Thyroidal Iodine Release Research Articles

Extracts and auto-oxidized constituents of certain plants inhibit the receptor-binding and the biological activity of Graves' immunoglobulins.

Freeze-dried extracts (FDE) of the plants Lycopus virginicus, Lycopus europaeus, Melissa officinalis, and Lithospermum officinale, as well as products of the oxidation of certain of their constituents, have been shown to exert antithyrotropic activity by virtue of their ability to form adducts with TSH that bind weakly, if at all, to the TSH receptor. The thyroid-stimulating immunoglobulin G (IgG) found in the blood of patients with Graves' disease (Graves'-IgG) resemble TSH in their ability to bind to the thyroid plasma membrane, probably at the TSH receptor, and to activate the gland. In view of this similarity, and since some of the aforementioned FDE have been used in the treatment of hyperthyroidism in Graves' disease, we undertook studies of the effect of these FDE and their constituents on the binding and biological action of Graves'-IgG. In all samples of Graves'-IgG tested, incubation with antithyrotropic FDE or their antithyrotropic auto-oxidized constituents decreased their TSH-binding inhibitory activity in a dose-dependent manner. FDE from L. officinale also inhibited in a dose-dependent manner the direct binding to human thyroid membranes of a 125I-labeled preparation of receptor-purified Graves'-IgG. As judged from both stimulation of adenylate cyclase activity in vitro (thyroid-stimulating Ig activity) and enhancement of thyroid iodine release in the McKenzie assay system (LATS activity), antithyrotropic FDE and their auto-oxidized constituents also inhibited the biological responses to Graves'-IgG. FDE and constituents lacking antithyrotropic activity had little or no effect on the TSH-binding inhibitory activity, thyroid-stimulating Ig activity, or LATS activities of Graves'-IgG. Evidence of some degree of specificity of the inhibitory effects of the active compounds on Graves'-IgG was obtained in the demonstration that they failed to inhibit both the direct binding of [125I]insulin to its receptors in human lymphoblastoid IM-9 cells and the ability of IgG preparations containing antiinsulin receptor antibodies to inhibit the binding of labeled insulin. These observations suggest that the active principles in those FDE and their oxidized constituents with antithyrotropic activity may interact with the pathogenically important components of Graves'-IgG to inhibit their ability to bind to the TSH receptor and activate the thyroid, as they do with TSH. Our findings provide a possible rationale for the empirical, though poorly documented, use of FDE in the treatment of Graves' disease and some support for the suggestion that Graves'-specific IgG may have structural similarities to TSH itself.

Perturbations of iodine metabolism by lithium

A kinetic study of the effects of lithium on iodine metabolism in hyperthyroidism is reviewed. The analysis, carried out in collaboration with Mones Berman, disclosed several unexpected findings. In addition to the inhibition of thyroid iodine release predicted by animal studies, an apparent decrease in extrathyroidal iodine disappearance was observed. This was confirmed by a direct study of the metabolic clearance of labeled thyroxine in hyperthyroid subjects. In euthyroid subjects, lithium did not alter thyroxine disappearance. Also unexpectedly, the lithium-induced perturbations did not promptly return to the control state after the serum lithium level had become undetectable. This suggested a delayed release of lithium from extravascular pools, a phenomenon later described in bone. These findings demonstrated the power of kinetic modeling when used as an analytical tool.

Inhibition of thyroidal iodine release by oestrogens in euthyroid subjects.

The effects of oestrogens on the release of thyroxine iodide (T4 I) and non-T4 I by the thyroid gland of 6 normal subjects and 3 thyrotrophin (TSH)-treated patients with hypopituitarism were assessed before, during and after treatment with 25 mg of Dienoestrol (Glaxo Lab.), orally, daily, during 8 days. Each subject received an iv injection of 150 microCi of 125I followed 6 days later by an iv injection of 75 microCi of [131I]T4. Blood samples and collections of urine were obtained every 12 h. From plasma and urinary (U) radioactivity, the ratio U[125I]/U[131I], U[125I]/PB[125I] and U[131I]/PB[131I] were obtained and served to calculate thyroidal iodine release and non-T4 I secretion by the thyroid gland. T4 I secretion was equivalent to T4 I disposal rate obtained by the semilogarithmic regression line of PB[131I]. In normal subjects, oestrogens decreased T4 I secretion from 491 +/- 57 (SD) nmol/day to 451 +/- 60 nmol (P less than 0.025), while in the same subjects serum TSH increased with oestrogens from 3.3 +/- 1.1 to 6.6 +/- 2.1 mU/l (P less than 0.01). The non-T4 I secretion had a mean of 585 +/- 307 nmol/day during control, 324 +/- 199 nmol during oestrogens (P less than 0.01) and 480 +/- 286 nmol oestrogens (P less than 0.05 vs oestrogens). In the TSH-treated patients oestrogens induced non-significant reductions in T4 I and non-T4 I secretion, although total iodine secretion decreased significantly (P less than 0.05). The data is consonant with a partial inhibition by oestrogens of thyroid gland release.

Inhibition of Thyroidal Iodine Release by Estrogens in Patients with Hyperthyroidism*

The effects of pharmacological doses (25 mg daily, orally) of the estrogen Dienoestrol on thyroidal iodine release of patients with untreated hyperthyroidism were examined. Thyroidal release was assessed by measuring the urinary radioiodide derived from deiodination of endogenously labeled [125I]T4 and the exogenously administered[131I]T4.The ratio of 125I to 131I in urine was plotted on semilogarithmic paper and depicted a slope which reflected thyroidal release. Estrogeninduced a sharp decline of the progressively rising slope in five of the six patients. The slope value for the whole group was 0.153 ± 0.103 in the control phase and 0.013 ± 0.032 during estrogen treatment (P < 0.025). The contribution of iodide recirculation to this effect was evaluated in four hyperthyroid patients who did not receive estrogens. Their mean 7¬day control slope was 0.167 ± 0.086. During days 14¬21, the time period correspondingto the estrogenic phase of the treated group and during which the probable effects of iodide re...

Effect of human chorionic gonadotropin on thyroid function in euthyroid men.

The effect of large doses of commercial hCG on thyroid function was studied in eight men who received 100,000 or 150,000 IU hCG iv. These large doses of hCG produced definite thyroidal iodine release (TIR) responses in all eight men. The TIR after hCG administration was more delayed and of lesser magnitude than the TIR responses to TSH and TRH. There were no significant changes in serum T4, T3, or TSH for 48 h after hCG administration. No clinical side effects were noted in the subjects after iv administration of these large doses of hCG. The results of this study indicate that hCG is a weak thyroid stimulator in man.

Failure of triiodothyronine to inhibit TSH-mediated thyroid hormone release in man.

We studied the effect of short-term triiodothyronine administration on thyroid gland responsivity to exogenous thyrotropin in four euthyroid human subjects. Thyroidal iodine release and serum thyroxine during daily im injections of bovine TSH were not significantly inhibited, despite a four-fold elevation in serum T3 concentrations. This negative finding contrasts with earlier positive reports of a regulatory "short-loop" effect of elevated circulating T3 on the thyroid gland. This difference may be due either to the use in previous murine or in vitro studies of non-physiologic, high doses of exogenous T3, or failure to control the withdrawal of the trophic effect of endogenous TSH in man on the subsequent glandular response.

Lack of indomethacin effect on thyroid function in man.

Administration of indomethacin 200 mg daily for 2 days to four euthyroid volunteers was without significant effect on serum triiodothyronine or thyroxine and caused no cinsistent alteration of serum TSH. There were minor and variable changes in the pattern of thyroidal iodine release (TIR) in these euthyroid subjects. In one subject both the TIR pattern and serum TSH concentration were altered in the same direction, suggesting that these minor changes were of central origin. Indomethacin also had no effect on the stimulated pattern of TIR in one euthyroid subject receiving daily exogenous TSH injections, or in a patient with untreated hyperthyroid Graves' disease. Prostaglandin A1 infusion in one subject did not alter serum TSH or thyroidal iodine release. It is concluded that prostaglandins probably have no obligatory physiological role in modulating TSH or thyroid hormone secretion in man.

The Effect of Elevated Doses of Thyrotropin on Mouse Thyroid

In the course of validating the McKenzie assay it was found that large doses of bovine or rat TSH have a retarding effect on hormonal secretion from the thyroid. TSH in doses less than 10 mU had a maximal effect on thyroidal secretion at about 2-3 h after administration. Doses of TSH in excess of 10 mU caused the peak of secretion to appear at about 9-10 h and caused, as well, a decreased thyroidal iodine release at earlier times. This effect was not due to changes in the pattern of iodocompounds secreted by the thyroid or to a change in the clearance of the blood [125I] thyroxine. An estimate of the integrated secretion with time was linear with log dose up to 100 mU TSH. This pattern of response to TSH is also seen when colloid droplet formation is the parameter studied. cAMP accumulation shows a different pattern of response to TSH. Control levels of cAMP were 1-2 pmoles/mg thyroid. Doses of TSH smaller than 5 mU caused no significant increase in cAMP. With a further increase in TSH up to 200 mU per mouse, cAMP levels increased linearly with the log of TSH and reached 400 pmoles/mg thyroid. Theophylline administered together with large doses of TSH increased the level of the thyroidal cAMP and further decreased the release of iodocompounds at 2 h. These results indicate that there may be an intrathyroidal mechanism which prevents a surge of secretion of thyroid hormones with acute changes in blood TSH levels. The mechanism sensitive to excess TSH is probably associated with steps in thyroidal activation between the accumulation of cAMP and colloid droplet formation.

Failure of propranolol to alter thyroid iodine release, thyroxine turnover, or the TSH and PRL responses to thyrotropin-releasing hormone in patients with thyrotoxicosis.

A dual isotope method allowing simultaneous analysis of both endogenous thyroidal release and peripheral thyroxine disposal was employed in four patients with thyrotoxicosis before and during propranolol therapy (160 mg/day) to determine whether beta adrenergic blockade with this agent affected the secretion or metabolism of thyroid hormone. Since catecholamines may be involved in the regulation of both thyrotropin (TSH) and prolactin (PRL) release from the pituitary, the effect of propranolol on the TSH and PRL responses to thyrotropin-releasing hormone (TRH) was also examined. In the dosage employed in these patients, propranolol had no demonstrable effect on either thyroid hormone secretion, the peripheral disposal of T4, or the TSH and prl responses to TRH.

The effects of lithium on thyroid iodine release in patients with primary affective disorder.

Thyroid iodine release measured by the double isotope method of Nicoloff was studied in patients with manic-depressive illness before, during and after treatment with lithium carbonate. The urinary 125I/131I isotope ratio was measured following administration of Na125I and 131I-thyroxine. In three of four subjects, lithium caused a transient decrease in diurnal variation and a temporary reduction in the normal increase of the 125I/131I ratio during the first week of therapy or after a lithium dose increase. In addition, in two of three subjects, a rebound increase in the isotope ratio occurred following cessation of lithium administration. These changes most likely represent a direct inhibitory effect of lithium on the thyroid iodine release process.

Assessment of thyrotropin-releasing hormone and thyrotropin reserve in man.

Endogenous thyrotropin-releasing hormone (TRH) reserve and pituitary thyrotropin (TSH) reserve were assessed in four normal subjects, three patients post-cryohypophysectomy, one patient with a hypothalamic lesion secondary to trauma, and four patients with Sheehan's syndrome. TSH reserve was determined by the immunoassayable TSH response to 500 mug TRH given i.v. (TRH stimulation test). TRH reserve was assessed by the rebound response in thyroidal iodine release (TIR) following withdrawal of pharmacologic doses of prednisolone (glucocorticoid withdrawal test). When compared with normals, the post-cryohypophysectomy patients demonstrated parallel impairment of TRH stimulation and glucocorticoid withdrawal testing. The patient with the hypothalamic lesion and the four patients with Sheehan's syndrome all had normal TRH stimulation tests, indicating adequate TSH reserve capacity, yet had abnormal glucocorticoid withdrawal tests, indicative of impairment in endogenous TRH reserve or neurohumoral transport. Three of the patients (hypothalamic injury and two Sheehan's) with impaired TRH reserve were euthyroid. THE FOLLOWING CONCLUSIONS WERE REACHED: (a) A combination of the TRH stimulation test and glucocorticoid withdrawal test may allow for differentiation between pituitary and suprahypophyseal disorders. (b) Certain cases of Sheehan's syndrome appear to have impaired endogenous TRH reserve or transport. (c) Euthyroidism can be maintained in spite of diminished TRH reserve.

Selective breeding for variations in thyroidal iodine release rate in mice.

SUMMARY Mice were selectively bred for high and low thyroidal 131I release rates. Two lines with sharp contrast in the selection criterion were produced, and an estimate of heritability was made. There were correlated differences in thyroid histology, protein-bound 131I, cholesterol level, haematocrit, adrenal and testicular weights, and some behavioural characteristics. It was concluded that multiple genetic factors affect the rate of thyroidal iodine release, and that the high release strain had greater thyroid activity than the low release strain. Some genetic aspects of thyroid function are discussed.

The use of lithium in the treatment of thyrotoxicosis.

Since lithium has been shown to inhibit release of iodine from the thyroid, we have investigated its therapeutic potential in thyrotoxicosis. Eight detailed (131)I kinetic studies were performed on seven thyrotoxic women and data was analyzed using a computer program. Lithium at serum levels of about 1 mEq liter decreased the loss of (131)I from the thyroid, led to a fall in serum (131)I levels and diminished urinary (131)I excretion. Computer simulation of the lithium effect required, in every case, that lithium inhibit hormonal and nonhormonal thyroid iodine release. In five cases a second lithium effect was required for a satisfactory fit of the model soluton with observed data: namely, an inhibition of hormone disappearance from serum. NEITHER INHIBITION OF RELEASE NOR OF HORMONE DISAPPEARANCE SEEMED TO BE AFFECTED BY METHIMAZOLE (RELEASE: 52% decrease without methimazole, 60% with methimazole; hormone disappearance: approximately 60% decrease in both). When Li(+) was discontinued, recovery of the iodine release rate and hormone disappearance rate over the observed time span was variable, ranging from no recovery to rates that exceeded pre-Li(+) values. When Li(+) is used alone its effect on serum hormone levels is diminished due to continued accumulation of iodide by the thyroid. Thus, serum thyroxine-iodine levels fell 21-30% in 6-8 days in patients who did not receive methimazole and 15-67% in the methimazole-treated subjects. For prolonged therapy, therefore, a thiocarbamide drug must be used in conjunction with Li(+). The similarity of inhibition of iodine release from the thyroid produced by Li(+) and iodides is discussed.

Alterations in thyroid iodine release and the peripheral metabolism of thyroxine during acute falciparum malaria in man.

Previous studies of thyroid function during various infections have yielded conflicting results, but most have suggested an acceleration of peripheral thyroxine (T(4)) turnover during the acute infectious illness. In the present studies, thyroid function was examined by a method allowing simultaneous analysis of both endogenous thyroidal release and peripheral T(4) disposal in normal volunteers after induction of acute falciparum malaria. Subjects received iodide-(125)I, followed in 5-7 days by (131)I-T(4) intravenously. 4 days later, infection was induced by the injection of parasitized red blood cells. Bidaily measurements of serum protein-bound (125)I and protein-bound (131)I, and urinary (125)I and (131)I, together with frequent estimates of serum (127)I-T(4) (Murphy-Pattee) and free T(4) (FT(4)), were made during a control period, during acute illness, and during convalescence. Alterations in the peripheral metabolism of (131)I-T(4) during infection included significant decreases in the fractional disappearance rate for T(4) [(k)], and in the clearance and daily disposal of T(4), all of which returned to control values during convalescence. Total serum (127)I-T(4) increased late in the infected period to become greater during convalescence than either before or during infection, while FT(4) did not increase significantly until convalescence. An analysis of serum (131)I-T(4)/(127)I-T(4) and (131)I-T(4)/PB(125)I ratios confirmed these observations. The slope with time of ratios for urinary (125)I/(131)I, a reflection of thyroidal iodine release, was decreased during infection, but rebounded to control values during the convalescent period. The observed increments in serum (127)I-T(4) concentration in the convalescent phase may reflect in part the slowing of (k), but together with the rising ratios of urine (125)I/(131)I suggests enhanced thyroidal T(4) secretion immediately after the acute illness. Thus, with malarial infection, there appears to be an initial depression followed by a rebound in rates of thyroidal iodine release. In contradistinction to other infections, fractional turnover and daily disposal of hormone is decreased in malaria, perhaps due to hepatic dysfunction and the consequent impairment in cellular deiodinative processes.

Estimation of the triodothyronine secretion rate in euthyroid man.

ABSTRACT Daily T3 secretion rates were estimated in 6 euthyroid subjects by administering increasing doses of triiodothyronine (T3) and utilizing suppressibility of thyroidal iodine release (TIR) as an endpoint. Daily T4 and T3 production rates were calculated so that T4 to T3 interconversion could be estimated. The estimated mean daily T3 secretion rate for the 6 subjects was 16 μg, while the T3 derived from peripheral interconversion was determined to be 12 μ/day. Therefore, approximately 58% of circulating T3 is derived from thyroid gland secretion and 42% from peripheral T4 to T3 interconversion. Since the mean daily T4 production was 92 μg, the amount of T4 metabolized via interconversion to circulating T3 would approximate 15%. The effects of pharmacological doses of T3 on TIR were also studied. It was noted that oral administration of 50 μg of T3 every 8 hr did not achieve full suppression of TIR. The addition of pharmacological doses of prednisolone, 20 mg every 8 hr to the high doses of T3, marke...

Comparison of the effects of various agents on thyroidal adenyl cyclase activity with their effects on thyroid hormone release.

SUMMARY Intact mouse thyroid glands were used to measure the formation of cyclic [3H]AMP from [3H]adenine, and the release of thyroidal iodine. These two parameters of thyroid activity responded to similar concentrations of human thyroid-stimulating hormone (TSH). Both were stimulated by prostaglandin E1, although the response was always very much less than to TSH. Both were inhibited by NaF, which appeared to have a toxic effect on the gland. The response to TSH was in each case reduced by lithium, suggesting that the antithyroid effect of Li+ is associated with a direct action on adenyl cyclase; however, Li+ also reduced thyroidal hormone secretion induced by dibutyryl cyclic AMP and may therefore have a second site of action. In general, the effects of these agents on cyclic [3H]AMP formation correlated well with their effects on thyroidal iodine release. The results support the hypothesis that the activation of adenyl cyclase is closely associated with, and precedes, thyroid hormone secretion.

KI and imidazole inhibition of TSH and c-AMP induced thyroidal iodine secretion.

We have previously reported that KI inhibits TSH-induced release of radioiodine (McKenzie TSH bioassay method) by 60%. In this investigation the action of KI was studied on c-AMP induced iodine release. A 55% inhibition was found. The results indicate that KI inhibits thyroidal iodine release at a step further than c-AMP formation. When imidazole was injected 20 min before the intravenous administration of TSH, a 50 % inhibition of the response in the McKenzie assay was observed. This drug failed to affect TSH-induced release of radioiodine when given 20 min after the iv injection of hormone, indicating that the triggering effect of the hormone is rapid. Although imidazole is known to increase phosphodiesterase activity and block c-AMP action in some tissues, we could not demonstrate this action in mouse thyroid homogenates. Similar inhibition of TSH action was observed when methylmercaptoimidazole, thiouracil, or thiourea was administered 20 min before TSH. The mechanism of the shortterm effect of these ...

Stimulation of release of thyroid iodine by serum of thyroid-immunized rabbits.

ABSTRACT A double-isotopic modification of the McKenzie assay has been devised. The serum of certain rabbits immunized with human thyroid microsomes caused true thyroid iodine release in the test mice, but also induced a marked shift of labeled T4 from tissues into plasma. This accounted for some of the apparent “thyroid stimulation” seen in the standard McKenzie assay of such sera. In the case of many thyroid-immunized sera of lower activity, the double-isotopic method revealed that thyroid stimulation was nonexistent.

The role of glucocorticoids in the regulation of thyroid function in man.

The diurnal variation in thyroidal iodine release previously observed in euthyroid subjects appears to correlate with variations in serum immunoassayable thyrotropin (TSH). The hypothesis is advanced that this diurnal rhythm seems to be primarily regulated by a negative feedback action of circulating hydrocortisone. The administration of maintenance doses of hydrocortisone to patients with primary adrenal insufficiency and pharmacological doses to euthyroid subjects was accompanied by an acute suppression in both thyroidal iodine release and serum TSH values. An escape from glucocorticoid suppression was observed to occur in 2 or 3 days with the resumption of a near-normal thyroidal iodine release rate but was accompanied by a dampening or absence of the normal diurnal rhythm. Withdrawal of pharmacological doses of glucocorticoids in euthyroid subjects and maintenance doses in primary hypoadrenal patients was accompanied by transient stimulation of both serum TSH and thyroidal iodine release values. The study of a patient before and after cryohypophysectomy indicated that the rebound response in thyroid release after steroid withdrawal may be a useful testing procedure to indirectly assess the hypothalamicpituitary reserve capacity of TSH.

A new method for the measurement of thyroidal iodine release in man.

A new method is described for the detection of variations in the release rate of all iodinated products by the thyroid gland in man. (125)I was employed to endogenously label the thyroid gland, and a parenterally administered (131)I thyroxine dose was used to generate a (131)I reference source. Thyroidal iodine release activity was quantitatively assessed by the measurement of variations in (125)I/(131)I ratio values obtained in timed urine samples. Diurnal variation in thyroid release patterns was observed in euthyroid subjects which was promptly suppressed by exogenous triiodothyronine administration and was simulated by the intramuscular injection of 0.25-0.50 U of bovine thyrotropin. The zenith value occurred at 4:00 a.m. +/-3.4 hr (SD) and the nadir at 5:00 p.m. +/-3.6 hr. The absence of a diurnal pattern in patients with thyrotoxicosis and in secondary hypothyroidism indicated that this diurnal fluctuation was under thyrotropin (TSH) regulation. This new method also promises to be a useful tool for the study of the intrathyroidal recycling of iodide from the iodotyrosine pool and the detection of factors which may acutely alter thyroid function.