Search

Introduction: Array comparative genomic hybridisation (array CGH) is a powerful method that detects alteration of gene copy number with greater resolution and efficiency than traditional methods. However, its ability to detect disease causing duplications in constitutional genomic DNA has not been shown. We developed an array CGH assay for X linked hypopituitarism, which is associated with duplication of Xq26-q27., Methods: We generated custom BAC/PAC arrays that spanned the 7.3 Mb critical region at Xq26.1-q27.3, and used them to search for duplications in three previously uncharacterised families with X linked hypopituitarism., Results: Validation experiments clearly identified Xq26-q27 duplications that we had previously mapped by fluorescence in situ hybridisation. Array CGH analysis of novel XH families identified three different Xq26-q27 duplications, which together refine the critical region to a 3.9 Mb interval at Xq27.2-q27.3. Expression analysis of six orthologous mouse genes from this region revealed that the transcription factor Sox3 is expressed at 11.5 and 12.5 days after conception in the infundibulum of the developing pituitary and the presumptive hypothalamus., Discussion: Array CGH is a robust and sensitive method for identifying X chromosome duplications. The existence of different, overlapping Xq duplications in five kindreds indicates that X linked hypopituitarism is caused by increased gene dosage. Interestingly, all X linked hypopituitarism duplications contain SOX3. As mutation of this gene in human beings and mice results in hypopituitarism, we hypothesise that increased dosage of Sox3 causes perturbation of pituitary and hypothalamic development and may be the causative mechanism for X linked hypopituitarism.

Background: A new form of congenital hyperinsulinism characterized by hypoglycemia and hyperammonemia was described recently. We hypothesized that this syndrome of hyperinsulinism and hyperammonemia was caused by excessive activity of glutamate dehydrogenase, which oxidizes glutamate to alpha-ketoglutarate and which is a potential regulator of insulin secretion in pancreatic beta cells and of ureagenesis in the liver., Methods: We measured glutamate dehydrogenase activity in lymphoblasts from eight unrelated children with the hyperinsulinism-hyperammonemia syndrome: six with sporadic cases and two with familial cases. We identified mutations in the glutamate dehydrogenase gene by sequencing glutamate dehydrogenase complementary DNA prepared from lymphoblast messenger RNA. Site-directed mutagenesis was used to express the mutations in COS-7 cells., Results: The sensitivity of glutamate dehydrogenase to inhibition by guanosine 5'-triphosphate was a quarter of the normal level in the patients with sporadic hyperinsulinism-hyperammonemia syndrome and half the normal level in patients with familial cases and their affected relatives, findings consistent with overactivity of the enzyme. These differences in enzyme insensitivity correlated with differences in the severity of hypoglycemia in the two groups. All eight children were heterozygous for the wild-type allele and had a mutation in the proposed allosteric domain of the enzyme. Four different mutations were identified in the six patients with sporadic cases; the two patients with familial cases shared a fifth mutation. In two clones of COS-7 cells transfected with the mutant sequence from one patient, the sensitivity of the enzyme to guanosine 5'-triphosphate was reduced, findings similar to those in the child's lymphoblasts., Conclusions: The hyperinsulinism-hyperammonemia syndrome is caused by mutations in the glutamate dehydrogenase gene that impair the control of enzyme activity.

We have recently developed a new bioassay for growth hormone (GH) in serum, which is based on the ability of GH to suppress glucose use in cultured murine adipocytes. We tested the hypothesis that bioactive GH (B-GH) concentrations would correlate better with the GH-dependent peptides, IGF-I, and IGF-binding protein-3 (IGFBP-3) than would GH determined by conventional RIA (RIA-GH). Twenty-five girls with Turner's syndrome were studied. The subjects had ages ranging from 4.8 to 15.9 y and height SD from the mean (SD score) ranging from -0.77 to -5.67. Blood samples were obtained every 15 or 20 min for 12 h overnight. For each girl, an equal aliquot of each overnight sample was pooled for determination of B-GH, RIA-GH, IGF-I, IGFBP-3, LH, FSH, and estradiol. Measurable estradiol concentrations were present in six girls and were sufficient to suppress gonadotropin concentrations in two girls, but they did not alter B-GH, RIA-GH, IGF-I, and IGFBP-3 concentrations compared with the age-matched girls without measurable estradiol concentrations. Hence, data for all girls were combined for subsequent regression analyses. RIA-GH did not correlate significantly with B-GH, IGF-I, or IGFBP-3. B-GH exhibited a significant correlation with IGF-I (r = 0.407, p < 0.05), and the correlation with IGFBP-3 was better than that for RIA-GH (r = 0.355 versus 0.064, B-GH and RIA-GH, respectively). None of the B-GH, RIA-GH, IGF-I, or IGFBP-3 concentrations had a significant correlation with height SD score or height velocity SD score.(ABSTRACT TRUNCATED AT 250 WORDS)

The approach to the evaluation of a neck mass requires careful history and physical examination to determine if the mass is thyroidal or non-thyroidal. Thyromegaly can be classified as diffuse or nodular, painless or painful, or associated with a solitary or multiple nodules. While the most common cause of diffuse enlargement is chronic lymphocytic thyroiditis, the presence of nodularity should prompt consideration of cancer. Results of a radionuclide scan, ultrasonogram, and/or a fine-needle aspiration of a cystic nodule should help guide the physician to those patients in need of an open thyroid biopsy.

To assess the relative roles of growth hormone-releasing hormone (GHRH) pulse and somatostatin withdrawal as potential generators of pulsatile growth hormone (GH) release in humans, we studied GH responses to iv bolus GHRH (1 microgram/kg) and to termination of a 4 h iv somatostatin infusion (7.2 micrograms.kg-1.h-1) in five normal young men, and in five men with previously diagnosed isolated GH deficiency. The patients were diagnosed 8-15 years previously on the basis of typical auxological and hormonal criteria, were treated with exogenous GH and were off GH therapy for 1.5-8.9 years prior to this study. Growth hormone rises to a bolus GHRH were similar between the controls and the patients (maximum GH 27.3 +/- 15.3 vs 8.0 +/- 4.0 micrograms/l). The controls exhibited only a small GH rise to somatostatin withdrawal (maximum GH 2.9 +/- 1.2 micrograms/l), while the patients did not (maximum GH 0.7 +/- 0.1 micrograms/l; p < 0.05). We conclude that somatostatin withdrawal by itself is an ineffective promoter of GH pulsatility. Periodic quiescence of somatostatinergic neurons must be associated with a concomitant GHRH pulse in order to result in a robust GH pulse.

Short-term administration of human growth hormone to children with idiopathic short stature can improve mean growth rate and predicted adult height. It is yet unknown whether therapy would alter pubertal development or affect final height. Three-year treatment results in a group of children with idiopathic short stature are reported. For year 1 of the study, 121 prepubertal children were randomly selected to receive somatotropin, 0.3 mg/kg per week, administered subcutaneously three times weekly (n = 63), or to be nontreatment control subjects (n = 58). After 1 year, all subjects were again randomly selected to receive either three-times-weekly or daily dosing at the same total dose. For the 92 subjects who completed 36 months of treatment, mean growth rate increased from a mean of 4.6 cm/yr before treatment to a mean of 8.0 cm/yr in the first year of treatment. Daily dosing resulted in a significantly faster mean growth rate (9.0 cm/yr) than three-times-weekly dosing (7.8 cm/yr) (p = 0.0005). Mean growth rates were 7.6 and 7.2 cm/yr during years 2 and 3, respectively, and did not differ by dosing group. Mean standardized height for all subjects improved from -2.7 to -1.6 after 3 years. When the growth rate was standardized for bone age, however, subjects who remained prepubertal had a significantly greater gain in mean height SD score than subjects who became pubertal during that 3-year period (p < 0.02). Mean standardized Bayley-Pinneau predicted adult height SD score increased from -2.7 to -1.6 and was independent of the timing of pubertal onset, but for individuals this score was more variable. Year-1 growth response, expressed as growth rate or change in height SD score, was the best predictor of growth in subsequent years. Responses to therapy could not be reliably predicted from baseline anthropometric variables, plasma insulin-like growth factor I SD score, growth hormone levels. Final height assessment will be needed to determine the ultimate benefit of therapy.

GH, in clinical practice, is determined by RIA, but RIA estimates may not accurately reflect serum GH bioactivity. The available measures of GH bioactivity lack either sensitivity, specificity, or a physiologically relevant end point. The objective of this research was to develop a physiologically relevant GH bioassay which would not only measure the bioactivity of purified GH preparations, but would also have sufficient sensitivity to measure GH bioactivity in human serum. The method consisted of incubating murine 3T3-F442A adipocytes in serum-free medium containing BSA, 14C-glucose, and increasing concentrations of GH or test materials for 24 h, followed by measurement of conversion of glucose to lipid. Interference by nonspecific serum factors was reduced by the addition of 10 micrograms/liter insulin, 25 nM dexamethasone, and 37 nM estradiol to the medium. In the presence of 10 micrograms/liter insulin, 50 micrograms/liter insulin-like growth factor-1 did not alter the ability of GH to suppress lipid accumulation. Epinephrine and glucagon could suppress lipid accumulation but only at concentrations greatly in excess of the physiological range in serum. Twenty two thousand dalton hGH produced dose-dependent suppression of lipid accumulation which was linear between 0.625 and 10 micrograms/liter (r = 0.926; P = 0.0001) with a half-maximal response of 3.0 +/- 0.2 micrograms/liter (n = six experiments). The intra- and interassay coefficients of variation were 7% and 19%, respectively. The assay was specific for GH since addition of human PRL produced suppression of lipid accumulation only at concentrations where contamination of the preparation by GH became a significant factor. ACTH also suppressed lipid accumulation but only at doses of 1000 micrograms/liter or greater. Human placental lactogen and hLH, hFSH, and hTSH did not cross-react with GH in this assay. Addition of human serum did not alter the slope of ED50 of the GH dose-response curve. Pools of serum from prepubertal and pubertal boys and girls, subjects treated with arginine or insulin, a diabetic girl, and a boy with gigantism who had a serum GH content of 80 micrograms/liter by RIA and 40 micrograms/liter by bioassay, produced dose response curves parallel to that of the GH standard curve. Serum from patients with hypopituitarism did not produce significant suppression of lipid accumulation in any assay. Recovery of 5 micrograms/liter GH added to human serum was 94%. Twenty thousand dalton GH also suppressed lipid accumulation in this assay, but was 2-fold less potent than 22,000 dalton GH.(ABSTRACT TRUNCATED AT 400 WORDS)

The purpose of this preliminary study was to evaluate tooth formation in children with idiopathic short stature, before and during treatment with recombinant growth hormone (rhGH). Twenty-nine short-statured children ages 6 to 13 years were assigned into two treatment groups, an "experimental" group (n = 18), which received rhGH, and a "control" group (n = 11), which was observed for 1 year before commencing rhGH treatment. Clinical and radiographic records were obtained at the initial, year 1, and year 2 visits. Tooth formation and stature were assessed by calculating Z-scores, appropriate for the age and gender of each child. Delta-Z scores, which measure the change in Z-score over time, were also calculated between annual visits. Height was measured and recorded every 3 months, and Z-score statural norms for age and gender were derived from the 1977 National Center for Health Services national probability sampling. Tooth formation standards were derived from Moorrees et al. A matched control sample for tooth development was derived from untreated children. Tooth formation was initially delayed although the degree of reduction in stature exceeded the initial degree of delay in tooth formation. During this 2-year study, rhGH therapy had a significant influence on acceleration or gain in stature, but did not have a significant influence on tooth formation.

We hypothesized that prepubertal girls with gonadotropin deficiency would produce less follicle-stimulating hormone (FSH) in response to synthetic gonadotropin-releasing hormone (GnRH) than would gonadotropin-sufficient children. To test this hypothesis, we performed 103 GnRH tests serially in 21 children who had idiopathic hypopituitarism with growth hormone deficiency. We tried to predict whether puberty would occur in the 17 girls with bone ages of 8 years or less. Of these 17 girls, 4 failed to have spontaneous secondary sexual characteristics by age 16 1/2 years, and 12 had spontaneous complete pubertal development. One girl had incomplete pubertal maturation with partial gonadotropin deficiency; her results were combined with those of the girls who had no spontaneous pubertal development. With increasing bone age, the girls with complete pubertal development had a decrease in the increment of FSH released in response to GnRH, although basal gonadotropin concentrations did not change. For GnRH tests performed at bone ages of 8 years or less, basal luteinizing hormone (LH) values did not differ between girls with complete puberty and those with absent or incomplete puberty. However, basal FSH and the incremental response of LH and FSH to GnRH were greater in those with complete puberty. Only two girls with prepubertal bone ages at the time of testing, who subsequently had complete puberty, had incremental FSH responses to GnRH that were less than 5 IU/L. Individual incremental LH responses to GnRH did not discriminate well between groups. None of the girls with adrenocorticotropic hormone deficiency, either originally or subsequently, had spontaneous puberty, but 4 of 12 girls with thyrotropin deficiency, either originally or subsequently, had complete puberty. We conclude that a significant increase in GnRH-stimulated FSH suggests that spontaneous pubertal development will occur in girls with idiopathic hypopituitarism. However, a low FSH response to GnRH may not be diagnostic of gonadotropin deficiency.

Fifty-two children with growth hormone (GH) deficiency were examined for factors that might influence development of hypoglycemia. Symptomatic and asymptomatic hypoglycemia occurred with equal frequency in children with isolated GH and multiple anterior pituitary deficiencies. Of 52 children, nine (17%) had symptomatic hypoglycemia and 14 (27%) had asymptomatic hypoglycemia. Symptomatic hypoglycemia was more frequent in children who were both young (less than 4 years of age) and lean (elevated height age/weight age [HA/WA] ratio). With HGH therapy, these children had decreases in HA/WA ratios and improvement in carbohydrate homeostasis. Insulin responses to oral glucose and intravenous arginine administration were substantially lowered in children with symptomatic hypoglycemia, A deficiency of gluconeogenic substrate or impairment of amino acid mobilization may be a factor in the development of hypoglycemia in hypopituitarism similar to that postulated for ketotic hypoglycemia.

The effect of hGH therapy on testicular response to hCG was studied in 7 pre-pubertal boys with known growth hormone deficiency. Each boy received 2000 IU hCG intramuscularly for 3 consecutive days either before starting hGH therapy or 4 months after temporarily discontinuing hGH therapy. A second 3 day series of hCG injections was administered after each boy had received 4 months of hGH treatment. Before each hCG challenge, serum concentrations of testosterone, LH and FSH were obtained and an iv GnRH test was performed. Growth hormone treatment either maintained or established linear growth velocities equal to or greater than expected for the patient's skeletal age. Testicular response off hGH therapy, either maximum serum concentration of testosterone or maximum rise above baseline, was not significantly different than testicular response while on hGH therapy. Testicular responses did not correlate significantly with either basal concentration of gonadotrophins or gonadotrophin responses to GnRH. Despite its effectiveness in stimulating growth, hGH did not effect testicular responsiveness to hCG in pre-pubertal boys with hGH deficiency.

The pubertal maturation of five boys (Group A) who were initially thought to be gonadotropin deficient was studied over 10 to 58 months (mean 36 months) by serial physical examinatons and standard GnRH tests. Four were seen because of obesity, delayed sexual maturation, depression, and poor school performance. The other boy had acquired hypothalamic hypopituitarism at 13 years of age. Gonadotropin responses during the initial GnRH test were either absent or abnormally low as related to the degree of skeletal maturation. Subsequent responses showed progressive maturation into the normal range for adult males. These boys had normal olfaction and moderate-to-marked obesity, but initial assessment of testicular size, basal gonadotropins, and testosterone or gonadotropin responses to GnRH did not distinguish these boys from seven patients with isolated gonadotropin deficiency (Group B). Contrary to previous reports and expectations, these studies indicate that an absent or markedly blunted response to synthetic GnRH is not diagnostic of gonadotropin deficiency, even when skeletal age is 12 years or greater. Furthermore, unless a patient is hyposomic or anosmic, or has an associated anomaly such as cleft palate, isolated gonadotropin deficiency cannot be diagnosed reliably until late adolescence or early adulthood.

Hypothyroidism affects linear growth less than it affects skeletal maturation, while hypopituitarism linear growth is more severely affected. By determining the mean age for the length of the second metacarpal and dividing by the skeletal age, a ratio R was obtained in 15 hypothyroid children and in 33 with hypopituitarism. R was more than 1 in most hypothyroids and less than 1 in most children with hypopituitarism. Thus, a distinction between these two entities can be made simply from a hand radiograph and appropriate reference sources for determining second metacarpal length age and skeletal age.

The dynamics of TSH and PRL secretion were studied in three patients with incomplete generalized resistance to thyroid hormones. Results in the first patient differed from those in the other two. The first patient had been treated previously with radioiodine but was clinically euthyroid when subsequently treated with supraphysiological quantities of T3 and T4. Increasing doses of T4 from 0.2-0.3 mg/day caused a decline in serum TSH levels and lesser increments in TSH to injected TRH in this patient. The other two patients had not been treated, but had basal TSH levels and TSH responses to TRH similar to those in the first patient. However, the TSH response to injected metoclopramide in the first patient was substantially higher than the responses in the other two patients. The basal levels of PRL in the first patient were elevated at both T4 doses; also, her PRL responses to TRH and metoclopramide were exaggerated and, compared to normal values, disproportionate to her TSH responses to these provocative agents. In contrast, the other two patients had normal basal PRL concentrations and normal or near-normal PRL responses to TRH and metoclopramide. We conclude that within the syndrome of resistance to thyroid hormones, there are heterogeneous patterns of PRL secretion. Dopaminergic tone on thyrotrophs and lactotrophs also differs among patients with the syndrome.

Thirty-six children with growth hormone deficiency were treated for up to 48 months with methionyl human growth hormone (hGH) synthesised by DNA recombinant methods. The growth rate for these children increased from 3.2 +/- 1.1 cm/yr to 10.5 +/- 2.2 cm/yr (mean +/- SD). This was similar to the effect of pituitary hGH in ten GH deficient children, 3.8 +/- 1.0 to 10.1 +/- 1.1 cm/yr. Serum somatomedin C rose from 0.26 +/- 0.23 U/ml to 0.79 +/- 0.53 U/ml after 6 months of methionyl-hGH therapy, similar to the effect of pituitary hGH. The incidence of antibody formation to methionyl-hGH was higher than that observed with pituitary hGH (Kabi) but poor growth was observed only in the one patient on methionyl-hGH who acquired high-titre high-binding-capacity antibodies to hGH. No consistent changes in levels of antibodies to Escherichia coli proteins were detected. No other allergic manifestations or systemic side-effects were demonstrable.

The effects of intravenous administration of potassium phosphate in the treatment of diabetic ketoacidosis were studied in nine children, ages 9 9/12 to 17 10/12 yr. During phosphate infusion (20--40 meq/L of fluid), all children maintained normal serum concentrations of phosphorus. Transient hypocalcemia occurred in six and transient hypomagnesemia in five patients. One child developed carpopedal spasms refractory to intravenous infusion of calcium gluconate but responsive to intramuscular injection of magnesium sulfate. In three patients, serum levels of intact parathyroid hormone were low at the time of hypocalcemia, an observation that suggests transient hypoparathyroidism. This study indicates that the use of potassium phosphate as the sole source of potassium replacement might potentiate ketoacidosis-induced hypocalcemia through multiple mechanisms.

Psychosocial Dwarfism, a syndrome caused by deprivation, emotional stress and/or neglect, occurs in both infants and children. The identification of children who are delayed because of such stress can be difficult. This article reviews historical and observational diagnostic clues including typical family interactional patterns and attitudes. Diagnosis of PSD is made by a demonstration of change, generally one that occurs upon removal of the child from the family environment. This removal is frequently the beginning of the intervention process, the goal of which is the reversal of physical and psychological delays, the elimination of bizarre behaviors, and the completion of catch-up growth and stabilization of normal growth. Too little is known about successful treatment methods in cases of PSD. The success of interventions is validated by change and can only be determined over long-term follow-up. There is a great need for research and it is important that all health care workers become aware of this challenging disorder.

Eleven girls, ages 10/12 to 76/12 years, were evaluated because of early and rapid breast development. Initial clinical presentations and serum gonadotropin or estradiol determinations did not differentiate patient types. However, patients could be divided into two groups based on their responses to synthetic gonadotropin-releasing hormone: Group A consisted of seven girls with suppressed or prepubertail-type responses, and Group B consisted of four girls with pubertal or adult-type responses. Subsequent evaluation revealed that Group A patients had intermittent or unsustained isosexual precocity, whereas Group B patients had isiopathic prococious puberty. During initial evaluation, increased serum or urinary estrogen values were noted in ten of ten patients who were studied. The greatest serum E2 values (162 and 117 pg/ml) were noted in two Group A patients; three months and two years later, those patients had normal prepubertal responses to GnRH and serum E2 values of less than 4 and 14 pg/ml, respectively. Unsustained sexual precocoity in girls may be secondary to autonomous ovarian production of estrogens, and the GnRH test may be useful in evaluation of girls with isosexual precocity.

Gonadotropin secretion is pulsatile in prepubertal and early pubertal boys, and the onset of puberty is characterized by a sleep-associated rise in LH pulse amplitude. To determine whether an augmentation in LH pulse frequency as well as amplitude occurs at the onset of puberty, we studied gonadotropin secretion in 21 early to midpubertal boys. Blood samples were taken every 20 min (every 15 min in 4 boys) for LH determinations. A 2-fold increase in LH pulse frequency occurred during the nighttime sampling period (2200-0400 h) compared to that in the hours when the boys were awake (1000-2200 h). The maximum frequency (0.7 pulses/h) occurred between 2400 and 0200 h. The mean plasma LH concentration increased during the night from 2.3 +/- 0.2 (+/- SE) mIU/mL (2.3 +/- 0.2 IU/L) between 2000-2200 h to a maximum of 6.2 +/- 0.4 (6.2 +/- 0.4 IU/L) between 0200-0400 h. The mean plasma LH decreased to 5.5 +/- 0.4 mIU/mL (5.5 +/- 0.4 IU/L) between 0400-0600 h and to 4.2 +/- 0.5 (4.2 +/- 0.5 IU/L) between 0600-0800 h. Plasma testosterone rose during the night to a mean maximum value of 2.4 +/- 0.5 (+/- SE) ng/mL (8.3 +/- 1.7 nmol/L). This finding suggested that the rise in testosterone might play a role in decreasing LH secretion during the later hours of sleep (after 0400 h). To address this question and to study further the effects of testosterone in early puberty, we measured plasma LH concentrations every 10 min from 2000-0800 h in 8 early to mid-pubertal boys before and during short term testosterone administration. Saline or testosterone at a concentration of 9.33 micrograms/mL (32 mumol/L) was infused at a rate of 10 mL/h from 2100-1200 h to shift the nighttime testosterone rise 3 h earlier than would occur spontaneously. Blood samples were obtained every 10 min for LH and every 30 min for testosterone determinations from 2000-0800 h. Pituitary responsiveness was assessed by administering sequential doses of synthetic GnRH (25 and 250 ng/kg) at 1000 and 1200 h, respectively. The nighttime increase in LH pulse frequency and mean plasma LH concentration occurred between 2300 and 0200 h despite testosterone infusion. However, testosterone infusion was associated with significantly lower mean plasma LH concentrations from 0200-0800 h compared to those on the night of the saline infusion. Pituitary responsiveness to synthetic GnRH was unaltered by testosterone administration.(ABSTRACT TRUNCATED AT 400 WORDS)

In the cord blood of seven infants with congenital hypothyroidism detected in our newborn screening programs, thyroxine values ranged from 2.5 to 6.7 mug/dl and thyrotropin, from 105 to 975 muU/ml; triiodothyronine values were normal. On follow-up, T3 levels increased to normal in five infants, there was a significant negative correlation between the T3 value and the severity of thyroprevia as reflected in the TSH levels and the number of clinical features present. This increase in T3 may explain in part why the diagnosis of this disease is difficult during the first few months of life and why early treatment is effective. This observation provides further rationale for the widespread institution of newborn screening programs for congenital hypothyroidism.

Multiple endocrine neoplasia type 2b (MEN 2b) is a rare genetic disorder. Affected individuals have malignant thyroid tumors, pheochromocytoma, and ganglioneuromatosis. The musculoskeletal manifestations of MEN 2b include a Marfanoid habitus, pes cavus, scoliosis, slipped capital femoral epiphysis, joint laxity, poor muscle development, and delayed maturation. The initial clinical presentation of MEN 2b frequently involves the musculoskeletal system. The characteristics ganglioneuromatosis of the lips and tongue, however, should alert the orthopedic surgeon to the underlying disorder. Effective treatment of the malignant neoplasms hinges on early diagnosis. The risk of perioperative hypertensive crisis is significant; it may be prevented by appropriate treatment of the pheochromocytoma.

To establish the incidence of Nelson's syndrome in children treated with total bilateral adrenalectomy (TBA) for Cushing's disease, a survey was made of members of The Lawson Wilkins Pediatric Endocrine Society. Thirty-one patients aged 10 months to 16 years had been treated with TBA for Cushing's disease; one had been treated with ortho para prime isomer of dichlorodiphenyldichloroethane alone. Postadrenalectomy hyperpigmentation was reported in 18 patients. Sella enlargement was detected in eight patients (25%) after 1 to 5.5 years (mean, three years) post-TBA. Five of these patients have had documented pituitary adenomas to date. This incidence is higher than the adult figure of 10% to 16%.

Thyroid antibodies were determined by three different techniques in the sera of 125 children and adolescents with thyroid disorders and in the sera of 53 short, normal children without thyroid dysfunction. The incidence of antithyroglobulin antibodies in patients with thyroiditis was highest when measured by radioimmunoassay (85%), less than when measured by hemagglutination (24%), and least by antimicrosomal antibodies (7%). No patient who had initially negative serum for RATA subsequently had positive tests during follow-up of five to 24 months, whereas eight of 31 patients with initially negative serum for ATA later developed positive tests. Treatment appeared to have a suppressive effect on RATA, but not on ATA titers, in hypothroid patients with clinical thyroiditis. The incidence of hypothyroidism in the patients with clinical thyroiditis on initial presentation was significant (37%) and suggests that identification of children and adolescents with thyroiditis is important to ensure adequate medical follow-up.

Sexual precocity in association with abnormalities of the central nervous system is well known, but its occurrence with hypothalamic hypopituitarism is most unusual. We report five females with septo-optic dysplasia, blindness, and multiple pituitary tropic hormone deficiencies: all were growth hormone and adrenocorticotropic hormone deficient; two had diabetes insipidus; one had sexual precocity, and one had early pubertal maturation, whereas three were prepubertal and responded to administration of synthetic gonadotropin-releasing hormone. These children retained ability to secrete gonadotropins despite the presence of anterior hypothalamic disease. Experimental data from primates plus our observations on these patients raise questions about the role of the anterior hypothalamus in gonadotropin secretion in man.

Serial concentrations of basal serum LH, FSH, testosterone, and LH and FSH responses to intravenous gonadotropin-releasing hormone were measured before and during six months of administration of fluoxymesterone or oxandrolone in 14 boys with constitutionally delayed growth and adolescence, in order to assess the effects of these androgens on maturation of the hypothalamic-pituitary-gonadal axis. Before therapy all boys had normal hormonal responses based on bone age. At the end of six months therapy 10 of the 14 boys had lower LH responses (34 to 89% reduction) to GnRH without consistent changes in FSH responses. With both androgens, there there was significant suppression of both basal serum FSH and testosterone. Eleven boys were restudied six months after completion of therapy; basal serum LH, FSH, and testosterone and responses to GnRH were equal to or greater than pretreatment levels, indicating recovery or progressive maturation of the HPGA. All boys had increased growth velocity and imporved weight gain without excessive bone age advancement; all had improved psychosocial adjustment.

To investigate whether GH secretion in acromegaly is subject to regulatory control by the hypothalamic GH-releasing hormone (GHRH) we studied GH secretion in 22 patients with acromegaly. Parameters of pulsatile GH secretion were assessed using frequent blood sampling (every 20 or 10 min for 24 h). Acute GH responses to GHRH-44 (0.1, 0.33, and 1.0 micrograms/kg BW, iv) were measured, and GH secretion during therapy with the long-acting somatostatin analog SMS 201-995 (Sandoz) was assessed. The results were compared to those in normal volunteers. Spontaneous GH pulse frequency was greater in patients with acromegaly than in 6 control subjects (8.6 +/- 0.6 vs. 4.3 +/- 1.1 pulses/24 h), as estimated by the 20-min sampling frequency. The 10-min sampling frequency revealed 12.9 +/- 0.7 pulses/24 h in acromegalics. Spontaneous GH pulse amplitude and acute GH rises in response to GHRH did not differ between control and acromegalic subjects. A similar degree of nocturnal augmentation of GH secretion was observed in both groups, and it persisted during SMS 201-995 therapy in patients with acromegaly. These observations suggest that GH secretion in acromegaly remains under stimulatory control by GHRH, which may be released at an abnormally high rate.

In the prepubertal child, the hypothalamic-pituitary-gonadal (H-P-G) axis is functional and extremely sensitive to negative feedback inhibition by low circulating levels of sex steroids. This feedback system may be under the control of unknown CNS inhibitory mechanisms. Clinical signs of puberty are preceded by increased pulsatile secretion of hypothalamic gonadotropin-releasing hormone (GnRH) followed by increased pituitary responsiveness to GnRH. Gonadotropin secretion, particularly LH, increases in both sexes, especially during sleep, resulting in gonadal stimulation, secretion of sex steroids, and progressive physical maturation. When any phase of the H-P-G axis malfunctions, abnormal puberty can result. Abnormal puberty may be precocious or delayed. When puberty is precocious it may be isosexual or heterosexual, complete or partial, intermittent (unsustained), or progressive. True (central) precocious puberty is usually progressive, and hormonally reflective of normal puberty, although occurring at an earlier age, whereas intermittent or unsustained precocious puberty usually is associated with immature patterns of gonadotropin secretion, or with complete gonadotropin suppression as in precocious pseudopuberty (ovarian or adrenal tumors). Cranial axial tomography, gonadotropin response to GnRH, and pelvic ultrasound in girls are useful tools to aid in the differential diagnosis of these conditions. Intermittent, or unsustained, puberty in girls is usually self-limited, requiring no medical or surgical intervention. True progressive central precocity may now be managed with GnRH analogues, which effectively arrest pubertal changes as well as slow rapid linear growth and skeletal maturation. Although a maturation lag usually explains most patterns of delayed puberty, it is often challenging to exclude other conditions that may contribute to slow pubertal progression, such as chronic illness, excessive exercise, emotional stress, anorexia, or drug use. Elevated serum gonadotropin levels direct further evaluation toward etiologies of gonadal failure, including gonadal dysgenesis, Klinefelter syndrome, and chemotherapy/irradiation damage. Both low gonadotropins and absence of or immature gonadotropin response to GnRH administration after a bone age of 11 years in girls and 13 years in boys point toward hypopituitarism or isolated hypogonadotropic hypogonadism. Management with administration of gradually incremented amounts of sex steroids at an appropriate psychologic age usually leads to enhanced linear growth, physical maturation, and improved self-esteem.

Administration of testosterone (T) can inhibit LH secretion in early pubertal boys. However, the GnRH pulse generator is relatively resistant to the effects of T, since T infusion beginning at 2100 h, 3 h before the usual nighttime increase in T, does not suppress the characteristic increase in LH pulse frequency or amplitude associated with the onset of sleep in early pubertal boys. To test the hypothesis that the hypothalamic-pituitary axis must be exposed to T for a longer duration to suppress the nocturnal rise in LH pulse frequency and amplitude, we infused saline or T at one third the adult male production rate (320 nmol/h), beginning at 1200 h on two consecutive weekends in each of eight early to midpubertal boys. Blood was obtained from 2000-0800 h every 10 min for LH and every 30 min for T measurements. T infusion increased the mean plasma T concentration from 6.9 +/- 1.7 to 11.8 +/- 1.4 nmol/L (P less than 0.01) between 2000-0800 h. Despite the T infusion, the nocturnal rise in mean LH concentration and LH pulse frequency persisted, suggesting that the nocturnal amplification of LH, and by inference GnRH, secretion is resistant to the negative feedback effects of T. A higher dose of T, approximating the adult male production rate (960 nmol/h), was given to eight additional boys beginning at 1200 h. The mean T concentration increased from 4.2 +/- 1.7 to 20.8 +/- 3.1 (P less than 0.001) nmol/L between 2000-0800 h. The mean plasma LH concentration was suppressed by T infusion from 5.2 +/- 0.5 to 2.9 +/- 0.4 IU/L, and LH pulse frequency decreased from 0.50 +/- 0.04 to 0.27 +/- 0.11 pulses/boy/h (P less than 0.01). There was no nocturnal amplification of LH secretion, but high amplitude LH pulses did occur during the night in six of the eight boys. The low dose T infusion had no effect on pituitary LH release by exogenous GnRH. With the high dose T infusion, however, the ability of GnRH, at 25 ng/kg but not at 250 ng/kg, to release pituitary LH was amplified. Thus, T supplementation at one third the adult male production rate does not blunt the sleep-associated nighttime rise in LH pulse frequency or LH concentration. T infusion approximating the adult male production rate suppresses the nocturnal increase in LH pulse frequency and mean LH concentration, and high amplitude, slow frequency LH pulses similar to patterns seen in adult men persist.(ABSTRACT TRUNCATED AT 400 WORDS)

The effects of opiate antagonism [naloxone infusion, 1 mg/(m2 X h)] on gonadotropin secretion were examined in four children (one female and three males: two late prepubertal and two pubertal; chronologic age, range 11.8-15.9 yr; bone age, range 8.5-13.5 yr) and in four women with hypothalamic amenorrhea (two at normal body weight and two at low body weight). Naloxone had no effect on daytime gonadotropin secretion in three children who were biologically the youngest in the group, two late prepubertal and one early pubertal [plasma luteinizing hormone (LH) means +/- SE: control day, 1.2 +/- 0.1; control night, 4.5 +/- 0.4; and naloxone day, 1.3 +/- 0.1 mIU/ml]. In contrast, opiate blockade produced a slight but discernible increase in plasma LH in the child whose hypothalamic-pituitary-gonadal axis was the most mature, a boy at mid-puberty. Naloxone produced a striking increase in plasma LH in the amenorrheic women at normal body weight (LH, means +/- SE: control day, 3.4 +/- 0.3; control night, 7.0 +/- 1.0; and naloxone day, 7.4 +/- 0.7 mIU/ml) as well as in those at low body weight (LH, means +/- SE: control day, 3.5 +/- 0.3; control night, 2.8 +/- 0.2; naloxone day, 4.9 +/- 0.4; and naloxone night, 6.7 +/- 0.5 mIU/ml). Antagonism of endogenous opiate activity increased LH pulse frequency in all four women.(ABSTRACT TRUNCATED AT 250 WORDS)

The presence of growth lines in the distal radius was evaluated prior to treatment in 23 psychosocial dwarfs and 25 patients with idiopathic hypopituitarism. The lines were very common in the psychosocial dwarfs and rare in the pituitary dwarfs (P = .0005). This finding can be explained by the fluctuating adverse environment to which the psychosocial dwarf is exposed and the constant lack of growth in hypopituitary patients. Therefore, in the absence of systemic disease, when growth lines are present in a patient with short stature or failure to thrive, a thorough review of the patient's psychosocial environment should be made.

Information about the site(s) of action as well as the age-dependent effects of sex steroids on gonadotropin-releasing hormone and gonadotropin secretion during human puberty is limited. To begin to address these questions, we evaluated the effects of a depot preparation of testosterone (testosterone enanthate) on gonadotropin secretion and pituitary responses to synthetic GnRH in 10, early to mid-pubertal boys who had either isolated GH deficiency (n-2) or delayed adolescent maturation (n-8). Chronological and bone age ranges were 13 1/12-16 1/12 and 11-14 yr, respectively. Frequent blood withdrawal studies (every 20 min for 20 consecutive h) were performed in the Clinical Research Center over two consecutive weekends. Following each study, gonadotropin responses to GnRH (0.25 microgram/kg iv bolus) were determined. During the initial study, all boys showed a sleep-entrained increase in luteinizing hormone (LH) and testosterone (T) secretion; mean nocturnal concentrations of LH and T were 2.3-fold greater than daytime values. At the end of the first study, testosterone enanthate was given im (0, 25, 50, or 75 mg/m2). Six days later, mean plasma T concentrations were in the pubertal to mid adult male range and were constant throughout the day: 25 mg/m2, 3.7 +/- 0.4 (SE) ng/ml; 50 mg/m2, 4.6 +/- 0.2 ng/ml; and 75 mg/m2, 6.7 +/- 0.4 ng/ml. T treatment had no effect on pituitary responses to GnRH: mean LH increment was 8.5 mIU/ml before and 10.0 mIU/ml after T treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

The diagnosis of partial peripheral and pituitary resistance to thyroid hormone was ultimately made in two boys, 7 and 9 years of age, and a 10-year-old girl who had goiters and hyperthyroxinemia. The boys were treated with propythiouracil and/or thyroidectomy or iodine 131 for suspected thyrotoxicosis but had poorly suppressible serum thyroid-stimulating hormone (TSH) post treatment in spite of the usual L-thyroxine replacement. The girl had increasing goiter size while receiving propylthiouracil, 100 mg every eight hours. These findings led to reevaluation of thyroid hormone dynamics in these children and their families. Twelve additional family members, 3 to 38 years of age, compatible with an autosomal dominant inheritance, were also found to have peripheral and pituitary resistance to thyroid hormone. All affected individuals had elevated serum thyroxine and triiodothyronine levels, normal to slightly elevated triiodothyronine resin uptakes, and a nonsuppressed serum TSH. The five individuals who were given thyrotropin-releasing hormone showed exaggerated TSH responses, which normalized on L-thyroxine therapy. Misdiagnosis in six of 15 family members led to significant morbidity (hypothyroidism, delayed growth, and therapy risk). A nonsuppressed serum TSH in a patient with suspected thyrotoxicosis should lead to suspicion of this disorder. Appropriate management for this condition includes L-thyroxine therapy to decrease goiter size and normalize TSH responses to thyrotropin-releasing hormone.

Chronic exposure to testosterone (T) increases growth hormone (GH) secretion. To determine whether acute exposure to T would also enhance GH secretion, we infused saline, followed 1 wk later by T, for 18-24 h at one-third the adult male production rate in 12 pubertal boys and at the adult male production rate in eight additional pubertal boys. Blood was obtained every 20 min for GH and every 30 min for T from 2000-0800 h. Though infusion significantly increased serum T concentrations in all 20 boys, mean GH concentration, GH pulse frequency, and GH pulse amplitude did not increase compared to the saline infusion night. The secretory dynamics of GH as a function of 3-h time blocks from 2000-0800 h were also determined in the eight boys who received the higher dose of T. The profile for mean GH concentration, pulse frequency, pulse amplitude, and peak area were not affected by acute infusion of T at concentrations sufficient to alter LH secretion. This suggests that, at least in pubertal boys, one must be exposed to T for a period longer than 12-18 h to induce increased GH secretion.

Current treatment of acromegaly (surgery, radiation, and bromocriptine) is often unsatisfactory, and a sizeable proportion of patients with this disease continue to have GH hypersecretion after all therapeutic modalities have been exhausted. Fifteen patients with active acromegaly (8 previously treated and 7 newly diagnosed) were treated with the long-acting somatostatin analog SMS 201-995 (Sandoz; 50-250 micrograms, sc, every 6-8 h for up to 21 months). The mean daily plasma GH concentration was significantly suppressed in 13 patients, and it became normal in 10. Two patients, however, did not have GH suppression by SMS 201-995 treatment alone; in 1, a significant decline in mean daily GH was achieved after the addition of bromocriptine. As expected, suppression of GH secretion was associated with normalization of plasma somatomedin-C values and significant clinical improvement. Plasma GH responses to synthetic GHRH-(1-44) and TRH were either abolished or blunted by SMS 201-995. Thyroid function remained normal, and glucose tolerance did not change. Significant shrinkage of pituitary tumors occurred in 7 previously untreated and 2 previously treated patients. Side-effects were minimal. SMS 201-995 is an effective agent for the treatment of acromegaly. Further studies are necessary to establish guidelines for identification of non-responders and to examine the effect of preoperative tumor shrinkage on subsequent surgical outcome.

A girl aged 3 years and 11 months, with recurrent episodes of unexplained metabolic acidosis, hepatomegaly, and fasting hypoglycemia unresponsive to glucagon, showed profound falls in blood glucose levels in response to oral fructose and glycerol challenge. In vitro analysis of her hepatic glycolytic and gluconeogenic enzymes demonstrated absent fructose-1,6-diphosphatase activity. A therapeutic trial of orally given folic acid, 30 mg daily, did not improve her tolerance for fructose and glycerol. Over the next two years she showed improvement in tolerance to fasting, and to fructose and glycerol loading on dietary management.

The gonadotropin secretory patterns of 22 sexually immature children were analyzed in detail to determine whether pulsatile secretion occurs before the onset of puberty. Eight endocrinologically normal children, 13 children with isolated GH deficiency, and 1 girl with 45X gonadal dysgenesis were divided into 2 groups according to bone age. Group A children had bone ages less than 10 yr, and group B had bone ages between 10-11.5 yr. Blood samples were drawn every 20 min for periods of 3-11 h during both the day and night; in addition, 12-h urine collections were made for gonadotropin determinations. Mean nocturnal concentrations of LH and FSH were significantly greater than daytime values in 8 of 15 and 5 of 15 children in group A and in 6 of 7 and 1 of 7 in group B, respectively. Nocturnal urinary excretion of LH and FSH was significantly greater in group A children. Eight children in group A, including 4 whose bone ages were less than 5 yr, and 4 group B children had discernible LH pulses. LH pulses were detected during the day and night in both groups. LH pulse amplitude was greater during the night in both groups, but was greatest in group B (A, 1.9 +/- 0.2 mIU/ml; B, 3.0 +/- 0.3 mIU/ml). In children who demonstrated pulsatile secretion, LH pulse frequency appeared to be similar during the day and night and was slightly faster in the older children (A, every 3 h; B, every 2 h). These studies demonstrated that LH is secreted in a pulsatile manner well before the onset of puberty. Furthermore, the gonadotropin secretory pattern characteristic of early puberty results from the amplification of an already existing circadian pattern of gonadotropin secretion.