Moral assessment of growth hormone therapy for children with idiopathic short stature

Subjects ranging in age from 50 to 89 years old, either with or without dementia were studied by both ELISA for anti-human T-cell lymphotropic virus type I (HTLV-I) gag 100-130 antibody and by cranial CT in order to clarify the relationship between HTLV-I infection and dementia. The frequency of anti-HTLV-I antibody was found to be significantly higher in the patients with dementia (24/130, 18.5%) than in those without dementia (11/139, 7.9%) (P=0.0169). Among the various types of dementia, HTLV-I seropositivity was found to be significantly associated with vascular dementia (11/48, 23%) (P=0.0087), but not with Alzheimer type dementia. In addition, HTLV-I seropositivity was also associated with Babinski sign, and the severity of cerebral infarction, ventricular dilatation and periventricular lucency on CT. The presence of HTLV-I therefore appears to be one of the risk factors for vascular dementia in HTLV-I endemic areas.     

Overnight urinary growth hormone in normally growing prepubertal children: effect of urine volume. The one-year growth study

Wear of the polyethylene tibial components is a potential cause of failure in total knee arthroplasty. In addition to pitting, burnishing, and scratching, subtle striations on the bearing portion of the tibial surface have been observed in components retrieved relatively early after implantation. The striated pattern most typically occurred in areas centrally located within the articulating surface. The striations were anteroposterior directed and were identified as local cold flow at the surface. There was a strong correlation between the medial and lateral striated areas, suggesting that these patterns are related to cyclic rolling of the knee. The general characteristics and alignment of the striations could be attributed to the compressive and tractive forces occurring during femoral rollback. For the clinician, these results suggest that kinematics, as well as contact stress, should be considered when evaluating wear of polyethylene components.     

Water and sodium retention during short-term administration of growth hormone to short normal children

OBJECTIVE: To find out whether leptin can attenuate hypometabolic torpor-like states of metabolic rate (MR) in adult lean animals, as it attenuates the morning suppression of thermoregulatory thermogenesis in suckling-age rat pups. DESIGN: Leptin effects on MR and food intake were studied in mice aged 4-7 months, in which a high incidence of exaggerated circadian reductions of MR had been induced by chronic food-restriction and, for comparison, in free-feeding mice. PROTOCOL: Continuous recordings of MR, for a group of seven mice maintained at an ambient temperature of 24 degrees C, while they were repeatedly-with pauses of at least six days-treated for three consecutive days with either recombinant murine leptin (20, 200 or 600 pmol x g(-1) x d[-1]) or saline. RESULTS: Leptin treatment caused dose-dependent 5-15% increases in energy expenditure by moderating the decreases in MR during the circadian minima, without affecting either the MR during the circadian maxima or food intake. Similar treatment of free-feeding mice caused dose-dependent decreases of food intake without changing MR. CONCLUSION: Leptin controls thermoregulatory energy expenditure when food supplies are scarce and changes food intake, rather than energy expenditure, when food is abundant.     

Short- and long-term (final height) data in children with normal variant short stature treated with growth hormone

Seventeen children with normal variant short stature and a predicted height below -2 SDS were treated with growth hormone (GH) six times a week for a period of 5 years. Patients were randomly selected to receive three different doses of GH, group 1 (n = 6) 3 IU/m2 per day, group 2 (n = 6) 4.5 IU/m2 per day and group 3 (n=5) 3 IU/m2 per day in the 1st year and 4.5 IU/m2 per day thereafter. There was a significant increase in height after 1 and 2 years for all patients and for all subgroups. However, this increase was not dependent on GH dose. The decrease in height velocity during the 2nd year was not prevented by the increase of GH dose in group 3. The change of predicted height after 2 years was +0.75 SDS (according to Tanner Whitehouse). Fourteen children have been treated for 4 years and 8 children for 5 years without a further change in height prediction. Nine patients have reached final height which was 2.4 cm (+0.41 SDS) above pretreatment height prediction. Final height was nearly identical to predicted height after 1 year of therapy. CONCLUSION: An increment in height prediction was observed during the first 2 years of GH treatment and maintained thereafter. However, there was only a minor increase in final height over predicted height which does not justify the general use of GH in children with normal variant short stature.     

The influence of growth hormone (rhGH) therapy on tooth formation in idiopathic short statured children

The purpose of this preliminary study was to evaluate tooth formation in children with idiopathic short stature, before and during treatment with recombinant growth hormone (rhGH). Twenty-nine short-statured children ages 6 to 13 years were assigned into two treatment groups, an "experimental" group (n = 18), which received rhGH, and a "control" group (n = 11), which was observed for 1 year before commencing rhGH treatment. Clinical and radiographic records were obtained at the initial, year 1, and year 2 visits. Tooth formation and stature were assessed by calculating Z-scores, appropriate for the age and gender of each child. Delta-Z scores, which measure the change in Z-score over time, were also calculated between annual visits. Height was measured and recorded every 3 months, and Z-score statural norms for age and gender were derived from the 1977 National Center for Health Services national probability sampling. Tooth formation standards were derived from Moorrees et al. A matched control sample for tooth development was derived from untreated children. Tooth formation was initially delayed although the degree of reduction in stature exceeded the initial degree of delay in tooth formation. During this 2-year study, rhGH therapy had a significant influence on acceleration or gain in stature, but did not have a significant influence on tooth formation.     

Serum growth hormone-binding protein is decreased in prepubertal children with idiopathic short stature

Every activity of a medical practitioner may be subjected to court control. This creates not only uncertainty gut also anger amongst most physicians. However, it is clear that no court judgement against a physician will be made without the competent support of independent medical experts. On the basis of the relevant legal literature and judgments, the present article is an attempt to consider medical errors in the administration of contrast media, to describe the required medical informed consent before such measures, and to discuss the ever increasing importance of adequate documentation in the light of malpractice proceedings. importance of adequate documentation in the light of malpractice proceedings. This is followed by a discussion of the very important medical necessity to inform the patient about recommended behaviour after injections of such contrast media, the responsibility question in both civil and criminal terms in case of an incident, and various tips for steps to be taken in the case of a liability action.     

Oral administration of arginine enhances the growth hormone response to growth hormone releasing hormone in short children

We have evaluated the effect of oral administration of arginine chlorhydrate on the growth hormone response to growth hormone releasing hormone in a group of nine short prepubertal children (six boys and four girls). Arginine chlorhydrate 10 g, administered orally 60 min before an i.v. bolus injection of growth hormone releasing hormone 1-29, 1 microgram/kg, significantly enhanced the growth hormone response to the neuropeptide, confirming the results of previous studies which used the i.v. route. Furthermore, our data strengthen the view that the effects of arginine chlorhydrate on growth hormone secretion are mediated by inhibition of endogenous somatostatin release.     

An early rise in urine N-telopeptide predicts the growth response of normal prepubertal short children to growth hormone therapy

The effects of growth hormone (GH) therapy on biochemical markers of bone turnover were investigated in 11 short prepubertal children without GH deficiency by measuring serum osteocalcin, a marker for bone formation, and urinary concentrations of pyridinium cross-linked amino acids of collagen (PCL), and the peptide-bound pyridinoline residue N-telopeptide (NT), which are specific markers for bone resorption. GH treatment for three months increased bone turnover in this group of children: urinary PCL concentrations increased from 69 +/- 6.2 to 114 +/- 9.3 nmol/mmol Cr (p < 0.01), and urinary NT levels increased from 512 +/- 65 to 766 +/- 74 pmol BCE/mumol Cr (p = 0.058). Serum osteocalcin concentrations increased from 13.64 +/- 2.57 ng/ml to 26.45 +/- 1.39 ng/ml (p < 0.01). The increment in 12-hour urinary concentrations of PCL was highly correlated with the increment in 12-hour urinary NT levels (r = 0.92, p < 0.01). Stepwise multiple regression analysis revealed that the urinary concentrations of NT after 3 months of GH therapy were the best predictor of growth after 12 months of treatment (r = 0.78, F = 7.9, p = 0.037).     

Dental maturity in children of short stature, with or without growth hormone deficiency

Macrophages are important constituents of the immune system by exerting phagocytosis on invading pathogens as well as secreting various immunoregulatory factors. Generation of human macrophage hybridoma has not been possible so far due to the lack of an appropriate fusion partner cell line. In the present study, an 8'-azaguanine resistant cell line, termed HL-60R, was established by drug selection of the promyelocytic cell line HL-60. This novel cell line showed resistance to high concentrations of 8'-azaguanine and was sensitive to aminopterin. These characteristics make it suitable for serving as a potential fusion partner cell line in the development of macrophage hybridoma. Cell-surface analysis by FACS revealed that HL-60R cells per se do not express MHC-class II molecules or the macrophage marker, CD11b. PEG-mediated fusion of HL-60R was performed with PBMC-derived human macrophages. Fluorescence labelling of ex vivo isolated macrophages prior to fusion and subsequent FACS analysis showed that PEG-4000 is a more effective fusion agent than PEG-1500. The generation of this novel fusion partner cell line opens the possibility for development of human macrophage hybridoma or other cell lines from myelocytic origin. Such hybridoma clones will not only enable a more convenient study of these cell but will also provide an excellent host site for the proper production and expression of various recombinant proteins from myelocytic origin in vitro.     

Effects of luteinizing hormone-releasing hormone analog-induced pubertal delay in growth hormone (GH)-deficient children treated with GH: preliminary results

To study the effect of delaying epiphyseal fusion on the growth of GH-deficient children, we studied 14 pubertal, treatment naive, GH-deficient patients (6 girls and 8 boys) in a prospective, randomized, placebo-controlled trial. Chronological age was 14.5 +/- 0.5 yr, and bone age was 11.6 +/- 0.3 yr (mean +/- SEM) at the beginning of the study. Patients were assigned randomly to receive GH and LH-releasing hormone (LHRH) analog (n = 8) or GH and placebo (n = 6) during 3 yr, with planned continuation of GH treatment until epiphyseal fusion. Patients were measured with a stadiometer and had serum LHRH tests, serum testosterone (boys), serum estradiol (girls), and bone age performed every 6 months. Patients treated with GH and LHRH analog showed a clear suppression of their pituitary-gonadal axis and a marked delay in bone age progression. We observed a greater gain in height prediction in these patients than in the patients treated with GH and placebo after 3 yr of treatment (mean +/- SEM, 14.0 +/- 1.6 vs. 8.0 +/- 2.4 cm; P < 0.05). These preliminary findings suggest that delaying epiphyseal fusion with LHRH analog in pubertal GH-deficient children treated with GH increases height prediction and may increase final height compared to treatment with GH alone.     

Insulin-like growth factor binding protein-I levels are strongly associated with insulin sensitivity and obesity in early pubertal children

In conditions associated with insulin resistance, insulin-like growth factor binding protein-I (IGFBP-I) levels have been shown to correlate inversely with insulin levels. Puberty is associated with insulin resistance and thus provides a model for comparing the relationship of IGFBP-I to both insulin levels and measures of insulin sensitivity. Our study population consisted of 104 healthy pubertal children, age 9.8-14.6 yr. Each subject had his/her insulin sensitivity (Si) assessed by the modified minimal model of Bergman, which employs a frequently sampled i.v. glucose tolerance test. Results showed that IGFBP-I levels were significantly higher in boys than in pubertally matched girls (P < 0.01). There was a strong positive correlation between IGFBP-I levels and Si (r = 0.65, P < 0.0001) and a weaker negative correlation with fasting insulin levels (r = -0.38, P < 0.0001). An inverse relationship was also found between IGFBP-I levels and body mass index (r = -0.46, P < 0.0001) and with IGF-I levels (girls only, r = -0.41, P < 0.003). Consequently, insulin sensitivity, obesity, and IGF-I are important predictors of IGFBP-I levels in pubertal children. It is possible that insulin-mediated suppression of IGFBP-I in obese children may increase free IGF-I levels and thus contribute to somatic growth. The same mechanism may operate in pubertal children, where insulin resistance and growth acceleration occur simultaneously.     

Histomorphometric study in children with idiopathic nephrotic syndrome

There is agreement on the clinical diagnostic criteria for acute inflammatory demyelinating polyneuropathy (AIDP/GBS) however, there is lack of consensus for detection of demyelination. In order to critically evaluate the prevailing criteria, sixty-six patients who fulfilled NINCDS criteria and had typical features of GBS were studied for electrophysiological abnormalities of peripheral nerves by using standard methods (median, common peroneal, sural and ulnar) between 1 to 12 weeks after the onset of symptoms. The commonest abnormality on motor nerve conduction study was prolonged distal latency (75%-83%) followed by reduction in CMAP amplitude (63%-82%), decreased velocity (48%-62%), conduction block (17%-39%) and f-wave abnormalities (37.8%-59%). Sensory conduction abnormalities were detected in over 20% of median, 25% of ulnar and 33% of sural nerves. All the patients had abnormality of at least two motor conduction parameters in one nerve when values beyond 2 SD of the mean were considered abnormal and over 70% of patients had three abnormalities in two nerves or two abnormalities in three nerves. Comparison with the prevailing criteria for demyelination revealed that the number of patients fulfilling them varied widely: Albers et al. (1985): 74.2%, Albers et al. (1989): 40.9% and Cornblath: 30.3%. We believe that the current criteria for detection of demyelination in acute neuropathy are too strict, underestimate the underlying pathology in GBS and need reassessment.     

Final height after combined growth hormone and gonadotrophin-releasing hormone analogue therapy in short healthy children entering into normally timed puberty

Four estrous beagles were inseminated with 1 x 10(8) sperm into both the right and left uterine horns, and the uterine horn and oviduct on one side were removed under anesthesia after 7 hr and 24 hr, respectively. The lumen of the uterine horns and oviducts was flushed with canine capacitation medium (CCM), and movement of the sperm in CCM was assessed by phase-contrast microscopy. In a second experiment, ejaculated sperm obtained from 5 normal beagles was incubated in CCM supplemented with oviductal flush fluid (OF-CCM) at 38 degrees C with 5% CO2 in air. Motility of sperm, and percentages of hyperactivated sperm (%HA) and acrosome-reacted sperm (%AR) among freely swimming (FS) sperm were investigated until 24 hr after the start of incubation. After 7 hr of incubation the sperm was coincubated with canine oocytes in OF-CCM for 2 hr, and the number of zona pellucida-binding (zona-binding) sperm was then counted. The %HA among the sperm in the oviductal flush fluid both 7 hr (mean +/- S.E.; 15.0 +/- 2.4%) and 24 hr (77.5 +/- 5.2%) after intrauterine insemination were significantly higher than in the uterine flush fluid (P < 0.05, 0.01, respectively). The motility and %HA among FS-sperm in OF-CCM were higher than in the control medium without oviductal fluid. However, there was no difference in the %AR between OF-CCM and control medium. The number of zona-binding sperm in OF-CCM (8 +/- 1) was significantly greater than in control medium (5 +/- 1) (P < 0.05). These results suggest that oviductal fluid in the estrous bitch maintains sperm motility and induces sperm capacitation.     

Increased proportion of circulating non-22-kilodalton growth hormone isoforms in short children: a possible mechanism for growth failure

Current knowledge about the interaction between GH and its receptor suggests that the molecular heterogeneity of circulating GH may have important implications for growth. The aim of this study was to investigate the proportion of circulating non-22-kDa GH isoforms in prepubertal children with short stature (height less than -2 SD score) of different etiologies. We have also evaluated the relationships among the ratio of non-22-kDa GH isoforms, auxology, and spontaneous GH secretion. The study groups consisted of 17 girls with Turner's syndrome (TS), aged 3-13 yr, 25 children born small for gestational age (SGA) without postnatal catch-up growth, aged 3-13 yr; and 24 children with idiopathic short stature (ISS), aged 4-15 yr. The results were compared with those from 23 prepubertal healthy children of normal stature (height +/- 2 SD score), aged 4-13 yr. Serum non-22-kDa GH levels, expressed as a percentage of the total GH concentration, were determined by the 22-kDa GH exclusion assay, which is based on immunomagnetic extraction of monomeric and dimeric 22-kDa GH from serum and quantitation of non-22-kDa GH using a polyclonal antibody-based GH assay. All samples were selected from spontaneous GH peaks in 24-h GH profiles. The median proportion of non-22-kDa GH isoforms was increased in children born SGA (9.8%; P = 0.05) and girls with TS (9.9%; P = 0.01), but not in the group of children with ISS (8.9%), compared with that in normal children (8.1%). Individually, increased proportions of non-22-kDa GH isoforms, with values more than 2 SD above the mean for the normal group, were observed in 5 girls with TS, 5 children born SGA, and 4 children with ISS. In children born SGA, the proportion of non-22-kDa GH isoforms was directly correlated with different estimates of spontaneous GH secretion [mean 24-h GH concentration (r = 0.41; P = 0.04), area under the curve over baseline (r = 0.41; P = 0.04), and GH peak area (r = 0.61; P = 0.003)], whereas it was inversely correlated with height SD score (r = -0.42; P = 0.04). In conclusion, an increased proportion of circulating non-22-kDa GH isoforms was observed at spontaneous GH peaks in some non-GH-deficient short children. Our results suggest that the ratio of non-22-kDa GH isoforms in the circulation may have important implications for normal and abnormal growth.     

Elevated blood lead levels in children are associated with lower erythropoietin concentrations

PURPOSE: We investigated the incidence of well-directed violent behavior and suicide attempts in patients with temporal lobe epilepsy, with special attention to postictal psychosis. METHODS: We compared 57 episodes of postictal psychosis with 62 episodes of acute interictal (or alternative) psychosis and with 134 complex partial seizures. All patients were matched for age and for age at onset of seizures. RESULTS: The incidence of well-directed violent behavior against human beings was significantly higher (23%) during postictal psychotic episodes than during acute interictal episodes (5%) and postictal confusion (1%). Suicide attempts were also more frequent during postictal psychosis (7%) than during either acute interictal psychosis (2%) or postictal confusion (0%). CONCLUSIONS: Our study showed that well-directed violent and self-destructive behavior was not a feature of epileptic psychosis in general but a specific hallmark of postictal psychosis.     

Pretreatment with somatostatin analog SMS 201-995 potentiates growth hormone (GH) responsiveness to GH-releasing factor in short children

Previous studies in children have shown inconsistent, poorly reproducible GH responses to exogenous GH-releasing factor (GRF), with wide individual variability. In the present study, we tested the hypothesis that prior administration of the long-acting somatostatin analog, SMS 201-995 (SMS), will enhance GH responsiveness to a subsequent GRF challenge. Two study protocols were employed in 37 children with short stature [M = 31, F = 6, ages 11.8 +/- 1.6 yr (mean +/- SEM), height -2.25 +/- 0.55 SDS (SD scores)]. In both studies, each subject served as his/her own control. In the first study, which was designed to determine optimal SMS dose and regimen, SMS, in doses ranging from 0.8-2.2 micrograms/kg sc, was randomly administered or omitted at 0800 h after an overnight fast, and a GRF bolus (50 micrograms, iv) was given 4 h later. In the second study, we employed a protocol identical to study 1 except for the use of standard doses of SMS (1 microgram/kg, sc) and GRF (1 microgram/kg, iv) and an additional 1-h delay of the GRF injection. Plasma GH levels were measured every 20 min from 0800 h until 2 h after the GRF injection in both studies. In study 1 (n = 12; M = 10, F = 2), SMS significantly suppressed spontaneous GH secretion (expressed as the mean +/- SEM GH AUC during the 4-h SMS-GRF interval, AUC 1:2.2 +/- 0.4 vs. 6.2 +/- 0.9 micrograms/L.h; P < 0.001), GH responsiveness to GRF (GH AUC during the 2 h after the GRF injection, AUC 2: 41.5 +/- 7.8 vs. 85.0 +/- 13.5 micrograms/L.h; P < 0.001), and the GH peak response (17.4 +/- 3.1 vs. 36.0 +/- 6.2 micrograms/L; P < 0.001), compared to control tests. In contrast, in study 2 (n = 25; M = 21, F = 4), whereas spontaneous GH secretion was still suppressed during the 5-h SMS-GRF interval (AUC 1:3.8 +/- 0.4 vs. 7.4 +/- 1.1 micrograms/L.h; P < 0.001), both the GH peak response (56.7 +/- 5.5 vs. 30.5 +/- 3.0 micrograms/L; P < 0.0001) and the GH AUC (AUC 2: 103.7 +/- 10.3 vs. 77.5 +/- 6.8 micrograms/L.h; P < 0.05) after GRF administration were significantly augmented by pretreatment with SMS, compared to control tests. Taken together, these results indicate that a priming SMS dose of 1 microgram/kg has a significant permissive effect on GH responsiveness to exogenous GRF administered 5 h later.(ABSTRACT TRUNCATED AT 400 WORDS)     

Normal growth hormone secretory reserve in men with idiopathic osteoporosis and reduced circulating levels of insulin-like growth factor-I

Many men with idiopathic osteoporosis have reduced circulating insulin-like growth factor-I (IGF-I) levels. The major source of circulating IGF-I is GH-mediated production by the liver. The known anabolic effects of GH on the skeleton raised the possibility of GH deficiency in these men. We sought to test this hypothesis in this study. Fourteen men (mean age, 52.1 +/- 3.2 yr, range 31-68) with idiopathic osteoporosis were studied. Mean lumbar spine bone mineral density (BMD) was 0.723 g/cm2, T score -3.5; femoral neck BMD was 0.642 g/cm2, T score, -3.07; distal (1/3) radius BMD was 0.708 g/cm2, T score, -2.05. Eleven of 14 (79%) had frank reductions in serum IGF-I levels compared with age and sex-matched values (158.5 +/- 50 SD vs. 180 +/- 45 SD). GH secretion was stimulated by iv arginine infusion (30 g) over 30 min followed 1 h later by oral L-dopa (500 mg). Serum GH was measured at time (t) = -15, 0, 30, 45, 60, 90, 120, 150, and 180 min. All patients responded to at least one stimulus with the majority (n = 9) responding to both. Five patients responded either to arginine or to L-dopa but not to both. Baseline GH for the entire group was 0.77 + 0.08 ng/mL (SEM). Peak GH following arginine (t = 45-60 min) was 14.0 +/- 2.8 ng/mL, a 17.7 +/- 2.8-fold rise. Peak GH following L-dopa (t = 120-180 min) was 5.7 +/- 1.0 ng/mL, a 9.2 +/- 2.2-fold rise. No difference in maximal secretion was observed between those with low or normal IGF-I levels. Neither IGF-I nor IGF binding protein-3 concentrations changed significantly during the short period of GH stimulation. These data suggest that men with osteoporosis and reduced IGF-I levels do not appear to have a deficiency in the GH axis. Other hormonal or local factors may be important in regulating IGF-I expression. Deficiencies of IGF-I production at skeletal sites may be important in the pathogenesis of this syndrome.     

Circulating thyroid hormone concentrations and placental thyroid hormone receptor expression in normal human pregnancy and pregnancy complicated by intrauterine growth restriction (IUGR)

Thyroid hormones are critical to growth and development of the human fetus. Abnormal placental development, a major cause of intrauterine growth restriction (IUGR), is associated with a high perinatal mortality and morbidity. Thyroid status has been postulated to play a role in the pathogenesis of such morbidity. In the present study, we have investigated fetal thyroid function and placental expression of thyroid hormone receptor (TR) alpha and beta variants during normal human pregnancy and in pregnancy associated with IUGR. Measurement of free thyroid hormones and TSH concentrations revealed significant rises in free T4 and free T3 between the second and third trimesters of normal pregnancy. Serum concentrations of free T4 and free T3 were lower in fetuses affected by IUGR, although serum TSH levels were not significantly different. Immunocytochemistry demonstrated the presence of TR alpha1, alpha2, and beta1 proteins within the nuclei of trophoblast and stromal placental cells. Immunostaining for these TR variants increased with increasing gestation in normal placenta. Comparison of IUGR placental samples with normal samples revealed greater immunostaining for TR alpha1, alpha2, and beta1 variants in IUGR. Examination of pretranslational expression of TR alpha1, alpha2, beta1, and beta2 variants by semiquantitative RT-PCR revealed increasing expression of TR alpha1, alpha2, and beta2 messenger RNAs with increasing gestation in normal pregnancy, which "mirrored" post-translational expression. However, and in contrast, there were no significant differences in expression of TR messenger RNAs in normal and IUGR placenta. The present findings of reduction in serum free thyroid hormones and increased expression of TR alpha and beta proteins in association with IUGR highlight the potential importance of thyroid status in influencing long-term fetal outcome in this condition.     

Growth hormone secretion and circulating insulin-like growth factor-I (IGF-I) and IGF binding protein-3 concentrations in children with sickle cell disease

Impaired growth involving both height and weight accompanying sickle cell disease (SCD) poses diagnostic and therapeutic problems. We undertook this study to test the hypothesis that this impaired growth is associated with abnormalities of the growth hormone (GH)/insulin-like growth factor-I (IGF-I)/IGF binding protein-3 (IGFBP-3) axis in 21 children with SCD and that SCD is associated with GH resistance. Nine of 21 children with SCD had a defective GH response to both clonidine and glucagon provocation (peak < 10 micrograms/L); these children differed from the 12 others in having slower linear growth velocity (GV and GVSDS), lower circulating concentrations of IGF-I and IGFBP-3, and either partial or complete empty sellae in computed tomographic scans of the hypothalamic-pituitary area. In this group of patients with SCD, it appears that defective GH secretion and consequent low IGF-I production are the major etiological factors causing the slow growth. The two groups with SCD did not differ significantly in dietary intake, body mass index (BMI), midarm circumferences, skinfold thickness, serum albumin concentration, or intestinal absorption of D-xylose. A single injection of GH produced a smaller increase in circulating IGF-I in children with SCD with or without defective GH secretion versus 10 age-matched children with idiopathic short stature (ISS) and 11 children with isolated GH deficiency (GHD), suggesting partial GH resistance in the SCD group. The presence of defective GH secretion, decreased IGF-I synthesis, and partial resistance to GH in short children with SCD suggests that treatment with IGF-I may be superior to GH therapy for improving growth.     

Overnight growth hormone secretion in achondroplasia: deconvolution analysis, correlation with sleep state, and changes after treatment of obstructive sleep apnea

The normal profile for overnight GH secretion in achondroplasia has not been previously studied. Factors that have been shown to influence GH secretion include age, obesity, sleep state, and the presence of obstructive sleep apnea (OSA). We assessed GH levels in a group of subjects with achondroplasia, during overnight polysomnography. Nineteen subjects with achondroplasia were studied at 11.3 y of age (median 6.7, range 1.8-30.9). Levels of GH were measured using time-resolved immunofluorometric assay (DELFIA, Pharmacia Biotech Inc.) and analyzed by a deconvolution method. Five subjects were restudied after treatment for OSA. Secretion rates of GH were greater in slow wave (SWS) and rapid eye movement (REM) sleep than in stage one and two (SI-II = light non-REM) sleep (p < 0.01). Total overnight GH secretion decreased with increasing age (r2 = 0.22 p < 0.04). Neither the frequency of arousals, frequency of sleep state transitions nor the severity of OSA correlated with measures of GH secretion. Levels of IGF-I correlated independently with age, body weight (percent ideal), and GH secretion rate (r2 = 0.76, p < 0.001). In a group of five subjects treated for OSA, improved respiratory distress index and reduced sleep state transitions were not associated with significant changes in GH secretion rate by sleep stage; SWS [from 0.62 +/- 0.28 mIU/L/min to 1.02 +/- 0.25 mIU/L/min (NS)] and SI-II sleep [from 0.26 +/- 0.07 mIU/L/min to 0.60 +/- 0.16 mIU/L/min (NS)]. However, in those five subjects, a GH secretion peak during the first 2 h of SWS was initially absent, appearing only after treatment of OSA (1.09 +/- 0.38 mIU/L/min) compared with (2.40 +/- 0.59 mIU/L/min (p = 0.01). A profile of overnight GH secretion is presented for subjects with achondroplasia.