bluuebunny/crossref_metadata_2025 huggingface dataset:
Overnight Urinary Growth Hormone in Normally Growing Prepubertal Children: Effect of Urine Volume
Authors: Gelander L. , Karlberg J.P.E. , Larsson L.A. , Rosberg S. , Albertsson-Wikland K.
Published: April 2003

Growth hormone excretion can easily be measured in the urine using ultrasensitive methods. The large day-to-day variation has, however, restricted its diagnostic usefulness. The present study aimed to evaluate the individual variation of GH in the urine (uGH) during normal prepubertal growth. Eighty-four prepubertal normally growing children were followed monthly for 13 months. During this period, 3,207 overnight urine samples were collected. The urine collection time was unrelated to the uGH concentration (p > 0.05), while there was a significant negative correlation between the uGH concentration and urine volume (the Spearman correlation coefficient of –0.33, p < 0.0001), while the calculated excretion of GH in the urine showed a positive correlation with the urine volume (r = 0.35; p < 0.0001). A reference chart, based on SD scores, was developed in order to avoid this volume dependency and to optimally normalize the skewed distribution of the uGH concentrations. The use of this model reduced the individual day-to-day variation of uGH from a coefficient of variation of 43 to 21%. Differences in mean cross-sectional urinary GH concentration was found between different months exceeding the expected methodological variation. This variation showed no seasonal pattern. Only 0.2% of triplicate values (three consecutive overnight uGH values) were all below –2 SD scores and 0.1% were above +2 SD scores. The mean uGH SD score for the boys was 0.01 (SD = 0.98), which was similar to that for the girls (–0.04; SD = 1.06). We found that uGH excretion can be estimated in a more robust way, using a SD score based reference chart that handles both the positive correlation between urinary GH and urine volume and the skewed distribution of urinary GH. This model reduced the day-to-day variability of uGH by half. Overestimation of GH in large urine volumes may be due to increased gradient between GH in urine and serum following increased urine volumes.
The Analysis of Short-Term Growth
Authors: Hermanussen Michael
Published: April 2003

The analysis of short-term growth needs repetitive measurements of body stature or of segments of the body. When body stature is measured at monthly intervals, an irregular incremental pattern becomes obvious with a number of large-scale components such as series of prepubertal and pubertal growth spurts, seasonal influences on height gain, and influences of the psychosocial and economic background. When measurement intervals decrease, incremental patterns appear even more irregular, and a number of short-scale components become apparent that are distinct from measurement error. The review summarizes the analysis of short-term growth, and presents the current findings supporting different views on how growth progresses at short term. In particular, observations are presented that suggest growth being a pulsatile, a periodic, a saltatory, and a chaotic event. Some recent animal studies and studies in human newborns are added in detail as they illustrate short-term growth on the basis of accurate 24-hour measurements of the lower leg. The latter investigations support the idea of short-term growth being characterized by chaotic series of ‘mini growth spurts’ that occur at intervals of approximately 4–5 days, not only in human neonates, but also in rats. The amplitude of mini growth spurts ranges between 2 and some 10 mm, and growth velocity of each spurt also varies considerably so that one spurt needs between less than 1 and up to several days for completion.
Serum Insulin-Like Growth Factors I and II Are Not Affected by Undernutrition in Children with Nonorganic Failure to Thrive
Authors: Phillip Moshe , Hershkovitz Eli , Rosenblum Hector , Savion Inbal , Segev Yael , Levy Jacob , Frazer Drora
Published: April 2003

The aim of our study was to determine the serum levels of IGF-I, IGF-II, and their binding proteins IGFBP-1 and IGFBP-3 in young children 3 months to 2 years of age with nonorganic failure to thrive (NOFTT). 29 children with NOFTT and 32 normal controls were recruited and studied for auxologic and hormonal parameters. The NOFTT group had significantly higher serum concentrations of IGFBP-1 than the control group: 57.7 ± 18 vs. 48 ± 19 µg/l (p < 0.05). IGF-I and IGF-II serum levels were highly correlated to serum IGFBP-3 but there were no differences in the serum IGF-I, IGF-II and IGFBP-3 levels between the groups. We conclude that IGF-I, IGF-II, and IGFBP-3 are not useful for the evaluation of nutritional status in children, under the age of 2 years, with NOFTT.
Central Hypothyroidism Reveals Compound Heterozygous Mutations in the Pit-1 Gene
Authors: Brown Milton R. , Parks John S. , Adess Matthew E. , Rich Barry H. , Rosenthal Ira M. , Voss Ty C. , VanderHeyden Thomas C. , Hurley David L.
Published: April 2003

Mutations in the gene encoding the Pit-1 transcriptional activator interfere with the embryologic determination and ultimate functions of anterior pituitary cells that produce growth hormone (GH), prolactin (Prl) and thyroid-stimulating hormone (TSH). Central hypothyroidism is often the presenting feature of combined pituitary hormone deficiency (CPHD), but it is not detected in screening programs that rely upon elevation of TSH. We report a child whose hypothyroidism was recognized clinically at age 6 weeks, and subsequently found to have GH and Prl as well as TSH deficiency. With thyroxine and GH replacement he has reached the 70th percentile for height and has normal intelligence. Molecular analysis of genomic DNA for Pit-1 revealed the presence of compound heterozygous recessive mutations: a nonsense mutation in codon 172 and a novel missense mutation substituting glycine for glutamate at codon 174. This case is the first demonstration of CPHD due to compound heterozygous Pit-1 point mutations, as most reported cases of the CPHD phenotype involve either the dominant negative R271W allele or homozygosity for recessive Pit-1 mutations. Therefore, in cases of CPHD, the possibilities of compound heterozygosity for two different Pit-1 mutations, or homozygosity for mutations in the epigenetic gene, Prop-1, should be considered.
Effects of Hormones on Sleep
Authors: Steiger A. , Antonijevic I.A. , Bohlhalter S. , Frieboes R.M. , Friess E. , Murck H.
Published: April 2003

Administration of hormones to humans and animals results in specific effects on the sleep electroencephalogram (EEG) and nocturnal hormone secretion. Studies with pulsatile administration of various neuropeptides in young and old normal controls and in patients with depression suggest they play a key role in sleep-endocrine regulation. Growth hormone (GH)-releasing hormone (GHRH) stimulates GH and slow wave sleep (SWS) and inhibits cortisol, whereas corticotropin-releasing hormone (CRH) exerts opposite effects. Changes in the GHRH:CRH ratio contribute to sleep-endocrine aberrations during normal ageing and acute depression. In addition, galanin and neuropeptide Y promote sleep, whereas, in the elderly, somatostatin impairs sleep. The rapid eye movement (REM)-nonREM cycle is modulated by vasoactive intestinal polypeptide. Cortisol stimulates SWS and GH, probably by feedback inhibition of CRH. Neuroactive steroids exert specific effects on the sleep EEG, which can be explained by γ-aminobutyric acidA receptor modulation.
Effects of Long-Term Growth Hormone Therapy on Adrenal Steroidogenesis in Turner Syndrome
Authors: Balducci R. , Toscano V. , Larizza D. , Mangiantini A. , Galasso C. , Municchi G. , Di Rito A. , Picone S. , Boscherini B.
Published: April 2003

It has been shown that growth hormone (GH) and insulin-like growth factor-1 (IGF1) enhance steroidogenesis responsiveness to ACTH in cultured adrenal cells. To investigate the GH effect on adrenal steroidogenesis in non-GH-deficient subjects, we studied 9 girls with Turner syndrome (chronological age 5.5–7.2 years; bone age 5–7 years). In all subjects an ACTH test (Synacthen depot, 0.25 mg i.v. with blood samples at 0 and 60  min) was performed basally at 8–9 a.m. and 6 months after GH therapy (1 IU/kg/week). 17-Hydroxypregnenolone (17PGN), 17-hydroxyprogesterone (17OHP), dehydroepiandrosterone (DHA), its sulfate (DHA-S), androstenedione and cortisol were evaluated by radioimmunoassay. Two groups of normal girls were selected as controls: group A age-matched the patients at the start of the study, and group B age-matched the patients at the end of the study. The responsiveness of each hormone to ACTH was expressed as the difference between stimulated and basal values. A p value of < 0.01 was considered to indicate significance. There were no significant differences between pre- and posttreatment basal values of 17PGN, 17OHP, DHA, androstenedione and cortisol in the Turner syndrome patients, whereas a significant increase was observed for basal DHA-S (1.57 ± 0.31; 1.89 ± 0.43 µmol/l, p < 0.01). Comparison of increments before and after GH treatment showed a significant increase in responsiveness to ACTH after GH therapy DHA (p < 0.01). The increase in 17PGN was evident (p < 0.02), but the established significant p value was not reached. No differences for 17OHP, androstenedione and cortisol were found. The stimulated 17PGN/17OHP ratio was significantly higher (p < 0.01) after GH, whereas the 17OHP/androstenedione ratio was considerably lower, but the p value was < 0.02. No differences between pretreatment values with the control group androstenedione was found, whereas basal and stimulated posttreatment values of DHA and stimulated values of 17PGN were higher in patients after GH therapy than in control group B. No differences between the 2 control groups were found. In conclusion our study showed that adrenal steroid responsiveness to ACTH increases in Turner syndrome after long-term treatment with high GH doses. An increase in the number of ACTH adrenal receptors and/or a modulation of enzyme activities may be suggested. The positive or negative pharmacological implications of these data remain to be determined especially when taking into consideration the wide use of GH therapy in non-GH-deficient subjects.
An Association of Hypothalamic Hamartoma, Central Precocious Puberty and Juvenile Granulosa Cell Tumour in Early Childhood
Authors: Feilberg Jørgensen N. , Brock Jacobsen B. , Ahrons S. , Starklint H.
Published: April 2003

A case of central precocious puberty from infancy due to a hypothalamic hamartoma and associated with an ovarian juvenile granulosa cell tumour is presented. Central precocious puberty was diagnosed by gonadotropin stimulation tests and LHRH agonist therapy was successful. A MR scan, but not a CT scan, demonstrated the hypothalamic hamartoma. The possible influence of early LH stimulation for the development of the granulosa cell tumour is discussed.
Aldosterone Overproduction and CYP11B2 mRNA Overexpression in Vessels of Spontaneously Hypertensive Rats
Authors: Wu Pingsheng , Guo Zhigang , Zhang Yuanhui , Liu Yili , Liang Xinwei , Zhang Ronghua , Lai Wenyan , Takeda Yoshiyu , Isamu Miyamori , Takeda Ryoyu
Published: April 2003

Aldosterone is synthesized in extra-adrenal tissues such as blood vessels and brain. Damage to blood vessels could play a crucial role in perpetuating hypertension. In this study, we determined both aldosterone production and aldosterone synthase gene-CYP11B2 mRNA expression in vessels of spontaneously hypertensive rats (SHR). The results showed that aldosterone was overproduced in the vasculature of SHR, by means of ex vivo mesenteric artery perfusion, HPLC, and RIA, and that CYP11B2 mRNA expression was upregulated in aortas of SHR, confirmed by RT-PCR and Southern blot.
Response to Long-Term hGH Therapy in Two Children with Schwachman-Diamond Syndrome Associated with GH Deficiency
Authors: Marseglia G.L. , Bozzola M. , Marchi A. , Ricci A. , Touraine J.L.
Published: April 2003

Schwachman-Diamond syndrome is a rare congenital disorder characterized by pancreatic insufficiency, metaphyseal anomalies, recurrent infections, hematologic abnormalities, and growth retardation. Slow growth in these patients has been attributed to nutritional deficits, recurrent infections, and skeletal anomalies. Two cases of Schwachman-Diamond syndrome associated with growth hormone deficiency have been previously reported. We report here on 2 additional cases with this unusual association. Therefore, growth failure in Schwachman-Diamond syndrome should not be assumed to be due to chronic illness or recurrent infections; other etiologies for growth failure should be sought. However, the presence of metaphyseal disorders probably interferes with the long-term efficacy of growth hormone substitutive therapy.
Serum Insulin-Like Growth Factor-I, IGF Binding Protein-3 and IGFBP-3 Protease Activity after Cranial Irradiation
Authors: Tillmann Vallo , Shalet Stephen M. , Price David A. , Wales Jeremy K.H. , Pennells Louise , Soden Joanne , Gill Matthew S. , Whatmore Andy J. , Clayton Peter E.
Published: April 2003

The relationship between peak growth hormone (GH), insulin-like growth factor I (IGF-I), IGF-I binding protein 3 (IGFBP-3) and IGFBP-3 protease activity was studied in 28 children and adolescents undergoing investigation of pituitary function 0.4–14.2 years after cranial or craniospinal irradiation for the treatment of CNS tumours distant from the hypothalamic-pituitary axis (n = 16) or prophylaxis against CNS leukaemia (n = 12). Seven out of 15 patients with GH deficiency (GHD) (defined as a peak GH concentration <7.5 ng/ml in a stimulation test) had IGF-I <–2 standard deviation score (SDS). None of the 28 patients had serum IGFBP-3 concentrations measured by radioimmunoassay (RIA) <–1.5 SDS with no difference between those with and without GHD. IGFBP-3 concentrations measured by RIA were strongly correlated to IGFBP-3 band density on Western ligand blot (WLB) (r = 0.71; p < 0.0001). IGFBP-3 protease activity was negatively correlated to IGFBP-3 by RIA (r = –0.55; p < 0.01) and to IGFBP-3 by WLB (r = –0.51; p < 0.01). Twenty-two patients had normal IGFBP-3 protease activity (<30% of the activity in pregnancy serum) indicating that serum IGFBP-3 protease activity does not account for the normal levels of IGFBP-3 in RIA.Low serum IGF-I but normal IGFBP-3 concentrations and in the majority normal IGFBP-3 protease activity was found in patients in the years after CNS irradiation. Neither serum IGF-I nor IGFBP-3 can be used as a reliable index of the development of radiation-induced GHD.
Occult T3 Toxicosis in McCune-Albright Syndrome
Authors: Brogan P. , Khadilkar V.V. , Stanhope R.
Published: April 2003

We report a girl with McCune-Albright syndrome who presented with Cushing syndrome from adrenal hypersecretion and gonadotrophin-independent precocious puberty in the first year of life. At age 5, she failed to gain weight and was found to have hyperthyroidism, which was occult in that she had T3 toxicosis without a goitre or thyroid ultrasound abnormality. The latter has not been previously reported in McCune-Albright syndrome.
Insulin-Like Growth Factor I Receptors Are Expressed by the Enteroendocrine Cell Line STC-1: Relationship with Proliferation and Cholecystokinin Expression
Authors: Ye Fei , Chevrier Anne-Marie , Langlois Dominique , Cuber Jean-Claude , Saez Jose M. , Chayvialle Jean-Alain , Abello Jacques
Published: April 2003

Receptors for insulin-like growth factors (IGF-I and IGF-II) are expressed in mammalian intestinal epithelium. No information on the presence of IGF receptors in intestinal endocrine cells is available. We tested for IGF-I receptors the endocrine cell line STC-1, which synthesizes and processes cholecystokinin (CCK) among other peptides, and assessed the effects of IGF-I on cell growth and CCK content. Cell monolayers in serum-free culture medium specifically bound [125I]IGF-I. Scatchard analysis was consistent with a single class of high affinity binding sites (KD = 0.91 nM; Bmax = 4,700 sites/cell). In competitive binding assays, unlabeled IGF-I, IGF-II and insulin displaced in a dose-dependent manner [125I]IGF-I binding with the following potencies (KI): IGF-I (0.74 nM) > IGF-II (3 nM) >> insulin (1 µM). Affinity cross-linking with [125I]IGF-I using disuccinimidyl suberate and SDS-PAGE under reducing conditions yielded a polypeptide band with apparent Mr 130,000, consistent with the α-subunit of the IGF-I receptor. IGF-I and IGF-II (0.3–30 nM) dose-dependently stimulated [3H]thymidine incorporation, with a maximal response of 110% above basal. IGF-II was approximately 10-fold less potent than IGF-I, suggesting a mediation through IGF-I receptors. In addition, the numbers of cells treated with 3 nM IGF-I amounted to 116, 130 and 159% of control values after 1, 2 and 4 days of incubation, respectively (p < 0.05). A significant increase in the cell CCK contents was observed after a 48-hour exposure to 3 or 30 nM IGF-I. These results demonstrate IGF-I receptor expression by the enteroendocrine cell line STC-1. IGF-I stimulates proliferation in short-term experiments, and increases intracellular levels of CCK.
Hypergonadotropic Hypogonadism in a 3-Year-Old Girl with Blepharophimosis, Ptosis, and Epicanthus inversus Syndrome
Authors: Ogata Tsutomu , Hasegawa Tomonobu , Tamai Shinya , Sato Seiji , Hasegawa Yukihiro , Matsuo Nobutake
Published: April 2003

We report on ovarian dysfunction in a 3-year-old girl with blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES). A gonadotropin releasing hormone test showed hyperresponses of luteinizing hormone (<0.2→7.2 mIU/ml) and follicle-stimulating hormone (7.1→44.8 mIU/ml), and a human menopause gonadotropin test yielded no estradiol response (13→11 pg/ml). The results suggest that primary ovarian failure in type I BPES can take place in early childhood.
Central Precocious Puberty: A Single Blood Sample after Gonadotropin-Releasing Hormone Agonist Administration in Monitoring Treatment
Authors: Salerno Mariacarolina , Di Maio Salvatore , Gasparini Nicoletta , Mariano Angela , Macchia Vincenzo , Tenore Alfred
Published: April 2003

This study was designed to evaluate whether a single blood sample drawn after the home injection of a long-acting gonadotropin-releasing hormone (GnRH) agonist (GnRHa) in patients treated for central precocious puberty (CPP) could be a more simple and inexpensive test with respect to the conventional GnRH stimulating test in assessing adequate suppression of the pituitary-gonadal axis. The response to the first therapeutic injection of the GnRHa triptorelin was studied in 14 newly diagnosed untreated females with CPP. The results were compared with the response that the same patients had to the conventional GnRH stimulation test performed at the time of diagnosis. A significant increase in LH, FSH and E2 levels was observed 12 h after the triptorelin intramuscular injection; serum peak values of LH (70.3 ± 58.5 IU/l), FSH (44.2 ± 21.7 IU/l) and E2 (489.7 ± 263.9 pmol/l) were significantly greater than those obtained with the conventional GnRH test (LH 31.4 ± 21.7, p = 0.002; FSH 19.8 ± 10.7, p = 0.001; E2 83.3 ± 25, p < 0.001). In particular, the E2 response, 12 h after triptorelin injection, was clearly consistent with gonadal activation compared to the modest E2 increase in response to the GnRH test. Thereafter 22 girls who were already being treated with triptorelin for CPP were evaluated to see whether a single blood sample drawn 12 h after the therapeutic home injection of GnRHa could be informative in assessing adequate suppression of the pituitary-gonadal axis. This response was also compared to the conventional GnRH stimulation test performed 2 days before the therapeutic triptorelin injection. In 7 girls with evidence of pubertal progression, the E2 response following the GnRHa injection (136.3 ± 44.4 pmol/l) was significantly higher with respect to the response after the GnRH stimulation test (73.0 ± 0.0; p < 0.02) indicating an inadequate suppression of the pituitary-gonadal axis. The present data suggest that a single blood sample drawn 12 h after the therapeutic home administration of triptorelin provides a simple, comfortable and inexpensive means of monitoring pituitary as well as gonadal function in girls treated for CPP.
Serum Leptin Levels in Young Females with Insulin-Dependent Diabetes and the Relationship to Hyperandrogenicity and Microalbuminuria
Authors: Rudberg S. , Persson B.
Published: April 2003

To investigate the relationship between leptin levels and IDDM with and without microalbuminuria, fasting serum levels of leptin, insulin, insulin-like growth factor-1 (IGF-1), sex hormone-binding globulin (SHBG), testosterone (SHBG) ratio, blood pressure and body mass index (BMI) were measured in 18 normo- and 11 microalbuminuric females with >5 years of IDDM, and 24 healthy controls in late puberty. Leptin levels were higher in micro- than normoalbuminuric IDDM patients, and lower in healthy controls than in both IDDM groups (p < 0.05, respectively). In multiple regression analysis, presence of IDDM and BMI independently contributed to increased leptin values (R2 = 0.34, p < 0.001). Including IDDM females only, solely low IGF-1 and high testosterone/SHBG were associated with leptin (R2 = 0.39, p = 0.009). Albumin excretion rate (AER) was correlated to leptin (r = 0.48, p = 0.01). With AER as the dependent variable only serum leptin and diastolic blood pressure added to the regression (R2 = 0.59, p < 0.001). In conclusion, serum leptin, independently of BMI, is: (1) increased in IDDM females of late puberty; (2) associated with low IGF-1 and hyperandrogenemia, and (3) related to increased albumin excretion rate in IDDM females.
Mechanism of the Stimulatory Action of Antisteroid RU486 on Follicle-Stimulating Hormone Secretion in the Cyclic Rat
Authors: Sánchez-Criado J.E. , Tébar M. , Gonzalez D.
Published: April 2003

These experiments explored the mechanism underlying FSH hypersecretion on estrous afternoon in rats injected with RU486 (RU) on proestrus. Four-day cyclic rats were injected with RU at 12:00 h on proestrus (1 or 4 mg/0.2 ml oil; s.c.), and its effects on LH and FSH secretion at 18:30 h on estrus were compared with those of antiprogestagens ZK299 (ZK) (1 or 4 mg/0.2 ml oil; s.c.) and Org31806 (OR) (2 or 8 mg/0.2 ml oil; s.c.). Additionally, rats treated with RU or nembutal (PB) (60 mg/kg; i.p. at 13:00 h on proestrus) were injected with an LHRH antagonist (LHRHa) at 10:00 h on estrus (1 mg/0.2 ml saline; s.c.) or progesterone (P) (7.7, 15.5 or 30.9 mg/0.2 ml oil; s.c.) on proestrus at 10:00 h in RU-injected rats and at 14:00 h in PB-injected rats. Animals were killed by decapitation at 18:30 h on estrus and serum LH and FSH concentrations were determined. Rats trated with 1 or 4 mg of RU or Org or 4 mg of ZK recorded increased serum FSH on estrous afternoon, while 1 mg ZK had no effect. PB increased mainly serum LH levels and, to a lesser extent, FSH levels. P decreased serum FSH concentrations in both RU- and PB-injected rats. LHRHa reversed the effects of PB on FSH secretions, but reduced FSH hypersecretion induced by RU only. These results are interpreted to mean that, in the absence of proestrous afternoon P-inhibitory action of the neural stimulus controlling LHRH release, FSH secretion on estrous afternoon involves two components: one is LHRH dependent while, in contrast to LH secretion, the other is LHRH independent, and only expressed in a low estrogen background.
Long-Term Follow-Up of an Infant with Thyrotoxicosis due to Germline Mutation of the TSH Receptor Gene (Met453Thr)
Authors: Lavard L. , Sehested A. , Brock Jacobsen B. , Muller J. , Perrild H. , Feldt-Rasmussen U. , Parma J. , Vassart G.
Published: April 2003

A 18-year clinical follow-up period in a male patient with a germline TSH-R gene mutation (Met453Thr) is described. Nonautoimmune thyrotoxicosis was diagnosed at the age of 7 months. The patient had exophthalmus, failure to thrive, advanced bone age and no goiter. Long-term antithyroid drug treatment (ATD) was necessary during childhood. At the age of 7 years he developed a goiter. Subtotal thyroidectomy was performed at the age of 9 years, followed by repeated ablative radiotherapy at the age of 9.5–13 years due to a toxic multinodular goiter. After 13 years ATD could be discontinued and the patient was euthyroid until 16 years of age, where L-thyroxine substitution had to be started. The exophthalmus diminished, and had disappeared at the age of 18 years, when CT scan of the orbit was performed. Conclusion: TSH-R mutation must be considered in early nonautoimmune thyrotoxicosis. A very agressive treatment strategy is necessary.
Validity of Height Velocity as a Diagnostic Criterion for Idiopathic Growth Hormone Deficiency and Turner Syndrome
Authors: van den Broeck Jan , Hokken-Koelega Anita , Wit Jan-Maarten
Published: April 2003

A deflecting growth curve over several years is sometimes the only indication for the possible presence of a growth disorder. In this study we looked at the potential diagnostic role of long-term downward deflection of the growth curve. It reports on the diagnostic validity of height velocity over 1, 2 or 3 years for isolated idiopathic growth hormone deficiency and for Turner syndrome in prepubertal children with a height that is still above –2.5 standard deviation scores (SDS). 1-year height velocity was found to have no diagnostic value because of an almost complete overlap of height velocity distributions with normal prepubertal children. However, height velocity over 3 years was found to have an acceptable validity in children 5–12 years old. In this age range a change in height SDS of –0.75 can be used as a valid criterion for further examination of karyotype and GH secretion capacity even if there are no other clear signs of a particular growth disorder.
Low-Dose Growth Hormone Treatment with Diet Restriction Accelerates Body Fat Loss, Exerts Anabolic Effect and Improves Growth Hormone Secretory Dysfunction in Obese Adults
Authors: Kim Kyung Rae , Nam Su Youn , Song Young Duk , Lim Sung Kil , Lee Hyun Chul , Huh Kap Bum
Published: April 2003

Growth hormone (GH) can induce an accelerated lipolysis. Impaired secretion of GH in obesity results in the consequent loss of the lipolytic effect of GH. Dietary restriction as a basic treatment for obesity is complicated by poor compliance, protein catabolism, and slow rates or weight loss. GH has an anabolic effect by increasing insulin-like growth factor (IGF)-I. We investigated the effects of GH treatment and dietary restriction on lipolytic and anabolic actions, as well as the consequent changes in insulin and GH secretion in obesity. 24 obese subjects (22 women and 2 men; 22–46 years old) were fed a diet of 25 kcal/kg ideal body weight (IBW) with 1.2 g protein/kg IBW daily and were treated with recombinant human GH (n = 12, 0.18 U/kg IBW/week) or placebo (n = 12, vehicle injection) in a 12-week randomized, double-blind and placebo-controlled trial. GH treatment caused a 1.6-fold increase in the fraction of body weight lost as fat and a greater loss of visceral fat area than placebo treatment (35.3 vs. 28.5%, p < 0.05). In the placebo group, there was a loss in lean body mass (–2.62 ± 1.51 kg) and a negative nitrogen balance (–4.52 ± 3.51 g/day). By contrast, the GH group increased in lean body mass (1.13 ± 1.04 kg) and had a positive nitrogen balance (1.81 ± 2.06 g/day). GH injections caused a 1.6-fold increase in IGF-I, despite caloric restriction. GH response to L-dopa stimulation was blunted in all subjects and it was increased after treatment in both groups. GH treatment did not induce a further increase in insulin levels during an oral glucose tolerance test (OGTT) but significantly decreased free fatty acid (FFA) levels during OGTT. The decrease in FFA area under the curve during OGTT was positively correlated with visceral fat loss. This study demonstrates that in obese subjects given a hypocaloric diet, GH accelerates body fat loss, exerts anabolic effects and improves GH secretion. These findings suggest a possible therapeutic role of low-dose GH with caloric restriction for obesity.
Three Cases of Congenital Growth Hormone Deficiency with Micropenis and Hypospadias: What Does Growth Hormone Have to Do with It?
Authors: Urzola Alejandro Velasquez , Leger Juliane , Czernichow Paul
Published: April 2003

This paper reports 3 cases of congenital GH deficiency with male pseudohermaphroditism. All 3 showed a normal male karyotype, hypospadias of different degrees, and, for 2 of them, micropenis. No müllerian structure was individualized since pelvic ultrasound and genitography were normal. Patient 1 was born with multiple anomalies and patient 3 showed partial agenesia of the corpus callosum. Only 1 patient showed complete anterior pituitary deficiency. Gonadotropin defects were not investigated. We postulate that GH might play a role in early testosterone stimulation, and thus in male sexual differentiation.
Growth Hormone Treatment of Children with Prader-Willi Syndrome: Effects on Glucose and Insulin Homeostasis
Authors: Lindgren Ann Christin , Hagenäs Lars , Ritzén E. Martin
Published: April 2003

Insulin and glucose homeostasis have been studied during growth hormone (GH) treatment in 19 prepubertal children with Prader-Willi syndrome (PWS) and compared with 11 healthy prepubertal obese children. Before treatment, insulin levels in children with PWS were lower (p < 0.01) than in healthy obese children. During GH treatment, fasting insulin levels increased in children with PWS (p < 0.001). Glucose levels were similar for PWS and obese children before treatment. Children with PWS showed a slow glucose disappearance rate (k = 1.7%) which deteriorated (k = 1.3%, p < 0.001) during GH treatment. HbA1c and fasting glucose levels remained normal. Thus, GH treatment of children with PWS resulted in increased insulin blood levels, unchanged fasting glucose and HbA1c but decreased glucose elimination rate after an intravenous glucose test. However, the observed dose-dependent increase in insulin levels during GH treatment, that reached supranormal concentrations in 6/19 patients, and the occurrence of NIDDM in 1 patient during follow-up suggest that close surveillance and low doses of GH should be applied, especially if the PWS patient is very obese.
Nitric Oxide Stimulates Growth Hormone Secretion in vitro through a Calcium- and Cyclic Guanosine Monophosphate-Independent Mechanism
Authors: Pinilla L. , Tena-Sempere M. , Aguilar E.
Published: April 2003

In the last years, nitric oxide (NO) has emerged as an important intra- and intercellular transmitter involved in the control of the hypothalamic-pituitary axis, and NO synthase (NOS) has been identified in pituitary cells. To determine the role of NO in the control of GH secretion acting directly at the pituitary level, we have studied GH release by hemipituitaries incubated in the presence of different concentrations (10–7–10–3 M) of sodium nitroprusside (SNP), a potent NO donor. We found that SNP (10–4–10–3 M) stimulated GH release. This effect was mediated by the release of NO since it was abolished in the presence of hemoglobin, a scavenger of NO, but preserved in the presence of rhodanese + sodium thiosulfate (inactivators of cyanides generated from SNP). To analyze the participation of cyclic guanosine monophosphate (cGMP), the second messenger for a wide range of NO actions, in SNP-stimulated GH secretion, hemipituitaries were incubated in the presence of 8-bromo-cGMP (8-Br-cGMP; 10–7–10–3 M). In addition, hemipituitaries were stimulated with SNP plus oxadiazoloquinoxaline (OQD) or LY 83,583 (inhibitors of guanylyl cyclases). We found that 8-Br-cGMP was ineffective in eliciting GH release, and that the stimulatory effect of SNP was maintained in presence of OQD and LY 83,583. Finally, to analyze calcium dependence, the SNP effect was studied in hemipituitaries incubated in free medium calcium, in the presence of nifedipine and verapamil (blockers of calcium channels) and after depletion of intracellular Ca2+ stores with caffeine. We found that the SNP-induced GH secretion is also detected after incubation of hemipituitaries in free calcium medium, in the presence of nifedipine and verapamil, and after caffeine preincubation. We conclude that NO stimulates GH secretion in vitro through a specific calcium-cGMP-independent mechanism.
Prolactinoma Causing Secondary Amenorrhea in a Woman with Ullrich-Turner Syndrome
Authors: Dötsch Jörg , Schoof Ellen , Hensen Johannes , Dörr Helmuth G.
Published: April 2003

This is the case report of a girl who was diagnosed as having Ullrich-Turner mosaic at the age of 12 years. She had normal pubertal development and menarche at the age of 15 years. The patient had regular menstrual cycles for 12 months before developing secondary amenorrhea. She was started on estrogen/gestagen replacement therapy by her gynecologist. Several months later a prolactinoma was diagnosed by laboratory and imaging techiques. A second-generation dopamine agonist led to almost regular cycles. Therefore, even in patients with susceptibility to ovarian failure secondary amenorrhea necessitates thorough diagnostic investigation.
Fetal Growth: Boys before Girls
Authors: de Zegher Francis , Devlieger Hugo , Eeckels Roger
Published: April 2003

At term birth, boys are heavier than girls. This difference is thought to be generated in part by androgen action; its time course has not been deciphered. Androgen action may not only increase weight gain, but may also alter its time course. We have tested this hypothesis by examining the difference in gestational age of 281,894 boys and girls with weights between 500–4,749 g. The age at which children are born with a given weight was found to depend on gender: boys were consistently younger than girls (p < 0.001), the age difference being most pronounced in the lower birth weight classes. Thus, the gender difference in fetal growth appears to be rather pronounced before the third trimester and relatively less marked towards term. In conclusion, the male conceptus seems to grow not only more, but also earlier than the female. Hence, some critical time windows of development may be slightly different in boys and girls, and this phenomenon may be one of the bases for gender differences in the sensitivity to fetal programming.
Management of Males with 45,X/46,XY Gonadal Dysgenesis
Authors: Müller Jørn , Ritzén E. Martin , Ivarsson Sten-A. , Rajpert-De Meyts Ewa , Norjavaara Ensio , Skakkebæk Niels E.
Published: April 2003

Males with the 45,X/46,XY karyotype and malformations of the external genitalia carry an increased risk of developing germ cell neoplasia of the gonads. We have studied gonadal tissue from 10 individuals, 0.3–17 years of age, with a male phenotype and either hypospadias and/or cryptorchidism. Four patients, 0.3–15 years of age, had carcinoma in situ, 1 boy had Sertoli-cell-only pattern and the remainder prepubertal histology. Gonadoblastoma or invasive carcinoma was not found. On the basis of our current knowledge we propose a strategy for management and follow-up of these boys in order to detect possible premalignant histological changes early and prevent development of a gonadal tumour.
Power Doppler Improves the Diagnostic Accuracy of Color Doppler Ultrasonography in Cold Thyroid Nodules: Follow-Up Results
Authors: Cerbone G. , Spiezia S. , Colao A. , Di Sarno A. , Assanti A.P. , Lucci R. , Siciliani M. , Lombardi G. , Fenzi G.
Published: April 2003

The usefulness of a recent color Doppler (CD) ultrasonography technique, named power Doppler (PD), was evaluated in the diagnosis of thyroid nodules showing low or absent uptake of 99mTc-pertechnetate, in order to investigate the possibility to improve the diagnostic accuracy of ultrasonography. The rationale was the evidence that at PD the color map displays the total integrated Doppler power in color, while CD generally displays an estimate of the mean Doppler shift. The vascular patterns recorded at PD and CD evaluation of 322 thyroid nodules were compared to the results of cytology and/or histology, when surgery was performed. In respect to the results of cytology, PD has a higher sensitivity (100 vs. 91%) and specificity (95.1 vs. 86.2%) than CD. A similar result was found when PD and CD were compared to the results of histology, sensitivity being 100 vs. 89% and specificity 98.1 vs. 93.7%, respectively. During the follow-up the 2 nodules considered false positive at PD resulted to be tumoral lesions. On this basis, the final specificity of PD in our series was 100%. In conclusion, in the current series including 322 thyroid nodules characterized by a low or absent uptake of 99mTc-pertechnetate, PD seems to provide a better characterization of thyroid nodules, possibly allowing a more accurate selection of the patients to subject to fine-needle biopsy.
Giant Prolactinoma Presented as Unilateral Exophthalmos in a Prepubertal Boy: Response to Cabergoline
Authors: Krassas G.E. , Pontikides N. , Kaltsas T.
Published: April 2003

We report the case of a giant prolactinoma in a 7-year-old boy, which was complicated by unilateral exophthalmos. The initial levels of prolactin (PRL) were about 80,000 µU/ml. Treatment with cabergoline (CAB) resulted in rapid normalization of serum PRL (6 weeks after initiation of treatment) and reduction of tumor size. In particular, magnetic resonance imaging (MRI), which was done 2.5 months after the patient was put on CAB, revealed tremendous improvement with a decrease in the size of the tumor which now showed no extrasellar extension. Subsequent MRI studies demonstrated further improvement. Exophthalmos, anisocoria and visual fields improved. In summary, this patient represents the first report of the therapeutic use of CAB as the primary mode of treatment in a 7-year-old boy with infiltrative giant prolactinoma complicated by unilateral exophthalmos. It is a noninvasive treatment that can preserve and restore vision, as well as pituitary function, and is preferable to surgery or radiation in the treatment of prolactin-secreting macroadenoma in childhood and adolescence.
Growth Hormone Treatment Downregulates Serum Leptin Levels in Children Independent of Changes in Body Mass Index
Authors: Elimam Amira , Lindgren Ann Christine , Norgren Svante , Kamel Ashraf , Skwirut Christine , Bang Peter , Marcus Claude
Published: April 2003

The changes in serum leptin levels during growth hormone (GH) treatment were studied in 27 children, 17 with GH deficiency (GHD), 10 with idiopathic short stature (ISS), and 9 with Prader-Willi syndrome (PWS). Within 1 month of GH treatment, serum leptin levels decreased by 40% in the GHD children (p < 0.01). There was no significant change in serum leptin level in the children with ISS. In children with PWS, the mean serum leptin level decreased by almost 60% after 3 months of treatment (p < 0.001). Thereafter, no further decline was observed in any of the 3 groups. Changes in body composition became evident first after the 3 months of treatment. In the GHD children, the BMI was unchanged while the mean body fat percentage was 2.7% lower after 1 year of GH treatment (p < 0.05). In the ISS children, neither BMI nor body fat percentage were significantly changed during treatment. The PWS children exhibited a significant decrease in BMI after 6 months of GH treatment without any further change during the remaining period of treatment. In this group, the mean body fat percentage decreased from 42 ± 2.4 to 28 ± 2.2% after treatment (p < 0.001). The finding that the fall in leptin occurs before changes in body composition become detectable suggests a direct effect of GH on leptin production, metabolism, or clearance.
Thyroid Autoimmunity in Children and Adolescents with Type 1 Diabetes mellitus
Authors: Holl R.W. , Bohm B. , Loos U. , Grabert M. , Heinze E. , Homoki J.
Published: April 2003

Type 1 diabetes is often associated with additional autoimmune phenomena. However, data reported on the frequency of thyroid autoimmunity differ vastly. Therefore, the prevalence of thyroid autoantibodies was evaluated at a large pediatric diabetes center in Southern Germany. 2,305 determinations (TPO and TG, ELISA) were performed in 495 patients with type 1 diabetes (234 boys, 261 girls; age at last measurement: 15.4 ± 0.3 years, duration of diabetes 7.5 ± 0.2 years). The prevalence of elevated thyroid antibodies increased dramatically with age: from 3.7% in patients less than 5 years of age up to 25.3% in the age group 15–20 years (p < 0.0001). For children older than 10 years, girls were significantly more affected than boys (p < 0.0001). Thyroid autoimmunity tended to be more prevalent in the subgroup of patients with the HLA type DR3/DR4 compared to patients with other HLA types (p = 0.08). In children older than 10 years, basal TSH concentrations were significantly elevated in antibody-positive patients (p < 0.05). In conclusion, thyroid autoimmunity is prevalent in children and adolescents with type 1 diabetes. Adolescent girls and young women are especially affected. Yearly routine determinations of thyroid antibodies are therefore recommended.
Bone Maturation Reflects the Secular Trend in Growth
Authors: Matsuoka Hisafumi , Sato Koshi , Sugihara Shigetaka , Murata Mitsunori
Published: April 2003

The aim of this study was to compare a series of X-rays from the mid–1990s with another taken in the mid–1980s in order to test the possibility that environmental causes affect the skeletal maturation. The first group of subjects included a total of 1,057 girls and 1,055 boys participating in a project for Japan and China health research in 1986. The second group of subjects included a total of 382 girls and 629 boys participating in a project for bone mineral density research in 1996. The skeletal maturity score using the Tanner-Whitehouse 2-RUS method was used as the fundamental datum. This score was used to represent each group. The Wilcoxon’s rank sum test was applied to examine the significance of the difference between the 1986 and the 1996 groups. The 1996 children had not matured more than the 1986 children; children in both groups reached the given scores at almost the same ages. In girls, there was little difference between the groups at 7 years of age, but it declined from 8 years of age onward. Some apparent differences arose at ages 14 and 15, but ceased by age 16 in girls. In boys, no differences were found in those aged from 7 to 17 years, except for 12-year-olds. We did not detect much of a difference in bone maturation between the 1986 and 1996 groups of children, and no differences in height during the same period. Our findings suggest that bone maturation reflects the secular trend in growth.
Influence of IGF-I and Cell Density on MDR1 Expression in the T-Lymphoblastoid Cell Line CCRF-CEM
Authors: Schwarze C.P. , Neu S. , Beck J. , Mavridou K. , Ranke M.B. , Binder G.
Published: April 2003

The debate about a direct or indirect effect of GH and IGF-I on the recurrence of malignancy, especially in the case of rhGH therapy in patients with leukemia, is still going on. Recent studies suggested that IGF-I plays a role in drug resistance during anticancer therapy. This resistance to diverse cytotoxic drugs, named multidrug-resistance (MDR), is mainly due to high levels of P-glycoprotein (P-gp). The gene encoding this membrane-associated transporter protein was named MDR1, and increased levels of P-gp are linked to enhanced MDR1 mRNA expression. Our aim was to investigate a possible effect of rhIGF-I on MDR1 gene expression in vitro. We cultured the T-lymphoblastoid cell line CCRF-CEM with different rhIGF-I concentrations (0, 5, 20 and 50 ng/ml) in serum-free medium for 3 days. CCRF-CEM cells are drug-sensitive and express MDR1 at low levels. MDR1 mRNA expression was measured by semiquantitative RT-PCR using a competitive assay with a heterologous DNA construct. In addition, GAPDH mRNA was amplified as an internal control for RNA integrity. P-gp activity was determined by a flow cytometric assay measuring rhodamine 123 accumulation. Furthermore, cell proliferation was monitored in all experiments. Our data do not support an effect of rhIGF-I on MDR1 mRNA expression, P-gp activity or cell proliferation in the CCRF-CEM cell line. MDR1 mRNA levels were inversely correlated to cell density with high significance (p < 0.0001). In conclusion, multidrug resistance linked to P-gp is not induced by IGF-I in CCRF-CEM cells. At high density, CCRF-CEM cells downregulate MDR1 gene expression. Our experimental model provides a very useful tool for monitoring the influence of growth factors on multidrug resistance in vitro.
Medium-Term Cardiovascular Effects of High-Dose Growth Hormone Treatment in Growth Hormone-Deficient Children
Authors: Radetti Giorgio , Crepaz Roberto , Paganini Claudio , Gentili Lino , Pitscheider Walter
Published: April 2003

Aim: To investigate the possible cardiac morphofunctional alterations inducd by prolonged and high-dose GH therapy in a group of 14 children with isolated GH deficiency. Patients and Methods: Patients were evaluated at phase 1, after 1.1 ± 0.6 years of treatment with GH 0.93 ± 0.13 U/kg/week, and at phase 2, after 5.5 ± 2.1 years of therapy 0.89 ± 0.11 U/kg/week. At each phase left ventricular volume, mass and systolic function were evaluated by two-dimensional guided M-mode echocardiography; left ventricular diastolic function was assessed by PW-Doppler sampling of transmitral flow. Results: Phase 1: diastolic blood pressure was lower (p < 0.05) and fractional shortening was not adequate for the level of afterload (stress shortening index p < 0.05) in patients compared to controls. Phase 2: diastolic blood pressure was lower (p < 0.01) and mass and mass/volume ratio were increased (mass index p < 0.05, mass/ volume ratio p < 0.05) in patients compared to controls. The increased mass/volume ratio, together with the normal systolic blood pressure, explains the reduction in peak systolic stress (p < 0.005). Among the parameters of left ventricular diastolic function, the peak E velocity/total area under mitral valve tracing and the area under E velocity/total area under mitral value tracing ratios were significantly decreased (p < 0.05). Conclusion: After a mean period of 5 years on high-dose GH treatment in GH-deficient children, subclinical morphofunctional alterations in the left ventricle were found.
Comparison between Low- and Standard-Dose ACTH Tests in Premature Infants at Risk for Chronic Lung Disease
Authors: Nykänen Päivi , Heinonen Kirsti , Voutilainen Raimo
Published: April 2003

In order to find a sensitive method to evaluate adrenocortical function in premature infants, we compared low- (0.5 μg/1.73 m2) and standard-dose (250 μg/1.73 m2) adrenocorticotropin tests (LD- and SD-ACTH) in 12 very-low-birth-weight infants before and 2 days after the end of dexamethasone therapy (duration 9–14 days) for chronic lung disease. Basal serum cortisol levels were inappropriately low in several infants already before dexamethasone therapy (median 190, range 60–357 nmol/l). The 95% confidence intervals of mean serum cortisol levels at 20 min were equal in LD- and SD-ACTH, while at 60 min, the low-dose gave a clearly lower response than the standard-dose test. The LD-ACTH can be used in premature infants as in older children and adults, but the criteria for adrenocortical insufficiency need to be defined.