Higher Free Thyroxine Levels Research Articles

Thyroid Function and the Risk of Atherosclerotic Cardiovascular Morbidity and Mortality: The Rotterdam Study.

Thyroid hormones have been linked with various proatherogenic and antiatherogenic processes. However, the relationship of thyroid function with manifestations of atherosclerosis remains unclear. To investigate the association of thyroid function with atherosclerosis throughout its spectrum; that is, subclinical atherosclerosis, incident atherosclerotic cardiovascular (ASCV) events, and ASCV mortality. This population-based study was embedded within the Rotterdam Study. The risk of atherosclerosis was evaluated by measuring (1) presence of subclinical atherosclerosis, assessed by coronary artery calcification score >100 AU; (2) ASCV events, defined as fatal and nonfatal myocardial infarction, other coronary heart disease mortality, or stroke; (3) ASCV mortality, defined as death because of coronary heart disease and cerebrovascular or other atherosclerotic diseases. Associations of thyroid-stimulating hormone and free thyroxine with the outcomes were assessed through logistic regression and Cox proportional hazard models, adjusted for potential confounders, including cardiovascular risk factors. A total of 9420 community-dwelling participants (mean age±SD, 64.8±9.7 years) were included. During a median follow-up of 8.8 years (interquartile range, 4.5-11.8 years), 934 incident ASCV events and 612 ASCV deaths occurred. Free thyroxine levels were positively associated with high coronary artery calcification score (odds ratio, 2.28; 95% confidence interval, 1.30-4.02) and incident ASCV events (hazard ratio, 1.87; confidence interval, 1.34-2.59). The risk of ASCV mortality increased in a linear manner with higher free thyroxine levels (hazard ratio, 2.41; confidence interval, 1.68-3.47 per 1 ng/dL) and lower thyroid-stimulating hormone levels (hazard ratio, 0.92; confidence interval, 0.84-1.00 per 1 logTSH). Results remained similar or became stronger among euthyroid participants. Free thyroxine levels in middle-aged and elderly subjects were positively associated with atherosclerosis throughout the whole disease spectrum, independent of cardiovascular risk factors.

Novel lincRNA Susceptibility Gene and Its Role in Etiopathogenesis of Thyrotoxic Periodic Paralysis.

Thyrotoxic periodic paralysis (TPP) is a life-threatening neuromuscular complication of thyrotoxicosis characterized by muscle weakness and hypokalemia and with an unclear etiopathogenesis. However, the 17q24.3 locus had been genetically linked to TPP, in which the genetic variant rs312691 (TC genotype) in long intergenic noncoding RNA (lincRNA) CTD-2378E21.1 is located downstream of inward-rectifier potassium (Kir) channel genes [KCNJ2 and its antisense KCNJ2 (AS-KCNJ2)]. A TPP patient with a suppressed thyroid-stimulating hormone level, a high free thyroxine level of (5.8 ng/dL), and low serum potassium level of (2 mEq/L) was evaluated for Kir channel expression during and after recovery from thyrotoxicosis. We observed that circulating lincRNA and Kir expression varied in accordance with thyroid status and TC genotype. To endorse this association of a lincRNA-rs312691 variant with a genetic risk of TPP, an additional series of 37 patients with TPP and 32 patients with thyrotoxic without paralysis (TWP) were assessed. We verified that the risk of minor allele C was greater in TPP than in TWP (odds ratio, 5.289; P = 0.0062), and protective major allele T was more frequent than observed in the 1000 genome controls (odds ratio, 11.90; P < 0.0001). AS-KCNJ2 was downregulated during thyrotoxicosis in the TWP controls carrying allele T and were upregulated in those with TPP with risk allele C. Moreover, KCNJ2 (Kir2.1) expression was reduced during thyrotoxicosis and restored in euthyroid status. We further excluded any other coding variant by performing targeted exome sequencing mutational screening in 17q24.3. Our data suggest that high lincRNA AS-KCNJ2 and CDT-2378E21.1 expression, possibly driven by the triiodothyronine regulatory mechanism, reduces the Kir2.1 expression observed during thyrotoxicosis. This finding could contribute to the understanding of the reduced inward-rectifying current observed during muscle weakness in genetically susceptible TPP patients.

FALSE ELEVATION OF FREE THYROXINE AND TRIIODOTHYRONINE DUE TO THE PRESENCE OF ANTIBODIES TO IODOTHYRONINES

The prevalence of autoimmune thyroid disease (AITD) has progressively increased. Circulating autoantibodies associated with AITD may affect the result of laboratory analyses and cause incorrect conclusions in the assessment of thyroid hormone status. In this report, we present a patient with Hashimoto’s thyroiditis with high thyrotrophin and free thyroxine (T4) and triiodothyronine (T 3 ) levels due to the presence of auto-antibodies to iodothyronines. Free T 4 and free T 3 levels measured by direct immunometric assays method were high, while those estimated by measurement of the serum T 4 -binding capacity were low. L-thyroxine replacement therapy was started. In patients with discrepant laboratory results, interference from autoantibodies should be considered. Key words: Thyroxine auto-antibody; hypothyroidism; false high free thyroxine; triiodothyronine levels.

TSH-Free Thyroxine Discordance in an Athyreotic Patient During Ipiluminab and Nivoluminab Therapy

ABSTRACT Objective: The objective of this case report is to illustrate the clinical confusion resulting from discordance between serum thyrotropin and free thyroxine measurements in an athyreotic patient receiving immunotherapy with ipiluminab and nivoluminab. Methods: The case of a 50-year-old athyreotic man with metastatic melanoma is described. The patient was discontinued from his levothyroxine replacement by his primary care physician based on an elevated free thyroxine concentration of 3.87 ng/dL. Shortly afterwards, the patient was started on immunotherapy with ipiluminab and nivoluminab. After a subtherapeutic levothyroxine dose of 0.68 μg/kg/day was initiated concurrently with his immunotherapy, the patient continued to have a high free thyroxine level but additionally developed an elevated serum thyrotropin value of 33 mIU/L. He also became symptomatically hypothyroid over a period of 4 months. Resumption of a full weight-based dose resulted in normalization of the patient's thyrotropin and free...

Higher free thyroxine levels are associated with sarcopenia in elderly Koreans

BackgroundSkeletal muscle is a major target of thyroid hormone action. Although sarcopenia is associated with adverse health outcomes in the elderly, few studies have examined the association between sarcopenia and thyroid hormone levels in elderly Asians. We investigated the relationship between thyroid hormone levels and sarcopenia in elderly Koreans. Methods658 individuals (324 males and 334 females) ≥60 years old who visited the Health Screening and Promotion Center at Ajou University Hospital were recruited for the study. Whole-body dual-energy X-ray absorptiometry was performed, and gait speed and hand grip strength were measured. The rate and odds ratios for sarcopenia were calculated for free thyroxine (fT4) and thyroid stimulating hormone (TSH) levels. ResultsThe fT4 concentration was negatively associated with muscle mass in males (r2 = 0.031, p = 0.001) and females (r2 = 0.019, ps = 0.011). The highest rate of sarcopenia occurred in the highest fT4 quartile in males and females. However, no significant differences were found among TSH quartiles in either sex. TSH was not significantly associated with the risk of sarcopenia in males or females, whereas the fT4 concentration was associated with the risk of sarcopenia in both sexes. ConclusionsHigher fT4 levels, not lower TSH levels might have an adverse effect on sarcopenia especially in elderly people.

Prevalence of c.2268dup and detection of two novel alterations, c.670_672del and c.1186C>T, in the TPO gene in a cohort of Malaysian–Chinese with thyroid dyshormonogenesis

ObjectivesThe c.2268dup mutation in the thyroid peroxidase (TPO) gene is the most common TPO alteration reported in Taiwanese patients with thyroid dyshormonogenesis. The ancestors of these patients are believed to...

Subclinical hypothyroidism or thyroid autoimmunity and variant angina: by chance? Or with a chance?

Refer to the page 125-130 Proper functioning of thyroid is of importance due to its effects on the cardiovascular system.1),2) Furthermore, the relationship between hyperthyroidism and coronary vasospasm is well-known and has been continuously reported since the first description in a case report in 1979.3,4,5) The most important treatment of thyroid disease is the control of thyrotoxicosis and the majority of cases showed excellent outcomes after treatment of thyroid problems.5) While the relationship with hypothyroidism, including subclinical hypothyroidism, and coronary vasospasm has not been well-established until date, Nishikawa et al.6) reported their experience with variant angina in a patient of isolated adrenocorticotropin deficiency, inappropriate vasopressin secretion, and Hashimoto's thyroiditis. However, the patient had additional endocrine problems and the authors concluded that this variant angina was more related with the isolated adrenocorticotropin deficiency rather than Hashimoto's thyroiditis. In 1979, an earlier report demonstrated a case of variant angina that was well controlled with nitrate administration, and aggravated with the development of hypothyroidism and concurrent use of propranolol. Authors extrapolated aggravation of variant angina by working on beta blockers, which mediated alpha-mediated coronary artery spasm rather than treating hypothyroidism alone.7) Hence, it is complicated to search previous evidence regarding the effect of hypothyroidism or subclinical hypothyroidism on coronary artery vasospasm. Nonetheless, there is some theoretical background that demonstrates the possibilities of hypothyroidism or thyroid autoimmunity-mediated coronary artery vasospasm. Most commonly accepted mechanisms for coronary artery spasm include endothelial dysfunction and primary hyperactivity of vascular smooth muscle cells,8) and there are several articles that show endothelial dysfunction in hypothyroidism or subclinical hypothyroidism. Napoli et al.9) reported patients with acute hypothyroidism after surgical thyroidectomy or primary chronic hypothyroidism related to impaired endothelial and non-endothelial vasodilation. Moreover, recent data shows relation between subclinical hypothyroidism due to autoimmune thyroiditis and impaired endothelial dysfunction (both endothelium dependent and independent) and increased inflammatory markers in patients when compared to healthy volunteers.10) They concluded that low grade chronic inflammation may be one of the factors that contribute to endothelial dysfunction in subclinical hypothyroidism with autoimmunity. In this regards, KCJ, Lee et al.11) demonstrated relationship of autoimmunity, positive anti-thyroperoxidase (TPO) antibodies, and subclinical hypothyroidism to variant angina, which was confirmed by ergonovine provocation. Although the study lacked strong statistical correlation, it provides us with clinical implication that subclinical hypothyroidism or autoimmunity-related endothelial dysfunction might be presented as variant angina. However, studying compositions of thyroid function status in the subjects with positive anti-TPO antibodies may provide more accurate information, because of heterogeneity of positive provocation test group; including euthyroidism and subclinical hyperthyroidism. Definition of subclinical hypothyroidism is clear with high thyroid stimulating hormone (TSH) and normal free thyroxine (T4) levels. Other variations of hypothyroidism include low triiodothyronine (T3) syndrome (low T3 with normal TSH and free T4) and overt hypothyroidism (elevated TSH and low free T4). Anti-TPO antibodies are positive in 90% of Hashimoto's thyroiditis cases, 75% of Graves' disease cases, 10-20% of nodular goiter or thyroid carcinoma cases and even in 10-15% of normal individuals.12) Even though variant angina is frequently observed in real world practice and has been well-known for decades, there are still a number of mechanisms and trigger factors that remain to be solved.8) In the absence of definite evidences of relationship of overt hypothyroidism and coronary vasospasm, the weak relationship of subclinical hypothyroidism or thyroid autoimmunity including heterogeneous entities with coronary vasospasm can be considered. that the results come either by chance or with chance. The results may weaken the relationship between coronary vasospasm and thyroid dysfunction including hyperthyroidism and hypothyroidism, but it is clear that the results may be a trigger for future studies on clarifying the relationship between hypothyroidism and its variations, coronary vasospasm, and the effects of thyroid hormone on treatment of coronary vasospasm, especially with respect to medically intractable cases.

The Relationships between Thyroid Hormones and Thyroid-stimulating Hormone with Lipid Profile in Euthyroid Men

Background and Aim: Alteration in lipid profile is a common observation in patients with thyroid dysfunction, but the current knowledge on the relationship between lipids and thyroid hormone levels in euthyroid state is insufficient. The current study aimed to determine the association between thyroid hormones and thyroid-stimulating hormone (TSH) with lipid profile in a euthyroid male population.Methods: A total of 708 Chinese and Malay men aged 20 years and above were recruited in this cross-sectional study. Their blood was collected for the determination of total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), triglyceride (TG), free thyroxine (FT4), free triiodothyronine (FT3) and TSH levels. The association was analyzed using multiple regression and logistic regression models with adjustment for age, ethnicity, body mass index and FT4/FT3/TSH levels.Results: In multiple regression models, TSH was positively and significantly associated with TG (p<0.05). Free T4 was positively and significantly associated with TC, LDL-C and HDL-C (p<0.05). Free T3 was negatively and significantly associated with HDL-C (p<0.05). In binary logistic models, an increase in TSH was significantly associated with higher prevalence of elevated TG in the subjects (p<0.05), while an increase in FT4 was significantly associated with higher prevalence of elevated TC but a lower prevalence of subnormal HDL in the subjects (p<0.05). Free T3 was not associated with any lipid variables in the logistic regression (p>0.05).Conclusions: In euthyroid Malaysian men, there are positive and significant relationships between TSH level and TG level, and between FT4 level and cholesterol levels.

Higher free thyroxine levels are associated with all-cause mortality in euthyroid older men: the Health In Men Study

Thyroid dysfunction predicts poorer health outcomes, but the relationship between thyroid hormone levels within the reference range and mortality in older adults remains unclear. In this study, we examined the associations between the concentrations of free thyroxine (FT4) and TSH and all-cause mortality in older men without thyroid disease. We performed a longitudinal study in community-dwelling men aged 70-89 years. Men with thyroid disease or taking thyroid-related medications were excluded. Baseline FT4 and TSH levels were assayed. Incident deaths were ascertained using data linkage. There were 3885 men without thyroid disease followed for (means.d.) 6.41.5 years, during which time 837 had died (21.5%). men who had died had higher baseline ft4 levels (16.22.3 vs 15.82.1 pmol/l, p0.001), but comparable tsh levels (2.41.5 vs 2.31.5 miu/l, P=0.250). After accounting for age, smoking, physical factors and medical comorbidities, higher circulating ft4 levels predicted all-cause mortality (quartile Q4 vs quartiles Q1Q3: FT4 levels ≥ 17.32 vs <17.32 pmol/l: adjusted hazard ratio (HR)=1.19, 95% CI=1.02-1.39, P=0.025). TSH levels did not predict mortality. After excluding men with subclinical hyperthyroidism or hypothyroidism, there were 3442 men and 737 who had died (21.4%). In these men, higher FT4 levels remained independently associated with all-cause mortality (quartile Q4 vs quartiles Q1-Q3: adjusted HR=1.19, 95% CI=1.02-1.41, P=0.032). Higher FT4 levels are associated with all-cause mortality in euthyroid older men, independently of conventional risk factors and medical comorbidities. Additional research is needed to determine whether or not this relationship is causal and to clarify the utility of thyroid function testing to stratify mortality risk in ageing men.

Lipid profiles are associated with lesion formation over 24 months in interferon-β treated patients following the first demyelinating event

ObjectivesTo investigate the associations of serum lipid profile with disease progression in high-risk clinically isolated syndromes (CIS) after the first demyelinating event.MethodsHigh density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol...

Higher free thyroxine levels are associated with frailty in older men: the Health In Men Study

Frailty is common in the elderly and predisposes to ill-health. Some symptoms of frailty overlap those of thyroid dysfunction, but it is unclear whether differences in thyroid status influence risk of frailty. We evaluated associations between thyroid status and frailty in older men. Cross-sectional epidemiological study. Community-dwelling men aged 70-89 years. Circulating thyrotropin (TSH) and free thyroxine (FT(4) ) were assayed. Frailty was assessed as ≥3 of the Fatigue, Resistance, Ambulation, Illnesses and Loss (FRAIL) scale's 5 domains: fatigue; resistance (difficulty climbing flight of stairs); ambulation (difficulty walking 100 m); illness (>5); or weight loss (>5%), blinded to hormone results. Of 3943 men, 27 had subclinical hyperthyroidism, 431 subclinical hypothyroidism and 608 were classified as being frail (15·4%). There was an inverse log-linear association of TSH with FT(4). There was no association between TSH and frailty. After adjusting for covariates, men with FT(4) in the highest two quartiles had increased odds of being frail (Q3:Q1, odds ratio [OR] = 1·32, 95% confidence interval [CI] = 1·01-1·73 and Q4:Q1, OR = 1·36, 95% CI = 1·04-1·79, P = 0·010 for trend). Higher FT(4) was associated with fatigue (P = 0·038) and weight loss (P < 0·001). The association between FT(4) and frailty remained significant when the analysis was restricted to euthyroid men. High-normal FT(4) level is an independent predictor of frailty among ageing men. This suggests that even within the euthyroid range, circulating thyroxine may contribute to reduced physical capability. Further studies are needed to clarify the utility of thyroid function testing and the feasibility of preventing or reversing frailty in older men.

Increased type 3 iodothyronine deiodinase activity in a regrown hepatic hemangioma with consumptive hypothyroidism

Infantile hepatic hemangioma with consumptive hypothyroidism is a rare condition. A 4-month-old girl presented with diffuse hepatic hemangiomas during treatment of congenital hypothyroidism. Serum reverse triiodothyronine was elevated, and her hypothyroidism improved concomitant with involution of the hemangioma following prednisolone and interferon-alpha administration. At 20 months of age, 7 months after discontinuing prednisolone and interferon-alpha, a focal hemangioma regrew from one of the previous lesions and was surgically resected. The expression and activity of type 3 iodothyronine deiodinase (D3) were elevated in the resected tumor tissue compared with placenta. Here, we describe a patient with consumptive hypothyroidism and diffuse infantile hepatic hemangiomas, one of which regrew after involution following pharmacotherapy. The etiology of elevated D3 activity is also discussed. It is important to identify infantile hepatic hemangioma in patients with hypothyroidism refractory to hormone replacement therapy, who have low free triiodothyronine despite high thyrotropin and normal free thyroxine levels, and long-term follow-up will be needed for these patients.

High free thyroxine levels are associated with QTc prolongation in males

The literature on the effect of excess thyroid hormone on ventricular repolarization is controversial. To study whether free thyroxine (T(4)) and TSH are associated with QTc prolongation we conducted population-based cohort study. This study was conducted as part of the Rotterdam Study and included 365 men and 574 women aged 55 years and older with an electrocardiogram, who were randomly sampled for the assessment of thyroid status (free T(4)/TSH) at baseline, after exclusion of participants with hypothyroidism, use of antithyroid drugs, thyroid hormones or digoxin, left ventricular hypertrophy, and left and right bundle branch block. Endpoints were the length of the QTc interval and risk of borderline QTc prolongation. The associations were examined by means of linear and logistic regression analysis, adjusted for age and gender, diabetes mellitus, myocardial infarction, hypertension, and heart failure. Overall, there was no significant association between TSH and QTc interval (0.8 ms (95% confidence interval (CI) -3.5, 5.2) in the first quintile compared with the fifth quintile). Subjects in the fifth quintile of free T(4) did not have an increased QTc interval (3.2 ms (95% CI -1.1, 7.6)); stratification on gender showed an increment of 10.9 ms (95% CI 3.4, 18.3) in the fifth quintile in men and 1.1 ms (95% CI -4.2, 6.3) in the fifth quintile of free T(4) in women. When compared with subjects in the first quintile, male subjects in the fifth quintile of free T(4) had a significantly increased risk of a borderline QTc interval and QTc prolongation (odds ratio 2.40 (95% CI 1.20, 4.80)). High levels of free T(4) are associated with substantial QTc prolongation in men of up to 10 ms. The fact that free T(4) is also associated with a significantly increased risk of borderline and prolonged QTc values with its risk of sudden cardiac death, endorses the clinical importance of our findings.

Prevalence of Subclinical Hypothyroidism in Patients with Metabolic Syndrome

Subclinical hypothyroidism (SCH) is a prevalent condition among adult population, however it is frequently overlooked. Thyroid functions affect metabolic syndrome (MetS) parameters including HDL cholesterol, triglycerides, blood pressure and plasma glucose. On the other hand, the relation between MetS and thyroid dysfunction is not clearly identified yet. The aim of the present study was to investigate the prevalence of SCH among MetS patients and to identify its relation with MetS parameters. Two hundred and twenty MetS patients (MetS group; 167 female, 53 male, mean age: 48.5 +/- 11.3) and 190 patients without MetS (Control group; 142 female, 48 male, mean age: 46.3 +/- 11.9) attending consecutively to Internal Medicine outpatient clinics were included in this study. Groups were compared in terms of SCH prevalence. SCH was defined as a condition with high thyrotrophin and normal free thyroxine levels. SCH was found in 36 (16.4%) cases in the MetS group and in 11 (5.8%) cases in the control group (p = 0.001). Only female gender was associated with the presence of SCH. About one sixth of MetS patients had SCH. This finding indicates a need for investigating the presence of SCH during the management of MetS patients.

Actual levels of soy phytoestrogens in children correlate with thyroid laboratory parameters

Thyroid hormones and thyroid autoantibodies, along with serum concentrations of two phytoestrogens of the isoflavone series, daidzein and genistein, were measured in 268 children without overt thyroid diseases, screened for iodine deficiency in one region of the Czech Republic. Since both phytoestrogens have been reported to inhibit thyroid hormone biosynthesis and in high concentrations to exert goitrogenic effects, we investigated whether their presence in the circulation could influence thyroid hormone function in a population where soy consumption is not common. Correlation analysis revealed a significant positive association of genistein with thyroglobulin autoantibodies and a negative correlation with thyroid volume. Multiple regression analysis of the relationships between actual phytoestrogen levels and measured thyroid parameters revealed only a weak but significant association between genistein and thyroid variables. Higher levels of free thyroxine were found in a subgroup of 36 children who ate soy food in the previous 24 h. In conclusion, only modest association was found between actual phytoestrogen levels and parameters of thyroid function. On the other hand, even small differences in soy phytoestrogen intake may influence thyroid function, which could be important when iodine intake is insufficient.

Is Subclinical Hypothyroidism Associated With Hyperhomocysteinemia?

To evaluate whether subclinical hypothyroidism is associated with hyperhomocysteinemia, in an attempt to determine whether hyperhomocysteinemia may explain the observed increased risk of coronary artery disease in patients with subclinical hypothyroidism, as has been shown in patients with overt hypothyroidism. We prospectively enrolled consecutive patients with newly diagnosed subclinical hypothyroidism and a parallel group of euthyroid control subjects in this study. Subclinical hypothyroidism was defined as high thyrotropin and normal free thyroxine levels. Fasting plasma total homocysteine, thyrotropin, and free thyroxine levels were measured in all participants, and persistent subclinical hypothyroidism was confirmed at least once. Forty-seven patients (42 women and 5 men; mean age, 38 +/- 15 years) with subclinical hypothyroidism and 50 control subjects (46 women and 4 men; mean age, 34 +/- 10 years) were enrolled in the study. The manufacturer's reference range for the total homocysteine assay was 5 to 15 micromol/L, and we defined our own reference range as 3.9 to 10.8 micromol/L. The mean values (+/-SE) for total homocysteine in patients and control subjects were 7.44 +/- 0.5 micromol/L and 7.22 +/- 0.2 micromol/L, respectively (P = 0.68). In this study, we found no association between subclinical hypothyroidism and hyperhomocysteinemia. Other contributing factors, such as associated hyperlipidemia, may explain the observed increased risk of coronary artery disease in patients with subclinical hypothyroidism.

Evidence for a slow tissue adaptation to circulating thyroxine in patients with chronic L-thyroxine treatment.

We measured serum procollagen-III-peptide in 67 women with long-term L-thyroxine treatment and compared the results with age-matched controls. The strong correlation between serum free thyroxine and procollagen-III-peptide concentrations previously found after 6 months of L-thyroxine treatment was not found after long-term treatment. There were slightly higher procollagen-III-peptide concentration values in those chronically treated patients who had high free thyroxine levels but this increase was less marked than in patients previously studied after short-term treatment. An increase in procollagen-III-peptide concentration reflects an increased biosynthesis of collagen III, which is present in connective tissues throughout the body, and our findings may be explained by slow tissue adaptation to increased levels of thyroxine. We conclude that the increased thyroxine levels found in L-thyroxine-treated patients are of less clinical importance than thought previously. We also conclude that peripheral markers of thyroid hormone peripheral effects such as procollagen-III-peptide may be of less use than thought previously due to this slow tissue adaptation to changes in thyroxine concentration.

Antithyroid Drug Therapy for Graves' Disease during Pregnancy

We compared fetal and maternal serum indexes of thyroid status at delivery in 70 patients with Graves' disease who required therapy with thionamides (such as propylthiouracil) during pregnancy. Forty-three mothers required thionamides until delivery (Group 1), whereas the drugs were discontinued during pregnancy after remission in 27 mothers (Group 2). Maternal free thyroxine levels were closely correlated with cord levels in both groups, being essentially identical in Group 2 but slightly lower in fetuses than in mothers in Group 1. Normal maternal free thyroxine levels did not preclude fetal hypothyroidism. The mothers and fetuses in Group 1 had a significantly higher incidence of antibodies that inhibit thyrotropin binding than did those of Group 2. However, a significant correlation between maternal levels of these antibodies and cord levels of free thyroxine or triiodothyronine was found only in Group 2, in which some maternal and cord thyroxine levels were in the thyrotoxic range at delivery, presumably because therapy was discontinued. These findings indicate that high free thyroxine levels and the presence of antibodies that inhibit binding of thyrotropin are useful indexes of the fetal need for antithyroid treatment, and that the thionamide dosage that maintains maternal free thyroxine levels in a mildly thyrotoxic range seems appropriate for maintaining euthyroid status in the fetus.