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Biomedical subjects

C T Cowell

Publications and source records attributed to C T Cowell.

At least 37 records · Page 2Linked to original sources
PubMed2000

Safety issues in children and adolescents during growth hormone therapy--a review.

The action of growth hormone (GH) via its receptor involves many organ systems and metabolic pathways. These diverse actions are reviewed in this paper in the context that they may represent unwanted side-effects of GH therapy for growth promotion. The monitoring of GH therapy in large multicentre international databases has demonstrated a low frequency of adverse events. Tumour recurrence or new malignancy are not increased. Headaches, especially in the first few months of therapy, require close evaluation as benign intracranial hypertension is found infrequently, especially in children with GH deficiency and chronic renal failure (CRF). Children at risk for slipped capital femoral epiphysis and scoliosis require close monitoring during therapy. Decreased insulin sensitivity that is dose-dependent is observed during GH therapy. Glucose homeostasis, however, is not affected, but a recent report of increased incidence of Type 2 diabetes mellitus in children undergoing GH therapy requires prospective surveillance.

Adolescent↗
PubMed2000

Effects of delaying puberty on bone mineralization in female rats.

The effect of delaying puberty on bone mineralization was studied using female rats as a model. Repeated injections of gonadotrophin-releasing hormone antagonist (GnRHa) were used to suppress the onset of puberty from the age of 6-10 weeks. A group of control female rats was given aqueous solution injections at the same age and for the same duration. The effect of delaying puberty on bone mineralization was examined using dual energy X-ray absorptiometry (DXA) and peripheral quantitative computerized tomography (QCT), both methods being adapted for small animals. Bone mineral parameters were measured at baseline and at the ages of 10, 17 and 24 weeks in total body, femur and spine. Compared to controls, bone mineral content (BMC) and bone mineral density (BMD), as measured by DXA, were significantly decreased in GnRHa-treated rats in total body and femur at 10 and 24 weeks of age (P < 0.05). The results were even more significant after adjusting for weight. After this adjustment, spine BMC and BMD at 10, 17 and 24 weeks were significantly lower in the treatment group (P < 0.05). Trabecular BMD at the distal femur in the GnRHa treated group as measured by peripheral QCT was significantly lower (P < 0.05). However, cortical bone in the mid-femur had higher BMD, concurrent with lower cortical thickness in the treatment group. In conclusion, a delay in the onset of sexual maturation may cause prolonged, possibly irreversible defect in bone mineralization.

Absorptiometry, Photon↗
PubMed2000

Bone markers and bone mineral density during growth hormone treatment in children with growth hormone deficiency.

Growth hormone (GH) has a positive impact on muscle mass, growth and bone formation. It is known to interact with the bone-forming unit, with well-documented increases in markers of bone formation and bone resorption within weeks of the start of GH therapy. These changes relate significantly to short-term growth rate, but it is not evident that they predict long-term response to GH therapy. The consequences of GH deficiency (GHD) and GH replacement therapy on bone mineral density (BMD) have been difficult to interpret in children because of the dependency of areal BMD on height and weight. Some studies have tried to overcome this problem by calculating volumetric BMD, but results are conflicting. The attainment of a normal peak bone mass in an individual is considered important for the future prevention of osteoporosis. From the limited data available, it appears difficult to normalize bone mass totally in GH-deficient individuals, despite GH treatment for long periods. Studies to date examining the interaction between GH and bone have included only small numbers of individuals, making it difficult to interpret the study findings. It is hoped that these issues can be clarified in future research by the direct measurement of bone density (using quantitative computer tomography). Mineralization is only one facet of bone strength, however; other important components (e.g. bone structure and geometry) should be addressed in future paediatric studies. Future studies could also address the importance of the degree of GHD in childhood; how GH dose and insulin-like growth factor-I levels achieved during therapy relate to the final outcome; whether or not the continuation of GH therapy after the attainment of final height may further enhance bone mass; whether the timing and dose of other treatments (e.g. sex hormone replacement therapy) are critical to the outcome; and whether GHD in childhood is associated with an increased risk of fracture.

Biomarkers↗
PubMed2000

The effects of growth hormone deficiency and growth hormone replacement therapy on bone. A meeting report.

Recently, several reports have described the effects of growth hormone (GH) deficiency (GHD) on bone and the associated potential benefits of GH therapy. Not all of these reports have, however, been consistent and the results are debated. Some of the contention surrounding this issue reflects disagreement about which bone parameters are the best indicators of bone strength and fracture risk. In November 1999, a meeting was held in Taormina, Italy, to discuss the assessment of bone in patients with GHD and the effects of GH therapy on the skeleton. The participants included endocrinologists, orthopaedists and biophysicists from around the world. During the meeting, the advantages and disadvantages of the various indicators of bone strength were defined. In considering GH therapy, the delegates agreed that it had beneficial effects on bone in adults with GHD, but that further studies were needed in GH-deficient children. Finally, the participants stressed the need for more data to clarify which indicator of bone strength is the most appropriate to use in adults and children with GHD, and to define fully the role of GH therapy in bone metabolism. It was recognized that pharmacoepidemiological surveys, such as KIGS (Pharmacia International Growth Database) and KIMS (Pharmacia International Metabolic Database), are valuable sources of such data, and are, therefore, important in the development of evidence-based medicine.

Absorptiometry, Photon↗
PubMed1999

Initial characterization of the GH-IGF axis and nutritional status of the Ati Negritos of the Philippines.

BACKGROUND AND OBJECTIVE: The Ati Negritos are a Pygmy-like aboriginal population from the Philippines with physical characteristics of short stature, dark skin and woolly, kinked hair. Their final height, components of their GH-IGF axis and various nutritional markers are described. SUBJECTS, DESIGN AND MEASUREMENTS: Auxological data and sera for the components of the GH-IGF axis and nutritional parameters were collected from 9 adult Ati Negritos in their native environment and 10 Filipinos in Sydney. RESULTS: The height SDS (- 3.66 +/- 1.1 vs. - 1.01 +/- 1.2), weight SDS (- 2.30 +/- 1.6 vs. 0.10 +/- 0.7), and BMI SDS (- 1.4 +/- 1.8 vs. - 0.2 +/- 0.5) between the two groups were significantly different (P < 0.01). The mean height of the 6 male Ati Negritos was 149 +/- 7 and 144 +/- 3 cm for the females and are comparable with the African Pygmies and the Mountain Ok people of Papua New Guinea. The Ati Negritos showed lower growth hormone binding protein (GHBP), insulin-like growth factor I (IGF-I), insulin-like growth factor binding protein 3 (IGFBP-3), acid labile subunit (ALS), zinc, albumin, ferritin, iron, iron saturation and much higher insulin-like growth factor binding protein 2 (IGFBP-2) and plasma transferrin concentrations. No differences were noted in random growth hormone (GH), plasma insulin-like growth factor II (IGF-II), nor in their plasma concentrations of prealbumin, thyroid stimulating hormone (TSH) and free thyroxine (T4). CONCLUSION: Perturbations of both the GH-IGF-I axis and nutritional markers exist in the Ati Negritos. These findings may be determinants of their stature; however, the aetiology of these changes remains to be fully elucidated.

Adult↗
PubMed1999

Effects of gender, body composition and birth size on IGF-I in 7- and 8-year-old children.

We investigated the relationship between IGF-I, gender, height, weight, body composition and birth size in 260 healthy 7- and 8-year-old children (139 females). All children were born term at Nepean Hospital, Western Sydney. Body composition was measured using dual energy X-ray absorptiometry. IGF-I levels were determined by radioimmunoassay. Girls had higher IGF-I levels than boys (20.2 +/- 6.5 nmol/l compared to 15.9 +/- 6.1 nmol/l, p < 0.001) but there was no correlation between age and IGF-I. IGF-I was positively correlated with height SDS (R(2) = 0.12), weight SDS (R(2) = 0.19), BMI SDS (R(2) = 0.18), total body fat (%) (R(2) = 0.14), and fat-free tissue/cm (R(2) = 0.03). After adjusting for gender and current weight, IGF-I-levels were inversely related to birth size - children with the lowest birth size and heaviest current weight had the highest IGF-I levels. This correlation between birth weight and IGF-I supports the hypothesis that the IGF-I axis is altered in babies who are small for gestational age.

Birth Weight↗
PubMed1999

Nutrition in early life: somatic growth and serum lipids.

This paper addresses the questions of whether early nutritional experience affects later somatic growth, the growth of the adipose tissue, or the levels of serum lipids among well-nourished children. The analyses are based on data from three prospective studies. Postnatal nutrition and growth: there were differences in growth between breast-fed and formula-fed children. There was no association between linear growth and differences in food energy or macronutrient intake. Birth size and postnatal growth: there was no association between ponderal index (PI) at birth and body mass index (BMI) in the second year. For boys, the PI at 3 and 6 months of age was significantly positively correlated with BMI at the ages of 8 and 15 years, but not for girls. Childhood growth and lipids: there was no association between lipids at the age of 8 years and either birth weight or length, but children who had had a low PI at birth had higher lipid levels at the age 8 years. A positive association was found between serum lipids and abdominal fat and BMI. We conclude that, although early diet may influence growth rate beyond infancy, the evidence for fat patterning resulting from differences in fetal or early postnatal nutrition is still open to question.

Adipose Tissue↗
PubMed1998

Vitamin D receptor alleles predict growth and bone density in girls.

OBJECTIVES: Polymorphism of the vitamin D receptor (VDR), collagen alpha I type I (Col I alpha I), and oestrogen receptor (ER) genes have been shown to account for some of the heritability of bone mineral density (BMD) in adults. This study examined this relation in prepubertal children. METHODS AND SUBJECTS: The relation between genotypes of VDR gene (Taq I, Bsm I, Fok I), Col I alpha I gene (Msc I), and ER gene (Pvu II) with areal BMD, volumetric BMD, and growth were examined in 114 (68 girls) healthy 7 year old, white children. RESULTS: The genotype of the VDR gene (Taq I) correlated with lumbar spine (L1-4) volumetric BMD in girls only, but at no other bone sites. In girls, VDR genotype affected areal BMD at all sites. After adjusting for height and weight, however, this effect was explained completely by the independent effect of the VDR genotype on growth. Girls with genotype TT, were 3.9 kg heavier and 4.1 cm taller than those with tt, but this relation was not present at birth. No relation was found between genotypes of the VDR gene (Fok I), Col I alpha I gene (Msc I), or ER gene (Pvu II) and BMD or growth variables. CONCLUSIONS: In prepubertal girls, VDR alleles contribute to lumbar spine volumetric BMD variance, but the areal BMD effect reflects the relation between areal BMD and growth. VDR alleles might affect postnatal growth regulation.

Alleles↗
PubMed1997

Fat distribution in children and adolescents--the influence of sex and hormones.

A significant proportion of the morbidity related to obesity is now recognized to be related to the regional distribution of fat. The advent of dual energy X-ray absorptiometry has facilitated the assessment of body composition in a number of investigations on body fat. From current data, including the authors' own study of trunk and leg fat in 335 children and young adults, it is evident that gender differences for total body fat, percentage of body fat and distribution of fat occur after the pubertal years. Males develop a distribution of fat which favours central deposition of fat irrespective of their total body fat--a distribution that is, unfortunately, associated with a number of adverse implications on health. Furthermore, this tendency to increasing abdominal fat is independent of adipose tissue mass. Hormonal regulators of adipose tissue, including growth hormone which is already known to increase free fatty acids and decrease fat cell mass, need to be studied to account for these gender differences.

Adipose Tissue↗
PubMed1996

Growth hormone therapy in Silver Russell syndrome: 5 years experience of the Australian and New Zealand Growth database (OZGROW).

UNLABELLED: Data were analysed on 33 children (22 males) with Silver Russell syndrome treated with growth hormone for periods up to 5 years. Baseline data (medians) at commencement of growth hormone (GH) therapy were age 6.7 years, bone age delay 1.7 years, height standard deviation score (SDS)-3.2, weight SDS -3.1, and growth velocity 5.7 cm/ year. All were prepubertal. Median birth weight SDS for gestational age was -3.2. GH was commenced at 14 IU/m2 per week and subsequently adjusted according to response. Growth velocity and growth velocity SDS for chronological age (CA) improved over baseline and gains in height SDS for CA were 1.0, 1.5 and 1.8 SD over 3, 4 and 5 years respectively (P < 0.001). No significant increase in height SDS for bone age was observed. Increased GH doses were required after the 1st year to maintain growth rates. Mean bone age advancement was 3.1 years after 3 years of treatment, and 6.0 years after 5 years treatment. Younger age was a predictor of the growth response over the 1st year. Predictors of response after 3 years were catch up growth, low weight SDS at birth and low height SDS for CA. Age at onset of puberty was normal, but height at onset of puberty was lower than normal means. CONCLUSION: We have demonstrated significant improvement in growth in Silver Russell syndrome after 3 years of GH therapy, however data on estimated mature height and final height are insufficient to conclude final outcomes. Further follow up is required to assess the long-term benefit.

Abnormalities, Multiple↗
PubMed1996

Growth hormone therapy for 3 years: the OZGROW experience.

OBJECTIVE: To examine the growth response over 3 years of growth hormone deficient (GHD) and non-GHD children who have received growth hormone (GH) in Australia. METHODOLOGY: A retrospective study of a group of patients (1362 children) who commenced GH prior to 1 September 1990. Data were collected at 12 growth centres located in major cities throughout Australia. The data were transferred after informed consent to the national OZGROW database located at the Royal Alexandra Hospital for Children, Sydney, NSW. Of the 1362 children, 898 had received 3 years or more GH therapy and were eligible for this analysis. This cohort was then categorized by diagnosis. Growth response was assessed using height standard deviation score, estimated mature height, growth velocity (GV), GH dose and bone age (years). RESULTS: For children who completed 3 years therapy, the baseline characteristics among diagnostic groups were similar with mean height standard deviation score (SDS) less than -3 SDS (except for the malignancy group) and mean GV ranging from 3.5 to 4.4cm/year. The GV during the first year improved in all groups (7.7-9.4cm/year)followed by an attenuated response during the second and third years of therapy. After 3 years GH therapy the GHD group with peak levels <10 mU/L demonstrated the greatest change in estimated mature height and height SDS. The GHD group with peak levels between > or = 10 but <2OmU/L had a growth response similar to the non-GHD children for all outcome parameters. Change in bone age ranged from 3.1 to 3.8 years with no differences being noted between the diagnostic groups, nor consistently with pubertal status. CONCLUSIONS: Australian GH guidelines have targeted very short children when compared to other series. This large cohort of non-GHD children has demonstrated short-term benefits of GH therapy; however, the long-term benefit remains unclear until these children reach final adult height.

Adult↗
PubMed1996

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.

Achondroplasia↗
PubMed1996

Volumetric bone mineral density in normal subjects, aged 5-27 years.

Concerns have been raised regarding the validity of using areal bone mineral density (aBMD) as a substitute for the true volumetric bone mineral density (vBMD) in the pediatric population. We studied 209 normal subjects (109 males), aged 5-27 yr, to examine the influence of age, gender and growth on vBMD. The femoral neck, midthird of the femoral shaft, and the four lumbar vertebral bodies (L1-L4) were studied. Using data on bone width and height obtained by dual energy x-ray absorptiometry, bone volume was calculated with the assumption that all three sites are cylinders. In contrast to aBMD, vBMD of the femoral neck bore no relationship to age or weight in both sexes, but was significantly related to height in females (r2 = 0.07; P = 0.01). Similarly, vBMD of the femoral shaft (vFBMD) did not change with age or height in either sex. In females, a significant inverse relationship was seen between vFBMD and weight (r2 = 0.14; P = 0.001). Male subjects had higher vFBMD than females (mean +/- SD, 0.73 +/- 0.11 vs. 0.70 +/- 0.12; P = 0.047), but no sex difference was seen in vBMD of the femoral neck. Conversely, vBMD of L1-L4 remained age and growth dependent, although the strength of the relationship was weaker than that for aBMD (data not shown). In conclusion, the vBMD of the femoral neck and shaft is independent of age and is less dependent on growth variables in children and young adults than is aBMD. These observations offer a different perspective from our previous concepts of aBMD.

Absorptiometry, Photon↗
PubMed1995

The "4A" syndrome: adrenocortical insufficiency associated with achalasia, alacrima, autonomic and other neurological abnormalities.

The triad of adrenocortical insufficiency with alacrima and achalasia is an unusual disease entity in paediatrics. The association of autonomic and peripheral neuropathies has more commonly been reported in older individuals. We describe four children (two siblings) with this disorder, aged between 3 and 6 years at diagnosis, all of whom had clinical neurological abnormalities when examined between 6 and 8 years of age. In addition, we performed cardiovascular autonomic testing in three subjects: heart rate variation during deep breathing was abnormal in all three; Valsalva ratio was abnormal in two; and postural systolic blood pressure response was abnormal in one. Pupillary reflexes were abnormal in the only subject in which they could be measured. These results indicate that subtle neurological and, in particular, autonomic abnormalities can be detected at an early age. We propose that autonomic neuropathy be considered as an integral feature of this rare condition and suggest the term "4A" syndrome as a useful mnemonic for the association of adrenocortical insufficiency, achalasia and alacrima with autonomic and other neurological abnormalities.

Adrenal Cortex Function Tests↗
PubMed1995

Body-composition assessment by dual-energy x-ray absorptiometry in subjects aged 4-26 y.

This cross-sectional study describes the body composition of 265 normal subjects (137 males and 128 females) aged 4-26 y determined by dual-energy x-ray absorptiometry (DXA). Lean tissue mass (LTM) and bone mineral content (BMC) increased with age in females until 13.4 and 15.7 y, respectively, and in males until 16.6 and 17.4 y, respectively. A strong relation between LTM and BMC was found for each sex (r = 0.98, P = 0.0001 for males; r = 0.98, P = 0.0001 for females). DXA percent body fat (%BFDXA) increased with age in females (r = 0.52, P < 0.001) but not in males and was higher in females than in males at all ages. Trunk to leg fat ratio (TLFR) was calculated as DXA trunk fat/leg fat. In post-pubertal age the TLFR was higher in males than in females (1.01 +/- 0.23 and 0.75 +/- 0.16, P = 0.001), but there was no sex difference in younger children. DXA weight underestimated scale weight by a mean of 0.83 kg. %BFDXA correlated with %BF by skinfold thickness measurement with good agreement for males but overestimated %BF by skinfold thickness for females. These normative data for body composition demonstrate significant sex differences in all body compartments after the pubertal years.

Absorptiometry, Photon↗
PubMed1995

'Exaggerated adrenarche' in children presenting with premature adrenarche.

OBJECTIVE: Previous reports of endocrinological profiles in children presenting with premature adrenarche have not shown consistent abnormalities. We therefore aimed to review the clinical and biochemical aspects of a large number of patients presenting with premature adrenarche without virilization and determine the relation between clinical and biochemical characteristics and the frequency of adrenal steroid disorders. DESIGN AND PATIENTS: Eighty-eight patients presenting with adrenarche without virilization during 1985-1992 were retrospectively reviewed. There were 72 girls and 16 boys. All were normotensive and had either prepubertal breasts or testes < 4 ml. In patients with high adrenal androgen levels, adrenal tumours had been excluded by either adrenal ultrasound or CT scan. MEASUREMENT: We recorded clinical manifestations, auxological data, bone age, biochemical results including basal 17OH-progesterone (b17OHP), dehydroepiandrosterone sulphate (DHEAS), androstenedione (delta 4A), testosterone, cortisol and stimulated 17OHP and cortisol. ACTH stimulation tests (using soluble Synacthen 250 micrograms intramuscularly and collecting blood at 0, 30 and 60 minutes) were performed when clinically indicated. 17OH-Pregnenolone (17OHPreg) was also measured during ACTH stimulation tests in 13 individuals to look for abnormalities of 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD). RESULTS: The age of onset ranged from 3 to 9.5 years (mean 6.8 +/- 1.3). There were no significant differences by sex for height SDS, weight SDS or % ideal body weight, but bone age advancement was greater in males (P < 0.02). The most common presenting clinical manifestation was premature appearance of pubic hair in 93.8%, the other 6.2% presenting with body odour, acne and/or hirsutism. Twelve patients had b17OHP > 6 nmol/l of whom 5 were diagnosed as having congenital adrenal hyperplasia (CAH) resulting from 21-hydroxylase deficiency after ACTH stimulation tests. A further 33 patients who had b17OHP < 6 nmol/l had normal 17OHP and cortisol responses to ACTH stimulation. Patients, after excluding those with CAH, were divided on the basis of their DHEAS levels into prepubertal (< 1.5 mumol/l), pubertal (1.5-6 mumol/l) and above pubertal range (> 6 mumol/l). The 8 patients with DHEAS values above the pubertal range were described as having 'exaggerated adrenarche'. There were no significant clinical differences between these 3 groups, but significant differences were found for bone age advancement and the steroids, b17OHP, delta 4A and testosterone. There was a strong correlation between DHEAS and delta 4A (r = 0.623, P < 0.001). The 'exaggerated adrenarche' group had higher 17 OHPreg/17OHP ratios at 60 minutes after stimulation but these were not diagnostic for 3 beta-HSD deficiency. CONCLUSION: The value of assessing basal steroids in children presenting with premature adrenarche is demonstrated in this series with 5.7% being diagnosed with 21-hydroxylase deficiency and 9.1% with 'exaggerated adrenarche'. No relation was found between adrenal steroids and clinical features except for the acceleration of bone age. The relation between 'exaggerated adrenarche' and future ovarian hyperandrogenism needs further evaluation.

17-alpha-Hydroxypregnenolone↗
PubMed1995

Cholestatic jaundice and congenital hypopituitarism.

OBJECTIVE: The prevalence of cholestatic jaundice as a presenting feature of congenital hypopituitarism is assessed. METHODOLOGY: A retrospective case record analysis of the presenting features in all patients diagnosed as having congenital hypopituitarism between 1973-93. RESULTS: Seven of the 20 patients with congenital hypopituitarism presented with cholestatic jaundice as the major initial manifestation of the disorder. Liver biopsy findings in three revealed intracellular bile pigment accumulation and variable giant cell formation. CONCLUSION: Cholestatic jaundice was the major manifestation of congenital hypopituitarism in 35% of patients presenting in the neonatal or early infancy period.

Age of Onset↗