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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.

Acute renal disease is common in sub-Saharan Africa, with high mortality. Its etiology is poorly understood; quartan malaria owing to Plasmodium malariae was implicated in previous series. Few previous studies have included histological data; furthermore, much of the literature pre-dates the human immunodeficiency virus (HIV) epidemic. We report prospective analysis of acute proteinuric renal disease in children in rural Uganda. Clinical and laboratory data are presented on 65 patients (aged 2-14 years, mean 8.4; 35 male, 30 female) in 41 of whom histological diagnosis was obtained by renal biopsy. The most frequent histological finding was endocapillary proliferative glomerulonephritis (GN) in 27/41 cases, in 20 of which eosinophils were very prominent. No cases showed features of HIV nephropathy. Malarial films were positive in 11 cases: all owing to Plasmodium falciparum. Patients were treated with diuretics, antihypertensives, and supportive measures. Corticosteroids were rarely used, being reserved for patients with minimal changes on renal biopsy. Clinical outcomes were fair: 91% of patients survived to discharge. We conclude that acute GN is common in children in Uganda, that an unusual eosinophilic proliferative GN is the most frequent histological finding, that HIV is not implicated as an important factor in this age group, and that good outcomes can be achieved using simple clinical and laboratory diagnostic methods. Renal biopsy in selected cases is feasible and helpful, especially in allowing rational use of corticosteroids and other potentially toxic treatments. Symptomatic treatments and careful supportive care will allow the majority of children to recover.

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.

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.

Objective: The purpose of this study was to evaluate the usefulness of 17 hydroxyprogesterone (17OHP) determination in dried filter paper blood samples from patients with congenital adrenal hyperplasia caused by 21-hydroxylase deficiency. It was hypothesized that these home samples would enhance patient treatment., Study Design: Results of 17OHP determination in simultaneously collected venous and dried filter paper blood samples were compared to establish assay reliability. Thereafter, parents mailed dried filter paper blood samples collected before each hydrocortisone dose., Results: The 17OHP levels in wet and dried blood samples correlated well (r = 0.98). Results did not change when stored for 2 weeks under various conditions. Blood sampling at different times of the day provided insights into the patterns of 17OHP secretion and identified times of inadequate adrenal suppression. Dose adjustments were then made considering the time of day when adrenal suppression was inadequate., Conclusion: Home monitoring of 17OHP is a reliable and practical approach for assessing adrenal steroid activity in patients with congenital adrenal hyperplasia. Considering the time of day of 17OHP elevations also facilitates hydrocortisone dosing adjustment.

Kallmann syndrome is characterized by hypogonadotropic hypogonadism and anosmia. Autosomal dominant, autosomal recessive, and X-linked patterns of transmission have been described. The X-linked form of Kallmann syndrome (XLKS) is the least common of the three modes of inheritance and is caused by mutations in the putative cell adhesion protein, KAL-1. In a large pedigree with XLKS, direct sequencing of the KAL-1 gene revealed a duplication of 11 base pairs in exon 1, resulting in a frameshift and a premature stop at codon 34 of the 680 amino acid protein. The clinical features of the affected individuals in this pedigree provide further evidence in support of the idea that XLKS is associated with neurologic features that are not seen in other forms of the syndrome., (Copyright 1998 Academic Press.)

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.

Interleukin-1 (IL-1) has been shown to stimulate corticosterone release from the adrenal gland directly, and indirectly through activation of the hypothalamic-pituitary-adrenal axis. The aim of this paper was to determine whether IL-1-stimulated corticosterone release occurs indirectly through the local release of catecholamines from the rat adrenal gland. To accomplish this, experiments were conducted on both quartered rat adrenal glands and primary cultures of dispersed adrenal cells. Incubation of quartered adrenals with adrenocorticotropic hormone (ACTH, 10(-12) to 10(-8) M) or IL-1 beta (10(-12) to 10(-8) M) resulted in dose-dependent increases (P less than 0.05) in corticosterone release. Corticosterone release stimulated by 10(-8) M doses of ACTH and IL-1 beta began to rise 30 min after incubation and peaked at 2 h. In primary cultures of adrenal cells, IL-1 alpha and IL-1 beta elevated corticosterone release after a 24-h incubation period. ACTH elevated corticosterone levels at 4 and 24 h. The stimulatory effect of IL-1 on corticosterone release was mimicked by epinephrine (10(-6) M), and was selectively blocked by the alpha-adrenergic antagonist phentolamine (10(-5) M). The beta-adrenergic antagonist propranolol (10(-5) M) did not change IL-1-induced corticosterone release. Neither phentolamine nor propranolol had an effect on ACTH-stimulated corticosterone release. Both IL-1 alpha and IL-1 beta significantly increased (P less than 0.05) epinephrine levels after a 24-h incubation period compared with media-treated controls.(ABSTRACT TRUNCATED AT 250 WORDS)

The hypothalamic-pituitary-ovarian hormone secretion patterns were evaluated in two women with 45,X Turner syndrome, spontaneous sexual development, and monthly menstrual periods. Each women had serum gonadotropin and sex steroid determinations during two or more menstrual cycles. During the follicular phase of a menstrual cycle, both women received 100 micrograms gonadotropin-releasing hormone (GnRH) s.c., and serum LH and FSH responses were determined. In addition, one woman collected daily overnight urine specimens for 40 consecutive days, spanning two menstrual periods, for the measurement of LH, FSH, estriol, and free progesterone. The randomly measured hormone results showed low serum progesterone concentrations during luteal phases, consistent with the interpretation of anovulation or inadequate corpus luteum function. At the time of the GnRH stimulation tests, baseline serum FSH concentrations and FSH responses to GnRH were within normal limits, whereas baseline LH levels and LH responses to GnRH were low. The pituitary gonadotropin secretion patterns were more consistent with patterns seen during early puberty than in the perimenopausal state. This interpretation was further confirmed by the urinary excretion patterns of gonadotropins, which were not significantly elevated. Furthermore, the urinary hormone profiles revealed that, although the intermenstrual period was of normal length, the follicular phase was prolonged, with normal levels of LH, FSH, and estriol excreted. The menstrual cycle studied was ovulatory but had a short luteal phase. The hormone results indicated that the dysgenetic ovary of women with 45,X Turner syndrome is capable of producing sufficient quantities of sex steroids and other regulatory factors to maintain gonadotropin secretion patterns that are reminiscent of early puberty.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of varying doses of purified human interleukin 1 (IL-1) on rectal temperature (Tr), hypothalamic corticotropin-releasing hormone (CRH), pituitary and plasma adrenocorticotropic hormone (ACTH), and plamsa corticosterone was examined in intact male rats at 24 degrees C; plasma ACTH and corticosterone responses were also studied in hypophysectomized rats. In addition, IL-1-induced changes in corticosterone concentration were investigated by means of adrenal organ cultures. Tr was measured with thermocouples. CRH and ACTH levels were determined by radioimmunoassay, and corticosterone by protein-binding assay. Intravenous administration of IL-1 (0.063-1.0 ng) resulted in hyperthermia, which began 20 min postinjection and continued for an additional 30 min. IL-1 at a dose of 0.5 ng resulted in no change in hypothalamic CRH, pituitary ACTH, or plasma ACTH levels compared with saline-treated rats. Plasma corticosterone was significantly (P less than 0.05) elevated 30 min after IL-1 administration and returned to control levels after 1 h. The higher dose of IL-1 (1.0 ng) did not affect hypothalamic CRH content, but pituitary ACTH began to rise at 15 min and was significantly (P less than 0.05) elevated 30 min after injection. Rats receiving this dose displayed elevated (P less than 0.05) plasma ACTH and corticosterone levels 30 and 60 min postinjection. No change in plasma corticosterone was observed in hypophysectomized rats administered either 1 ng of IL-1 or 1 microgram of recombinant IL-1 beta (rIL-1 beta); adrenal organ cultures treated with IL-1 (10(-11) M) responded similarly.(ABSTRACT TRUNCATED AT 250 WORDS)

The gonadotropin-releasing hormone-like agonist D-Trp6-Pro9-NEt-LHRH (LHRHa) has been shown to induce a reversible short-term suppression of gonadotropins and gonadal steroids in patients with central precocious puberty. Since accelerated statural growth and bone maturation are clinical features of precocity not well controlled by conventional therapies, we examined the effects of prolonged LHRHa therapy for 18 consecutive months on growth and skeletal maturation in nine girls with neurogenic or idiopathic precocious puberty. Suppression of gonadotropin pulsations and gonadal steroids was maintained in all subjects. Growth velocity fell from a mean rate (+/- S.E.M.) of 9.35 +/- 0.64 cm per year during the 19 months before treatment to 4.58 +/- 0.60 cm per year during treatment (P less than 0.001). Bone age advanced a mean of 9.4 +/- 2.3 months during treatment. These changes resulted in a mean increase of 3.3 cm in predicted height (P less than 0.01). Complete suppression of the pituitary-gonadal axis can be maintained by LHRHa therapy, resulting in slowing of excessively rapid growth and skeletal maturation and in increased predicted adult height in girls with precocious puberty.

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.

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.

Bolus intracerebroventricular delivery of corticotropin-releasing factor (CRF) elicits acute responses of both the pituitary-adrenal axis and the sympathetic nervous system. We examined whether these stresslike responses could be maintained over a period of days by central delivery of CRF in nonstressed rats, as would be predicted if this peptide participates in the central nervous system regulation of chronic stress. CRF (4.3 or 21.5 micrograms/day) was continuously delivered into the cerebral ventricle via Alzet minipumps. In contrast to saline-infused controls, rats receiving CRF exhibited elevated excretions of corticosterone, norepinephrine, and urea nitrogen for several days. Thereafter, an attenuation of CRF responsiveness occurred when corticosterone excretion returned to basal levels despite continued central CRF infusion. However, CRF delivered intravenously during attenuation stimulated adrenocorticotropic hormone and corticosterone secretion, implicating a hypothalamic rather than pituitary locus for central CRF resistance. The present data do not permit a conclusion on whether the attenuation of the CRF response with time is the result of an ultrashort-loop negative-feedback mechanism or CRF receptor desensitization.

We have studied the effect of caloric intake on metabolic rate in normal and burned (20-25% body surface area, BSA) guinea pigs. Food intake was standardized by means of infusing a liquid diet (48 kcal/day) through chronic gastrostomy tubes continuously for 16 hours per day. We found that feeding control animals a diet insufficient to meet their daily caloric requirements nevertheless resulted in a significantly higher basal oxygen consumption (VO2) 8 hours after food than during fasting. The incremental increase in basal VO2 induced by feeding burned animals (20-25% BSA) was even greater than in controls. Thus, although basal VO2 was similar in control fasted and burned-fasted animals, basal VO2 in burned-fed animals was significantly greater than in control-fed animals.

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.

It has been suggested that complete catch-up growth is achieved with treatment in patients with juvenile acquired hypothyroidism. We tested this assumption by examining long-term growth in 18 girls (mean [+/- SD] age, 11.4 +/- 2.7 years; bone age, 6.2 +/- 3.1 years) and 6 boys (age, 10.6 +/- 4.7 years; bone age, 6.4 +/- 2.7 years) with severe primary hypothyroidism (serum thyroxine level 1.1 +/- 0.3 micrograms per deciliter [13 +/- 4 nmol per liter]). At diagnosis, heights were 4.04 +/- 0.5 and 3.15 +/- 0.4 SD below the mean heights for age of normal girls and boys, respectively. The patients were treated with levothyroxine (3.4 +/- 0.3 micrograms per kilogram of body weight per day) to maintain normal thyroid function. During the first 18 months of therapy, the children's skeletal maturation exceeded the maturation expected for their statural growth, regardless of whether or not they were undergoing pubertal development. Predictions of decreased adult height were based on these observations. At maturity, girls and boys stood approximately 2 SD below normal adult stature, at 149 +/- 5.0 cm and 168 +/- 5.1 cm, respectively. Heights at maturity were also lower than midparental heights (P less than 0.01) and lower than pre-illness standard-deviation scores for height (P less than 0.01). The deficit in adult stature was significantly related to the duration of hypothyroidism before treatment (P less than 0.01). We conclude that despite treatment, prolonged juvenile acquired hypothyroidism results in a permanent height deficit related to the duration of thyroxine deficiency before treatment.

Males with Down's syndrome frequently present incomplete sexual development and are presumed to be sterile. The intent of this study is to clarify the aetiology of diminished sexual function in men with trisomy 21. Single dose LH-RH stimulation tests were performed in 6 men with Down's syndrome. Compared to a control group of 6 mentally retarded, institutionalized males, the subjects with Down's syndrome had markedly elevated basal FSH and slightly elevated basal LH concentrations. The FSH response to LH-RH stimulation was notably increased in the Down's syndrome group, while the LH response showed a lesser increase. Testosterone concentrations were found to be comparable in the two groups. The results are consistent with the clinical assumption that males with Down's syndrome have decreased spermatogenesis and infertility and that their Leydig cell function is less affected.

The existence of endemic goiter, caused by iodine deficiency and the presence of a dietary goitrogen, has been noted in eastern Zaire by a number of authors (De Visscher et al.: Journal of Clinical Endocrinology and Metabolism 21:175-188, 1961; Delange et al.: Journal of Clinical Endocrinology and Metabolism 34:1059, 1972). In the Ituri Forest of Huate-Zaire, two distinct populations, the Efe (pygmy) and Lese (Bantu), live in association with each other and have similar diets. The goiter survey reported here documents differences in goiter prevalence and severity between the nomadic pygmy and village-living Bantu populations. While the Efe have an overall goiter prevalence of 9.4%, the Lese have a goiter prevalence of 42.9%. Furthermore, Efe women living in Lese villages and subsisting on a Lese diet have a prevalence of goiter similar to that of forest-living Efe women. Village-living individuals born of Efe mothers and Lese fathers have a prevalence of goiter greater than that of pure Efe but less than that of Lese. While our data cannot exclude dietary explanations for the difference in goiter prevalence between the Efe and Lese, they do support the hypothesis that the Efe possess an adaptation to an iodine-deficient environment that does not result in the development of goiters.

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 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.

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)

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.

Recent evidence suggests that a group of children exists in whom premature sexual maturation occurs in the absence of pubertal levels of gonadotropins; that is, they have gonadotropin-independent precocious puberty. We compared six boys and one girl with this disorder with four boys and five girls with central precocious puberty, in which there is a pubertal pattern of gonadotropin release. The two groups were similar in age of onset, degree of sexual development, growth velocity, and rate of skeletal maturation. A family history of precocity was noted in four of the boys with gonadotropin-independent precocity, and the girl had McCune-Albright syndrome. Children with central precocious puberty demonstrated a pulsatile release of gonadotropins, pubertal responses to luteinizing hormone-releasing hormone, and complete suppression of gonadarche after exposure to an analogue of luteinizing hormone-releasing hormone (LHRHa). In contrast, children with gonadotropin-independent precocity demonstrated an absence of gonadotropin pulsations, variable responses to luteinizing hormone-releasing hormone, lack of suppression of puberty in response to LHRHa, and cyclic steroidogenesis. Tissue from testicular biopsies performed in five of six boys with gonadotropin-independent precocity showed a range from incipient pubertal development of the tubules with proliferation of Leydig cells to the appearance of normal adult testes. We conclude that gonadotropin-independent precocious puberty is a distinct syndrome, of unknown cause, that may be familial and may have been responsible for many previously reported cases of precocious puberty.

In vivo injection of isoproterenol(IPR) (4 mg/kg) in normal rats caused fat cell adenylate cyclase to become desensitized to stimulation by IPR in vitro. In contrast, adenylate cyclase from tissues of burn-injured rats (20% body surface, full-thickness scald) remained fully responsive to stimulation by IPR for several days after injury even though catecholamine excretion was elevated more than twofold. Furthermore, fat cell adenylate cyclase from burn-injured animals was not desensitized after acute in vivo IPR injections, whereas adenylate cyclase from the shams did become desensitized after acute IPR injections. To determine whether the apparent resistance to desensitization in burn-injured rats might be an adaptation to the chronic elevation of catecholamines that follows burn injury, two other rat models in which catecholamines are chronically elevated were studied: one was produced by a twice daily schedule or IPR (1 mg/kg) injections for 3 weeks; the other by 3 weeks' cold exposure (0--4 degrees C). As had been observed in burn injury, adenylate cyclase remained fully responsive to IPR in both models, and adenylate cyclase from the cold-acclimated rats was resistant to desensitization by acute injections of IPR. It therefore seems likely that chronic elevations of catecholamines evoke regulatory mechanisms in target cells to circumvent the desensitizationwhich would otherwise occur consequent to acute exposures to catecholamines. In burn injury this may result in an inadvertent adaptation which contributes to hypermetabolism.

The jejunoileal bypass is, of all the current therapeutic possibilities, the only permanent method for the successful treatment of a patient with hypothalamic obesity. Pre-operatively, it is advisable, however, to reduce the body weight by exclusive alimentation with Vivonex, in order to improve lung function and diminish the operation risks. Putting a smaller section of the bowel at rest will prevent major weight loss, as well as more severe complications. The disturbances of the calcium and potassium metabolism and of liver function, which frequently occur after jejunoileal bypass operation, were not observed, when on both sides of the immobilised bowel section a section of small bowel 23 to 38 cm long was maintained in normal function.

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.

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.

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.

Gonadal and olfactory features of Kallmann's syndrome, usually considered to be inherited as an X-linked recessive trait, were found in a father and son who both had cryptorchidism, hypogonadism, and hyposmia. The father's fertility had been induced with chorionic gonadotropin, leading to the birth of three children. Olfactory and gonadal functions were normal in the mother and two siblings. The father had low basal plasma testosterone and subnormal follicle stimulating hormone (FSH) response to luteinizing hormone-releasing hormone (LH-RH). The affected son and his healthy brother were prepubertal. Their basal plasma total and free testosterone, serum FSH and luteinizing hormone (LH), and response to LH-RH were similar. The clinical presentation and formal olfactory function studies were considered most helpful for the suggestive diagnosis of Kallmann's syndrome in children. The occurrence of this syndrome in this family is consistent with autosomal dominant inheritance.