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Biomedical subjects

L Wartofsky

Publications and source records attributed to L Wartofsky.

At least 109 records · Page 6Linked to original sources
PubMed1983

T3 may be a better agent than T4 in the critically ill hypothyroid patient: evaluation of transport across the blood-brain barrier in a primate model.

Thyroid hormone transport across the blood brain barrier in hypothyroid patients is clinically important yet poorly understood. To study this question, 200 micrograms of thyroxine (T4), 100 micrograms of 3,5,3'-triiodothyronine (T3) and 100 micrograms of 3,3',5'-triiodothyronine (reverse T3) were administered separately to 3 baboons, first iv and at a later date intrathecally (IT). Six animals were used. Three received the iv injections and three received the IT injections. In each of the 18 experiments, cerebrospinal fluid (CSF) and serum specimens were collected serially for 6 h after injection. Mean maximal elevations from baseline in CSF iodothyronine levels were 100 +/- 10 ng/dl after iv T4, 3921 +/- 293 ng/dl after iv T3 and 31 +/- 17 ng/dl after iv reverse T3. When given IT in the same dosages, the mean maximal increases in serum iodothyronine concentrations were: 1670 +/- 600 ng/dl for T4, 806 +/- 405 ng/dl for T3, and 210 +/- 43 ng/dl for reverse T3. In every animal studied, rapid bidirectional transfer of T3 from serum to CSF and CSF to serum occurred, whereas iv T4 resulted in delayed minimal increments in CSF T4 concentration. Isotopic experiments were also performed and the results analyzed using a kinetic model. When 125I-T3 was given iv, the equilibrium point in CSF was observed within 90 min with 1.7% of the administered dose/L able to be counted in CSF at any moment in time. When labeled T4 was given iv, only 0.6% of the administered dose/L was counted in CSF and the equilibrium point was not reached until 360 min. These data suggest: (a) T4, T3, and reverse T3 are all capable of bidirectional transfer across the blood brain barrier, (b) T3 may be a better agent than T4 in treating patients with myxedema coma because T3 crosses more rapidly and more completely from serum to CSF.

Animals↗
PubMed1982

Investigations into the etiology of elevated serum T3 levels in protein-malnourished rats.

Thyroid function studies and the peripheral metabolism of thyroid hormone were examined in rats fed a low protein diet (9% casein) for 4-8 wk. Compared to animals fed a normal protein diet ad libitum, both the low protein rats and a pair-fed control group weighed less at the end of the study. However, serum total T3 levels were significantly higher only in the protein deficient rats. The elevated serum T3 was not explainable by enhanced peripheral T4 to T3 conversion, as there was no evidence of any change in hepatic or renal 5'-deiodinase activity when homogenates were examined for conversion of T4 to T3, reverse T3 to 3,3'-diiodothyronine, or 3',5'-diiodothyronine to 3'-monoiodothyronine. Neither was there an effect on hepatic T3 receptor maximal binding capacity (204 +/- 24 versus 168 +/- 15 fmol/mg DNA control) or binding affinity (2.07 +/- 0.38 versus 2.49 +/- 0.24 x 10(-10) M control). In two separate experiments the dialyzable fraction of T3 was significantly lower in the low protein group while free T3 concentrations were unchanged or reduced. In contrast, serum total and free T4 were either normal or reduced and dialyzable T4 was unaffected by protein deficiency. We conclude that while serum total T3 is elevated in rats chronically fed a low protein diet, this elevation is not due to enhanced T4 to T3 conversion. Rather, the increased T3 levels can be accounted for by a striking alteration in protein binding to T3. Moreover, the failure to demonstrate similar changes in serum total and dialyzable T4 suggests that in the rat, protein deficiency has different effects on binding to the two major thyroid hormones. Dietary induced changes in serum thyroid hormone binding must be kept in mind in nutrition studies in the rat.

Animals↗
PubMed1982

Effects of thyroid hormone on the insulin receptor in rat liver membranes.

Although many studies have investigated the complex interrelationships between thyroid hormone levels and insulin-glucose secretion and action, there is at present a lack of information concerning the effects of various thyroid hormone levels on insulin receptors. In the present study, rat liver membranes were prepared from control, hyperthyroid [10 micrograms L-T4 (T4)/100 g BW for 14 days], and hypothyroid rats and the binding characteristics of [125I]iodoinsulin to these membranes were studied. In addition, serum T3, T4, glucose, and insulin levels were measured. The mean (+/- SD) serum T4 and T3 levels were higher (P less than 0.05) in the T4-injected rats than in the hypothyroid rats (T4, 9.1 +/- 0.6 vs. 1.7 +/- 0.4 microgram/dl; T3, 144 +/- 18 vs. 30 +/- 16 ng/dl). When compared to controls, glucose levels were higher in the hypothyroid rats (116 +/- 11 vs. 141 +/- 14 mg/dl; P less than 0.05) and were statistically unaltered in thyrotoxicosis. Plasma insulin levels were increased in hypothyroidism (6.5 +/- 0.8 vs. 10.8 +/- 2.9 microU/ml; P less than 0.05) and decreased in thyrotoxicosis (7.5 +/- 0.5 vs. 28.3 +/- 15 microU/ml; P less than 0.05). Despite these alterations, membrane binding and the derived Scatchard plots were not significantly different in the hyperthyroid or hypothyroid groups. In summary, the present studies indicate that plasma membrane insulin receptor number and affinity are unaltered regardless of the thyroid state of the rat.

Animals↗
PubMed1982

The effect of experimental hyperthyroidism and hypothyroidism on 5'-monodeiodination of 3,3',5'-triiodothyronine and 3',5'-diiodothyronine by rat liver and kidney.

To study the effect of alterations in thyroid status on 5'-monodeiodinase activity, conversions of rT3 to 3,3'-diiodothyronine and 3',5'-diiodothyronine (3',5'-T2) to 3'-monoiodothyronine were examined in vitro. Rats were injected either with T4 (10 micrograms/100 g BW, ip, daily for 12 days) to make them thyrotoxic or thyroidectomized to render them hypothyroid, and liver and kidney homogenates were prepared. Liver homogenates from hyperthyroid animals demonstrated a 2-fold increase in 5'-monodeiodination of both rT3 and 3',5'-T2; both reactions were also significantly increased in the kidneys of hyperthyroid rats. Hypothyroidism produced a significant decrease in 5'-deiodination of both rT3 and 3',5'-T2 in liver and kidney homogenates. These data indicate that the in vitro 5'-deiodination of both rT3 and 3',5'-T2 is increased in hyperthyroidism and decreased in hypothyroidism and suggest that these two iodothyronines are metabolized in a similar fashion in rat liver and kidney homogenates in states of altered thyroid function.

Animals↗
PubMed1982

Iodothyronine levels in human cerebrospinal fluid.

Iodothyronines were measured by RIA in concentrated human cerebrospinal fluid (CSF). In measurements performed in one laboratory at a 4-fold concentration of CSF, rT3 was detected in all 30 patients in whom the measurement was attempted and averaged 15.1 +/- 2.8 ng/dl (mean +/- SE). IN an independent laboratory, rT3 measurements at this 4-fold concentration were performed on 11 different samples and averaged 9.3 +/- 0.9 ng/dl, while at a 40-fold CSF concentration, rT3 averaged 13.1 +/- 0.72 ng/dl. CSF T3 values were detected in only 4 of 30 patients as a 4-fold concentration and averaged 8.2 +/- 3.1 ng/dl, while in pooled CSF at a 40-fold concentration, 4 of 4 samples were detectable and averaged 2.6 +/- 0.4 ng/dl. Levels of T4 could only be detected in CSF concentrated 40-fold and averaged 0.22 +/- 0.04 microgram/dl. Values for the percent dialyzable thyronines were 0.44 +/- 0.03% for T4, 4.39 +/- 0.29% for T3, and 0.91 +/- 0.04% for rT3. TSH was detected in CSF concentrated 4-fold, averaging 0.43 +/- 0.05 microunits/ml; in an independent assay with CSF concentrated 40-fold, TSH averaged 0.06 +/- 0.02 microunits/ml. Thyroid binding globulin was undetectable (less than 0.1 mg/dl). We have confirmed the presence of thyroid hormones (T4 and T3) in human CSF and have shown that rT3 is present as well. The role these hormones play in the development, function, and nourishment of the central nervous system and the role the CSF plays in the transport of these hormones into the central nervous system remains to be determined.

Humans↗
PubMed1982

Hyperthyroidism due to a thyrotropin-secreting pituitary adenoma. Studies of thyrotropin and subunit secretion.

A 58-year-old man had symptoms of hyperthyroidism and congestive heart failure. While hyperthyroid, his serum thyrotropin (TSH) level was inappropriately elevated at 6.1 microunits/mL. The molar ratio of alpha subunit to TSH was 2.5, suggesting the presence of a TSH-secreting pituitary tumor. Further evaluation disclosed an enlarged sella turcica with posterior erosion, and an intrasellar mass was visualized on computed tomographic scan. Neither serum TSH nor alpha subunit levels became elevated after administration of thyrotropin-releasing hormone, nor were they suppressed by a dopamine infusion. Serum TSH but not alpha subunit levels rose during antithyroid drug therapy. Estrogens produced a partial reduction in serum alpha subunit concentration (presumably reflecting the nontumorous gonadotroph contribution to circulating alpha subunit). Dexamethasone completely suppressed serum TSH level but had no effect on the alpha subunit level, suggesting a differential feedback of glucocorticoids on TSH and alpha secretion. The patient was treated with pituitary irradiation rather than surgery because of his underlying heart disease.

Adenoma↗
PubMed1981

Measurement of serum T4 concentration by high performance liquid chromatography.

Although RIA techniques for the measurement of serum T4 have been extremely useful, this methodology has several disadvantages, including the requirement for the use of radioisotopes, various levels of thyronine cross-reactivity, and the ability to measure only a single iodothyronine in one assay. We have developed a high performance liquid chromatography (HPLC) method for quantitating serum T4 that utilizes the detection of dansyl-T4 compounds and obviates the problems described for RIA techniques. Serum samples were extracted with ethanol and then chloroform, reacted with dansyl chloride, and, after n-heptane extraction, placed directly on column. Utilizing this technique, dansyl-T4 was easily separated and identified. The sensitivity of detection of the dansylated-T4 in serum was 1 microgram/dl, and linearity was observed when increasing standard T4 concentrations were employed. Sensitivity to 10 ng/dl (100 fmol on column) was achieved when T4 was added to buffer. The coefficients of variation were 4.8% and 2.1% for normal and high serum samples, respectively. When 39 random serum samples were anayzed both by HPLC and RIA, there was concordance of these techniques, since the derived correlation coefficient was 0.94. In summary, the present study demonstrates that serum T4 concentrations can be measured by HPLC and that these measurements agree remarkably well with those obtained by RIA. Because of the inherent advantages of HPLC methodology over that of RIA, this technique of measurement of T4 may have wide applicability to the measurement of iodothyronines.

Chromatography, High Pressure Liquid↗
PubMed1981

Pituitary and thyroid function in male cynomolgus monkeys.

In four male cynomolgus monkeys, serum thyroxine was 6.2 +/- 0.9 micrograms/dl, and triiodothyronine was 207 +/- 12 ng/dl (mean +/- SE). Kinetic studies using 131I-thyroxine and 125I-triiodothyronine showed that the disappearance of both hormones was non-linear and best fit a biexponential equation. The metabolic clearance rates and production rates for thyroxine were 21.5 +/- 0.6 ml/kg/day and 1.34 +/- 0.23 micrograms/kg/day, respectively, and T1/2(beta) = 29.6 +/- 2.0 hours. For triiodothyronine, the metabolic clearance rate was 156.6 +/- 12.0 ml/kg/day, the production rate was 0.33 +/- 0.04 micrograms/kg/day, and T1/2 (beta) was 13.3 +/- 1.3 hours. Basel serum thyrotropin levels in five euthyroid animals were 1.4 +/- 0.6 microU/ml and increased after thyrotropin-releasing hormone to 6.7 +/- 2.2 microU/ml. Serum prolactin was 5.8 +/- 0.7 ng/ml, and it increased to 26.6 +/- 4.5 ng/ml after thyrotropin-releasing hormone. Four animals received chronic dexamethasone therapy (1 mg twice daily for 5.5 months). While baseline and thyrotropin-releasing hormone stimulated thyrotropin values were lower (0.8 +/- 0.2 microU/ml and 3.2 +/- 0.5 microU/ml, respectively), these reductions were not significant.

Animals↗
PubMed1980

Anaplastic giant and spindle-cell carcinoma of the thyroid: a different therapeutic approach.

The prognosis of giant and spindle cell carcinoma of the thyroid is extremely poor. It does appear, however, that a multisciplinary approach to treatment of this aggressive cancer is more effective than a single-treatment modality. Operative ablation of gross tumor, postoperative irradiation therapy, and chemotherapy have demonstrated encouraging results. A different therapeutic approach with the addition of immunotherapy to surgical resection, postoperative irraditation, and chemotherapy is described in this case report. The preliminary result is encouraging.

BCG Vaccine↗
PubMed1980

Nature of suppressed TSH secretion during undernutrition: effect of fasting and refeeding on TSH responses to prolonged TRH infusions.

TSH responses to 4-hr continuous TRH infusions of approximately 0.8 microgram/min were assessed during feeding (1500 Kcal), fasting, and refeeding (1500 Kcal) intervals in 9 euthyroid obese subjects. The total area under the TSH response curve was 1854 +/- 322 muU/ml . 4-hr during feeding, decreased to 1359 +/- 199 muU/ml . 4-hr (p less than 0.01) on the 10th day of fasting, and remained low, being 1405 +/- 185 muU/ml . 4-hr, despite refeeding a 1500 Kcal diet (40% carbohydrate, 40% fat, 20% protein) for 5 days. Baseline serum T3 concentrations were 167 +/- 11 ng/dl during feeding, 86 +/- 8 ng/dl during fasting, and 119 +/- 12 ng/dl during refeeding. The observed decreases in TSH release appeared to correlate with decreased biologic action on the thyroid gland since the net rise in T3 during the infusion was less in fasting and refeeding than in the control (fed) period. Basal serum rT3 levels were 42 +/- 5 ng/dl during feeding, rose as expected to 56 +/- 5 ng/dl during fasting (p less than 0.005), and were completely restored to normal during refeeding (36 +/- 5 ng/dl). These data suggest that: (1) TSH responsiveness to prolonged TRH infusion is diminished during fasting and does not return to control (fed) values despite 5 days of refeeding a 1500 Kcal diet; (2) net T3 increases observed during the TRH infusion are greater in the fed period than in the fasting or refeeding periods; and (3) 5 days of refeeding a 1500 Kcal diet (40% carbohydrate, 40% fat, 20% protein) did not return the T3 to its original fed value whereas rT3 was completely restored to control values. Lastly, since the TSH response was lower both during the early and late phases of the infusion, the decrease in delta TSH to a bolus of TRH during fasting appears to represent one manifestation of a more general suppression of TSH neogenesis associated with caloric deprivation.

Adult↗