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To develop a test of pituitary-thyroid responsiveness to thyrotropin-releasing hormone that would obviate the need for measuring serum thyrotropin, we determined serum thyrotropin, thyroxine, and tri-iodothyronine concentrations before and at frequent intervals after the intramuscular administration of 2 mg of thyrotropin-releasing hormone in normal subjects and in patients with a variety of thyroid disorders. In specimens obtained four and five hours after administration of the hormone to normal subjects, serum thyroxine concentration increased 2.4 plus or minus 0.7 mug per 100 ml (mean plus or minus S.D.) over base-line values, the magnitude of increase being greater than 1.5 mug per 100 ml in 32 of 34 subjects. Serum thyroxine concentrations after administration of thyrotropin-releasing hormone did not increase in 11 hyperthyroid patients. Of 13 with hypothyroidism, increases in 12 were 0 to 0.7 mug per 100 ml; in one the increment was 1.2 mug per 100 ml. Measurement of the serum thyroxine response to intramuscular thyrotropin-releasing hormone will usually suffice to determine the integrity of the hypothalamic-pituitary-thyroid complex.

In 9 euthyroid obese volunteers, 4 weeks of total caloric deprivation resulted in striking decreases in both total and free triiodothyronine (T3) concentrations in serum together with a slight increase in free thyroxine (T4) concentration. These changes were not associated with alterations in the basal serum TSH concentration or in the TSH or T3 responses to exogenous TRH. It is suggested that the decrease in serum T3 concentration that occurs during starvation results from decreased peripheral conversion of T4 to T3 and may explain, at least partially, the decreased serum T3 seen in clinical states associated with inanition.

The pattern of response of serum thyrotropin (TSH), thyroxin (T4), triiodothyronine (T3) and the thyroidal uptake of carrier free 131I was evaluated in adult male rats receiving a single, large SC injection of TRH (100 µg). Serum TSH was strikingly increased 1 hr after TRH and remained elevated at 2 hr. This increase in endogenous TSH stimulated the release of T3 and T4 from the thyroid. The peak rise in serum T3 concentration above base line values was proportionally greater than that observed for serum T4. Finally, the increase in serum TSH resulted in an initial decrease followedby an increase in the thyroid 131I uptake.(Endocrinology 95: 1767, 1974)

In 9 euthyroid obese volunteers, as previously reported, 4 weeks of total caloric deprivation resulted in a striking decrease in serum 3,5;3'-triiodothyronine (T3) concentration. The present studies reveal that this decrease in serum T3 is accompanied by a proportionately similar increase in the serum concentration of 3,3',5' -T3 (reverse T3; rT3). In four additional obese volunteers given suppressive doses of sodium-Lthyroxine (T4) for 1 month prior to fasting, serum T3 concentration declined sharply during a 6-11 day period of fast, while rT3 concentration increased strikingly. Concentrations of both T3 and rT3 returned to control values during a 5 day period of refeeding. The findings indicate that caloric deprivation results in an alteration in peripheral T4 metabolism away from generation of T3 and toward the generation of rT3. Since the former is more active than T4, and the latter is essentially inactive, caloric deprivation appears to shunt peripheral T4 metabolism from activating to inactivating pathways.

The administration of exogenous iodides (saturated solution of potassium iodide, SSKI) to normal male volunteers resulted in a significant decrease in the serum concentration of thyroxine (T(4)) and triiodothyronine (T(3)) and a significant increase in serum concentration of thyrotropin (TSH). During the control period (phase I), serum concentrations of T(4) averaged 6.9+/-1.8 mug/100 ml (mean +/-SD), T(3) 106+/-15 ng/100 ml, and TSH 3.7+/-1.3 muU/ml. During the administration of 1 drop of SSKI twice daily for 11 days (phase II), there was a small but significant decrease in the serum concentration of T(4) and T(3) (5.8+/-1.6 mug/100 ml and 91+/-19 ng/100 ml, respectively) and a small but significant increase in the serum concentration of TSH (6.0+/-3.5 muU/ml). During the administration of 5 drops of SSKI twice daily (phase III) over the following 12-19 days, these changes persisted, except for a small increase in the serum concentration of T(3) (97+/-20 ng/100 ml), which was statistically significant when compared to values obtained during phase II. Values returned to control levels 14 days after withdrawal of SSKI. Almost all these observed changes took place within the limits of the normal range. It is postulated that, in euthyroid individuals, iodides specifically inhibit release of T(4) and probably of T(3). The resulting slight decrease in values for serum T(4) and T(3) elicits a small increase in TSH secretion which, it is postulated, antagonizes the inhibition of hormone release induced by iodides. As a result, a new equilibrium is reached which maintains the euthyroid state.

The iodinated compounds in the nodular and paranodular tissues of 19 cases of nodular goitre have been separated by thin-layer chromatography. A high monoiodotyrosine/di-iodotyrosine ratio was found in “cold” nodules, and a low one in “hot” nodules. Two unknown iodinated compounds have been detected in the nodular and paranodular tissue in some cases, and evidence is presented suggesting that these are iodinated lipids. Their possible role in diverting iodine from the normal metabolic pathway is discussed.

A case of a partial defect of the iodide trapping mechanism is presented. The patient, a 9-yr-old boy, had a goiter, and a bone and mental age of 5 yr. The thyroidal radioiodine uptake and clearance were decreased and did not increase after TSH stimulation. Although the saliva/plasma ratio of iodide was definitely decreased, the iodide-trapping capacity of the salivary glands was not entirely absent. The thyroid/medium ratio of iodide in slices of thyroid tissue was 1.7. Light and electron microscopic studies were consistent with a functionally hyperactive gland. Biochemical investigation of the thyroid tissue showed a low iodine concentration and a poor iodination of thyroglobulin.

In 6 castrated patients with the complete testicular feminization syndrome, values for total and free thyroxine (T4) concentration in serum, as well as the T4-binding capacities of thyroxine binding globulin (TBG) and thyroxine binding prealbumin (TBPA), were within normal limits. As expected, patients with TFS responded to 0.02 mg ethinyl estradiol daily with increases in both the T4-binding capacity of TBG and the concentration of serum T4 and a decrease in the proportion of free T4. The magnitude of the responses was similar to that obtained in 3 normal patients given the same dose of ethinyl estradiol. In a normal patient receiving ethinyl estradiol, norethandrolone (40 mg daily) produced the expected decrease in TBG and total T4 concentration and increase in the percentage of free T4. In contrast, in 4 patients with TFS receiving ethinyl estradiol, norethandrolone did not influence TBG, total serum T4 concentration, or the proportion of free T4. A similar lack of effect of norethandrolone on TBG was ...

Studies of the effect of norethandrolone on the transport and peripheral metabolism of thyroxine were carried out in four patients lacking thyroxine-binding globulin. Before norethandrolone administration, values for serum protein-bound iodine (PBI) were decreased (1.8 ±0.5 μg/100 ml) and the proportion of free thyroxine increased (0.036 ±0.008%). As a result, values for the absolute concentration of free thyroxine iodine were at the lower end of the normal range (0.63 ±0.12 mμg/100 ml). During the control thyroxine-turnover study, the thyroxine distribution space was strikingly increased (18.2 ±7.9 liters) and the fractional rate of thyroxine turnover moderately increased (17.1 ±11.3%/day), as compared to the expected mean values for normal subjects. Therefore, calculated values for the daily rate of thyroxine clearance were increased even more, ranging between 255 and 500% of normal values. However, owing to the low PBI in these patients, the daily disposal of thyroxine iodine was similar to that expected in normals on the basis of age and weight. During the administration of norethandrolone, the thyroxine-binding capacity of the thyroxine-binding prealbumin increased strikingly in all patients, values averaging 162% of those found during the control period. This increase was associated with a highly significant increase in PBI (133% of control values) and a small but significant decrease in the proportion of free thyroxine, resulting in no significant change in the absolute concentration of free thyroxine iodine. In all four patients, administration of norethandrolone was associated with a pronounced decrease in the thyroxine distribution space to values which averaged 69% of those found during the control period. Values for the fractional rate of thyroxine turnover increased slightly. As a result, thyroxine-clearance rate decreased in all patients. Owing to the reciprocal changes in clearance rate and PBI, no significant change in total daily thyroxine disposal was observed. The present studies reveal that when the thyroxine-binding prealbumin is increased in patients lacking thyroxine-binding globulin, several indices of peripheral thyroxine transport and metabolism are altered. However, these changes were small, even in the absence of thyroxine-binding globulin. It is suggested, therefore, that the effect of changes in thyroxine-binding prealbumin would be even smaller in individuals in whom thyroxine-binding globulin is present.

Studies of the effect of L-thyroxine administration (0.3 mg daily for 7-9 wk) on the peripheral metabolism of (131)I-labeled triiodothyronine (T(3)) and (125)I-labeled thyroxine (T(4)) and on the concentration and binding of T(4) and T(3) in serum were carried out in 11 euthyroid female subjects. Administration of L-thyroxine led to consistent increases in serum T(3) concentration (137 vs. 197 ng/100 ml), T(3) distribution space (39.3 vs. 51.7 liters), T(3) clearance rate (22.9 vs. 30.6 liters/day) and absolute T(3) disposal rate (30 vs. 58 mug/day), but no change in apparent fractional turnover rate (60.3 vs. 60.6%/day). The proportion and absolute concentration of free T(3) also increased during L-thyroxine administration. Increases in serum total T(4) concentration (7.3 vs. 12.8 mug/100 ml) and in both the proportion and absolute concentration of free thyroxine also occurred. In five of the subjects, the kinetics of peripheral T(4) turnover were simultaneously determined and a consistent increase in fractional turnover rate (9.7 vs. 14.2%/day), clearance rate (0.84 vs. 1.37 liters/day), and absolute disposal rate (64.2 vs. 185.0 mug/day) occurred during L-thyroxine administration. Despite these increases in the serum concentration and daily disposal rate of both T(4) and T(3), the patients were not clinically thyrotoxic. However, basal metabolic rate (BMR) values were marginally elevated and, as in frank thyrotoxicosis, T(4)-binding capacities of thyroxine-binding globulin (TBG) and thyroxine-binding prealbumin (TBPA) reduced, suggesting that subclinical thyrotoxicosis was present. Thus, the often recommended replacement dose of 0.3 mg L-thyroxine daily may be greater than that required to achieve the euthyroid state. The studies have also provided additional evidence of the peripheral conversion of T(4) to T(3) in man and have permitted the calculation that approximately one-third of exogenously administered T(4) underwent deiodination to form T(3). To the extent that a similar fractional conversion occurs in the normal state, it can be calculated that a major fraction of the T(3) in serum derives from the peripheral deiodination of T(4) and that only a lesser fraction derives from direct secretion by the thyroid gland.

The degree of exophthalmos and the width of the palpebral fissure were studied serially in 58 previously thyrotoxic patients, who were divided into 6 treatment groups: 1. guanethidine eye drops; 2. oral thyroxine; 3. guanethidine eye drops and oral thyroxine; 4. guanethidine and prednisolone eye drops; 5. napththazoline nitrate 0.1% and zine sulfate 0.5% eye drops; and 6. metronidazole orally. Exophthalmos increased significantly in the first and third group, and the palpebral fissure decreased in the first group. It was concluded that guanethidine eye drops should be given when there is marked lid retraction with minimal exophtalmos; that prednisolone eye drops are not indicated in endocrine exophthalmos; and that the combination of guanethidine eye drops with oral thyroxine in different dosages is worth further study.

Studies were performed in 6 patients with proven Hashimoto's disease and one patient with probable Hashimoto's disease who were initially euthyroid, as judged from clinical findings, serum thyroxine (T4) and serum TSH concentrations. When these patients were given saturated solution of potassium iodide (5 drops containing approximately 180 mg of iodide daily), 4 of the 7 developed hypothyroidism within 4 to 6 weeks as evidenced by clinical findings, subnormal values for serum T4, and elevated values for serum TSH concentration. Values quickly returned to normal when iodides were withdrawn. In the remaining 3 patients, evidence of hypothyroidism did not develop despite continuation of iodide administration for as long as 17–30 weeks. No obvious differences between the 4 patients who developed iodide myxedema and the 3 who did not were evident in respect to known duration of the disease, size of goiter, initial level of thyroid function or intensity of the auto-immune process as judged by circulati...

The administration of pharmacologic quantities of iodine such as iodides for the treatment of pulmonary disease, organic iodine present in medications and x-ray contrast dyes, and the ingestion of iodine-rich natural foods, may result in goiter, hypothyroidism, or hyperthyroidism, especially in patients with underlying thyroid disease. Medications containing iodide may induce hypothroidism in euthyroid patients with Hashimoto's thyroiditis, 131I or surgically treated Graves' disease, or following hemithyroidectomy for nodules; and they may induce hyperthyroidism in patients with endemic iodine-deficient goiter, autonomous nodules or nontoxic nodular goiter, or in patients recently treated with antithyroid drugs for Graves' disease. Rarely, hypothyroidism or hyperthyroidism may develop in patients with completely normal thyroid function during administration of iodide. The etiology of iodide-induced goiter and hypothyroidism in patients with cystic fibrosis remains obscure. Iodide-induced myxedema may also occur in patients receiving drugs which alter thyroid function, such as lithium, phenazone, and sulfisoxazole. Finally, iodides do have a role in the treatment of hyperthyroidism but their use should probably be restricted to thyroid storm, preoperative preparation of the hyperthyroid patient, and following 131I treatment.

To determine whether pituitary thyrotropin (TSH) responsiveness to thyrotropin-releasing hormone (TRH) is enhanced by small decreases in serum thyroxine (T4) and triiodothyronine (T3), 12 euthyroid volunteers were given 190 mg iodide po daily for 10 days to inhibit T4 and T3 release from the thyroid. Basal serum T4, T3, and TSH concentrations and the serum T4 and TSH responses to 400 mug TRH i.v. were assessed before and at the end of iodide administration. Iodide induced small but highly significant decreases in basal serum T4 (8.0+/-1.6 vs. 6.6+/-1.7 mug/100 ml; mean +/- SD) and T3 (128+/-15 vs. 110+/-22 ng/100 ml) and increases in basal serum TSH (1.3+/-0.9 vs. 2.1+/-1.0 muU/ml). During iodide administration, the TSH response to TRH was significantly increased at each of seven time points up to 120 min. The maximum increment in serum TSH after TRH increased from a control mean of 8.8+/-4.1 to a mean of 13.0+/-2.8 muU/ml during iodide administration. As evidence of the inhibitory effect of iodide on hormonal release, the increment in serum T3 at 120 min after TRH was significantly lessened during iodide administration (61+/-42 vs. 33+/-24 ng/100 ml). These findings demonstrate that small acute decreases in serum T4 and T3 concentrations, resulting in values well within the normal range, are associated both with slight increases in basal TSH concentrations and pronounced increases in the TSH response to TRH. These results demonstrate that a marked sensitivity of TSH secretion and responsiveness to TRH is applicable to decreasing, as well as increasing, concentrations of thyroid hormones.

Many studies of TRH physiology have been based on the radioimmunoassay of TRH in urine. In view of the inability of serum to deactivate urine TRH and the interference of urea with the TRH assay, measurement of urine TRH by radioimmunoassay may not be a true reflection of the actual concentration of TRH.

Studies of pituitary and thyroid function were conducted in adult rats with the syndrome of neonatal thyrotoxicosis (NT) produced by the administration of large doses of L-thyroxine during the first week of postnatal life. As compared to normal controls,adult NT rats displayed decreased thyroid I31I uptake, an increase in the proportion ofthyroid organic 131I present as monoiodotyrosine and a decreased proportion of the iodothyronines,thyroxine (T4)and triiodothyronine, findings consis-)tent with those seen in association with deficiency of TSH. In addition,serum T4 concentrations were consistently lower in adult NT than in control rats. Adult NT rats displayed marked decreases in TSH secretory reserve, as indicated by lower values of basal serum TSH concentration following thyroidec-tomy and far lower increments in serum TSH concentration following standard doses of TRH iv, even when NT and control rats had all been thyroidectomized and maintained for long periods on replacement doses of L-thyroxine. Abn...

The serum thyrotropin (TSH) response to thyrotropin-releasing hormone (TRH, 100 mug i.v.) was evaluated prior to and at various times following the oral administration of single doses of liothyronine (100 mug) given at weekly intervals. The TSH response to TRH was mildly depressed when TRH was given 1 hr after liothyronine administration when the serum triiodothyronine (T3) concentration was strikingly elevated, was markedly reduced 16 and 24 hr after liothyronine, was essentially abolished 3 days after liothyronine when the serum T3 concentration was normal, and was normal 7 days after liothyronine administration. These findings suggest that the more prolonged suppression of TRH responsiveness, observed following the withdrawal of long-term excess endogenous or exogenous thyroid hormones, cannot be ascribed to the intrinsic duration of action of the hormone present at the time of withdrawal, but rather to the prolonged extent of the suppression itself.

The effect of a single large intramuscular injections of TRH (2 mg) on the thyroid 131I uptake in normal man was assessed at varying intervals following the administration of TRH. When the 131I was given simultaneously with TRH, the 3- and 5-hour 131I uptake decreased. When the 131I was administered 8 hours after TRH, the thyroid 131I increased significantly. This response in uptake is similar to that observed in the rat following TSH stimulation. The present study defines the time course of the thyroid 131I uptake response to endogenous TSH stimulation.

The effect of small doses of cyclohex-imide (CH) (0.5 µg/g body wt) on the intrathyroid metabolism of carrier-free 13II and stable iodide iniodine-sufficient and iodine-deficient rats and on thyroglobulin (Tgb) maturation in iodine-deficient rats was studied. This dose of CH had no apparent toxicity but strikingly inhibited the incorporation of l4C-labeled amino acids into thyroid and plasma proteins. In iodine-sufficient rats, CH did not affect T/S (I−) ratios, but did enhance the sensitivity of the thyroid to the acute inhibitory effects of stable iodide on the organification mechanism (Wolff-Chaikoff effect). CH produced unusual effects on the intrathyroid metabolism of 131I in these iodine-sufficient rats: a decrease in 13II uptake, an increase in labeled DIT and a decrease in MIT so that MIT/DIT ratio declined, and a decrease in the proportionate synthesis of the iodothyronines T4 and T3. In iodine-deficient rats, CH also sensitized) the thyroid to the acute Wolff-Chaikoff effect but produced changes...

The pattern of thyrotropin secretion was analyzed in seven euthyroid women, before and after withdrawal of long-term thyroid hormone, by serial measurements of thyroid 131l uptake, serum thyroxine, tri-iodothyronine, and thyrotropin concentrations, and the response to thyrotropin-releasing hormone. During exogenous hormone administration, 131l uptake was suppressed, and serum thyrotropin concentrations before and after administration of thyrotropin-releasing hormone were undetectable. After withdrawal of exogenous hormone, thyrotropin secretory function was transiently impaired, as indicated by undetectable basal thyrotropin concentrations together with absence of response to thyrotropin-releasing hormone, and subsequently by normal values of basal thyrotropin concentration and normal responses to releasing hormone while serum thyroxine and tri-iodothyronine concentrations were subnormal. Decreased thyrotropin reserve persisted for two to five weeks. Detectable values of serum thyrotropin (less than 1.2 muU per milliliter) and a normal 131l uptake usually occurred concurrently in two to three weeks. Serum thyroxine concentration returned to normal at least four weeks after hormone withdrawal.

The daily administration of propranolol (5–20 mg/kg) to the intact male rat does not effect the serum thyroxine concentration or the peripheral metabolism of 131 I-labeled thyroxine. Except for a small decrease in 131 I-labeled triiodothyronine, propranolol did not effect the intrathyroidal metabolism of 131 I. These findings further suggest that the efficacious use of propranolol in the treatment of many of the signs and symptoms of thyrotoxicosis may not be associated with alterations in thyroid gland function or in the peripheral metabolism of thyroxine.

A simple, highly reproducible, and accurate method for the specific measurement of thyroxine in serum is described. This method depends upon the competitive protein-binding principle developed by Murphy and Pattee, but the method appears to be far simpler and more convenient than other methods based upon this principle. The results obtained by the present method and by a standard Murphy-Pattee technique in various clinical states are essentially indistinguishable, are not influenced by iodine containing compounds, accurately diagnose the presence of hyperthyroidism or hypothyroidism, and are affected in the expected manner by changes in the activity of the thyroxine-binding proteins.

The serum concentrations of triiodothyronine (T3) and thyrotropin (TSH) measured by radioimmunoassay, and that of thyroxine (T4), measured by competitive protein binding assay, were assessed in goitrous and nongoitrous subjects residing in an area of moderate iodine deficiency in Greece. Results were compared to those obtained in a group of age-matched control subjects residing in Boston, an area of adequate iodine intake. Serum T4 concentrations were within the normal range in both goitrous and non-goitrous Greek subjects, but were nevertheless significantly lower than in the Boston controls. Serum T3 concentrations in the nongoitrous Greek subjects were similar to those in the Boston group, but values in the goitrous Greek subjects were significantly increased. Serum TSH concentrations in the Greek subjects were, with one exception, within the normal range and were almost identical to those in the Boston controls. It is suggested that endemic iodine deficient goiter in Greece is the result of a...

The syndrome of iodide-induced hyperthyroidism (Jodbasedow) is not common and has been reported to occur in patients with iodine-deficient goiter after iodide replenishment. As part of a larger study to assess the effects of iodide administration on thyroid hormone synthesis in normal subjects and in patients with various underlying disorders of the thyroid, iodides (5 drops of a saturated solution of potassium iodide) were administered to eight patients with nontoxic goiter residing in Boston, an area of iodine sufficiency. Hyperthyroidism developed during and after iodide administration in four of the eight — an unexpectedly high frequency. This finding suggests that the homeostatic mechanism controlling thyroid hormone synthesis and release in these patients is not functioning normally. We recommend that large doses of iodides not be administered to patients with nontoxic goiter.

Corticosteroid therapy of acute nonsuppurative thyroiditis is often the treatment of choice. However, relapse either during or following corticosteroid withdrawal is frequent. It is suggested that steroid therapy be maintained until the thyroidal 131I uptake returns to normal or above normal.

The serum concentrations of testosterone, estradiol-17β, FSH and LH were measured in 22 male subjects addicted to heroin or methadone. Serum testosterone concentration was decreased in many of these subjects without consistent abnormalities in the other hormones. It is suggested that decreased sexual function in male addicts may be partially due to a decrease in serum testosterone concentration.

The chronic use of methadone or heroin results in various abnormalities in the transport and peripheral metabolism of thyroxine (T4). An increase in the thyroxine-binding capacity of the t...

Excerpt To the editor: Bilateral adrenal hemorrhage with resultant acute adrenal insufficiency has been recognized as a fatal complication of anticoagulant therapy (1, 2). Only rarely has this medi...