The effects of thyroid hormones on circulating markers of cell-mediated immune response, as studied in patients with differentiated thyroid carcinoma before and during thyroxine withdrawal

OBJECTIVE: To address the influence of thyroid hormones on circulating markers of cell-mediated immune response in an in vivo human model. SUBJECTS AND DESIGN: Twenty-two patients with stage I differentiated thyroid carcinoma were studied on the last day of thyroxine suppressive treatment, 4-7 days after withdrawal, and the day before whole body scanning. Three patients were excluded because of residual disease. Twenty euthyroid individuals served as controls. Serum thyrotrophin and thyroid hormones were measured by an immunometric assay, circulating cytokines by enzyme-linked immuno-sorbent assay and lymphoid populations by flow cytometry. RESULTS: Thyroid function in patients changed from subclinical or mild hyperthyroidism at the first visit, to a situation of normal circulating levels of free thyroxine and triiodothyronine at the second, ending in a state of overt hypothyroidism. Thyroxine suppressive treatment in patients increased serum interleukin-18 concentrations (IL-18, mean+/-s.d., 280+/-122 vs 183+/-106 pg/ml, F = 3.192, P = 0.029), soluble interleukin-2 receptor levels (sIL-2R, 4368+/-1480 vs 2564+/-846 pg/ml, F = 21.324, P < 0.001), and the percentage of natural killer (NK) cells in peripheral blood (15.9+/-8.6 vs 10.5+/-3.6%, F = 4.977, P = 0.004) compared with controls. After thyroxine withdrawal, serum levels of IL-18, sIL-2R and the percentage of NK cells decreased progressively. CONCLUSION: Our present results suggest that thyroid hormones modulate the cell-mediated immune response in humans.     

Serum thyroglobulin levels after thyroxine withdrawal in patients with low risk papillary thyroid carcinoma.

We hypothesized that elevated levels of serum thyroglobulin (Tg) are frequently found as the only index of residual neoplasm in patients with low-risk papillary thyroid carcinoma. The records of patients operated on for papillary thyroid carcinoma over a 2-year period were reviewed, and the patients were allocated to risk groups by a validated staging method that does not include Tg levels. Of the 35 patients who manifested a low-risk carcinoma, 9 (26%) exhibited elevated Tg concentrations (11-53 ng/mL) during thyroxine withdrawal after therapies, while clinical, scintigraphic, and radiographic studies at least 1 year later showed no evidence of tumor. Prior scintigraphic imaging of therapeutic doses of 131I in 8 of 9 patients demonstrated no distant metastases, further confirming the low-risk status of this group. The staging method predicts that only 0.9% of patients with low-risk papillary carcinoma will have a cause specific death in 20 years. Elevated Tg concentrations have not been shown to forecast independently the survival of patients with low-risk papillary carcinoma. Thus, although frequently encountered, elevated Tg concentrations are unlikely to predict shortened survival in patients with papillary carcinoma for whom low risk has been determined from other data.     

Relationship between serum lipid profile and thyroid function after thyroid hormone withdrawal in patients with differentiated thyroid carcinoma

<正>Objective To observe the relationship between serum lipid concentration profiles and thyroid function after thyroid hormone withdrawal(THW)in patients with differentiated thyroid carcinoma(DTC).Methods Sixtyfive post-operative DTC patients who prepared to receive radioiodine ablation were included in this study.Serum     

Decreased serum vascular endothelial growth factor-D levels in metastatic patients with differentiated thyroid carcinoma

Objective Vascular endothelial growth factor‐D (VEGF‐D) has been identified as one of the lymphangiogenic growth factors involved in metastatic diffusion. The aim of this study is to evaluate the serum VEGF‐D levels in patients with differentiated thyroid cancer at different conditions of disease. Design and Patients We studied prospectively the VEGF‐D plasma levels in 96 subjects affected by differentiated thyroid cancer. The patients were divided into three groups according to the clinical and biochemical findings: patients with no evidence of disease (Cured), patients with pathological (>1 ng/ml) stimulated thyroglobulin (Tg) (Path‐Tg/rhTSH) levels only after rhTSH and patients with elevated basal Tg levels (Path‐Tg/LT4). Results The serum VEGF‐D concentrations in patients of group Cured were not different from the controls, while group Path‐Tg/rhTSH showed baseline serum VEGF‐D levels significantly lower than group Cured and controls (P < 0·001 and P < 0·01, respectively). Moreover, the patients of group Path‐Tg/LT4 showed median serum cytokine concentrations at baseline not significantly different from the patients of group Path‐Tg/rhTSH. The rhTSH stimulation did not modify the difference in serum VEGF‐D levels in patients of group Cured and group Path‐Tg/rhTSH. Conclusions Our data demonstrate that the VEGF‐D serum levels are reduced in patients with metastases of differentiated thyroid cancer, regardless of the degree of metastatic spread. It is possible that some other molecule produced by the tumoral tissue could affect the VEGF‐D physiologically produced of from different tissues, thus conducting to a decrease in the VEGF‐D found in blood of patients with evidence of metastatic differentiated thyroid cancer.     

原发性肝癌患者血清甲状腺激素变化

目的观察原发性肝癌（ＰＨＣ）患者血清甲状腺激素的变化。方法应用放射免疫法（ＲＩＡ）检测２４例ＰＨＣ患者的血清Ｔ３，Ｔ４，ＴＳＨ和ｒＴ３，并以２４例健康成人作对照。结果ＰＨＣ组血清Ｔ３为１．６０±０．１４ｎｍｏｌ／Ｌ，而对照组为２．３７±０．０８ｎｍｏｌ／Ｌ（Ｐ＜０．００１）。ＰＨＣ切除组血清Ｔ３，Ｔ４和ｒＴ３分别为１．９４±０．１６ｎｍｏｌ／Ｌ，１３４．３４±１１．４９ｎｍｏｌ／Ｌ和２．６１±０．３９；而ＰＣＨ未切除组分别为１．２２±０．１７ｎｍｏｌ／Ｌ（Ｐ＜０．０５），１０４．０１±７．２４ｎｍｏｌ／Ｌ（Ｐ＜０．０５）和１．３５±０．３６（Ｐ＜０．０５）。结论ＰＨＣ患者血清Ｔ３降低，晚期患者出现血清Ｔ４降低和Ｔ３／ｒＴ３比值降低。     

Revisiting serum thyroglobulin in the follow-up of patients with differentiated thyroid carcinoma

This study analyzed serum thyroglobulin (Tg) during hypothyroidism in 207 patients with differentiated thyroid carcinoma treated with total thyroidectomy and radioiodine ablation and undetectable anti-Tg antibodies. Disease staging was defined by clinical examination, stimulated Tg, pre- and post-ablative radioiodine scanning, and other imaging methods (X-Ray, US, CT and MIBI-scan). The average interval from initial therapy was 2.3 years. 153 patients (74%) had no evident disease, 34 (16.4%) presented neck/mediastinal disease, and 20 (9.6%) had distant metastases (Mt). The best cut-off for Tg was 1 ng/ml, showing 100% sensitivity for distant Mt and 88.2% for local recurrence or lymph node Mt, and 88.8% specificity for any Mt and 74.8% for distant Mt. In patients with Tg <1 ng/ml, 2.8% showed cervical lymph nodes Mt. Cervical or mediastinal disease were 26% of cases with Tg between 1 and 5 ng/ml. Tg from 5 to 10 ng/ml was associated to distant Mt in 14.2% of the cases and others showed lymph nodes Mt. In patients with Tg >10 ng/ml, 51.3% presented distant Mt. We suggest the need for neck US even in cases with Tg <1 ng/ml. In addition, patients with Tg levels <5 ng/ml should be investigated by neck US and mediastinal CT only, and empirical therapy should be limited to patients with a minimum Tg level >5 ng/ml.     

Chronic thyrotropin-suppressive therapy with levothyroxine and short-term overt hypothyroidism after thyroxine withdrawal are associated with undesirable cardiovascular effects in patients with differentiated thyroid carcinoma

To evaluate cardiovascular functionality in patients with thyroid cancer, we have performed echocardiography and ambulatory blood pressure monitoring in 19 women with differentiated thyroid carcinoma during thyroxine withdrawal, at three time points: the last day on TSH-suppressive thyroxine doses (subclinical or mild hyperthyroidism), 4-7 days after withdrawal (normal free thyroxine (FT4) and free triiodothyronine (FT3) levels), and before 131I whole body scanning (overt hypothyroidism). Twenty-one healthy euthyroid women served as controls. When compared with the values at visit 2, when patients had normal serum FT4 and FT3 levels, night-time systolic and mean blood pressure were increased when the patients were mildly hyperthyroid, and night-time systolic, diastolic and mean blood pressure were increased during overt hypothyroidism. The proportion of nondippers (absence of nocturnal decline in blood pressure) was markedly increased compared with healthy controls (7%), when patients were hyper- or hypothyroid (58% and 50% respectively), but not when patients had normal FT4 and FT3 levels (12%). No changes were observed in office blood pressure or in daytime ambulatory blood pressure readings. Diastolic function worsened during thyroxine withdrawal (E and A waves (early and late mitral flow) decreased, and the E/A ratio and the isovolumic relaxation time increased), and cardiac output decreased in parallel with the decrease in heart rate and systolic blood flow. In conclusion, the chronic administration of TSH-suppressive doses of thyroxine and the withdrawal of thyroxine frequently used for the management of differentiated thyroid carcinoma, are associated with undesirable cardiovascular effects.     

Suppression of the TSH response to TRH by thyroxine therapy in differentiated thyroid carcinoma patients.

Absent response of serum thyrotrophin (TSH) after stimulation with 200 micrograms synthetic thyrotrophin-releasing hormone (TRH) was used as a criterion of adequate suppression of TSH in the treatment of thyroid carcinoma patients with thyroxine. The mean causing total suppression of the response was 223 micrograms of thyroxine per day. At this dose level about 40% of the patients had serum thyroxine concentrations above the upper reference interval and only 10% had elevated triiodothyronine concentrations. In some patients the TSH response to TRH varied between absent and low normal when tested at long intervals. The ideal dose of thyroxine is obviously slightly higher than the smallest one causing total suppression of the TSH response to TRH, i.e. about 250 micrograms a day. The individual dose must be found using the TRH stimulation test because serum thyroid hormone levels cannot be used as a guideline for adequate dosage. In some patients the thyroid remnant of apparently normal thyroid tissue was not totally suppressed although the thyroxine dose was definitely above the level causing suppression of the response to TRH.     

Circulating adiponectin concentrations were related to free thyroxine levels in thyroid cancer patients after thyroid hormone withdrawal

Because it is unclear whether adipose-derived hormones are related to thyroid hormone metabolism, this study evaluated the relationship between adiponectin concentrations and changes in the thyroid hormones in athyreotic patients after thyroid hormone withdrawal. Twenty-eight athyreotic thyroid cancer patients (4 male and 24 female; mean age, 52.2 ± 11.3 years) were analyzed on the final day of levothyroxine treatment and 1 day before serum thyroglobulin and radioiodine scanning examinations after an average of 4 weeks of thyroid hormone withdrawal. Evaluations included analysis of thyroid function test, serum adiponectin, body composition by bioimpedance analysis, and insulin sensitivity index as determined by the homeostasis model assessment of insulin resistance (HOMA-IR). Discontinuation of thyroid hormone treatment resulted in a significant change in thyroid-stimulating hormone (82.1 ± 9.8 vs 1.0 ± 0.4 mL/L, P < .05), free thyroxine (FT4) (5.7 ± 0.4 vs 18.7 ± 2.3 pmol/L, P < .05), and free triiodothyronine levels (1.8 ± 0.2 vs 3.4 ± 0.2 pmol/L, P < .05) as compared with the prewithdrawal values, whereas circulating adiponectin levels (5.7 ± 0.6 vs 5.4 ± 0.6 mg/L), body fat mass (20.3 ± 1.2 vs 19.4 ± 1.2 kg), and insulin sensitivity index (1.8 ± 0.2 vs 2.2 ± 0.3) remained unaltered. A positive correlation between adiponectin and FT4 (r = 0.61, P < .01) independent of age, sex, fat body mass, HOMA-IR, and other potential covariates known to affect thyroid hormone metabolism, such as renal and liver functions, was observed after thyroid hormone withdrawal. In addition, baseline circulating adiponectin levels were correlated with a diminished postwithdrawal reduction of FT4 concentrations after adjusting for baseline FT4 levels and changes in body mass index, fat body mass, and HOMA-IR (r = 0.71, P < .01). In conclusion, adiponectin concentrations were associated with FT4 levels in the athyreotic patients after thyroid hormone withdrawal. The relevant roles of adiponectin in the regulation of thyroid hormone metabolism require further investigation.     

Rapid rise in serum thyrotropin concentrations after thyroidectomy or withdrawal of suppressive thyroxine therapy in preparation for radioactive iodine administration to patients with differentiated thyroid cancer

Patients with differentiated thyroid cancer are often treated transiently with T(3) in preparation for radioactive iodine (RAI) therapy. We questioned the value of using T(3) transiently in patients requiring RAI therapy.Two groups of patients requiring RAI therapy were investigated. One group included patients studied immediately after thyroidectomy, whereas the other included those withdrawn from chronic suppressive T(4) therapy that followed thyroidectomy and postoperative RAI ablation. Serum TSH concentrations were serially measured two to three times weekly until they reached more than 30 mU/liter, after which RAI therapy was administered.Serum TSH concentrations reached more than 30 mU/liter 8-26 d (mean +/- sd, 14.2 +/- 4.8) after thyroidectomy or 9-29 (18.1 +/- 4.1) d after T(4) withdrawal. That level of TSH elevation was achieved 18 d after thyroidectomy and 22 d after T(4) withdrawal in more than 95% of patients. Minimal symptoms of hypothyroidism were noted in either group when RAI was administered.Serum TSH concentrations increased rapidly without transient therapy with T(3). To minimize symptoms of hypothyroidism, serum TSH levels should be measured twice weekly, starting 10 d after thyroidectomy or T(4) withdrawal. The data cast doubt about the value and benefits from using T(3) in preparing patients for RAI therapy.     

How to deal with undetectable and low measurable serum thyroglobulin levels in the follow-up of patients with differentiated thyroid carcinoma?

Serum thyroglobulin (Tg) was measured in 52 patients 3 months to 15 years (mean 5.3 years) after thyroidectomy with or without subsequent radioablation for differentiated thyroid carcinoma, before and after the interruption of suppressive thyroxine (T4) replacement therapy for 5 weeks. Whole body scintigraphy was carried out at the end of the T4 withdrawal period. Serum Tg was undetectable (less than 3 micrograms/l) in 38 patients on T4 therapy, in 18 the scintigraphy showed a minimal accumulation in the neck region and in 20 no uptake anywhere after withdrawal of T4. In the former group Tg rose in 10 patients to 4-21 micrograms/l when off T4 which seemed to correspond to the normal tissue left in situ, in the latter group Tg rose only in 2 patients to 5 and 21 micrograms/l, respectively. Two patients out of 14 with detectable Tg on T4 had pulmonary metastases as uncovered by whole body scintigraphy (in one of them Tg rose from 12 micrograms/l on T4 to 1200 micrograms/l off T4) and 6 patients were suspected for having recidual cancer tissue (2 patients had a negative scintigraphy) because the Tg rose (66-215 micrograms/l) over the upper limit of the reference range (less than 50 micrograms/l) after T4 withdrawal. In conclusion, in the follow-up of patients with differentiated thyroid carcinoma no routine scans are needed as long as serum Tg remains undetectable but further examinations are shortly warranted when detectable Tg is obtained during T4 suppression.     

Outcomes of patients with differentiated thyroid carcinoma following initial therapy.

This analysis was performed to determine the effect of initial therapy on the outcomes of thyroid cancer patients. The study setting was a prospectively followed multi-institutional registry. Patients were stratified as low risk (stages I and II) or high risk (stages III and IV). Treatments employed included near-total thyroidectomy, administration of radioactive iodine, and thyroid hormone suppression therapy. Outcome measures were overall survival, disease-specific survival, and disease-free survival. Near-total thyroidectomy, radioactive iodine, and aggressive thyroid hormone suppression therapy were each independently associated with longer overall survival in high-risk patients. Near-total thyroidectomy followed by radioactive iodine therapy, and moderate thyroid hormone suppression therapy, both predicted improved overall survival in stage II patients. No treatment modality, including lack of radioactive iodine, was associated with altered survival in stage I patients. Based on our overall survival data, we confirm that near-total thyroidectomy is indicated in high-risk patients. We also conclude that radioactive iodine therapy is beneficial for stage II, III, and IV patients. Importantly, we show for the first time that superior outcomes are associated with aggressive thyroid hormone suppression therapy in high-risk patients, but are achieved with modest suppression in stage II patients. We were unable to show any impact, positive or negative, of specific therapies in stage I patients.     

Effects of low-iodide diet on postsurgical radioiodide ablation therapy in patients with differentiated thyroid carcinoma

OBJECTIVE: Most patients with differentiated thyroid carcinoma (DTC) undergo total thyroidectomy followed by routine radioiodide thyroid remnant ablation. Most centres that routinely perform radioiodide ablation prescribe a low-iodide diet (LID) to increase the radioiodide accumulation in thyroid remnants. The efficacy of an LID on thyroid remnant ablation, however, has never been demonstrated convincingly. DESIGN AND METHODS: In a retrospective study, we studied two groups of DTC patients without distant metastases, who had received either a standard diet or an LID during ablation (LID group, n = 59, and control group, n = 61). Both groups were compared for radioiodide uptake in thyroid remnants during ablation and efficacy parameters of remnant ablation, 6 months after ablation. A subgroup without extrathyroidal tumour growth was analysed separately (stages T1-3, N0). RESULTS: In the total group, the LID during ablation decreased the 24-h urinary iodide excretion to 26.6 micro g compared with 158.8 micro g in controls whereas radioiodide uptake in thyroid remnants was increased by 65% (P < 0.001). Six months after ablation, patients were investigated after thyroid hormone withdrawal. In the total group, no significant effects of the LID during ablation were observed on thyroglobulin (Tg) or the percentage of patients with persistent neck activity after 185 MBq 131I. However, in the LID group, 65% of patients without Tg antibodies had undergone successful ablation (defined by absent neck activity and Tg < 2 micro g/l) compared with 48% in the control group (P < 0.001). In the subgroup (T1-3, N0), 8% of the patients who had undergone the LID had Tg >/= 2 micro g/l vs. 32% in the control group (P = 0.012), whereas successful ablation was achieved in 71% of patients without Tg antibodies in the LID vs. 45% in the control group (P < 0.001). CONCLUSION: We conclude from this study that a low-iodide diet during thyroid remnant ablation improves the efficacy of this treatment.     

Levothyroxine suppression of thyroglobulin in patients with differentiated thyroid carcinoma

For patients with differentiated thyroid carcinoma, the appropriate degree of TSH suppression by levothyroxine (L-T4) is still unknown. To find the target level of TSH suppression, we analyzed the relationship between the degree of TSH suppression determined by third generation assay and thyroglobulin (Tg) response during the titration of the dosage of L-T4. Ninety-two patients with differentiated thyroid carcinoma (19 males and 73 females; age, 40.5+/-13.5, mean +/- SD) were included. All of the recruited patients had near-total thyroidectomy, 30-150 mCi 131I thyroid ablation, and negative Tg autoantibodies. They were classified into 3 groups. Group A was composed of 25 patients with local or distant relapse. Group B was composed of 12 patients without clinically detectable relapse, but Tg levels either above 2 ng/mL under L-T4 suppression or above 3 ng/mL off L-T4 therapy. Group C included 55 patients who had no active disease and Tg levels below 2 and 3 ng/mL during and off L-T4 suppression, respectively. Serum TSH and Tg were measured simultaneously at the end of 8-12 weeks of a certain dose of L-T4 therapy during dosage titration and also after withdrawal of L-T4 for 4-6 weeks for the total body scan. Wilcoxon signed ranks test was used to compare paired samples of Tg, and Spearman rank correlation was used to determine the correlation of relative changes in TSH to changes in Tg calculated by individual. The results showed that 1) Tg levels were significantly higher during the period off L-T4 therapy than on L-T4, therapy in all 3 groups (P < 0.01); 2) during L-T4, therapy, within the same treatment course, mean Tg levels were higher when TSH levels were normal than when TSH levels were suppressed, statistically significant in group A (P = 0.001), nonsignificant in group B (P = 0.09), and nonsignificant in group C (P = 0.30); and 3) when TSH was suppressed below normal, there was no correlation between the relative changes in TSH and Tg by individual in all 3 groups (P > 0.05). The data suggest a stratified postoperative thyroid hormone management of patients with differentiated thyroid carcinoma. TSH should be lowered to below normal in patients with active disease. If patients are clinically disease free with Tg levels below 2 ng/mL, TSH can be kept within the normal range. For the most controversial group B patients, it is recommended that the TSH be suppressed and be closely followed up.     

Investigating patients with differentiated thyroid carcinoma and elevated serum thyroglobulin but negative whole-body scan

Findings of elevated thyroglobulin (Tg) and a negative whole-body scan (WBS) are not uncommon during the follow-up of differentiated thyroid carcinoma. In 12% of our patients submitted to thyroidectomy and radioiodine with Tg >10 ng/ml during hypothyroidism had a negative diagnostic WBS. This finding generally corresponds to a false-negative WBS. Inadequate preparation in terms of iodine exposure and insufficient elevation of TSH should be excluded. Micrometastases which do not accumulate sufficient iodine to be detected by low radioiodine activity and the loss of the capacity to express the sodium/iodine symporter explain many cases. In patients with elevated Tg, metastases can be identified after the administration of a therapeutic radioiodine dose, with this procedure being indicated in cases with Tg >10 ng/ml during hypothyroidism or >5 ng/ml after recombinant TSH, after exclusion of lung and cervical macrometastases. In the present study, 5 of 7 patients with these criteria showed ectopic uptake on post-therapy WBS. If the post-therapy scan is negative or reveals discrete uptake in the thyroid bed, other methods (e.g. FDG PET) can be performed, and the physician should not insist on radioiodine therapy. If WBS detect lymph node metastases, surgery is indicated, while in cases of diffuse lung metastases radioiodine is indicated until the occurrence of a negative WBS or normalization of stimulated Tg levels. Patients with a positive post-therapy scan may show a significant reduction in Tg, with even complete remission in some cases after radioiodine, but the impact of this treatment on mortality remains controversial.     

Quality of life in cured patients with differentiated thyroid carcinoma

OBJECTIVE: This study was performed to evaluate the impact of cured differentiated thyroid carcinoma (DTC) on quality of life. Previous studies on quality of life in patients with DTC were hampered by small patient numbers or limited quality-of-life parameters or were uncontrolled. DESIGN: This was a cross-sectional case-control study. METHOD: We assessed quality of life in 153 cured DTC patients with a median duration of cure of 6.34 yr (range 0.3-41.8) and studied the contribution of disease-specific, biochemical, and social variables, focusing on the degree of TSH suppression. Four validated health-related questionnaires were used (Short Form-36, Multidimensional Fatigue Index-20, Hospital Anxiety and Depression Scale, and Somatoform Disorder Questionnaire), including multiple aspects of physical, psychological, and social functioning. Patients were compared with 113 controls selected by patients themselves (control group I) and 336 pooled age- and gender-matched controls from other Leiden quality-of-life studies (control group II). RESULTS: Patients had significantly decreased quality of life in 11 of 16 subscales when compared with control group I. In comparison with control group II, decreased scores in 13 of 16 items were observed. An important independent predictor for quality of life was duration of cure. Quality-of-life parameters were not influenced by serum TSH levels both measured at the time of quality-of-life assessment and measured over time since initial therapy. CONCLUSIONS: Patients cured for DTC have impaired quality of life, independently of TSH level. Quality-of-life parameters were inversely affected by duration of cure and consequently may be restored after prolonged follow-up.     

Effects of evening vs morning thyroxine ingestion on serum thyroid hormone profiles in hypothyroid patients

OBJECTIVE: Standard drug information resources recommend that l-thyroxine be taken half an hour before breakfast on an empty stomach, to prevent interference of its intestinal uptake by food or medication. We observed cases in which TSH levels improved markedly after changing the administration time of l-thyroxine to the late evening. We therefore conducted a pilot-study to investigate whether l-thyroxine administration at bedtime improves TSH and thyroid hormones, and whether the circadian rhythm of TSH remains intact. DESIGN Patients were studied on two occasions: on a stable regimen of morning thyroxine administration and two months after switching to night-time thyroxine using the same dose. On each occasion patients were admitted for 24 h and serial blood samples were obtained. PATIENTS: We investigated 12 women treated with l-thyroxine because of primary hypothyroidism, who used no medication known to interfere with l-thyroxine uptake. MEASUREMENTS: Patients were admitted to hospital and blood samples were obtained at hourly intervals for 24 h via an indwelling catheter. Following this first hospital admission, all women were asked to switch the administration time from morning to bedtime or vice versa. After 2 months they were readmitted for a 24-h period of hourly blood sampling. Blood samples were analysed for serum TSH (immunometric assay), FT4 and T3 (competitive immunoassay), T4 and rT3 (radioimmunoassay), serum TBG (immunometric assay) and total protein and albumin (colourimetric methods). RESULTS: A significant difference in TSH and thyroid hormones was found after switching to bedtime administration of l-thyroxine. Twenty-four-hour average serum values amounted to (mean +/- SD, morning vs bedtime ingestion): TSH, 5.1 +/- 0.9 vs 1.2 +/- 0.3 mU/l (P < 0.01); FT4, 16.7 +/- 1.0 vs 19.3 +/- 0.7 pmol/l (P < 0.01); T3, 1.5 +/- 0.05 vs 1.6 +/- 0.1 nmol/l (P < 0.01). There was no significant change in T4, rT3, albumin and TBG serum levels, nor in the T3/rT3 ratio. The relative amplitude and time of the nocturnal TSH surge remained intact. CONCLUSIONS: l-thyroxine taken at bedtime by patients with primary hypothyroidism is associated with higher thyroid hormone concentrations and lower TSH concentrations compared to the same l-thyroxine dose taken in the morning. At the same time, the circadian TSH rhythm stays intact. Our findings are best explained by a better gastrointestinal uptake of l-thyroxine during the night.