bluuebunny/crossref_metadata_2025 huggingface dataset:
Disorders of the Aldosterone Synthase and Steroid 11β-Hydroxylase Deficiencies
Authors: Peter M. , Dubuis J.-M. , Sippell W.G.
Published: April 2003

The most potent corticosteroids are 11β-hydroxylated compounds. In humans, two cytochrome P450 isoenzymes with 11β-hydroxylase activity, catalysing the biosynthesis of cortisol and aldosterone, are present in the adrenal cortex. CYP11B1, the gene encoding 11β-hydroxylase (P450c11), is expressed on high levels in the zona fasciculata and is regulated by ACTH. CYP11B2, the gene encoding aldosterone synthase (P450c11Aldo), is expressed in the zona glomerulosa under primary control of the renin-angiotensin system. Aldosterone synthase has 11β-hydroxylase activity as well as 18-hydroxylase activity and 18-oxidase activity. The substrate for CYP11B2 is 11-deoxycorticosterone, that of CYP11B1 is 11-deoxycortisol. Mutations in CYP11B1 cause congenital adrenal hyperplasia (CAH) due to 11β-hydroxylase deficiency. This disorder is characterized by androgen excess and hypertension. Mutations in CYP11B2 cause congenital hypoaldosteronism (aldosterone synthase deficiency) which is characterized by life-threatening salt loss, failure to thrive, hyponatraemia and hyperkalaemia in early infancy. Both disorders have an autosomal recessive inheritance. Classical and nonclassical forms of 11β-hydroxylase deficiency can be distinguished. Studies in heterozygotes for classical 11β-hydroxylase deficiency show inconsistent results with no or only mild hormonal abnormalities (elevated plasma levels of 11-deoxycortisol after ACTH stimulation). In infants with congenital hypoaldosteronism, a comparable frequency of 18-hydroxylase deficiency (aldosterone synthase deficiency type I) and of 18-oxidase deficiency (aldosterone synthase deficiency type II) can be found. Molecular genetic studies of the CYP11B1 and CYP11B2 genes in 11β-hydroxylase deficiency or aldosterone synthase deficiency have led to the identification of several mutations. Transfection experiments showed loss of enzyme activity in vitro. In some of the patients with 18-oxidase deficiency (aldosterone synthase deficiency type II) no mutations in the CYP11B2 gene were identified. Refined methods for steroid determination are the basis for the diagnosis of inborn errors of steroidogenesis. Molecular genetic studies are complementary; on the one hand, they have practical importance for the prenatal diagnosis of virilizing CAH forms and on the other hand, they are of theoretical importance in terms of our understanding of the functioning of cytochrome P450 enzymes.
Pubertal Growth as a Determinant of Adult Height in Boys with Constitutional Delay of Growth and Puberty
Authors: Rensonnet Claudie , Kanen François , Coremans Christine , Ernould Christian , Albert Adelin , Bourguignon Jean-Pierre
Published: April 2003

In boys with constitutional delay of growth and puberty, adult height may be inconsistent with parental (target) height. We aimed at studying which period of growth was important to account for adult height being above or below target height. In this retrospective study, adult height measured after 20 years in 39 patients was compared with target height and height data obtained at about 6 and 12 years of age and at diagnosis of delayed puberty (mean 14.6 years). Twenty-eight patients were untreated while 11 received testosterone enanthate (50 or 100 mg/month for 6 months). The growth data from both groups were pooled since they were not different. On average, the adult height standard deviation score (–0.6 ± 0.8, mean ± SD) was similar to target height (–0.5 ± 0.6). There were, however, marked individual differences since adult height varied between 1.7 SD (11 cm) below target height and 1.4 SD (9.5 cm) above target height. Multiple regression analysis showed that the most significant determinant of the difference between adult height and target height was height catch up during puberty (p < 0.002). We conclude that the magnitude of height catch up during puberty is a significant determinant of adult height in boys with constitutional delay of growth and puberty. Thus, optimizing pubertal growth may be a relevant therapeutic aim for adult height in boys with short stature and delayed puberty.
PCR Protocol to Detect Parental Origin and Hidden Mosaicism inSex Chromosome Aneuploidies
Authors: Martínez-Pasarell Olga , Templado Cristina , Egozcue Josep , Vicens-Calvet Enric , Nogués Carme
Published: April 2003

In this study, we report an accurate method to determine the parental origin of sex chromosome aneuploidies or polyploidies and to detect low percentage mosaicisms. We have amplified by polymerase chain reaction (PCR) five polymorphic markers along the X chromosome (DXS1283E, DYS II, DMD49, AR and DXS52) and three markers along the Y chromosome (SRY, DYZ3 and DYZ1). False-negative results were discarded by the simultaneous amplification of Y markers and of internal controls. We have applied this protocol to a series of 14 Turner syndrome patients with a 45,X karyotype. We have detected sex chromosome mosaicisms in two patients. The parental origin of the syndrome has been determined in the other 12 patients.
Leptin and Leptin Receptor Expression in a Lipoblastoma in an 8-Year-Old Girl
Authors: Deutscher Jens , Meyer Kerstin , Blütters-Sawatzki Renate , Franke Folker E. , Kiess Wieland
Published: April 2003

Leptin is a hormone that is produced by adipocytes. Leptin acts on specific receptors in the hypothalamus. RNA was isolated from a lipoblastoma of an 8-year-old girl and the expression of leptin and leptin receptor mRNA was analyzed by RT-PCR. The lipoblastoma tumor, a rare form of childhood tumors, expressed leptin and leptin receptors in a fashion similar to normal adipose tissue. We hypothesize that the peripheral action of leptin via its receptors could play a role in the development and/or progression of lipoblastoma. Whether or not leptin and leptin receptor expression play a role in the development and/or progression of lipoblastoma and other tumors is not clear to date.
Maldescendus testis
Authors: Toppari Jorma , Kaleva Marko
Published: April 2003

Maldescendus testis is a common congenital abnormality occurring in 2–5% of full-term boys at birth in the Western countries. By 3 months of age, the incidence rate spontaneously reduces to 1–2% in this group. The etiology of the disorder is not known, but normal hypothalamo-pituitary-gonadal axis is usually a prerequisite for normal descent of the testes. Abnormal sexual differentiation is associated with maldescent. However, the majority of boys with maldescended testes show no endocrine abnormalities after birth. Several defects in developmental genes, such as homeobox genes and Insl3, have been described to cause cryptorchidism in mice, and disturbances in the regulation of these genes or their mutations may explain etiology of a large part of human testicular maldescent in the future. Increased degeneration of germ cells can be observed in undescended testes after the first year, and therefore early treatment is recommended. Surgical treatment is the most effective and reliable method to bring testes into the scrotum, but hormone treatment with either hCG or GnRH analogues can be considered, particularly in cases where testes can be palpated in high scrotal position. The efficacy of hormone treatment is less than 20% and depends on the initial location of the testis. Nonpalpable testes rarely descend with hormone treatment. Both surgery and hormone treatment can have untoward effects. Treatment with hCG has been associated with an inflammation-like reaction in the testes and an increased rate of apoptosis of germ cells leading to a reduced adult size of the testes. Vascular complications can occur during surgery, particularly in staged orchidopexies. Men with a history of undescended testis have an increased risk of testicular cancer. Impaired fertility is another long-term risk associated to maldescended testes. Fertility potential may be improved by early treatment. Although our knowledge on cryptorchidism has increased considerably during the last decades, many questions remain to be answered: Is the incidence rate increasing? What is causing maldescent? Do hormones have any role in the treatment?
Auxological and Biochemical Evaluation of Pubertal Suppression with the GnRH Agonist Leuprolide Acetate in Early and Precocious Puberty
Authors: Mul D. , de Muinck Keizer-Schrama S.M.P.F. , Oostdijk W. , Drop S.L.S.
Published: April 2003

We studied the auxological effects of treatment with the GnRH agonist leuprolide acetate (Lucrin®) at 3.75 mg/ 28 days in 38 children with early or precocious puberty. We present our newly developed scoring system, the Puberty Suppression Score (PSS), in which clinical and biochemical parameters determine whether suppression was effective. Leuprolide acetate suppressed pubertal development in the majority of cases. During treatment there was a significant correlation between the number of times that PSS was >0 and gain in predicted adult height (PAH) compared to initial prediction at the start of treatment. After 6 months of treatment, ineffective suppression measured by PSS was associated with the magnitude of gain in PAH. We conclude that a leuprolide acetate dosage of 3.75 mg every 28 days effectively suppresses puberty. PSS is helpful in monitoring the suppressive capacity of a GnRH agonist. We recommend to start with leuprolide acetate at 3.75 mg/28 days and to increase the injection frequency or dose in case PSS is >0 after 6 months of treatment.
Dominant Expression of Progesterone Receptor Form B mRNA in Ovarian Endometriosis
Authors: Misao Ryou , Iwagaki Shigenori , Fujimoto Jiro , Sun Wen-Shu , Tamaya Teruhiko
Published: April 2003

This study was designed to examine the biological implications of progesterone receptor form A (PR-A) and B (PR-B) mRNA expressions in human ovarian endometriosis (ectopic endometrium). A high ratio of PR-B to PR-AB (PR-A+PR-B) mRNA expression was found in 8 of 14 cases of endometriosis, compared with the ratio in eutopic endometrium. The mean ratio in ectopic endometria was significantly (p < 0.01) higher than in eutopic endometria. The ratio in eutopic and ectopic endometria showed no significant change during the menstrual cycle. The mean ratio in ectopic endometria in the proliferative and secretory phases of the endometrium was significantly (p < 0.01) higher than in eutopic endometria. In conclusion, PR-B mRNA was relatively highly expressed in some endometriomas, which might lead to aberrations in the control of progestational effects involving responsiveness to sex steroidal growth regulation.
Insulin-Like Growth Factor Binding Protein (IGFBP)-3-Bound IGF-I and IGFBP-3-Bound IGF-II in Growth Hormone Deficiency
Authors: Belgorosky Alicia , Rivarola Marco A.
Published: April 2003

In blood, circulating IGFs are bound to six high-affinity IGFBPs, which modulate IGF delivery to target cells. Serum IGFs and IGFBP-3, the main carrier of IGFs, are upregulated by GH. The functional role of serum IGFBP-3-bound IGFs is not well understood, but they constitute the main reservoir of IGFs in the circulation. We have used an equation derived from the law of mass action to estimate serum IGFBP-3-bound IGF-I and IGFBP-3-bound IGF-II, as well as serum free IGF-I and free IGF-II, in 129 control children and adolescents (48 girls and 81 boys) and in 13 patients with GHD. Levels of serum total IGF-I, total IGF-II, IGFBP-1, IGFBP-2 and IGFBP-3 were determined experimentally, while those of IGFBP-4, IGFBP-5 and IGFPB-6, as well as the 12 affinity constants of association of the two IGFs with the six IGFBPs, were taken from published values. A correction for in vivo proteolysis of serum IGFBP-3 was also considered. In controls, serum total IGF-I, total IGF-II, IGFBP-3, IGFBP-3-bound IGF-I, IGFBP-3-bound IGF-II and free IGF-I increased linearly with age, from less than 1 to 15 years, in the two sexes. The concentrations of serum free IGF-I and free IGF-II were approximately two orders of magnitude below published values, as well as below the affinity constant of association of IGF-I with the type-1 IGF receptor. Therefore, it is unlikely that these levels can interact with the receptor. In the 13 patients with GHD, mean (± SD) SDS of serum IGFBP-3-bound IGF-I was –2.89 ± 0.97. It was significantly lower than serum total IGF-I, free IGF-I or IGFBP-3 SDSs (–2.35 ± 0.83, –1.12 ± 0.78 and –2.55 ± 1.07, respectively, p = 0.0001). The mean SDS of serum total IGF-II, IGFBP-3-bound IGF-II and free IGF-II were –1.25 ± 0.68, –2.03 ± 0.87 and 0.59 ± 1.10, respectively, in GHD. In control subjects, 89.8 ± 4.47% of serum total IGF-I and 77.3 ± 9.4% of serum total IGF-II were bound to serum IGFBP-3. In patients with GHD, the mean serum IGFBP-3-bound IGF-I and IGFBP-3-bound IGF-II were 8.63 ± 8.53 and 19.1 ± 14.7% below the respective means of control subjects (p < 0.02). In conclusion, in GHD there was a relative change in the distribution of serum IGFs among IGFBPs, due to the combined effects of the decrease in both total IGF-I and IGFBP-3. As a result, serum IGFBP-3-bound IGF-I and IGFBP-3 bound IGF-II, the main reservoirs of serum IGFs, were severely affected. This suggests that the decrease in serum IGFPB-3-bound IGF-I and IGFBP-3-bound IGF-II might have a negative effect for growth promotion and other biological effects of IGF-I and IGF-II. Finally, the estimation of serum IGFBP-3-bound IGF-I, or the percentage of total IGF-I and IGF-II bound to IGFBP-3, might be useful markers in the diagnosis of GHD.
Diagnosis of ACTH Deficiency
Authors: Rose Susan R. , Lustig Robert H. , Burstein Stephen , Pitukcheewanont Pisit , Broome Dean C. , Burghen George A.
Published: April 2003

Test sensitivity and accuracy of 250 μg/m2 ACTH test, 1 μg/m2 ACTH test, and overnight metyrapone test were evaluated in 158 children at risk for ACTH deficiency. Of 38 given high-dose ACTH, 20 had normal responses to metyrapone and to high-dose ACTH. 14 had low response to metyrapone; of these only 2 had low cortisol response (<550 nmol/l) to high-dose ACTH. Of 120 given low-dose ACTH, 64 had normal responses to metyrapone and to low-dose ACTH. All 24 with low metyrapone response had low or borderline response to low-dose ACTH. The remaining children had an inconclusive metyrapone response. In conclusion, high-dose ACTH misses most diagnoses of ACTH deficiency (21% sensitivity, 100% specificity, 63% accuracy). In contrast, the low dose ACTH test accurately diagnoses 90% of patients with ACTH deficiency (100% sensitivity, 68% specificity). The low-dose ACTH test can serve as an accurate and practical screening test for adequacy of ACTH reserve.
Growth-Suppressive Effect of Intra-Articular Glucocorticoids Detected by Knemometry
Authors: Heuck Carsten , Wolthers Ole D. , Herlin Troels
Published: April 2003

After one intra-articular injection of 20 mg triamcinolone hexacetonide in the knee, the length of the contralateral lower leg was found to be reduced in 2 boys with juvenile rheumatoid arthritis.
Peritoneal Carcinomatosis following Laparoscopic Resection of an Adrenocortical Tumor Causing Primary Hyperaldosteronism
Authors: Deckers S. , Derdelinckx L. , Col V. , Hamels J. , Maiter D.
Published: April 2003

A clinical syndrome combining hypertension and hypokalemic alkalosis led to the diagnosis of primary hyperaldosteronism, caused by a right-sided, 2 cm large, apparently benign aldosterone-producing adenoma. The adrenal tumor was completely resected by laparoscopic adrenalectomy. Six months after surgery, the patient exhibited a severe relapse of hyperaldosteronism. Extensive peritoneal metastases of a mixed aldosterone- and cortisol-secreting adrenocortical carcinoma were found at abdominal laparotomy. In the light of this case report, we discuss the possibility that laparoscopic resection of adrenocortical tumors might contribute to their subsequent peritoneal dissemination.
Acute Watery Diarrhea as the Initial Presenting Feature of a Pheochromocytoma in an 84-Year-Old Female Patient
Authors: van Eeckhout Pascal , Shungu Hélène , Descamps François-Xavier , Lanthier Philippe , Castelain Thierry , Saey Jean-Pierre , Rettman Roland , Drese Christian , Colin Ides M.
Published: April 2003

We report the case of an 84-year-old woman who was initially admitted to the emergency room of our institution for frank dehydration caused by acute and severe secretory diarrheas along with acidosis and hypokalemia. After extensive gastrointestinal investigations, the etiology of the diarrhea remained unclear. Because clinical symptoms and ionogram parameters worsened, despite intravenous fluids and electrolyte replacement, an abdominal CT scan was performed and unexpectedly revealed a 4.5-cm mass in the right adrenal gland. Several separate 24-hour urine catecholamines were shown to be highly elevated. The diagnosis of pheochromocytoma was confirmed by MIBG scintigraphy and MRI. Before the admission, the patient never experienced symptoms suggestive of pheochromocytoma, except dry mouth and fear of impending death on several occasions. After 2 weeks, the diarrhea stopped abruptly and spontaneously without specific medication but after adequate rehydration. The patient subsequently underwent surgical removal of the adrenal medullary mass. Postoperatively, urinary catecholamines returned to normal values. Immunohistochemical study of the tumor confirmed the diagnosis of pheochromocytoma and revealed the presence of VIP-positive cells organized as islets in scattered areas of the tissue. This case illustrates the protean mode of presentation of pheochromocytoma, as well as the ability of medullary neural crest-derived cells to produce various neuropeptides potentially responsible for a large variety of symptoms.
Autoantibodies Predicting Diabetes mellitus Type I in Celiac Disease
Authors: Galli-Tsinopoulou A. , Nousia-Arvanitakis S. , Dracoulacos D. , Xefteri M. , Karamouzis M.
Published: April 2003

Celiac disease (CD) and diabetes mellitus type I (DM-I) are both autoimmune diseases. Abnormal first-phase insulin response (FPIR) is associated with the prediabetic phase. Glutamic acid decarboxylase (GAD) and islet cell antibodies (ICAs) – especially the tyrosine phosphatase-like protein IA-2 antibodies – are considered to be serological markers of DM-I future development. The aim of this study is to investigate the presence of autoantibodies (GAD, IA-2) in individuals with CD, on a gluten-free diet, who have normal intestinal morphology. Thirty patients with CD (4–22, mean 15 years), 30 newly diagnosed diabetic children (2.5–16, mean 10 years) and 30 healthy subjects (7–35, mean 18 years) were investigated. Serum GAD and IA-2 autoantibodies were assessed by a quantitative enzyme-linked immunosorbent assay (ELISA) method in all patients and controls. Seven CD patients (23%), 28 diabetic children (93%) and none in the control group had positive GAD and IA-2 antibodies. The FPIR was normal in CD patients (≥46 mU/l). Conclusions: GAD and IA-2 antibodies are detected in 23% of patients with CD. These patients may be at risk to develop DM-I. Regular follow-up and determination of FPIR for the early diagnosis of the prediabetic phase in patients with CD having circulating autoantibodies is recommended.
Aspects of Ovarian Follicle Development throughout Life
Authors: Macklon N.S. , Fauser B.C.J.M.
Published: April 2003

The pool of primordial follicles present in the female ovary reaches its maximum number around 20 weeks of gestational age and then decreases in a logarithmic fashion throughout life until complete depletion occurs around the age of the menopause. Reproductive life is initiated when less than 10% (0.5 million) of primordial follicles are left. The entire growth trajectory of the follicle takes at least 3 months. Follicle growth up to the antral stage occurs during fetal life and infancy. While the role of gonadotropins in early follicular development remains controversial, the last 2 weeks of development are FSH dependent. The intercycle rise in FSH and decreasing levels thereafter are crucial for recruitment of a cohort of healthy, early antral follicles and subsequent single dominant selection. Following puberty, anovulation may persist for years and this may presage the development of adult anovulatory infertility. The menopause is preceded by a period of reduced fertility. The development of reliable and sensitive markers for ovarian ageing will be the challenge of the near future.
Zinc Supplementation Increases the Level of Serum Insulin-Like Growth Factor-I but Does Not Promote Growth in Infants with Nonorganic Failure to Thrive
Authors: Hershkovitz Eli , Printzman Ludmilla , Segev Yael , Levy Jacov , Phillip Moshe
Published: April 2003

We investigated in a randomized double-blind placebo-controlled study the effects of zinc supplementation (2 mg/kg/day) for 12 weeks on growth, serum insulin-like growth factor-I (IGF-I) and insulin-like factor binding protein-3 (IGFBP-3) on 3- to 9-month-old infants with nonorganic failure to thrive (NOFTT). 25 infants completed the study, 14 received zinc supplementation (group A), and 11 received placebo (group B). The control group for baseline measurements was composed of 10 age-matched normal growing infants. There were no significant changes in weight for age, length for age, or weight for length during the entire study period in either group A or B. Serum IGF-I levels at baseline were similar in all the groups. After 12 weeks of therapy, serum IFG-I levels increased significantly only in the zinc-supplemented group, from 40.3 ± 7 ng/ml at baseline to 65 ± 8 ng/ml (p < 0.05). There was a marked difference in serum IGF-I levels between the zinc-supplemented group and the placebo group after 12 weeks: 65 ± 8 vs. 49.4 ± 5 ng/ml (p = 0.058, 95% CI of difference 9.88–21.31). No change was demonstrated in serum IGFBP-3 levels in either study group. We conclude that although zinc supplementation increased serum IGF-I levels, it did not improve the growth parameters of infants with NOFTT.
Insulin Sensitivity Is Not Affected by Mutation of Codon 972 of the Human IRS-1 Gene
Authors: Ito Kuninobu , Katsuki Akira , Furuta Masahiko , Fujii Masashi , Tsuchihashi Ken , Hori Yasuko , Yano Yutaka , Sumida Yasuhiro , Adachi Yukihiko
Published: April 2003

We investigated the relationship of codon 972 polymorphism of the insulin receptor substrate-1 (IRS-1) gene with insulin resistance in the Japanese population. Among 130 patients with type-2 diabetes mellitus (DM), we identified 6 who were heterozygous for the Gly972Arg mutation. Among 144 healthy subjects, 6 were heterozygous and 1 was homozygous for the mutation. A hyperinsulinemic euglycemic clamp study was performed in 3 of 6 diabetic patients with the heterozygous Gly972Arg mutation and in 60 without it. Both groups showed almost the same levels of insulin sensitivity (glucose infusion rate, GIR = 50.2 ± 3.0 vs. 51.3 ± 12.1 μmol/kg/min). Similarly, there was no difference in insulin sensitivity between healthy subjects with and without the mutation using the homeostasis model assessment (HOMA index = 1.14 ± 0.50 vs. 1.02 ± 0.63). The frequency of the Gly972Arg allele was not increased in diabetic patients compared with control subjects even in aged (>50 years old) or obese (BMI ≥25) subjects. Among healthy subjects, we identified a 25-year-old male with the homozygous Gly972Arg allele. He was slightly obese (BMI = 25.5) but showed relatively high insulin sensitivity, almost equal to that of healthy subjects without the mutation (GIR = 67.2 vs. 71.8 ± 22.0 μmol/kg/min). Because the GIR in healthy subjects was significantly higher compared with that in type-2 DM patients, we speculate that another genetic or environmental factor producing a more deleterious effect on insulin sensitivity may exist in diabetic patients. We conclude that this gene abnormality does not play a role in the pathogenesis of insulin resistance and type-2 DM.
Liquorice, Growth Retardation and Addison’s Disease
Authors: Doeker Beate M. , Andler W.
Published: April 2003

An 11-year-old boy had hypoparathyroidism and Addison’s disease. During treatment with calcitriol, calcium, hydrocortisone and 9-α-fluorocortisol, he developed an apparent mineralocorticoid excess and growth retardation. Pseudohyperaldosteronism even persisted after treatment with 9-α-fluorocortisol was stopped and hydrocortisone was reduced to 6 mg/m2. The boy reported an excessive daily intake of 300–400 g liquorice corresponding to 600–800 mg glycyrrhizic acid because of salt craving. After complete withdrawal of liquorice all symptoms of hypermineralocorticoidism diminished and growth velocity increased. We hypothesise that inhibition of 11β-hydroxysteroid dehydrogenase by liquorice caused hypermineralocorticoidism and growth retardation via increased levels of free cortisol in this patient. We conclude that self-medication with liquorice in children with Addison’s disease should be considered during treatment.
Neonatal Thyroid-Stimulating Hormone Screening as an Indirect Method for the Assessment of Iodine Deficiency in Estonia
Authors: Mikelsaar Ruth V. , Viikmaa Mart
Published: April 2003

According to neonatal thyroid screening the incidence of congenital hypothyroidism in Estonia is 1:2,860. Transient hyperthyrotropinemia with a raised thyroid-stimulating hormone level of 5 μU/ml occurred in 17.7% of infants and was not associated with low birth weight, small birth length, low gestational age or congenital anomalies. Based on WHO criteria (WHO/UNICEF, 1994) it corresponds to mild iodine deficiency in Estonia (3% or less is in iodine-sufficient areas). This is in agreement with the previously reported median urinary iodine content of 65 μg/l in children. The frequency of infants with TSH >5 μU/ml was 16.4, 21 and 17.2% in three regions (north, central and south) of Estonia, respectively, indicating mild to moderate iodine deficiency. These findings show the possibility of using the results of newborn screening for congenital hypothyroidism to assess the severity of iodine deficiency in Estonia. The introduction of universal iodine prophylaxis is recommended.
Gulliver G-100 – A New Device to Evaluate Daily Growth Measurement in Comparison with Harpenden Stadiometer
Authors: Glock M. , Hermanussen M. , Keller E. , Hartmann K.K.P.
Published: April 2003

To reduce the time to monitor success of growth hormone therapy, Gulliver G-100 (G-100), a new portable height measurement device based on ultrasound technology, was developed and compared with a conventional determination system, the Harpenden stadiometer (HS). In addition, growth of 12 children was monitored at home twice per day 3 months before and 3 months during GH therapy. Mean body height of 101 children was 144.67 cm using G-100 compared to 145.16 cm using HS. The coefficient of variability of 3 measurements from each patient was 0.29 and 0.18 using G-100 or HS, respectively. Statistic analysis of these data revealed no significant difference between G- 100 or HS. Statistical analysis of short-time growth of 12 patients revealed an increase of growth velocity for 8 patients (p < 0.01) after 3 months. Calculated growth velocity using data revealed from short-time growth analysis with G-100 and using long-term growth analysis with HS did not show any significant difference. Our data reveal that G-100 is able to produce accurate results in height measurement comparable to the HS. Using G-100, the patient can be classified as a ‘responder‘ of GH therapy already after 3 months.
Effect of Growth Hormone and Oxandrolone Treatment on Glucose Metabolism in Turner Syndrome
Authors: Joss E.E. , Zurbrügg R.P. , Tönz O. , Mullis P.-E.
Published: April 2003

In 18 girls with Turner syndrome, glucose tolerance was studied before treatment and after 6 and 24 months of growth-promoting treatment with recombinant human growth hormone (24 IU/m2/week; 8 mg/m2/week) and oxandrolone (0.06 mg/kg/day), as well as after termination of the treatment. One girl developed an overt non-ketotic diabetes mellitus 50 months after termination of treatment. The results of the remaining 17 girls in whom the effect of treatment on glucose metabolism was reversible are presented as a group. Their median age at the beginning of the treatment was 10.4 years (range 6.9–15.9), and 15.0 years (range 12.1–19.9) at the final assessment. There was a moderate, but not significant rise in fasting glucose throughout the course of the longitudinal study. At oral glucose tolerance testing (oGTT), the area under the curve for glucose rose significantly (p = 0.013) during the period of treatment and returned to the basic value thereafter. Fasting insulin and especially the integrated insulin values (AUCi; area under the curve for insulin) during oGTT increased continuously during treatment, declined after termination of treatment but were still significantly (p = 0.04) higher than before treatment. Considering the fact that in untreated girls with Turner syndrome the fasting insulin and the AUCi increase with age, one can conclude that the insulinaemia returned to age-specific norm after termination of treatment. Thus the effect of a combined growth hormone and oxandrolone growth-promoting treatment on glucose metabolism was fully reversible in these 17 girls with Turner syndrome.
Androgen Insensitivity Syndrome (AIS): Emotional Reactions of Parents and Adult Patients to the Clinical Diagnosis of AIS and Its Confirmation by Androgen Receptor Gene Mutation Analysis
Authors: Slijper F.M.E. , Frets P.G. , Boehmer A.L.M. , Drop S.L.S. , Niermeijer M.F.
Published: April 2003

The emotional reactions of parents and adult patients on disclosure of the clinical diagnosis of androgen insensitivity syndrome (AIS) and its later confirmation by gene mutation analysis were assessed. A semistructured interview and three questionnaires were used. Parents came from 18 different families with a total of 20 children (15 complete AIS, 5 partial AIS), 19 raised as girls, 1 as a boy. Ten adult women with complete AIS came from six families. The short-term reaction upon the clinical diagnosis was in the majority of both parents and adult patients associated with shock, grief, anger, and shame and in the mothers and adult patients with guilt. Emotional reactions were more long-lasting in mothers and adult patients than in fathers. The confirmation by DNA analysis did not alter the actual feelings of both parents. Adolescents with AIS should be informed completely – but in a step-by-step way – about their condition, since adult patients indicated that they had suffered from being not at all or misinformed about AIS in their adolescence.
Control of Catecholamine Release and Blood Pressure with Octreotide in a Patient with Pheochromocytoma: A Case Report with in vitro Studies
Authors: Koriyama Nobuyuki , Kakei Masafumi , Yaekura Kazuro , Okui Hideki , Yamashita Tsuminori , Nishimura Hiroaki , Matsushita Shinji , Tei Chuwa
Published: April 2003

A 65-year-old male patient with pheochromocytoma, whose hypertensive episodes were uncontrolled using conventional therapy, was successfully treated with octreotide (SMS 201-995). The serum catecholamine level and the urinary excretion of catecholamines decreased after 300 μg/day of octreotide was administered. To clarify the mechanisms of octreotide that lower catecholamine released from a tumor, we studied the in vitro effects of octreotide on membrane potentials and voltage-dependent Ca2+ channel (VDCC) current using the whole-cell patch-clamp technique in single pheochromocytoma cells dispersed after tumor resection. The action potentials were reversibly inhibited with 10 μM octreotide. In addition, the VDCC current evoked by depolarized pulses from the holding potential of –60 mV was inhibited with 10 μM octreotide. Octreotide is useful for controlling blood pressure before surgery in some patients with uncontrolled hypertension caused by a pheochromocytoma.
Determination of 17-Hydroxyprogesterone in Plasma by Stable Isotope Dilution/Benchtop Liquid Chromatography-Tandem Mass Spectrometry
Authors: Wudy Stefan A. , Hartmann Michaela , Svoboda Michal
Published: April 2003

An assay based on stable isotope dilution liquid chromatography-tandem mass spectrometry (ID/LC-MS-MS) was developed for the quantification of 17-hydroxyprogesterone, the most important indicator of 21-hydroxylase deficiency in human plasma. Plasma was extracted using ethyl acetate and Extrelut® columns. LC was performed on a reversed-phase C18 column using a water/methanol gradient. A benchtop triple quadrupole mass spectrometer, operating in selected reaction monitoring mode, served as mass detector. The analytical run time was 9 min per sample. The sensitivity was high: 0.06 pmol of 17-hydroxyprogesterone yielded a signal-to-noise ratio of 13. Precision (CV) and accuracy (relative error) derived from the analyses of unspiked and spiked validation samples were 7.4–12.0% and 6.4%, respectively. When analyzing the same samples – median (range), in nanomoles per liter – from neonates and adults independently by ID/LC-MS-MS as well as by ID/gas chromatography (GC)-MS, corresponding results were obtained: neonates (n = 10), ID/LC-MS-MS 3.99 (0.48–16.05), ID/GC-MS 5.39 (1.57–13.02); adults (n = 10), ID/LC-MS-MS 2.66 (1.39–6.15), ID/GC-MS 2.54 (0.51–5.12). The technique permitted reliable detection of classical and nonclassical forms of 21- hydroxylase deficiency. The much simpler sample preparation, the faster analytical run time and the operational ease possible with ID/LC-MS-MS permit a considerable increase of sample testing per day without compromising on analytical sensitivity and specificity. We expect that benchtop tandem mass spectrometry will open new avenues in clinical steroid analysis.
Response to Treatment in Patients with Partial Androgen Insensitivity due to Mutations in the DNA-Binding Domain of the Androgen Receptor
Authors: Lundberg Giwercman Yvonne , Nikoshkov Andrej , Lindsten Kristina , Byström Birgitta , Pousette Åke , Knudtzon Jørgen , Alm Jan , Wedell Anna
Published: April 2003

The androgen insensitivity syndrome is a disorder caused by deficient function of the androgen receptor, characterized by varying degrees of undermasculinization in karyotypic males. We have identified four mutations in the androgen receptor gene, in the region encoding the DNA-binding domain of the protein. Two mutations, R607X and R615G, were found in patients with complete insensitivity to androgens, whereas the other two, S578T and A596T, were found in patients with partial insensitivity. The functional consequences of the three missense mutations were assayed in vitro after transient expression of the receptors in COS cells. All mutants showed normal androgen binding but abnormal abilities to stimulate transcription of an androgen-responsive reporter gene. R615G abolished transactivation whereas S578T and A596T were partially malfunctional. The function of A596T, but not of S578T, was normalized at high androgen concentrations in vitro, reflecting the in vivo situation. Thus, patients with specific mutations in the DNA-binding domain of the androgen receptor may benefit from androgen treatment.
New Paradigms for Growth Hormone Therapy in Children
Authors: Wetterau Lawrence , Cohen Pinchas
Published: April 2003

Much has been learned over the last two decades regarding the management of growth hormone (GH) deficiency (GHD) in children and adolescents. However, significant divergence and debate continue to exist on the ideal approach to the management of GHD. Despite active controversy, several paradigms have recently emerged which should guide the treatment of GHD patients as we head into the new millennium. The primary objectives of GH therapy remain the normalization of height in childhood and the attainment of normal adult height, but the recognition of the metabolic roles of GH define additional therapeutic benefits. A daily subcutaneous injection of recombinant human GH in a dose range of 25–50 μg/kg/day has been established as the mainstay of therapy. Alternative modes of treatment including GH-releasing hormone (GHRH), GH secretagogues and depot GH have been developed, but evaluation of their clinical utility remains incomplete. Careful monitoring and follow-up of pediatric GHD patients by a pediatric endocrinologist are essential. Accurate determination of height velocity and interval height increases (expressed as the change in height z score) continue to be the most important parameters in monitoring the response to treatment. Monitoring serum insulin-like growth factor (IGF)-I and IGF-binding protein-3 has gained utility in the assurance of compliance and safety, but does not always correlate well with the growth response. A clear role for a biochemical as well as an auxological monitoring approach has nonetheless been established. The comparison of attained growth response to that which has been calculated by various modeling approaches is also becoming a valuable monitoring tool. Significant side effects of GH therapy are quite rare and are easily identified and addressed during close follow-up. Despite previous concerns, it now appears that in the absence of additional risk factors there is no evidence that long-term recipients of GH are at any increased risk of developing diabetes, slipped capital femoral epiphysis, brain tumor recurrence or leukemia. Although GHD may or may not persist into adult life, adult GHD diagnostic criteria and the importance of GH therapy in adult GHD patients have recently been established. Therefore, the pediatric endocrinologist now has a crucial role in guiding the transition to adult GHD management in collaboration with the adult endocrinologist. In the years to come, with the continued investigation and collaborationof experts from around the world, the approach to GH treatment will undoubtedly continue to evolve and improve.
Management of Pituitary Tumours: Strategy for Investigation and Follow-Up
Authors: Lissett C.A. , Shalet S.M.
Published: April 2003

Investigation of a patient presenting with evidence of a pituitary tumour has three main objectives: investigation of any hormonal hypersecretion; assessment of residual pituitary function, and examination of any mass effect of the tumour. A prolactin-secreting adenoma is often easily diagnosed by performance of a basal prolactin level. Biochemical assessment to exclude acromegaly or Cushing’s disease should only be performed if clinically indicated. The standard investigations for acromegaly consist of establishing the degree of growth hormone (GH) suppression following a glucose load and estimating the basal insulin-like growth factor-I level. Before detailed investigation for Cushing’s disease is initiated, the presence of Cushing’s syndrome must be established. The second requirement is to determine the presence of any pituitary hyposecretion. Whilst the remainder of pituitary function can be assessed by baseline hormonal estimations, the evaluation of ACTH and GH secretion necessitates dynamic function testing. Lastly, the impact of the mass itself requires careful examination. Both neuroradiology, preferably magnetic resonance imaging at a centre specialized in examination of the pituitary fossa, and careful detailed clinical examination of the visual fields should be performed. The follow-up requirements in an individual patient are affected by a number of factors including the size and nature of the underlying tumour and any treatment administered. In patients with a hormone-secreting tumour, the hormone levels themselves provide a ‘tumour marker’ to aid follow-up. An important caveat, however, is that on some occasions tumour size and hormone levels do not change in parallel. Patients who have undergone pituitary surgery should have dynamic assessment of pituitary function performed approximately 6 weeks after surgery. There is no reason to suspect any further impairment of pituitary function after this date. In direct contrast, pituitary hormone deficiencies after radiotherapy are unlikely less than 6 months after treatment. Patients should undergo testing of pituitary reserve at 6 months, and then at yearly intervals for at least 10 years after radiotherapy, if they have not already developed panhypopituitarism. Even after this period, if patients develop new symptoms the possibility of further pituitary hormone deficits should be considered. Neuroradiology should be performed approximately 6 weeks to 3 months after surgery. If radiotherapy is not administered, neuroradiology should be performed yearly for at least 10 years. If the patient has received radiotherapy, tumour recurrence is much less likely and therefore in these individuals neuroradiology does not need to be performed with such regularity. In conclusion, when planning the investigation and follow-up of an individual patient, one should take into account the size and characteristics of the tumour, as well as the treatment modalities.
New Medical Approaches in Pituitary Adenomas
Authors: Colao Annamaria , Di Sarno Antonella , Marzullo Paolo , Di Somma Carolina , Cerbone Gaetana , Landi Maria Luisa , Faggiano Antongiulio , Merola Bartolomeo , Lombardi Gaetano
Published: April 2003

Recently, the medical approach to patients with secreting and clinically non-functioning pituitary adenomas has received great impulse thanks to the availability of new, selective and long-lasting compounds with dopaminergic activity, such as cabergoline, and of somatostatin analogues provided in slow-release formulations, such as lanreotide and octreotide long acting release (LAR). In particular, the use of cabergoline has induced control of hyperprolactinaemia and tumour shrinkage in the great majority of patients with micro- and macroprolactinomas. Cabergoline treatment restores fertility both in women and men, and partially improves osteoporosis, one of the major complications of hyperprolactinaemia. In acromegaly, disease control (growth hormone [GH] <2.5–1.0 μg/l as a fasting or glucose-suppressed value, respectively, together with age-normalised insulin-like growth factor [IGF]-I) is achievable in more than half of patients receiving treatment with lanreotide or octreotide-LAR. Improvement in cardiomyopathy, sleep apnoea and arthropathy has been reported during GH/IGF-I suppression after pharmacotherapy. A synthetic GH analogue, B2036-PEG, that antagonises endogenous GH binding to its receptor-binding sites and a GH-releasing hormone antagonist that blocks the effect of this releasing factor on the hypothalamus and pituitary are presently under investigation in acromegaly. Preliminary studies have clearly demonstrated the effectiveness of the GH receptor antagonist in suppressing IGF-I levels in acromegalic patients previously unresponsive to somatostatin analogues. Beneficial effects of subcutaneous octreotide and lanreotide have also been reported in adenomas secreting thyroid-stimulating hormone, while the results of treatment with dopamine agonists or somatostatin analogues remain disappointing in patients with clinically non-functioning adenomas. In these patients the possibility of visualising in vivo the expression of D2 receptors using specific radiotracers such as 123I-methoxybenzamide has allowed selection of patients likely to respond to cabergoline. Scant effects of pharmacotherapy have also been reported in patients with adenomas secreting adrenocorticotropic hormone. However, some preliminary data suggest a potential use of cabergoline in combination with ketoconazole, or alone, in selected cases of Cushing’s disease or Nelson’s syndrome.
Normative Data for Total and Free Acid-LabileSubunit of the Human Insulin-Like Growth Factor-Binding Protein Complex in Pre- and Full-Term Newborns and Healthy Boys and Girls throughout Postnatal Development
Authors: Barrios V. , Pozo J. , Muñoz M.T. , Buño M. , Argente J.
Published: April 2003

Insulin-like growth factors (IGFs) circulate in plasma as part of a 150-kD complex that also contains IGF-binding protein-3 (IGFBP-3), a protein that binds IGF-I and IGF-II with high affinity, and an acid-labile subunit (ALS) that does not directly bind IGFs. Because the ALS assay methods currently being used are relatively new, there is a need for updated normative reference data. We report the normative data in 17 preterm infants (10 males and 7 females), 30 normal full-term newborns (15 males and 15 females) and 150 normal children who where divided into 5 groups according to their Tanner stage (15 males and 15 females per group). Serum levels of total and free ALS were significantly lower in premature infants than in full-term newborns, but all newborns had significantly lower levels than Tanner stage-I children (p < 0.001, ANOVA). A significant increase was seen between Tanner stages I–III in both sexes (p < 0.001, ANOVA). No differences were found between sexes at any developmental age studied. Significant correlations (p < 0.001) were seen between total and free ALS concentrations and IGF-I (r = 0.50 and 0.60, respectively), free IGF-I (r = 0.37 and 0.36), IGF-II (r = 0.37 and 0.27), IGFBP-1 (r = –0.48 and –0.49), IGFBP-2 (r = –0.44 and –0.51) and IGFBP-3 (r = 0.67 and 0.59) at all Tanner stages. However, no correlation was found with IGFBP-1, -2 or -3 levels at birth. This study shows normal values in a population of preterm infants and healthy Spanish newborns and subjects of both sexes at all stages of pubertal development and indicate the different relationships between the components of the IGF system during intra- and extrauterine life.
Case of XXXXY Syndrome
Authors: Dötsch Jörg , Foerster Wolfgang , Holl Reinhard , Rascher Wolfgang , Kiess Wieland
Published: April 2003

49,XXXXY syndrome is a very rare condition that is associated with a considerable more severe phenotype than classic 47,XXY Klinefelter syndrome. We present a patient with 49,XXXXY syndrome, who was first presented to an endocrinological unit at the age of 12.5 years with prepubertal genitalia. He was then lost from follow-up and showed clear clinical and biochemical signs of hypergonadotropic hypogonadism when presenting again at the age of 16 years. The patient was started on testosterone replacement therapy. This case is reported to underline the need for thorough endocrinological follow-up examinations in males with X polysomies.
Hormonal Factors Influencing Weight and Growth Pattern in Craniopharyngioma
Authors: Pinto G. , Bussières L. , Recasens C. , Souberbielle J.C. , Zerah M. , Brauner R.
Published: April 2003

Patients operated on for craniopharyngioma frequently suffer from hyperphagia and are obese, but their statural growth is normal despite growth hormone (GH) deficiency. We have evaluated the hormonal factors influencing changes in weight and growth in 17 children before and 1, 3–6, 12, and/or 24 months after surgical resection of a craniopharyngioma performed at 7.7 ± (SE) 1 years of age. Of these, 15 patients had a GH deficiency before surgery, and all had complete pituitary deficiency after it. The plasma fasting insulin concentrations before surgery were positively correlated with body mass index (BMI, kg/m2; p < 0.05), plasma insulin-like growth factors (IGFI, p = 0.03, and IGFII, p = 0.04), and leptin (p = 0.03). They increased significantly 1 month after surgery and continued to increase thereafter, whereas leptin increased significantly only 3–6 months after surgery, paralleling changes in BMI. The plasma fasting insulin concentrations before surgery were also positively correlated with the weight changes (12.3 ± 2.3 kg, p < 0.01) during the 12 months after surgery, but not with changes in BMI SDS (3.1 ± 0.5, p = 0.07). Both expressions of weight change were correlated with the concomitant growth rates (4.8 ± 0.7 cm, p < 0.01). IGFI was above the 10th percentile for children with idiopathic short stature in 10 of 15 patients with craniopharyngioma-induced GH deficiency and IGF-binding protein 3 in 14 of 15 patients. Craniopharyngioma itself modified the control of insulin secretion, and surgery increased the insulin secretion which continued in the same way in a given patient after surgery. The increased insulin secretion in turn increases weight and keeps IGFI nearly normal. This may explain the normal growth rate despite the complete lack of GH.