MEASUREMENT OF THYROXIN SYNTHESIS WITH I131—A Test for Evaluation of Thyroid Function in Equivocal States

As the function of the thyroid gland is the synthesis and secretion of thyroxin, a test which correctly measures this process is best for diagnosis of thyroid disorder and for determining the success of therapy. The rate of secretion can be measured with a Geiger counter which indicates what proportion of radioactive iodine in a serum specimen is in the form of thyroxin. The normal proportion is 2 to 10 per cent; in hyperthyroidism the proportion is 50 to 70 per cent, and in hypothyroidism less than 1 per cent.The same test has served to detect metastases of thyroid carcinoma following total thyroidectomy.     

TRIIODOTHYRONINE—Clinical Effects in Patients with Suboptimal Response to Other Thyroid Preparations

Thirty patients with evidence of hypometabolism or a clinically related condition were given triiodothyronine after suboptimal response to thyroxin or desiccated thyroid. DL- and L-isomers of triiodothyronine were used and compared. Thirteen patients (43.3 per cent) were improved and 17 (56.6 per cent) were unimproved or became worse. Side effects occurred in 9 of 34 trials (26 per cent), and could not always be eliminated by decreasing the dosage. The highest percentage of good response occurred in a small group (four of five) who received a combination of desiccated thyroid or thyroxin with supplemental triiodothyronine. Despite careful analysis of the data, no basis was found on which to predict which patients would receive benefit from the triiodothyronine. However, the occasional improvement, sometimes dramatic, suggested that a therapeutic trial with triiodothyronine in difficult or unresponsive cases of hypometabolism or hypothyroidism is justified.     

Triiodothyronine; clinical effects in patients with suboptimal response to other thyroid preparations

Thirty patients with evidence of hypometabolism or a clinically related condition were given triiodothyronine after suboptimal response to thyroxin or desiccated thyroid. DL- and L-isomers of triiodothyronine were used and compared. Thirteen patients (43.3 per cent) were improved and 17 (56.6 per cent) were unimproved or became worse. Side effects occurred in 9 of 34 trials (26 per cent), and could not always be eliminated by decreasing the dosage. The highest percentage of good response occurred in a small group (four of five) who received a combination of desiccated thyroid or thyroxin with supplemental triiodothyronine. Despite careful analysis of the data, no basis was found on which to predict which patients would receive benefit from the triiodothyronine. However, the occasional improvement, sometimes dramatic, suggested that a therapeutic trial with triiodothyronine in difficult or unresponsive cases of hypometabolism or hypothyroidism is justified.     

Correlations of central nervous system and thyroid function under chronic emotional stress

Experiments on cats exposed to chronic emotional stress induced during one week by 4-hour immobilization of the animals in conjunction with aperiodic electrocutaneous stimulation were made to study correlations of the time course of changes in the EEG of the cortical and subcortical structures and the content of thyroxin in the peripheral blood at varying time of the experiments. It was demonstrated that in the course of stress, the EEG manifests the cycles of "burst" activity of slow waves, which are first recorded in the posterior hypothalamus and then get generalized. This is accompanied by a significantly high thyroxin secretion. As the stress exposures are repeated, the EEG changes become dominant, also corresponding with high thyroxin secretion. After the experiments are over, the cycles of "burst" activity accompanied by enhanced thyroid function are still recordable over several days.     

Selective and/or overlapping effect of pituitary hormones (thyrotropin, gonadotropin) on serum thyroxin and testosterone level in newly hatched cockerels

Follicle-stimulating hormone and thyrotropin administered perinatally to cockerels have an overlapping effect on the testis and on the thyroid gland. Both hormones when given in one single dose considerably increased the serum level of both thyroxin and testosterone. In the case of chronic treatment performed in the perinatal period, the thyroxin level will similarly increase, though to a smaller extent, while the testosterone level decreases. The experiments studying the direct effect on hormone secretion proved the overlapping effect of the hormones in the perinatal period.     

Concanavalin A as a peripherally acting inhibitor of thyroxin-mediated metamorphosis in amphibians

Stimulated by reports that Concanavalin A (Con A), a plant protein and lectin from jack bean, has an inhibitory effect on thyroid activation induced by thyrotropin, we set out to test whether Con A inhibits thyroid action on hormone-sensitive target tissues in amphibians. We noted that premetamorphic tadpoles injected with 0.15 ml of thyroxin (T₄ 0.24 μM) responded by accelerating metamorphic change as indicated by precocious disappearance of the tail, and appreciable growth of the hind limbs and changes in mouth-part morphology. Tadpoles given an injection of thyroxin immediately followed by an injection of Con A (9.6 μM) showed no such metamorphic changes. In the second series of experiments tail fin discs obtained from premetamorphic tadpoles when placed in cultures supplemented with T₄ (0.24 μM) had completely shrunk within 96 hr. Tail fin discs that were raised in vitro in medium containing Con A as well as thyroxin failed to regress. In the third series of experiments tail discs were initially cultured in medium containing thyroxin and transferred within 48 hr to medium containing Con A. When Con A was added after this 48-hr exposure to thyroxin it was no longer effective in preventing tail fin disc resorption. We conclude tentatively (1) that Con A is a peripheral inhibitor of thyroxin and (2) this it somehow binds to the tissue or interacts with thyroxin rendering it ineffective before the hormone has a chance to act. The significance of finding a peripherally active inhibitor of thyroid hormone for studies of mechanism of action of this hormone on development and differentiation of hormone-sensitive target structures is obvious.     

Effect of thyrotropic hormone on the membrane potential of thyroid gland cells and thyroid hormone secretion with aging

Effect of thyrotropic hormone (TTH) on membrane potential (MP) of thyroid cells and thyroid hormone secretion was studied in experiments on male rats of two age groups (7--12- and 27--32-month-old animals). It was found that during the first 3 hours after TTH administration (5 U/100 g i. v.) the depolarization of secretory cell membranes of adult rats was done pronounced and developed more rapidly than in old ones and that an increase in free thyroxin (T4) correlation with MP changes with time. In a dose of 0.5 U/100 g TTH caused a significant rise in T4 secretion only in old rats. The cAMP level in the thyroid gland declined with aging. In a dose of 5 U/100 g TTH provoked a significant increase in the cAMP content in adult rats and had no effect on its content in old ones. A relationship between the MP level of thyroid secretory cells and thyroid hormone secretion is discussed.     

Homeostatic control of thyroxin concentration expressed by a set of linear differential equations

The purpose of this work is to express current concepts on the relationship between the rates of secretion of thyroxin and of thyroid stimulating hormone (TSH) by a set of linear differential equations (two attempts have been made previously in this direction; cf. Roston,Bull. Math. Biophysics,21, 271–282, 1959; Danziger and Elmergreen,Bull. Math. Biophysics,16, 15–21, 1954), and to show that the solutions to these equations fulfill two criteria: that they correctly express the previously observed behavior of thyroxin and TSH, and that they allow certain predictions to be made which are amenable to experimental verification or disproval by currently existing techniques. This mathematical model is necessarily only an approximation of reality.     

Chemical composition and rate of synthesis of the larval salivary secretion of the fly Rhynchosciara americana

The salivary secretion of Rhynchosciara americana was chemically analysed. The secretion shows a yellow colour, with a pH of 7·5 and protein as its major component (94·5 per cent of the secretion dry weight). Carbohydrates are minor components of the secretion which amount to 3·4 per cent of the secretion dry weight, of which 2·3 per cent are neutral carbohydrates and 1·1 per cent are galactosamine. The major amino acids present in the secretion proteins are aspartic acid, glycine, serine, and glutamic acid. The salivary secretion proteins can be separated into eleven protein fractions by urea-acrylamide gel electrophoresis from which nine fractions are PAS positive. The salivary pigment moves together with the protein fraction No. 8, which is quantitatively the most important one, and has spectral characteristics identical to a haemolymph pigment. The higher rate of gland protein labelling by ¹⁴C-phenylalanine determined in vivo and in vitro occurs around the middle of the spinning stage at the same time as the appearance of the large chromosomal puffs. The rôle of the salivary secretion in cocoon production is discussed.     

On the mechanism of action of thyroxin, an amino acid analog of tyrosine

The concept of a hormone inevitably carries with it a set of specific connotations and prejudices which in the case of thyroxin may obscure rather than elucidate its mechanism of action. Viewed as a hormone, the very number and broad range of thyroxin effects defy resolution. Viewed as an amino acid analog, the behavior of this molecule becomes coherent, in that it resembles the behavior of amino acids in general and tyrosine in particular, with distinguishing characteristics appropriate to its own structure and its analog status.Thyroxin is only one of a number of amino acids appearing in the course of phylogeny, derived from modifications of aminoacyl residues in protein. Comparative physiologic studies suggest that the biogenesis of iodine-modified tyrosines long preceded their useful biological function. Eventually their presence in threatened aquatic forms may have provided survival advantage with regard to terrestrial adaptation.Both structure and function of the vertebrate thyroid gland reflect its foregut ancestry. Iodoproteins within the lumen of the thyroid follicle are subject to a process similar to gastric digestion of ordinary dietary proteins. Free iodoamino acids together with other amino acid constituents of the digest are then absorbed into the blood stream. As expected of an amino acid, thyroxin leaving the extracellular space enters into and influences the function of almost all cells and subcellular organelles, including the nucleus. Its analog properties are reflected in the fact that only small fractions of the available thyroxin pools participate at any one time in biological reactions.The diverse actions of thyroxin are compatible with the model set by the parent amino acid tyrosine, which is notably active at a number of branch points in its own metabolism. Thyroxin effects on growth and development conform with the known alterations in genetic response which occur in the presence of false protein amino acids and are also consistent with the rapid turnover and remodelling of protein systems which follow the incorporation of false amino acid residues into protein. Its effects on overall metabolic processes are consistent with the known propensity of tyrosine-like compounds to become converted to false transmitters in the adrenergic nervous system, which in the case of thyroxin, would result in the development of iodothyronine-derived adrenergic transmitter substances. Altered pigment metabolism in patients with thyroid disease and localization of iodoamino acids in pigment-bearing cells of many vertebrate species suggest that thyroxin may be an alternate substrate in the melanin biosynthetic pathway.Since thyroxin is required for normal body function, it may be classified as an indispensable amino acid along with the other biologically more ancient members of its class.     

Role of the glycerophosphate shunt in regulating oxidation of cytoplasmic NADH and ATP synthesis by liver mitochondria during rat ontogeny

The activity of alpha-glycerophosphate dehydrogenase rate of alpha-glycerophosphate oxidation and ATP synthesis were determined in the liver mitochondria of 1, 3, 12 and 24-month old rats in norm and two days after thyroxin daily administration in a dose of 0.25 mg per 100 g of body mass. The value of the studied parameters decreases with the age, most considerably--from one to three months and then--from 3 to 24-month age. This evidence for the fact that the role of glycerophosphate shuttle in the energy supply of cells falls with ageing; thyroxin administration evoked almost a two-fold increase of the mentioned parameters in one-month rats and more than three-fold in 12 and 24-month animals. A decrease in the alpha-glycerophosphate dehydrogenase activity with ageing is supposed to be connected with the thyroid gland function.     

Reduction in the latent period of the response to thyroxin by tadpole tail discs fused to discs pretreated with thyroxin.

It has been previously shown that tissue blocks prepared from the tail fins of tadpoles (Rana pipiens) survive in vitro for several weeks and respond to thyroxin by shrinkage after a latent period of four or more days (20°C). It has been postulated that this shrinkage corresponds to that of normal tail tissue during metamorphic climax. The long latent period of thyroid action is presumed to depend upon the time required to form the necessary cellular or biochemical intermediates. If such intermediates are activated by thyroxin in the amphibian tail tissue, it may be possible to shorten the latent period of the thyroxin response of fin tissue by fusing untreated blocks to blocks previously treated with thyroxin. Experiments are reported here in which tail fin blocks obtained from tadpoles previously immersed in thyroxin for 3 days were docked to recipient blocks not exposed to this hormone. Such recipient tissues responded with characteristic resorptive activity within 24 hr, instead of the minimum of 4 days required by control tissues exposed directly to thyroxin. It is inferred that some component other than thyroxin which is active in inducing resorption is transmitted from the treated to the untreated block. Presumably, this is a product normally present late in the latent period of thyroxin action.     

Insulin versus oral agents in the management of Cystic Fibrosis Related Diabetes: a case based study

Background

Although thyroxin therapy clearly is beneficial to children with frank hypothyroidism there is little data on the effects of thyroxin in children with compensated or subclinical hypothyroidism. The objective of this study was to determine the effect of thyroxin therapy on cognitive function in children with compensated hypothyroidism. The hypothesis was that thyroxin therapy would change neuropsychological function.

Methods

Eleven patients with a history of sub clinical hypothyroidism entered the study. At the start of the study, six out of the 11 were on thyroxin therapy, while 5 were off therapy. All patients underwent a battery of neuropsychological testing and thyroid function tests at the start of study. Based on the results of thyroid function tests, two of the 5 patients who were off thyroxin were started back on thyroxin. All of the 6 patients who were on thyroxin were taken off thyroxin. All patients then underwent repeat neuropsychological testing and thyroid functions after an average of 91 days.

Results

Thyroxin therapy could not be shown to have an effect on neuropsychological function in this short term study. Our patients had attention problems as compared to the normal population. No significant differences were found between our subjects and normal population standards in verbal processing, visual processing, motor speed/coordination and achievement.

Conclusion

In this small, short term study, thyroxin therapy could not be shown to affect neuropsychological function in children with compensated hypothyroidism. These children may have attention problems but appear to have normal verbal and visual processing, motor speed/coordination and achievement.     

Extensive scleral perforation with complete recovery

Sixty patients with abnormally high I(131) uptake were treated with liothyronine (L-triiodothyronine) for seven or eight days and then tested again. Fifty-five patients showed a suppression of iodine uptake sufficient to eliminate the possibility of hyperthyroidism. Also the therapeutic trial of liothyronine indicated whether they were euthyroid, or hypothyroid with iodine deficiency. Six of the patients showed insignificant change in the I(131) uptake after treatment with thyroid hormone-that is, the change from the original uptake was less than 30 per cent. These six patients were later confirmed to be hyperthyroid. In four patients the uptake at the second test was less by between 35 and 52 per cent than at the first. These four patients, like the remainder with even greater suppression in thyroid uptake, remained clinically euthyroid.The repeat I(131) uptake test was thus seen to be considerably more accurate than the single test and well worth the time required to perform it.     

HYPERTHYROIDISM—Diagnosis by Failure of Triiodothyronine to Suppress Uptake of Iodine131

Sixty patients with abnormally high I¹³¹ uptake were treated with liothyronine (L-triiodothyronine) for seven or eight days and then tested again. Fifty-five patients showed a suppression of iodine uptake sufficient to eliminate the possibility of hyperthyroidism. Also the therapeutic trial of liothyronine indicated whether they were euthyroid, or hypothyroid with iodine deficiency. Six of the patients showed insignificant change in the I¹³¹ uptake after treatment with thyroid hormone—that is, the change from the original uptake was less than 30 per cent. These six patients were later confirmed to be hyperthyroid. In four patients the uptake at the second test was less by between 35 and 52 per cent than at the first. These four patients, like the remainder with even greater suppression in thyroid uptake, remained clinically euthyroid.The repeat I¹³¹ uptake test was thus seen to be considerably more accurate than the single test and well worth the time required to perform it.     

Effect of thyroliberin (thyrotropin-releasing-hormone) on secretion of thyrotropic hormone and prolacting in a monolayer cultrue of rat adenohypophysis]

Cells of the adenohypophysis in the primary 5--8 day monolayer culture responded to the administration of the thyrotropin-releasing-hormone (TRH) by a rapid dose-dependent release of thyrotropic hormone (TTH) and prolactin into the culture medium. This effect is independent of the serum content in the nutrient medium. Thyroxin, the thyroid gland hormone, blocks the stimulating action of TRH with respect to the TTH secretion, but not to prolactin. The blocking effect of thyroxin is apparently expressed not on the cell membranes, but in the cytoplasm, distal to cAMP, by way of the hormonal signal transmission.     

Comparison between the oral glucose tolerance test and the glucose infusion test in the characterization of protodiabetes]

Within 3 days the 2-hour glucose infusion test (GIT) and the 50gm oral glucose tolerance test (oGTT) were performed in 113 normal weight and 33 obese persons suspected to protodiabetes and in 14 control subjects respectively. The results are compared with criteria from a group of healthy persons without any heredity of diabetes worked out in our laboratory. In about 66 per cent of the investigated subjects a concordance between both tests could observed in carbohydrate tolerance. Abnormal results were found more frequently after the oral glucose application. From these finding it was concluded a higher sensitivity of the oGTT. On the other hand followup studies of the disagreed diagnosis have shown that in 91 per cent the test results of the GIT were reproduced. The insulin secretion pattern agreed in 70 per cent between both tests. Whereas the insulin secretion pattern during the oGTT does not allowed to differ between the groups using the glucose infusion test we were able to observe a significant diminished hormone release in the initial as well as in the late phases, if the carbohydrate tolerance was pathologically. Summarizing the results we concluded that the GIT is characterized by a good reproducibility and a higher diagnostic importance than the 50 gm oGTT.     

Changes in Sleeping and Basal Energy Expenditure and Substrate Oxidation Induced by Short Term Thyroxin Administration in Man

The present study was designed to explore the thermogenic effect of thyroid hormone administration and the resulting changes in nitrogen homeostasis. Normal male volunteers (n=7) received thyroxin during 6 weeks. The first 3-week period served to suppress endogenous thyroid secretion (180μg T₄/day). This dose was doubled for the next 3 weeks. Sleeping energy expenditure (respiratory chamber) and BMR (hood) were measured by indirect calorimetry, under standardized conditions. Sleeping heart rate was continuously recorded and urine was collected during this 12-hour period to assess nitrogen excretion. The changes in energy expenditure, heart rate and nitrogen balance were then related to the excess thyroxin administered. After 3 weeks of treatment, serum TSH level fell to 0.15 mU/L, indicating an almost complete inhibition of the pituitary-thyroid axis. During this phase of treatment there was an increase in sleeping EE and sleeping heart rate, which increased further by doubling the T₄ dose (ΔEE: +8.5 ± 2.3%, Δ heart rate +16.1 ± 2.2%). The T₄ dose, which is currently used as a substitutive dose, lead to a borderline hyperthyroid state, with an increase in EE and heart rate. Exogenous T₄ administration provoked a significant increase in urinary nitrogen excretion averaging 40%. It is concluded that T₄ provokes an important stimulation of EE, which is mostly mediated by an excess protein oxidation.     

Evaluation of long term thyroid replacement treatment. Swansea Vocational Training Scheme.

A group study was designed to test the need for the continued prescribing of thyroid replacement treatment. Seven doctors who were attending the vocational training scheme at Swansea studied a total of 75 patients. A withdrawal test for 21 days was used to assess the need for continued prescribing of thyroid medication. Sixty per cent (45) of the group studied had had either the wrong diagnosis or an incorrect maintenance dosage, 28% (21) did not need thyroid treatment after the withdrawal test, and 32% (24) had been prescribed an incorrect maintenance dosage of thyroxine as judged by the results of the initial estimation of thyroxine concentration. The medical and economic consequences of an appreciable rate of misdiagnosis and treatment are apparent.     

The genetics of urinary tract malformations

In this discussion I have excluded consideration of the genetics of purely renal malformations, such as polycystic kidneys, and of functional disorders of the kidney. Systematic family studies are available for renal agenesis, duplication of the ureters, vesico-ureteric reflux (each probably due to maldevelopment of the ureteric bud), bladder exstrophy and hypospadias as isolated malformations. Renal agenesis has a birth frequency of about 1.2 in 10 000 and the proportion affected of sibs is about 3 per cent. Duplication of the ureter has a birth frequency of about 1 per cent and the proportion affected of sibs and parents of probands is about 12 per cent. Vesico-ureteral reflux also has a prevalence in early childhood of about 1 per cent and the proportion of sibs affected is about 10 per cent. Bladder exstrophy has a birth frequency of about 1 in 20 000 and perhaps about 1 per cent of sibs are affected. Hypospadias has a birth frequency in boys of about 1 in 300 and the proportion affected of brothers is about 10 per cent. Further family studies are needed of these malformations when they occur in isolation. Either the multifactorial threshold model or dominant inheritance with reduced penetrance and varied expressivity would fit the data available.