Iodide-induced hypothyroidism: a potential hazard during perinatal life.

The administration of iodide to pregnant and nursing rats induces hypothyroidism in the term fetus and neonatal rat through age 10 days as indicated by an increase in the serum concentration of thyroid-stimulating hormone and a decrease in the serum of thyroxine and triiodothyronine. Thyroid function returned to normal from age 18 through 60 days in spite of continued iodide administration, strongly suggesting that resistance to the inhibitory effect of iodide on thyroid hormone synthesis is developed at approximately 18 days of age. This perinatal rat model can be used to study the mechanisms responsible for iodide-induced hypothyroidism and goiter in human newborns whose mothers received iodide-containing medications during pregnancy.

The effects of amiodarone on the thyroid.

Amiodarone is a benzofuranic-derivative iodine-rich drug widely used for the treatment of tachyarrhythmias and, to a lesser extent, of ischemic heart disease. It often causes changes in thyroid function tests (typically an increase in serum T(4) and rT(3), and a decrease in serum T(3), concentrations), mainly related to the inhibition of 5'-deiodinase activity, resulting in a decrease in the generation of T(3) from T(4) and a decrease in the clearance of rT(3). In 14-18% of amiodarone-treated patients, there is overt thyroid dysfunction, either amiodarone-induced thyrotoxicosis (AIT) or amiodarone-induced hypothyroidism (AIH). Both AIT and AIH may develop either in apparently normal thyroid glands or in glands with preexisting, clinically silent abnormalities. Preexisting Hashimoto's thyroiditis is a definite risk factor for the occurrence of AIH. The pathogenesis of iodine-induced AIH is related to a failure to escape from the acute Wolff-Chaikoff effect due to defects in thyroid hormonogenesis, and, in patients with positive thyroid autoantibody tests, to concomitant Hashimoto's thyroiditis. AIT is primarily related to excess iodine-induced thyroid hormone synthesis in an abnormal thyroid gland (type I AIT) or to amiodarone-related destructive thyroiditis (type II AIT), but mixed forms frequently exist. Treatment of AIH consists of L-T(4) replacement while continuing amiodarone therapy; alternatively, if feasible, amiodarone can be discontinued, especially in the absence of thyroid abnormalities, and the natural course toward euthyroidism can be accelerated by a short course of potassium perchlorate treatment. In type I AIT the main medical treatment consists of the simultaneous administration of thionamides and potassium perchlorate, while in type II AIT, glucocorticoids are the most useful therapeutic option. Mixed forms are best treated with a combination of thionamides, potassium perchlorate, and glucocorticoids. Radioiodine therapy is usually not feasible due to the low thyroidal radioiodine uptake, while thyroidectomy can be performed in cases resistant to medical therapy, with a slightly increased surgical risk.

Transient congenital hypothyroidism in an iodine-replete area is not related to parental consanguinity, mode of delivery, goitrogens, iodine exposure, or thyrotropin receptor autoantibodies.

OBJECTIVE: To assess transient congenital hypothyroidism (TCH) etiologies in two Iranian cities. MATERIALS AND METHODS: Cord dried blood spot samples were collected from neonates in Tehran and Damavand. Serum TSH and T4 were measured in those with cord TSH > or =20 mIU/l. Normal serum values at 2-3 weeks of age confirmed transient hyperthyrotropinemia (THT), while persistently abnormal levels revealed congenital hypothyroidism (CH). Normal serum TSH and T4 4-6 weeks after levothyroxine replacement therapy discontinuation at 2-3 yr of age differentiated TCH from persistent CH. RESULTS: Among 50,409 screened newborns, 9 (1:5601 births) were diagnosed as TCH and compared to 88 full-term neonates (>/=37 weeks' gestation) with THT and 45 normal (cord TSH<20 mIU/l) neonates. At a median age of 11 days, median (range) serum TSH values in TCH, THT, and normal neonates were 36.8 (13-130), 3.6 (0.1-13.3), and 2.9 (0.7-8.0) mIU/l (p<0.0001) and serum T4 values were 97 (36-168), 142 (74-232), and 160 (79-228 nmol/l), respectively (p=0.002). Urinary iodine concentration (UIC) >220 microg/l was observed in 5 (55.6%) of TCH neonates. The occurrence of TCH was not associated with gender, parental consanguinity, mode of delivery, pre- or post-natal consumption of goitrogens and/or thyroid affecting medications, TSH receptor autoantibodies, or neonatal UIC. CONCLUSIONS: Elevated UIC was the most frequent finding in newborns with TCH but the distribution of excessive UIC was not significantly different among TCH, THT, and normal neonates. Since no other etiologies were found in TCH neonates without elevated UIC values, evaluation of other environmental and/or genetic factors is warranted.

National Health and Nutrition Examination Survey III thyroid-stimulating hormone (TSH)-thyroperoxidase antibody relationships demonstrate that TSH upper reference limits may be skewed by occult thyroid dysfunction.

CONTEXT: The setting of the TSH upper reference limit impacts the diagnosis of mild hypothyroidism and is currently controversial. OBJECTIVE: Our objective was to evaluate factors influencing the TSH reference range. DESIGN: Nonpregnant subjects aged 12 yr and older from National Health and Nutrition Examination Survey III were used to study the relationships between TSH, thyroid peroxidase antibodies (TPOAb), and thyroglobulin antibodies in different ethnic groups. RESULTS: TPOAb prevalence was lowest (<3%) when TSH was between 0.1 and 1.5 mIU/liter in women and between 0.1 and 2.0 mIU/liter in men and progressively increased to above 50% when TSH exceeded 20 mIU/liter. TSH reference range parameters (2.5th, 50th, and 97.5th percentiles) were analyzed according to thyroid antibody status, race/ethnicity, and age for the 14,202 subjects made up of non-Hispanic Blacks (B), non-Hispanic whites (W), and Mexican-Americans (M) who did not report thyroid disease or taking thyroid-altering medications and whose total T(4) was within the reference range. For each age group of each ethnicity, the inclusion of antibody-positive subjects increased TSH medians and upper limits (97.5th percentiles). The TSH upper limit was lower for the entire B cohort vs. W or M. However, this difference was lost when age cohorts with a similar prevalence of TPOAb (B age 40-49 yr vs. W and M age 20-29 yr) were compared. CONCLUSIONS: Ethnic differences in TSH were not present when populations with the same relative frequency of thyroid antibodies were compared. TSH upper reference limits may be skewed by TPOAb-negative individuals with occult autoimmune thyroid dysfunction.

Thyroid hormone transport in the serum of patients with thyrotoxic Graves' disease before and after treatment.

Multiple indices of thyroid hormone binding have been studied in sera obtained from patients with thyrotoxic Graves' disease, before and after treatment, and in sera from a group of carefully matched normal controls. Specimens from patients with thyrotoxicosis displayed a decrease in the thyroxine (T(4))-binding capacities of T(4)-binding globulin (TBG) and T(4)-binding prealbumin (TBPA), an increase in serum protein-bound iodine (PBI), and an increase in both the proportion and absolute concentration of free T(4). In addition, a smaller than normal proportion of (131)I-labeled T(3) was associated with TBG during filter paper electrophoresis. After treatment of thyroxicosis, the only residual abnormality detected was a very slight persistent decrease in the T(4)-binding capacity of TBPA, which did not appear to influence the overall thyroid hormone-plasma protein interaction significantly, regardless of whether this was assessed under basal conditions or after enrichment of specimens with stable T(4). It is concluded that the persistent abnormalities in the peripheral metabolism of T(4), previously reported to occur in some patients with treated Graves' disease, probably do not stem from residual abnormalities in the transport of T(4) in the plasma but must arise from abnormalities in T(4) accumulation or metabolism within the tissues themselves.

Thyrotropin-releasing hormone is not required for thyrotropin secretion in the perinatal rat.

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.

Conversion of thyroxine (T4) to triiodothyronine (T3) in athyreotic human subjects.

Studies of the possibility that thyroxine (T4) is converted to 3.5,3'-triiodo-L-thyronine (T3) in the extrathyroidal tissues in man have been conducted in 13 patients, all but two of whom were athyreotic or hypothyroid, and all of whom were receiving at least physiological replacement doses of synthetic sodium-L-thyroxine.T3 was found in the sera of all patients, in concentrations ranging between 243 and 680 ng/100 ml (normal range 170-270 ng/100 ml). These concentrations were far in excess of those which would have been expected on the basis of the T3 contamination of the administered T4, as measured by the same technique employed in the analysis of serum. When oral medication was enriched with (125)I-labeled T4 for 8 or more days, labeled T3 and tetraiodothyroacetic acid (Tetrac or TA(4)) were found in the serum to the extent of approximately 2-5% of total radioactivity, as assessed by unidimensional paper chromatography. The same results were obtained with a specially purified lot of radioactive T4 containing less than 0.1% T3 as a contaminant. The identities of the (125)I-labeled T3 and TA(4) were verified by two-dimensional chromatography as well as by specific patterns of binding in serum. The labeled T3 isolated was bound by albumin and by T4-binding globulin (TBG), but not by T4-binding prealbumin (TBPA): in contrast the labeled TA(4) was bound by albumin and TBPA, but not by TBG. To exclude the possibility that the conversion of T4 to T3 was a peculiarity of the oral route of administration, the sera of two additional patients were obtained 48 hr after 7-day courses of daily intravenous injections of a mixture of stable and (125)I-labeled T4. Both stable and labeled T3 were likewise found in these sera. In contrast to earlier experiments in humans in which (131)I-labeled T3 was not definitively demonstrated in serum after a single intravenous injection of (131)I-labeled T4, the present findings are taken to provide conclusive evidence of the extrathyroidal conversion of T4 to T3 in man. These results raise once again the question of the extent to which the metabolic effect of T4 is mediated through the peripheral generation of T3.

Effect of physiological variations in free fatty acid concentration on the binding of thyroxine in the serum of euthyroid and thyrotoxic subjects.

The effect of variations in the concentration of free fatty acids (FFA) on the binding of thyroid hormones in serum has been studied in 20 euthyroid subjects and 19 thyrotoxic patients. In the euthyroid group, neither the pronounced decreases in FFA induced by the oral administration of glucose or the intravenous administration of nicotinic acid, nor the marked increases in FFA which followed the administration of nicotinic acid or 2-deoxyglucose were accompanied by significant changes in the per cent of free thyroxine (T(4)), the protein-bound iodine (PBI), the per cent of endogenous T(4) bound by the T(4)-binding globulin (TBG) or T(4)-binding prealbumin (TBPA), or the resin sponge uptake of triiodothyronine (T(3)). In the thyrotoxic group, the decline in FFA concentration which followed glucose administration was accompanied by slight, but statistically significant, decreases in the PBI and both the per cent and absolute concentration of free T(4). Such changes might have been indicative of an increased intensity of T(4) binding secondary to the decrease in FFA. The serum PBI was decreased, however, a change contrary to that which would be expected to follow an increase in the intensity of T(4) binding. Furthermore, comparable changes in free T(4) and PBI did not accompany the decrease in FFA induced by the administration of insulin. Neither manipulation significantly affected the protein binding of endogenous T(4) or the resin sponge uptake of T(3). It is concluded that within a wide physiological range of concentration, FFA do not significantly influence the transport of T(4) in the serum of euthyroid subjects. In the serum of patients with thyrotoxicosis, FFA may have a slight effect on the binding of T(4), but the nature of any such effect is obscure, since parallel, rather than contrary changes in PBI and the proportion of free T(4) followed alterations in FFA concentration.

Control of thyroid hormone secretion in normal subjects receiving iodides.

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 role of sulfhydryl groups on the impaired hepatic 3',3,5-triiodothyronine generation from thyroxine in the hypothyroid, starved, fetal, and neonatal rodent.

The role of nonprotein sulfhydryl groups (NPSH) in the decreased in vitro hepatic 3',3,5-triiodothyronine (T(3)) generation from thyroxine (T(4)) in the starved, hypothyroid, fetal and 1- to 4-d-old neonatal rat and dwarf mouse was assessed. NPSH were measured in fresh 25% liver homogenates prepared in 0.1 M PO(4)/10 mM EDTA buffer. As compared with values in adult male rats, NPSH concentration was decreased in the 2-d-starved (1.1+/-0.04 (mean+/-SE) vs. 2.2+/-0.15 mmol/250 g wet liver weight, P < 0.001), fetal (1.0+/-0.04 vs. 3.2+/-0.08, P < 0.001), 1-d-old neonatal (1.1+/-0.03 vs. 2.1+/-0.04, P < 0.001), and hypothyroid (thyroidectomized 60 d) (1.4+/-0.06 vs. 2.2+/-0.15 P < 0.001) rat. NPSH were also decreased in the hypothyroid, hypopituitary dwarf mouse as compared with values in their normal litter mates (1.3+/-0.03 vs. 2.0+/-0.2, P < 0.01). Chronic administration of T(3) (0.5 mug/100 g body wt per d) markedly increased hepatic T(3) generation from T(4) in the thyroidectomized rat and in the dwarf mouse to values similar to those observed in the normal rodent without affecting NPSH concentration. In contrast, T(3) administration to the starved rat did not alter either hepatic T(3) generation from T(4) or NPSH. Reduced glutathione concentration was also markedly decreased in the starved rat (fed; 1.05+/-0.075 mmol/250 g wet tissue vs. starved 0.38+/-0.02, P < 0.001). Dithiothreitol (DTT), a thiol reducing agent, increased hepatic T(3) generation from T(4) in the normal adult male rat by 45+/-5% in six experiments. When compared to DTT-stimulated control homogenates, the addition of DTT completely restored hepatic T(3) generation in starved rats, partially restored T(3) generation in 1- and 4-d-old neonates, but had little or no effect in the fetal and hypothyroid rat and dwarf mouse. Liver homogenates stored for 6 mo at -20 degrees C lost their capacity to generate T(3) from T(4). NPSH concentrations in the frozen homogenates decreased progressively with increasing storage and were absent by 6 mo. 5'-Deiodinase activity correlated with NPSH concentration in the stored homogenates (r = 0.95, P < 0.005). Addition of DTT partially restored hepatic T(3) generation in the frozen homogenate. It is concluded that NPSH are important for the action of the liver 5'-deiodinase. The decreased hepatic T(3) generation in the starved rat is associated with decreased NPSH but not with a decrease in the absolute quantity of 5'-deiodinase because provision of sulfhydryl groups restored hepatic T(3) generation to normal. In contrast, the decreased hepatic T(3) generation in the adult hypothyroid rodent and in the fetal rat is probably due to a decrease in the enzyme concentration per se. In the 1- and 4-d neonatal rat, the decrease in hepatic T(3) generation is secondary to a decrease in NPSH and the deiodinating enzyme.

The physiological role of thyrotropin-releasing hormone in the regulation of thyroid-stimulating hormone and prolactin secretion in the rat.

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.

Maternal thyroid function is the major determinant of amniotic fluid 3,3',5'-triiodothyronine in the rat.

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).

Rapid alteration in circulating free thyroxine modulates pituitary type II 5' deiodinase and basal thyrotropin secretion in the rat.

TSH secretion is decreased by both T4 and T3. This negative feedback control of TSH secretion has been correlated with an increase in pituitary nuclear T3 content, and it is not clear whether T4 exerts its effect directly on the thyrotroph or after its deiodination to T3. However, levels of the pituitary enzyme catalyzing T4 to T3 conversion, 5'D-II, are decreased in the presence of an increased amount of T4. Thus, it is unclear why the thyrotroph would have a mechanism for modulating the production of T3, if T3 is, in fact, the sole bioactive signal providing negative feedback inhibition. To examine this apparent paradox, we administered EMD 21388, a compound which inhibits the binding of T4 to transthyretin resulting in a rapid increase in circulating free T4 levels, to rats pretreated with radiolabeled T4 and T3. We observed increases in pituitary and liver T4 content of greater than 150%, without increases in the respective tissue T3 contents. The EMD 21388-treated rats also exhibited a 25% decrease in pituitary 5'D-II activity (103.8 +/- 15.8 fmol 125I released.mg protein-1.h-1, vs. control, 137.4 +/- 15.9, mean +/- SE), as did rats treated with sodium salicylate, another compound that inhibits T4-TTR binding (100.8 +/- 7.1). TSH levels significantly decreased 2 h after the administration of EMD 21388. These data demonstrate that despite a T4-mediated decrease in pituitary 5'D-II activity, an increase in T4 independently decreases TSH secretion.

Inner-ring deiodination of 3,5,3'-triiodothyronine in the in situ perfused guinea pig placenta.

Broken cell preparations of rat and human placentas contain an inner (tyrosyl)-ring iodothyronine deiodinase enzyme with greatest activity when the substrate is 3,5,3'-triiodothyronine (T3). This report describes the deiodination of T3 in the intact placenta and the effect of sodium iopanoate (IA) and propylthiouracil (PTU) on T3 deiodination. Under nembutal anesthesia, the placenta of 60-65-d-old pregnant guinea pigs was surgically exposed, a single umbilical artery and the umbilical vein were cannulated, and the fetus was removed. In a temperature-controlled chamber (37 degrees C), the fetal side of the placenta was perfused through the umbilical artery at a rate of 1 ml/min with 3% bovine serum albumin Krebs-Henseleit buffer containing 0.14 nM outer ring labeled [125I]T3. Placenta effluent fractions were collected at timed intervals from the umbilical vein cannula throughout a 120-min perfusion period. The contents of the perfusion buffer and the various effluent fractions were analyzed for their iodothyronine content by high pressure liquid chromatography. In five experiments, the percent composition of 125I-labeled iodothyronines in the perfusion buffer and placenta effluent was 95.3 +/- 1.0 (mean +/- SE) and 70.2 +/- 2.1 for T3 (P less than 0.01), 2.5 +/- 0.7 and 20.1 +/- 1.8 for 3,3'-T2 (P less than 0.01), and 0 and 8.2 +/- 0.9 for 3'-T1. There was no difference between the percent [125I]iodide in the perfusion buffer and in the placenta effluents. When placentas were perfused with IA and [125I]T3, after perfusion with [125I]T3 alone, there was a significant increase (P less than 0.01) in the percent [125I]T3 in the placenta effluents, and a significant decrease in [125I]3,3'-T2 (P less than 0.01) and [125I]3'-T1 (P less than 0.01). In contrast, PTU did not affect the composition of labeled iodothyronines in the placenta effluents, despite the fact that the addition of PTU significantly (P less than 0.001) inhibits the inner-ring deiodination of [125I]T3 in human or guinea pig placenta microsomes in the presence of low (0.25 mM) concentrations of dithiothreitol. The present studies demonstrate that T3 is actively deiodinated in the inner ring to 3,3'-T2 by the intact guinea pig placenta. A portion of 3,3'-T2 is further deiodinated in the inner ring to generate 3'-T1. No outer ring deiodination of T3 was seen under the conditions employed. IA, but not PTU, inhibits T3 deiodination in the placenta perfused in situ. We conclude that the placenta is probably a site for fetal T3 metabolism.

Hyperresponse to thyrotropin-releasing hormone accompanying small decreases in serum thyroid hormone concentrations.

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.

Effects of replacement doses of sodium L-thyroxine on the peripheral metabolism of thyroxine and triiodothyronine in man.

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 thyroid gland is a major source of circulating T3 in the rat.

In rats, the respective contribution of the thyroid and peripheral tissues to the pool of T3 remains unclear. Most, if not all, of the circulating T3 produced by extrathyroidal sources is generated by 5'-deiodination of T4, catalyzed by the selenoenzyme, type I iodothyronine 5'-deiodinase (5'D-I). 5'D-I in the liver and kidney is almost completely lost in selenium deficiency, resulting in a marked decrease in T4 deiodination and an increase in circulating T4 levels. Surprisingly, circulating T3 levels are only marginally decreased by selenium deficiency. In this study, we used selenium deficiency and thyroidectomy to determine the relative contribution of thyroidal and extrathyroidal sources to the total body pool of T3. Despite maintaining normal serum T4 concentrations in thyroidectomized rats by T4 replacement, serum T3 concentrations remained 55% lower than those seen in intact rats. In intact rats, restricting selenium intake had no effect on circulating T3 concentrations. Decreasing 5'D-I activity in the liver and kidney by > 90% by restricting selenium intake resulted in a further 20% decrease in serum T3 concentrations in the thyroidectomized, T4 replaced rats, suggesting that peripheral T4 to T3 conversion in these tissues generates approximately 20% of the circulating T3 concentrations. While dietary selenium restriction markedly decreased intrahepatic selenium content (> 95%), intrathyroidal selenium content decreased by only 27%. Further, thyroid 5'D-I activity actually increased 25% in the selenium deficient rats, suggesting the continued synthesis of this selenoenzyme over selenoproteins in other tissues in selenium deficiency. These data demonstrate that the thyroid is the major source of T3 in the rat and suggest that intrathyroidal T4 to T3 conversion may account for most of the T3 released by the thyroid.

Effects of norethandrolone on the transport and peripheral metabolism of thyroxine in patients lacking thyroxine-binding globulin. Observations on the physiological role of thyroxine-binding prealbumin.

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 mug/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 mmug/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.

Serum thyrotropin receptor antibodies concentrations in patients with Graves' disease before, at the end of methimazole treatment, and after drug withdrawal: evidence that the activity of thyrotropin receptor antibody and/or thyroid response modify during the observation period.

AIM AND METHODS: We performed a quantitative retrospective analysis of serum thyrotropin receptor antibody (TRAb) concentrations measured by a second-generation radioreceptor assay in 58 patients with Graves' disease (GD) at the onset of the disease, at the end of 18 month methimazole (MMI) treatment, and after MMI withdrawal in order to evaluate the correlation between the presence of these antibodies and the relapse of hyperthyroidism. Sixty healthy subjects were enrolled as a control group. RESULTS: Before MMI treatment the best cutoff TRAb value for identifying patients with GD was 1.45 UI/L (specificity, 100%; sensitivity, 98.3%). At the end of MMI treatment, serum TRAb concentrations were significantly lower (p < 0.001) than those measured at baseline, but they were still significantly higher (p < 0.001) than those found in the control subjects. At the end of MMI treatment, 44 patients (75.9%) had positive TRAb values (>1.45 UI/L). After MMI withdrawal (median, 15 months), 34 patients (58.6%) became hyperthyroid, 4 patients (6.9%) became hypothyroid, and 20 patients (34.5%) remained euthyroid. There was a significant correlation between serum TRAb concentrations at the end of MMI treatment and the percentage of patients who became hyperthyroid (r: 0.56; p < 0.001) and the time of appearance of hyperthyroidism (r: -0.38; p = 0.03). All 4 patients with TRAb values below 0.9 UI/L at the end of MMI treatment remained euthyroid throughout the follow-up period. Among the 27 patients who had serum TRAb values higher than 4.4 UI/L, 23 developed hyperthyroidism and 4 hypothyroidism. The TRAb values between 0.9 and 4.4 UI/L did not discriminate between the 27 patients (46.6%) who remained euthyroid from those who had relapse of hyperthyroidism. Thus a different TRAb end of treatment cutoff was calculated to identify patients who became again hyperthyroid. This TRAb cutoff value was 3.85 UI/L (sensitivity, 85.3%; specificity, 96.5%). All but 1 patient who had serum TRAb values above 3.85 UI/L became hyperthyroid after MMI was withdrawn (positive predictive value, 96.7%). In these patients, relapse of hyperthyroidism was independent of the changes in serum TRAb concentrations (r: 0.27; p = 0.15) and occurred after a median period of 8 weeks (range, 4-48). Hyperthyroidism also developed in 5 of 24 patients who had serum TRAb concentrations lower than 3.85 UI/L at the end of MMI treatment. In these 5 patients the relapse of hyperthyroidism occurred after a median period of 56 weeks (range, 24-120) and was always accompanied by an increase in serum TRAb concentrations. CONCLUSIONS: TRAb persist in the blood of most patients with GD after 18 months of MMI treatment. Both the frequency and the time of appearance of hyperthyroidism are closely correlated with serum TRAb concentrations at the end of MMI treatment. Our data would suggest that TRAb maintain stimulating activity after a full course of MMI treatment in the large majority of patients with GD. However, it is likely that the potency of these antibodies and/or the thyroid response to them change during treatment, as suggested by the different values measured in euthyroid control subjects and in euthyroid patients after MMI treatment.

Lymphocytic thyroiditis and diabetes in the BB/W rat. A new model of autoimmune endocrinopathy.

The Bio Breeding/Worcester (BB/W) rat develops spontaneous insulin-dependent diabetes mellitus secondary to lymphocytic infiltration and destruction of the pancreatic beta-cells. This destructive process in the pancreas has been postulated to be based on a thymus-dependent cell-mediated autoimmune process. In view of the well recognized association in man of diabetes mellitus and another autoimmune endocrinopathy, chronic thyroiditis (Hashimoto's thyroiditis), the present studies were carried out to determine whether lymphocytic thyroiditis occurred with increased frequency in the diabetic, insulin-treated BB/W rat. The incidence of lymphocytic thyroiditis was strikingly increased in 8-10-mo-old diabetic rats (59%) as compared with their nondiabetic cohorts (11%) (P less than 0.001). Relative thyroid weight was significantly greater in diabetic as compared with nondiabetic rats (P less than 0.01) and in diabetic rats with thyroiditis than in diabetic rats without thyroiditis (P less than 0.025). Lymphocytic thyroiditis was not accompanied by any consistent changes in serum T4, T3, and TSH concentrations or in the serum TSH response to thyrotropin-releasing hormone (TRH) suggesting that the thyroiditis was not of sufficient severity or duration to induce primary thyroid gland failure. The BB/W rat represents the first animal model of multiple autoimmune endocrinopathies and provides a unique opportunity to study the pathogenesis of these disorders.