Use of a potent, long acting agonist of gonadotropin-releasing hormone in the treatment of precocious puberty.

Studies utilizing the administration of GnRH in various GnRH-deficient models have revealed the critical importance of the dose and mode of delivery of this releasing factor in determining the subsequent pituitary response. Chronic administration of long acting GnRH agonists (GnRHa), like continuous infusion of high doses of the native peptide, results in suppression of pituitary gonadotropin secretion. This selective and reversible suppression of gonadotropin secretion suggested several therapeutic applications for these analogs, particularly in the treatment of central precocious puberty (CPP), a disorder for which the previously available therapies lacked uniform efficacy and were associated with potential side effects. In our series, 74 children with CPP have been treated during the last 5 yr with the potent GnRH agonist, [D-Trp6, Pro9-ethylamide(NEt)]GnRH. Having selected a dose and route of administration that produced uniform suppression of spontaneous and stimulated pituitary gonadotropin secretion, GnRHa therapy resulted in a fall of gonadal sex steroid levels into the prepubertal range, a halting or regression of secondary sexual development, and a complete cessation of menses. Growth velocity slowed during therapy, with this slowing more pronounced during prolonged treatment periods and among those patients with more advanced chronological and skeletal ages. Skeletal maturation was retarded to a greater degree than linear growth, with resultant increases in the predictions for adult stature. Moreover, these benefits have been achieved in the absence of significant side effects. Complete reversal of the suppression of gonadarche has followed discontinuation of therapy; however, patterns of growth and skeletal maturation after discontinuation of GnRHa administration remain to be characterized. Thus, the impact of GnRHa therapy on final height must await further longitudinal study. The selective nature of GnRHa suppression of gonadarche also permits an investigation of the natural history of adrenarche and its discrete influences upon skeletal growth and maturation. In addition, GnRHa therapy of CPP provides a unique opportunity to study the effects of gonadal sex steroids on GH secretion and somatomedin-C (Sm-C) generation during sexual maturation. Finally, the detailed characterization of children with precocious puberty has helped to define more precisely a subset of patients whose precocity occurs in the absence of demonstrable gonadotropin secretion.(ABSTRACT TRUNCATED AT 400 WORDS)

Sexual precocity associated with an abdominal tumor in an African boy.

We report a 3 year-old boy in Tanzania with an abdominal mass and isosexual precocity due to an hCG-secreting hepatoblastoma. Due to the limited availability of local diagnostic testing, surgery and chemotherapy were completed before immunohistochemical and endocrine results were available.

Partial target organ resistance to thyroid hormone.

An 8-year old boy with a small goiter, normal basal metabolic rate (BMR), and elevated serum thyroid hormone levels (thyroxine [T(4)] 19.5 mug per 100 ml, free T(4) 4 ng per 100 ml, triiodothyronine [T(3)] 505 ng per 100 ml) was studied. He had measurable serum thyroid-stimulating hormone (TSH) levels (average 5.5 muU per ml), and the thyroxine-binding proteins, hearing, and epiphyseal structures were normal. There was no parental consanguinity nor were there thyroid abnormalities either in the parents or six siblings.Methimazole, 50 mg daily, depressed thyroxine synthesis (T(4) 10.5, free T(4) 2.5) and caused a rise in TSH to 11 muU per ml. After discontinuation of treatment, TSH declined to 4.2 muU per ml and chemical hyperthyroidism returned (T(4) 21.0 mug per 100 ml, free T(4) 4.2, and total T(3) 475 ng per 100 ml, radioactive iodine [RAI] uptake 68%), but studies of BMR and insensible water loss showed the patient to be clinically euthyroid. Thyrotropin-releasing hormone (TRH), 200 mug i.v., caused a brisk rise in TSH to 28 muU per ml, with T(4) rising to 28 mug per 100 ml, free T(4) to 5.6, and T(3) to 730 ng per 100 ml, thus indicating that the pituitary-thyroid system was intact and that the patient's TSH was biologically active. The unusual sensitivity of the pituitary cells to TRH in spite of the markedly elevated serum thyroid hormone levels also suggested that the pituitary was insensitive to suppression by T(3) or T(4). Serum dilution studies gave immunochemical evidence that this patient's TSH was normal. Neither propranolol, 60 mg, chlorpromazine, 30 mg, nor prednisone, 15 mg daily, influenced thyroid indices. Steroid treatment, however, suppressed the pituitary response to TRH, T(3) in doses increased over a period of 12 days to as much as 150 mug daily caused a rise in serum T(3) to above 800 ng per 100 ml, a decline of T(4) to euthyroid levels (T(4) 9.5 mug per 100 ml, free T(4) 1.6 ng per 100 ml), suppression of the RAI uptake from 68% to 35%, and marked blunting of the responses to TRH, but the BMR and insensible water loss remained normal. The data suggest that the patient's disorder is due to partial resistance to thyroid hormone.

Adrenarche and skeletal maturation during luteinizing hormone releasing hormone analogue suppression of gonadarche.

During puberty the effects of adrenal androgens upon skeletal maturation are obscured by the influence of gonadal steroids. Suppression of gonadarche with an analogue of luteinizing hormone releasing hormone (LHRHa) affords an opportunity to examine the onset and progression of adrenarche in the absence of pubertal levels of gonadal steroids in a controlled fashion and to explore the relationship between adrenal androgens and the rate of epiphyseal maturation. In 29 children with central precocious puberty, gonadarche was suppressed with LHRHa administration for 1-4 yr. During LHRHa exposure, dehydroepiandrosterone sulfate (DHAS) levels, as an index of adrenal maturation, were constant or increased in an age-expected manner. The change in bone age for change in chronologic age decreased from 1.7 +/- 0.1 to 0.49 +/- 0.05 (P = 0.00005), indicating that the LHRHa-induced return to a prepubertal gonadal steroid environment was associated with a slowing of skeletal maturation. DHAS levels were correlated with the rate of skeletal advancement before (r = 0.57, P = 0.001) and during 12 to 48 mo of exposure to LHRHa (r = 0.52, P = 0.003). A negative correlation of DHAS values with subsequent increases in predicted mature height was observed (r = -0.49, P = 0.007). Thus, in children with central precocious puberty, adrenarche progressed normally during LHRHa suppression of gonadarche. In children with the onset of progression of adrenarche during maintenance of a prepubertal gonadal steroid milieu, there was less evidence than in preadrenarchal children of a restraint upon skeletal maturation. These data suggest that adrenal androgens contribute importantly to epiphyseal advancement during childhood.

Hypercorticosteronuria and diminished pituitary responsiveness to corticotropin-releasing factor in obese Zucker rats.

Metabolic defects in obese (fa/fa) Zucker rats have previously been shown to be reversed by adrenalectomy; however, hypercorticosteronemia has not been demonstrated. We now report that the total daily excretion of corticosterone and urea nitrogen are significantly greater (P less than 0.01) in obese Zucker rats than in age-matched lean Zucker rats. This excessive excretion of corticosterone is not of autonomous adrenal origin, since dexamethasone treatment (20 micrograms/kg X day) for 2 days induced a proportionate reduction in corticosterone excretion (approximately 50%) in both obese and lean Zucker rats. Corticosterone excretion was further suppressed to levels not different from those in lean rats after 2 days of dexamethasone (40 micrograms/kg X day). Both the peak and total pituitary beta-endorphin secretion in response to an iv bolus of corticotropin-releasing factor (CRF) were diminished in obese Zuckers. The response to CRF in obese Zucker rats was dampened and superimposable on that of dexamethasone-treated lean Zucker rats, suggesting the existence of chronic hypercorticosteronemia as a component of this genetic obesity. These observations provide evidence for a compensatory alteration of the pituitary-adrenal axis. We suggest that corticosterone turnover may be increased in obese Zucker rats.

Enhanced hepatic insulin sensitivity and peripheral glucose uptake in cold acclimating rats.

Cold-exposed rats exhibit hypermetabolism, hyperphagia, and increased glucose oxidation. Their counterregulatory hormone secretion is markedly elevated, while insulin levels fall acutely, gradually returning to basal during acclimation. We assessed both hepatic and peripheral sensitivity to insulin in rats in the basal state and after 5 days of cold (5 C) exposure. The contribution of gluconeogenesis to total glucose turnover was measured and compared to daily urinary corticosterone excretion. Hepatic glucose production was equally suppressed by the infusion of insulin at 1.2 mU/kg X min in both control and cold-acclimated rats, but enhanced hepatic sensitivity to low dose (0.6 mU/kg X min) insulin infusion was only observed after cold exposure. The metabolic clearance of glucose was elevated with cold stress and was insensitive to the infusion of insulin at either level. Insulin resistance was not observed. Urinary excretion of corticosterone and urea nitrogen were markedly increased, but creatinine excretion was unchanged, suggesting that the concurrent increase in gluconeogenesis resulted from increased protein intake rather than increased catabolism of muscle protein.

Methimazole pharmacology in man: studies using a newly developed radioimmunoassay for methimazole.

A RIA for the antithyroid drug methimazole [1-methyl-2-mercaptoimidazole (MMI)] has been developed. A MMI derivative, 5-COOH-MMI, was conjugated to porcine thyroglobulin, and antibodies to the conjugate were raised in rabbits. [35S]MMI was used as the tracer. At a final antibody dilution of 1:100, the assay could detect MMI in amounts as low as 2.5 ng. The putative MMI metabolites 3-methyl-2-thiohydantoin and 1-methylimidazole had minor cross-reactivities of 2.1% and 0.5%, respectively. There was no effect of serum proteins on MMI immunoactivity. MMI was given orally to normal subjects (n = 6), hyperthyroid patients (n = 5), patients with hepatic cirrhosis (n = 4), and normal lactating women (n = 4). After a single dose of 60 mg, peak MMI levels were similar in the normal subjects and the hyperthyroid patients (approximately 1.5 micrograms/ml). Patients with hepatic cirrhosis had similar peak MMI serum levels [1.31 +/- 0.3 (+/- SEM) micrograms/ml], but the half-time of MMI disappearance from serum was significantly prolonged compared with the normal value (21.2 vs. 6.0 h; P less than 0.001). The lactating women received 40 mg MMI as a single dose. Over the next 8 h, mean MMI levels in serum and milk were nearly identical, with a mean serum to milk ratio of 1.03 +/- 0.16. A total of 70.0 +/- 6.0 micrograms MMI was excreted in the milk over the 8-h time period. This amount of MMI could affect neonatal thyroid function.

17Beta-hydroxysteroid dehydrogenase-3 deficiency: diagnosis, phenotypic variability, population genetics, and worldwide distribution of ancient and de novo mutations.

17Beta-hydroxysteroid dehydrogenase-3 (17betaHSD3) deficiency is an autosomal recessive form of male pseudohermaphroditism caused by mutations in the HSD17B3 gene. In a nationwide study on male pseudohermaphroditism among all pediatric endocrinologists and clinical geneticists in The Netherlands, 18 17betaHSD3-deficient index cases were identified, 12 of whom initially had received the tentative diagnosis androgen insensitivity syndrome (AIS). The phenotypes and genotypes of these patients were studied. Endocrine diagnostic methods were evaluated in comparison to mutation analysis of the HSD17B3 gene. RT-PCR studies were performed on testicular ribonucleic acid of patients homozygous for two different splice site mutations. The minimal incidence of 17betaHSD3 deficiency in The Netherlands and the corresponding carrier frequency were calculated. Haplotype analysis of the chromosomal region of the HSD17B3 gene in Europeans, North Americans, Latin Americans, Australians, and Arabs was used to establish whether recurrent identical mutations were ancient or had repeatedly occurred de novo. In genotypically identical cases, phenotypic variation for external sexual development was observed. Gonadotropin-stimulated serum testosterone/androstenedione ratios in 17betaHSD3-deficient patients were discriminative in all cases and did not overlap with ratios in normal controls or with ratios in AIS patients. In all investigated patients both HSD17B3 alleles were mutated. The intronic mutations 325 + 4;A-->T and 655-1;G-->A disrupted normal splicing, but a small amount of wild-type messenger ribonucleic acid was still made in patients homozygous for 655-1;G-->A. The minimal incidence of 17betaHSD3 deficiency in The Netherlands was shown to be 1: 147,000, with a heterozygote frequency of 1:135. At least 4 mutations, 325 + 4;A-->T, N74T, 655-1;G-->A, and R80Q, found worldwide, appeared to be ancient and originating from genetic founders. Their dispersion could be reconstructed through historical analysis. The HSD17B3 gene mutations 326-1;G-->C and P282L were de novo mutations. 17betaHSD3 deficiency can be reliably diagnosed by endocrine evaluation and mutation analysis. Phenotypic variation can occur between families with the same homozygous mutations. The incidence of 17betaHSD3 deficiency is 0.65 times the incidence of AIS, which is thought to be the most frequent known cause of male pseudohermaphroditism without dysgenic gonads. A global inventory of affected cases demonstrated the ancient origin of at least four mutations. The mutational history of this genetic locus offers views into human diversity and disease, provided by national and international collaboration.

Low serum reverse T3 concentration in burned children: its relationship to nutritional state.

The correlation between protein turnover and serum thyroid hormone levels was studied in 10 children, ages 1 to 16 years subsequent to severe burn injuries. In contrast to published studies that have shown depression of triiodothyronine (T3) and elevations of reverse T3 (rT3) in stressed patients, no change was found in the mean level of T3 and a 69% decrease in rT3 compared to healthy controls of similar age. Whole body rates of protein synthesis and breakdown were determined using a [15N]glycine turnover technique. The difference between synthesis and breakdown was negatively correlated with the ratio, rT3/T3 in serum. Thus, in burned children, a decrease in N balance was associated with a rise in rT3/T3 which is qualitatively similar to that observed in fasted individuals or in stressed patients who may be semistarved.

Mitigation of cretinism by breast-feeding.

An athyrotic infant had hypothyroidism at 1 year of age. He had grown at an above-average velocity until age 10 months when breast-feeding was discontinued, yet his bone age remained that of a newborn. These observations suggested that breast-feeding had attenuated hypothyroidism by providing significant quantities of thyroid hormones in the milk. To test this hypothesis, thyroxine (T4), 3,5,3'-triiodothyronine (T3), and 3,3,5'-triodothyronine (reverse T3) were measured in breast milk samples collected serially from three months before to four months after delivery. Mean breast milk T4 content fell from 1.4 to 0.7 microgram/dl within 48 hours after delivery, while T3 content rose from 136 to 286 ng/dl. Reverse T3 content remained unchanged. The shift in the T4/T3 ratio after delivery was observed in samples of all five donors; the highest postpartum T4 level was 1.1 microgram/dl and the highest postpartum T3 level was 405 ng/dl. It is concluded that breast-feeding may deliver sufficient thyroid hormones to the athyrotic infant to mitigate severe hypothyroidism and to prevent impaired neurological development.

A useful radiologic sign for the diagnosis of Turner's syndrome.

A new X-ray sign of gonadal dysgenesis is described. In this series nine out of ten patients with Turner's syndrome have a coarse, reticular pattern of the carpal bones. A comparison with other previously described roentgenographic characteristics on hand and wrist films of these children leads to the conclusion that the new sign is more reliable and specific.

X-linked Kallmann syndrome and renal agenesis occurring together and independently in a large Australian family.

Males with X-linked Kallmann syndrome (XLKS) may have renal agenesis. We studied a large kindred with a history of eight males affected by XLKS born in five generations. Their XLKS was shown to be due to an intragenic mutation of the KAL-1 gene. We also documented three male neonatal deaths due to bilateral renal agenesis (BRA), five males with unilateral renal agenesis (URA), and one female with a pelvic ectopic kidney in this kindred. Of four XLKS males who had renal imaging studies, two had URA. The kindred's KAL-1 mutation was not present in three of the males with URA, the female with the ectopic kidney, nor in preserved autopsy tissue from one infant with BRA. The high frequency of renal agenesis in this family, in the presence and absence of the KAL-1 mutation, suggests an autosomal dominant or X-linked gene which may independently or co-dependently contribute to renal agenesis.

Bronchial carcinoid tumors in pediatric patients.

Bronchial carcinoid tumors (BCT) are the most frequent primary pulmonary neoplasms of childhood. Seventeen of 208 patients diagnosed as having BCT at the Massachusetts General Hospital were between 10 and 21 years of age. We reviewed our records of the 17 patients and 8 other pediatric cases and compared their findings with those of seven large series of adults. Distribution was equal between the sexes. The average age at diagnosis was 17 years; 4 patients were < or = 15 years old. The duration of symptoms prior to diagnosis varied from 2 weeks to 2.6 years, with a median duration of 8.5 months. In contrast to adults, no child was asymptomatic. The majority of children presented with wheezing and atelectasis in addition to the characteristic adult triad of cough, hemoptysis, and pneumonitis. Five patients presented with weight loss and one patient presented with hoarseness. One of the 17 pediatric patients presented with Cushing's syndrome and a functional BCT. Twelve of 14 patients were disease free for 9 months to 34 years after surgical resection. We conclude that BCT should be suspected in children with pneumonitis resistant to therapy, atelectasis, wheezing, and hemoptysis. Surgical resection will result in symptom-free recovery in the majority of cases in spite of low-grade malignancy.

In vivo total body electrical conductivity following perturbations of body fluid compartments in rats.

Total body electrical conductivity (TOBEC) provides a rapid and safe noninvasive technique for the assessment of total body water in animals and man. An instrument employing this principle has been shown to measure body water in healthy Sprague-Dawley rats. With the exception of adult obesity in humans, alterations in body fluid compartments that could theoretically affect the utility of conductivity measurements have not been studied. We, therefore, applied the total body electrical conductivity measurement in rats following perturbations of body fluid/electrolyte spaces including obesity, furosemide diuresis, severe burn, and low protein diet. Our findings confirm that total body water can be accurately measured by TOBEC in conditions of abnormal body fluid distribution. However, when the ratio of intracellular to extracellular fluid is significantly reduced, such as the severe burn or low protein intake, TOBEC does not reflect the intracellular (potassium) space but does predict total water and extracellular (sodium) space.

The analysis of glucose kinetics using a single jugular catheter in awake rats.

The rates of glucose production and utilization can be estimated by a primed-constant infusion technique using separate catheters for the infusion of radiolabelled glucose and periodic blood withdrawal. In rats, a carotid artery catheter is most often combined with a jugular or femoral venous catheter in such studies. We presently describe a method which utilizes a single jugular catheter for both infusion and sampling in the awake rat. This method is directly compared with simultaneous carotid artery sampling during both the dynamic steady state and a nonsteady state induced by a constant infusion of insulin. Our results demonstrate the validity of a single vein design for the analysis of glucose kinetics in either state. Rapid sampling and complete flushing prevent disruption of infusate equilibrium and sample contamination respectively. This single catheter method requires less technical skill for placement, reduces surgical intervention and enhances the comfort of the awake rat.