10 years of successful treatment with dextrothyroxine in a girl with TSH-induced hyperthyroidism.

14 years ago, a 5.7-year-old healthy girl was treated with desiccated thyroid for a goiter and elevated TSH levels. The goiter disappeared and TSH levels were normalized. However, hyperthyroidism appeared. Without therapy, the goiter reappeared and hyperthyroidism aggravated. Based on hormone values, TSH-induced hyperthyroidism was diagnosed. After exclusion of neoplastic TSH secretion, treatment with dextrothyroxine (DT4) was initiated at age of 10 years and continued during the last 10 years (except for short periods). The girl became euthyroid, has no goiter and normal TSH values. Since thyrotrophs and peripheral tissues are probably normally sensitive to T4, we postulate that her hypothalamopituitary-thyroid control is operating on a higher set point level for T4.

A physiological mode of puberty induction in hypogonadal girls by low dose transdermal 17 beta-oestradiol.

Transdermal 17 beta-oestradiol administration (17 beta-E2), used mainly in menopausal women, allows a continuous 17 beta-E2 delivery through the skin into the systemic circulation, avoiding intestinal and hepatic passage. In order to explore whether transdermal 17 beta-E2 could be used for the induction of puberty, 17 beta-E2 patches with low dose delivery were administered in nine prepubertal girls with Turner syndrome (bone age greater than 10.5 years) for a mean period of 2.2 years. Treatment schedule: 5 micrograms/day for 6-9 months, 10 micrograms/day for 6-9 months, 25 micrograms/day for long-term substitution; addition of cyclic gestagen p.o. after 18-24 months. Breast development started within 3 months of therapy and menstruation occurred after 2 years. Growth rate increased from 3.2 to 5.0 cm/year during the 1st year of therapy, height prediction did not change. Serum oestradiol (E2) and urinary E2 conjugates increased proportionally with 17 beta-E2 doses, serum oestrone (E1) rose much less. The possibility to imitate time course, clinical events and hormonal changes of normal puberty, the absence of adverse drug reactions and the excellent acceptance and easy mode of application suggest that transdermal 17 beta-E2 is optimally suited for hormonal substitution in girls with hypogonadism.

Discordant immune and growth response to pituitary and biosynthetic growth hormone in siblings with isolated growth hormone deficiency type IA.

Two brothers with familial isolated growth hormone deficiency type IA homozygous for the same 6.7 kb deletion on chromosome 17 including the growth hormone gene were intermittently treated with various forms of hGH for more than 7 years. While the elder brother (Patient 1) showed a good growth response to pituitary hGH, the younger one (Patient 2) developed high titre growth blocking hGH antibodies early in the course of treatment and grew only 2.2-3.9 cm/year on a hGH dose of 12-26 IU/m2 per week. When the younger brother was changed to a higher dose (33 IU/m2 per week) of biosynthetic methionyl hGH he had striking catch-up growth and he has subsequently maintained a height velocity of 10.0 cm/year for the last 2 years. During this time his antibody titres have decreased over 1000-fold. These findings demonstrate that therapy with biosynthetic methionyl hGH may provide an effective form of treatment for subjects with isolated growth hormone deficiency type IA who do not grow in response to native hGH, and imply that biosynthetic methionyl hGH may be less antigenic than pituitary derived hGH.

[Developmental quotient/intelligence quotient (DQ/IQ) in children with congenital hypothyroidism]. / Cociente de desarrollo (CD)/cociente intelectual (CI) en niños con hipotiroidismo congénito.

The aim of neonatal thyroid screening is prevention of mental retardation by early diagnosis and early institution of thyroid replacement therapy. With relatively simple and inexpensive means it should be possible to shift the distribution curve of developmental and intelligence quotients as it was found in hypothyroid patients before the screening towards that one of healthy children. The results of our collaborative study show that we are approaching this aim. However, this study also demonstrates, that risk factors and associated findings may have a considerable influence on mental development and therefore should not be neglected in such an investigation. In response to our inquiry of 1985 we received detailed data on mental outcome of nearly 1,000 individual patients with CH representing not less than 14% of all children with CH detected in Europe since the introduction of neonatal thyroid screening. This shows that in many screening centers, a large number of children have not only been diagnosed and treated, but also followed carefully with respect to their development.

[Mental development in congenital hypothyroidism. Results of a survey in 14 European countries]. / Geistige Entwicklung bei angeborener Hypothyreose. Ergebnisse einer Umfrage in 14 europäischen Ländern.

Although newborn screening for congenital hypothyroidism was introduced into Europe as late as 1975, its high acceptance rate has quickly led to its wide use in most European countries. One would expect early diagnosis with early onset of treatment to result in normalization of previously impaired mental development. One may conclude from results obtained in 790 children up to the age of seven years that normal mental development is assured if levothyroxine is administered within the first four weeks of life. This also applies to children with athyroidism: their mental development is not different from that of children with an ectopic thyroid.

The ulnar-mammary syndrome: an autosomal dominant pleiotropic gene.

A family is described in which four male patients spanning three generations present a consistent clinical entity, the major features of which include: ulnar finger and fibular toe ray defects; delayed growth and onset of puberty, obesity, hypogenitalism and diminished sexual activity; hypoplasia of nipples and apocrine glands with subsequently diminished ability to perspire. Additional findings in single cases include pyloric, anal and subglottic stenosis. To date, another 12 patients in three families have been described with this syndrome. The condition appears to be inherited as an autosomal dominant trait with full penetrance and highly variable expression.

Lack of bromocriptine-induced reduction of predicted height in tall adolescents.

Fifteen girls and five boys with excessive predicted adult height (chronological age, 10.1-14.6 yr; bone age, 11.0-14.0 yr) were treated with bromocriptine (two doses; 2.5 mg/day) to reduce their final height. After a mean treatment period of 1.14 yr (range, 0.6-1.75 yr) we did not find a reduction of predicted adult height [difference, -0.5 +/- 3.5 (+/- SD) cm according to Bayley and Pinneau's tables (P = NS) and +0.2 +/- 2.5 (+/- SD) cm according to the method of Tanner (P = NS)]. Mean peak plasma GH concentrations after TRH administration before and during bromocriptine were 51.5 +/- 49.4 and 58.5 +/- 50.7 mU/L, respectively. The wide range of the GH values may be explained by physiological variation in this age group. After ingestion of 2.5 mg bromocriptine a significant increase in plasma GH occurred within 3 h in six adolescents tested. Our results do not support the concept that bromocriptine may reduce predicted adult height in tall adolescents by decreased GH secretion or acceleration of skeletal maturation.

Thyrotropin enzyme-immunoassay in dried blood spots: a spectrophotometric method for neonatal thyroid screening.

We describe an enzyme-immunoassay with photometric endpoint determination, suitable for the measurement of thyrotropin (TSH) in dried blood spotted on filter paper. Using reagents of a commercially available test kit provided for the measurement of thyrotropin in 200 microliter serum, we have adapted the method to the determination of thyrotropin in blood spots containing ca. 10 microliter blood. This was achieved by prolongation of the assay time from 3 to 20 hours, and by increasing the amount of enzyme-antibody complex. Precision and sensitivity of the blood spot assay are comparable to those of our in-house thyrotropin RIA, and the RIA/EIA correlation coefficient is 0.987 (n = 150). The advantages of EIA are the simplicity of the photometric end point determination (although strict time control has to be observed in order to avoid drifts in results), the long stability of reagents, and the non-isotopic label. The method therefore appears to be a suitable alternative to thyrotropin RIA for the determination of thyrotropin in neonatal thyroid screening.

Sixty children with congenital hypothyroidism detected by neonatal thyroid: mental development at 1, 4, and 7 years: a longitudinal study.

A prospective study of mental development has been carried out in 60 unselected children with congenital hypothyroidism (C.H.) detected between 1976 and February 1985. Treatment with 1-thyroxin was initiated at the age of 10.4 +/- 2.5 days and supervised by T4 and TSH monitoring in 3-6 monthly intervals. Although clinical signs were mild or missing, skeletal maturation was prenatal in more than half. Developmental testing was carried out at 1, 4 and 7 years by the Brunet-Lezine (n = 60), the non-verbal Snijders-Oomen (n = 40), and the german version of the Wechsler intelligence test (n = 20), respectively. The global DQ/IQ in all but a few children at each age group are within the 3rd and 97th percentile of the DQ/IQ distribution in a control group tested during the same period of time. The mean values of all global and subscores, however, are lower than that one in the control group, differences being highly significant at 1 year. In 21 of our 60 children, associated findings and/or risk factors were present. The DQ/IQ in children without risk factors are identical to that of the control group. There are no significant DQ/IQ differences neither between athyroidism and ectopic thyroid glands, nor between prenatal bone age and normal skeletal maturation at diagnosis. We assume that the favourable results in our children with C.H. may be ascribed to the early onset of thyroid hormone replacement and the strictly controlled compliance.

Comparison of growth hormone binding and metabolic response in rat adipocytes of epididymal, subcutaneous, and retroperitoneal origin.

We undertook a comparison of human growth hormone (hGH) binding and metabolic responses in rat adipocytes of epididymal, subcutaneous, and retroperitoneal origin to determine whether the site of fat depot biopsy might affect the response to hGH stimulation. The results showed highest specific binding in epididymal (3.6%), followed by subcutaneous (2.3%) and retroperitoneal adipocytes (1.5%); half-maximal binding was achieved at 14-18 ng/ml hGH for the three sites. Scatchard analysis of the binding data from each site was linear; there was no significant difference in binding affinities (2.1 to 3.3 X 10(9), M-1), but the number of binding sites was statistically higher in epididymal (9.8 X 10(3) as compared to subcutaneous (7.5 X 10(3), P less than 0.05) and retroperitoneal cells (3.3 X 10(3), P less than 0.01). Stimulation with 5 to 2500 ng pituitary hGH produced a dose-related increase in glucose incorporation, with the largest increase in epididymal fat cells (31%, P less than 0.05) followed by subcutaneous cells (18%, P less than 0.05); no significant increase was seen with retroperitoneal cells. Biosynthetic hGH produced a similar pattern of glucose incorporation in the three sites. Addition of hGH antibodies blocked the glucose incorporation in epididymal adipocytes using both pituitary-derived and biosynthetic hGH. It seems clear that this insulin-like effect is caused by hGH, not an insulin-like impurity. We conclude that the number of binding sites, perhaps related to adipose cell size, differs in adipose tissue from different locations and this influences the metabolic response to hGH stimulation.

Head circumference, height, bone age and weight in 103 children with congenital hypothyroidism before and during thyroid hormone replacement.

Head circumference, height, bone age and weight were studied in 103 children with congenital hypothyroidism before and up to 8 years of thyroid replacement therapy. The patients were divided into 4 groups according to the age at start of treatment: group I (diagnosed by neonatal screening): less than 2 weeks (n = 55); group II: 1-3 months (n = 7); group III: 4-12 months (n = 15); group IV: greater than 1 year of age (n = 26). Before treatment, group I showed a head circumference significantly larger than normal and a delay in bone maturation in the presence of normal length and weight. In the other groups length as well as bone age were significantly lower than normal, head circumference, in contrast, was normal (groups II and III) or even increased (group IV). During therapy, head circumference and bone age of group I became normal as were length and weight from the beginning. In the other groups, therapy led to a further increase of head size resulting in a mean head circumference significantly larger than normal during 8 years of observation in group IV. There was a catch-up of height, bone age and weight in groups II, III and IV; mean height of late treated children (group IV), however, remained significantly lower than normal even after 8 years of therapy. - Our study shows that congenital hypothyroidism is associated with increased head circumference, either absolutely or in relation to stature. Thyroid hormone therapy resulted in a normalization of head growth when treatment was initiated early, and in a further increase when treatment was started late. There was a catch-up of height, bone age and weight; complete normalization, however, occurred only in those children treated before one year of age.

Effect of venous drainage to the vena cava and denervation on endocrine function of pancreatic segments in dogs.

IVGTTs and OGTTs (0.5 g/kg glucose) were performed in 36 normal dogs (group N) and one to two weeks postoperatively in 22 dogs after partial pancreatectomy [( ppx ] group I); nine dogs after ppx and pancreatic venous drainage to the inferior vena cava (group II); nine dogs after ppx and pancreatic denervation (group III); and in seven dogs after ppx , venous drainage to the vena cava, and denervation (group IV). Fasting glucose and insulin were in the same range in all dogs. In IVGTT peak insulin levels were diminished by ppx , but total insulin secretion was similar in all dogs. Systemic venous drainage and denervation had no effect on glucose tolerance, peak insulin, and total amount of insulin appearing in the peripheral circulation. In groups II and IV, there was a linear correlation between individual K values and the area under the insulin curve, whereas there was no such correlation in groups I and III. In OGTTs , glucose tolerance and the total amount of insulin were equal in groups I through IV but diminished compared to group N. Venous transposition resulted in an early increase of insulin secretion and a late insulin peak. Thus, glucose load and islet cell mass are the determinants of glucose tolerance and insulin secretion in this model. Neither drainage of the pancreatic blood to the vena cava nor denervation have measurable influence on magnitude and effectivity of fasting and stimulated insulin secretion.

An analysis of the variation of incidence of congenital dysgenetic hypothyroidism in various countries.

The seasonal and chronological distributions of birth dates of 820 patients with congenital hypothyroidism due to thyroid dysgenesis were analysed in eight areas in the world. The incidence had some seasonal variations in certain areas. These observations suggest that some environmental factors cause this disease.

Insulin-like growth factors I and II, prolactin, and insulin in 19 growth hormone-deficient children with excessive, normal, or decreased longitudinal growth after operation for craniopharyngioma.

We studied insulin-like growth factors (IGF) I and II, prolactin, and the insulin response to arginine in 19 children with craniopharyngioma and documented growth hormone deficiency. Patients were divided into three groups according to their growth rate during the first postoperative year. Seven patients with excessive growth (Group A) had hyperinsulinism, normal IGF values, elevated basal prolactin levels, and a delayed thyrotropin response to thyrotropin-releasing hormone, which was compatible with hypothalamic lesions. In the six patients with normal growth (Group B), the insulin level was low; all other hormone values were similar to those of Group A. In the six patients with decreased growth (Group C), levels of IGF I, insulin, prolactin, and thyrotropin were low, indicating the presence of severe pituitary damage and explaining the failure to grow. Patients in all groups had low or undetectable basal levels of growth hormone. We conclude that in Group B, normal IGF permitted normal growth, and prolactin hypersecretion may have been responsible for normal IGF I values. Excessive growth in Group A may have been caused by hyperinsulinism associated with hyperphagia and obesity of hypothalamic origin.

Thyroxine binding globulin radioimmunoassay in dried blood spotted on filter paper.

A method is described for the determination of thyroxine binding globulin (TBG) in dried blood spotted on filter paper using reagents from a test kit for the measurement of TBG in plasma. By minor modifications of the recommended procedure it was possible to improve precision, sensitivity and tracer displacement. Appropriate TBG standard samples were prepared in 'artificial blood' consisting of a suspension of erythrocytes in buffer with bovine serum albumin (50 milligrams). There is a good correlation between plasma TBG RIA results and blood spot TBG RIA results (r = 0.93). Attention must be paid to the stability of the TBG in blood: our experiments show a decrease of TBG content if filter paper cards with dried blood are stored longer than one month.