Echocardiographic dimensions and function in adults with primary growth hormone resistance (Laron syndrome)

Patients with primary growth hormone (GH) resistance-Laron Syndrome (LS)-have no GH signal transmission, and thus, no generation of circulating insulin-like growth factor-I (IGF-I), and should serve as a unique model to explore the controversies concerning the longterm effect of GH/IGF-I deficiency on cardiac dimension and function. We assessed 8 patients with LS (4 men, 4 women) with a mean (+/- SD) age of 38+/-7 years (range 22 to 45), and 8 aged-matched controls (4 men, 4 women) with a mean age of 38+/-9 years (range 18 to 47) by echocardiography at rest, following exercise, and during dobutamine administration. Left ventricular (LV) septum, posterior wall, and end-diastolic diameter were significantly reduced in untreated patients with LS compared with the control group (p<0.05 for all). Systolic Doppler-derived parameters, including LV stroke volume, stroke index, cardiac output, and cardiac index, were significantly lower (p<0.05 for all) than in the control subjects, whereas LV diastolic Doppler parameters, including mitral valve waves E, A, E/A ratio, and E deceleration time, were similar in both groups. LV ejection fraction at rest as well as the stress-induced increment of the LV ejection fraction were similar in both groups. Our results show that untreated patients with long-term IGF-I deficiency have reduced cardiac dimensions and output but normal LV ejection fraction at rest and LV contractile reserve following stress.     

Reduced exercise capacity in untreated adults with primary growth hormone resistance (Laron syndrome)

OBJECTIVE: Primary IGF-I deficiency (Laron syndrome, LS) may decrease exercise capacity as a result of a lack of an IGF-I effect on heart, peripheral muscle or lung structure and/or function. METHODS: Eight patients (six females) who had never received treatment with IGF-I, with mean age of 36 +/- 10 (SD) years (range 21-48), weight 47 +/- 9 kg (31-61), height 126 +/- 12 cm (112-140) and body mass index of 29 +/- 4 kg/m2 (24-34), and 12 age-matched controls, underwent lung function tests and incremental cycling to the limit of tolerance (CPX, MedGraphics). Predicted values for the patients were derived from adult equations based on height. RESULTS: In LS patients, lung function was near normal; vital capacity was 84 +/- 11% of expected (66-103). Peak exercise O2-uptake and the anaerobic threshold were reduced, 57 +/- 20% of predicted and 33 +/- 9% of predicted peak (P = 0.005 vs. controls), despite normal mean exercise breathing reserve. All parameters were normal in the controls. CONCLUSION: Exercise capacity in untreated adults with LS is significantly reduced. The limitation for most patients was not ventilatory but resulted either from low cardiac output and/or from dysfunction of the peripheral muscles. However, the relative contribution of each of these elements and/or the role of poor fitness needs further study.     

Craniofacial and brain abnormalities in Laron syndrome (primary growth hormone insensitivity)

OBJECTIVE: To investigate abnormalities in the craniofacial structures and in the brain in patients with Laron syndrome. DESIGN: Eleven patients with classical Laron syndrome, nine untreated adults aged 36-68 years and two children aged 4 and 9 years (the latter treated by IGF-I), were studied. METHODS: Magnetic resonance images of the brain were obtained in all the patients. One patient also underwent computed tomography. The maximal diameter of the maxillary and frontal sinuses was measured and compared with reference values, the size of the sphenoid sinus was evaluated in relation to the sella, and the mastoids were evaluated qualitatively (small or normal). The brain was evaluated for congenital anomalies and parenchymal lesions. RESULTS: In the adult untreated patients, the paranasal sinuses and mastoids were small; in six patients, the bone marrow in the base of the skull was not mature. The diploe of the calvaria was thin. On computed tomography in one adult patient, the sutures were still open. A minimal or mild degree of diffuse brain parenchymal loss was seen in ten patients. One patient demonstrated a lacunar infarct and another periventricular high signals on T2-weighted images. Two patients had cerebellar atrophy. CONCLUSIONS: The present study has demonstrated the important role IGF-I plays in the development of the brain and bony structures of the cranium.     

Receptor-active growth hormone in Laron dwarfism.

The hepatic radioreceptor assay for hGH has been applied to the detection of hGH in the sera of patients with high growth hormone dwarfism (Laron dwarfism). Substantial quantities of receptor-active hGH were found in the sera of all 7 patients studied. In one patient, arginine infusion elicited a prompt increase in both immunoactive and receptor-active hGH. These observations suggest that circulating hGH in Laron dwarfism is biologically active and support the concept that the disease may be caused by a generalized defect in hGH receptors.     

A novel growth hormone receptor gene deletion mutation in a patient with primary growth hormone insensitivity syndrome (Laron syndrome).

OBJECTIVE: Growth hormone (GH) insensitivity syndrome (Laron syndrome) is known to be caused by genetic disorders of the GH-IGF-1 axis. Although many mutations in the GH receptor have been identified, there have been only a few reports of deletions of the GH receptor gene. DESIGN: A Japanese adult female patient with Laron syndrome was subjected to chromosome analysis with basic G-banding and also with a high accuracy technique. Each exon of the GH receptor gene was amplified by means of PCR. Since this patient was diagnosed with osteoporosis, the effects of alendronate on bone mineral density (BMD) were also examined. RESULTS: The chromosome analysis with the high accuracy technique demonstrated a large deletion of the short arm in one allele of chromosome 5 from p11 to p13.1 [46, XX, del (5) (p11-p13.1)]. PCR amplification of exons of the GH receptor gene showed that only exons 2 and 3 were amplified. Low-dose IGF-1 administration (30microg/kg body weight) failed to increase her BMD, whereas alendronate administration resulted in an increase associated with a decrease in urinary deoxypyridinoline (DPD) and serum osteocalcin concentrations. CONCLUSIONS: The GH receptor gene of the patient was shown to lack exons 4-10. To the best of our knowledge, this is the third case report of Laron syndrome with large GH receptor deletion. Alendronate was effective for the enhancement of BMD.     

Growth Hormone Insensitivity (Laron Syndrome)

Reviews in Endocrine and Metabolic Disorders -     

Acquired growth hormone resistance in adults

Acquired growth hormone resistance (AGHR) may be defined as the combination of a raised serum growth hormone (GH) concentration, low serum insulin-like growth factor-1 (IGF-1) concentration and a reduced anabolic response to exogenous GH. A wide range of conditions exhibit the syndrome to a variable degree, including sepsis, trauma, burns, AIDS, cancer, and renal or liver failure. The primary defect seems to be a reduction in IGF-1 concentration which then leads to increased GH concentration by a loss of negative feedback. It is not clear whether IGF-1 concentration falls because of decreased production or increased clearance from the circulation, or both. Treatment to reverse the biochemical defect by restoring IGF-1 levels, either by the administration of GH or IGF-1, has resulted in improvements in a wide range of metabolic parameters and, more recently, to definite clinical benefit in well-defined groups, such as patients with AIDS. These results cannot be extrapolated to other groups with AGHR as a recent unpublished report suggested increased mortality in critically ill patients treated with GH. Research needs to focus on the molecular basis of AGHR if we are to develop therapies for catabolism.     

Absence of serum growth hormone binding protein in patients with growth hormone receptor deficiency (Laron dwarfism).

It has recently been recognized that human serum contains a protein that specifically binds human growth hormone (hGH). This protein has the same restricted specificity for hGH as the membrane-bound GH receptor. To determine whether the GH-binding protein is a derivative of, or otherwise related to, the GH receptor, we have examined the serum of three patients with Laron-type dwarfism, a condition in which GH refractoriness has been attributed to a defect in the GH receptor. The binding of 125I-labeled hGH incubated with serum has been measured after gel filtration of the serum through an Ultrogel AcA 44 minicolumn. Nonspecific binding was determined when 125I-hGH was incubated with serum in the presence of an excess of GH. Results are expressed as percent of specifically bound 125I-hGH and as specific binding relative to that of a reference serum after correction is made for endogenous GH. The mean +/- SEM of specific binding of sera from eight normal adults (26-46 years of age) was 21.6 +/- 0.45%, and the relative specific binding was 101.1 +/- 8.6%. Sera from 11 normal children had lower specific binding of 12.5 +/- 1.95% and relative specific binding of 56.6 +/- 9.1%. Sera from three children with Laron-type dwarfism lacked any demonstrable GH binding, whereas sera from 10 other children with other types of nonpituitary short stature had normal relative specific binding. We suggest that the serum GH-binding protein is a soluble derivative of the GH receptor. Measurement of the serum GH-binding protein may permit recognition of other abnormalities of the GH receptor.     

Effect of alendronate on bone mineral density in adult patients with Laron syndrome (primary growth hormone insensitivity).

Severe short stature resulting from a deficiency in insulin-like growth factor-I (IGF-I) is a prominent feature of Laron syndrome (LS). Whether patients with LS are osteopenic or not, and whether they need treatment with bisphosphonates, remains uncertain. The aim of this study was to investigate the action of alendronate on the IGF-I-deficient bones of adult patients with LS and osteoporosis, as determined by dual X-ray absorptiometry . Seven patients (5 women and 2 men) of mean age 40.8+/-7.6 years and mean bone mass density (BMD) 0.843+/-0.06 g/cm2 (T score -2.9+/-0.5) at the lumbar spine and 0.734+/-0.11 g/cm2 (T score -2.2+/-0.9) at the femoral neck were treated with alendronate 70 mg once/weekly over a 12-month period. Treatment led to an increase of 5.3% in BMD (p=0.038) at the femoral neck. There was a similar trend at the lumbar spine, but the difference was not statistically significant (2.3%, p=0.34). Mean total alkaline phosphatase decreased by 14% from normal range at baseline (p=0.007). Urinary deoxypyridinoline levels, which were elevated at baseline (10+/-2.3 nM/mMcre), showed a nonsignificant change during treatment. Our study suggests that treatment with alendronate may have positive effects in patients with LS and low BMD on dual X-ray absorptiometry.     

The effect of recombinant human insulin-like growth factor-I treatment on growth hormone secretion in two subjects with growth hormone insensitivity (Laron syndrome)

OBJECTIVE Growth hormone (GH) secretion Is increased in conditions of GH insensitivity such as Laron syndrome, with elevation of both basal and peak levels. We have studied the effect of recombinant IGF-I therapy on the pattern of GH secretion in two subjects with GH insensitivity. SUBJECTS Two pubertal subjects with GH insensitivity (female, 16.4 years, breast stage 3; male 13.6 years, genital stage 2) were investigated after 6 months of IGF-I therapy (120 μg/kg twice daily s.c. at 0800 and 1900 h). GH profiles taken before the start of IGF-I therapy, when both subjects were prepubertal (aged 14 0 and 11 5 years respectively), were used for comparison. METHODS GH profiles were performed with blood samples taken every 20 minutes between 2000 and 0800 h from an indwelling cannula. MEASUREMENTS Serum samples were assayed for GH by immunoradiometric assay and IGF-I, IGFBP-1 and insulin by radioimmunoassay. RESULTS Before IGF-I therapy, GH profile studies demonstrated pulsatile GH secretion. Basal GH was elevated with no value falling below the limit of detection of the assay and an increase in peak levels (maximum 203 and 206 μ/I at 0000 h and 0020 h respectively). After 6 months IGF-I therapy, the GH profiles were significantly different. With the onset of puberty a further increase in GH secretion would have been expected; nevertheless, following administration of IGF-I at 1900 h, GH secretion decreased with a reduction in mean overnight GH levels from 65 to 33 μ/l and 53 to 11 μ/l respectively. GH pulsatility was also suppressed in the two subjects, for the first 3.5 and 6 hours overnight respectively. Pulsatile GH secretion then returned with peak levels reaching 130 and 63 μ/l respectively. Prior to therapy IGF-I levels were at the lower limit of assay detection. On IGF-I therapy serum IGF-I levels reached a peak within 3 hours (298 and 438 μg/l) coinciding with the suppression of GH secretion. IGF-I levels fell rapidly overnight to 92 and 101 μg/l at 0800 h prior to the next injection. The fall in serum IGF-I coincided with the return of GH secretion. IGFBP-1 levels increased overnight both before and during IGF-I therapy, rising from 24 to 83 and 22 to 110 μg/l before therapy and 13 to 60 and 13 to 71 μg/l during therapy. This rise in IGFBP-1 appeared to be inversely related to the fall in serum insulin levels overnight and appeared not to be affected by IGF-I therapy. CONCLUSION GH secretion is suppressed by exogenous IGF-I therapy in GH insensitive subjects. The failure to maintain high serum IGF-I levels overnight, presumably due to a persisting defect in serum IGFBP-3 levels, was associated with an early return of GH secretion. These findings may have implications for the dose and regimen of IGF-I therapy in subjects with growth hormone insensitivity.     

Growth hormone receptor gene mutations in two Italian patients with Laron Syndrome

Laron Syndrome (LS) represents a condition characterized by GH insensitivity caused by molecular defects in the GH receptor (GHR) gene or in the post-receptor signalling pathway. We report the molecular characterization of two unrelated Italian girls from Sicily diagnosed with LS. The DNA sequencing of the GHR gene revealed the presence of different nonsense mutations, occurring in the same background haplotype. The molecular defects occurred in the extracellular domain of the GHR leading to a premature termination signal and to a truncated non-functional receptor. In one patient, a homozygous G to T transversion, in exon 6, led to the mutation GAA to TAA at codon 180 (E180X), while in the second patient a homozygous C to T transition in exon 7 was detected, causing the CGA to TAA substitution at codon 217 (R217X). Both probands presented the polymorphisms Gly168Gly and Ile544Leu in a homozygous state in exons 6 and 10, respectively. The E180X represents a novel defect of the GHR gene, while the R217X mutation has been previously reported in several patients from different ethnic backgrounds but all from countries located in the Mediterranean and Middle Eastern region.     

Mice severely deficient in growth hormone have normal hematopoiesis

OBJECTIVE: Many studies suggest that growth hormone (GH) is important for hematopoietic stem cell (HSC) function. The objective of this study is to determine if the genetic absence of GH reduces hematopoietic function and recovery, by testing various points in hematopoiesis, from numbers and functional abilities of primitive stem cells to the maintenance of normal numbers of differentiated cells. MATERIALS AND METHODS: Analyses were conducted on blood and bone marrow to compare GH-deficient C57BL/6J-Ghrhr(lit) / Ghrhr(lit) (lit/lit) mice with their normal (lit/+) littermates. Flow cytometric analysis was used to measure numbers of HSC and progenitor cells based on antigenic markers. Spleen colony-forming units (CFU-S) were examined to determine function of common myeloid progenitor (CMP) cells. Competitive repopulation assays were conducted to test whether normally functional HSCs are produced and supported in the lit/lit hematopoietic environment. RESULTS: The lit/lit mutant mice produced HSC and progenitor cells at least as well as their lit/+ control littermates. In CFU-S assays, the CMP from the lit/lit mice functioned as well as those from the lit/+ controls. Marrow cells from lit/lit mice repopulated irradiated recipients long-term better than did marrow cells from C57BL/6J(+/+) controls; thus, HSC produced in the absence of GH can replenish irradiated recipients. When lit/lit mice were used as irradiated recipients, they supported HSC function as well as lit/+ control recipients did; thus, the lit/lit hematopoietic environment can support normal hematopoiesis.     

Low-dose growth hormone administration mobilizes endothelial progenitor cells in healthy adults.

OBJECTIVE: Endothelial progenitor cells (EPCs) mobilize from the bone marrow secondary to a stimulus and home to sites of injury, where they differentiate into endothelial cells and contribute to the repair of damaged vasculature. We hypothesized that growth hormone (GH) administration would increase the number of circulating EPCs in adults and thereby represent a mechanism to enhance vascular health. DESIGN: A prospective trial of low-dose GH (0.03mg/kg/week for 4 weeks followed by 0.06mg/kg/week for a maximum of four additional weeks) in 10 healthy adults (6 males and 4 females; mean age 37 years, range 26-65). Primary outcomes measured included the number of circulating EPCs as assessed by colony-forming unit (CFU) assay and flow cytometry. Secondary outcomes included plasma measurements of known mediators of EPC mobilization and indices of nitric oxide (NO). Outcomes were measured at baseline and at study completion. RESULTS: GH administration increased serum IGF-1 (143ng/mL [IQR 121-164] to 222 [IQR 194-244]; P=0.005). The increase in early-outgrowth EPCs (13 CFU per high-power field [IQR 6-24] to 19 [IQR 13-40]; P=0.005) correlated with the peak IGF-1 after adjustment for the baseline number of early-outgrowth EPCs (r=0.719 [95% CI 0.06, 0.93]; P=0.027). The number of late-outgrowth EPCs as well as CD34+, VEGFR2(KDR)+, and AC133+ cells did not significantly change. Other mediators of EPC mobilization were stable while plasma nitrite trended upwards (1.3micromol/L [IQR 0-2.5] to 3.7 [IQR 2.2-8.9]; P=0.052). CONCLUSIONS: GH administration selectively augments the early-outgrowth EPC population in healthy individuals. These findings both support GH replacement in the setting of GH deficiency to maintain vascular integrity and have implications for the use of GH in future regenerative cell-based therapies. Furthermore, the decrease in EPCs observed with aging may in part be explained by the declining somatotropic axis, and thereby contribute to cardiovascular senescence.     

Effects of 17 months treatment using recombinant insulin-like growth factor-I in two children with growth hormone insensitivity (Laron) syndrome

OBJECTIVE With the availability of recombinant insulin-like growth factor-I (recIGF-I), it was possible to study whether this peptide could promote growth without noticeable side-effects in patients with growth hormone insensitivity syndrome (Laron syndrome). We report data obtained before and during 17 months treatment using recIGF-I, 40 μg/kg s.c. twice a day, in two Lebanese siblings. PATIENTS The boy and the girl showed very short stature (-6.8 and ?6.1 SDS), high GH (79 and 147 IU/I), low plasma IGF-I (0.12 and 0.18 U/ml) and undetectable GH-binding protein. Height velocities were 4.3 and 3.8 cm/year before treatment which started at 8.4 and 6.8 years of age, respectively. RESULTS After 1–8 weeks of therapy, biological evidence of IGF-I effect was obtained from reduction in serum GH and increase in procollagen-I. During the first 6 months of treatment, height velocity increased to 7.8 and 8.4 cm/year without any clinical evidence of side-effects. Between 6 and 12 months, growth response decreased to 6.6 and 6.3 cm/year. Between 12 and 17 months, growth rate returned to pretreatment values. Changes in bone mineral density paralleled growth response and bone maturation increased by 1 5 and 2 0 years during the first 12 months of treatment. Daily assessment of blood sugar showed asymptomatic low values (< 2 8 mM/I) in 11/730 and 22/730 measurements in the boy and the girl, respectively. CONCLUSIONS Treatment of two patients with growth hormone insensitivity syndrome using 40 μ g/kg of IGF-I twice a day resulted in increased linear bone growth and bone mineralization as well as increased bone maturation without remarkable adverse events. After 1 year of therapy, growth response could no longer be observed in these two patients.     

Pituitary size in patients with Laron syndrome (primary GH insensitivity)

OBJECTIVE: The purpose of the present study was to investigate whether lifelong secretion of high levels of GH, characteristic of Laron syndrome, leads to an increase in the size of the pituitary gland. METHODS: Eleven patients (six females, five males) with Laron syndrome underwent magnetic resonance imaging of the pituitary region with a system operating at 0.5 T. There were nine adults aged 36-68 Years and two children, a 4-Year-old boy and a 9-Year-old girl. The latter patient had been treated with IGF-I (150-180 mg/kg per day) since the age of 3 Years; all the other patients were untreated. The height of the adenohypophysis was measured on the sagittal images and compared with reference values for age and sex. RESULTS: The height of the adenohypophysis was within the normal range for age and gender in all patients, except for one male, who had a small gland. No congenital anomalies of the pituitary-hypothalamic region were detected. CONCLUSION: Despite the lifelong high levels of GH, no pituitary hypertrophy was detected. The anatomy of the pituitary-hypothalamic region in Laron syndrome is normal.     

Regular fluctuations in growth hormone (GH) release determine normal human growth.

Growth hormone (GH) is the principal hormone associated with growth through childhood, but in a normal child the amount of GH secretion does not appear to be critical in the generation of normal growth rates. We have assessed the relationship between growth and urinary GH (uGH) output in a longitudinal study of 29 healthy prepubertal schoolchildren (13 male, 16 female; age 5.7-7.8 years) over 1 year. Height and uGH were measured three times a week. Individual height velocity curves were derived using non-linear regression. Growth was expressed in terms of the total increment over the year (DeltaHt, cm), height velocity standard deviation score (HVSDS) and the average size of individual growth spurts. Urinary GH data (ng) were expressed as a weekly average.Mean uGH did not correlate with stature or growth over the year. However, the coefficient of variation of uGH was correlated with height standard deviation score (HtSDS, r = 0.38, P< 0.05), while the relative constancy of short-term change in uGH (coefficient of incremental change, DeltaINC) was inversely correlated with DeltaHt (r = - 0.44) and HVSDS (r = - 0.42, both P< 0.05) but not with HtSDS. DeltaINC was also inversely correlated with the average size of individual growth spurts derived from the height velocity curves (r = - 0.45, P< 0.05). Using time series analysis to identify rhythms in uGH excretion, a positive correlation was found between the magnitude of rhythms of a period of 2 to 4 weeks and HtSDS (r = 0.40, P< 0.05). These data demonstrate that variability in GH is a more important determinant of normal childhood growth rate than the amount of GH alone. Stature is correlated to the overall variability in GH release, while increment in height and the magnitude of individual growth spurts are influenced by the constancy of the GH profile. This would imply that once the GH dose has been replaced in GH deficiency, optimal growth could only be achieved by varying the pattern of GH administration.     

Long-term growth hormone treatment in growth hormone deficient adults.

Growth hormone treatment in GH-deficient adults has proved beneficial in recent short-term trials, but long-term results have not yet been reported. Thirteen GH-deficient adults (4 females, 9 males; mean (SEM) age 26.4 (1.7) years), who had completed 4 months of GH therapy in a double-blind placebo-controlled cross-over study were followed, for further 16.1 (0.8) months of uninterrupted GH therapy in an open design. A significant mean increase of 1.3 cm in linear height was recorded, whereas body mass index remained unchanged. Mean muscle volume of the thigh, estimated by computerised tomography, increased significantly compared with that of the initial placebo period (p = 0.01), and a slight decrease was recorded in adipose tissue volume of the thigh (p = 0.10) and subscapular skinfold thickness (p = 0.10). Still, the muscle to fat ratio of the thigh was significantly lower compared with that of normal subjects (72.6/27.4 vs 77.9/22.1) (p less than 0.01). The mean isometric strength of the quadriceps muscles increased significantly during long-term GH therapy (p less than 0.01), but remained lower compared with that of normal subjects (1.66 (0.10) vs 2.13 (0.11) Nm/kg body weight). Exercise capacity performed on a bicycle ergometer increased significantly after long-term therapy (p less than 0.05), but still did not reach the values seen in normal subjects (22.5 (3.4) vs 37.4 (4.2) watt.min.kg-1. No adverse reactions were recorded during long-term therapy and hemoglobin A1c remained unchanged. These data suggest that long-term GH replacement therapy in GH-deficient adults has beneficial effects on several physiological features which are subnormal in these patients.