Cerebrospinal fluid ACTH as a marker of central nervous system metastases from small cell carcinoma of the lung.

Adrenocorticotrophic hormone (ACTH) concentrations were measured in the plasma and cerebrospinal fluid (CSF) of 107 consecutive patients with known or suspected central nervous system (CNS) metastases secondary to small cell carcinoma of the lung. The combined results of computerized tomography scans, neurologic examination, and autopsy were used to determine the presence or absence of CNS metastases. On the basis of such an assessment, definitive conclusions were possible in 77 patients. CNS metastases were present in 52 cases and absent in 25. The median CSF ACTH level was 30 ng/ml in both groups. None of five patients with very high CSF ACTH concentrations had elevated ACTH concentrations in plasma. Considering the 95th percentile of patients without CNS metastases as the upper limit of normal, 12 patients with metastases and one without had an elevated CSF ACTH value. Eleven patients with leptomeningeal carcinomatosis (MC) did not constitute a special subgroup in this respect. The median ratio of CSF ACTH and plasma ACTH was 1.0 in patients with CNS metastases and 0.4 in those without (P less than 0.05). Patients with MC had a median ratio of 1.3, which was significantly different from that of both of the other groups (P less than 0.05). Ten patients with CNS metastases (one with MC) and one without exceeded the upper 95th percentile of the CSF/plasma (ACTH) ratio in patients without CNS metastases. The significance levels of these findings disappeared, however, when patients with signs of an elevated ACTH concentration in plasma were excluded. Patients with ectopic ACTH production into CSF do not necessarily have ectopic ACTH production outside the CNS, despite the presence of extracerebral metastases. With the criteria employed in this study, an elevated level of CSF ACTH diagnosed too few patients for the authors to recommend its determination as a single test in diagnosing CNS metastases or MC secondary to small cell carcinoma of the lung.

Serum free T4, T3, rT3, 3,3'-diiodothyronine and 3',5'-diiodothyronine measured by ultrafiltration.

A simple and accurate method for estimation of the free fractions (FFT) of T4, T3, rT3, 3,3'-diiodothyronine (3,3'-T2) and 3',5'-diiodothyronine (3',5'-T2) in serum is presented. The method is based on ultrafiltration of serum pre-incubated with tracers of high specific activity, followed by purification of the ultrafiltrate on small Sephadex columns. The addition of tracer only dilutes serum negligible (about 5%) and the ultrafiltration procedure only removes about 7% of the volume of serum, thus probably not disturbing the equilibrium between the free and protein bound fraction of iodothyronine. Progressive reduction of tracer to less than 10% of the amount usually used did not reduce the FFT of any of the iodothyronines. In contrast, addition of T4 to serum led to an increase of all FFTs except that of 3',5'-T2. These data suggest that FFT of T4, T3, rT3 and 3,3'-T2 primarily is determined by the amount of T4 present in serum and that significant amounts of these iodothyronines are bound to TBG, whereas 3',5'-T2 possibly primarily is bound to albumin. The median FFT of T4, T3, rT3, 3,3'-T2 and 3',5'-T2 in serum from euthyroid subjects (n = 38) was: 0.030, 0.29, 0.14, 1.10 and 1.07%, respectively. The corresponding median free concentrations in pmol/l were: 30, 4.79, 0.59, 0.44 and 0.77, respectively. Pregnant women in 3rd trimester had normal levels of free T4, free T3 and free rT3, whereas the median free 3,3'-T2 was reduced in contrast to elevated median free 3',5'-T2.(ABSTRACT TRUNCATED AT 250 WORDS)

131I treatment of diffuse and nodular toxic goitre with or without antithyroid agents.

The results of 131I treatment in combination with pre- and post-treatment with carbimazole (n = 122) were compared to the results of 131I used as the only antithyroid treatment (n = 203). The two groups of patients were fully comparable in regard to age, size of goitre and time of observation, and the same diagnostic criteria and dosage regimen of 131I were used. The incidence of early myxoedema in patients with diffuse goitre was significantly reduced after combination therapy, 5 per cent, compared to 16 per cent after 131I as the only antithyroid therapy (P less than 0.05). The incidence of late myxoedema was 6 per cent in both groups 3 years after the last treatment, and fully compensated myxoedema was found in 13 and 22 per cent (n.s.). No severe acute side effects were observed after 131I therapy in any of the two groups. It is concluded that--in diffuse toxic goitre--a lower early incidence of myxoedema was obtained on the combined regimen because of either a possibly lower absorbed radiation dose or a more fractionate therapy. A major advantage of the combination therapy is also, that the patients are rendered euthyroid shortly after the diagnosis and remain so during the prolonged period of treatment. 131I treatment in combination with carbimazole is advocated in all patients with diffuse and nodular toxic goitre if the patient is above fertile age and thyroidectomy is not indicated.

Urinary excretion of free and conjugated 3',5'-diiodothyronine and 3,3'-diiodothyronine.

RIAs for the estimation of 3',5'-diiodothyronine (3',5'-T2) and 3,3'-diiodothyronine (3,3'-T2) in human urine have been established. The urinary excretion of both glucuronide and sulfate conjugates of T2 and of T4, T3, and rT3 were estimated by means of enzymatic deconjugation. In healthy controls, the mean excretion (picomoles per 24 h) of free T4 was 1820, that of free T3 was 813, that of free rT3 was 77, that of free 3',5'-T2 was 13, and that of free 3,3'-T2 was 674. The total excretion of free and conjugated T4 was 2941, that of T3 was 1283, that of rT3 was 791, that of 3',5'-T2 was 709, and that of 3,3'-T2 was 2688. Significant amounts of sulfated T4 and T3 could not be demonstrated, amounts of sulfated T4 and T3 could not be demonstrated, whereas the excretion of sulfated rT3 was higher than that of glucuronidated rT3 (P less than 0.001). In contrast, glucuronidated and sulfated 3',5'-T2 as well as glucuronidated and sulfated 3,3'-T2 were found in the urine in equal amounts. In hyperthyroidism, the excretions of free and glucuronidated iodothyronines were increased, whereas the increase of the excretions of sulfated iodothyronines were less pronounced, only reaching statistical significance for 3,3'-T2 (P less than 0.02). In hypothyroidism, the excretions of both free, glucuronidated and sulfated iodothyronines were reduced. Significant amounts of sulfated T4 and T3 could not be demonstrated in urine from hyperthyroid or hypothyroid patients. Our data demonstrate that the amounts of free iodothyronines excreted in the urine vary considerably, suggesting active renal handling. The amounts of urinary glucuronidated and sulfated conjugates of the different iodothyronines studied vary considerably and are affected by thyroid function.

Urinary excretion of thyroxine, triiodothyronine, 3,3',5'-triiodothyronine (reverse T3) and renal function in human newborns.

The urinary excretion and serum levels of thyroxine (T4), triiodothyronine (T3) and 3,3',5'-triiodothyronine (reverse T3) was estimated in a longitudinal study of human newborns. The maternal and cord blood was also studied. Neonatal renal function was evaluated using endogenous creatinine clearance. In cord blood serum T3 was found to be lower than in maternal blood, but reverse T3 highly elevated. During the first 5 days of life serum T4 and T3 increased with maximum at 48 and 24 h in contrast to reverse T3 which remained high and then declined rapidly after 4 days. Creatinine clearance during the first 3 days of life increased from 5.3 to 21.9 ml/min/1.73 m2. In the same period the urinary T4 excretion increased from 79 to 281 ng/24 h, urinary T3 excretion from 16 to 44 ng/24 h and urinary reverse T3 from 4 to 15 ng/24 h. The renal excretion of thyroid hormones, corrected for body surface, was decreased compared to adult controls, corresponding to an immature renal function. The lack of ability to excrete thyroid hormones involved primary T3 and reverse T3 suggesting particular immaturity of tubular secretion of these hormones during the neonatal period.

Urinary excretion of 3,3',5'-triiodothyronine (reverse T3).

A simple and sensitive radioimmunoassay for reverse T3 in urine using small Sephadex G25 fine columns is described. The recovery of rT3 added to urine was on average 101.0 +/- 4.2% (mean +/- SEM). Detection limit was 4 pg/column. Urine excretion of rT3 (mean +/- SD) was 72.0 +/- 32.1 ng/24 h in 61 healthy euthyroid subjects with a slight increase with age (P less than 0.05), 28.8 +/- 18.2 ng/24 h in 12 hypothyroid patients and 183.6 +/- 79.7 ng/24 in 25 hyperthyroid patients.

Extrathyroidal effects of propylthiouracil and carbimazole on serum T4, T3, reverse T3 and TRH-induced TSH-release in man.

A possible extrathyroidal effect of propylthiouracil (PTU) and carbimazole on serum levels of thyroxine (T4), triiodothyronine (T3), 3,3',5'-triiodothyronine (reverse T3) and on thyrotrophin-releasing hormone (TRH) induced thyrotrophin (TSH) release was estimated in 19 patients with severe hypothyroidism treated with T4. During PTU medication a significant decrease in serum T3 from 90 +/- 16 (SD) to 79 +/- 23 ng/100 ml (P less than 0.01) and a reciprocal increase in serum reverse T3 from 51 +/- 14 (SD) to 58 +/- 20 ng/100 ml (P less than 0.025) were found. No significant changes in serum T4, basal serum TSH or response to TRH could be demonstrated. Carbimazole did not change any of the parameters studied.

Radioimmunoassay of thyroxine and triiodothyronine in urine using extraction and separation of Sephadex columns.

Radioimmunological methods for the determination of thyroxine (T4) and triiodothyronine (T3) in urine have been developed. The methods are based on trapping of T4 and T3 from unextracted urine, followed by separation between free and antibody bound hormone on the same Sephadex column. The T4 method has been compared to a competitive protein binding (CPB) assay using ethyl acetate extraction. The methods are evaluated in sixty-seven euthyroid controls, twenty-four hyperthyroid and seven hypothyroid patients. In the T4 RIA detection limit was 3.9 pg, intra-assay coefficient of variation (cv) was 5.2% and inter-assay cv was 6.9%. In the T3 RIA detection limit was 7.2 ng, intra-assay cv 3.9% and inter-assay cv 10.8%. Recovery of added amounts of hormones and serial dilutions gave satisfactory results. The CPB assay was found unreliable with unspecific and false high values. In euthyroid controls 24 h urinary T4 excretion as measured by RIA was 1.8 +/- 0.5 nmol, and urinary T3 excretion was 0.7 +/- 0.3 nmol. T4 and T3 excretion was greatly elevated in hyperthyroid patients and decreased in hypothyroidism.

Intravenous and peroral TRH stimulation in sporadic atoxic goitre.

Thyrotrophin releasing hormone (TRH) stimulation test with 200 microng iv was performed in 35 patients with atoxic sporadic goitre. In 23 patients with diffuse goitre 7 showed a lack of increase in serum thyrotrophin (TSH) at a significantly increased frequency compared to controls (P = 0.0028). In 4 patients with solitary nodules 2 showed no significant response to TRH (negative), while 3 of the 8 patients with multinodular goitres had negative TRH test. Only 6 of the 12 TRH negative patients also had non-suppressible 131I uptake following T3. No significant difference in age and thyroid parameters was found between the TRH negative and TRH positive patients. In 7 TRH negative patients the test was repeated with 400 microng TRH but all remained negative. Five of these patients were given TRH perorally 80 mg daily for 2 weeks resulting in a significant increase in serum T4 and T3. No detectable increase in TSH was found. The response to iv bovine TSH in 4 TRH negative patients was found to be normal, suggesting that there was normal thyroid sensitivity to TSH. Our findings suggest that patients with TRH negative atoxic goitre can release biological active TSH following prolonged TRH stimulation. The high frequency of a negative standard TRH test in atoxic goitre seems to diminish the diagnostic value of the standard TRH test.

Outcome of long-term antithyroid treatment of graves' disease in relation to iodine intake.

Seventy-seven patients with Graves' disease, with an average of 56 years of age were treated with carbimazole in the period 1968-1975. The duration of therapy was on an average, 17.9 months and the follow-up on an average, 28.5 months. Remission was found only in 32% of the patients. Data on the urinary iodine excretion from a total of 127 euthyroid controls and 15 patients with Graves' disease living in the same area were collected during the periods: 1962-1964, 1965-1968, 1971-1973 and 1972-1974. No significant difference was found in the urinary iodine excretion in the period 1962-1973 and no significant difference was found in the urinary iodine excretion between the patients with Graves' disease and the euthyroid controls. Our data demonstrate a high relapse rate following long-term treatment with anti-thyroid drugs in an area with relative low iodine intake.

The clinical value of serum triiodothyronine, thyroxine and thyrotropin estimations during medical antithyroid treatment.

The relation between clinical status and serial determinations of serum T3, serum T4 and serum TSH has been evaluated in the early phase of medical antithyroid treatment in 12 unselected hyperthyroid patients, and in 19 patients who later during treatment accidentally developed low serum T4 values. Determination of both serum T3 and serum T4 was found necessary to avoid undertreatment. Two patients with signs of hypothyroidism in the early phase developed low serum T4, while serum T3 and serum TSH remained normal. In all of the 19 patients selected with low serum T4, serum T3 was normal. Serum TSH was elevated in 5 patients without hypothroid symptoms, while 2 developed hypothyroid symptoms in spite of normal serum TSH values. Our results suggest that serum T4 is a more sensitive parameter than both serum TSH and serum T3 in avoiding overtreatment during medical antithyroid treatment.

Thyroid hormone response to varying doses of TSH.

Fifty-five normal subjects were studied following intravenous injection of increasing doses of bovine thyrotropin (b-TSH) from 0.5 to 250 mU/kg. Serum triiodothyronine (T3) and thyroxine (T4) were measured 1, 2, 3 and 4 h after the TSH injection. Dose-related increments in serum T3 and T4 were demonstrated with doses of b-TSH = 2.5 mU/kg and a maximum response was obtained after approximately 100 mU/kg. The fractional increase in serum T3 was greater than in serum T4, but the ratio between the increase in serum T4 and serum T4 and serum T3 (21.3/l ng/ng) was independent of the dose of b-TSH and time after TSH stimulation. The T3 response was reproducible and unaffected by sex and age.