Search

Reverse T3 (3,3',5'-triiodothyronine, rT3), a major product of the peripheral monodeiodination of thyroxine (T4), was administered to normal male volunteers in doses sufficient to sustain an elevated serum rT3 concentration similar to that frequently observed in patients with nonthyroidal illness. No changes in basal serum T4, T3, TSH and prolactin concentrations, nor in the T3, TSH and prolactin responses to iv TRH were observed during rT3 administration. These findings suggest that physiologic increases in serum rT3 concentration probably do not inhibit T4 to T3 conversion or the anterior pituitary TSH and prolactin responses to thyrotropin-releasing hormone (TRH).

To determine the role of thyrotropin-releasing hormone (TRH) in the regulation of thyroid-stimulating hormone (TSH) secretion in the perinatal period, a physiological approach of neutralizing circulating TRH in the fetal and early neonatal rat was employed. TRH-antiserum (TRH-AS) raised in rabbits and administered daily to low iodine-propylthiouracil (LID-PTU)-fed pregnant rats from days 12 to 19 of gestation markedly impaired the rise in serum TSH to LID-PTU when compared with normal rabbit serum-treated controls. In contrast, fetal serum TSH was unaffected by TRH-AS. The binding capacity of TRH-AS in the fetal serum (111 ng/ml) far exceeded circulating TRH in the fetus. Similarly, acute TRH-AS administration to the pregnant rat fed LID-PTU markedly decreased the serum TSH concentration in the mother, but not in the fetus, 60 min after TRH-AS administration. Chronic TRH-AS administration to neonatal rats whose nursing mothers were fed LID-PTU was in-effective in decreasing the elevated serum TSH in the neonate through day 8 of life, whereas a slight but significant decrease in serum TSH was observed on day 10. Chronic daily TRH-AS administration to neonatal rats through day 10 of life had no effect on the later development of the hypothalamic-pituitary-thyroid axis. These findings suggest that TRH does not participate in TSH regulation during the perinatal life in the rat and that thyroid hormones are probably the main regulators of TSH secretion during this period. Placental TRH is not important in regulating TSH secretion in the fetal rat. Furthermore, TRH “deprivation” during neonatal life does not prevent normal later development of the hypothalamic-pituitary-thyroid axis.

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.

Chronic diphenylhydantoin (DPH) administration (5 mg x 100 g body wt-1 x day-1) to the normal rat is associated with a decrease in the serum thyroxine (T4) and triiodothyronine (T3) concentrations without an appropriate rise in the serum thyrotropin (TSH) concentration, suggesting a possible direct effect of DPH on TSH secretion. To further study this possibility, DPH was administered chronically to thyroidectomized, hypothyroid rats. In the hypothyroid rats treated chronically with DPH, serum TSH did not increase, pituitary TSH content was significantly decreased, and the serum TSH response to thyrotropin-releasing hormone (TRH) was decreased compared to that of diluent-treated, hypothyroid rats. Hypothalamic TRH content was similar in DPH and diluent-treated rats. These findings suggest that DPH suppresses pituitary TSH secretion, probably as a thyroid hormone agonist. The effect of a single large dose of DPH (20 mg/100 g body wt) administered to thyroidectomized rats also decreased serum tSH but, in contrast to the findings in chronically treated rats, hypothalamic TRH and pituitary TSH content and the serum TSH responses to TRH were increased. These differences may be due to the acute inhibitory effect of a large dose of DPH on hypothalamic TRH release. Furthermore, because the effect of thyroid hormone on regulating pituitary TSH synthesis and release is dose and time dependent, the effect of DPH as a thyroid hormone agonist on pituitary TSH dynamics may also be variable.

The physiological role of thyrotropin-releasing hormone (TRH) in the regulation of thyrotropin (thyroid-stimulating hormone, TSH) and prolactin (Prl) secretion has been assumed but not proven. Stimulation of their release requires pharmacologic doses of TRH. Lesions of the hypothalamus usually induce an inhibition of TSH secretion and an increase in Prl. To determine whether TRH is essential for TSH and Prl secretion in the rat, 0.1 ml of TRH antiserum (TRH-Ab) or normal rabbit serum was administered to normal, thyroidectomized, cold-exposed, and proestrus rats through indwelling atrial catheter. Serum samples were obtained before and at frequent intervals thereafter. Serum TSH concentrations in normal, thyroidectomized, cold-exposed, and proestrus rats were not depressed in specimens obtained up to 24 h after injection of normal rabbit serum. In contrast, serum TSH was significantly decreased after the administration of TRH-Ab in all normal (basal, 41+/-8 muU/ml [mean+/-SE]; 30 min, 6+/-2; 45 min, 8+/-3; 75 min, 4+/-2); thyroidectomized (basal, 642+/-32 muU/ml; 30 min, 418+/-32; 60 min, 426+/-36; 120 min, 516+/-146); coldstressed (basal, 68+/-19 muU/ml; 30 min, 4+/-3; 180 min, 16+/-8); and proestrus (basal, 11 a.m., 57+/-10 muU/ml; 1 p.m., 20+/-3; 3 p.m., 13+/-4; 5 p.m., 19+/-3) rats. However, 0.1 ml of TRH-Ab had no effect on basal Prl concentrations in normal or thyroidectomized rats and did not prevent the Prl rise in rats exposed to cold (basal, 68+/-7 ng/ml; 15 min, 387+/-121; 30 min, 212+/-132; 60 min, 154+/-114), or the Prl surge observed on the afternoon of proestrus (basal 11 a.m., 23+/-2 ng/ml; 1 p.m., 189+/-55; 3 p.m., 1,490+/-260; 5 p.m., 1,570+/-286). These studies demonstrate that TRH is required for TSH secretion in the normal, cold-exposed and proestrus rat and contributes, at least in part, to TSH secretion in the hypothyroid rat, but is not required for Prl secretion in these states.

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.

To evaluate the effect of starvation, oral and i.v. nutriments, and hypothyroidism on the peripheral conversion of thyroxine (T4) to 3,3', 5-triiodothyronine (T3) in the rat and mouse, an in vitro system for assessing T4 conversion to T3 by fresh liver homogenates was used. A 2-day starvation in the rat reduced hepatic T3 generation from T4 by 47% +/- 3.5% (mean +/- SE) in six separate experiments and also impaired the metabolism of 125I-r-T3. Administration of carbohydrate (CHO) and amino acids (P), but not lipid (L), significantly increased T3 generation above values observed in the starved rat. The mean serum glucose concentration was similar in all nutriment-infused groups, but serum insulin was significantly greater in the CHO- and P-infused as compared to the L-infused rats. These findings suggest that CHO and P, but not L, are important modulators of hepatic outer ring thyronine deiodination in the rat, perhaps due to increased intracellular glucose. Hypothyroidism in the rat induced by thyroidectomy and congenital secondary hypothyroidism in the dwarf mouse resulted in a striking decrease in hepatic conversion of T4 to T3. This decrease was restored to normal by the daily s.c. administration of physiologic doses of T4 (1.5 microgram/100 g) or T3 (0.5 microgram/100 g) for 14 days, and was increased above normal following treatment of normal rate with greater than physiologic doses of T4 (3microgram/100 g) or T3 (1 microgram/100g). In vitro hepatic conversion of T4 to T3 is, therefore, dependent upon thyroid function. Since 2-days starvation in the rat was associated with decreased serum concentrations of T4, T3, and TSH, and hypothyroidism resulted in decreased conversion of T4 to T3, the effect of a constant 2-day infusion of physiologic doses of T4 or T3 in the starved rat on the in vitro deiodination of T4 was assessed. Thyroid hormone replacement did not enhance the conversion of T4 to T3 in the starved rat. These observations suggest that the starvation-induced decrease in hepatic generation of T3 from T4 is not due to hypothyroidism and that the mechanism(s) of the decreased T3 production observed in starvation and hypothyroidism is different.

Studies were carried out on various aspects of hypothalamic-pituitary-thyroid function in normal and gonadectomized adult male and female rats. Consistent increases in the serum TSH concentration and the serum TSH response to TRH were observed in the male rat compared to values in the female. Orchiectomy induced a decrease in the serum TSH concentration and the serum TSH response to TRH, and these functions were equal in gonadectomized male and female rats. Oophorectomy did not affect basal and TRH-stimulated serum TSH concentrations. Replacement doses of testosterone (0.33 mg/day) to orchiectomized rats increased and restored these values to those observed in the normal male rat, while replacement doses of estradiol (0.33 microgram/day) to the oophorectomized rat had no effect on basal or TRH-stimulated TSH concentrations. No sex-related differences in pituitary TSH and hypothalamic TRH contents or in serum T4 and T3 concentrations were observed. The present studies strongly suggest that the increased TSH responsiveness observed in male compared to female rats is due to the presence of testosterone. (Endocrinology 108: 529, 1981)

The metabolic effects of rT3 and its role in regulating the metabolic activity of T4 by altering the peripheral monodeiodination of T4 to T3 was studied in normal and thyroidectomized (Tx) rats constantly infused through indwelling atrial catheters. The infusion of 100 μg rT3/100 g BW in normal rats decreased the conversion of T4 to T3 by liver homogenates by 50% (P < 0.001), decreased serum T3 by 21% (P < 0.001), increased serum T4 by 21% (P < 0.001) and had no effect on serum and pituitary GH concentrations. Tx rats were infused with saline, rT3 (100 μg/100 g BW), T4 (2–5 μg/100 g BW), T3 (1 μg/100 g BW), T4 plus rT3, and T3 plus rT3. The infusion of rT3 had no effect on serum and pituitary TSH and GH concentrations. T4 infusion in the Tx rat increased the low in vitro hepatic T3 generation observed in hypothyroidism, decreased serum TSH, increased serum and pituitary GH, and restored the metabolic effect of GH on the epididymal fat pad. The simultaneous infusion of rT3 and T4 partially blocked the meta...

The metabolic clearance and production rates of thyroxine (T4) and triiodothyronine (T3) were measured in 9 obese euthyroid patients prior to and during prolonged starvation. The metabolic clearance rates (MCR) and serum concentrations of T4, and, therefore, the metabolic degradation or production rates of T4 were unchanged during starvation. Serum T3 concentrations decreased strikingly during starvation, from 145 +/- 7 ng/dl (mean +/- SE) to 66 +/- 9 ng/dl (P < 0.001), while the mean MCR of T3 was unchanged, with the result that T3 degradation or production rates were markedly decreased (36.4 +/- 4.5 μg/d vs. 11.2 +/- 0.7 μg/d; P < 0.001). These findings suggest that the decrease in serum T3 concentration observed during starvation results from a decrease in the peripheral conversion of T4 to T3.

Diet-induced alterations in thyroid hormone concentrations have been found in studies of long-term (7 mo) overfeeding in man (the Vermont Study). In these studies of weight gain in normal weight volunteers, increased calories were required to maintain weight after gain over and above that predicted from their increased size. This was associated with increased concentrations of triiodothyronine (T3). No change in the caloric requirement to maintain weight or concentrations of T3 was found after long-term (3 mo) fat overfeeding. In studies of short-term overfeeding (3 wk) the serum concentrations of T3 and its metabolic clearance were increased, resulting in a marked increase in the production rate of T3 irrespective of the composition of the diet overfed (carbohydrate 29.6 +/- 2.1 to 54.0 +/- 3.3, fat 28.2 +/- 3.7 to 49.1 +/- 3.4, and protein 31.2 +/- 2.1 to 53.2 +/- 3.7 microgram/d per 70 kg). Thyroxine production was unaltered by overfeeding (93.7 +/- 6.5 vs. 89.2 +/- 4.9 microgram/d per 70 kg). It is still speculative whether these dietary-induced alterations in thyroid hormone metabolism are responsible for the simultaneously increased expenditure of energy in these subjects and therefore might represent an important physiological adaptation in times of caloric affluence. During the weight-maintenance phases of the long-term overfeeding studies, concentrations of T3 were increased when carbohydrate was isocalorically substituted for fat in the diet. In short-term studies the peripheral concentrations of T3 and reverse T3 found during fasting were mimicked in direction, if not in degree, with equal or hypocaloric diets restricted in carbohydrate were fed. It is apparent from these studies that the caloric content as well as the composition of the diet, specifically, the carbohydrate content, can be important factors in regulating the peripheral metabolism of thyroid hormones.

Oral cholecystographic agents induce a decrease in serum T3 and an increase in serum T4 and rT3 concentrations in normal subjects. However, their effect on TSH secretion in man is unclear. In the present study, the serum TSH concentration was increased above baseline values 5 days after the administration of 3 g iopanoic acid (IA) in five of six euthyroid volunteers (an increase of borderline significance), and the TSH response to TRH was significantly augmented after IA administration. In four other euthyroid subjects who had received IA 3 days earlier, the administration of T3 (5 microgram, five times daily) for the next 2 days restored the serum T3 concentration toward baseline values and prevented the IA-induced increase in TRH-stimulated serum TSH concentrations. It is concluded from the present study that IA enhances pituitary thyrotroph sensitivity to TRH and that this effect may be related, at least in part, to the IA-induced decrease in circulating T3 as well as the previously demonstrated inhibitory effect of IA on the pituitary conversion of T4 to T3. This decrease in the serum T3 concentration after IA administration is due primarily to inhibition of peripheral 5-monodeiodination of T4 and, possibly, to a direct inhibitoy effect of excess iodide on the release of T3 from the thyroid.

The effect of starvation on the peripheral metabolism of rT3 was evaluated in four obese euthyroid patients. During starvation, the serum rT3 concentration increased by 69% while the MCR of rT3 decreased in all four patients from control values of 96 +/- 23 (mean +/- SD) to 68 +/- 17 liters/70 kg . day, resulting in a slight increase in the mean production rate of rT3. These findings are in contrast to the marked decrease in T3 production rate associated with fasting, indicating that inner and outer ring deiodination of T4 can be varied independently.

Woodchuck plasma was collected during four seasons of the year and assayed for total and dialyzable (free) T4 and T3 and for rT3. Plasma concentrations of total and free T4 and T3 were higher in the spring (T4, 5.4 +/- 0.6 microgram/dl; free T4, 3.0 +/- 0.4 ng/dl; T3, 202 +/- 22 ng/dl; free T3, 0.51 +/- 0.04 ng/dl) and lower in the prehibernatory fattening period in summer (T4, 2.3 +/- 1.0 microgram/dl; free T4, 1.2 +/- 0.5 ng/dl; T3, 45 +/- 27 ng/dl; free T3, 0.16 +/- 0.10 ng/dl) and fall (T4, 3.2 +/- 1.0 microgram/dl; free T4, 1.3 +/- 0.2 ng/dl; T3, 130 +/- 12 ng/dl; free T3, 0.25 +/- 0.02 ng/dl). In spite of the extremely high concentrations of T3 in the winter (437 +/- 32 ng/dl), free T3 concentrations (0.034 +/- 0.003 ng/dl), when measured at the appropriate temperature for hibernation, were significantly lower than those found at other seasons of the year. Plasma binding of T3 was lower during the summer and increased again to approximately double the spring value during the winter. rT3 was at or below the sensitivity of the method (6 ng/dl) at all seasons. It is suggested that the wide seasonal variations in thyroid hormone concentrations and altered plasma protein binding may represent important adaptations influencing the metabolic rate and the process of hibernation in the woodchuck.

Chromatography of serum on columns of Sephadex G-25 superfine after the iv administration of 125I-labeled T4 consistently yielded labeled iodide, iodoprotein, T3, and a labeled peak that eluted from the column before the T3, termed "pre-T3." Much larger quantities of pre-T3 were generated after the iv administration of 125I-labeled T3 and rT3. The ratio of [125I]pre T3:[125I]T3 and [125I]pre T3:[125I]rT3 plateaued at approximately 10 h and 2 h, respectively, after the iv administration of the labeled hormone, and averaged approximately 15% in euthyroid subjects. As pre-T3 behaves like its precursors in the TCA precipitation-ethanol extraction or anion exchange chromatographic procedures used to separate labeled iodide and iodoprotein from administered labeled T3 and rT3, concentrations of labeled hormone measured by these techniques will be in error, because pre-T3 will be included. Thus, the MCR of labeled T3 and rT3 measured by Sephadex chromatography will always be higher than values obtained by the other two separative techniques and the magnitude of change will be similar to the ratio of pre-T3 to precursor T3 or rT3. The Sephadex chromatographic technique is laborious, but appears to be the method of choice where greatest accuracy of measurement is required. As the generation of pre-T3 from labeled T4 is sufficiently slow, the present chromatographic technique is not necessary in studying peripheral T4 turnover.

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.

Summary Drugs and dietary substances which may induce goiter and hypothyroidism are reviewed. Another group of pharmacological agents alter the serum or cellular binding of thyroxine and triiodothyronine but do not induce hypothyroidism in animals and man whose hypothalamic-pituitary-thyroid axis is intact. In view of the widespread clinical use of many of these therapeutic agents, it is essential that the physician be aware of the effects of these drugs on thyroid function in order to avoid true hypothyroidism or misinterpretation of thyroid function tests.

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...

In view of the reported enhanced sensitivity to iodide-induced hypothyroidism in patients with cystic fibrosis, studies were carried out to determine the possible mechanism of this abnormality. The intrathyroid organification of iodide, as assessed by the iodide-perchlorate discharge test, was normal in patients with cystic fibrosis, strongly suggesting that an organification defect was not present. The serum TSH response to TRH was not significantly different from the response in normal children and adolescents. Serum T4 concentration was normal whereas that of T3 was decreased in patients with cystic fibrosis, strongly suggesting decreased peripheral conversion of T4 to T3, as commonly occurs in nonthyroid illness. Our findings do not delineate the mechanism whereby patients with cystic fibrosis develop iodide-induced hypothyroidism.

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.

Serum concentrations of T4 and T3 are markedly decreased without an appropriate increase in TSH concentration in the neonatal rat. Since TRH does not appear to regulate TSH secretion in the perinatal rat, and intrapituitary 5′-monodeiodination of T4 to T3 is a major modulator of TSH secretion, it seemed possible that enhanced pituitary generation of T3 from T4 might play a role in the inappropriately low serum TSH level in the neonatal rat. The conversion of T4 to T3 in pituitary homogenates was studied in rats varying in age from 1 day to 1 yr and compared to values obtained in 10-week-old male rats. Pools of neonatal and individual adult pituitaries were homogenized in 1 ml Trisbuffer, pH 7.4, containing 0.5 μg T4 and 20 mm dithiothreitol, and the T3 generated was measured in ethanolic extracts by RIA. Pituitary T3 generation from T4 in the 1-day-old neonates was similar to that obtained from 10-week-old males. However, by 5 days of age, pituitary T3 generation from T4 was markedly increased (226 ± 16.3...

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.

The present studies were undertaken to evaluate possible sex-related differences in the peripheral outer ring deiodination of T4 to T3 in vitro by fresh liver homogenates. Hepatic T3 generation from T4 in female rats was similar to that observed in age-matched male rats from days 1-24. However, at 30 days of age, a significant decrease in T3 generation was observed in the female rat, becoming more pronounced with increasing age until puberty and then remaining approximately 50% of that observed in age-matched male rats through 90 days of age. In vitro addition of dithiothreitol, a thiol-protecting agent, did not affect these sex-related differences, suggesting a decrease in the 5′-deiodinating enzyme per se in the female rat rather than decreased concentrations of reducing cofactor(s). The sex-related differences in hepatic T4 to T3 conversion are related, at least in part, to sex steroids, since prepubertal castration at 20 days of age prevented these sex-related changes, and peripubertal castration at 4...

Total starvation in the rat for 2 days did not alter the hypothalamic content of thyrotropin-releasing hormone (TRH), but did decrease both pituitary TSH content and serum TSH concentration. Five days starvation resulted in a significant decrease in serum TSH and a slightly enhanced serum TSH response to exogenous TRH, suggesting that the pituitary retains its sensitivity to TRH. Fasting for 5 days resulted in a decreased 1 and 4th, but an increased 24th thyroid 131I uptake. Other starvation-induced abnormalities of intrathyroid 131I metabolism were a consistent increase in the percent of organified 131I present as MIT and DIT and a decreased percent 131I labeled T4 AND T3. These alterations in the intrathyroid metabolism of 131I in the starved rat probably reflect both a decrease in serum TSH concentration and a decrease in urinary and fecal loss of administered 131I. The serum total and free T4 and total and free T3 concentrations were decreased following 2 and 5 days of starvation.

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 the deiodination of T4 and rT3 were carried out in the perinatal rat. As compared to the adult male, the in vitro hepatic homogenate conversion of T4 to T3 was strikingly reduced in the 14 and 19 day-old fetal rat, increased progressively after birth, and reached adult male values by day 5. T4 or T3 administration enhanced and starvation decreased in vitro hepatic T3 generation from T4 in the neonatal rat. A highly significant decrease in in vitro degradation of [l25I]rT3 was also observed in the perinatal rat and adult values were reached by day 5. In vivo disposal of iv administered [125I]rT3 was studied in perinatal rats. Ten minutes after iv [125I]r3, the percentage of total 125I- remaining in the serum as [125I]r3 in the 20-day-old fetal rat was 70% and decreased progressivel towards adult values throughout the neonatal period. The metabolic clearance rate of rT3 was much slower in the 10-day-old neonate as compared to the adult rat (1.4 ml/min-100 g vs. 6.7). In comparison to adult values...

Oocyte depletion and ovarian aging results in profound alterations at the biological level. The reduction in numbers of follicles leads to reduction of circulating inhibin and increased serum FSH, characteristic marker of ovarian failure. The remaining follicles are overstimulated and premature ovulation may ensue. This, leads to luteal deficiency and reduction in progesterone production and relative hyperestrogenemia. The above changes characterize the premenopausal period. In a second phase, anovulatory cycles interchange with premature and occasionally normal ovulatory cycles. This phase is characterized by increased FSH and LH and decreased progesterone/estradiol ratio resulting in irregular bleeding, endometrial hyperplasia, polyps, fibromas, mammary dystrophies, disturbance of mood, appetite and thermoregulation. Lastly, the sensitivity of ovarian follicles to FSH and LH is lost with a decline of E2 below 20 pg/ml produced almost exclusively from peripheral conversion from circulating androgens. The beneficial effects of E2 are lost resulting in atrophy of the sensitive tissues, decreased calcium absorption, increased bone resorption, accelerated bone loss and osteoporosis, rise in serum triglycerides, increased VLDL and LDL lipoproteins, increased LDL/HDL cholesterol, a profile which favors atherosclerosis.

A simple and reproducible hemagglutination technique for detecting microsomal and thyroglobulin antibodies has been evaluated in normal subjects and in patients with thyroid disease. Microsomal antibodies were detected in 89 percent of all patients with autoimmune thyroid disease and in 97 percent of patients with biopsy proven Hashimoto's thyroiditis. In contrast, thyroglobulin antibodies were present in only 55 percent of patients with biopsy proven Hashimoto's thyroiditis and in 44 percent of all patients with suspected autoimmune thyroid disease. It is suggested, therefore, that measurement of microsomal antibodies by a simple hemagglutination techniques be carried out in all patients with suspected thyroid disorders.

1. Thyrotropin-releasing hormone (TRH), norepinephrine (NE), epinephrine (E), dopamine (DA), serotonin (5-HT), tyrosine hydrxylase (TH), and tryptophan hydrosylase (TpOH) were measured in several areas of the brains of woodchucks studied prior to, during, and immediately after hibernation. 2. TRH was highest in the hypothalamus. TRH increased markedly in the hypothalamus, septum, and striatum during hibernation, but remained unchanged in the other areas. 3. Hypothalamic NE and E were significantly decreased during hibernation, and DA and NE in the spring. No changes in 5-HT were detected. 4. During hibernation midbrain TH activity decreased, while TpOH increased in striatum and brainstem. 5. These results suggest that TRH and the neurotransmitters may play a role in the mechanism of hibernation.

Equal quantities of rabbit antithyrotropin-releasing hormone serum (TRH-AS) or normal rabbit serum (NRS) were administered to rats made hypothyroid by chronic feeding of propylthiouracil. TRH-AS produced a 37% decrease in plasma thyrotropin (TSH) (P < 0.01) in intact rats, but caused no significant decrease in plasma TSH concentration in hypophysectomized rats bearing three heterotopic pituitary transplants under the kidney capsule. NRS had no significant effect on plasma TSH in either group. This supports other data indicating that secretion of TSH and prolactin by heterotopic pituitaries is not under significant control by TRH in the general circulation.

Ophthalmopathy associated with autoimmune thyroid disease (Graves' ophthalmopathy) may occur years after irradiation of the neck for nonthyroid malignant disease. Two patients developed this complication 2 and 18 years after irradiation treatment of Hodgkin's disease: one with hypothyroidism associated with Hashimoto's thyroiditis and the other with hyperthyroidism. Careful long-term observation of thyroid function following neck irradiation is recommended in view of this unusual complication and the frequent occurrence of hypothyroidism.

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...

3,3',5'-triiodothyronine, (rT(3)), is easily measured in human amniotic fluid (AF) during the second and third trimesters. To determine if AF rT(3) levels are maintained by either maternal or fetal thyroid function, or both, models of fetal hypothyroidism (FH), maternal hypothyroidism (MH), and combined maternal and fetal hypothyroidism (MFH) were developed in pregnant rats. Hormone analyses of maternal and fetal serum and AF were performed at term. Thyroxine (T(4)) and 3,3',5-triiodothyronine (T(3)) were not detectable in the sera and AF of term fetuses in all groups. MFH rats were prepared by administration of methimazole to the dams, and in some experiments, by maternal thyroidectomy and a low iodine diet as well. In the MFH groups from the three experiments serum thyrotropin (TSH) was markedly elevated in the dams and in the fetuses. FH rats were prepared by administering T(4) by various routes to dams treated according to the MFH protocols and serum TSH was elevated in fetal serum. Analysis of FH maternal serum T(4), T(3), and TSH concentrations suggested mild maternal hyperthyroidism or hypothyroidism depending upon the schedule of T(4) administration. The MH groups were prepared by maternal thyroidectomy and in all experiments the fetuses had normal serum TSH concentrations. The degree of maternal hypothyroidism in the MH and MFH groups was equivalent. The mean concentration of AF rT(3) in normal rats in three experiments was 28.4+/-2.5 ng/dl (+/-SEM). In the three experiments, AF rT(3) was undetectable or markedly reduced in the MH and MFH rats and was normal in the FH rats. These results in the amniotic fluid could not be explained by transfer of rT(3) from fetal serum to the AF because fetal serum rT(3) concentrations in these various models did not correlate with AF rT(3) concentration. Furthermore, infusion of large doses of rT(3) in MFH dams resulted in a 35-fold elevation in maternal serum rT(3) concentration, a twofold elevation in fetal serum rT(3) concentration, and only a minimal increase in AF rT(3). These studies demonstrated that, in the rat, the maternal thyroid has the dominant role in maintaining AF rT(3), whereas little effect of fetal thyroid status on AF rT(3) could be demonstrated. Transfer of maternal rT(3) or of fetal rT(3) derived from maternal T(4) to the AF do not appear to be the mechanisms whereby the maternal thyroid maintains AF rT(3).

The 24-h LH secretory pattern in women during the early follicular phase is characterized by inhibition during the early sleep period. Methysergide maleate was administered to six normal women to test the hypothesis that the effect of sleep on LH secretion is due to serotonergic mechanisms. The results demonstrated no change in the sleep effect on LH secretion after drug administration. The 4-h average deviation after sleep onset from the 24-h mean was −27.7% for the control studies and −25.5% after methysergide maleate. The data suggest that serotonergic pathways are not critically involved in the control of the 24-h LH secretory program in women.

The present studies were carried out to determine whether pyridoxine (B6) inhibits PRL release in the rat and to define its site of action. Adult female rats were injected with 50 mg B6 of diluent (C) ip at 1200 h on proestrus. B6 prevented the increase in PRL secretion normally observed at 1300 h and this inhibition was prolonged until at least 1500 h by a second injection of B6 at 1400 h. All B6-treated and control animals had normal proestrous LH surges and ovulated the next day. To determine whether the inhibitory effect of B6 on PRL release was due to enhanced dopamine synthesis or to a direct effect on the pituitary, ovariectomized rats were treated with a potent inhibitor of dopamine synthesis, α-methyl-p-tyrosine (α-MPT). The administration of B6 either with or 4 h after α-MPT significantly decreased the PRL rise observed in animals treated with α-MPT alone. B6 also significantly suppressed the TRH-induced PRL rise in both α-MPTtreated and normal rats, but had no effect on the TRHinduced rise in p...

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.