The effect of alpha-MSH on plasma growth hormone, cortisol and TSH in children.

The effect of synthetic alpha-MSH injected intravenously in a uniform dose of 3 mg was studied in 19 prepubertal children. A marked growth hormone (GH) response was seen only in 2 out of 8 constitutionally small children with a normal GH response to insulin and arginine stimulation. Three of of 11 children suffering from hypopituitarism with documented GH and other hormone deficiencies, unexpectedly, showed a significant rise of GH after alpha-MSH: all three had craniopharyngiomas. Alpha-MSH led to an increase of plasma cortisol in all except 3 patients who had secondary adrenal insuffciency. The increase of cortisol after alpha-MSH and after insulin was of the same extent: but the hypoglycemia and stress responsible for the insulin effect were not observed after alpha-MSH. It is possible that alpha-MSH acts by an ACTH-like direct stimulation on the adrenals. There was no effect of alpha-MSH on plasma TSH or on blood glucose.

Elevated plasma TSH and hypothyroidism in children with hypothalamic hypopituitarism.

Basal TSH levels were found to be elevated in 6 patients with documented growth hormone deficiency and hypothyroidism. TRH (200 mug/m2 administered intravenously) led to an exaggerated TSH response. This is in contrast to the results in other GH-deficient children, with either a delayed rise of TSH (hypothalamic hypothyroidism due to TRH deficiency, n = 22), an absent TSH response (pituitary hypothyroidism due to TSH deficiency, n = 7), or a normal increase of TSH (isolated GH deficiency, n = 20). Elevated plasma TSH in the presence of hypothyroidism as seen in 6 of our patients with idiopathic hypopituitarism or craniopharyngioma, indicates an intact feedback action between the pituitary and the thyroid gland. TSH, however, seems to be inadequate for the maintenance of normal thyroid function. It is suggested that in certain patients with hypothalamic disorders, TSH is secreted in a biologically less active form.

Transient rise in luteinizing hormone and follicle stimulating hormone secretion during puberty studied in 113 healthy girls with tall stature.

To establish normal values for the LRH test in females around the age of puberty, we had the opportunity to study 113 health girls with tall stature. Plasma LH and FSH levels were determined before and after a bolus injection of LRH (25 microgram/m2). Hormone results could not be correlated with chronological age, bone age, height, weight, or public hair stages. However hormone results showed significant differences when grouped according to breast development and menarche. There was a continuous rise of gonadotropin levels, particularly of basal and peak LH values, in parallel with breast maturation, and a remarkable fall in girls after menarche when tested during the first half of the menstrual cycle. It appears that a transient rise in gonadotropin secretion is essential for the maturation of ovarian function, which, in turn, switches pituitary-gonadal regulation from the pubertal tonic to the adult cyclic type.

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.

Pseudohypoparathyroidism and idiopathic hypoparathyroidism: relationship between serum calcium and parathyroid hormone levels and urinary cyclic adenosine-3',5'-monophosphate response to parathyroid extract.

Forty patients with hypocalcemia and/or Albright's hereditary osteodystrophy were studied. Based on the estimation of serum calcium and parathyroid hormone (PTH) levels as well as the urinary cAMP response to infusions with parathyroid extract, it was possible to classify all of the patients studied as cases with idiopathic hypoparathyroidism (n = 6, low PTH, normal cAMP response), pseudohypoparathyroidism (PHP) type I (n = 18, high PTH, low cAMP response) and type II (n = 2, high PTH, normal cAMP response), as well as pseudopseudohypoparathyroidism (n = 14, normal PTH, normal cAMP response). In three cases studied at the age of 12, 17, and 23 yr, the signs of Albright's hereditary osteodystrophy were not observed. PTH levels were unusually high for a given serum calcium concentration in some patients with PHP, the increased PTH levels were, however, normalized during iv calcium infusions. In two young children with PHP, a gradual increase of serum PTH levels occurred despite persistent normocalcemia over a period of 3 yr. This suggests that factors other than hypocalcemia or frequent small unobservable falls of the serum calcium concentration, such as a deficient formation of 1,25-dihydroxyvitamin D3, secretion of an abnormal PTH, or an abnormal metabolism of the hormone, may contribute to the secondary hyperparathyroidism in PHP.

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.

Intellectual, school and occupational performance in patients with idiopathic hypothalamo-pituitary hypothyroidism and primary hypothyroidism.

Intelligence quotient (IQ), school and professional performance were reviewed in 33 patients with idiopathic hypothalamo-pituitary hypothyroidism. Diagnosis was based on low T4 values and clinical signs. All were treated with growth hormone (HGH). In some, hypothyroidism became manifest only after HGH therapy. Birth history revealed breech delivery in 24 and perinatal asphyxia in 15 of them. Thyroid treatment was started at a mean age of 9.8 (range 4-18 years). The mean IQ was 103.4 +/- 16.7 (SD). 9 patients had IQs below 90, 8 of them were born by breech delivery, 3 had severe perinatal asphyxia, one recurrent symptomatic hypoglycemia, and one a micropenis. Of those patients who have reached the respective age, 7 attended college, 3 university, and 9 had skilled professions. Only 7 required special education. For comparison, 52 patients with primary hypothyroidism were studied. Their mean IQ was with 89.3 +/- 18.1 (SD) significantly lower (p < 0.001) than the mean IQ of patients with hypothalamo-pituitary hypothyroidism. The best IQ (96.8 +/- 16.9) was attained when thyroid treatment was started before the age of 4 months, the lowest IQ (78.2 +/- 19.2) was found in the group of patients in whom thyroid substitution was initiated between 5 and 12 months. Patients who were treated after one year of age, had a mean IQ of 90.0 +/- 15.7. This group includes patients with ectopic thyroid glands or acquired hypothyroidism such as Hashimoto's thyroiditis.

The use of a low-dose LHRH test for the distinction of delayed adolescence and isolated gonadotropin deficiency.

In order to evaluate the diagnostic usefulness of a low-dose LHRH test (LHRH HOE 471, bolus injection of 25 micrograms/m2 i.v.), we have reviewed the data of 30 boys with delayed growth and insufficient or lacking sexual development around the age of puberty, and of 8 boys with multiple pituitary hormone deficiencies. In 14 out of 22 boys with delayed adolescence, this diagnosis could be established on the basis of normal LH and FSH results; in 8 boys who also had a delayed but spontaneous pubertal development, gonadotropin response to LHRH was inadequate presumably due to a transiently reduced sensitivity of the "pituitary gonadotroph"; a second LHRH test carried out 12-32 months later revealed normal results. There is some evidence that exogenous or endogenous testosterone is important for the maturation of the adult gonadotropin secretion pattern. Eight patients with isolated true gonadotropin deficiency and all with idiopathic multiple pituitary hormone deficiencies had an insufficient gonadotropin response. This study shows that the low-dose LHRH test allows a good distinction between benign delayed adolescence and gonadotropin deficiency. False-negative results in some boys with delayed adolescence may be due to a decrease of pituitary responsiveness which will normalize with time.

Success, relapse and failure after intranasal LHRH treatment of cryptorchidism in 55 prepubertal boys.

Synthetic LHRH was given intranasally to 55 prepubertal boys with 67 undescended testes. After a 4-5 week period while receiving a daily dose of 1.2 mg complete testicular descent was seen in 24 testes. Follow-up over 6 to 24 months showed relapse in 4 boys who responded successfully to a second trial with LHRH. In boys with insufficient or no response to an initial trial further treatment with LHRH in 11 cases or HCG in 5 cases also was without effect. Surgical correction after unsuccessful LHRH treatment in 32 boys with 35 undescended testes showed anatomical abnormalities in 28 testes, mostly an open processus vaginalis with or without hernia. Because of its simple and painless administration and the absence of unwanted side effects, intranasal LHRH is well-suited as initial treatment of cryptorchidism, particularly in young children.

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.

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.

Early detection of neonatal hypothyroidism by serial TSH determination in dried blood. Six months experience with a reliable, efficient and inexpensive method.

Mass newborn screening for primary hypothyroidism was introduced in Switzerland on January 1st, 1977, using a radioimmunoassay of TSH in dried blood spotted on filter paper. After incubation for 38 h at 20 degrees C, bound and free TSH is separated by double antibody precipitation. The filter paper discs of 6.5 mm diameter remain in the test tubes. At present, one TSH determination costs approx. SFr. 4.40. All reagents used are commercially available and their costs amount to not more than 15% of the total expenses. During the first 8 months of 1977, of 21862 newborns tested routinely on day 5 (together with the Guthrie-test), 7 infants with primary hypothyroidism were discovered owing to blood TSH values of greater than 100 muU/ml. Diagnosis was not recognized clinically although all of the infants showed some symptoms. Thyroxin therapy was started within the second week of life. The incidence of about 1 in 3000 newborns is higher than reported so far. It has to be shown whether this is due to genetic or geographic factors, to the occurrence of transitory forms, or to a higher efficiency of screening by the TSH (versus T4) assay.

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.

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.

[Longterm observation of latent diabetes mellitus in a prepubertal girl (author's transl)]. / Langzeitbeobactungen eines latenten diabetes mellitus bei einen präpuberalen Mädchen

In a girl with latent diabetes mellitus, glucose tolerance and insulin release were regularly examined from 6 to 12 years of age. Under diet height and weight increased normally, the glucose intolerance disappeared, and the hypoinsulinism turned into hyperinsulinism with reactive hypoglycemia. This observation demonstrates that in a longitudinal study, the same patient may present in one period with glucose intolerance (latent diabetes) and insulin deficiency and in another period with normal glucose tolerance (prediabetes) and insulin excess.