Divergent prognostic effects of pre-existing and treatment-emergent thyroid dysfunction in patients treated with immune checkpoint inhibitors.

BACKGROUND: Thyroid dysfunction is among the most common autoimmune diseases and immune checkpoint inhibitor (ICI)-induced immune-related adverse events (irAE). We determined the association between longitudinal thyroid function and clinical outcomes in patients treated with ICI. METHODS: We identified all patients treated with ICI at UT Southwestern Medical Center from January 1, 2011, through December 31, 2020. We defined normal thyroid stimulating hormone (TSH) and free thyroxine (FT4) levels according to institutional reference range. We defined clinical thyroid dysfunction using established criteria incorporating labs and treatment. We determined the association between thyroid function and overall survival (OS) using Kaplan-Meier curves, log-rank tests, and multivariate Cox proportional hazards model. RESULTS: A total of 1781 patients were included in analyses, of whom 381 (21%) had abnormal baseline TSH. Patients with abnormal baseline TSH were more likely to be female, have kidney cancer, and initiate levothyroxine after ICI initiation (all P < 0.001). Patients with abnormal baseline TSH had inferior OS (median 16 vs 27 months; P < 0.001). Among patients with normal baseline TSH, those who had abnormal TSH after ICI initiation had improved OS (median 41 vs 22 months; P < 0.001). In a multivariate Cox model, abnormal baseline TSH was associated with worse OS (HR 1.62; 95% CI, 1.30-2.02; P < 0.001), while initiation of levothyroxine after ICI initiation was associated with improved OS (HR 0.62; 95% CI, 0.44-0.88; P = 0.008). CONCLUSIONS: ICI-induced thyroid dysfunction is associated with improved survival, although abnormal TSH prior to ICI initiation is associated with inferior survival. PRECIS: Thyroid abnormalities occur commonly in the general population and as immunotherapy toxicities. We found that immunotherapy-induced thyroid dysfunction is associated with better survival, but pre-existing thyroid abnormalities convey worse outcomes.

Effect of TSH Suppression Therapy on Bone Mineral Density in Differentiated Thyroid Cancer: A Systematic Review and Meta-analysis.

CONTEXT: Because subclinical hyperthyroidism increases the risk of osteoporosis and fractures, concerns are growing about the long-term skeletal safety of TSH suppression therapy after total thyroidectomy in patients with differentiated thyroid cancer (DTC). OBJECTIVE: We aimed to determine the effect of TSH suppression therapy on bone mineral density (BMD) in DTC patients. METHODS: We searched PubMed, Embase, the Cochrane library, and other sources. Eligible observational studies included DTC patients who underwent TSH suppression therapy and BMD measurement. Two independent reviewers extracted data on the studies' characteristics and outcomes and determined their risk of bias. Data were extracted from each study for postmenopausal/premenopausal women's and men's lumbar spine (LS), femoral neck (FN), and total hip (TH) BMD and summed using a random-effects meta-analysis model. The weighted mean differences with 95% CIs are expressed for the differences in outcome measurements between groups. RESULTS: Seventeen studies (739 patients and 1085 controls) were included for quantitative analysis. In postmenopausal women, TSH suppression therapy showed a significant decrease in LS BMD (-0.03; -0.05, -0.02), and a similar trend was seen in TH. In premenopausal women, TSH suppression therapy significantly increased LS BMD (0.04; 0.02, 0.06) and FN BMD (0.02; 0.01, 0.04). In men, there was no significant association between TSH suppression therapy and BMD at any site compared with the controls. CONCLUSION: Evidence from observational studies suggests that postmenopausal women treated with TSH suppression therapy are at risk for lower BMD. Attention should be paid to long-term skeletal safety in DTC survivors.

TSH-suppressive therapy can reduce bone mineral density in patients with differentiated thyroid carcinoma: a meta-analysis.

OBJECTIVE: To evaluate the effect of TSH-suppressive therapy on the bone mineral density in patients with differentiated thyroid carcinoma (DTC). MATERIALS AND METHODS: The cross-sectional, cohort, prospective controlled, and case-control studies on the bone mineral density change in patients with DTC after TSH-suppressive therapy from databases were searched, including PubMed, Embase, and Cochrane library databases. The effect of TSH-suppressive therapy on bone mineral density of lumbar, femoral neck, femoral greater trochanter, and Ward triangle was analyzed. Data from the database establishment to January 2019 were all reviewed. Meta-analysis was performed with RevMan 5.3 software after two reviewers independently screened the date. The categorical variables were expressed as odds ratios, while the numerical variables were expressed as mean differences. Based on the heterogeneity of the study, a comprehensive analysis was performed by using fixed or random effect models. RESULTS: A total of 11 studies involving 434 patients with differentiated thyroid cancer were included. No significant difference in the bone mineral density of lumbar indications between the experimental and control groups was observed (MD=0.00, 95% CI=-0.03-0.03, p=0.96). The bone mineral density of the femoral neck indications (MD=-0.01, 95% CI=-0.04-0.03, p=0.70). A significant difference between experimental and control groups in the bone mineral density of femoral trochanter indications was observed (MD=-0.11, 95% CI=-0.14-0.07, p<0.00001). The bone mineral density of Ward's triangle indications (MD=-0.06, 95% CI=-0.11-0.01, p=0.02). CONCLUSIONS: TSH-suppressive therapy in patients with DTC mainly reduces the proximal femur bone mineral density.

Acute airway compromise after recombinant human TSH administration: A case report and review of the literature.

Radioiodine ablation is a commonly utilized treatment for differentiated thyroid carcinoma. Uptake of radioiodine can be enhanced by pretreatment with thyroid hormone withdrawal or administration of recombinant human thyroid-stimulating hormone (rhTSH). rhTSH is generally well-tolerated with minimal adverse effects. However, in patients with extensive tumor burden in confined anatomic spaces, rapid enlargement of normal or neoplastic thyroid tissue secondary to rhTSH administration can result in significant compressive effects. In this report, we describe a case of rapid airway deterioration requiring intubation in a patient with involvement of the thyroid cartilage by papillary thyroid carcinoma. Laryngoscope, 122:0000-0000, 2019 Laryngoscope, 130:2725-2727, 2020.

Arterial stiffness in hyperthyroid patients is deteriorated due to thyroid hormones

ABSTRACT Objective The aim of this study is to evaluate and compare arterial stiffness, which is an independent risk indicator for cardiovascular diseases (CVDs), between patients with overt hyperthyroidism, subclinical hyperthyroidism, euthyroidism by antithyroid therapy and healthy volunteers with pulse wave analysis (PWA). Subjects and methods A total of 102 volunteers were included in the study (30 in the overt hyperthyroid group, 28 in the subclinical hyperthyroid group and 14 with euthyroidism by antithyroid therapy and 30 healthy). The arterial stiffness measurements of the participants in the study were performed with the Mobil-O-Graph PWA device (I.E.M. GmBH, Stolberg, Germany), which makes cuff based oscillometric measurement from the brachial artery. Results Systolic blood pressure, pulse rate, central systolic blood pressure, cardiac output, heart rate-corrected augmentation index (Aix@75) and pulse wave velocity (PWV) measurements were significantly higher in the hyperthyroid group than in the control group. The heart rate and PWV in the subclinical hyperthyroid group were significantly higher than the control group. In the euthyroid group, systolic blood pressure, central systolic blood pressure, cardiac output, cardiac index and PWV were found significantly higher than the control group. There was also a negative correlation between Aix@75 and thyroid-stimulating hormone (TSH), and a positive correlation between Aix@75 and free thyroid hormones. Conclusion In our study, we observed that the arterial stiffness was adversely affected by an overt or subclinical increase in thyroid hormones and this correlated with thyroid hormone levels. We recommend that PWV measurement, which is a simple method for detecting CVD risk, can be used in these patients.

Arterial stiffness in hyperthyroid patients is deteriorated due to thyroid hormones.

OBJECTIVE: The aim of this study is to evaluate and compare arterial stiffness, which is an independent risk indicator for cardiovascular diseases (CVDs), between patients with overt hyperthyroidism, subclinical hyperthyroidism, euthyroidism by antithyroid therapy and healthy volunteers with pulse wave analysis (PWA). SUBJECTS AND METHODS: A total of 102 volunteers were included in the study (30 in the overt hyperthyroid group, 28 in the subclinical hyperthyroid group and 14 with euthyroidism by antithyroid therapy and 30 healthy). The arterial stiffness measurements of the participants in the study were performed with the Mobil-O-Graph PWA device (I.E.M. GmBH, Stolberg, Germany), which makes cuff based oscillometric measurement from the brachial artery. RESULTS: Systolic blood pressure, pulse rate, central systolic blood pressure, cardiac output, heart rate-corrected augmentation index (Aix@75) and pulse wave velocity (PWV) measurements were significantly higher in the hyperthyroid group than in the control group. The heart rate and PWV in the subclinical hyperthyroid group were significantly higher than the control group. In the euthyroid group, systolic blood pressure, central systolic blood pressure, cardiac output, cardiac index and PWV were found significantly higher than the control group. There was also a negative correlation between Aix@75 and thyroid-stimulating hormone (TSH), and a positive correlation between Aix@75 and free thyroid hormones. CONCLUSION: In our study, we observed that the arterial stiffness was adversely affected by an overt or subclinical increase in thyroid hormones and this correlated with thyroid hormone levels. We recommend that PWV measurement, which is a simple method for detecting CVD risk, can be used in these patients.

Interrupted 131I Procedures for Patients With Differentiated Thyroid Cancer: Comparing Thyroxine Withdrawal With Recombinant Thyrotropin Preparation Techniques.

OBJECTIVE: In patients with differentiated thyroid carcinoma scheduled to receive doses of I for diagnostic or therapeutic purposes, we compared patients prepared with thyroid hormone withdrawal (THW) versus recombinant human thyroid stimulating hormone (rh-TSH) to evaluate the incidence of cancelled procedures because of inadequate thyroid stimulation. METHODS: Thyroid cancer patients after thyroidectomy who were scheduled for diagnostic or therapeutic I procedures between January 2012 and June 2015 were retrospectively reviewed. Patients were divided based on preparation modality (THW vs rh-TSH), and the incidence of cancelled procedures was compared. RESULTS: Charts from 761 patients were reviewed, 292 THW and 569 rh-TSH. A total of 10 patients (3.4%) in the THW group had cancelled procedures because of insufficient thyroid stimulation (TSH < 20 mU/L). If a TSH threshold of 30 mU/L were used, 57 patients (17.1%) would have been cancelled. Comparing the groups with chi-squared analysis for both TSH thresholds yielded significantly more cancellations in the THW group (P < 0.001). CONCLUSIONS: Our study has shown that THW in preparation for I procedures leads to significantly more cancellations because of insufficient thyroid stimulation as compared with rh-TSH, which led to no cancellations. The added cost and inconvenience to this cancer population should therefore be considered when selecting a preparation modality. LEVEL OF EVIDENCE: Retrospective cohort-Level III.

Single-Photon Emission Computed Tomography for Preclinical Assessment of Thyroid Radioiodide Uptake Following Various Combinations of Preparative Measures.

BACKGROUND: MicroSPECT/CT imaging was used to quantitatively evaluate how iodide uptake in the mouse thyroid is influenced by (i) route of iodine administration; (ii) injection of recombinant human thyrotropin (rhTSH); and (iii) low iodide diet (LID) in euthyroid and triiodothyronine (T3)-treated mice. METHODS: Pertechnetate (99mTcO4-) and 123I thyroid uptake in euthyroid and T3-treated animals fed either a normal-iodine diet (NID) or an LID, treated or not with rhTSH, and radiotracer administered intravenously, subcutaneously, intraperitoneally or by gavage, were assessed using microSPECT/CT imaging. Western blotting was performed to measure sodium/iodide symporter expression levels in the thyroid. RESULTS: Systemic administration of radioiodide resulted in a higher (2.35-fold in NID mice) accumulation of iodide in the thyroid than oral administration. Mice fed LID with systemic radioiodide administration showed a further two-fold increase in thyroid iodide uptake to yield a ∼5-fold increase in uptake compared to the standard NID/oral route. Although rhTSH injections stimulated thyroid activity in both euthyroid and T3-treated mice fed the NID, uptake levels for T3-treated mice remained low compared with those for the euthyroid mice. Combining LID and rhTSH in T3-treated mice resulted in a 2.8-fold higher uptake compared with NID/T3/rhTSH mice and helped restore thyroid activity to levels equivalent to those of euthyroid animals. CONCLUSIONS: Systemic radioiodide administration results in higher thyroidal iodide levels than oral administration, particularly in LID-fed mice. These data highlight the importance of LID, both in euthyroid and T3-treated, rhTSH-injected mice. Extrapolated to human patients, and in the context of clinical guidelines for the preparation of differentiated thyroid cancer patients, our data indicate that LID can potentiate the efficacy of rhTSH treatment in T3-treated patients.

Ipilimumab-Induced Autoimmune Hypophysitis: Diagnostic and Management Challenges Illustrated by a Clinical Case.

Autoimmune hypophysitis has been described in patients on ipilimumab, a humanised monoclonal antibody increasingly used in the treatment of metastatic melanoma. A 67-year-old woman presented with severe fatigue, nausea and headaches following the third dose of ipilimumab, which was being given as treatment for metastatic melanoma (four administrations at three-weekly intervals). Hormonal evaluation confirmed hypocortisolism, with low gonadotrophins and a low thyroid-stimulating hormone with normal free T4 (she was on long-standing levothyroxine because of past surgery for a multinodular goitre). Magnetic resonance imaging scanning revealed pituitary enlargement compatible with autoimmune hypophysitis. She was commenced on replacement with hydrocortisone with significant improvement of her symptoms. The enlarged pituitary was reduced in size 4 months later. The patient is currently asymptomatic on glucocorticoid and levothyroxine replacement. This case highlights relevant clinical, diagnostic and management aspects of ipilimumab-induced autoimmune hypophysitis, and emphasises the need for increasing awareness for potential side-effects of these new immunomodulatory therapies, including autoimmune hypophysitis.

Avoiding the prenatal programming effects of glucocorticoids: are there alternative treatments for the induction of antenatal lung maturation?

BACKGROUND: The long-term outcomes of antenatal glucocorticoids (GCs) vary between reports, and have generated controversy in terms of repeated and single-course events, causing irreversible effects on endocrine set points. AIM: This study aimed to assess the effects of alternative therapeutic agents other than synthetic glucocorticoid GC administration for fetal lung maturation. METHODS: A review of literature from PubMed, EMBASE, Cochrane Library, and Google Scholar was conducted to assess the use of alternative therapies to synthetic GCs using recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement (PRISMA). End points included the rates of respiratory distress syndrome (RDS), mRNA expression for pneumocyte type II, concentration of surfactant proteins in alveolar lavage, morphological differences, histological proof of lung maturation, and angiogenesis or quantification of the surfactant pool. RESULTS: In all 41 studies examined, we found that ambroxol showed positive effects on lung maturation, but it has yet to be analyzed with sufficient significance in humans. Interleukins and TNF-alpha produce accelerated lung maturation, but have only been evaluated in basic research/experimental studies. Growth factors promote structural and functional growth in all phases of lung maturation, but little is known about their reciprocal effects and exact mechanisms as therapeutics. Thyroid releasing hormone or vitamin A cause detrimental side effects or were less effective for lung maturation. CONCLUSIONS: The efficacy and safety of these alternative agents are differentiated and none up to now can be recommended as an alternative to GCs.

Strategies of radioiodine ablation in patients with low-risk thyroid cancer.

BACKGROUND: It is not clear whether the administration of radioiodine provides any benefit to patients with low-risk thyroid cancer after a complete surgical resection. The administration of the smallest possible amount of radioiodine would improve care. METHODS: In our randomized, phase 3 trial, we compared two thyrotropin-stimulation methods (thyroid hormone withdrawal and use of recombinant human thyrotropin) and two radioiodine ((131)I) doses (i.e., administered activities) (1.1 GBq and 3.7 GBq) in a 2-by-2 design. Inclusion criteria were an age of 18 years or older; total thyroidectomy for differentiated thyroid carcinoma; tumor-node-metastasis (TNM) stage, ascertained on pathological examination (p) of a surgical specimen, of pT1 (with tumor diameter ≤1 cm) and N1 or Nx, pT1 (with tumor diameter >1 to 2 cm) and any N stage, or pT2N0; absence of distant metastasis; and no iodine contamination. Thyroid ablation was assessed 8 months after radioiodine administration by neck ultrasonography and measurement of recombinant human thyrotropin-stimulated thyroglobulin. Comparisons were based on an equivalence framework. RESULTS: There were 752 patients enrolled between 2007 and 2010; 92% had papillary cancer. There were no unexpected serious adverse events. In the 684 patients with data that could be evaluated, ultrasonography of the neck was normal in 652 (95%), and the stimulated thyroglobulin level was 1.0 ng per milliliter or less in 621 of the 652 patients (95%) without detectable thyroglobulin antibodies. Thyroid ablation was complete in 631 of the 684 patients (92%). The ablation rate was equivalent between the (131)I doses and between the thyrotropin-stimulation methods. CONCLUSIONS: The use of recombinant human thyrotropin and low-dose (1.1 GBq) postoperative radioiodine ablation may be sufficient for the management of low-risk thyroid cancer. (Funded by the French National Cancer Institute [INCa] and the French Ministry of Health; ClinicalTrials.gov number, NCT00435851; INCa number, RECF0447.).

Cognitive functions and mood during chronic thyrotropin-suppressive therapy with L-thyroxine in patients with differentiated thyroid carcinoma.

BACKGROUND: Subclinical thyroid dysfunctions may cause cognitive deficits and mood disorders. Chronic TSH-suppressive therapy with L-T(4) causing subclinical hyperthyroidism has been widely used in treatment of patients with thyroid differentiated carcinoma. The impact of this therapy on cognitive functions and mood have not been systematically studied. The aim of this study was to asses executive functions, working memory, attention, and depression in patients with subclinical hyperthyroidism in the course of TSH-suppressive therapy. METHODS: Thirty-one patients with subclinical hyperthyroidism in the course of suppressive treatment with L-T(4) following the total thyroidectomy and radioiodine ablative therapy were included in the study. Cognitive functioning in patients and control group were investigated using the battery of neuropsychological tests [Wisconsin Card Sorting Test (WCST), The Oral Word Association Test (OWAT), Trail Making Test, The Stroop Color-Word Interference test and Digit span]. Psychometric evaluation was performed using 17-items the Hamilton Depression Rating Scale (HDRS) and Beck Depression Inventory (BDI). RESULTS: The performance on tests assessed executive functions, psychomotor speed, and attention was significantly lower in patients group. There was no differences in results of Stroop test and Digit Span forward and backwards between both groups. The intensity of depressive symptoms negatively correlated with a number of completed categories on WCST and results of OWAT. Cognitive deficits were still observed when patients with concomitant general medical conditions and depression were excluded from the analysis. CONCLUSION: Our findings provide evidence of neuropsychological impairment in patients with differentiated thyroid carcinoma treated with chronic TSH-suppressive therapy.

Modified-release recombinant human TSH (MRrhTSH) augments the effect of (131)I therapy in benign multinodular goiter: results from a multicenter international, randomized, placebo-controlled study.

BACKGROUND: Recombinant human TSH (rhTSH) can be used to enhance (131)I therapy for shrinkage of multinodular goiter (MG). OBJECTIVE, DESIGN, AND SETTING: The objective of the study was to compare the efficacy and safety of 0.01 and 0.03 mg modified-release (MR) rhTSH as an adjuvant to (131)I therapy, vs. (131)I alone, in a randomized, placebo-controlled, international, multicenter study. PATIENTS AND INTERVENTION: Ninety-five patients (57.2 ± 9.6 yr old, 85% females, 83% Caucasians) with MG (median size 96.0, range 31.9-242.2 ml) were randomized to receive placebo (group A, n = 32), MRrhTSH 0.01 mg (group B, n = 30), or MRrhTSH 0.03 mg (group C, n = 33) 24 h before a calculated activity of (131)I. MAIN OUTCOME MEASURES: The primary end point was a change in thyroid volume (by computerized tomography scan, at 6 months). Secondary end points were the smallest cross-sectional area of the trachea; thyroid function tests; Thyroid Quality of Life Questionnaire; electrocardiogram; and hyperthyroid symptom scale. RESULTS: Thyroid volume decreased significantly in all groups. The reduction was comparable in groups A and B (23.1 ± 8.8 and 23.3 ± 16.5%, respectively; P = 0.95). In group C, the reduction (32.9 ± 20.7%) was more pronounced than in groups A (P = 0.03) and B. The smallest cross-sectional area of the trachea increased in all groups: 3.8 ± 2.9% in A, 4.8 ± 3.3% in B, and 10.2 ± 33.2% in C, with no significant difference among the groups. Goiter-related symptoms were effectively reduced and there were no major safety concerns. CONCLUSION: In this dose-selection study, 0.03 mg MRrhTSH was the most efficacious dose as an adjuvant to (131)I therapy of MG. It was well tolerated and significantly augmented the effect of (131)I therapy in the short term. Larger studies with long-term follow-up are warranted.

Exploring new applications for Rhodiola rosea: can we improve the quality of life of patients with short-term hypothyroidism induced by hormone withdrawal?

Patients treated for differentiated thyroid cancer (DTC) are subjected to periodic surveillance that includes serum thyroglobulin measurements followed by radioiodine administrations for diagnostic and therapeutic purposes if necessary. Both procedures require adequately elevated blood levels of thyroid-stimulating hormone (TSH), which can be achieved by two approaches: parenteral administration of recombinant human TSH (rhTSH) or stopping thyroid hormone replacement until optimal levels of endogenous TSH are achieved. Although rhTSH administration does not require hormone withdrawal, it is not inexpensive and carries the risk of secondary effects. The latter option is simpler but induces a profound state of hypothyroidism, which results in physical and mental complaints that may interfere severely with the patient's activities of daily living. Rhodiola rosea is a popular plant in traditional medical systems in Eastern Europe and Asia with a reputation for stimulating the nervous system, decreasing depression, enhancing work performance, and eliminating fatigue, all features of clinical hypothyroidism. Investigators have also suggested additional benefits such as cardioprotection or even tumor growth inhibition. Here, we propose R. rosea as a viable alternative treatment for the symptoms of short-term hypothyroidism in patients with DTC who require hormone withdrawal.

Role of recombinant human TSH in the management of large euthyroid multinodular goitre: a new therapeutic option? Pros and cons.

Conventional 131I treatment has been used in the last 20 years for large nodular goitres when patients present high surgical risk or simply refuse surgery. 131I therapy causes a mean goitre volume reduction of about 40% after one year. However, the individual response is variable and for low radioiodine uptake and very large goitres, high 131I activities are needed in order to have a adequate 131I accumulation in the thyroid. rhTSH is approved for thyroid cancer management and has been tested off label in large goitres, in whom increases 131I uptake, thus reducing the 131I amount to be administered. The use of lower 131I activities allows to reduce the radiation burden to body and the time of social life restriction. Moreover, depending on the radiation regulations of the different countries, the 131I therapy could be carried out either as outpatients or in a shorter hospitalization period, implying a decrease of costs. The effects of rhTSH on goitre may be due not only to the 131I uptake increase, but also to a more homogeneous distribution of 131I in the gland, and to the thyroid cell activation that makes them more radiosensitive. Acute adverse effects are due to the surge of thyroid hormone in blood and to the goitre volume increase, that cause cardiac symptoms and tracheal compression, respectively. These effects are probably dose dependent and are negligible for rhTSH lower doses.

Radioiodine plus recombinant human thyrotropin do not cause acute airway compression and are effective in reducing multinodular goiter.

Recombinant human thyrotropin (rhTSH) reduces the activity of radioiodine required to treat multinodular goiter (MNG), but acute airway compression can be a life-threatening complication. In this prospective, randomized, double-blind, placebo-controlled study, we assessed the efficacy and safety (including airway compression) of different doses of rhTSH associated with a fixed activity of 131I for treating MNG. Euthyroid patients with MNG (69.3 +/- 62.0 mL, 20 females, 2 males, 64 +/- 7 years) received 0.1 mg (group I, N = 8) or 0.01 mg (group II, N = 6) rhTSH or placebo (group III, N = 8), 24 h before 1.11 GBq 131I. Radioactive iodine uptake was determined at baseline and 24 h after rhTSH and thyroid volume (TV, baseline and 6 and 12 months after treatment) and tracheal cross-sectional area (TCA, baseline and 2, 7, 180, and 360 days after rhTSH) were determined by magnetic resonance; antithyroid antibodies and thyroid hormones were determined at frequent intervals. After 6 months, TV decreased significantly in groups I (28.5 +/- 17.6%) and II (21.6 +/- 17.8%), but not in group III (2.7 +/- 15.3%). After 12 months, TV decreased significantly in groups I (36.7 +/- 18.1%) and II (37.4 +/- 27.1%), but not in group III (19.0 +/- 24.3%). No significant changes in TCA were observed. T3 and free T4 increased transiently during the first month. After 12 months, 7 patients were hypothyroid (N = 3 in group I and N = 2 in groups II and III). rhTSH plus a 1.11-GBq fixed 131I activity did not cause acute or chronic changes in TCA. After 6 and 12 months, TV reduction was more pronounced among patients treated with rhTSH plus 131I.