced by the metabolic control of diabetes, but did not directly reflect blood glucose.

Decreased cyclic guanosine 3',5' monophosphate and guanylate cyclase activity in leprechaunism: evidence for a postreceptor defect.

ABSTRACT. Patients with leprechaunism have hyperinsulinemia and extreme insulin resistance. The mechanism of the insulin resistance has not been delineated. To examine postreceptor events in this unusual syndrome we have assayed the enzyme guanylate cyclase [E.C.4.6.12], which is modulated by insulin, and the concentration of the intracellular messenger cyclic GMP in liver from two children with leprechaunism and extreme insulin resistance. Both patients exhibited down regulation of the red blood cell insulin receptors, but normal insulin receptor binding to Ebstein-Barr transformed IM-9 lymphocytes and monocytes. There was no evidence of antireceptor or antiinsulin antibodies. Activity of liver guanylate cyclase expressed as pmol/mg protein/10 min incubation in the soluble and paniculate fractions were, respectively, Ark-1 133 ± 18, 25 ± 6; Ark-2 129 ± 17, 23 ± 8; control children (six average) 287 ± 16, 55 ± 9. The concentration of cyclic GMP was also 50% lower (0.08 ± 0.03 in Ark-1 and 0.07 ± 0.04 in Ark-2), compared to 0.19 ± 0.07 pmol/mg protein/min in the control livers. There was no change in adenylate cyclase activity in children with leprechaunism versus the control children. These data suggest an abnormality of a postreceptor event in this rare genetic disease. These data, however, do not rule out that in some cases of leprechaunism a receptor binding abnormality may be the primary defect. We speculate that a defect in insulin action distal to plasma membrane receptor binding may be etiological in this unusual syndrome.

Stimulant Medication Use and Response to Growth Hormone Therapy: An NCGS Database Analysis

Background/Aims: Determine (1) frequency of attention-deficit hyperactivity disorder (ADHD) treatment and (2) growth responses in growth hormone (GH)-treated children who are receiving ADHD medication versus GH alone. Methods: Prepubertal children with idiopathic short stature (ISS) or GH deficiency (IGHD) enrolled in Genentech’s National Cooperative Growth Study. ADHD treatment was determined by documentation of psycho-stimulant medication use at enrollment. Results: ADHD medication use increased from 0.8% (7/850) in 1985 to 5.8% (752/12,113) in 2005. First-year GH treatment response for ADHD + IGHD versus IGHD: 8.5 ± 2.0 vs. 9.4 ± 2.6 cm/year, but when adjusted for age, sex, and enrollment body mass index, the difference is clinically insignificant (–0.4 cm/year). First-year growth was similar in all ISS: 8.1 ± 1.9 versus 8.6 ± 2.1 cm/year (ADHD + ISS vs. ISS, an adjusted –0.2-cm/year difference). Conclusion: Increasing numbers of GH-treated children are taking ADHD medications and their growth responses during the first year of GH therapy are similar to those not taking ADHD medications.

Hypothalamic-Hypophyseal Dysgenesis as a Neuroimaging Correlate of Pituitary Hormone Deficiency in Anophthalmia

PURPOSE To document the association of neurohypophyseal dysgenesis with hypopituitarism in a child with primary bilateral anophthalmia. METHODS An infant with bilateral anophthalmia underwent magnetic resonance imaging and endocrinologic evaluation. RESULTS Magnetic resonance imaging showed dysgenesis confined to the hypothalamus and hypophyseal stalk. Endocrinologic testing showed low serum cortisol and pituitary gonadotropin levels. CONCLUSION Magnetic resonance imaging can help predict which children with anophthalmia will have endocrinologic deficiencies.

Managing idiopathic short stature: role of somatropin (rDNA origin) for injection.

Idiopathic short stature (ISS) is a term that describes short stature in children who do not have growth hormone (GH) deficiency and in whom the etiology of the short stature is not identified. Between 1985 and 2000, more than 40 studies were published regarding GH therapy for ISS. Only 12 of these had data to adult height, of which only 4 were controlled studies. A subsequent placebo-controlled study that followed subjects to adult height indicated that there was a gain of 3.7–7.5 cm in height with GH treatment. In 2003, the US Federal Drug Administration (FDA) approved GH for treatment of short stature. Even before FDA approval, patients with ISS made up about 20% of patients in GH databases, which is largely unchanged since FDA approval. There remains some controversy as to whether GH should be used to treat ISS. This controversy centers on the fact that there has been no definitive demonstration that short stature results in a disadvantage or problems with psychological adjustment, and thus, no demonstration that GH therapy results in improvement in quality of life.

Epidermal Growth Factor Concentrations in Growth Hormone-Deficient Children

SummaryUrinary epidermal growth factor/creatinine (EGF/Cr) excretion increases after prolonged therapy with 0.09 to 0.1 mg/kg body weight/week pituitary-derived growth hormone (GH) given 3 times weekly to GH-deficient children. We studied the short term and 1-month effects of 0.3 mg/kg/week of recombinant human growth hormone (rhGH) administered either daily (n=12, 0.043 mg/kg/day) or 3 times weekly (n=7, 0.1 mg/kg/day) on plasma and urinary EGF/Cr excretion in newly diagnosed GH-deficient children (all male, mean age 12.8 ± 3.3 years). Total 24-hour urinary EGF/Cr excretion was greater immediately after a single dose of rhGH 0.1 mg/kg compared with that after a single dose of 0.043 mg/kg (195.6 ± 27.4ng EGF/mg Cr vs 138.9 ± 10.2 ng/mg, respectively, p = 0.04). After 1 month, total 24-hour urinary EGF/Cr excretion of the daily group increased from 138.9 ± 10.2 ng/mg initially to 225.8 ± 38.8 ng/mg (p=0.03), and was virtually identical to that of the 1-month 3-times-weekly 24-hour excretion (216.9 ± 38.7 ng/mg). During a 24-hour period, urinary EGF excretion varied with rhGH dose, time and duration of therapy. Plasma EGF concentrations did not change after 1 month of either daily (1.6 ±0.1 ng/ml vs1.3 ± 0.2 pretreatment) or 3-times-weekly ( 1.3 ± 0.4 ng/ml vs1.1 ± 0.2 pretreatment) rhGH. We conclude that urinary EGF/Cr but not plasma EGF concentrations increase as a function of both rhGH dosage and duration of treatment in children with GH deficiency.

Brain–endocrine connection – for good or ill

Hypothalamic–Pituitary Development. Genetic and Clinical Aspectsedited by Raphael Rappaport and Serge Amselem. Karger, 2001. CHF188.00/k124.76/US

Chronic Low Dose Growth Hormone Treatment Stimulates Both Hypertrophy and Hyperplasia of Remnant Kidneys in Uraemic Rats

163.50 (x + 180 pages) ISBN 3805572395Endocrine disorders were first described as primarily clinical and/or anatomical entities with limited understanding of their pathogenesis. Gradually, as biochemical and neuroradiological techniques became more sophisticated, insight was gained into hormone physiology and regulation. We are now moving into an era characterized by a greater appreciation of the underlying molecular and genetic bases of normal and abnormal endocrine function. This book is a comprehensive update of the etiologies of congenital hypothalamic–pituitary defects and developmental endocrinology (i.e. the relationships of such defects to clinical disorders).The book opens with a succinct introduction to normal hypothalamic–pituitary development, structure and function, concluding with a list of 27 currently known genetic mutations responsible for various abnormalities in development. The remainder of the text details varying aspects of normal and abnormal development and function. Topics include pituitary embryogenesis, the molecular basis of developmental defects, growth hormone releasing receptors, pituitary transcription factors and magnetic resonance imaging. Chapters are also devoted to the morphological and molecular bases of several clinical entities that originate from central nervous system disorders, including septo-optic dysplasia, Kallmann Syndrome, hypothalamic–pituitary hypogonadism and central diabetes insipidus.The authors succeed in their stated goal to ‘integrate complex knowledge from various scientific and medical fields’. However, a clinician in a busy pediatric or endocrine practice might find the information in this text to have little immediate impact on patient care. Rather, the ideas presented here will provide a much greater appreciation of underlying pathogenesis and should stimulate further clinical and laboratory research. This text belongs in the library of academic endocrinologists and others interested in this emerging field.