Reciprocal relation of thyroid-stimulating hormone and thyroid-stimulating immunoglobulin in a patient with endogenous subclinical hyperthyroidism.

A 72-year-old white woman with an abnormal serum thyroid-stimulating hormone (TSH) concentration was referred to our facility for a comprehensive evaluation. Circulating thyroxine (T4) and free thyroxine (FT4) concentrations were all in the normal range. Tri-iodothyronine (T3) concentrations were in the low end or slightly below the normal range. TSH was detectable but was below the limits of the normal range. The patient was clinically euthyroid and was receiving medication only for treatment of hypertension. The clinical and laboratory thyroid function status was consistent with a diagnosis of subclinical hyperthyroidism. The physical examination did not reveal thyroid enlargement, nor was there any evidence for the presence of thyroid nodules or ocular changes suggestive of Graves disease. Among thyroid autoantibodies of particular interest was the presence of a moderate thyroid-stimulating immunoglobulin (TSI) level that was stable and consistently present during a 7-month observational period. At 13 months after the initial visit, TSI antibodies were absent and TSH concentration had returned to the normal range. Based on the TSH agonist activity of TSI and the observed reciprocal relation of TSI and TSH, there was no need to suggest pituitary hypersensitivity to thyroid hormone.

Potentiation of thyroxine 5-deiodination by aminotriazole.

Aminotriazole, a goitrogen, in addition to its known inhibitory effects on the thyroid, demonstrated a unique effect on peripheral deiodination of thyroxine (T4). In contrast to the well-known peripheral effects of goitrogens such as propylthiouracil in inhibiting 5'-deiodinase activity, i.e., to effect a decrease in T4 to triiodothyronine (T3) conversion, aminotriazole had no effect on the 5'-deiodinative pathway. Rather, this goitrogen appeared to stimulate the alternative pathway, viz. T4 5-deiodination, resulting in an increased reverse triiodothyronine (rT3) serum concentration. This was shown in comparisons of serum T4, T3 and rT3 concentrations and serum T3/T4 and rT3/T4 ratios between rats treated with aminotriazole and T4, and rats treated with T4 alone. The finding that aminotriazole may specifically enhance T4 5-deiodination, independently of T4 5'-deiodination, is novel, as this has not been observed in the case of other goitrogens. It is of interest that this goitrogen is devoid of sulphur, which is a prominent constituent of thiourylene compounds which have been noted to affect 5'-deiodination. The potentiating effect of aminotriazole on 5-deiodination of T4 was not attributable to dietary factors.

Hypothyroxinemia in cardiac arrest.

Thyroid function was evaluated in cardiac arrest (CA), a condition associated with marked activation of the pituitary-adrenal axis. Blood samples were obtained in 24 patients immediately after diagnosis of CA and again ten minutes later. Samples were also obtained from 22 patients admitted consecutively to the intensive care unit (ICU). Abnormalities of thyroid indexes among patients on the ICU who had not experienced CA were low triiodothyronine (T3) in 45%, low thyroxine (T4) in 32%, low free T4 (equilibrium dialysis) in 21%, and elevated reverse T3 levels in 36%. The alterations of thyroid values were both more common and marked in patients with CA, with abnormally low T3 in 84% of the patients, low T4 in 65%, low free T4 in 65%, and high reverse T3 in 80%. Thyroxine-binding globulin and prealbumin concentrations were below the normal range in 40% and 21% of patients with CA. A thyroid hormone-binding inhibitor was detected in 38% of patients with CA. Thyroglobulin level was slightly high in patients with CA but not significantly different from controls on the ICU. The abnormalities present at zero minutes were further exaggerated ten minutes after CA. We conclude that abnormalities on tests measuring thyroid function are extremely common during the cardiovascular emergency of CA.

Radioimmunoassay of reverse triiodothyronine.

rT3 RIA standard curves were generated using rT3 standards from various sources. The rT3 antiserum and the method of free and bound hormone separation used were the same in all assays. The slopes of rT3 RIA curves differed considerably; standard curves generated with Henning (Berlin) rT3 standard had the steepest slope. Because of the differences in slopes of standard curves, bound to free estimates, when extrapolated from standard curves generated with various rT3 standards, resulted in 2- to 3-fold differences in rT3 assay values in the same sera. Circulating rT3 concentration in human sera was 20 ng/100 ml when Henning rT3 standard was used in the assay, whereas with Jorgensen's rT3 standard, a value of 42 ng/100 ml was noted. As the rT3 antiserum and assay conditions used were identical in all comparisons (except rT3 standards), the 2- to 3-fold differences in rT3 values noted in the same sera suggested variability in potency of rT3 standards. The differences in rT3 values in the same sera (resulting from extrapolation from standard curves using different rT3 standards) were of the same magnitude as that noted in normal human sera in various studies, suggesting that the reported rT3 variations in sera of euthyroid individuals may also be due to differences in rT3 standards employed in the assay.

Hepatic bioavailability of thyroxine and testosterone in familial dysalbuminemic hyperthyroxinemia.

The bioavailability of [125I]T4 or [3H]testosterone in serum obtained from normal subjects and from subjects with familial dysalbuminemic hyperthyroxinemia (FDH) was studied with a portal vein injection technique in ketamine-anesthetized rats. In the present studies this technique was modified by performing uptake measurements in the presence of serum loaded with either 25 microM T4 or 1 microM testosterone. Loading of serum with these high concentrations displaced the labeled hormone from the lower capacity globulin or prealbumin-binding sites to the high capacity albumin or dysalbumin-binding sites, and allowed for the analysis of hormone availability in liver when the labeled hormone was delivered to the tissue bound either to albumin or to dysalbumin binding sites. In the presence of normal serum, 33 +/- 3% (SE) of T4 was available to rat liver, as opposed to 20 +/- 2% for FDH serum. When normal serum was loaded with 25 microM T4, the bioavailable T4 increased to 97 +/- 2%, consistent with the availability of T4 bound to albumin. However, the hepatic bioavailability of T4 in the presence of 25 microM T4 in FDH serum was only 33 +/- 4%. Testosterone bioavailability was similar in normal and in FDH sera, and was 49 +/- 7% in the absence and 99 +/- 4% in the presence of 1 microM testosterone. These studies suggest that T4 bound to the FDH albumin binding site is not readily available for entry into liver, whereas T4 bound to the normal albumin binding site is freely available for uptake in vivo. The differential bioavailability of T4 is compatible with the model that the normal and FDH binding sites are situated on different parts of the albumin molecule, and that only T4 bound to the normal binding site is freely available for delivery to the liver.

Increased free thyroxine in a euthyroid patient with thyroxine-binding globulin deficiency.

An unusual finding of elevated free thyroxine (FT4) concentration coexistent with familial low thyroxine-binding globulin (TBG) is described in a euthyroid patient. Clinical and other laboratory tests were normal and consistent with a clinical diagnosis of euthyroidism. Low TBG (TBG capacity 3-10 mug/100 ml) was confirmed by various electrophoretic procedures and by TBG immunoassay (0.9 mg/100 ml). Serum T4 concentration was low (2.0-5.5 mug/100 ml). Triiodothyronine (T3) resin uptake was increased (88-93%) and the free thyroxine index was normal. Twenty-four-hour thyroidal 131I uptake was normal and varied between 13-20%. Serum thyroid-stimulating hormone (less than 2 muunits) and T3 concentration (80 ng/100 ml) were also normal. Long-acting thyroid stimulator (LATS) was not present. Free T4 concentration measured by dialysis procedure was markedly elevated (9.2-12.1 ng/100 ml). Pulse T3 and T4 tracer kinetic studies by the single compartmental method revealed accelerated blood disappearance of T4 (t 1/2 = 3.7 days) but normal disappearance of T3 (t 1/2 = 2.1 days). Extrathyroidal hormonal iodine pool (569 mug) was in the range of normals. T4 degradation rate (144 mug/70 kg/day) was moderately elevated over the euthyroid mean values, but was still close to or within the upper normal range. T3 degradation was normal (34 mug/day). Failure to develop hyperthyroidism in the presence of elevated free T4 levels, but with normal T3 concentration and dynamics, may suggest that T3, not T4, plays a major role in regulating metabolic activity; alternatively, euthyroidism in this low-TBG patient despite elevated free T4 concentration may simply be explained on the basis of a daily T4 disposal rate which was not clearly abnormal.

Coexistence of familial dysalbuminemic hyperthyroxinemia with familial hypercholesterolemia and multiple lipoprotein type hyperlipidemia.

Familial dysalbuminemic hyperthyroxinemia (FDH), an autosomal disorder characterized by an increase in serum albumin binding of thyroxine, has been encountered in a family who was also found to have both familial hypercholesterolemia (FHC) and multiple lipoprotein type hyperlipidemia (MLH). One subject with FHC and two subjects with MLH had FDH. Although some of the laboratory parameters in hyperlipidemic patients with FDH were suggestive of hyperthyroidism, the dialyzable free thyroxine concentrations were in the normal range and the patients were clinically euthyroid. The significance of the occurrence of FDH in hyperlipidemic subjects with hypothyroidism has been discussed, especially in regard to the longer time interval that may be needed to achieve an amelioration of the hypothyroid state during treatment with a normal maintenance dose of thyroxine. Treatment of FDH patients with other drugs may require an altered dosage if the drug binds to the atypical albumin fragments characterizing this disorder.

Euthyroid familial hyperthyroxinemia due to abnormal thyroid hormone-binding protein.

A family is described in which three members had an elevated total serum thyroxine level and free thyroxine index. Each affected subject was clinically euthyroid and had a normal pulse wave arrival time (QKd), serum triiodothyronine and free thyroxine levels, and a normal serum thyroxine-binding globulin (TBG) concentration. Electrophoresis of their serum with 125I-labeled thyroxine revealed increased thyroxine binding in the albumin region. In addition, this abnormal protein, like thyroxine-binding globulin, bound 125I-labeled triiodothyronine and 125I-labeled reverse triiodothyronine. However, electrophoresis of serum treated by sialidase (neuraminidase) digestion suggested that this abnormal protein is not an anomalous form of thyroxine-binding globulin "buried" in the albumin area. These cases of euthyroid familial hyperthyroxinemia due to an abnormal thyroid hormone-binding protein show that an elevated serum thyroxine level or free thyroxine index is not always sufficient to confirm the presence of thyrotoxicosis.

A simple and rapid radioimmunoassay of triiodothyronine in unextracted serum.

A simple, accurate, and rapid procedure for radioimmunoassay (RIA) of triiodothyronine (T3) is described. Serum is denatured by sodium trichloroacetate and the T3 released is allowed to react with 125I-T3-labeled T3 anti-serum. The displaced 125I-T3 is rapidly taken up by an anionic-resin sponge, and this uptake is linearly related to serum T3 concentration. The entire assay procedure was completed in the same tube in about 1 hr. The T3 antibody was specific, and T4-to-T3 conversion in the assay did not occur. Recovery of exogenously added T3 was virtually complete. The mean T3 concentration in 92 euthyroid subjects (142 ng/100 ml) is comparable to the values described in a number of radioimmunoassays for T3.

Low triiodothyronine and raised reverse triiodothyronine levels in patients over fifty years of age who have type II diabetes mellitus: influence of metabolic control, not age.

Several studies have demonstrated that the uncontrolled diabetic state in both type I as well as type II diabetes mellitus is characterized by altered thyroid hormone metabolism, which results in the lowering of serum triiodothyronine (T3) levels and a reciprocal elevation of T3 (rT3) levels. Because the majority of type II diabetics are over 50 years of age and because numerous previous reports have implicated aging as a cause of low T3 and high rT3 levels, we studied 220 type II diabetics from 40-85 years of age to assess the influence of aging and metabolic control on thyroid hormone levels. Serum thyroxine (T4) free T4, T3 resin uptake, and thyroid-stimulating hormone (TSH) measurements in diabetic patients were not significantly altered compared with 37 young normal control subjects, irrespective of age or the grade of metabolic control. Serum T3 levels declined and rT3 levels rose in the diabetic patients with worsening of the metabolic control. However, with comparable metabolic control, the levels were not significantly different from the younger patients. Therefore, low T3 and high rT3 levels observed in patients of any age who have type II diabetes mellitus may be exclusively caused by deranged metabolic control of their disease.

Effects and clinical significance of exogenous thyroxine therapy in patients with circulating thyroid hormone autoantibodies.

The effects of exogenous L-thyroxine therapy (0.2-0.3 mg/day) on spontaneously occurring thyroid hormone autoantibodies (THAA) and on serum levels of thyroxine (T4), triiodothyronine (T3) and reverse triiodothyronine (rT3) are described in a boy with lymphocytic thyroiditis. Prior to T4 medication, THAA bound virtually all thyroid hormones as noted by serum gamma globulin binding of tracer hormones. During T4 therapy, however, gamma globulin binding of tracer thyroid hormones decreased markedly. T4 and T3 levels as determined by radioimmunoassay (RIA) were grossly distorted prior to thyroxine therapy and bore no relation to clinical status, the single antibody technics yielding falsely low values whereas the double antibody procedures spuriously exaggerating serum hormone concentration. That spontaneously occurring THAA interfered in RIA hormone measurements was clearly shown by the lack of inconsistencies in laboratory and clinical evaluation when hormone determinations were performed in protein free serum extracts (to remove circulating THAA), or when RIAs were carried out in sera during thyroxine therapy when THAA were saturated by exogenous hormones. The thyroid stimulating hormone (TSH) level prior to therapy was 300 microunits/ml which decreases to less than 3 microunits/ml during T4 medication (0.3 mg/day). There was a gross inverse correlation between TSH secretion and T4 antibody saturation. The marked inhibition of antibody binding of tracer thyroid hormones observed during therapy suggested possible masking of thyroid hormone antibody activity during T4 treatment; experiments involving addition of tracer thyroid hormones to hormone stripped serums from thyroxine treated patients confirmed the hypothesis in two cases of hypothyroidism--one of which was diagnosed in the boy with chronic thyroiditis and the other a woman with postradioactive iodine-induced hypothyroidism. The pathophysiologic significance of thyroid hormone autoantibodies in the transport of thyroid hormones is briefly discussed.

Association of prealbumin deficiency with alpha-1-antitrypsin deficiency.

Prealbumin (PA) measurements were made by electrophoretic and radial immunodiffusion techniques in three alpha-1-antitrypsin deficient Pi-D) serum samples. The deficiency was characterized as phenotype ZZ (homozygous). In two out of three serums PA was undetectable, as revealed by the absence of radiothyroxine distribution in the PA area, whereas quantitative estimates of PA by radial immunodiffusion showed very low levels (2--7 mg/100 ml) thus corroborating electrophoretic observations; low PA binding of T4 tracer was noted in another Pi-D serum. The total protein and laboratory thyroid function (thyroxine, triiodothyronine, and free thyroxine index concentration) measurements were normal, and the decrease in PA could not be explained on the basis of surgery, protein malnutrition, or cirrhosis. These and other observations described in this preliminary communication have served to raise the possibility of severe prealbumin deficiency being associated with alpha-1-antitrypsin deficiency, while the presence of low-but-not-absent PA in another Pi-D case might also suggest subgroup classification of the phenotype ZZ based on degrees of PA deficiency.

Studies on obesity. III. effect of triiodothyronine (T3) on thyroglobulin autoantibodies in euthyroid obese subjects.

Effect of T3 therapy on tanned red cell agglutinating thyroglobulin (TRC-TG) antibodies in 10 obese subjects without apparent thyroid disease was investigated. Six other obese subjects without thyroid dysfunction and of approximately the same mean age who also had circulating TRC-TG antibodies served as control subjects and were untreated. In vitro thyroid tests (TSH, total and free T4) performed before T3 therapy, as well as clinical examination, showed thyroid function to be normal in all subjects, and there was no evidence of thyroiditis. TRC-TG antibodies were present in low to moderate titers of 40-1280 in control subjects as well as in subjects selected for T3 treatment. Therapy with T3 was started at 50 mug/day and gradually increased to a maximum of 250 mug/day, depending on clinical needs. T3-treated as well as untreated obese control subjects were all maintained on a high protein, low fat, low carbohydrate diet. Duration of T3 therapy varied from 2-8 mo, and in all but one T3-treated subject, TRC-TG antibodies completely disappeared. In the one exceptional case, TRC-TG antibody titer decreased from 1280 to 80 after 7 mo of therapy. In non-T3-treated obese control subjects, antibody titers remained at the same levels throughout the observation period, thereby indicating a lack of spontaneous regression of circulating immune response. Therapy with T3, by inhibiting TSH, may have caused regression of inapparent immunologic thyroid lesion, thus leading to the disappearance of circulating TRC antibodies; alternatively, T3 specifically may have accelerated catabolism of thyroid antibodies. The latter possibility is favored in the absence of clinical and laboratory evidence of thyroiditis in T3-treated subjects.

Modulation of thyroid parameters by exogenous thyroxine in familial dysalbuminemic hyperthyroxinemia.

A patient with familial dysalbuminemic hyperthyroxinemia (FDH) was given graded doses of exogenous thyroxine (0.2 mg/d for 2 weeks; 0.4 mg/d for 2 weeks; 0.6 mg/d for 2 weeks) to study modulation of various thyroid parameters. The plasma concentration of the serum transport proteins, thyroxine binding globulin (TBG), sex hormone binding globulin (SHBG), and cortisol binding globulin (CBG) as well as serum thyroxine (T4), triiodothyronine (T3), absolute free thyroxine (FT4), and serum protein binding of T4 tracer were measured. At the end of T4 treatment, T4 and T3 were increased by 151% and 78%, respectively. The FT4 increased (157%), while the percent dialyzable free T4 fraction (DFT4) showed no significant change. SHBG, a protein sensitive to thyroid hormone (TH) action, increased 148% (from 0.23 to 0.57 micrograms/dL) after treatment but this concentration was still in the normal range; TBG and CBG decreased by about 16%. Analysis of the electrophoretic 125I-T4 distribution pattern in serum during T4 treatment showed essentially no change in TBG-bound T4 (percent tracer carriage X total T4), while there was a progressive increase in albumin-bound T4 (341% increase over pretreatment value) and a lesser increase in prealbumin (TBPA)-bound T4 (187%). These observations describing alterations in TH action, serum T4-protein binding, and the failure of percent DFT4 to increase with elevation in serum total T4 are of clinical significance in evaluating thyroid function parameters in FDH patients undergoing TH treatment.

Ethanol feeding and thyroid hormone monodeiodination.

Adult male rats were placed on a 3 week regimen of ethanol (as 20% of total calories) in a nutritionally adequate diet, and controls were matched equicalorically without ethanol. Serum measurements of T4, T3, FT4, rT3, and TSH were performed in both the fed and the fasted state (18 hours). In the fed state, serum hormone measurements did not differ between control and ethanol-treated rats. Overnight fasting had a significant effect in decreasing serum T3 level in both experimental and control rats and in decreasing serum T4 level in ethanol-treated animals; FT4 and rT3 levels were not affected. Fasting also decreased in vitro hepatic T4 to T3 production to an equivalent degree in control and ethanol-treated rats, but did not alter hepatic T4 to rT3 production rates in control animals. In the fed state, hepatic rT3 neogenesis in animals given ethanol declined relative to the levels observed in control fed rats; fasting restored the depressed rT3 neogenesis to the levels noted in the fed state. Because decreased rT3 production in ethanol-treated rats in the fed state could not be explained on the basis of a change in 5'-deiodinase activity, it is suggested that ethanol administered with a nutritionally adequate diet may inhibit hepatic rT3 generation by inhibiting T4(5)-deiodinase.

Inhibition of serum protein binding of thyroxine in a hypothyroid patient with familial dysalbuminemic hyperthyroxinemia.

OBJECTIVE: To investigate unusual free thyroxine (FT4) responses to T4 replacement doses in a hypothyroid patient with familial dysalbuminemic hyperthyroxinemia (FDH). METHODS: In this FDH hypothyroid patient, serum FT4 concentration by equilibrium dialysis and T4, triiodothyronine (T3), and thyroid stimulating hormone (TSH) determinations were supplemented by thyroxine binding globulin (TBG) and thyroxine binding prealbumin (TBPA) measurements. RESULTS: Initial thyroid function tests were compatible with hypothyroidism and FDH (T4 = 78 nmol/L, T3 = 1.08 nmol/L, FT4 = 11.6 pmol/L, TSH = 45 mU/L). When she was initially treated with T4 (0.112-0.088 mg/day) there was an increase in FT4 concentration to hyperthyroid levels accompanied by TSH inhibition (FT4 = 31-51 pmol/L, TSH = <0.03 mU/L); the patient also complained of intolerance and nervousness, and T4 treatment was discontinued. Concentrations of thyroxine binding globulin (TBG) and thyroxine binding prealbumin (TBPA) were normal. When T4 therapy was later resumed at a dosage of 0.075 mg/day, there was a marked increase in percent dialyzable T4. The elevation in percent dialyzable T4 during T4 replacement in a patient with FDH is unusual in view of the very large T4 binding capacity of FDH albumin. The presence of an inhibitor that reduced T4 binding by both TBG and FDH albumin probably explains the elevation in percent dialyzable T4 during T4 treatment. CONCLUSIONS: This FDH patient represents the first case of a putative inhibitor of T4 binding to both TBG and FDH albumin. The inhibition of T4 binding by these disparate proteins suggests that the inhibitor effect is mediated nonspecifically.

Cerebral vascular amyloid deposition in rabbits with induced thyroglobulin immunity.

Cerebral amyloid angiopathy (CAA) occurs in humans along with the neuritic amyloid plaques in Alzheimer's disease, in several familial (inherited) syndromes, and in a sporadic form that increases in prevalence with age to attain a rate of about 60% after age 90. In the non-Alzheimer conditions, it is often accompanied by cerebral hemorrhage and sometimes also by dementia. We report here the experimental induction of cerebrovascular amyloid (CVA) in thyroglobulin (Tg)-immunized rabbits. The vascular deposits in these rabbits are comparable to that seen in humans in that they primarily involve arterioles, venules, and capillaries and exhibit microscopic and ultrastructural characteristics similar to the human lesion. Prominent congophilic vascular lesions in the brain were seen in three out of six Tg-immunized rabbits, whereas less striking basement membrane thickening was evident in three other experimental animals, probably reflecting individual variations in vascular responses to actively induced Tg immunity. Occasional primitive amyloid plaques were also encountered adjacent to vascular lesions. These observations are of particular interest since in other experimental models, cerebral vascular amyloid deposits have not been observed, thus suggesting that immunopathogenic events induced by active Tg immunization may be unique in their effects on the cerebral vasculature.

A simple and rapid thyroxine radioimmunoassy (T4-RIA) in unextracted human serum; a comparison of T4-RIA and T4 displacement assay, T4(D), in normal and pathologic sera.

A simple, rapid and accurate thyroxine radioimmunoassay (T4-RIA) in unextracted serum or plasma has been described, and for comparison T4 determinations have also been made by a T4(D) procedure using Abbott Tetrasorb kits. T4-RIA procedure basically involved denaturation of serum to dissociate T4-protein bond, and T4 released was allowed to react with [125I]T4-labeled T4 antiserum elicited by immunizing rabbits against bovine thyroglobulin. The displaced unbound [125I]T4 was rapidly taken up by an anionic resin sponge within 15 min and this sponge [125I]T4 uptake was linearly related to T4 present in standards or serum. The denaturation of serum effected by trichloroacetic acid-sodium hydroxide permitted virtually 100% T4 extraction recovery in normal, pregnancy, hypo- and hyperthyroid sera whereas 72.9-87.6% T4 recovery from normal serum (and with large individual differences) was noted with lower alcohols in T4(D) procedure. Cumbersome and/or tedious steps such as pre-extraction, centrifugation, time consuming bound and unbound hormone separation procedures, etc. are obviated in T4-RIA and the entire assay can be completed in the same tube in approximately an hour. These attributes along with increased sensitivity and specificity and the need for only microamounts of test sera (25-50 mul) in T4-RIA offer distinct advantages over T4(D) procedures, and in simplicity excel even other T4-RIAs. T4-RIA values in physiological and pathological states were highly correlated (r = 0.97) with T4(D) measurements and no differences between these two techniques were found. The reported discrepancies between T4-RIA and T4(D) measurements in human sera and some of the reasons for attributing these inconsistencies to probable methodological errors and variations are discussed.

Circulating thyroid hormones in a patient with hyperviscosity syndrome.

The elevated T4 levels by one RIA in the patient with hyperviscosity syndrome were probably caused by the interference of the increased protein concentration in the T4 assay rather than by hyperthyroidism or binding of T4 by immunoglobulins.

Effect of pregnancy on thyroxine binding globulin (TBG) in partial TBG deficiency.

An unusual opportunity was afforded to study the effect of endogenous increase in estrogen on thyroxine binding globulin (TBG) throughout pregnancy in a partially TBG-deficient female who conceived subsequent to initial examination. TBG binding of 125I-thyroxine (T4) before and up to four months of pregnancy was low in comparison to normal. Starting from six months and up to the end of pregnancy, TBG activity showed a definite increase although still below normal. TBG binding capacity increased from a low value of 4.2 microgram T4/100 ml ,efore pregnancy to a value 9.3 microgram T4/100 ml in the last month of pregnancy. This was accompanied by an increase in immunoassayable TBG from less than 1 mg/100 ml in the second month of pregnancy to 1.9 mg/100 ml in the last month, and an increase of T4 from 3.1 microgrom/100 ml to 4.3 microgram/100 ml. Two weeks after delivery, TBG binding of 125I-T4 showed a precipitous decline to the abnormally low distribution noted prior to and during the early months of pregnancy. TBG binding activity was normal in the cord blood of the infant. These studies provide the first direct evidence that increase in endogenous estrogen results in detectable increases in TBG concentration in the human with partial TBG deficiency.