Victor Martinez

Bone Mineral, Histomorphometry, and Body Composition in Adults with Growth Hormone Receptor Deficiency

Growth hormone (GH) and insulin‐like growth factor I (IGF‐I) deficiencies have been associated with osteopenia in both children and adults. To examine the effects of growth hormone resistance on bone mineral and body composition, we studied 11 adults (mean age 30 years) with growth hormone receptor deficiency (GHRD, Laron syndrome) and 11 age‐ and gender‐matched controls from Southern Ecuador. Bone mineral and body composition were determined by dual‐energy X‐ray absorptiometry. Bone physiology was assessed with biochemical markers of bone turnover and dynamic bone histomorphometry. Bone size and body composition differed markedly between subjects with GHRD and controls. Affected adults were 40 cm shorter than controls, had significantly less lean body mass, and had increased percent body fat. Bone mineral content and density (BMD) at the spine, femoral neck, and whole body were significantly lower in adults with GHRD than in controls. Mean BMD Z scores were −1.5 to −1.6 at all sites in affected women and −2.2 to −2.3 in men with GHRD. Estimated volumetric bone density (BMAD) at the spine and femoral neck, however, was not reduced in GHRD. Spine BMAD was 0.210 ± 0.025 versus 0.177 ± 0.021 for affected women versus controls (p < 0.05) and 0.173 ± 0.018 versus 0.191 ± 0.025 for men with GHRD versus normals (p = 0.31). Urinary pyridinoline concentrations were significantly greater in adults with GHRD than in controls, while type I collagen C‐telopeptide breakdown products and markers of bone formation did not differ. Differences in histomorphometry were limited to a reduction in trabecular connectivity; bone volume and formation rate were similar to controls. These data confirm the importance of the GH/IGF axis in regulating bone size and body composition. The contribution of these peptides to the acquisition and maintenance of bone mineral is less certain since volumetric bone density was preserved despite low levels of IGF‐I and IGFBP‐3 associated with GH resistance.

Heart rate increases in patients with growth hormone receptor deficiency treated with insulin-like growth factor I

Cardiac function was measured in 16 prepubertal Ecuadorean patients with growth hormone receptor deficiency given insulin‐like growth factor I (IGF‐I) during part of a clinical trial. The IGF‐I was given subcutaneously twice daily at a dose of 40 μg/kg on days 1 and 2, 80 μg/kg on days 3 and 4, and 120 μg/kg thereafter. Heart rate was determined at baseline (pretreatment) and on days 1–7 by repeated palpation of the radial artery and at baseline and on days 2, 4 and 7 by continuous portable Holter monitoring. Heart rate measured by both methods rose progressively with increasing doses of IGF‐I. The mean palpated pulse exceeded baseline on each treatment day and was significantly higher on day 5 than day 4 and significantly higher on day 3 than day 2. The mean Holter heart rate was significantly higher on day 4 than on day 2 and significantly higher on day 2 than at baseline. Non‐significant glucose and electrolyte changes did not appear to be associated with the cardiac events.

Long-term effects of insulin-like growth factor (IGF)-I treatment on serum IGFs and IGF binding proteins in adolescent patients with growth hormone receptor deficiency

OBJECTIVE The aim of this investigation was to study the effect of relatively high dose IGF‐I therapy given for several months, on serum levels of IGF‐I, IGF‐II and IGFBP‐3, and on IGF‐I pharmacokinetics In patients with growth hormone insensitivity due to GH receptor dysfunction.

Body changes in adolescent patients with growth hormone receptor deficiency receiving recombinant human insulin-like growth factor I and luteinizing hormone-releasing hormone analogue: Preliminary results

Auxological and body composition changes were studied in three adolescent patients (2 female, 1 male) with growth hormone receptor deficiency (GHRD) given insulin‐like growth factor I (IGF‐I), 120 μg/kg s.c. twice daily, plus a monthly intramuscular injection of 7.5 mg of a luteinizing hormone‐releasing hormone (LHRH) analogue. Preliminary results from the first 12 months of the study show that height velocity was increased compared with the pretreatment values. This increase was probably due to the IGF‐I therapy, as the LHRH analogue would have suppressed gonadotrophins and gonadal steroid production. There was a reduction in percentage body fat, and increases in lean mass and the leamfat ratio, whole body mineral content and body calcium content, even when expressed per kg body weight. There was also a trend towards increased bone mineral density of the whole skeleton, lumbar spine and femoral structures, as well as a maturation of facial features. These preliminary results indicate that concomitant therapy with IGF‐I and an LHRH analogue is safe and efficacious in inducing growth without advancing bone age in patients with GHRD.

Natural history of growth hormone receptor deficiency

Rosenbloom AL, Martinez V, Kranzier JH, Bachrach LK, Rosenfeld RG, Guevara‐Aguirre J. Natural history of growth hormone receptor deficiency. Acta Pædiatr 1999; Suppl 428: 153–6. Stockholm. ISSN 0803–5326

An initial investigation of validation of the Matrix Analogies Test-Expanded Form in Ecuador.

This is a first preliminary study of the validity and reliability of the Matrix Analogies Test–Expanded Form in South America. Participants were 104 Spanish-speaking children between the ages of 5 and 17 years living in Ecuador. Values of Cronbach alpha ranged from .87 to .92 for the 4 groups of items and was .95 for the total score. Raw scores on the MAT increased across ages. Scores of boys did not differ significantly from those of girls. Total test scores correlated significantly with scores on the Raven Standard Progressive Matrices (r = .62, p<.005; r = .82 before controlling for age). A principal factor analysis conducted to provide evidence of the tests construct validity indicated that all four sets of items loaded substantially on one unrotated factor, presumed to be g. In sum, these results suggest that the test is a valid and reliable nonverbal measure of general cognitive ability in this population.

CHANGES IN BODY AND BONE COMPOSITION IN ADOLESCENT GROWTH HORMONE RECEPTOR DEFICIENT (GHRD) PATIENTS RECEIVING rhIGF-I AND A GnRH ANALOG

We observed the body and bone composition changes in two adolescent GHRD patients receiving 120 ug/g of rhIGF-I twice daily sc. A GnRH analog was administered im once monthly. LHRH testing demonstrated a blunted response during therapy. All safety parameters remain within normal ranges. The main characteristics of the individuals at baseline and at a six months evaluation are provided: SUBJECT #1: Age 17 8/12vs18 2/12 y; Height 115.5vs119.6 cm; Weight 28.6vs30.8 kg; BMI 30.0vs21.5; Bone age 13vsl3 y; Body mass 28,604vs30,813 g; Lean mass 14,653v5l6,891 g; Fat mass 13,951vsl3,922 g; Fat percentage 48.8vs45.2 %; L/F ratio 1.05vs1.21; Body Calcium 326vs327; Total BHD 0.72vs0.83; Spine BMD 0.69vs0.70; Femur BMD 0.58vs0.63.SUBJECT #2: Age 18vs18 6/12 y; Height 114.3vs118.4 cm; Weight 22vs21.7 kg; BMI 16.8vsl5.47; Bone age 3.6vs13.6 y; Body mass 22,009vs21,674 g; Lean mass 13,146vs14,830; Fat mass 8,863vs6,844; Fat percentage 40.3vs31.6 %; L/F ratio 1.48vs2.16 g; Body Calcium 224vs240 g; Total BMD 0.7vs0.7 g/cm2; Spine BMD 0.65vs0.55 g/cm2; Femur BMD 0.59vs0.67 g/cm2.Two adolescent patients receiving concomitant therapy with rhIGF-I and a GnRH analog for six months, showed an increase in height without an advancement in bone age. Body compositions changes included a decrease in body mass index, increments in lean mass, decreases in fat mass with associated height L/F ratio. Despite a diminishment in spine BMD in patient #2, bone mineral accretion was observed, with increases in total body mineral an calcium content, as well as in total and regional bone mineral density.

TWO YEARS TREATMENT OF GH RECEPTOR DEFICIENCY (GHRD) WITH IGF-I: COMPARISON OF 2 DOSE LEVELS. † 520

TWO YEARS TREATMENT OF GH RECEPTOR DEFICIENCY (GHRD) WITH IGF-I: COMPARISON OF 2 DOSE LEVELS. † 520