Thyroid Radioiodide Uptake Research Articles

Rutin Scavenges Reactive Oxygen Species, Inactivates 5'-Adenosine Monophosphate-Activated Protein Kinase, and Increases Sodium-Iodide Symporter Expression in Thyroid PCCL3 Cells.

Thyroid iodide uptake, mediated by the sodium-iodide symporter (NIS), is essential for thyroid hormone synthesis and also for treatment of thyroid diseases, such as thyroid cancer, through radioiodine therapy. Therefore, compounds able to increase thyroid iodide uptake could be clinically useful, and it is of great importance to unravel the mechanisms underlying such an effect. It has been shown previously that the flavonoid rutin increases thyroid radioiodide uptake in vivo in rats. This study aimed to investigate the mechanisms involved in the stimulatory effect of rutin on iodide uptake. This study evaluated iodide uptake, NIS expression and its subcellular distribution, iodide efflux, reactive oxygen species levels, and the intracellular pathways involved in NIS regulation in a rat thyroid PCCL3 cell line treated with rutin. Similar to previous results found in vivo, rutin increased radioiodide uptake in PCCL3 cells, which was accompanied by increased NIS expression (at both the mRNA and protein levels) and a reduction of radioiodide efflux. Moreover, the results suggest that rutin could regulate NIS subcellular distribution, leading to higher levels of NIS at the cell membrane. In addition, rutin decreased the levels of intracellular reactive oxygen species and phospho-5'-adenosine monophosphate-activated protein kinase. The flavonoid rutin seems to be an important stimulator of radioiodide uptake, acting at multiple levels, an effect that can be due to decreased oxidative stress, reduced 5'-adenosine monophosphate-activated protein kinase activation, or both. Since thyroid iodide uptake is crucial for effective radioiodine therapy, the results suggest that rutin could be useful as an adjuvant in radioiodine therapy.

Single-Photon Emission Computed Tomography for Preclinical Assessment of Thyroid Radioiodide Uptake Following Various Combinations of Preparative Measures

MicroSPECT/CT imaging was used to quantitatively evaluate how iodide uptake in the mouse thyroid is influenced by (i) route of iodine administration; (ii) injection of recombinant human thyrotropin (rhTSH); and (iii) low iodide diet (LID) in euthyroid and triiodothyronine (T3)-treated mice. Pertechnetate (99mTcO4-) and 123I thyroid uptake in euthyroid and T3-treated animals fed either a normal-iodine diet (NID) or an LID, treated or not with rhTSH, and radiotracer administered intravenously, subcutaneously, intraperitoneally or by gavage, were assessed using microSPECT/CT imaging. Western blotting was performed to measure sodium/iodide symporter expression levels in the thyroid. Systemic administration of radioiodide resulted in a higher (2.35-fold in NID mice) accumulation of iodide in the thyroid than oral administration. Mice fed LID with systemic radioiodide administration showed a further two-fold increase in thyroid iodide uptake to yield a ∼5-fold increase in uptake compared to the standard NID/oral route. Although rhTSH injections stimulated thyroid activity in both euthyroid and T3-treated mice fed the NID, uptake levels for T3-treated mice remained low compared with those for the euthyroid mice. Combining LID and rhTSH in T3-treated mice resulted in a 2.8-fold higher uptake compared with NID/T3/rhTSH mice and helped restore thyroid activity to levels equivalent to those of euthyroid animals. Systemic radioiodide administration results in higher thyroidal iodide levels than oral administration, particularly in LID-fed mice. These data highlight the importance of LID, both in euthyroid and T3-treated, rhTSH-injected mice. Extrapolated to human patients, and in the context of clinical guidelines for the preparation of differentiated thyroid cancer patients, our data indicate that LID can potentiate the efficacy of rhTSH treatment in T3-treated patients.

Modulation of thyroidal radioiodide uptake by oncological pipeline inhibitors and Apigenin.

Targeted radioiodine therapy for thyroid cancer is based on selective stimulation of Na+/I- Symporter (NIS)-mediated radioactive iodide uptake (RAIU) in thyroid cells by thyrotropin. Patients with advanced thyroid cancer do not benefit from radioiodine therapy due to reduced or absent NIS expression. To identify inhibitors that can be readily translated into clinical care, we examined oncological pipeline inhibitors targeting Akt, MEK, PI3K, Hsp90 or BRAF in their ability to increase RAIU in thyroid cells expressing BRAFV600E or RET/PTC3 oncogene. Our data showed that (1) PI3K inhibitor GDC-0941 outperformed other inhibitors in RAIU increase mainly by decreasing iodide efflux rate to a great extent; (2) RAIU increase by all inhibitors was extensively reduced by TGF-β, a cytokine secreted in the invasive fronts of thyroid cancers; (3) RAIU reduction by TGF-β was mainly mediated by NIS reduction and could be reversed by Apigenin, a plant-derived flavonoid; and (4) In the presence of TGF-β, GDC-0941 with Apigenin co-treatment had the highest RAIU level in both BRAFV600E expressing cells and RET/PTC3 expressing cells. Taken together, Apigenin may serve as a dietary supplement along with small molecule inhibitors to improve radioiodine therapeutic efficacy on invasive tumor margins thereby minimizing future metastatic events.

Establishment of an Effective Radioiodide Thyroid Ablation Protocol in Mice

Due to the high variance in available protocols on iodide-131 (¹³¹I) ablation in rodents, we set out to establish an effective method to generate a thyroid-ablated mouse model that allows the application of the sodium iodide symporter (NIS) as a reporter gene without interference with thyroidal NIS. We tested a range of ¹³¹I doses with and without prestimulation of thyroidal radioiodide uptake by a low-iodine diet and thyroid-stimulating hormone (TSH) application. Efficacy of induction of hypothyroidism was tested by measurement of serum T₄ concentrations, pituitary TSHβ and liver deiodinase type 1 (DIO1) mRNA expression, body weight analysis, and ^99mTc-pertechnetate scintigraphy. While 200 µCi (7.4 MBq) ¹³¹I alone was not sufficient to abolish thyroidal T₄ production, 500 µCi (18.5 MBq) ¹³¹I combined with 1 week of a low-iodine diet decreased serum concentrations below the detection limit. However, the high ¹³¹I dose resulted in severe side effects. A combination of 1 week of a low-iodine diet followed by injection of bovine TSH before the application of 150 µCi (5.5 MBq) ¹³¹I decreased serum T₄ concentrations below the detection limit and significantly increased pituitary TSHβ concentrations. The systemic effects of induced hypothyroidism were shown by growth arrest and a decrease in liver DIO1 expression below the detection limit. ^99mTc-pertechnetate scintigraphy revealed absence of thyroidal ^99mTc-pertechnetate uptake in ablated mice. In summary, we report a revised protocol for radioiodide ablation of the thyroid gland in the mouse to generate an in vivo model that allows the study of thyroid hormone action using NIS as a reporter gene.

The Use of PBPK Models to Inform Human Health Risk Assessment: Case Study on Perchlorate and Radioiodide Human Lifestage Models

Physiologically-based pharmacokinetic (PBPK) models are often submitted to or selected by agencies, such as the U.S. Environmental Protection Agency (U.S. EPA) and Agency for Toxic Substances and Disease Registry, for consideration for application in human health risk assessment (HHRA). Recently, U.S. EPA evaluated the human PBPK models for perchlorate and radioiodide for their ability to estimate the relative sensitivity of perchlorate inhibition on thyroidal radioiodide uptake for various population groups and lifestages. The most well-defined mode of action of the environmental contaminant, perchlorate, is competitive inhibition of thyroidal iodide uptake by the sodium-iodide symporter (NIS). In this analysis, a six-step framework for PBPK model evaluation was followed, and with a few modifications, the models were determined to be suitable for use in HHRA to evaluate relative sensitivity among human lifestages. Relative sensitivity to perchlorate was determined by comparing the PBPK model predicted percent inhibition of thyroidal radioactive iodide uptake (RAIU) by perchlorate for different lifestages. A limited sensitivity analysis indicated that model parameters describing urinary excretion of perchlorate and iodide were particularly important in prediction of RAIU inhibition; therefore, a range of biologically plausible values available in the peer-reviewed literature was evaluated. Using the updated PBPK models, the greatest sensitivity to RAIU inhibition was predicted to be the near-term fetus (gestation week 40) compared to the average adult and other lifestages; however, when exposure factors were taken into account, newborns were found to be populations that need further evaluation and consideration in a risk assessment for perchlorate.

A clinically euthyroid child with a large goiter due to a thyroglobulin gene defect: clinical features and genetic studies

A 10-year old child born to consanguineous parents presented with an extremely large goiter, a low free T4 level and free T4 index, and normal TSH concentration. The findings of undetectable thyroglobulin (TG) and low free T4, and an elevated free T3/free T4 ratio suggested the possibility of a defect in TG synthesis. Noteworthy aspects of this case were the extremely elevated thyroidal radioiodide uptake despite a normal TSH concentration and the fact that the reduction in the size of her goiter only occurred when her TSH was suppressed below the normal range. Gene sequencing revealed that the patient was homozygous for a donor splice site mutation in intron 30 (IVS30+1G>C). Isolation of RNA obtained from the thyroid gland by fine needle aspiration and sequencing of the TG cDNA confirmed the prediction that exon 30 was skipped, resulting in an in-frame loss of 46 amino acids.

Small molecule TSHR agonists and antagonists

TSH activates the TSH receptor (TSHR) thereby stimulating the function of thyroid follicular cells (thyrocytes) leading to biosynthesis and secretion of thyroid hormones. Because TSHR is involved in several thyroid pathologies, there is a strong rationale for the design of small molecule “drug-like” ligands. Recombinant human TSH (rhTSH, Thyrogen ®) has been used in the follow-up of patients with thyroid cancer to increase the sensitivity for detection of recurrence or metastasis. rhTSH is difficult to produce and must be administered by injection. A small molecule TSHR agonist could produce the same beneficial effects as rhTSH but with greater ease of oral administration. We developed a small molecule ligand that is a full agonist at TSHR. Importantly for its clinical potential, this agonist elevated serum thyroxine and stimulated thyroidal radioiodide uptake in mice after its absorption from the gastrointestinal tract following oral administration. Graves’ disease (GD) is caused by persistent, unregulated stimulation of thyrocytes by thyroid-stimulating antibodies (TSAbs) that activate TSHR. We identified the first small molecule TSHR antagonists that inhibited TSH- and TSAb-stimulated signalling in primary cultures of human thyrocytes. Our results provide proof-of-principle for effectiveness of small molecule agonists and antagonists for TSHR. We suggest that these small molecule ligands are lead compounds for the development of higher potency ligands that can be used as probes of TSHR biology with therapeutic potential.

Small-molecule agonists for the thyrotropin receptor stimulate thyroid function in human thyrocytes and mice

Seven-transmembrane-spanning receptors (7TMRs) are prominent drug targets. However, small-molecule ligands for 7-transmembrane-spanning receptors for which the natural ligands are large, heterodimeric glycoprotein hormones, like thyroid-stimulating hormone (TSH; thyrotropin), have only recently been reported, and none are approved for human use. We have used quantitative high-throughput screening to identify a small-molecule TSH receptor (TSHR) agonist that was modified to produce a second agonist with increased potency. We show that these agonists are highly selective for human TSHR versus other glycoprotein hormone receptors and interact with the receptor's serpentine domain. A binding pocket within the transmembrane domain was defined by docking into a TSHR homology model and was supported by site-directed mutagenesis. In primary cultures of human thyrocytes, both TSH and the agonists increase mRNA levels for thyroglobulin, thyroperoxidase, sodium iodide symporter, and deiodinase type 2, and deiodinase type 2 enzyme activity. Moreover, oral administration of the agonist stimulated thyroid function in mice, resulting in increased serum thyroxine and thyroidal radioiodide uptake. Thus, we discovered a small molecule that activates human TSHR in vitro, is orally active in mice, and could be a lead for development of drugs to use in place of recombinant human TSH in patients with thyroid cancer.

Rapid regulation of thyroid sodium–iodide symporter activity by thyrotrophin and iodine

Transport of iodide into thyrocytes, a fundamental step in thyroid hormone biosynthesis, depends on the presence of the sodium-iodide symporter (NIS). The importance of the NIS for diagnosis and treatment of diseases has raised several questions about its physiological control. The goal of this study was to evaluate the influence of thyroid iodine content on NIS regulation by thyrotrophin (TSH) in vivo. We showed that 15-min thyroid radioiodine uptake can be a reliable measurement of NIS activity in vivo. The effect of TSH on the NIS was evaluated in rats treated with 1-methyl-2-mercaptoimidazole (MMI; hypothyroid with high serum TSH concentrations) for 21 days, and after 1 (R1d), 2 (R2d), or 5 (R5d) days of withdrawal of MMI. NIS activity was significantly greater in both MMI and R1d rats. In R2d and R5d groups, thyroid iodide uptake returned to normal values, despite continuing high serum TSH, possibly as a result of the re-establishment of iodine organification after withdrawal of MMI. Excess iodine (0.05% NaI for 6 days) promoted a significant reduction in thyroid radioiodide uptake, an effect that was blocked by concomitant administration of MMI, confirming previous findings that iodine organification is essential for the iodide transport blockade seen during iodine overload. Therefore, our data show that modulation of the thyroid NIS by TSH depends primarily on thyroid iodine content and, further, that the regulation of NIS activity is rapid.

High incidence of thyroid dysfunction despite prophylaxis with potassium iodide during (131)I-meta-iodobenzylguanidine treatment in children with neuroblastoma.

Treatment modalities like targeted radiotherapy with (131)I-meta-iodobenzylguanidine ((131)I-MIBG) improve survival rates after neuroblastoma (NB). Radiation to the thyroid gland can lead to hypothyroidism and even malignancy. Because hypothyroidism after (131)I-MIBG treatment was reported, the current KI prophylaxis against thyroidal radiation damage was evaluated. The incidence, pathogenesis, and consequences of thyroid dysfunction among 42 NB patients treated with (131)I-MIBG were evaluated retrospectively. Efficacy of KI prophylaxis was established by measuring thyroidal radioiodide uptake. Thyroid damage was expressed as thyrotropin elevation (TE, plasma concentration of thyroid stimulating hormone > or = 4.5 mU/L). The mean followup was 2.3 years (range, 0.1-8.5). The mean number of treatments with (131)I-MIBG was 3.3. Of 428 scintigrams, uptake of (131)I in the thyroid was visible in 92 (21.0%). Twenty two patients (52.4 %) presented TE after a mean period of 1.4 years (range, 0.1-5.8). Clinical signs of hypothyroidism were not observed. Eight patients received suppletion therapy with thyroxine. Thyrotropin elevation was transient in four patients. Of 25 survivors, with a mean followup of 3.5 years, 16 (64%) developed TE. No correlation was found between TE and thyroid visualization after (131)I-MIBG administration or the number of treatments. No abnormalities were seen by ultrasound imaging of the thyroid. Occurrence of thyroid dysfunction after treatment with (131)I-MIBG for NB is high, in spite of KI prophylaxis. Close followup of thyroid function and structure is required in patients treated with (131)I-MIBG. New ways of protecting the thyroid during exposure to radioiodine should be developed.

Administration of a Single Low Dose of Recombinant Human Thyrotropin Significantly Enhances Thyroid Radioiodide Uptake in Nontoxic Nodular Goiter

Administration of a Single Low Dose of Recombinant Human Thyrotropin Significantly Enhances Thyroid Radioiodide Uptake in Nontoxic Nodular Goiter

Improved radioimmunoassay for measurement of mouse thyrotropin in serum: strain differences in thyrotropin concentration and thyrotroph sensitivity to thyroid hormone.

We report an improved heterologous radioimmunoassay (RIA) for the measurement of thyrotropin (TSH) in mouse serum. The assay components are: antirat thyrotropin (rTSH) serum from the National Hormone and Pituitary Program, a commercial [125I]-labeled rTSH and mouse thyrotropin (mTSH) serum standards produced by dilution of a serum pool from hypothyroid mice with high TSH with a serum pool from mice treated with excess levothyroxine (LT4) (mTSH-0). Sensitivity was increased by reducing the amount of antibody and tracer and by taking advantage of the disequilibrium technique. Accuracy was greatly improved by the preparation of mouse serum TSH standards. TSH in serial dilutions of individual mice with high TSH of different etiologies paralleled the mTSH standard curve but not that of rTSH or a crude mouse TSH/luteinizing hormone (LH) reference preparation. The high-mTSH-serum standard contained 20 mU TSH per milliliter, measured in a bioassay utilizing a cell line stably transfected with human TSH receptor cDNA, and a relative TSH concentration of 40 ng/mL. The sensitivity of the RIA is 0.01 to 0.02 ng/mL, depending on the quality of the tracer and the preparation of mTSH-0 serum. The intra-assay and interassay coefficients of variations were, respectively: 16% and 27% at 0.04 ng/mL; 6.3% and 8.2% at 0.4 ng/mL; 5.4% and 9.8% at 1.7 ng/mL; 10% and 24% at 4.0 ng/mL. The mean TSH concentration in serum of 60-80-day-old male mice was four-fold higher than that in females of the same age. The assay was able to distinguish differences in serum TSH concentrations in five different strains of mice. Baseline serum TSH concentrations (mean +/- SD) of 70-day-old male mice were: 0.143 +/- 0.065 ng/mL in the CD-1 strain; 0.229 +/- 0.042 ng/mL in C57BL/6 mice; 0.084 +/- 0.017 ng/mL in SWR/J mice; 0.133 +/- 0.057 ng/mL in NOD SCID mice, and 0.266 +/- 0.122 ng/mL in FVB mice. Mean serum thyroxine (T4) concentrations were also significantly different among the mouse strains but did not correlate with the serum TSH level. Administration of levotriiodothyronine (LT3) suppressed the serum TSH to a greater degree in mice with higher baseline TSH values. Suppression of the thyroidal radioiodide uptake with LT3 correlated with that of serum TSH.

Effects of chlorine dioxide on thyroid function in the African green monkey and the rat.

In a previous study from this laboratory, chlorine dioxide (ClO2) treated drinking water depressed thyroxine (T4) levels in the African green monkey. The present study again demonstrated a decrease in T4 levels in the same species after 4 wk of oral exposure. However, after 8 wk of treatment T4 levels rebounded to above pretreatment levels, coinciding with an increase in thyroid radioiodide uptake. This T4 rebound phenomenon and increased iodide uptake may be due to a compensatory endocrinological mechanism. In rats, T4 levels dropped during the 8-wk ClO2 treatment period in a dose-dependent manner, and no rebound effect was observed. Iodide uptake values in the rat were not affected. It appears that ClO2 may have an effect on thyroid function in both species.

Influence of potassium thiocyanate on thyroid function of rainbow trout, Salmo gairdneri

Sublethal doses of potassium thiocyanate (KSCN), an iodide competitor, depressed thyroidal radioiodide uptake of fed laboratory rainbow trout at 11°, but did not depress either plasma levels of T 4 ( l-thyroxine) and T 3 (triiodo- l-thyronine) or radioiodide incorporation into plasma iodothyronines. Furthermore, plasma T 4 levels of KSCN-treated trout increased to levels comparable to those of control trout in response to bovine TSH. The apparent inability of KSCN to inhibit thyroid hormone synthesis and release may be due to noncarrier-mediated iodide diffusion into the thyroid from the high iodide concentration normally found in plasma of freshwater salmonids. In conclusion, KSCN is not a practical inhibitor of thyroid hormone release in laboratory trout, and thyroid radioiodide uptake is a highly misleading index of thyroidal status.

Clinical Significance of Endogenously Labelled Thyroid Hormones in the Diagnosis of Thyroidal Autonomy

The clinical value of the determination of 123I concentration in serum 48 hrs after tracer administration (123I)48 is investigated with special regard to thyroidal autonomy. Serum radioiodine concentration, thyroid radioiodide uptake at 4 and at 48 hrs were measured in 74 healthy subjects and patients with simple goiter, in 36 patients with thyroidal autonomy (diagnosis by thyroid suppression test), and in 20 hyperthyroid patients. 83% of the patients with elevated radioiodine concentration belonged to the group of thyroidal autonomy. The product of radioiodine concentration and thyroid radioiodide uptake is a much better parameter. 95% of the patients in which this product was elevated, belonged to the autonomy group (5% diagnostic error). Also in the control group the diagnostic error was 5%. The combination of (123I)48 with the result of the TRH-test is very useful in excluding thyroidal autonomy, if (123I)48 is normal and the TRH-test is positive (100% of the patients have regulated thyroid glands). 94% of the patients having elevated (123I)48 and a negative TRH-test belonged to the group of thyroidal autonomy. A very useful combination for the diagnosis of borderline hyperthyroidism is the determination of the product of (123I)48 and the uptake48 together with the pulse rate or fine tremor of the fingers (or TRH-test). The results suggest that the determination of (123I)48 is a very good parameter of thyroidal autonomy beside the thyroid suppression test. It may be used alone for the diagnosis of thyroidal autonomy if the suppression test is contraindicated. In the diagnosis of borderline hyperthyroidism its determination makes the suppression test unnecessary in many instances.

Effects of temperature on plasma thyroxine and lodide kinetics in rainbow trout, Salmo gairdneri

Plasma levels of thyroxine (T 4) and iodide and their plasma kinetics were studied in fed immature rainbow trout maintained at 11° and then held for up to 14 d (days) at 5, 11, or 19°. Elevation (5°) or depression (19°) of plasma T 4 occurred during the first 3 d following abrupt transfer from 11°, but by 7 and 14 d plasma T 4 did not differ markedly between the three temperatures. In contrast, the T 4 plasma degradation rate increased fourfold from 5 to 19°, due largely to an increased plasma T 4 distribution space and plasma T 4 pool. The proportion of plasma T 4 undergoing deiodination and the T 4 to T 3 conversion rate also increased with temperature. The plasma iodide level and plasma iodide pool were greater at 5° than at 11 or 19°, but both the fractional rate of plasma iodide loss and plasma iodide clearance rate increased with temperature, resulting in a greater loss of plasma iodide at 19° than at 5 or 11°. Thyroid radioiodide uptake was greater at 11 and 19° than at 5°. In conclusion, maintenance of trout at higher temperatures increased the plasma T 4 degradation rate and rate of T 4 to T 3 conversion, implying elevated thyroidal secretion of T 4 into the blood and elevated thyroidal status at higher temperatures. This trend was reflected neither in thyroid radioiodide uptake nor in plasma levels of T 4 or iodide.

The influence of testosterone propionate on thyroid function of immature rainbow trout, Salmo gairdneri Richardson

Testosterone propionate (TP) was injected intramuscularly (five injections at 4-day intervals) into fed immature rainbow trout at 11–12°; controls were sham injected. TP increased thyroxine (T 4) degradation rate, T 4 deiodination rate, T 4 conversion to 3,5,3′-triiodo- l-thyronine (T 3), plasma T 3 levels, and thyroid uptake of radioiodide 48–96 hr after radioiodide injection. However, plasma T 4 levels responded inconsistently to TP, while thyroid radioiodide uptake measured earlier than 24 hr was suppressed by TP. In conclusion, (i) TP, either directly or indirectly, stimulates many aspects of thyroid function, including conversion of T 4 to T 3, and (ii) plasma T 4 level and thyroidal uptake of radioiodide can be highly misleading indexes of thyroid function.

Changes in thyroid activity of Ambystoma gracile (Baird) during different larval, transforming, and postmetamorphic phases

Thyroid activity for two populations of Ambystoma gracile acclimated to laboratory conditions was assessed by thyroid radioiodide (125I) uptake and serum thyroxine level determined by radioimmunoassay. Both populations exhibited a gradual rise in thyroid activity preceding the mean size for metamorphosis. Larval and transformed salamanders also exhibited a decline in thyroid activity following attainment of this mean size, and this decline was observed for both transformed and neotenous animals. Thyroid activity and serum thyroxine levels were greatest during metamorphic climax. Neoteny was attributed to the generally lower thyroid activity preceding the mean size for metamorphosis which was observed for the high altitude population (having greater neotenic tendencies).

Abnormal thyroid function in spontaneously hypertensive rats.

Thyroid weight, thyroidal radioiodide uptake, and cyclic AMP-dependent protein kinase activity of a thyroid supernatant fraction were increased significantly in spontaneously hypertensive rats (SHR), apparently because of increased secretion of pituitary TSH. However, the thyroids of SHR did not make supernormal amounts of thyroxine (T4), and thyroidal radioiodine release was apparently impaired. In the SHR, proteolytic enzyme activity was less than normal and the thyroglobulin was more resistant to normal proteolytic enzyme than was control thyroglobulin. Presumably because of these abnormalities, plasma T4 was significantly lower than normal, but triiodothyronine (T4) was normal, as a result of compensatory processes occurring in T3 synthesis and hydrolysis of thyroglobulin. T4 and T3 were less effective in depressing pituitary TSH synthesis and secretion in SHR than in controls, possibly because of an abnormal setting of the "hormostat." Although the hypothalamic content of TRH was normal in SHR, the exact site of the abnormality in the "hormostat" is not delineated in the present study.

The influence of temperature on histological and radiochemical measurements of thyroid activity in the eastern brook trout, Salvelinus fontinalis Mitchell

Histological and radiochemical techniques for assessing thyroid activity were compared on yearling brook trout acclimated at 5, 12, and 15 °C.The mean thyroid follicle epithelial cell height was 7.4 μ (range 6.0–8.6 μ) at 5 °C; 3.5 μ (range 2.9–3.9 μ) at 12 °C, and 2.3 μ (range 1.9–2.9 μ) at 15 °C. Assuming that a taller epithelial cell height indicates greater thyroid activity, then an inverse relationship between thyroid activity and acclimation temperature exists.Both the uptake of radioiodide by the thyroid (T/S) and the clearance of radioiodide from the serum were greater at higher temperatures. Serum PB125I production was negligible within 8 days after radioiodide injection and the conversion ratio could not be applied as an index of thyroid function, Assuming, however, that the thyroid radioiodide uptake is an index of thyroid activity, then there is a direct relationship between thyroid activity and acclimation temperature.In view of the marked discrepancy between these histological and radiochemical techniques, fractional rates of turnover of serum thyroxine were compared by determining the biological half-life (t½) for serum PB125I after L-thyroxine-125I intraperitoneal injection at different temperatures. The serum PB125I clearance curves were complex and tentative t½ values of 18.0 days (5 °C, 3.2 days (12 °C), and 1.5 days (15 °C) were obtained. These results indicate a more rapid serum PBI turnover at higher temperatures and support the radiochemical measurements.