bluuebunny/crossref_metadata_2025 huggingface dataset:
The Development of the Skeletal System in Children and the Influence of Muscular Strength
Authors: Schönau Eckhard
Published: April 2003

In a study on 14 healthy children aged from 6 to 13 years, the volumetric spongiosa bone density (SBD), cortical bone density (CBD), bone cross-sectional area (BCSA), cortical area (CA), and bone strength index (BSI) at the distal radius were analyzed using peripheral quantitative computer tomography (pQCT Bone Scanner XCT-900, Stratec, Pforzheim, Germany). BSI values were calculated on the basis of the moment of resistance and cortical density using system integrated software. These parameters were correlated with grip strength measurements obtained using a grip dynamometer. There were age-dependent increases in BCSA (r = 0.68), CA (r = 0.78), BSI (r = 0.79). SBD and CBD, however, did not show an increase with age. Grip strength correlates strongly with the parameters of bone geometry BCSA (r = 0.8), CA (r = 0.86), and BSI (r = 0.9) at p < 0.01. SBD and CBD showed no significant correlation to grip strength. The results of this study suggest that an increase in cortical thickness and cross-sectional area represent the most important adaptation mechanisms of the growing bones in response to biomechanical usage. These parameters represent the most important factors of bone strength. Volumetric bone density (material characteristic) of spongiosa and cortical bone is an age-independent parameter which does not change significantly with increasing muscular strength in healthy subjects. These relationships must be considered when selecting parameters to be used as success criteria in studies on the influence of physical exercise on bone status.
Quality of Life in Short Adults
Authors: Busschbach J.J.V. , Rikken B. , Grobbee D.E. , De Charro F.T. , Wit J.M.
Published: April 2003

The use of (costly) growth hormone (GH) treatment in short children is often justified by the assumption that short stature considerably reduces quality of life in adults. We tested this assumption in 5 groups of short adults: 25 patients with isolated GH deficiency; 17 male patients with childhood onset renal failure; 25 women with Turner syndrome and 26 patients who were presented as a child to a paediatrician for idiopathic short stature. A group of 44 short individuals with presumably idiopathic short stature, who had not been presented to a paediatrician for short stature, was sampled from the general population (‘normal shorts’). We measured quality of life in terms of socio-economic variables, the Nottingham Health Profile and time trade-off. The mean height of most groups was close to the 3rd percentile. The chance of having a partner was low for all groups, except for the normal shorts. Problems with job application were only reported in Turner syndrome. The scores on the Nottingham Health Profile were all within the normal range, but GH-deficient adults had a higher score on the domain energy than normal shorts. Women with Turner syndrome, individuals with renal failure, and those with idiopathic short stature had a wish to be taller, with an estimated reduction in quality of life of 2–4% (time trade-off). As the normal shorts did not show any sign of a reduced quality of life, we falsify the assumption of a direct relation between short stature and quality of life. The complaints of patients with idiopathic short stature around the 3rd percentile seem to be the result of unsuccessful coping strategies.
Body Mass Index in Growth Hormone Deficient Children before and during Growth Hormone Treatment
Authors: Baars J. , van den Broeck J. , le Cessie S. , Massa G. , Wit J.M.
Published: April 2003

Growth hormone deficiency (GHD) is associated with truncal obesity. We aimed at identifying factors that determine the body mass index (BMI) of untreated GHD children and the changes in BMI during 2 years of GH therapy in 348 Dutch GHD children registered in the National GH Registration Database. BMI was expressed as a standard deviation score (SDS). Before GH therapy, the mean (95% CI) BMI-SDS in all GHD children (0.09 (–0.05 to 0.24) SDS) was comparable to normal children. Patients with GHD due to a cranial tumour have a higher BMI (1.03 (0.69–1.36) SDS; p < 0.0001) as well as those with multiple pituitary hormone deficiencies (0.35 (0.14–0.57) SDS; p = 0.005) and patients who are in puberty at start of GH therapy (0.60 (0.13–1.08) SDS; p = 0.036). During GH therapy BMI initially decreased to reach a nadir of –0.28 (–0.35 to –0.21) SDS at 6 months. Thereafter BMI progressively increased to –0.09 (–0.18 to –0.04) SDS after 24 months. A higher initial BMI-SDS resulted in a larger decrease in BMI-SDS. We showed that this can be sufficiently explained by a regression to the mean effect.
Molecular Investigation of Two Male Subjects with Short Stature and a 45,X/46,X,Ring(Y) Karyotype
Authors: Sher Ellen S. , Addelston Miriam B. , Plotnick Leslie , Urban Maria D. , Berkovitz Gary D.
Published: April 2003

We studied 2 subjects with a 45,X/46,X,ring(Y) karyotype. Both of them were evaluated because of short stature and a subnormal rate of linear growth. One patient had additional features of the Ullrich-Turner syndrome. Both subjects had normal male external genitalia. Two copies of the pseudoautosomal gene, MIC2, were present in DNA of each individual. All sequences examined on the Y-specific portion of the short arm, including those for the sex-determining region Y (SRY) gene, were present. By contrast, portions of the long arm of the Y chromosome were missing from DNA of both subjects. In subject 1, deletion intervals 6 and 7 were missing. In subject 2, deletion interval 5, distal to 5B, was missing in addition to intervals 6 and 7. The most likely explanation for the ring formation in these subjects is a chromosomal break in the long arm and in the pseudoautosomal region of the short arm distal to MIC2 with subsequent ligation of the remaining sequences on the long arm and short arm. However, a complex rearrangement cannot be excluded.
Evaluation of Glucose Tolerance and Insulin Secretion in Cystic Fibrosis Patients
Authors: Peraldo Massimo , Fasulo Adele , Chiappini Elena , Milio Claudia , Marianelli Lore
Published: April 2003

Blood glucose profile and insulin levels during the oral glucose tolerance test were retrospectively analyzed in 52 cystic fibrosis (CF) patients aged 10–33 years (mean 18 years). Thirty-seven subjects (71.1%) had normal glucose tolerance; 6 patients (11.5%) had impaired glucose tolerance and 9 patients (17.3%), with fasting blood glucose levels below 7.2 mmol/l were classified as diabetic, according to WHO diagnostic criteria. No significant differences in the total amount of secreted insulin (expressed as area under the curve) were detected in CF patients with or without glucose intolerance, but a significant delay in the insulin peak time appeared to be related to a compromised nutritional status. Our data indicate a significantly increased risk of glucose metabolism impairment related to poor nutritional condition (RR 5.40; 95% CI: 1.5–19.7) and worse clinical status (RR 4.27; 95% CI: 1.05–17.2). In particular, glucose tolerance abnormalities were found in 50% of CF patients with an unsatisfactory nutritional condition versus 15.6% of CF patients with good nutritional status. Conclusions: Since CF-related diabetes is often underdiagnosed and associated with deterioration in patients’ overall clinical status, it is very important to identify subjects at risk of developing diabetes by strict monitoring of glucose metabolism when deterioration in nutritional and clinical conditions is seen which cannot be otherwise explained.
Therapeutic Applications of Melatonin and Related Compounds
Authors: Defrance R. , Quera-Salva M.A.
Published: April 2003

Increasing knowledge of the pharmacological effects of melatonin has suggested various possible therapeutic applications for the hormone. Because, as a natural substance, melatonin cannot be patented, melatonin-related compounds have been synthesized by industrial groups. The scope of such compounds is also to specifically target the recently discovered melatonin receptor subtypes. The sleep-inducing properties of melatonin are disputed, but are distinct from those of benzodiazepines. The observed effects on sleep latency or sleep efficiency, which remain to be confirmed, could be accounted for by the effects of melatonin on core body temperature and on circadian rhythms. There is also an urgent need for safety data, both in animals and in humans, particularly when long-term use is envisaged.
Gonadotropin Pulsations across Development
Authors: Hayes Frances J. , Crowley Jr. William F.
Published: April 2003

Initiation and maintenance of the reproductive axis in the human is contingent upon the pulsatile secretion of gonadotropin-releasing hormone (GnRH) from the hypothalamus. In man, tracking endogenous GnRH secretion relies on frequent peripheral sampling of three glycoprotein products of the gonadotrope, luteinizing hormone (LH), follicle-stimulating hormone (FSH) and free α-subunit (FAS). FAS is superior to LH as a surrogate marker of GnRH secretory dynamics in those circumstances where GnRH secretion is rapid or where the pituitary LH response is low. The pattern of GnRH secretion is constantly changing across development; from high levels during the neonatal period, through a period of quiescence in mid-childhood, followed by sleep-entrained reactivation of the reproductive axis at the onset of puberty, ultimately culminating in the adult pattern of pulsatile secretion which in the male is approximately every 2 h and in the female varies with the stage of the menstrual cycle. This episodic mode of secretion allows differential impact of feedback mechanisms on the GnRH neurons and facilitates the maintenance of the reproductive axis during periods of stress by allowing frequency and amplitude modulations.
Central Nervous System Control of Thyrotropin Secretion during Sleep and Wakefulness
Authors: Behrends J. , Prank K. , Dogu E. , Brabant G.
Published: April 2003

Thyrotropin (TSH) is a pulsatile secreted hormone with a pronounced circadian rhythmicity and a characteristic nightly surge based on an augmentation of pulsatile release. A number of physiological factors influence TSH secretion via an alteration in the amount of pulsatile released hormone. An increase in somatostatinergic tone during fasting appears to decrease TSH pulse amplitude and sequentially mean TSH serum levels. In contrast, blockade of dopaminergic tone by metoclopramide infusion when circulating TSH levels are low during the afternoon hours increase TSH pulse amplitude to levels comparable to the nightly TSH surge suggesting a physiological dampening of TSH pulse amplitude by dopamine during the daytime.
The Roles of Time of Day and Sleep Quality in Modulating Glucose Regulation: Clinical Implications
Authors: Scheen André J. , van Cauter Eve
Published: April 2003

Consistent variations in glucose regulation across the 24-hour cycle are present in normal subjects. These diurnal variations are altered in various states of impaired glucose tolerance (aging, obesity, diabetes). Changes in insulin secretion, clearance and/or action across the day have been demonstrated. Studies in subjects receiving continuous intravenous glucose infusion have shown that major alterations of glucose tolerance occur during sleep and that sleep quality markedly influences glucose utilization. Diurnal variations in glucose tolerance result from the alternation of wake and sleep states as well as from intrinsic effects of circadian rhythmicity. The important roles of physiological variations in levels of counterregulatory hormones which are markedly dependent on sleep (i.e. growth hormone) or circadian rhythmicity (i.e. cortisol) have only begun to be appreciated. The modulatory effects of sleep and circadian rhythmicity on glucose regulation may have important clinical implications for the diagnosis and treatment of abnormalities of carbohydrate metabolism.
Effect of Cell Density on Hormonal Secretion from Human Pituitary Adenomas in vitro
Authors: Atkin Stephen L. , Hipkin Leslie J. , Landolt Alex M. , Jeffreys Richard V. , Foy Patrick M. , White Michael C.
Published: April 2003

Cell density effects were investigated on tumorous hormonal secretion from 10 pituitary adenomas: 3 somatotrophinomas secreting GH and PRL; 7 gonadotrophinomas, 3 co-secreted both FSH and LH, all 7 secreted LH. Enzymatically dispersed tissue was plated out in 24-well plates at 5 ×105, 105, 5 ×104 and 104 cells/well in serum-free media. Media were collected weekly for 2 weeks. Results: In 3 of 3 somatotrophinomas, GH and PRL secretion was higher (p < 0.05) at both week 1 and 2 from 104 cells/well, but similar at other cell densities. In all 3 gonadotrophinomas, the FSH secretory rate was highest at 5 ×105 cells/well which fell as cell density decreased. Conversely, in 7 of 7 gonadotrophinomas the LH secretory rate was highest at 104 cells/well (p < 0.01) which fell as cell density increased. Conclusion: These data suggest that paracrine factors may modulate tumorous GH, PRL, FSH and LH secretion, and show that FSH and LH secretion vary inversely as cell density increases.
Relation of Race, Age, and Sex Hormone Differences to Serum Leptin Concentrations in Children and Adolescents
Authors: Ambrosius Walter T. , Compton Joyce A. , Bowsher Ronald R. , Pratt J. Howard
Published: April 2003

We explored the effects of race, age, and sex hormones on the serum leptin concentrations in 203 white and 88 black children and adolescents (ages 9.3–20.5 years). A significant sex by race interaction on serum leptin levels (p = 0.0301) was observed with lower serum leptin concentrations, adjusted for subscapular thickness and age, in black boys than in white boys. Girls had serum leptin levels that were on average 2.15 times those of boys (p < 0.0001). There was an age by sex interaction (p < 0.0001) with serum leptin concentrations decreasing in boys but not in girls with age. A strongly inverse relationship of serum testosterone levels with serum leptin levels in boys (p = 0.0067) appeared to explain this effect of age. In conclusion, the serum leptin concentration is slightly lower in black boys. A higher testosterone level in boys appears to account for an age-related decline in serum leptin in boys and the overall lower levels in boys than in girls.
Radioiodine Treatment of Graves’ Disease in Young People
Authors: Cheetham T.D. , Wraight P. , Hughes I.A. , Barnes N.D.
Published: April 2003

In Europe young patients with Graves’ disease are usually treated with antithyroid drugs initially, then if hyperthyroidism recurs after a prolonged course of such medication, they are offered definitive treatment by subtotal or total thyroidectomy. Neither of these forms of treatment is free from problems. Impressed with the simplicity and safety record of radioiodine therapy, we have treated 8 young patients with radioiodine. The patients all presented with typical Graves’ disease and relapsed after 18–24 months of treatment with antithyroid drugs. They were then given the option of a further course of antithyroid medication or definitive treatment with radioiodine or surgery. Those who opted for radioiodine were treated with 131iodine in a dose of 300 MBq with the intention of ablating the thyroid. Antithyroid medication was resumed for 4–6 months and then withdrawn. Four patients became hypothyroid after a single dose of radioiodine but 4 needed a second dose. All became hypothyroid within 2 years. No adverse effects were observed, in particular no patient showed any deterioration in their eye disease. Radioiodine offers a simple, effective and inexpensive method of treatment for Graves’ disease in young patients. There are no immediate adverse effects and, although some theoretical concerns remain, to date the long-term safety record of thyroid ablation is excellent and the potential risks seem to us to be outweighed by the advantages. Even when a moderately high initial dose of radioiodine is used, a second dose may be needed.
Serum Leptin Is Suppressed by Growth Hormone Therapy in Growth Hormone-Deficient Children
Authors: Rauch Frank , Westermann Frank , Englaro Piera , Blum Werner F. , Schönau Eckhard
Published: April 2003

Leptin is a hormone which is exclusively synthesized and secreted by adipocytes. As of yet, little is known about the complex interplay of hormones in the modulation of circulating leptin levels. To investigate the effect of growth hormone (GH) therapy on leptin, leptin serum concentrations were measured by a specific radioimmunoassay in 29 children with GH deficiency (21 boys, 8 girls; age range 3–14 years) before and after 1, 3 and 6 months of treatment with recombinant human GH. At baseline, serum leptin levels were identical to those of healthy children. Serum leptin correlated with body mass index (BMI; r = 0.60, p < 0.001) and weight (r = 0.48, p = 0.004), but not with height, age, insulinlike growth factor 1, or insulinlike growth factor-binding protein 3, and there was no sex difference (p > 0.05). After 1 month of treatment, the leptin levels had decreased to 73 ± (SEM) 13% of individual pretreatment levels (p = 0.002) and remained constant thereafter. While the correlation between leptin, BMI, and weight persisted throughout the study period, the changes in leptin concentrations during treatment were not associated with changes in BMI, weight, height, insulinlike growth factor 1, and insulinlike growth factor binding protein 3. In conclusion, this preliminary study demonstrates that serum leptin decreases during GH treatment in children with GH deficiency.
Induction of Early Puberty in a Boy after Treatment with Oxandrolone?
Authors: Doeker B. , Müller-Michaels J. , Andler W.
Published: April 2003

We report on a 9-year-old boy with early puberty who had been treated with oxandrolone because of constitutional delay of growth. Treatment was started at the age of 6.25 years. During the treatment with oxandrolone over 22 months, the height velocity increased above the 97th percentile, and bone age developed twice as fast as chronological age. After discontinuing the medication, the growth velocity did not decrease, and the bone age still accelerated. When he was 9.1 years old, testicular volume had increased to 12 ml, pubic hair stage had progressed and he developed a mild facial acne. We hypothesize that oxandrolone could have induced an early onset of puberty in this boy. We conclude that treatment with oxandrolone in young children should be considered carefully and be used for short periods only. Potential side effects might include the rapid acceleration of puberty and skeletal maturation.
Insulin Pulsatility in Obese and Normal Prepubertal Children
Authors: Radetti G. , Ghizzoni L. , Paganini C. , Iughetti L. , Caselli G. , Bernasconi S.
Published: April 2003

Objective: To assess whether in prepubertal children insulin secretion is pulsatile as in adults and to study the influence of body weight on the pattern of insulin secretion. Design and Patients: Insulin profiles were obtained by 4-min sampling for 2 h, starting at 08.00 a.m. after an overnight fast in 10 prepubertal obese children (BMI-SDS 4.9 ± 1.6) and in 6 healthy age-matched controls. Five of the obese children were also studied after weight reduction (Δ BMI-SDS 1.6 ± 0.4). The data have been analyzed by the Pulsar program. Results: Obese children had higher mean insulin levels, insulin secretory areas under the curve above 0 (AUC₀), and AUC above baseline (AUCb), with more frequent peaks of larger amplitude and duration compared to controls. Following weight reduction there was a normalization of AUC₀ and mean insulin levels while AUCb, peak frequency, amplitude and duration did not change significantly. Correlation analysis revealed that BMI-SDS was strictly related to the parameters of pulsatile insulin secretion such as AUC₀, AUCb, mean insulin level, peak amplitude and peak frequency. Conclusions: Insulin secretion in children is pulsatile and its secretory pattern is influenced by body weight.
Craniofacial Growth and Dental Maturation in Short Children Born Small for Gestational Age: Effect of Growth Hormone Treatment
Authors: van Erum Ria , Mulier Greet , Carels Carine , de Zegher Francis
Published: April 2003

Short children born small for gestational age (SGA) may be candidates for treatment with growth hormone (GH). We examined craniofacial growth and dental maturation in a cohort of short SGA children. The general growth failure of these children is reflected to a differential extent within the craniofacial complex. As a group, these children have a small retrognathic face with a relatively increased lower anterior face height; in contrast to skeletal maturation, dental age is not delayed. GH treatment in short prepubertal SGA children leads to craniofacial catch-up growth, which is particularly pronounced in regions where interstitial cartilage is involved, the result being that the facial profile becomes less convex; dental maturation does not appear to be influenced by GH treatment. In conclusion, in short SGA children, GH treatment does not only result in an increase of body stature but also in a trend towards normalization of craniofacial growth and this without notable advancement of dental maturation.
Potential Role for Growth Hormone in Human Lactation Insufficiency
Authors: Milsom Stella R. , Rabone Diana L. , Gunn Alistair J. , Gluckman Peter D.
Published: April 2003

In order to evaluate the galactopoietic response to rhGH in mothers of normal babies with idiopathic lactation insufficiency arising in the early postpartum period, we performed a preliminary, randomised, single blind trial of 3 different doses of hGH: either 0.05, 0.1, or 0.2 IU/kg/day to a maximum of 16 IU/day, for 7 days. Total 24-hour milk production was determined in each mother 1 day prior to initiating therapy and on the last day of therapy. Milk production rose by 36.0 ± 12.6% in the group receiving 0.2 IU/kg/day (n = 6) but by only 4.7 ± 9.7%, (p < 0.04) in the combined lower dose group (n = 10). In conclusion, these data suggest that moderate dose hGH therapy in mothers with lactation insufficiency can improve galactopoiesis.
Congenital Hypothyroidism Screening in the West Bank: A Test Case for Screening in Developing Regions
Authors: Sack Joseph , Feldman Inbar , Kaiserman Igor
Published: April 2003

Screening for congenital hypothyroidism (CH) among the Arab population of the West Bank began in May 1987 as part of the neonatal screening program in Israel. In the West Bank many infants are born at home or are released from the hospital on the 1st day after birth and thus cannot be screened. However, we tried to reach the infants before the age of 1 month at the maternal and child health centers, where they receive immunization. In this screening program, 64% of the infants were sampled by the 1st week and 93% by 3 weeks of life. In contrast to the screening in Israel, where thyroxine determination is followed by thyroid-stimulating hormone measurement, in the West Bank thyroid-stimulating hormone was tested first in order to decrease the recall rates. From June 1990 to February 1994, 49,694 infants were screened in the West Bank, of whom 24 with CH were detected (an incidence of 1:2,070). From January 1987 to February 1994, 28,938 infants were screened in East Jerusalem, of whom 20 with CH were detected (incidence 1:1,447). There were differences between the incidence rates in the various districts. The incidence rates were higher than those reported from industrialized countries, but similar to those found in Saudi Arabia. This may be due to the high degree of consanguineous marriages among Arab populations and to environmental factors. In conclusion, in spite of the many difficulties, both practical and political, CH screening in the West Bank is feasible. Although screening all newborns shortly after birth is not possible, this study shows that a high percentage of them can be screened at a time when they can still be effectively treated. Our results could be used in due time as a baseline for a future independent screening program.
Lumbar Spine Bone Mineral Density in Diabetic Children with Recent Onset
Authors: De Schepper J. , Smitz J. , Rosseneu S. , Bollen P. , Louis O.
Published: April 2003

To detect early abnormalities in bone mineralization, the lumbar spine bone mineral density (BMD) of diabetic children with a diabetes onset of less than 5 years and treated with a similar insulin treatment scheme was measured at the level of the lumbar spine by dual-energy X-ray absorptiometry (DEXA), a most sensitive technique for detecting osteopenia in children. Fifteen male and 8 female children and adolescents (mean age ± SD: 12.5±3.7 years), 1–5 years after the clinical onset of their diabetes, were studied. Measurements of the lumbar spine (L1–L4) BMD, expressed in gHA/cm2 and as a z-score for age, were performed with a commercial DEXA apparatus (Hologic QDR 1000 W, Hologic Inc., Waltham, USA). Calcium-phosphorus metabolism was studied by measuring the circulating levels of calcium, phosphorus, alkaline phosphatase, osteocalcin, 25-OH-vitamin D and parathyroid hormone and the urinary excretion of calcium and phosphorus. The mean BMD of the studied group was 0.75 (0.16) gHA/cm2 giving a mean z-score of –0.31±0.95. Only 1 of the patients had a BMD lower than –2 SD. No sex difference in BMD z-score existed. BMD SD was positively correlated with height SD (R = 0.56, p < 0.005), but not with the age of the patients, the duration of the disease, the degree of metabolic control or the studied parameters of the calcium-phosphorus metabolism. In conclusion, diabetic children have a normal lumbar spine BMD during the first years of the disease, when a good metabolic control and no abnormalities in the calcium-phosphorus metabolism are present. As in normal children, areal BMD by DEXA is highly dependent on the body height, necessitating corrections if abnormalities in skeletal growth or pubertal development exist.
Response of the Free Alpha-Subunit to GnRH Distinguishes Individuals with ‘Functional’ from Those with Permanent Hypogonadotropic Hypogonadism
Authors: Mainieri Alberto Scofano , Viera José Gilberto H. , Elnecave Regina Helena
Published: April 2003

The aim of this study was to compare the responses of pituitary gonadotropins and the free α-subunit (FAS), measured by sensitive immunofluorometric assays at 0, 30 and 60 min after 100 µg GnRH i.v. in a group of 32 normal prepubertal boys (NB) and a group of 17 adult males with complete hypogonadotropic hypogonadism (HH). At time 0 min, medians of the serum levels of LH, FSH and FAS were not different in both groups. At 30 min (29.81 and 8.56 pmol/l) and 60 min (24.10 and 7.74 pmol/l) as well as peak levels (29.76 and 8.56 pmol/l), ‘deltas’ (peak minus baseline; 25.89 and 0.34 pmol/l) and ‘fold’-increase (peak divided by baseline; 7.0-fold and 1.6-fold), the medians were significantly higher in NB than in HH, respectively. There were fewer overlapping values of FAS between the 2 groups and they occurred in only 4% of the total number of subjects when ‘fold’ was considered. The measurement of FAS by a very sensitive immunofluorometric assay, after GnRH, distinguishes responses of NB from those of adult men with HH, that is of functional from permanent HH.
Hypercalcemia in Malignant Paraganglioma due to Parathyroid Hormone-Related Protein
Authors: Loh Keh-Chuan , Matthay Katherine K. , Hoover Margo , Bracho Francisco A. , Cortez Alan B. , Conte Felix A. , Albanese Craig T. , Miller Theodore R. , Price David C. , Flores Alonzo J. , Kaviani Ali , Shoback Dolores
Published: April 2003

A 15-year-old boy had hypercalcemia in association with malignant retroperitoneal paraganglioma. He had suppressed circulating levels of intact parathyroid hormone, whereas parathyroid hormone-related protein (PTHrP) immunoreactivity was elevated in plasma. Both the serum 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels were normal. Preoperatively the patient required control of hypercalcemia with intravenous pamidronate therapy. His circulating calcium and PTHrP concentrations became normal after a successful surgical resection of the primary retroperitoneal tumor. To our knowledge, this is the first reported case of elevated PtHrP levels in a patient with paraganglioma which resolved postoperatively.
Adrenocortical Carcinoma Evolving after Diagnosis of Preclinical Cushing’s Syndrome in an Adrenal Incidentaloma
Authors: Höfle G. , Gasser R.W. , Lhotta K. , Janetschek G. , Kreczy A. , Finkenstedt G.
Published: April 2003

A 43-year-old female patient underwent abdominal ultrasonography and CT scan because of uncharacteristic abdominal pain. A 3-cm homogeneous adrenal tumor was diagnosed. The endocrine tests revealed an adrenal preclinical Cushing’s syndrome (PCS). Due to the latent hormone excess we decided to operate on the adrenal tumor. Since the tumor was small, laparoscopic adrenalectomy was performed. Histological evaluation showed an adrenocortical tumor of undetermined nature. Four months later the patient presented with a metastasizing cortisol- and androgen-producing adrenocortical carcinoma (ACC). After pretreatment with ketoconazole to suppress the biosynthesis of adrenal steroids under substitution with hydrocortisone, we reduced the tumor load by surgery. Postoperatively we continued ketoconazole and started o,p′-dichlorodiphenyldichloroethane as well as chemotherapy with doxorubicin and suramin. However, the patient died from ACC 7 months after adrenalectomy. It is known from several reports that PCS may persist clinically silently or may progress to full-blown Cushing’s syndrome. This is the first time a malignant course of PCS is described. Independent of the initial therapeutic strategy of PCS, i.e. surgery or regular follow-up visits, we must be aware that also relatively small adrenal tumors can harbor malignancy.
Androgens and Fetal Growth
Authors: de Zegher Francis , Francois Inge , Boehmer Annemie L.M. , Saggese Giuseppe , Müller Jørn , Hiort Olaf , Sultan Charles , Clayton Peter , Brauner Raja , Cacciari Emanuele , Ibáñez Lourdes , van Vliet Guy , Tiulpakov Anatoly , Saka Nurçin , Ritzén Martin , Sippell Wolfgang G. , Androgens and Fetal Growth Study Group A
Published: April 2003

Boys are heavier than girls at term birth. Children with a 46,XY karyotype and androgen insensitivity syndrome (clinically complete form and/or proven mutations in the androgen receptor gene) were found to have a birth weight comparable to that of girls. These findings support the hypothesis that the difference in birth weight between boys and girls is generated by androgen action.
Nocturnal TSH Surge and TRH Test Response in the Evaluation of Thyroid Axis in Hypothalamic Pituitary Disorders in Childhood
Authors: Gruñeiro-Papendieck Laura , Chiesa Ana , Martínez Alicia , Heinrich Juan Jorge , Bergadá Cesar
Published: April 2003

We studied, by means of TSH nocturnal secretion and TRH test, 42 children (4.2–19.9 years) with hypothalamic pituitary disorders and 24 healthy euthyroid children (5.7–15.4 years) as control group. Patients were divided according to their serum values of FT4 in group 1 (n = 27) with FT4 ≥10.3 pmol/l and group 2 (n = 15) with FT4 <10.3 pmol/l. TSH was measured by immunoradiometric assay. TSH nadir, TSH peak and TSH surge were calculated. Both groups differed significantly from control group in TSH surge values: group 1 (p < 0.05), group 2 (p < 0.01). TRH test was abnormal in 11/27 patients of group 1 and 10/15 patients of group 2. In group 1, 7 patients had normal tests, 2 had abnormalities in both tests, 9 had only TSH nocturnal surge altered and 9 showed only TRH alterations. All patients of group 2 presented thyroid axis abnormalities. In conclusion, in patients with hypothalamic pituitary disorders with low FT4, no further investigation is required to demonstrate thyroid axis alterations, however in patients with normal FT4, nocturnal TSH secretion and TRH test may be required to evidence thyroid abnormalities.
Catch-Up Growth after Childhood-Onset Substitution in Primary Hypothyroidism: Is It a Guide towards Optimal Growth Hormone Treatment in Idiopathic Growth Hormone Deficiency?
Authors: Ranke M.B. , Schwarze C.P. , Mohnike K. , von Mühlendahl K.E. , Keller E. , Willgerodt H. , Kiess W.
Published: April 2003

Catch-up growth was analyzed in 20 prepubertal children with primary hypothyroidism (PH) starting treatment at an age of 4.4 (1.2–10.1) years and a height (HT) SD score (HT SDS) of –3.1 (±0.8). All patients were followed for at least 3 prepubertal years. HT velocity was 12.3 ± 2.3, 9.0 ± 1.8 and 7.5 ± 2.2 cm/year, and change in HT SDS was 1.60 ± 0.56, 0.57 ± 0.33 and 0.28 ± 0.38 during the 1st, 2nd and 3rd year, respectively. The 11 children followed to adult height reached a HT SDS of –0.11 ± 1.1, all within their target HT range. HT gain (ΔHT SDS) during the 1st year was correlated with the degree of catch-up growth (r2 = 0.78, p < 0.001). While catch-up growth in childhood-onset PH is complete, this is not the case in GH deficiency (GHD). Based on the auxological characteristics of the patients with PH, HT velocities during the first 2 years were predicted applying prediction models devised for prepubertal children with idiopathic GHD. The modalities of GH treatment observed in the models were used to calculate predicted HT velocities of the PH patients. Observed HT velocities in PH were higher than predicted HT velocities during the 1st (10.67 ± 1.37 cm/year, p < 0.01) and 2nd (8.35 ± 0.86 cm/year, p = 0.128) year. The data show that catch-up potential in idiopathic GHD of childhood onset is reduced compared to PH. Since early catch-up as well as total HT recovery in children with GHD are often not reached by present treatment modalities, catch-up growth in PH may serve as a model towards optimizing GH treatment. The data suggest that initial GH doses of 1.0 IU/kg/week, rather than the presently recommended 0.6 IU/kg/week, need to be given in GHD in order to achieve the degree of early catch-up observed in PH and to consequently improve the final outcome.
Study of Serum Leptin in Cafeteria-Diet-Overfed Rats
Authors: De Schepper J. , Zhou X. , De Bock S. , Smitz J. , Louis O. , Hooghe-Peters E. , Vandenplas Y.
Published: April 2003

In a group of 15 male Wistar rats overfed with cafeteria foods (delivering a mean fat percentage of 60%) during 5 months from the age of 8 weeks and in a control group of 15 rats fed with a standard chow for the same period, serum leptin, insulin and corticosterone were measured by RIA and body composition was determined by dual-energy X-ray absorptiometry. Significantly higher fasting serum concentrations of leptin, insulin and corticosterone were found in the cafeteria-diet group. Fasting leptin concentrations were significantly higher in rats with a body fat percentage of more than 25% compared to the others, irrespective of the type of feeding. The log serum leptin correlated positively with body fat percentage and fasting insulin concentration but not with corticosterone concentration. Leptin concentration corrected for body fat mass was, however, comparable between the two diet groups, while the leptin/insulin ratio was lower in the cafeteria-diet group. In conclusion, chronic overfeeding resulting in an increased body fat percentage in rats is associated with hyperleptinemia, hyperinsulinemia and hypercorticism. Serum leptin levels appear to primarily track total body fat percentage and are unaffected by dietary fat manipulation in cafeteria-diet-induced obese rats.
Longitudinal Analysis of Maternal Serum Leptin Levels during Pregnancy, at Birth and Up To Six Weeks after Birth: Relation to Body Mass Index, Skinfolds, Sex Steroids and Umbilical Cord Blood Leptin Levels
Authors: Schubring C. , Englaro P. , Siebler T. , Blum W.F. , Demirakca T. , Kratzsch J. , Kiess W.
Published: April 2003

Leptin is an important regulator of body fat mass and energy expenditure during adult life. The mechanisms by which maternal and fetal weight are regulated during pregnancy are poorly understood. In order to gain more insight into a potential role of leptin during gestation, a prospective, longitudinal study was carried out to measure leptin concentrations in maternal serum of 29 healthy women during pregnancy up to 6 weeks after birth and also in umbilical cord blood of their newborns. Leptin concentrations were measured using a specific RIA. In addition, estradiol, testosterone, and sex hormone binding globulin were determined using commercially available RIAs. The mothers’ skinfolds were determined at four sites using a Holtain caliper.Leptin levels increased continuously during pregnancy and reached 25.8 ± 14.7 ng/ml at 38–40 weeks. At birth, leptin concentrations were 23.5 ± 15.4 ng/ml. Three days after delivery a significant decrease of leptin levels to 10.6 ± 6.0 ng/ml was observed. Six weeks after birth the leptin concentration in maternal serum was 13.8 ± 8.6 ng/ml. At birth, maternal serum levels were significantly higher than levels in cord blood and did not correlate with leptin levels in cord blood or neonatal weight. Furthermore, leptin levels did not correlate with maternal sex steroids and sex hormone binding globulin levels. At 6–8 weeks of pregnancy, maternal leptin serum levels correlated significantly with BMI (r = 0.81). The correlation coefficients (leptin vs. BMI) dropped with increasing gestational age and at birth only a poor correlation persisted (r = 0.50). Six weeks after birth there was again a high correlation between leptin levels in maternal serum and BMI (r = 0.76). Subscapular skinfold thickness was correlated to leptin concentrations in maternal serum during the whole period of the investigation.In conclusion, maternal leptin levels continuously increased from 6–8 weeks up to 38–40 weeks of pregnancy. Maternal leptin levels decreased dramatically after birth. Six weeks after delivery, leptin levels were comparable to the values measured at the beginning of pregnancy. We hypothesize that leptin might play an important role during pregnancy and fetal development.
Systemic Administration of Epidermal Growth Factor Reduces Fat Mass in Rats: Effects on the Hormone-Sensitive-Lipase, Lipoprotein Lipase and Leptin
Authors: Kristensen Kurt , Pedersen Steen B. , Vinter-Jensen Lars , Flyvbjerg Allan , Richelsen Bjørn
Published: April 2003

We examined whether the reduction in fat mass induced by EGF treatment in mature animals was via activation of hormone-sensitive lipase (HSL) and thereby the induction of lipolysis, or through inhibition of lipoprotein lipase activity thus reducing fat uptake in adipose tissue. Sixteen male rats were treated with placebo or EGF 150 µg/kg/day for 7 days via mini-osmotic pumps. The results demonstrate that systemic EGF treatment reduces the amount of adipose tissue, most likely due to increased lipolysis as HSL activity as well as HSL mRNA were increased. The circulating levels of free fatty acids were slightly increased and leptin levels reflected the decrease in adipose tissue mass.
Interpretative Difficulties with Growth Hormone Provocative Retesting in Childhood-Onset Growth Hormone Deficiency
Authors: VandenBroeck Jan , Hering Patrick , VandeLely Aart-Jan , Hokken-Koelega Anita
Published: April 2003

A review of literature demonstrates that there are many ill-understood factors that determine the results of GH provocative (re)testing, so that these results should be interpreted with extreme caution when used for diagnosis or confirmation of diagnosis of GHD. GH provocation tests are probably of no value at all for what has been called ‘partial GHD’. The phenomenon of ‘normalization’ of test results after long-term treatment with GH needs no ‘transient GHD’ hypothesis as it can be largely explained by the very low reproducibility of the tests and by a regression to the mean effect. Moreover, it is possible that ‘normal values’ increase with age. Other determinants of normal peak values may also change from childhood to adulthood and contribute to ‘normalization’.
Effects of Recombinant Human Growth Hormone on Height and Skeletal Maturation in Growth Hormone-Deficient Children with and without Severe Pretreatment Bone Age Delay
Authors: Frindik J. Paul , Kemp Stephen F. , Sy Judy P.
Published: April 2003

The relative effects of growth hormone (GH) on GH-deficient (GHD) children with and without severely delayed skeletal maturation prior to treatment are unclear. Methods: Pre-pubertal GHD children enrolled in the National Cooperative Growth Study were divided into two groups: severe pretreatment BA delay (BA Z-score ≤–2, group 1) and mild to moderate delay (BA Z-score between –2 and 0, group 2). BA Z-scores (BAZ), height Z-scores and predicted adult height (PAH) Z-scores at pubertal onset were determined after initiation of recombinant human GH (rhGH) therapy. Results: Height Z-scores increased from baseline to the start of puberty in both groups (group 1: mean difference of +0.99, males and +1.02, females; group 2: +0.68, males and +0.75, females). Mean BAZ also increased in all group 1 children (+1.62, males and +1.08, females) with no corresponding change in mean BAZ in group 2. PAH Z-scores increased in both groups. There was no evidence of undue advance in BA since mean BAZ remained well below zero in group 1 and was unchanged in group 2. Conclusion: rhGH has a beneficial effect on growth in prepubertal GHD children at all levels of pretreatment BA delay.
Insulin-Like Growth Factor Binding Proteins: New Proteins, New Functions
Authors: Ferry Jr. Robert J. , Cerri Ruben W. , Cohen Pinchas
Published: April 2003

The insulin-like growth factors (IGFs), IGF binding proteins (IGFBPs), and IGFBP proteases regulate somatic growth and cellular proliferation both in vivo and in vitro. IGFs are potent mitogens whose actions are determined by the availability of free IGFs to interact with IGF receptors. IGFBPs comprise a family of six proteins that bind IGFs with high affinity and specificity and thereby regulate IGF-dependent actions. IGFBPs have recently emerged as IGF-independent regulators of cell growth. Cleavage of IGFBPs by specific proteases modulate levels of free IGFs and IGFBPs and thereby their actions. IGFBP-related proteins (IGFBP-rPs) bind IGFs with low affinity and also play important roles in cell growth and differentiation. The GH-IGF-IGFBP axis is complex and powerful. Future research on its physiology promises exciting insights into cell biology as well as therapies for diseases such as cancer and diabetes mellitus.
Ten-Year Follow-Up in a Boy with Leydig Cell Tumor after Selective Surgery
Authors: Konrad Daniel , Schoenle Eugen J.
Published: April 2003

In a 48/12-year-old boy with precocious puberty and an enlarged right testis, a Leydig cell tumor was diagnosed. Surgical exploration revealed an encapsulated tumor which was selectively removed without orchiectomy. Within 1 year the signs of precocious puberty disappeared. Ten years later, the patient remained free of disease and had developed normal spontaneous puberty. Despite of highly advanced bone age at the time of diagnosis (13 years according to Greulich and Pyle), his height at age 15 was in the upper normal range and within the familial target height. Most of these prepubertal patients affected by this tumor underwent orchiectomy, although no malignant course of Leydig cell tumors before puberty has been reported. This work provides the first example of long-term follow-up of a prepubertal boy after testis-sparing surgery for a Leydic cell tumor. We conclude that selective removal of the tumor may be the procedure of choice in this entity.
Clinical Usefulness of TSAb Assay with High Polyethylene Glycol Concentrations
Authors: Ochi Y. , Inui T. , Kouki T. , Yamashiro K. , Takasu N. , Kajita Y. , Sato Y. , Nagata A.
Published: April 2003

We previously demonstrated the stimulatory effect of polyethylene glycol (PEG) on thyroid-stimulating antibody (TSAb)-IgG-stimulated cAMP production (thyroid stimulating (TS) index) in porcine thyroid cell (PTC) assay. In the present study the clinical usefulness of the practical method using high PEG concentrations was examined. TS activity using PEG 22.5% precipitated fraction (PF) was significantly higher compared to standard TSAb activity using 12.5% PF from TSAb-positive serum, but the maximum TS activity was observed with PEG 12.5% PF + 4% PEG or PEG 22.5% PF + 2% PEG. In all cases of untreated Graves’ patients, TSAb activity determined by PEG 22.5% PF was higher compared to standard TSAb activity using PEG 12.5% PF from test serum, but the highest TSAb activity was observed by PEG 12.5% PF + 4% PEG without increased cAMP production to normal serum. TSAb was positive in 85% (40/47), 98% (46/47) and 100% (47/47) of untreated Graves’ patients by the method of PEG 12.5% PF, PEG 22.5% PF and PEG 12.5% + 4% PEG, respectively. Increased TSAb activity by PEG 12.5% PF + 4% PEG method was also observed even if the standard TSAb activity using PEG 12.5% PF method was negative in the euthyroid states of Graves’ patients during antithyroid drug therapy. The stimulatory effect of PEG on TS activity was not found in other thyroidal diseases [thyroiditis chronica (with high serum TSH), thyroid stimulation-blocking antibody (TSBAb)-positive sera (with low serum TSH), adenomatous goiter, subacute thyroiditis, and thyroid cancer]. The stimulatory effect of 5% PEG on TS activity produced directly by small amounts of Graves’ serum (50 μl) was also found, although the sensitivity was lower than with PEG-precipitated IgG from 0.2 ml serum. The clinical usefulness of the sensitive TSAb assay using PEG-precipitated IgG or direct serum assay in the presence of high PEG concentrations was demonstrated.
Near-Normal Linear Growth in the Setting of Markedly Reduced Growth Hormone and IGF-1
Authors: Murashita Mari , Tajima Toshihiro , Nakae Jun , Shinohara Nozomi , Geffner Mitchell E. , Fujieda Kenji
Published: April 2003

A 14.2-year-old prepubertal boy diagnosed with complete-type growth hormone deficiency and tertiary hypothyroidism, keeps growing in the height range between –1 and –2 SD. He has been treated with levothyroxine only. To understand the growth mechanism of this boy, we analyzed the serum growth hormone (GH) with a radioimmunoassay (RIA), serum GH bioactivity with Nb2 and erythroid progenitor cell bioassays, and growth hormone-binding protein (GHBP) with a ligand-mediated immunofunctional assay (LIFA). In addition, IGF-1 and free IGF-1 were analyzed by immunoradiometric assay (IRMA) and insulin-like growth factor-binding protein-3 (IGFBP-3) by Western immunoblot. Peak GH-RIA responses to insulin, arginine and GH-releasing factor, and nocturnal GH secretion, were low (0.5–2.3 ng/ml); bioactive GH was low (0.313 ng/ml), and GHBP was elevated (84 ng/ml). The serum levels of IGF-1 and free IGF-1 were continuously low, 17.1–39.3 and 0.17–0.26 ng/ml, respectively. Moreover, serum IGFBP-3 levels were low (1.68– 1.39 mg/l) and IGFBP-3 protease activity was negative. Prolactin and insulin were in the normal range. The result of the assay for growth-promoting activity showed that the patient’s serum stimulated normal erythroid progenitor cells twice as potently as did healthy thin adult control serum. These results suggest that GH and IGF-1 are not indispensable for maintaining physical growth in this boy. Thus, it appears that circulating GH and IGF-1 are not mandatory requirements for maintaining normal physical growth, and other, as yet uncharacterized, pathways or growth factors might be sufficiently compensatory under certain conditions.