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Background/Aims: Growth hormone (GH) treatment regimens do not account for the pubertal increase in endogenous GH secretion. This study assessed whether increasing the GH dose and/or frequency of administration improves pubertal height gain and adult height (AH) in children with low GH secretion during stimulation tests, i.e. idiopathic isolated GH deficiency. Methods: A multicenter, randomized, clinical trial (No. 88-177) followed 111 children (96 boys) at study start from onset of puberty to AH who had received GH 33 µg/kg/day for ≥1 year. They were randomized to receive 67 µg/kg/day (GH67) given as one (GH67×1; n = 35) or two daily injections (GH33×2; n = 36), or to remain on a single 33 µg/kg/day dose (GH33×1; n = 40). Growth was assessed as heightSDSgain for prepubertal, pubertal and total periods, as well as AHSDS versus the population and the midparental height. Results: Pubertal heightSDSgain was greater for patients receiving a high dose (GH67, 0.73) than a low dose (GH33×1, 0.41, p < 0.05). AHSDS was greater on GH67 (GH67×1, -0.84; GH33×2, -0.83) than GH33 (-1.25, p < 0.05), and heightSDSgain was greater on GH67 than GH33 (2.04 and 1.56, respectively; p < 0.01). All groups reached their target heightSDS. Conclusion: Pubertal heightSDSgain and AHSDS were dose dependent, with greater growth being observed for the GH67 than the GH33 randomization group; however, there were no differences between the once- and twice-daily GH67 regimens.

Aim: The objective of this study was to determine estradiol levels and assess their relationship to pubertal growth in girls. Methods: Thirty-seven 24-hour profiles of serum 17β-estradiol were retrospectively analyzed in relation to growth in 27 healthy girls admitted for short/tall stature (n = 20) or recruited as healthy volunteers at Göteborg Pediatric Growth Research Center (GP-GRC). Inclusion Criteria: Birth weight and length above –2 SDS, gestational age 37–42 weeks, prepubertal height and weight within ±3 SDS and normal growth hormone secretion. Serum estradiol was determined by a validated ultrasensitive extraction radioimmunoassay (detection limit 4 pmol/l). A sixth-grade polynomial was fitted to each girl’s growth data. Growth velocity and age at peak height velocity (PHV) was calculated. Results: A dose-response model was used to find the morning 17β-estradiol level at which half of the maximal pubertal growth up to PHV had occurred, EC50, which was 20 pmol/l with a 95% confidence interval of 13–31. When 17β-estradiol exceeds early pubertal levels (Tanner breast stage 2, 10–51 pmol/l), less than 25% of the potential pubertal growth velocity up to PHV remains. Conclusions: Morning 17β-estradiol in the low early pubertal range (13–31 pmol/l) is associated with increasing growth velocity.

The serum levels of thyroxine (T4), 3,5,3'-triiodothyronine (T3), 3,3',5'-triiodothyronine (reverse T3, rT3), thyroxine-binding globulin and thyroid-stimulating hormone have been monitored in 13 patients with acute myocardial infarction. The major changes recorded were a transient decrease in T3 and a transient increase in rT3. They reached a nadir and a peak, respectively, within three days. A conceivable explanation for these alterations is that the monodeiodination of T4 is diverted from the activating pathway (T4 to T3) to the inactivating pathway (T4 to rT3).

We report a child with multiple target organ pseudohypoaldosteronism type 1 with frequent recurrent pulmonary infections caused by Pseudomonas aeruginosa and Pasteurella multocida and high levels of chloride in sweat, urine and nasal secretion. Repetitive faecal chymotrypsin samples have all shown pathological values in spite of no other sign of exocrine pancreas dysfunction. The similarities with cystic fibrosis and the importance of the salt content in bronchial fluid are discussed.

Girls adopted from developing countries often have early or precocious puberty, requiring treatment with gonadotrophin-releasing hormone (GnRH) analogues. During such treatment, decreased growth velocity is frequent.To study whether the addition of growth hormone (GH) to GnRH analogue treatment improves final height in girls with early or precocious puberty.Forty-six girls with early or precocious puberty (ageor =9.5 y) adopted from developing countries were randomized for treatment for 2-4 y with GnRH analogue, or with a combination of GH and GnRH analogue.During treatment, the mean growth velocity in the GH/GnRH analogue group was significantly higher compared to the control group. Combined GH/GnRH analogue treatment resulted in a higher final height: 158.9 cm compared to 155.8 cm in the GnRH analogue-treated group. Three out of 24 girls (13%) in the combined group and nine of the 22 girls (41%) treated with GnRH analogue alone attained a final height below -2 standard deviation scores (SDS).The difference between the two groups is statistically significant, and possibly of clinical importance. A future challenge is to identify a subgroup with clinically significant advantage of GH addition to GnRH analogue treatment. Being very short on arrival in Sweden and being short and young at start of treatment are possible indicators.

This paper reports results from an ongoing, randomized, multicentre national trial. The aim is to elucidate whether a dose of growth hormone (GH) of 0.2 IU/kg (0.07 mg/kg), given either as once-daily or twice-daily injections during puberty, is more effective than a once-daily dose of 0.1 IU/kg/day (0.03 mg/kg/day) in improving final height in children with GH deficiency (GHD). The twice-daily regimen comes closer to the spontaneous GH secretion pattern in puberty. Ninety-two children with GHD who had been receiving GH therapy for at least 1 year, and with spontaneous puberty or who were prepubertal and due to be started on replacement therapy to induce puberty, were randomly assigned to receive GH as follows: group A, 0.1 IU/kg/day (0.03 mg/kg/day), administered once daily; group B, 0.2 IU/kg/day (0.07 mg/kg/day), administered once daily; and group C, 0.2 IU/kg/day (0.07 mg/kg/day), divided into two equal injections given at 12-hour intervals. Pubertal height gain was 0.7, 0.7 and 1.3 SDS for groups A, B and C, respectively. The gain in height during puberty was thus most marked in group C. Mean final height, when corrected for parental height, was between 0 and 1 SDS in all treatment groups. All but seven children reached a final height within +/- 2 SD of the general population. There was a wide range of final heights in all three treatment groups. This variation in response suggests the need to individualize treatment in order to achieve an appropriate final height for most individuals.

We report a child with multiple target organ pseudohypoaldosteronism type 1 with frequent recurrent pulmonary infections caused by Pseudomonas aeruginosa and Pasteurella multocida and high levels of chloride in sweat, urine and nasal secretion. Repetitive faecal chymotrypsin samples have all shown pathological values in spite of no other sign of exocrine pancreas dysfunction. The similarities with cystic fibrosis and the importance of the salt content in bronchial fluid are discussed.

The aims of this study were to evaluate the efficacy and safety of different doses of growth hormone (GH) treatment in prepubertal short children born small-for-gestational-age (SGA). Forty-eight children born SGA from Sweden, Finland, Denmark and Norway were randomly allocated to three groups: a control group of 12 children received no treatment for 2 y, one group was treated with GH at 0.1 IU/kg/d (n=16), and one group was treated with GH at 0.2 IU/kg/d (n=20). In total 42 children completed 2 y of follow-up, and 24 children from the treated groups completed 3 y of treatment. Their mean (SD) age at the start of the study was 4.69 (1.61) y and their mean (SD) height was -3.16 (0.70) standard deviation scores (SDS). The children remained prepubertal during the course of the study. No catch-up growth was observed in the untreated group, but a clear dose-dependent growth response was found in the treated children. After the third year of treatment, the group receiving the higher dose of GH, achieved their target height. The major determinants of the growth response were the dose of GH used, the age at the start of treatment (the younger the child, the better the growth response) and the family-corrected individual height deficit (the higher the deficit, the better the growth response). Concentration of insulin-like growth factor-I (IGF-I) and IGF-binding protein-3 increased during treatment. An increase in insulin levels was found without negative effects on fasting glucose levels or glycosylated haemoglobin levels. GH treatment was well tolerated. In conclusion, short prepubertal children born SGA show a dose-dependent growth response to GH therapy, and their target height SDS can be achieved within 3 y of treatment given GH at 0.2 IU/kg/d. However, the long-term benefit of different regimens of GH treatment in children born SGA remains to be established.

The spontaneous growth process in Turner's syndrome is characterized by a progressive decline in height velocity during childhood and no pubertal growth spurt. Therefore, therapy aimed at improving height during childhood as well as increasing final height is desirable for most girls with Turner's syndrome. Forty-five girls with Turner's syndrome, 9-16 yr of age (mean age, 12.2 yr), were allocated to three study groups. Group 1 (n = 13) was initially treated with oxandrolone alone; after 1 yr of treatment, GH without (group 1a; n = 6) or with (group 1b; n = 7) ethinyl estradiol was added. Group 2 (n = 17) was treated with GH plus oxandrolone. Group 3 (n = 15) was treated with GH, oxandrolone, and ethinyl estradiol. The dosage were: GH, 0.1 IU/kg.day; oxandrolone, 0.05 mg/kg.day; and ethinyl estradiol, 100 ng/kg.day. A height of 150 cm or more was achieved in 61%, 75%, and 60% of the girls in groups 1, 2, and 3, respectively. The most impressive increase in height was seen in group 2. In this group the mean final height was 154.2 cm (SD = 6.6), which is equivalent to a mean net gain of 8.5 cm (SD = 4.6) over the projected final height. In group 3, in which ethinyl estradiol was included from the start of therapy, the initially good height velocity decelerated after 1-2 yr of treatment. Their mean final height was 151.1 (SD = 4.6) cm, equivalent to a mean net gain of 3.0 cm (SD = 3.8). A similar growth-decelerating effect of ethinyl estradiol was seen in group 1b. We conclude that in girls with Turner's syndrome who are older than 9 yr of age, treatment with GH in combination with oxandrolone results in significant growth acceleration, imitating that in normal puberty, leading to a more favorable height during childhood. This mode of treatment also results in a significantly increased final height, permitting a great number of the girls to attain a final height of more than 150 cm. However, early addition of estrogen decelerates the height velocity and reduces the gain in height.

In a retrospective study of 36 children aged 3-16 years, undergoing 'radical' surgery for craniopharyngioma, postoperative radiography showed tumour excision to have been complete in 25 cases and partial in 11 cases. The recurrence rate was 40% among those treated with surgery alone (N = 27), whereas there were no recurrences among those given adjunctive radiotherapy (RT) (N = 9). Although surgery in the hypothalamic region carries a high risk of severe lasting sequelae, long-term follow-up (mean duration 15 years) showed no difference in this respect between the RT and non-RT subgroups. Until large, preferably international, prospective studies may resolve the lack of consensus regarding the optimal treatment of craniopharyngioma, the authors advocate a more individualised approach, the choice between different treatment modalities and combinations being based on tumour size, location and structure.

Craniopharyngiomas are situated in immediate vicinity of sleep regulating structures in the basal forebrain area, and the tumor and its treatment might influence the regulation of sleep and wakefulness. In 10 patients treated for craniopharyngioma nighttime sleep quality and daytime vigilance were examined with polygraphic sleep records and multiple sleep latency tests (MSLT). Two girls and 8 boys, 7.1-22.9 years of age, were studied after a follow-up time of 1.5-16.1 years postoperatively. The results were compared to those of 18 normal children. The regulation of the ultradian sleep rhythm was normal but the ability to maintain nighttime sleep was severely disturbed. The patients had an increased number of awakenings and spent long time awake during two recorded nights. Two patients had excessive daytime somnolence during this examination, one after severe sleep disturbance, the other without any known cause. The pattern of sleep and vigilance did not change in puberty in the expected fashion. The disturbances may well have an impact on the psychosocial situation of the patients.

The blood concentrations of lidocaine and its main active metabolites, methylethylglycinexylidide (MEGX) and glycinexylidide (GX), were measured in 24 newborn infants during anticonvulsive treatment with an iv infusion of lidocaine. After a bolus dose of 1.5-2.2 mg/kg and continuous infusion of lidocaine (4.7-6.3 mg/kg/h) there was accumulation of the drug and MEGX within 24 h. After termination of the iv infusion, both lidocaine and the metabolites were eliminated within 24-48 h. The anticonvulsive effectiveness--estimated by clinical observation and continuous amplitude integrated EEG monitoring (cerebral function monitor)--was immediate in 15 infants (nine term and six preterm). There was no correlation between blood concentrations of lidocaine and metabolites, and anticonvulsive effect (i.e. good, intermediate or no response). No differences in blood concentrations were found between full-term and preterm babies, or between infants with or without birth asphyxia. In combination with a fast withdrawal of the drug, few adverse reactions were seen with the dosages used, even though blood concentrations were high. Routine measurements of lidocaine concentrations during anticonvulsive treatment in neonates seem to be of little clinical value. For evaluation of the anticonvulsive effect and for early detection of seizure activity during lidocaine withdrawal, continuous EEG monitoring is preferable.

VERY TALL CHILDREN HAVE SIMILAR 24-H-CH LEVELS AS SHORT CHILDREN BUT HIGHER CIRCULATING INSULIN AND LESS IGFBP-1

The influence of extra phosphorus (P) and calcium (Ca) on the incidence of rickets was studied in 40 infants with a birthweight below 1.5 kg. All were fed breastmilk and all received vitamin D 1200 IU/day. Half of the infants were supplemented with P 20 mg/kg/day and Ca 30 mg/kg/day. Rickets, diagnosed with X-ray at 5 to 7 weeks of age, developed in 12 infants, 11 of whom weighed below 1.0 kg. In infants below 1.0 kg rickets was significantly more common in the group not receiving extra P and Ca. After diagnosis all were substituted and radiographic healing occurred in all. Serum Ca concentrations were normal in both groups whereas serum P was significantly lower in non-supplemented patients. Serum alkaline phosphatases (ALP) were normal in all patients at the time of diagnosis demonstrating the risk of using ALP as a diagnostic test for rickets in very low birthweight.

The effect of 6-propylthiouracil (PTU) on the peripheral conversion of thyroxine (T4) to 3,5,3′-triiodothyronine (T3) and 3,3′,5′-triiodothyronine (reverse T3, rT3) was investigated by assessments of the concentrations of T4, T3, and rT3 in peripheral venous blood from T4-treated healthy volunteers given PTU, 4 × 150 mg daily. Within on day of PTU administration, serum T3 concentrations were reduced, and those of rT3 enhanced. These deviations lasted as long as PTU was given (five days), and there was a rapid return towards normal within one day after PTU administration ceased. It seems probable that, in man, PTU can evoke a diversion of T4 monodeiodination, less being converted to the metabolically active T3 and more to the metabolically inactive rT3. It is possible that the rapidity whereby PTU can reduce T3 levels can offer an advantage in the treatment of hyperthyroidism.

Growth, weight gain, and human growth hormone secretion were studied for 3 to 7 years in 27 children with acute leukemia in complete continuous remission. Growth and weight gain were matched for sex and age by calculating the standard deviation score. The mean SD score for height velocity was subnormal during the three years of therapy. A catch up in growth and weight gain occurred during the first year after the cessation of therapy. The loss of final attained height was small. HGH secretion was studied at the end of therapy and at yearly intervals thereafter by two provocative tests; glucagon and sleep. No significant difference in secretion was seen between the group studied and a control group of children. Acute leukemia, children, growth, growth hormone, irradiation, weight gain.

The secretion of iodothyronines from the normal human thyroid gland was assessed by radioimmunoassay analyses of the concentrations of thyroxine (T4), 3,5,3′-triiodothyronine (T3) and 3,3′,5′-triiodothyronine (reverse T3, rT3) in thyroid venous and peripheral venous blood. The subjects studied were euthyroid patients undergoing parathyroid surgery. Measurements were carried out both under apparently normal conditions, following peroral T3 pre-treatment, and before and after acute administration of TSH into a thyroid artery. In the control subjects, significant gradients between thyroid venous and peripheral venous concentrations were recorded both for T4, T3 and rT3, suggesting that all three iodothyronines are secreted by the normal human thyroid. T3 pre-treatment seemed to reduce this secretion, and acute administration of TSH promoted rapid, marked, and concomitant increments in the thyroid venous concentrations of all three iodothyronines. Hence, it appears that not only T4 but also T3 and rT3 are secreted by the normal human thyroid gland, and that TSH stimulates the secretion of all three iodothyronines. On the other hand, calculations of the relative secretion rates yielded the relation T4:T3:rT3 as 85:9:1. This indicates that, in euthyroid subjects, most of T3, and almost all of rT3, is produced by extrathyroidal conversion of T4 and not by direct thyroidal secretion.

Fluorescence histochemistry was used to study the sympathetic innervation of the thyroids from adult individuals of six different species; mouse, rat, hamster, dog, sheep, and pig. In addition, thyroids from very young rats and from very old mice were examined. Generally, thyroidal sympathetic, adrenergic nerve terminals were found not only as a network around vessels, but also as single terminals between, and sometimes around, follicles. Interfollicular terminals were numerous in thethyroids of adult mice, sheep and hamsters, but they were few in the thyroids of adult rats and dogs, and even fewer in the porcine thyroid. In contrast to the findings in thyroids from adult mice and rats, several interfollicular terminals were found in thyroids from very young rats while very few such terminals were detected in the thyroids from very old mice. The observations suggest that there is a pronounced interspecies variation in the number of thyroidal interfollicular sympathetic nerve terminals and that, at least in the rat and the mouse, there is also a variation with age. Since, in mice, sympathetic activation appears to induce thyroid hormone secretion by a direct action of norepinephrine released from intrathyroidal sympathetic fibers, the recorded variations are presumed to have functional importance.

The significance of the sympathetic nervous system in the secretion and metabolism of thyroid hormone in the mouse was studied by a combination of electron microscopic autoradiography, fluorescence histochemistry, light microscopy, and bioassay. In order to eliminate the influence of TSH, the secretion of this hormone was abolished by exogenous thyroxine. Sympathetic, norepinephrine (NE)-containing nerve terminals were present in a network around thyroid vessels and as single terminals close to thyroid follicles. Within 2 h after administration, 6-hydroxydopamine (6-OH-DA, 200 mg/kg iv) evoked a depletion of NE from thyroidal as well as from other sympathetic nerve terminals. Subsequently, 6-OH-DA caused a destruction of the terminals, demonstrable within 24 h. Administration of dopamine (DA) in the same dosage did not visibly affect the sympathetic nerve terminals. In animals, part of whose endogenous thyroid hormone had been labeled by 125I pretreatment, injection of 6-OH-DA or DA promoted the formation...

The sympathetic innervation of the normal human thyroid was investigated by a combination of fluorescence histochemistry and electron microscopic autoradiography. Sympathetic, adrenergic nerve fibers were numerous in the human thyroid, and they were mainly found in two locations: in relation to vessels, and in interfollicular spaces. The terminals of the vascular nerves were located very close to smooth muscle cells in the vessel wall, and the interfollicular nerve terminals had a similarly close relation to follicle cells; only the respective basement membranes intervened. It is concluded that, in man, there is a morphological basis for an influence of the sympathetic nervous system not only on thyroid vessels but also directly on thyroid follicle cells.

The anticonvulsive effect of lidocaine was evaluated in 46 newborn infants with severe, recurrent seizures. Before the lidocaine all infants were being given phenobarbital, and 22 infants were also treated with diazepam. Different dosages of lidocaine were tested. A loading dose of 2 mg/kg followed by i.v. infusion of 6 mg/kg/hour was the most effective dosage and had an immediate anticonvulsive effect in 18 of 25 infants; within 30 min the same effect was attained in another five of the infants, with an overall seizure control in 92% of the sample population. During the lidocaine treatment cerebral electrical activity was followed continuously with a cerebral function monitor (CFM), which also enabled evaluation of the treatment. No serious side effects on blood-pressure, heart-rate or cerebral electrical activity were registered. For newborn infants with severe recurrent seizures not responding to other drugs, lidocaine is an effective additional mode of treatment.

Seven paediatric patients with central diabetes insipidus were studied in an open dose ranging study in hospital followed by a six month study on an outpatient basis to assess the efficacy and safety of peroral administration of DDAVP (desmopressin) tablets. In the dose ranging study a dose dependent antidiuretic response was observed. The response to 12.5-50 mcg was, however, less effective in correcting baseline polyuria than were doses of 100 mcg and above. Patients were discharged from hospital on a preliminary dosage regimen ranging from 100 to 400 mcg three times daily. After an initial adjustment in dosage in three patients at one week follow up, all patients were stabilised on treatment with tablets and reported an adequate water turnover at six months. As with the intranasal route of administration dosage requirements varied from patient to patient, and a dose range rather than standard doses were required. A significant correlation, however, was found for the relation between previous intranasal and present oral daily dosage. No adverse reactions were reported. No clinically significant changes were noted in blood chemistry and urinalysis. All patients expressed a preference for the oral over existing intranasal treatment. Treatment with tablets offers a beneficial alternative to the intranasal route, particularly in patients with chronic rhinitis or impaired vision.

The possible significance of thyroid mast cells in the regulation of thyroid blood flow and capillary permeability was investigated in rats whose TSH secretion had been eliminated by exogenous T4. Mast cells were identified by their abundance of metachromatic granules, and their content of histamine and 5-hydroxytryptamine (5-HT) was examined by fluorescence histochemistry. Thyroid histamine levels were determined by fluorometry. The tissue uptake of 86Rb was used as an indicator of blood flow and permeability. Numerous histamine- and 5-HT-containing mast cells were found within the thyroid and in connective tissue adjacent to the thyroid, whereas juxtathyroidal muscle tissue was virtually devoid of mast cells. Administration of compound 48/80 evoked a prompt depletion of 5-HT, histamine and metachromatic granules from thyroid mast cells, and a concomitant increase in the thyroidal uptake of 86Rb. The 86Rb uptake by juxtathyroidal muscle tissue was unaffected. Exogenous 5-HT and histamine both induced prompt increments in thyroidal 86Rb uptake, and 5-HT also stimulated 86Rb uptake in juxtathyroidal muscle tissue. TSH, previously shown to induce a gradual amine release from mast cells within, but not outside, the thyroid, evoked a gradual increase in thyroidal, but not in muscular, uptake of 86Rb. The findings support the concept that, in the rat, histamine and/or 5-HT, released from intrathyroidal mast cells by TSH, stimulate thyroid blood flow and/or permeability.

Ten days of total energy deprivation evoked the following endocrine changes in 12 healthy, normal-weight males: early and marked reductions and increments in the blood levels of T3 and reverse T3, respectively, with rapid returns to pre-starvation levels after refeeding; a slight and late decrease in the blood levels of T4; a minute reduction of the blood levels of TSH; a pronounced increase in the blood levels of growth hormone, but a return towards pre-exposure levels even before discontinuation of starving; a minor and gradual enhancement of the blood levels of cortisol, and an increase in nocturnal urinary adrenaline excretion. It is assumed that these changes reflect a complex regulatory mechanism, the purpose of which is to secure adequate energy supply to vital organs.

The effect of 6-propylthiouracil (PTU) on the peripheral conversion of thyroxine (T4) to 3,5,3'-triiodothyronine (T3) and 3,3',5'-triiodothyronine (reverse T3 rT3) was investigated by assessments of the concentrations of T4 T3 and rT3 in peripheral venous blood from T4-treated healthy volunteers given PTU, 4 X 150 mg daily. Within on day of PTU administration, serum T3 concentrations were reduced, and those of rT3 enhanced. These deviations lasted as long as PTU was given (five days), and there was a rapid return towards normal within one day after PTU administration ceased. It seems probable that, in man, PTU can evoke a diversion of T4 monodeiodination, less being converted to the metabolically active T3 and more to the metabolically inactive rT3. It is ppossible that the rapidity whereby PTU can reduce T3 levels can offer an advantage in the treatment of hyperthyroidism.

A new basis for the understanding of respiratory insufficiency of the premature infant was established when Avery and Mead [1] showed that the hyaline membrane disease, HMD, also called idiopathic respiratory distress syndrome, IRDS, was associated with surfactant deficiency of the alveolar air liquid interface. Particularly in the early seventies therapeutic progress was marked. However, new obstacles to further progress called for a deeper understanding of the pathophysiology behind respiratory insufficiency of the premature infant. The purpose of this paper is to illustrate some aspects of the physiological background to the respiratory distress syndrome in neonates and in older subjects and its treatment by respiratory therapy.

Sixteen children (10 boys, 6 girls) on treatment for some years with i.m. injections twice or thrice weekly of human growth hormone (hGH; Crescormon Kabi Vitrum), participated in a prospective study. The weekly amount of hGH (8, 12, or 16 IU) was kept the same in each child, but divided into daily (7) s.c. injections at bedtime. The growth rate increased in all children during the first year on s.c. daily hGH (5.3 to 7.4 cm/year; 1.95 to 4.27 SDS). This increased growth rate did not persist during the second year on daily s.c. hGH, but an increased growth rate did not persist during the second year on daily s.c. hGH, but an increased predicted final height was found. The plasma profile of hGH was followed: i.m. injected hGH gave mostly a high (200 mU/l) plasma level of some hours (wide intra- and interpatient variation), and s.c. injected hGH a lower max level of longer duration (wide inter patient variation). The daily s.c. regimen of hGH was extremely well accepted by the children and their parents and no GH-antibodies or other adverse effects were found. We recommend daily s.c. injection of hGH as an alternative in the treatment of GH-deficient children.

In man, as well as in the mouse, there is morphologic and functional evidence for a direct, stimulatory influence of the sympathetic nervous system on the secretion of thyroid hormone by noradrenaline (NA), released from interfollicular adrenergic nerve terminals. In mice and rats, an age-related reduction of the sympathetic innervation of the thyoid has recently been observed. In the present study, possible age-related variations of the sympathetic innervation and the concentration of NA in human thyroid tissue were examined. Interfollicular adrenergic nerve terminals were studied by fluorescence histochemistry, and the tissue concentration of NA was measured by fluorometry. In apparently normal thyroid tissue, obtained from fetuses, young (20-45), and elderly (greater than 60) euthyroid people with thyroid cancer or hyperparathyroidism, the number of interfollicular adrenergic nerve terminals appeared to be reduced with increasing age, and the thyroid tissue concentration of NA was significantly lower in elderly than in young people. These findings may have functional importance.

The effect of somatostatin on thyroid hormone secretion stimulated by TSH in man was studied. The injection of TSH into a thyroid artery during surgery was followed by an increase in the serum concentration of iodothyronines in the corresponding thyroid vein. This increase was significantly lower (p less than 0.02) when somatostatin was given as a bolus injection into a peripheral vein 5 min prior to the administration of TSH, and followed by a continuous infusion for 60 min. Since somatostatin-like immunoreactivity has been localized to some cells of the thyroid gland being in a parafollicular location, it is suggested that somatostatin may be an intrathyroidal regulator of thyroid activity in man.

The influence on thyroid hormone secretion of the nonselective beta-adrenergic stimulant isoproterenol (IPNE), of a selective betar adrenergic stimulant, l-isopropylamino-3-(2-thiazoloxy)- 2-propanol (ITP), and of a selective beta2- adrenergic stimulant, terbutaline, was investigated in mice. A combination of light microscopy (colloid droplet formation) and bioassay (blood radioiodine— BRI—measurements) was used. IPNE and terbutaline induced formation of colloid droplets and increased BRI levels, whereas ITP was ineffective. The responses to IPNE and terbutaline were abolished or reduced by p etreatment with L-propranolol, but were not inhibited by pretreatment with D-propranolol or phentolamine. The results indicate that secretion of thyroid hormone can be induced through the mediation of beta2- adrenergic receptors. (Endocrinology 97: 332, 1975)

The recent discovery of somatostatin-containing cells within the thyroid gland infers that somatostatin may influence thyroid activity. This possibility was investigated by measurements of radio-iodine release in mice pre-treated with 125I and T4. The animals were treated with TSH, isoprenaline or dibutyryl-cyclic AMP with and without concomitant injection of somatostatin. It was found that somatostatin reduced the blood 125I increase in response to each of the three thyroid-stimulating agents. The elimination rates of 125I-labelled T4 and T3 were unaffected by somatostatin. The observations suggests that somatostatin may participate in the regulation of thyroid hormone secretion, by an inhibitory effect exerted within the thyroid gland.

Previous in vivo studies in mice have shown that polyphloretin phosphate (PPP), a polyionic polyester of phosphoric acid and the dihydrochalcone phloretin, can inhibit thyroid hormone secretion induced by TSH and by the long-acting thyroid stimulator of Graves' disease (LATS), but not that induced by catecholamines or 5-hydroxytryptamine (5-HT). The present study was undertaken to explore further the mechanism of this effect, particularly the possibility that PPP interferes with the synthesis of endogenous prostaglandins (PG). Therefore, the effects of PPP and some of its subfractions and congeners were compared with those of indomethacin, a known inhibitor of PG synthesis, with respect to their influence on the blood radioiodine (BRI) increase in response to TSH, 5-HT, and isoprenaline (IPNE) in 125I- and T4-pre-treated mice. When given alone, neither indomethacin nor PPP or its subfractions reduced the BRI levels. Instead, small increments were seen in occasional experiments. Indomethacin did not inhibit the BRI increase in response to any of the thyroid-stimulating agents, but rather enhanced the responses in occasional experiments. PPP and some of its high-molecular weight subfractions reduced the BRI increases in response to TSH but not those to 5-HT or IPNE. The findings do not support the concept that de novo synthetized PG mediates TSH activation of thyroid hormone secretion, but they favour the view that PPP inhibits the action of TSH at its receptor site.

Pubertal growth was studied in 10 girls previously treated for acute lymphoblastic leukemia. The average age at menarche was 12.2 years, which is significantly lower (p less than 0.01) than the expected 13.1 years. Compared with normal girls, these girls showed a subnormal (p less than 0.05) peak height velocity during the second year before menarche. The remaining growth before menarche as well as the total postmenarchal growth was close to the normal average. The average final standing height was 1 SD less than what would be expected from their height 1 year after the cessation of therapy. A relative growth hormone deficiency in combination with early onset of puberty could account for this loss in final height.

The spontaneous secretion of growth hormone during a 24 hour period and the response of growth hormone to growth hormone releasing hormone was studied in 13 girls who had received treatment for acute lymphoblastic leukemia that included cranial irradiation with 20-24 Gy in 12-14 fractions. At the time of investigation the girls were at varying stages of puberty and had normal concentrations of thyroid hormones. The mean interval between the end of treatment and investigation was 4.6 years. The mean age at onset of the disease was 3.2 years and at investigation 10.7 years. The average attained height equalled -0.3 SD at onset, and -1.0 SD at the time of investigation. Secretion of growth hormone was substantially reduced compared with controls and did not increase during puberty. A prompt rise in growth hormone secretion was seen after injection of growth hormone releasing hormone, but the mean maximum growth hormone concentration was, however, only 25 mU/l. There was no correlation between the 24 hour secretion and growth hormone response to growth hormone releasing hormone, or the time since irradiation. These results confirm earlier work that suggested that girls who had received treatment for acute lymphoblastic leukaemia, that included cranial irradiation, have a comparative growth hormone insufficiency characterised by normal prepubertal growth and slow growth during puberty because of an inability to respond to the increased demands for growth hormone at that time.

A total of 23 previously untreated and 28 previously treated GH deficient children were included for at least 12 months in a trial of recombinant somatropin, 0.1 IU/kg/day given by subcutaneous injection. All the children increased their height velocity over the pretreatment values, to nearly 11 cm/year, corresponding to a significant increase in height of 1 SD score for chronological age. The increase in height SD score for bone age was also statistically significant. No adverse effects were recorded, though one child experienced local itching and redness at the injection site which did not recur after a short cessation of therapy. One child developed detectable antibodies to recombinant somatropin, but the binding capacity was low and no clinical symptoms or growth attenuation occurred. Recombinant somatropin was shown to be safe and effective during the first year of therapy in children with GH deficiency.

The serum levels of 3,5,3'-triiodothyronine (T3) and thyroxine (T4) in children, adolescents, adults, and elderly subjects have been measured by radioimmunoassays. It was found that while the T4 levels were essentially equal in all age groups examined, the T3 levels were markedly different. In children and adolescents (1-15 years), high values were recorded; indeed, they exceeded the upper normal limit in adults (20-80 years). From the age of 20, the T3 levels remained unaltered until the age of 80, after which there was a further reduction, to values approaching the lower normal limit for T3 in middle-aged subjects. The findings emphasize that separate normal values must be established for different age groups, in order to avoid diagnostic misinterpretations and therapeutic failures.

The changes in the plasma or serum concentration of thyrotrophin (TSH), thyroxine (T4), 3,5,3'-triiodothyronine (T3), 3,3',5-triiodothyronine (reverse T3, rT3) and cortisol were examined in patients undergoing elective cholecystectomy (n = 10) or acute laparotomy due to peritonitis (n = 11). TSH and T4 showed no essential changes in either group. T3 was reduced already during initiation of anaesthesia and continued to fall during and after surgery in both groups. In the peritonitis group, T3 was reduced already before medical intervention. rT3 displayed changes opposite to those of T3. An increase in cortisol peceded the changes in T3 and rT3 in both groups. T3 and rT3 returned towards normal levels when the patients recovered and resumed oral nutrition. It seems likely that both elective and acute uncomplicated surgery is accompanied by a transient reduction in the extrathyroidal production of the most active hormone, T3, and by a reciprocal increase in the levels of the virtually inactive rT3. The underlying mechanism behind this metabolic adaptation is unclear but may be related to adrenocortical activation and/or to changes in the mode of nutrition.

The identity and distribution of amines in the calf thyroid was investigated by histochemistry and cytospectrofluorometry, and the possible significance of these amines in the synthesis of thyroid hormone was assessed by testing their influence on the uptake and organifkation of iodine in calf thyroid cells, dispersed by continuous-flow trypsinization. The calf thyroid was found to contain four different amine-storing cell systems: 1. Norepinephrine (NE) was present in sympathetic nerve fibres that were located both as a network around vessels and as single fibres running close to the follicles. 2. Dopamine (DA) and histamine (Hi) were demonstrated in mast cells that were numerous and occurred both in perifollicular and perivascular spaces. 3. DA was also found in parafollicular cells (C cells), which were relatively few. 4. Numerous acetylcholine-(ACh)-containing nerve fibres were seen around vessels and between follicles. Histochemical examinations of smears of thyroid cell suspensions revealed that, ap...