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.

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)

ABSTRACT: 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 woman 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 µg 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. Some of the menstrual periods may be anovulatory, whereas others exhibit prolongation of the follicular phase, presumably due to difficulty in follicle recruitment, and short luteal phase due to inability to maintain normal corpus luteum function.

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.

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)

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.

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.

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.

Intracerebroventricular (icv) bolus injection of cortico-tropin releasing factor (CRF) induces hypermetabolism, catecholamine surge and excess adrenocortical hormone secretion. Chronic icv CRF infusion in rats induces this stress-like picture for 2-3 days. However, corticosterone (B) excretion falls below that of sham rats by day 5. This dampened response to sustained CRF resembles the “adrenal exhaustion” phenomenon described in severe trauma and led to the present study: Jugular catheters were placed prior to icv cannulation and chronic delivery of CRF 20 ug/d or of saline. Hypersecretion of B on day 2 (0.7 ±0.15 ug/d) in CRF rats was suppressed on day 5 (0.3 ±.05, n=8, p<0.01). A 10 ug iv CRF bolus on day 5 caused exaggerated ACTH coupled with elevated plasma B: These results suggest: a suppressed adrenal function induced by chronic icv CRF similar to that after severe trauma and 2) a hypothalamic abnormality rather than primary pituitary or adrenal failure.

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.

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.

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.

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.