Dissociated thyromimetic effects of 3, 5, 3'-triiodothyroacetic acid (TRIAC) at the pituitary and peripheral tissue levels

Although TRIAC is bound at least twice as avidly to nuclear receptor as T3, its thyromimetic potency is relatively low and its effect at the pituitary level on thyrotropin (TSH) secretion seems to be dissociated from that at the peripheral tissue level. In order to gain further insight into the complex effects of this thyroid hormone analog, we studied the effects of long-term TRIAC administration (2.8 mg/day for 2 months) on TSH secretion, circulating free thyroid hormone (FT4 and FT3) levels and some parameters able to evaluate the peripheral thyroid hormone action, in 5 mild obese subjects on low caloric diet (1200 kcal/day). The results were compared to those obtained in 5 mild obese subjects matched for age, sex and weight on low caloric diet alone. TRIAC administration completely inhibited the secretion of both basal and TRH-stimulated TSH in few days, and consequently serum FT4 and FT3 concentrations progressively dropped to very low levels, while no significant changes in both TSH and free thyroid hormone levels were recorded in the control group. The body weight significantly fell in both groups, without any difference between TRIAC treated and untreated patients. The heart rate was constant throughout the course of the study in both groups of patients. Serum total cholesterol, triglyceride and total lipid concentrations significantly decreased in both groups, and the decrement recorded in TRIAC treated patients was not significantly different from that found in patients on diet alone.(ABSTRACT TRUNCATED AT 250 WORDS)     

Factors affecting suppression of endogenous thyrotropin secretion by thyroxine treatment: retrospective analysis in athyreotic and goitrous patients

Factors affecting TSH suppression by L-T4 administration were retrospectively evaluated in 452 patients: 180 who were athyreotic after total thyroidectomy and remnant radioiodine ablation for differentiated thyroid carcinoma and 272 with nontoxic diffuse or nodular goiter. All patients were considered clinically euthyroid. TSH secretion was assessed by iv TRH stimulation testing. The T4 dose associated with an undetectable basal serum TSH level and no increase in serum TSH after TRH administration (suppressive dose) averaged 2.7 +/- 0.4 (SD) micrograms/kg body weight (BW)/day in athyreotic patients and 2.1 +/- 0.3 micrograms/kg BW/day in goitrous patients (P less than 0.001). The 25th-75th percentile intervals were 2.5-2.9 micrograms/kg BW/day for athyreotic patients and 1.9-2.3 micrograms/kg BW/day for goitrous patients. The suppressive dose of T4 was dependent in both groups on patient age, younger patients needing higher doses than older patients. The duration of treatment also proved to be an important parameter, since in both groups the percentage of patients with suppressed TSH secretion increased if TRH testing was carried out after at least 6 months after the initiation of therapy. Serum total T4, total T3, free T3 (FT3), free T4 (FT4) index, and FT3 index values did not differ in the two groups and were significantly higher (P less than 0.001) than in normal subjects. Mean serum FT4 was significantly higher in athyreotic patients than in goitrous patients with suppressed TSH secretion. Among athyreotic patients with suppressed TSH secretion, 24% had elevated serum FT4 and FT3, and 47% had elevated serum FT4 alone. Of goitrous patients with suppressed TSH secretion, 20% had elevated serum FT4 and FT3, and 27% had elevated serum FT4 alone. On the other hand, 35% of athyreotic patients and 14% of goitrous patients whose TSH secretion was not suppressed had elevated serum FT4. Serum sex hormone-binding globulin concentrations were measured in 3 groups of goitrous women. Values above normal limits were found in 13/26 patients (50%) with high serum FT4 and FT3, in 4/30 patients (13%) with elevated serum FT4 alone, and in 1/25 patients (4%) with normal FT4 and FT3. In conclusion: TSH suppression requires daily doses of T4 between 2.5 and 2.9 micrograms/kg BW in athyreotic patients and between 1.9 and 2.3 micrograms/kg BW in goitrous patients, with appropriate adjustments in relation to the age of the patient; Assessment of the adequacy of treatment should not be carried out before 6 months after the institution of therapy.     

Levothyroxine dose requirements for thyrotropin suppression in the treatment of differentiated thyroid cancer.

We have compared the dose of levothyroxine (L-T4) required to suppress serum TSH to given levels in two clinical groups: 1) 44 patients with thyroid cancer whose thyroid glands had been ablated by surgical thyroidectomy and 131I treatment, and 2) 113 patients with thyroidal failure due either to spontaneous primary hypothyroidism (31 patients) or after 131I treatment for Graves' hyperthyroidism (82 patients). The dose of L-T4 needed to attain serum TSH levels in the euthyroid range (0.5-6.2 microU/mL) was significantly greater (P less than 0.01) in patients with thyroid cancer (2.11 micrograms/kg.day) than in the patients with primary hypothyroidism associated with nonmalignant disease (1.63 micrograms/kg.day). Similarly, patients with thyroid cancer required a higher dose of L-T4 to suppress serum TSH to a given subnormal level. These findings suggest that the secretion of hormone from residual thyroid tissue in patients who have not been subjected to near-total thyroid ablation contributes substantially to the circulating levels of serum T4 and T3. We, therefore, infer that residual thyroidal secretion in the patients with hypothyroidism due to benign causes is relatively independent of TSH stimulation. Further subdivision of patients with benign hypothyroidism revealed that patients with Graves' who developed hypothyroidism after 131I treatment showed a lower mean dose requirement than patients with spontaneous hypothyroidism. This raises the possibility that continued secretion of thyroid-stimulating immunoglobulin in such patients might account for the lower dose requirement in the combined group with hypothyroidism. Our studies also have allowed us to make serial observations in 4 patients with thyroid cancer who exhibited elevated levels of serum thyroglobulin. In this limited series, maximal suppression of serum thyroglobulin was produced by doses of L-T4, which reduced circulating TSH to 0.4 mU/L.     

3,5,3''-TRHODOTHYROACETIC ACID MINIMIZES THE PITUITARY THYROTROPHIN SECRETION IN PATIENTS ON LEVO-THYROXINE THERAPY AFTER ABLATIVE THERAPY FOR DIFFERENTIATED THYROID CARCINOMA

The aim of this study was to examine the influence of 3,5,3'-triiodothyroacetic acid (TRIAC) on serum thyrotrophin (TSH) concentration in 25 patients on levo-thyroxine (L-T4) therapy after ablative therapy for differentiated thyroid carcinoma. The daily L-T4 intake amounted to 2.6 +/- 0.7 micrograms/kg body weight (+/- SD). Serum TSH concentration was determined by means of a sensitive radioimmunometric method (lower detection limit 0.03 mU/l). The median (means) basal TSH concentration under L-T4 amounted to 0.11 mU/l (range less than 0.03 mU/l-7.39 mU/l). During supplementary intake of 500 micrograms TRIAC daily the median basal TSH decreased to 0.04 mU/l range less than 0.03 mU/l-0.24 mU/l; P less than 0.0003). The TRIAC-induced decrease in 17 out of 20 basal TSH-concentrations exceeding 0.03 mU/l ranged from 38% to as much as 98%. TRIAC reduced the median TRH-stimulated TSH concentration from 0.25 mU/l (range less than 0.03 mU/l-47.3 mU/l) to 0.04 mU/l (range less than 0.03 mU/l-1.43 mU/l; P less than 0.0001). A blunted TSH-response to TRH occurred in 8.7% prior to and in 52% of the patients during TRIAC medication. Side effects such as nervousness, cardiac arrhythmia or tachycardia under supplementary TRIAC (500 micrograms daily) were observed in four patients. The conclusion is that the supplementary medication of 500 micrograms TRIAC daily in euthyroid patients on L-T4 medication after thyroid gland ablation for differentiated thyroid cancer is an effective means to minimize serum-TSH concentration.     

TRH test as an index of suppression compared with the thyroid radioiodine uptake in euthyroid goitrous patients treated with thyroxine.

To determine an index of adequate suppression of pituitary TSH secretion in euthyroid goitrous patients treated with sodium levothyroxine (T4), TSH responses to 500 micrograms TRH given iv were compared with thyroid 24-h radioiodine uptakes during therapy with T4 in 12 euthyroid goitrous patients. The patients received sequentially 100, 150, 200, 250, and 300 micrograms T4 with the doses increased at 4-6 week intervals. The mean dose of T4 that reduced the peak TSH response to TSH to the lower limit of normal (TSH = 5 microU/ml) was 130 micrograms; the mean T4 dose that suppressed the TSH response to one-half the lower limit of normal (TSH = 2.5 microU/ml) was 165 micrograms. The mean T4 dose that nearly obliterated the TSH response was 200 micrograms; this degree of suppression occurred with doses of 100-300 micrograms T4 in individual patients. Suppression of thyroid uptake correlated closely with suppression of the TSH response to TRH. The goiter diminished in size significantly in 6 of the 12 patients during the 6 months of observation adn did not enlarge in any patient. The data indicate that suppression of the TSH response to TRH is a convenient technique to assess the adequacy of suppressive therapy of goiter.     

EFFECTS OF THYROID HORMONES (T4, T3), BROMOCRIPTINE AND TRIAC ON INAPPROPRIATE TSH HYPERSECRETION

Inappropriate TSH hypersecretion was diagnosed in a 38-year-old woman (case 1) and in a 38-year-old man (case 2). Both of them had earlier been treated by ablative therapy for hyperthyroidism. The present diagnosis was based on elevated basal serum TSH levels despite elevated serum free thyroid hormone levels. Both of them had exaggerated TSH responses to TRH (peak value 240 mU/l in case 1 and 408 mU/l in case 2). Their albumin and prealbumin levels were normal. The serum TBG level was normal in case 1 but was elevated in case 2. Serum levels of alpha-subunits of TSH, and pituitary CT scans were normal. Despite mild clinical hyperthyroidism, peripheral indices of thyroid hormone action were normal. They had also relatives with apparent resistance to thyroid hormones. In view of the possibility that prolonged pituitary thyrotrophic stimulation is detrimental, various therapeutic approaches to suppress TSH levels were tried. Both T3 and T4 treatments lowered serum TSH levels, but were poorly tolerated. Acute administration of L-dopa or bromocriptine reduced serum TSH levels, but this was not seen during long-term therapy. TRIAC treatment lowered serum TSH levels, and the drug was well tolerated. Serum TSH responses to TRH were not blunted during T3, T4 or TRIAC treatments. Somatostatin also reduced serum TSH levels, but did not potentiate the effect of low dose T3 therapy. Our results suggest that the patients had unbalanced pituitary and peripheral thyroid hormone resistance, predominantly at the pituitary level. Of the drugs studied, TRIAC seemed to be the most suitable therapy.     

Thyroxine therapy in patients with severe nonthyroidal illnesses and low serum thyroxine concentration

A randomized prospective study was done to assess the response of hypothyroxinemic patients with severe nonthyroidal illnesses to T4 therapy. Patients admitted to a medical intensive care unit who had a total serum T4 concentration less than 5 micrograms/dl were randomly assigned to a control (12 patients) or a T4 treatment group (11 patients). L-T4 in a dose of 1.5 micrograms/kg was given iv each day for 2 weeks. In the treatment group, serum T4 and free T4 concentrations significantly increased by day 3 and were normal on day 5. Serum TSH levels decreased significantly in the T4 treatment group, as did the TSH response to TRH. A significant rise in serum T3 occurred in the control group on day 7, but was delayed until day 10 in the treatment group. Mortality was equivalent in the 2 groups (75% control vs. 73% treatment). Regardless of group assignment, survivors and nonsurvivors were completely separable based on baseline T3 to T4 ratios [17.0 +/- 1.8 (+/- SE) ng/micrograms in survivors vs. 7.0 +/- 0.7 in nonsurvivors; P less than 0.001]. Angiotensin-converting enzyme was significantly reduced in the T4 treatment group, but did not rise significantly in response to treatment. T4 therapy was not beneficial in this population of intensive care unit patients, and by inhibiting TSH secretion, it may suppress an important mechanism for normalization of thyroid function during recovery.     

EFFECTS OF LOW DOSE ORAL IODIDE SUPPLEMENTATION ON THYROID FUNCTION IN NORMAL MEN

Previous studies have demonstrated that short-term oral iodide administration, in doses ranging from 1500 micrograms to 250 mg/day, has an inhibitory effect on thyroid hormone secretion in normal men. As iodide intake in the USA may be as high as 800 micrograms/d, we investigated the effects of very low dose iodide supplementation on thyroid function. Thirty normal men aged 22-40 years were randomly assigned to receive 500, 1500, and 4500 micrograms iodide/day for 2 weeks. Blood was obtained on days 1 and 15 for measurement of serum T4, T3, T3-charcoal uptake, TSH, protein-bound iodide (PBI) and total iodide, and 24 h urine samples were collected on these days for measurement of urinary iodide excretion. TRH tests were performed before and at the end of the period of iodide administration. Serum inorganic iodide was calculated by subtracting the PBI from the serum total iodide. We found significant dose-related increases in serum total and inorganic iodide concentrations, as well as urinary iodide excretion. The mean serum T4 concentration and free T4 index values decreased significantly at the 1500 micrograms/day and 4500 micrograms/day doses. No changes in T3-charcoal uptake or serum T3 concentration occurred at any dose. Administration of 500 micrograms iodide/day resulted in a significant increase (P less than 0.005) in the serum TSH response to TRH, and the two larger iodide doses resulted in increases in both basal and TRH-stimulated serum TSH concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)     

Influence of cortisol on the larval bullfrog thyroid axis in vitro and in vivo and on plasma and ocular melatonin

Adrenal (interrenal) steroids have an important role in amphibian development, antagonizing the metamorphic changes induced by the thyroid at first and then synergizing with the thyroid hormones as their level rises during metamorphosis. Because most of the studies of corticoids at metamorphosis have focused on peripheral tissues, we investigated the effect of cortisol (hydrocortisone; HC) in vitro and in vivo on the thyroid of Rana catesbeiana (bullfrog) tadpoles on 12:12 light/dark (LD) cycles. Plasma and ocular melatonin, which is altered by changes in thyroxine (T(4)) levels, were also assayed in some experiments. Thyroids from premetamorphic tadpoles secreted less T(4) into culture media when incubated with 10 micrograms/ml HC and 0.2 micrograms/ml ovine thyrotropin (TSH) than with TSH alone and when cultured in the absence of TSH following 5 days of 10-micrograms HC injections, indicating that HC inhibited the thyroid at young stages. The effect of 10 micrograms/ml HC at older stages was investigated by culturing thyroids and pituitaries separately on the first day in control or HC media and then incubating the thyroids on the second day in homologous pituitary-conditioned media as a bioassay for pituitary TSH. HC had no effect on baseline T(4) secretion by the thyroids of prometamorphic or climax tadpoles on the first day but increased T(4) secretion over the control on the second day. Thyroids cultured with TSH and HC showed no increase in T(4) secretion over the control TSH group on the second day, indicating that, in the previous experiments, HC had enhanced pituitary secretion of TSH, rather than the response of the thyroid to TSH. In vivo, 5 days of injections of 10 micrograms HC increased plasma T(4) at prometamorphosis and decreased it at climax. There was no marked effect of HC on plasma or ocular melatonin levels. The findings showed that the nature of the effect of HC on the thyroid axis changes during metamorphosis from inhibition at early stages to a positive influence at prometamorphosis and finally to a negative effect on the T(4) level in the plasma at climax.     

Anti-iodothyronine autoantibodies in a girl with hyperthyroidism due to pituitary resistance to thyroid hormones.

In the present study, we report the uncommon case of a 9.6-yr-old girl with circulating anti-T3 autoantibodies (T3-Ab) and hyperthyroidism due to inappropriate secretion of TSH (IST). The diagnosis of IST was based on the findings of normal TSH levels (2.4 mU/L) in the presence of high free T4 (28.2 pmol/L) and free T3 (FT3) levels, as measured by direct measurement methods based on "one-step" analog tracer (28.0 pmol/L) and "two-step" Lisophase (13.3 pmol/L) techniques. The discrepancy between the two measurements suggested a methodological interference due to T3-Ab in "one-step" technique, being the "two-step" methodology unaffected by the presence of such autoantibodies. T3-Ab were documented by high nonspecific binding of serum to labeled T3 (38.0% vs 4.3 +/- 2.1% in controls). The clinical picture of hyperthyroidism, the qualitatively normal TSH responses to TRH and T3 suppression tests, the normal pituitary imaging and the values of some parameters of peripheral thyroid hormone action compatible with hyperthyroidism indicated that the patient was affected by pituitary resistance to thyroid hormones (PRTH). Chronic treatment with dopaminergic agent bromocriptine (7.5 mg/day) did not cause TSH secretion to be suppressed, while the administration of thyroid hormone analog TRIAC (1.4 mg/day) inhibited TSH release (from 2.4 to 0.2 mU/L). As a consequence, circulating thyroid hormone levels normalized and euthyroidism was restored. During TRIAC administration, FT3 levels, measured by "one-step" analog tracer technique, gave spuriously high values due to the methodological interference of T3-Ab (15.2 vs 4.3 pmol/L as measured by "two-step" Lisophase technique).(ABSTRACT TRUNCATED AT 250 WORDS)     

Prenatal diagnosis of thyroid hormone resistance

A 29-yr-old woman with pituitary resistance to thyroid hormones (PRTH) was found to harbor a novel point mutation (T337A) on exon 9 of the thyroid hormone receptor beta (TRbeta) gene. She presented with symptoms and signs of hyperthyroidism and was successfully treated with 3,5,3'-triiodothyroacetic acid (TRIAC) until the onset of pregnancy. This therapy was then discontinued in order to prevent TRIAC, a compound that crosses the placental barrier, from exerting adverse effects on normal fetal development. However, as the patient showed a recurrence of thyrotoxic features after TRIAC withdrawal, we sought to verify, by means of genetic analysis and hormone measurements, whether the fetus was also affected by RTH, in order to rapidly reinstitute TRIAC therapy, which could potentially be beneficial to both the mother and fetus. At 17 weeks gestation, fetal DNA was extracted from chorionic villi and was used as a template for PCR and restriction analysis together with direct sequencing of the TRbeta gene. The results indicated that the fetus was also heterozygous for the T337A mutation. Accordingly, TRIAC treatment at a dose of 2.1 mg/day was restarted at 20 weeks gestation. The mother rapidly became euthyroid, and the fetus grew normally up to 24 weeks gestation. At 29 weeks gestation mild growth retardation and fetal goiter were observed, prompting cordocentesis. Circulating fetal TSH was very high (287 mU/L) with a markedly reduced TSH bioactivity (B/I: 1.1 +/- 0.4 vs 12.7 +/- 1.2), while fetal FT4 concentrations were normal (8.7 pmol/L; normal values in age-matched fetuses: 5-22 pmol/L). Fetal FT3 levels were raised (7.1 pmol/L; normal values in age-matched fetuses: <4 pmol/L), as a consequence of 100% cross-reactivity of TRIAC in the FT3 assay method. To reduce the extremely high circulating TSH levels and fetal goiter, the dose of TRIAC was increased to 3.5 mg/day. To monitor the possible intrauterine hypothyroidism, another cordocentesis was performed at 33 weeks gestation, showing that TSH levels were reduced by 50% (from 287 to 144 mU/L). Furthermore, a simultaneous ultrasound examination revealed a clear reduction in fetal goiter. After this latter cordocentesis, acute complications occured, prompting delivery by cesarean section. The female neonate was critically ill, with multiple-organ failure and respiratory distress syndrome. In addition, a small goiter and biochemical features ofhypothyroidism were noted transiently and probably related to the prematurity of the infant. At present, the baby is clinically euthyroid, without goiter, and only exhibits biochemical features of RTH. In summary, although further fetal studies in cases of RTH are necessary to determine whether elevated TSH levels with a markedly reduced bioactivity are a common finding, our data suggest transient biochemical hypothyroidism in RTH during fetal development. Furthermore, we advocate prenatal diagnosis of RTH and adequate treatment of the disease in case of maternal hyperthyroidism, to avoid fetal thyrotrope hyperplasia, reduce fetal goiter, and maintain maternal euthyroidism during pregnancy.     

Difference in pituitary-thyroid feedback regulation in hypothyroid patients, depending on the severity of hypothyroidism.

In an attempt to study pituitary-thyroid interplay during replacement therapy for hypothyroidism, T4 (75-150 micrograms/day) was administered for at least 3 months. A small dose of T4 (75 micrograms/day) significantly depressed basal and TRH-stimulated TSH levels in normal subjects without significantly elevating serum T4 and T3 concentrations. In patients with severe hypothyroidism and marked enlargement of the sella turcica, T4 (2.53 micrograms/kg BW) normalized the serum T4 and slightly elevated the serum T3 but failed to normalize basal and TRH-stimulated TSH levels. In patients with moderate hypothyroidism and moderate enlargement of the sella turcica, T4 (2.0 micrograms/kg BW) normalized serum T4, T3, and basal TSH concentrations but failed to normalize TRH-stimulated TSH levels. In patients with slight hypothyroidism and slight enlargement of the sella turcica, T4 (1.84 micrograms/kg BW) normalized serum T4, T3, and TSH (both basal and TRH stimulated) concentrations. In five patients, an apparent paradoxical increase of basal serum TSH level was found shortly after starting thyroid hormone treatment. It is suggested that pituitary-thyroid interplay during the first 3-6 months of replacement therapy for hypothyroidism varies greatly depending on the severity of hypothyroidism.     

Thyroid vascular conductance: differential effects of elevated plasma thyrotropin (TSH) induced by treatment with thioamides or TSH-releasing hormone

We have reported previously that thyroid gland blood flow, expressed as vascular conductance (C) per mass, is decreased at very low and increased at very high chronic plasma TSH concentrations, but is apparently unchanged over a broad range of plasma TSH concentrations encompassing normal levels. The aim of the present study was to examine the apparently very steep dose-response relationship between elevated plasma TSH and thyroid vascular C/mass. In the first series of experiments, endogenous plasma TSH concentrations were manipulated by treating male Sprague-Dawley rats (250-280 g) for 6 days as follows: 1) controls (0.5 ml saline/day, ip), 2) propylthiouracil injections (2.0 mg PTU/day, ip), 3) PTU plus partial thyroid hormone replacement (2.0 mg PTU/day and 0.3-0.9 microgram T4 plus 0.075-0.225 microgram T3/100 g.day via continuous sc infusion), or 4) TRH (9-1200 micrograms TRH/100 g.day via continuous iv infusion). The vascular C values of the thyroid gland, salivary gland, kidney, and pancreas were determined using the reference sample version of the radioactive microsphere technique. PTU treatment led to the expected hypothyroidism, increased plasma TSH concentrations (959 +/- 66 vs. 154 +/- 22 ng/dl), increased thyroid weight (9.19 +/- 0.36 vs. 4.60 +/- 0.15 mg/100 g), and increased thyroid vascular C/mass (495 +/- 51 vs. 127 +/- 20 microliters/mm Hg.g/min). PTU-treated rats receiving partial thyroid hormone replacement demonstrated a dose-related suppression of plasma TSH, thyroid weight, and thyroid vascular C. Although, TRH treatments resulted in increased plasma TSH concentrations (e.g. 1200 micrograms TRH, 706 +/- 46 ng/dl) and thyroid weight (e.g. 1200 micrograms TRH, 7.45 +/- 0.41 mg/100 g), thyroid vascular C per tissue mass was not significantly increased after any TRH treatment (e.g. 1200 micrograms TRH, 166 +/- 19 microliters/mm Hg.g/min). Thus, at similarly elevated plasma TSH concentrations, the thyroid vascular C/mass of PTU- and TRH-treated rats constituted separate populations. Both PTU- and TRH-induced thyroid growth were accompanied by similar alterations in thyroid gland morphology (i.e. increased cellular mass with little change in the total amount of colloid). To investigate the mechanisms involved, groups of rats were treated for 6 days as follows: 1) control, 2) PTU or methimazole (25 mg MMI/day, ip), 3) PTU or MMI plus thyroid hormone replacement (1.2 micrograms T4 plus 0.3 microgram T3/d.100 g), 4) TRH (12 micrograms/100 g.day), and 5) PTU or MMI, thyroid hormones, and TRH.(ABSTRACT TRUNCATED AT 400 WORDS)     

Continuous infusion of interleukin-1 beta induces a nonthyroidal illness syndrome in the rat.

We studied the effects of continuous administration of recombinant human interleukin-1 beta (IL-1) on pituitary-thyroid function. Rats were equipped with minipumps loaded with either IL-1 (delivery rate, 0.5, 2.0, or 4.0 micrograms/day, ip, for 1 week) or saline. Infusion of 2.0 and 4.0 micrograms IL-1/day caused a significant decrease in plasma free T4 levels during the first 2-4 days, whereas plasma total T4 levels and T4 binding were significantly lowered throughout the week of the study. The infusion of 0.5 micrograms IL-1/day did not significantly change plasma TSH or total and free T4 levels. During the infusion of 2.0 micrograms IL-1/day, the decrease in plasma free T4 levels was paralleled by a significant decline in plasma TSH values and an impaired TSH responsiveness to TRH administration on the second day of infusion. IL-1 (2.0 micrograms/day) treatment significantly lowered plasma levels of T4-binding prealbumin, whereas it did not influence the plasma T3/T4 ratio or hepatic 5'-deiodinase activity. Plasma rT3 levels remained undetectable in both control and IL-1-treated rats. Chronic infusion of rats with 4.0 micrograms IL-1/day induced prolonged fever, whereas at the lower doses of IL-1, temperatures were elevated only on the first 2 days. IL-1 at doses of 2.0 and 4.0 micrograms/day induced a transient decrease in food intake and a suppression of body weight gain. Restriction of food consumption to the level observed in the 2.0 micrograms IL-1 experiment caused small decreases in T3, total and free T4, and TSH levels compared to those in ad libitum fed rats, but had no effects on T4 binding. We conclude that 1) continuous infusion of rats with 2.0 and 4.0 micrograms IL-1/day induces changes in thyroid economy commonly seen during infectious diseases and other systemic illnesses in rats [decreased plasma levels of TSH, T3, and (free) T4; diminished T4 binding; and decreased plasma T4-binding prealbumin levels], 2) the decrease in food intake during IL-1 treatment cannot completely explain the observed changes in thyroid hormone and TSH levels; and 3) it is highly unlikely that the decrease in thyroid hormone binding during chronic IL-1 infusion is caused by decreased food intake. Further studies are needed to clarify whether the observed alterations in thyroid economy during IL-1 infusion reflect direct effects of IL-1 per se or indirect effects caused by the mild illness induced by the cytokine.     

Hyperthyroidism due to familial pituitary resistance to thyroid hormone: successful control with 3, 5, 3' triiodothyroacetic associated to propranolol.

We herein describe a family with thyroid hormone resistance. Thyroid hormones and basal TSH were elevated. Pituitary tumor or abnormality in thyroid hormone binding proteins were ruled out by appropriate tests. Mother and sister of the propositus presented similar abnormal hormonal features but no hyperthyroidism. Initially the patient was treated with carbimazole (30 mg/day): three months later a dramatic increase in the size of the thyroid gland and in TSH levels (12.5 to 28 mU/l) were noted. Thereafter, dextrothyroxine (D-T4) and 3, 5, 3'-triiodothyroacetic acid (TRIAC) were given consecutively and treatment was accompanied by a decrease of TSH levels (2 mU/l) but thyroid hormone remained elevated. The symptoms and signs of hyperthyroidism improved with the addition of propranolol (30-60 mg/day). In conclusion, the present report describes a new family with the syndrome of THR and variable degrees of involvement among relatives. We suggest the usefulness of TRIAC therapy to decrease TSH levels and propranolol to improve thyrotoxicosis due to pituitary resistance to thyroid hormone.     

Hyperthyroidism due to inappropriate secretion of thyroid-stimulating hormone: diagnosis and management

The case histories of three patients with hyperthyroidism due to overproduction of thyroid-stimulating hormone (TSH) by the pituitary gland are described. In the first patient treatment with the T3-metabolite 3,5,3'-triiodothyroacetic acid (TRIAC) led to complete clinical and biochemical normalization. In the second patient treatment with the dopaminergic agonist bromocriptine led to a temporal amelioration of hyperthyroidism. In the third patient, who was the only one with a proven pituitary adenoma, hypersecretion of TSH could be controlled by administration of the somatostatin analogue octreotide. It is emphasized that patients with this disorder should preferably not be treated with thyrostatic drugs, radioactive iodine or thyroid surgery. The success rate of these treatment modalities is lower than normal, they may lead to an increase of goiter size, and they potentially may promote growth or development of a TSH-producing adenoma. Treatment should be aimed at diminishing TSH hypersecretion.     

Comparative efficacy and side effects of the treatment of euthyroid goiter with levo-thyroxine or triiodothyroacetic acid

Euthyroid goiter is usually treated with TSH-inhibitory doses of levo-T(4) (L-T(4)). Because triiodothyroacetic acid (TRIAC) decreases TSH levels, the following study was perfomed: 36 euthyroid goitrous female patients (no cancer or chronic thyroiditis) were randomized to TRIAC (19.6 micro g/kg) (n = 19) or L-T4 (1.7 microg/kg) (n = 17) treatment during 11 months. Goiter volume; lumbar and femoral bone mineral density; serum osteocalcin; deoxypyridinoline; TSH; free T(4); total, high-density lipoprotein, and low-density lipoprotein cholesterol; and triglycerides were measured before and after the study period. Student's t test and chi(2) analysis were performed. TSH values (microunits per milliliter) in the TRIAC and L-T(4) groups were: 1.91 +/- 0.6 (basal) and 0.180 +/- 0.1 (after) and 2.1 +/- 2.5 (basal) and 0.180 +/- 0.3 (after), respectively. Thyroid volume decreased 37.9 +/- 35.4% in the TRIAC patients and 14.5 +/- 39.5% in the L-T(4) group (P = 0.069). Forty-two percent of the goiters with TRIAC reduced more than 50% their initial volume vs. 17.7% with L-T(4) (P = 0.15). With TRIAC, patients experienced fewer side effects. No differences in the changes of bone mineral density, serum deoxypyridinoline, osteocalcin, or the lipid profile were observed between both groups. The present results show that TRIAC is more effective than L-T(4) in the reduction of goiter size, with comparable effects on peripheral parameters.     

Effect of in vivo administration of recombinant acidic fibroblast growth factor on thyroid function in the rat: induction of colloid goiter.

We have recently demonstrated that the iv administration of 0.6-60 micrograms/kg.day of acidic fibroblast growth factor (acidic FGF) increases thyroid weight in male and female rats. Interestingly, measurement of serum TSH and thyroid hormones in rats treated with 6 micrograms/kg.day acidic FGF for 30 days revealed only a slight increase in serum T4 and reverse T3 concentrations. Since thyroid function was only examined 24 h after the 30th daily treatment, we performed a series of experiments to evaluate the effects of acidic FGF on thyroid function following single and 6 multiple injections of acidic FGF. There was a small increase in the serum TSH concentrations at 2, 4, 8, and 24 h after a single high dose iv injection of acidic FGF (60 micrograms/kg). In contrast, serum T3 concentrations were slightly decreased at 2, 4, and 8 h after acidic FGF administration. There was no effect of a single injection of acidic FGF on serum T4, reverse T3, or thyroglobulin concentrations. After 6 days of treatment, there was a 34% increase in the thyroid weights of rats treated with acidic FGF. Analysis of serum hormones revealed a slight increase in serum TSH, T3, and T4 concentrations in acidic FGF-treated rats, but no change in serum reverse T3 or thyroglobulin concentrations. There was no effect of acidic FGF administration on thyroid radioiodine uptake, the intrathyroidal metabolism of radioiodine, or the relative amounts of thyroidal thyroglobulin or peroxidase messenger RNAs, or on liver 5'-deiodinase activity. In hypophysectomized rats, with no detectable levels of serum TSH, acidic FGF failed to increase thyroid weight. These data suggest that FGFs may participate with TSH in the regulation of thyroid weight and colloid accumulation, and that autocrine or paracrine growth factors may be involved in the pathogenesis of colloid goiter.     

Free thyroxine, free triiodothyronine, and thyrotropin concentrations in hypothyroid and thyroid carcinoma patients receiving thyroxine therapy

Free thyroxine (FT4) and free triiodothyronine (FT3) concentrations in serum were measured by direct equilibrium dialysis methods in patients receiving thyroxine replacement or suppression therapy. Four of 50 hypothyroid patients euthyroid on replacement therapy (mean thyroxine dose 120 micrograms/day) had supranormal FT4 concentrations, whereas the FT3 concentrations were normal in all. Forty-one of 56 operated thyroid carcinoma patients on suppressive therapy (mean thyroxine dose 214 micrograms/day) had raised FT4 concentrations, whereas the FT3 concentrations was elevated in only one patient. There was a large difference in mean FT4 values for hypothyroid and thyroid carcinoma patients (17.2 vs 29.5 pmol/l), whereas the difference in mean FT3 values was small (5.0 vs 6.1 pmol/l), suggesting a decreased peripheral conversion of T4 to T3 with increasing concentrations of FT4. Serum TSH concentrations, as determined by an immunoradiometric assay, varied from less than 0.02 to 11.9 mU/l in treated hypothyroid patients; 21 patients (42%) had values outside the reference limits. As a single test, serum TSH is therefore not very useful for the assessment of adequate thyroxine dosage in patients with primary hypothyroidism. In thyroid carcinoma patients, the TSH concentrations were less than 0.18 mU/l; 45 patients had values less than 0.02 mU/l indicating sufficient suppression of TSH secretion in the majority of cases. On the basis of these results we recommend the combination of FT3 and TSH tests for monitoring thyroxine replacement and suppression therapy. FT4 appears less useful than FT3 for this purpose even if special reference values values were adopted for each patient group.     

Congenital goitrous hypothyroidism: discordant systolic time intervals, pituitary and peripheral responses to high daily doses of T4 or T3 therapy

Left ventricular performance was studied by a noninvasive technique through the measurement of the systolic time intervals (total eletromechanical systole, left ventricular ejection (LVET) time, preejection period (PEP) and PEP/LVET ratio (Systolic Quotient) in 8 young adults with congenital goitrous hypothyroidism. All subjects showed lengthening of PEP, shortening of LVET and an increased PEP/LVET ratio associated with low serum T3 and T4, an exaggerated TSH response to TRH, high levels of serum cholesterol, triglycerides and carotene. They were treated with increasing L-T4 at monthly intervals (100, 200 and 400 micrograms daily), followed by L-T3 (50 and 200 micrograms daily) after stopping medication for another month. Systolic time intervals and the systolic quotient promptly reversed to the normal range with physiologic L-T4 (100 micrograms) or L-T3 (50 micrograms) replacement, but the TSH peak response to TRH was still present and exaggerated. Further reductions of the systolic quotient occurred with 200 micrograms L-T4, but not with supraphysiological doses (400 micrograms L-T4 or 200 micrograms L-T3) of thyroid hormones. The highest dose of L-T3 (200 micrograms/day) induced a significantly lower mean systolic quotient than 400 micrograms L-T4 daily, while 5 patients still had a significant TSH response to TRH. This was interpreted as discordant pituitary and cardiac response to L-T3 and L-T4 therapy. Serum cholesterol and triglycerides were considered as very sensitive index of thyroid hormone peripheral action. These had a significant positive correlation with changes in the left ventricular performance. Serum carotene, although decreasing significantly with L-T4 or L-T3 treatment, had no significant correlation with the systolic quotient.(ABSTRACT TRUNCATED AT 250 WORDS)