bluuebunny/crossref_metadata_2025 huggingface dataset:
Metabolic Status of Children with Growth Hormone Insensitivity Syndrome and Responses to Treatment with IGF-I
Authors: Brain C.E. , Hubbard M. , Preece M.A. , Savage M.O. , Aynsley-Green A.
Published: April 2003

Studies to date on the treatment with insulin-like growth factor I (IGF-I) of children with growth hormone (GH) insensitivity syndrome (GHIS) have concentrated principally on the effects of IGF-I therapy on the GH-IGF-I axis and on growth velocity. Little is known, however, about the metabolic status of children with GHIS and the consequences of IGF-I treatment on circulating intermediary metabolites involved in glucose homeostasis. We have studied 5 children with GHIS, aged 4.5–9 years, 3 male and 2 female, before and after 3 months of treatment with recombinant IGF-I, 80 µg/kg s.c. twice a day. The children were short (height SDS –3.8 to –7.3) and growing slowly (height velocity 1.8–3.4 cm/year). All were neurodevelopmentally normal at the time of the study with no history of severe symptomatic hypoglycaemia, in particular during the neonatal period. Before treatment, 4 of the 5 children demonstrated spontaneous hypoglycaemia (blood glucose <2.6 mmol/l), particularly at night, accompanied by substantial hyperketonaemia (range 1.43–4.63 mmol/l) and hyperfattyacidaemia (range 1.11–3.08 mmol/l). After 3 months of IGF-I treatment, the blood glucose concentrations in the diurnal profile were increased, with improvement in spontaneous hypoglycaemia and with increased fasting tolerance. The postprandial insulin-to-glucose ratio was reduced. GHIS is thus associated with asymptomatic nocturnal hypoglycaemia without apparent neurological deficit. Despite functional GH deficiency, brisk counter-regulation to hypoglycaemia occurred as evidenced by hyperfattyacidaemia and hyperketonaemia. Treatment with IGF-I twice a day improved fasting glucose tolerance, diurnal blood glucose concentrations, and postprandial insulin-to-glucose ratios. There was no exacerbation of hypoglycaemia on treatment. We suggest that in severe GH resistance, a protective mechanism exists for the brain from the effects of hypoglycaemia, at least partially mediated by excessive production of counter-regulatory metabolic fuels.
Multiple Endocrine Involvement in Two Pediatric Patients with Kearns-Sayre Syndrome
Authors: Artuch Rafael , Pavía Carlos , Playán Ana , Vilaseca Maria Antònia , Colomer Jaume , Valls Carme , Rissech Miquel , González María Antonia , Pou Adolf , Briones Paz , Montoya Julio , Pineda Mercé
Published: April 2003

We present 2 cases of progressively severe Kearns-Sayre syndrome (KSS) with multisystemic affectation and atypical endocrine and cutaneous features, a 16-year-old patient (case 1) and a 5-year-old patient (case 2). Endocrine studies showed high glucose and glycohemoglobin concentrations with normal pancreatic reserve and low values of ACTH, cortisol, LH and FSH in case 1. Normal ACTH values with low concentrations of cortisol and PTH were observed in case 2. Southern blot analysis and PCR amplification revealed the presence of a deletion of approximately 6.7 kb in the mitochondrial DNA of both patients. Endocrinological studies suggest that adrenal insufficiency may be an additional feature of KSS that worsens the clinical evolution of the patients. In spite of a normal pancreatic reserve, insulin therapy should be considered in patients with diabetes mellitus of mitochondrial origin.
Steroid Receptor mRNA Levels in Human Corpus luteum
Authors: Misao Ryou , Nakanishi Yoshihito , Fujimoto Jiro , Tamaya Teruhiko
Published: April 2003

To understand the biology of sex steroids in the human corpus luteum, the expression of estrogen receptor alpha, progesterone receptor, and androgen receptor mRNA levels was determined by semiquantitative reverse-transcription polymerase chain reaction-Southern blot analysis. Expression of all receptor mRNAs was detected in all samples analyzed. Each steroid receptor mRNA level was significantly lower (p < 0.05) during the late secretory phase than that during the early or the mid-secretory phase of the endometrium. These findings support the concept of a local role for sex steroids in modulating the function and life span of the human corpus luteum.
Does a Positive Oestrogen Feedback on the Hypothalamic-Pituitary Axis Exist Concurrently with a Defective Testosterone Feedback in Klinefelter’s Syndrome?
Authors: Goh V.H.H. , Lee K.O.
Published: April 2003

The oestrogen provocation and GnRH challenge tests were carried out in 5 subjects with Klinefelter’s syndrome who had no history of previous hormonal therapy. The oestrogen provocation test consisted of an intramuscular injection of 10 mg of oestradiol valerate and blood samples were collected daily from day 0 to day 5. In 2 subjects, three GnRH challenge tests were carried out before (day 0) and on days 2 and 4 after the intramuscular injection of oestradiol valerate. During each GnRH challenge test, 7 blood samples were collected at 30-min intervals, 30 min and immediately before and for 150 min after the bolus dose of GnRH. Plasma concentrations of FSH, LH, testosterone and oestradiol were measured by established radioimmunoassays. Plasma levels of oestradiol rose significantly a day following the intramuscular injection of 10 mg of oestradiol valerate, reaching a peak on day 2 and then falling significantly to lower levels by days 4 and 5, although these levels were still significantly higher than the corresponding baseline levels. In the presence of high levels of oestradiol, the high basal levels of FSH were significantly suppressed, and remained suppressed throughout the 5 days of the study. LH, on the other hand, had a biphasic response; an initial significant suppression by day 1 persisting to day 3, but by days 4 and 5 a rebound in basal LH levels was noted. However, the levels on day 5 were not significantly higher than baseline levels. The pituitary responsiveness as far as the LH and FSH secretions were concerned reflected the baseline levels. The results of the present study refuted the claim that a positive oestrogen feedback exists in men including Klinefelter’s syndrome as a result of the removal of or reduced testosterone. In addition, the attenuated testosterone feedback in Klinefelter’s syndrome is responsible for the greatly amplified pituitary responsiveness to the trophic action of GnRH and this, in part, may be responsible for the elevated levels of FSH and LH seen in such patients.
Homozygous Deletion of Arginine-173 in the CYP11B2 Gene in a Girl with Congenital Hypoaldosteronism
Authors: Peter M. , Nikischin W. , Heinz-Erian P. , Fussenegger W. , Kapelari K. , Sippell W.G.
Published: April 2003

The first child of consanguineous parents presented with failure to thrive and feeding problems at age 6 weeks. Important laboratory findings were low plasma sodium and elevated potassium and renin. Salt wasting was caused by an enzymatic defect in the terminal aldosterone biosynthesis. The biochemical diagnosis of corticosterone methyloxidase (CMO) deficiency type II was established on the basis of plasma multisteroid analysis, showing a pathologic increase of 18-OH-corticosterone/aldosterone ratio. Sequence analysis of the CYP11B2 gene which encodes aldosterone synthase (P450c11Aldo), the enzyme required for the terminal steps in aldosterone biosynthesis, revealed a hitherto undescribed homozygous deletion of codon 173. CYP11B2 is polymorphic at this position, encoding arginine or lysine. Both parents were heterozygous carriers of the mutation. Amino acid residue 173 in P450c11Aldo is positioned in α-helix D. We presume that the secondary structure of the enzyme is changed by the single amino acid deletion. This report describes a novel mutation in the CYP11B2 gene, the third known mutation associated with CMO deficiency type II.
Ectopic ACTH Cushing’s Syndrome: V3 Vasopressin Receptor But Not CRH Receptor Gene Expression in a Pulmonary Carcinoid Tumor
Authors: Chabot Valdo , de Keyzer Yves , Gebhard Sandra , Uské Antoine , Bischof-Delaloye Angelika , Rey François , Dusmet Michel , Gomez Fulgencio
Published: April 2003

In the etiological diagnosis of ACTH-dependent Cushing’s syndrome, it may be difficult to distinguish pituitary disease from ectopic ACTH production, specially when this is due to a benign neuroendocrine tumor. We describe a patient with partial dexamethasone suppression consistent with Cushing’s disease, an absent response to CRH suggesting ectopic ACTH production and an atypical, apparent circadian rhythm. Bilateral cavernous sinus catheterization suggested a nonpituitary source of ACTH and, in the search of an ectopic tumor, somatostatin receptor scintigraphy, abdominal CT scan, and duodenopancreatic endoscopic echography were performed and failed to reveal any abnormality. Thoracic CT scan disclosed a tiny right lung nodule that showed a definite tracer uptake on MIBG scintigraphy. After resection, the nodule proved to be an 8-mm typical pulmonary carcinoid, with positive immunostaining for the classical neuroendocrine markers and for ACTH, and showing tissue expression of the POMC gene. However, the CRH receptor gene was not expressed, explaining the absent CRH response in vivo, whereas the V3 vasopressin receptor gene was expressed in the tumor tissue. The latter feature appears to be characteristic of benign carcinoids and may contribute to explaining the CRH-independent circadian rhythm observed in this case.
Growth Hormone Replacement in an Adult with Mild Growth Hormone Deficiency and Hereditary Motor and Sensory Neuropathy: Growth Hormone Restores Independent Mobility
Authors: Lissett Catherine A. , Toogood Andrew A. , Didi Mohammed , Shalet Stephen M.
Published: April 2003

We present the case of an adult patient with growth hormone (GH) insufficiency and hereditary motor and sensory neuropathy type 1. Stopping GH replacement at the attainment of final height was associated with a marked reduction in power and mobility, resulting in the patient becoming wheelchair bound. GH replacement was assessed in a double-blind placebo-controlled trial. During the GH replacement arm of the trial, the patient’s mobility and independence returned to previous levels. We suggest that the indications for GH replacement in adults should take account of other medical problems, in particular neuromuscular disorders, as well as the degree of GH deficiency.
Sexual Differentiation: From Genes to Gender
Authors: Migeon Claude J. , Wisniewski Amy B.
Published: April 2003

A person’s sex can be considered across various levels. To illustrate, genes, hormones, and genitalia can all be considered physical markers of a person’s sex. In addition to physical markers, behaviors such as gender role, gender identity and sexual orientation can be perceived as stereotypically male or female. The purpose of this review is to summarize current knowledge of sexual differentiation which emphasizes genetic and hormonal mechanisms that result in male and female development of gonads and genitalia. Finally, consideration is given to associations between genetic sex, gonadal sex, and hormonal sex with gender.
Different Effects of Continuous and Intermittent Patterns of Growth Hormone Administration on Lipoprotein Levels inGrowth Hormone-Deficient Patients
Authors: Laursen Torben , Lemming Lone , Jørgensen Jens O.L. , Klausen Ib C. , Christiansen Jens S.
Published: April 2003

Background: Lipoprotein (a) (Lp(a)) is a risk marker for the development of atherosclerotic coronary heart disease. Growth hormone (GH) administration to GH-deficient (GHD) adults increases serum Lp(a) concentrations, and the levels of Lp(a) and GH are correlated in patients with acromegaly. Studies in rats have demonstrated differential effects of constant and intermittent GH patterns on levels of certain lipoproteins. The aim of the present studies was to describe the impact of intermittent and continuous patterns of GH delivery to GHD patients on serum levels of Lp(a) and other lipoproteins. Methods: In one study (A) 10 GHD patients received in random order a fixed GH dose intravenously as: (1) continuous infusion; (2) eight bolus injections, and (3) a combination of 1 and 2. Each study lasted 36 h and was preceded by at least 4 weeks without GH. In another study (B) 13 GHD patients received GH in random order as: (1) continuous subcutaneous (s.c.) infusion, and (2) daily s.c. injections in the evening for 1 month each. The patients were studied during steady-state conditions at the end of each treatment period. Results: In study A Lp(a) levels increased significantly following continuous (p < 0.05) and combined patterns (p < 0.02) of GH administration to GH-deprived GHD patients, whereas the increase after GH bolus injections alone was not significant (p = 0.14). In study B significantly higher (p < 0.05) serum levels of Lp(a) were obtained after continuous s.c. infusion as compared with daily s.c. injections of GH. Concentrations of the high-density lipoprotein (HDL) cholesterol were significantly lower (p < 0.02) after the continuous GH pattern. Similarly, the HDL fraction Apo A-1 tended to be lower with constant GH delivery (p = 0.052). Serum levels of total cholesterol, triglyceride and Apo B were similar on the two occasions. Conclusion: Short-term GH administration to GH-deprived GHD patients increased serum Lp(a), but only significantly with continuous delivery. During more prolonged GH exposure, constant s.c. infusion of GH resulted in slightly raised Lp(a) levels and reduced HDL and Apo A1 levels as compared with intermittently administered GH. The findings are consistent with the more effective induction of serum IGF-I levels after continuous patterns of GH delivery previously reported in GHD patients. Longer-term data are needed before conclusions with respect to the impact of the pattern of GH administration on, e.g., the risk of developing coronary heart disease can be drawn.
Altered Bone Mineral Density in Patients with Complete Androgen Insensitivity Syndrome
Authors: Bertelloni Silvano , Baroncelli Giampiero I. , Federico Giovanni , Cappa Marco , Lala Roberto , Saggese Giuseppe
Published: April 2003

Androgens have major influences on the regulation of bone mineralization. Because of their unique peripheral metabolism androgens may act on bone via activation of the androgen and/or estrogen receptor. Patients with complete androgen insensitivity syndrome (cAIS) are natural models to assess androgen actions on bone. We studied bone mineral density (BMD) in 10 patients with cAIS (mean age 13.70, range 4.7–19.8 years); 3 patients were studied before gonadectomy; the others were castrated and 6 were on hormonal replacement therapy. The BMD area (aBMD) was measured by dual energy X-ray; lumbar ‘apparent’ volumetric density (vBMD) was calculated using the formula vBMD = aBMD × [4/(π × width)]. In the patients, aBMD (0.72 ± 0.16 g/cm2) and vBMD (0.23 ± 0.04 g/cm3) were significantly (p < 0.001) reduced in comparison with those of a control group (n = 15, age 5.0–20.5 years: aBMD 1.028 ± 0.20 g/cm2; vBMD 0.35 ± 0.04 g/cm3). Both aBMD and vBMD were also reduced in comparison with normal values for males (aBMD –2.66 ± 0.99 SDS, p < 0.001; vBMD –3.08 ± 1.53 SDS, p < 0.0005) and females (aBMD –2.88 ± 1.05 SDS, p < 0.001; vBMD –2.84 ± 1.18 SDS, p < 0.0007). Real lumbar bone density, assessed by computed tomography in 1 patient, was also reduced (–6.2 SDS and –3.5 SDS for male and female normal values, respectively). Biochemical markers of bone metabolism were normal and not significantly different in patients and controls. Girls with cAIS did not have more fractures than controls. In conclusion, both aBMD and vBMD are reduced in cAIS patients, while bone turnover and the fracture risk seem not to be increased. Our data indicate that both androgens and estrogens may be required for acquisition of bone density during childhood.
Diagnosis and Treatment of Growth Hormone Deficiency in Children and Adolescents: Towards a Consensus
Authors: Saggese G. , Ranke M.B. , Saenger P. , Rosenfeld R.G. , Tanaka T. , Chaussain J.L. , Savage M.O.
Published: April 2003

This article summarizes the content of an international workshop on the diagnosis and treatment of growth hormone deficiency (GHD) in children and adolescents that was held in Pisa, Italy, in March 1998. The issues discussed are divided into those addressing the definition and diagnosis, and the treatment of GHD in children and adolescents, and those concerning the transition of patients with GHD from adolescence to adulthood. Recommendations are presented for improving the diagnosis and management of children and adolescents with GHD and issues are highlighted that require further studies to be undertaken before recommendations can be made.
Leptin Values in Placental Cord Blood of Human Newborns with Normal Intrauterine Growth after 30–42 Weeks of Gestation
Authors: Gómez Lourdes , Carrascosa Antonio , Yeste Diego , Potau Neus , Riqué Susana , Ruiz-Cuevas Pilar , Almar Jordi
Published: April 2003

Objective: To evaluate leptin values in placental cord blood of newborns with normal intrauterine growth after 30–42 weeks of gestation. Design: Leptin, a protein encoded by the ob gene, plays an important role in the regulation of feeding behaviour and energy balance in rodents, primates and humans. The presence of leptin in human amniotic fluid and cord blood has recently been reported in human gestations at term and the possible role of leptin in human fetal growth suggested. However, little is known of leptin synthesis during human foetal development. Thus, the aim of our work was to measure leptin (RIA, Linco Research, Inc.) in placental cord blood of human newborns at different fetal ages. Patients: One hundred and twenty-six healthy newborns with normal intrauterine growth were studied. Twenty-nine were preterm (15 males and 14 females; gestational age: 30–36 weeks) and 99 were at term (49 males and 48 females; gestational age: 37–42 weeks). Results: Leptin values increase progressively throughout gestation from 1.30 ± 0.53 ng/ml at 30 weeks of gestation to 7.98 ± 4.96 ng/ml (mean ± SD) at term, and correlate positively with birth weight (r = 0.56, p < 0.005, n = 126), length (r = 0.37, p < 0.005, n = 126), BMI (r = 0.57, p < 0.005, n = 126), head circumference (r = 0.37, p < 0.005, n = 126), gestational age (r = 0.48, p < 0.005, n = 126) and placental weight (r = 0.38, p < 0.003, n = 59). Leptin values are statistically significantly lower (p < 0.005) preterm (median: 2.05 ng/ml; range: 0.7–8.3 ng/ml) than at term (median: 7.0 ng/ml; range: 1.1–28.1 ng/ml). Leptin values are also significantly (p < 0.005) higher in females (median: 7.2 ng/ml; range: 0.9–23.6 ng/ml, n = 62) than in males (median: 4.8 ng/ml; range: 0.7–28.1 ng/ml, n = 64), although there are no differences in weight (2,864 ± 536 g in females vs. 2,937 ± 744 g in males). Multiple regression analysis shows weight to be a positive sex-independent predictor of serum leptin values (p < 0.0005). Sex also proves to be a predictor of leptin, independently of weight and is higher in females than in males (p < 0.003). Conclusion: Leptin is present in placental human cord blood after 30–42 weeks of gestation. Newborn weight and sex are independent predictors of leptin values.
Suppression of Growth Hormone by Oral Glucose in the Evaluation of Tall Stature
Authors: Holl Reinhard W. , Bucher Peter , Sorgo Wolfgang , Heinze Eberhard , Homoki Janos , Debatin Klaus-Michael
Published: April 2003

Excess secretion of growth hormone is a rare diagnosis in children or adolescents with tall stature. An oral glucose tolerance test (OGT) with determination of growth hormone is generally recommended to exclude this disorder. In order to test the validity of this approach in pediatric subjects, OGT tests were performed in 126 tall subjects (age: 12.4 ± 1.8 years; height: 3.1 ± 0.8 SDS). Nonsuppression was present in 39 subjects, however, anthropometric analysis and follow-up excluded the diagnosis of eosinophilic pituitary adenoma in all patients. The lowest GH concentration was reached 90 min after ingestion of oral glucose, GH rose above baseline at 180 min. Plasma concentrations of glucose and insulin did not differ between suppressors and nonsuppressors. In conclusion, absent suppression of growth hormone by oral glucose is common in tall children and adolescents. The test is therefore not recommended as a general screening for excess growth hormone. Prolonging the test beyond 120 min does not increase the diagnostic value.
Acute N-Methyl-D,L-Aspartate Administration Stimulates the Luteinizing Hormone Releasing Hormone Pulse Generator in the Ovine Fetus
Authors: Bettendorf M. , de Zegher F. , Albers N. , Hart C.S. , Kaplan S.L. , Grumbach M.M.
Published: April 2003

To assess whether fetal luteinizing hormone releasing hormone (LH-RH) neurosecretory neurons have the capacity to respond to an exogenous stimulus, a synthetic excitatory amino acid analogue, N-methyl-D-L-aspartate (NMDA; 15 mg/kg), was given rapidly intravenously to 8 chronically catheterized fetuses (130–142 days of gestation; term 147 ± 3 days). All 8 fetuses exhibited a rise in plasma ovine luteinizing hormone (oLH) and ovine follicle-stimulating hormone (oFSH) within 5 min. The mean maximal increments of oLH (2.25 ± 0.36 ng/ml) and oFSH (1.21 ± 0.32 ng/ml) were significantly greater than in 6 normal saline-injected controls (oLH p < 0.0002; oFSH p < 0.03). The secretion of ovine prolactin (oPRL) and ovine growth hormone (oGH) was unaffected. LH-RH (5 μg) evoked a greater oLH response (p < 0.0009) and a greater oFSH response (p < 0.03) than NMDA (n = 6). Desensitization of the fetal gonadotrope by a potent LH-RH agonist, D-Trp6Pro9NEt-LH-RH (10 μg/day i.v. × 4 days), abolished the fetal oLH and the oFSH response to NMDA (n = 5). Moreover, D,L-2-amino-5-phosphonovalerate, a specific competitive antagonist for the NMDA receptor, completely inhibited the fetal oLH and oFSH response to NMDA, whereas D-L-2-amino-5-phosphonovalerate alone did not affect the plasma oLH or oFSH levels, the gonadotropin response to LH-RH, or the release of oGH or oPRL (n = 3). In primary ovine fetal pituitary cell cultures, NMDA (10–10 to 10–6 M) had no effect on oLH, oFSH, oGH, or oPRL secretion, whereas LH-RH stimulated oLH (10–8 M; p < 0.0004) and oFSH (10–8 M; p < 0.0001) release, evidence that NMDA did not have a direct pituitary effect. The results suggest that NMDA induces oLH and oFSH secretion by stimulation of the fetal LH-RH pulse generator and is mediated by central NMDA receptors. Fetal LH and FSH secretion and the response to LH-RH decrease in late gestation in the ovine and human fetus. The relative importance of sex steroid dependent and sex steroid independent central nervous system inhibition in this developmental change is unclear. It appears that central neural inhibition in addition to sex steroid negative feedback contributes to the decrease in fetal gonadotropin concentrations in late gestation. NMDA did not affect fetal oGH or oPRL secretion.
Androgen Receptors in Bone-Forming Tissue
Authors: Noble B. , Routledge J. , Stevens H. , Hughes I. , Jacobson W.
Published: April 2003

Androgen receptors (AR) were stained in sections of normal human growth plate of the costo sternal junction obtained at postmortem from one 4-day-old and two 5-day-old male infants, and in osteoblasts, grown in culture obtained from the femora of 3 male patients undergoing orthopaedic surgery for osteoarthritis. In the growth plate AR were found mostly in a narrow band of chondrocytes occupying an area about midway between the proximal and distal end of the epiphysis. Nearly all AR were in the cytoplasm and appeared in a granular form; there was no diffuse staining and the nuclei were either completely devoid of AR or only contained a few. Less-differentiated chondroblasts, perichondrial cells and hypertrophic chondrocytes contained few or no AR. Osteoblasts (and osteocytes) contained numerous AR and almost all were in the cytoplasm. Normal human osteoblasts, in their second or third passage, were grown on coverslips either in a medium with no added androgen or in the presence of 5α-dihydrotestosterone or methyltrienolone for a period of 24 h or longer. In control cultures, with vehicle and no added androgen, nearly all AR were found in the cytoplasm, with hardly any in the nucleus. In the presence of added androgen some osteoblasts from two of the specimens demonstrated a clear translocation of AR into the nucleus, whilst osteoblasts from a third specimen failed to translocate. These preliminary results indicate that AR translocation to the nucleus occurs in osteoblastic cells derived from osteoarthritic subjects. However, the ability to translocate may depend on the state of differentiation of the osteoblast and on culture conditions.
Male Pseudohermaphroditism Related to Complications at Conception, in Early Pregnancy or in Prenatal Growth
Authors: Francois I. , van Helvoirt M. , de Zegher F.
Published: April 2003

We examined whether male pseudohermaphroditism, when unexplained, is associated with reduced prenatal growth. Birth weight SD scores of 29 children with male pseudohermaphroditism were compared. The scores of children with an unexplained condition (median –2.1 SD) were found to be lower (p = 0.0001) than those of children with an explained condition (median –0.4 SD). In the majority of cases of unexplained male pseudohermaphroditism, there was a complicated history before conception or in early pregnancy. In conclusion, hitherto unexplained male pseudohermaphroditism was found to be associated with reduced prenatal growth and complications at conception or in early pregnancy.
Prevalence of Coeliac Disease in Patients with Thyroid Autoimmunity
Authors: Valentino Rossella , Savastano Silvia , Tommaselli Antonio Pasquale , Dorato Maurizio , Scarpitta Maria Teresa , Gigante Marianna , Micillo Maria , Paparo Francesco , Petrone Emma , Lombardi Gaetano , Troncone Riccardo
Published: April 2003

The occurrence of autoimmune thyroid disorders among patients with coeliac disease (CD) is well documented, but the exact prevalence of CD among patients with autoimmune thyroid diseases (ATD) is as yet unclear. We screened 150 newly diagnosed patients with ATD by serum endomysial antibody detection (EmA). In 5 subjects (3.3%) EmA positivity was found; all underwent jejunal biopsy. On gluten-free diet an excellent clinical and histological response was recorded with an improvement of hypothyroidism and reduction of the thyroxine dosage. Our data suggest a significant high prevalence (3.3%) of CD in patients with ATD, in particular with Hashimoto’s thyroiditis.
A Novel Frameshift Mutation in the First Exon of the 21-OH Gene Found in Homozygosity in an Apparently Nonconsanguineous Family
Authors: Ezquieta B. , Oyarzábal M. , Jariego C.M. , Varela J.M. , Chueca M.
Published: April 2003

Congenital adrenal hyperplasia is most frequently due to steroid 21-hydroxylase (21-OH) deficiency. Due to the existence of a pseudogene in tandem duplicated with the 21-OH gene, asymmetric recombination causes the majority of the molecular defects underlying this deficiency: gene conversions and deletions of the functional gene. Screening for a small array of mutations, those existing in the pseudogene together with deletions, allows the characterization of most mutated alleles, 91% in the Spanish population. We report the case of a boy from a nonconsanguineous family, diagnosed during the neonatal period of a salt-wasting form of the deficiency, in which this screening did not allow the characterization of the paternal or the maternal allele. This infrequent finding in a nonconsanguineous family was further investigated. Single-strand conformation polymorphism screening for new mutations revealed an abnormally migrating pattern when polymerase chain reaction fragments from 21-OH gene exon 1 of the patient and relatives were analyzed. Upon direct sequencing, the insertion of a T at position 64 (64insT, frameshift generating a stop codon at exon 2) was found in homozygosity in the patient. Microsatellite typing in the HLA region revealed the patient to be homozygous for five markers (heterozygosities 0.62 to 0.74). Apparently this new mutation was generated several generations ago and has been preserved for years. Consanguinity had been discarded for several generations, although both families could be traced back to a small rural area in Navarra (Spain).
Vitamin-D Receptor Genotype Does Not Predict Bone Mineral Density, Bone Turnover, and Growth in Prepubertal Children
Authors: Baroncelli Giampiero I. , Federico Giovanni , Bertelloni Silvano , Ceccarelli Cinzia , Cupelli Domenico , Saggese Giuseppe
Published: April 2003

We examined whether the polymorphism for BsmI restriction enzyme in the vitamin-D receptor (VDR) gene influenced radial (distal third) and lumbar (L2–L4) bone mineral density (BMD), phospho-calcium metabolism (calcium, phosphate, intact parathyroid hormone, 25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D), biochemical markers of bone formation (osteocalcin and carboxy-terminal propeptide of type-I procollagen) and bone resorption (carboxy-terminal telopeptide of type-I collagen and urinary cross-linked N-telopeptides of type I collagen), insulin-like growth factor I and insulin-like growth factor-binding protein 3, and growth in 209 healthy prepubertal children (112 males and 97 females) aged 7.1–10.0 years. Genotype frequencies were BB 19%, Bb 46%, and bb 35% in the pooled group of children. Clinical findings, dietary calcium intake, calcium density, and physical activity rate were not different (p NS) among the VDR genotypes. Radial BMD, lumbar BMDarea and lumbar BMD adjusted for the apparent bone volume (BMDvolume), and all the biochemical parameters did not differ (p NS) in relation to the VDR genotype. In conclusion, our data show that polymorphism for BsmI restriction enzyme in the VDR gene is not associated with radial and lumbar BMD, parameters of phospho-calcium metabolism and bone turnover, growth hormone-dependent growth factors, and growth in prepubertal children.
Evidence for the Synthesis of Corticosteroid-Binding Globulin in Human Placenta
Authors: Misao Ryou , Iwagaki Shigenori , Sun Wen-Shu , Fujimoto Jiro , Saio Masanao , Takami Tsuyoshi , Tamaya Teruhiko
Published: April 2003

We demonstrated the expression of corticosteroid-binding globulin (CBG) in human placenta using reverse transcription-polymerase chain reaction-Southern blot analysis and immunohistochemical and immunoblotting studies. In the RT-PCR-Southern blot analysis, only one predicted PCR product was detected without nonspecific products in all samples of human placenta and 3A (tPA-30-1) human placental cells. In Western blot analysis, polyclonal anti-CBG antibodies recognized a protein of approximately 55 kD in the protein extracts prepared from 3A (tPA-30-1) cells. Additionally, CBG mRNA expression was demonstrated by in situ hybridization in the syncytiotrophoblasts. Immunohistochemical studies performed on the placenta demonstrated the presence of specific immunoreactivity in the syncytiotrophoblast layer surrounding the chorionic villi. These findings suggest that CBG is synthesized in human placenta during pregnancy in addition to its synthesis in the liver.
Increased Urinary Excretion of Collagen Crosslinks in Type 1 Diabetic Children in the First 5 Years of Disease
Authors: Valerio G. , Franzese A. , Esposito-Del Puente A. , Formicola S. , Di Maio S. , Contaldo F. , Rubino A.
Published: April 2003

To analyze possible early abnormalities in bone resorption in type 1 diabetes mellitus the urinary excretion of the collagen crosslinks pyridinoline and deoxypyridinoline was evaluated by immunoassay in 26 prepubertal diabetic patients (mean age 7.8 ± 1.6 years, mean duration 3.0 ± 1.1 years) and 46 healthy children (age 8.3 ± 1.3 years). Relationships with growth parameters (height-standard deviation score, body mass index and height velocity during the year preceding the study) and metabolic control were sought. Longitudinal and ponderal growth was normal in diabetic children. Urinary collagen crosslink excretion was 88.4 ± 25 nmol/mmol creatinine (median 86, range 44–146) in diabetic patients and 65.6 ± 19 nmol/mmol creatinine (median 61, range 32–108) in controls (p = 0.0002). It was positively influenced by diabetic status (beta = 20.5) and negatively by age (beta = –6.41), controlling by sex and BMI (p = 0.0001). A positive correlation was found between collagen crosslinks and blood glucose (r = 0.48, p = 0.01) or HbA1c levels (r = 0.44, p = 0.02) evaluated at the time of the study, while no significant correlation was found with the mean HbA1c values assessed in the last year or throughout the whole duration of diabetes. Collagen crosslink excretion was significantly increased in patients who presented worsening of their metabolic control in the last 3 months. No relationship was found with the duration of disease or growth parameters. In conclusion, the elevated urinary excretion of collagen crosslinks in diabetic children indicates that bone resorption may be disturbed. Poor metabolic control influences the increased rate of bone resorption and may expose growing diabetic patients to a risk of bone loss.
Effects of 1-Year Ipriflavone Treatment on Lumbar Bone Mineral Density and Bone Metabolic Markers in PostmenopausalWomen with Low Bo ne Mass
Authors: Ohta Hiroaki , Komukai Shigeyuki , Makita Kazuya , Masuzawa Toshihide , Nozawa Shiro
Published: April 2003

In vitro studies have shown that ipriflavone affects both bone formation and bone resorption, but the effect in early-stage postmenopausal women with low bone mass and a high turnover of bone metabolism is unknown. In this prospective study, we randomly assigned 60 patients with postmenopausal osteopenia or osteoporosis to receive either 600 mg/day of ipriflavone or 0.8 g/day calcium lactate, and compared the effects on bone mineral density (BMD) from the 2nd to 4th lumbar vertebrae (L2–4) and bone metabolic markers before and after one year of treatment. In the iprifravone-treated (IP) group, L2–4 BMD was similar before and after treatment (0.78 and 0.77 g/cm2, respectively), but in the calcium lactate-treated (CL) group, L2–4 BMD decreased significantly from 0.81 to 0.79 g/cm2 after 1 year of treatment (p < 0.0001). Furthermore, the rate of the decrease in L2–4 BMD was significantly greater in the CL group than in the IP group (p < 0.01). The median deoxypyridinoline (Dpd) level was significantly lower after 1 year of treatment (5.8 mmol/mmol creatinine [Cr]) than the baseline value (10.2 mmol/mmol Cr) in the IP, but not in the CL group, suggesting that IP treatment suppresses bone resorption.
Association of Angiotensin-Converting Enzyme Gene Polymorphism with Lipid Profiles in Children and Adolescents with Insulin-Dependent Diabetes mellitus
Authors: Kobayashi Kisho , Amemiya Shin , Mochizuki Mie , Kobayashi Koji , Matsushita Kyoko , Sawanobori Emi , Ishihara Toshihide , Higashida Kosuke , Shimura Yoshie , Kato Kiyohiko , Nakazawa Shinpei
Published: April 2003

We attempted to clarify the association between angiotensin-converting enzyme (ACE) gene polymorphism and the other predictive factors for macroangiopathy in children and adolescents with uncomplicated insulin-dependent diabetes mellitus (IDDM). Sixty-three patients were divided into 3 groups according to the ACE genotypes. The lipid profiles were evaluated according to ACE genotypes. The level of lipoprotein(a) (Lp(a)) in the II genotype was significantly lower than that in groups with the D allele. Lp(a) significantly correlated with apo B/apo A-I (p < 0.001, r = 0.63) and atherogenic index (AI = (total cholesterol – high-density lipoprotein cholesterol)/high-density lipoprotein cholesterol; p = 0.004, r = 0.36). We suggest that the D allele may affect the level of Lp(a) and the other lipid profiles in IDDM.
Pronounced Adrenarche and Precocious Pubarche in Boys
Authors: Potau Neus , Ibáñez Lourdes , Riqué Susanna , Sanchez-Ufarte Carmen , de Zegher Francis
Published: April 2003

In girls, pronounced adrenarche with precocious pubarche (PP) has been related to reduced fetal growth and to a cluster of endocrine-metabolic abnormalities. We examined whether these associations are also evident in boys with PP. The study population consisted of matched groups of boys (n = 58; age range 5–15 years) without or with a history of PP. After stratification for pubertal development, non-PP and PP boys displayed comparable results for the studied variables, including serum insulin-like growth factor I, sex hormone binding globulin, insulin-like growth factor binding proteins 1 and 3, indices of circulating glucose and insulin responsiveness to an oral glucose load, and birth weight SD score. In conclusion, the present results indicate that adrenarche-driven PP in boys is, in contrast to PP in girls, not associated with a cluster of endocrine-metabolic abnormalities and is not related to reduced fetal growth. These observations support the view that adrenarche-driven PP in boys may be regarded as a variant of normal development.
Solitary Thyroid Nodules in 93 Children and Adolescents
Authors: Hung Wellington
Published: April 2003

Over a period of 35 years from 1963 to 1998, 93 patients under the age of 18 years, 74 girls and 19 boys, were seen for evaluation of a solitary nodule of the thyroid gland. All patients had preoperative scintiscans of the thyroid gland and had their solitary nodule excised. Seventy-seven of the patients had a cold nodule on scintiscanning. The most common cause of solitary thyroid nodules was follicuar adenoma (68.9%). Fifteen of the 77 cold nodules were malignant (19.9%). The frequency of carcinoma in males was 26.3%, while in females it was 13.5%. Our experience suggests that the incidence of thyroid carcinoma may be decreasing in pediatric patients not exposed to known risk factors. Available diagnostic methods for attempting differentiation of benign from malignant solitary nodules are reviewed and recommendations to the clinical management are presented.
Ontogenetic Diurnal Variation of Adrenal Responsiveness to ACTH and Stress in Rats
Authors: Leal Ângela M.O. , Carvalho Jordana , Moreira Ayrton C.
Published: April 2003

We performed studies in 8-, 16-, 24-, 30 and 35-day-old Wistar rats at 8.00 h (AM) and 20.00 h (PM) to investigate the relationship between the diurnal variations of basal plasma corticosterone (compound B, CB) and its responses to ACTH and ether stress during the postnatal period. Basal plasma CB levels increased at PM from 8 to 35 days of age and an AM-PM difference was observed at 16 days. Although an AM-PM difference in CB responsiveness to ACTH was detected only at 24 and 35 days, ACTH induced an increasingly higher CB response at PM than at AM from 8 to 35 days. A stress-induced CB response was observed starting at 8 days of age and presented an age-dependent increase; however, no AM-PM difference was observed at any age. The stress-induced CB levels were higher than ACTH-induced CB values at all ages tested except at PM in 8-day old rats. These data demonstrate that the basal CB levels and adrenal sensitivity to ACTH rise during the evening as a function of neonatal development.
Panhypopituitarism Associated with Diabetes insipidus in a Girl with a Suprasellar Arachnoid Cyst
Authors: Mohn A. , Fahlbusch R. , Dörr H.G.
Published: April 2003

We report on a female patient with a large suprasellar arachnoid cyst (3.5 × 2.5 cm) combined with right optic nerve hypoplasia. She developed growth hormone deficiency and hypothyroidism at the age of 8.5 years, adrenal insufficiency at the age of 11 years, diabetes insipidus and hypogonadotropic hypogonadism at the age of 15 years. When last seen at the age of 19 years she was extremely obese (+5.9 BMI SDS). The endocrine picture suggests that arachnoid cysts might be involved in far more complex hypothalamic-pituitary disturbances than previously thought.
Pituitary Adenoma Showing Intermittent Secretion of High Molecular Weight Adrenocorticotropin without Evidence of Cushing’s Disease
Authors: Hashimoto Kozo , Kaneda Tadafumi , Nagano Isao , Asaba Koichiro , Takeda Kyoko , Takao Tosihiro
Published: April 2003

A 29-year-old woman was admitted in March 1998 due to high plasma ACTH levels, amenorrhea and uncontrolled diabetes mellitus (DM) which had persisted since 1991. Plasma ACTH levels showed a wide range of changes: they were usually high (59–240 pg/ml), intermittently very high (336–942 pg/ml), and sometimes normal or low. Plasma cortisol levels were usually normal but were sometimes high when the ACTH levels were very high. However, even when the plasma ACTH levels were very high, she did not show any cushingoid features. DM was diagnosed as non-insulin-dependent DM. Plasma ACTH showed an excessive response to CRH, while cortisol showed a delayed response. Plasma cortisol showed a poor response to ACTH-(1–24). ACTH receptor gene analysis revealed no mutations in the ACTH receptor-coding region. MRI showed a nonenhancing mass on the left side of the pituitary. Cavernous sinus sampling showed a very high plasma ACTH level in the left cavernous sinus compared with the levels in the right cavernous sinus and peripheral blood. Sephadex G-75 gel filtration of plasma ACTH immunoreactivity in plasma obtained by cavernous sinus sampling showed mainly high molecular forms of ACTH, probably proopiomelanocortin and ACTH-β-lipotropin. This case is a very rare form of pituitary adenoma showing intermittent secretion of high molecular ACTH unaccompanied by cushingoid features.
Final Height, Armspan, Subischial Leg Length and Body Proportions in Juvenile Chronic Arthritis
Authors: Zak Marek , Müller Jørn , Karup Pedersen Freddy
Published: April 2003

Objective: Assessment of growth disturbances in adults with a history of juvenile chronic arthritis (JCA). Material and Methods: Sixty-five subjects, 52 premenopausal females and 13 males with a mean age (range) of 32.2 years (22.3–49.4) participated. Mean age at disease onset was 5.7 years (0.8–15.8) and mean disease duration was 12.4 years (0.4–32). The follow-up time ranged from 18.7 to 46.9 years with a mean of 26.4 years. For each participant standard deviation scores (z-scores) for final height, delta-height (the difference between observed and expected height), armspan, subischial leg length and sitting height ratio, were calculated. Results: The study group as a whole did not exhibit linear growth impairment. The categorical distribution of heights differed significantly from a expected distribution in a healthy population (p < 0.001). A height z-score < –2 SD was present in 10.7% of the study group, of whom all had polyarticular course of JCA. Polyarticular and systemic course of JCA (versus pauciarticular) (p = 0.022), systemic steroid treatment (p = 0.006) and Steinbrocker functional class II–IV (vs. I) in 1979 (p = 0.043) were variables associated with reduced delta-height. In linear regression analyses, disease severity defining variables were statistically significant predictors of reduced final height and armspan. 27% of the study subjects had significantly reduced arm span (p < 0.001). Subischial leg length and body proportions (sitting height ratio) were normal. Conclusion: Our findings suggest that functionally impaired polyarticular and systemic JCA patients treated with systemic steroids may be at an increased risk of developing reduced final height and armspan. Disease control achieved by an aggressive therapeutic approach, if possible with a minimal use of systemic steroids, may reduce growth impairment in JCA.
Effect of Short-Term Testosterone Treatment on Leptin Concentrations in Boys with Pubertal Delay
Authors: Adan L. , Bussières L. , Trivin C. , Souberbielle J.C. , Brauner R.
Published: April 2003

Testosterone administration increases growth hormone (GH) secretion and decreases the plasma leptin concentration in men. We evaluated the effect of increased GH secretion due to short-term testosterone treatment on leptin concentrations. Ten boys aged 14.8 ± 0.2 (mean ± SE) years with transient GH deficiency caused by pubertal delay were evaluated before and after (3 months) 4 intramuscular injections of 100 mg testosterone heptylate, given at 15-day intervals. The leptin concentration decreased from 5.4 ± 1.3 to 3.6 ± 1.1 μg/l (p < 0.001), despite a weight gain of 3.4 ± 0.5 kg. There were significant increases in body mass index (BMI), from –0.2 ± 0.5 to 0.2 ± 0.5 SD, p < 0.005, in GH peak after stimulation test, from 6.3 ± 0.5 to 21.7 ± 2.9 μg/l, p < 0.0003, in plasma testosterone, from 0.6 ± 0.1 to 6.5 ± 1.3 μg/l, p < 0.001, in insulin-like growth factor-I (IGF-I), from 152 ± 21 to 330 ± 30 μg/l, p < 0.0001, and in IGF-binding protein-3 (IGFBP-3), from 4.2 ± 0.5 to 5.4 ± 0.4 mg/l, p < 0.01. But there were no changes in blood glucose (4.7 ± 0.1 and 4.8 ± 0.1 mmol/l), or plasma fasting insulin (9.0 ± 1.2 and 8.1 ± 1.3 mIU/l). The leptin concentrations were positively correlated with the BMI before (p < 0.03) and after (p < 0.04) testosterone, but not with the GH peak after stimulation, or with plasma testosterone, IGF-I or IGFBP-3. The leptin and insulin concentrations after testosterone treatment were positively correlated (p < 0.04). Thus, short-term testosterone treatment of boys with pubertal delay decreases their leptin concentrations. The lack of correlation with GH secretion or with its changes, despite the dramatic increase in GH secretion, and the lack of change in insulin are additional features suggesting that testosterone increases the leptin concentration mainly by an effect on adipose tissue.
Serum Osteocalcin and Insulin-Like Growth Factor I Levels in Children with Congenital Adrenal Hyperplasia
Authors: Hargitai G. , Hosszú É. , Halász Z. , Sólyom J.
Published: April 2003

Patients with the virilizing forms of congenital adrenal hyperplasia (CAH) need a life-long glucocorticoid replacement therapy and also an additional mineralocorticoid replacement in cases with the salt-wasting form of the disease. Glucocorticoids are reported to decrease the serum osteocalcin levels and to inhibit the effects of insulin-like growth factor I (IGF-I). To collect data on the age related patterns of osteocalcin and IGF-I production in patients with CAH, measurements of these compounds have been carried out in a considerably large sample of treated CAH patients and control subjects in childhood and adolescence. Data of 62 patients between 0.3–19 years of age were compared to the data of 188 control children. Osteocalcin and IGF-I were determined by radioimmunoassay. A lower than normal level of serum osteocalcin was found in both male and female patients at chronological ages above 11.6 and 9.6 years, respectively. Furthermore, no pubertal osteocalcin peak could be seen when data were evaluated according to the bone age. Serum IGF-I levels were higher in male CAH patients at the chronological age of 0.3–15.5 years and in female patients at the chronological age of 4.6–9.5 years. In pubertal years serum IGF-I concentrations were lower in CAH patients when data were evaluated according to the bone age. We conclude that serum osteocalcin is decreased during and after puberty in CAH patients on replacement doses of glucocorticoids. Normal to elevated serum levels of IGF-I in treated CAH cases suggest that the shorter final height of these patients may not be due to the decreased activity in the growth hormoneIGF-I axis, but rather to the advanced bone maturation and the premature epiphyseal fusion.