Plasma TSH and Serum T-4 Levels in Long-term Follow-up of Patients Treated with 131I for Thyrotoxicosis

In February 1972 58% of patients euthyroid after iodine-131 therapy given for thyrotoxicosis between 1954 and 1966 had a high plasma TSH (>7·4 μU/ml) and 42% a normal plasma TSH level. A group of 69 of the euthyroid patients with high plasma TSH levels (25·0±2·0 μU/ml) in 1972 were re-examined 15 and 24 months later. The mean plasma TSH in the 66 patients remaining euthyroid at 15 months was 22·6±1·8 μU/ml, while three patients had become hypothyroid. At 24 months 64 of the patients were still available for study, of whom 61 remained euthyroid with a mean plasma TSH of 21·6±2·0 μU/ml, and a further three had become hypothyroid.All of a group of 61 of the euthyroid patients with normal plasma TSH levels (4·0±0·2 μU/ml) in 1972 remained euthyroid at 24 months with a mean plasma TSH of 4·1±0·3 μU/ml, though the plasma TSH level had become slightly raised in three.The mean serum T-4 level in the euthyroid patients with a high plasma TSH was significantly lower, though still in the normal range, than that in the euthyroid patients with a normal plasma TSH both in 1972 and in 1974.Since no patient with a normal plasma TSH level after iodine-131 treatment six to 18 years earlier for thyrotoxicosis developed hypothyroidism over a two-year period, the follow-up of such patients need not be so rigorous as that of similarly treated euthyroid patients with raised plasma TSH levels in whom hypothyroidism developed at the rate of 5% per year.     

Radioimmunoassay of Human Serum Thyrotrophin

The double antibody radioimmunoassay of serum thyroid-stimulating hormone (TSH) allows measurement of circulating levels of the hormone in most normal subjects. The serum TSH level in normal subjects is 1·6 ± 0·8μU/ml. Patients with non-toxic goitre and acromegaly have normal TSH levels. Values are always raised in hypothyroid patients (with primary thyroid disease) and are significantly lowered in those with hyperthyroidism. Of the many stimuli used in an attempt to raise TSH levels in normal adult subjects only three—synthetic thyrotrophin-releasing hormone, ethinyloestradiol, and carbimazole plus iodides—have been effective. The major clinical application of the TSH immunoassay lies in the diagnosis of minor degrees of hypothyroidism. An impaired response of serum TSH to synthetic thyrotrophin-releasing hormone should also help in the diagnosis of hypopituitarism affecting TSH production.     

Thyroid function after subtotal thyroidectomy for hyperthyroidism.

Among 76 patients who had had a subtotal thyroidectomy for hyperthyroidism from one to seven years previously recurrent hyperthyroidism was found in three and hypothyroidism in 13. The remaining 60 subjects were clinically euthyroid but a raised level of serum thyroid-stimulating hormone (TSH; greater than 5-0 mu U/ml) was found in 39. Analysis of the data showed that their serum thyroxine was significantly lower than in the subjects with a normal TSH. The serum triiodothyronine (T-3) was similar in both groups. It is concluded that subjects with a raised TSH remain clinically euthyroid by maintaining a normal serum T-3 concentration. There was no evidence of any long-term progressive deterioration of thyroid function after subtotal thyroidectomy.     

Technetium-99m in the Diagnosis of Thyrotoxicosis

The thyroid uptake at 20 minutes of intravenously administered Technetium-99^m (^99mTc) was measured in 117 patients with a standard scintillation counter. Patients were divided into three groups on the basis of clinical assessment, four-hour ¹³¹I uptake, triiodothyronine (T-3) resin uptake, and protein-bound iodine measurements.In 31 patients with no evidence of thyroid disease the mean ^99m Tc uptake was 1·8% ±S.D. 1·1%. In 32 patients with thyroid enlargement who were euthyroid the mean uptake was 2·5% ±S.D. 2·2%. In 54 thyrotoxic patients the mean uptake was 17·7% with a range of 4·1 to 44%, all cases having an uptake above the upper limit of normal (4·0%). These results agree closely with reported uptake studies using scanning techniques. In seven patients the extrathyroidal neck activity was measured by using a scanner, and the mean was 6·3% of the extrathyroidal total body radioactivity comparing favourably with an assumed 6% used in our calculations.We have shown that the measurement of the thyroid uptake of ^99mTc with a scintillation counter is of value, and that it is not necessary to use scanning techniques in the diagnosis of thyrotoxicosis. Advantages of ^99m Tc are minimal radiation, reduction in patient and laboratory time, and low cost.     

Radioimmunoassay of Triiodothyronine in Unextracted Human Serum

Serum triiodothyronine (T-3) concentrations have been estimated by radioimmunoassay using unextracted serum. The serum T-3 concentrations have been shown to be similar in two separate European populations (0·76-1·67 ng/ml). Raised T-3 values have been observed in all subjects with hyperthyroidism. Low values are seen in hypothyroidism although there is some overlap with the normal range. There is a good correlation between serum T-3 and serum thyroxine (T-4) concentrations, and estimation of T-3 seems likely to prove a practical and reliable test of thyroid function.     

Pituitary-Thyroid Function in Pendred's Syndrome

Pendred''s syndrome is reported in three siblings. All were euthyroid, with large goitres and deaf mutism and all had an unusual deposition of pigment in the retina. All had raised circulating levels of triiodothyronine (T-3) and an exaggerated response of thyroid-stimulating hormone (TSH) to thyrotrophin-releasing hormone (TRH). It appears that their compensated euthyroid state was maintained by the raised T-3 levels. We suggest that preferential T-3 production is maintained by increased TSH secretion in subjects with intrathyroidal iodine deficiency secondary to thyroid organification defect.     

Metabolic Effects of Oestrogen Treatment in Patients with Carcinoma of Prostate: A Comparison of Stilboestrol and Conjugated Equine Oestrogens

Serum cholesterol and triglyceride levels were estimated and oral glucose tolerance tests performed on 16 patients with carcinoma of the prostate before treatment and while receiving stilboestrol in doses of 1 mg, 7·5 mg, and 15 mg daily and conjugated equine oestrogens (Premarin) 15 mg daily. Serum triglyceride levels were greater than 170 mg/100 ml in nearly all the patients while receiving Premarin or stilboestrol 7·5 mg and 15 mg daily. In six out of 10 patients who were given stilboestrol 1 mg daily the serum triglycerides remained within the normal range. No significant effects on serum cholesterol levels or glucose tolerance tests were observed with the various oestrogen regimens. The results support previous suggestions that a daily dose of 1 mg of stilboestrol should be regularly used in the treatment of carcinoma of the prostate.     

Weight loss in obese subjects on a restricted diet given BRL 26830A,a new atypical β adrenoceptor agonist

A double blind placebo controlled study was carried out in 40 subjects newly referred for treatment for obesity to determine the effects of the new thermogenic β adrenoceptor agonist BRL 26830A. The subjects were randomised to receive either BRL 26830A, 200 mg daily for two weeks then 400 mg daily, or placebo for 18 weeks, and all were instructed to follow a 3·35 MJ diet that was low in fat and high in fibre. Weight loss was 15·4 (SD 6·6) kg in subjects given BRL 26830A compared with 10·0 (5·9) kg in those given placebo (p=0·02). The relative weight loss was 0·93 (0·39)% a week with BRL 26830A and 0·61 (0·38)% with placebo (p=0·02). Urinary excretion of nitrogen was similar in both groups, whereas measurements of skinfold thickness indicated a 4·1 kg difference in the amount of fat lost, suggesting that weight loss with BRL 26830A was mainly from adipose and not lean tissue. BRL 26830A had no effect on resting pulse rate or pressor effects on either diastolic or systolic blood pressure. No significant differences were found between the two groups in serum cholesterol concentration, percentage of high density lipoprotein cholesterol, plasma concentrations of glucose and insulin, the ratio of glucose to insulin, serum concentrations of triiodothyronine and thyroxine, and creatinine clearance. Short term administration of BRL 26830A to six subjects who had taken the drug for 18 weeks showed that the expenditure of energy increased by 11·6% during the second hour after administration, which suggests that BRL 26830A may enhance weight loss thermogenically.BRL 26830A may be a useful drug in the treatment of obesity.     

Ophthalmic Graves's disease: natural history and detailed thyroid function studies.

Of 27 patients with ophthalmic Graves''s disease (OGD) who had been clinically euthyroid three years previously, one became clinically hyperthyroid and seven overtly hypothyroid. Improvement in eye signs was associated with a return to normal of thyroidal suppression by triiodothyronine (T3) and of the response of thyroid-stimulating hormone (TSH) to thyrotrophin-releasing hormone (TRH). Of a further 30 patients with OGD who had not been studied previously, three were overtly hypothyroid. Of the combined series, 46 patients were euthyroid, 18 (40%) of whom had an impaired or absent TSH response to TRH, and 3(6-7%) an exaggerated response. Eleven out of 37 patients (29-7%) had abnormal results in the T3 suppression test. There was a significant correlation between thyroidal suppression by T3 and the TSH response to TRH. Total serum concentrations of both T3 and thyroxine (T4) were closely correlated with T3 suppressibility and TRH responsiveness. Free T4 and T3 (fT3) concentrations were normal in all but three patients, in whom raised fT3 was accompanied by abnormal TSH responses and thyroidal suppression. The presence of normal free thyroid hormone concentrations in patients with impaired or absent TSH responses to TRH is interesting and challenges the concept that free thyroid hormones are the major controlling factors in the feedback control of TSH.     

Long-term intramuscular administration of thyrotropin-releasing hormone tartrate in patients with cerebrovascular disease: effects on the pituitary-thyroid axis.

We studied the effects of long-term (30 days) refracted daily intramuscular administration of 4 mg TRH tartrate (TRH-T) on the pituitary-thyroid axis in 20 euthyroid patients affected by cerebrovascular disease (CVD). All subjects were assayed for T4, T3, FT4, FT3, TSH and TBG plasma levels before treatment (D0), after 15 and 30 treatment days (D15, D30), and after a 15-day washout (D45). In addition, TSH response to 200 micrograms intravenous TRH was assessed at D0, D30 and D45. We observed a significant increase in T4, FT4 and FT3 levels in the face of decreased TSH concentrations. A blunted TSH response to TRH bolus persisted at D30. These data demonstrate that the down-regulation mechanism may be partially overcome in vivo when thyrotrophs are chronically exposed to pharmacological TRH-T doses and that TSH pattern is mainly due to the negative feedback of thyroid hormones, even though pituitary TSH reserves may become depleted. Furthermore, prolonged TRH-T administration does not produce hyperthyroidism in euthyroid CVD patients.     

Recovery of Adrenocortical Function during Long-term Treatment with Corticosteroids

The recovery of adrenocortical function during very slow withdrawal of corticosteroids was studied in a homogeneous group of patients suffering from sarcoidosis. All patients had been treated with gradually decreasing doses of prednisone for at least two years. The initial dose had been 40 mg. daily in all cases. Determination of the cortisol production rate and of plasma fluorogenic corticosteroids was done under basal conditions and after tetracosactrin stimulation. There was good correlation between cortisol production rate and plasma fluorogenic corticosteroids throughout all the tests. Cortisol production rate and plasma fluorogenic corticosteroids started to rise when the dosage of prednisone was lowered to 7·5 mg. daily and reached normal values when the dosage was reduced to 2·5 mg. The response to tetracosactrin began to increase at the same dosage level, but was not normal at 2·5 mg., or when prednisone treatment was stopped. At a dosage level of 7·5 mg. of prednisone plasma fluorogenic corticosteroids already showed a nyctohemeral rhythm.It may be calculated that even very low dosages of prednisone given during the last stage of a treatment schedule enhance total corticosteroid activity beyond the normal level, which would account for their therapeutic value.     

Continuous Intravenous Infusion of Small Doses of Insulin in Treatment of Diabetic Ketoacidosis

Continuous intravenous infusion of small amounts of insulin has been used in the management of a series of patients with diabetic ketoacidosis. In 13 patients with a plasma glucose level on admission of 725 mg/100 ml (± 80 S.E. of mean) and an arterial pH of 7·07 ± 0·05 a mean loading dose of 6·5 ± 0·82 units of soluble insulin was administered intravenously, and thereafter a sustaining infusion of 6·5 ± 0·82 U/hr was continued until ketosis was corrected and the plasma glucose fell below 300 mg/100 ml. The total insulin dose needed to achieve this was 39·2 ± 6·6 units given over a 3 to 10-hour period. Plasma insulin was measured in patients who had not previously received insulin and the mean level at an infusion rate of 4 U/hr was 75·6 ± 8·0 μU/ml. Plasma glucose fell at a regular rate of 101 ± 11 mg/100 ml/hr, and ketosis improved in parallel. Plasma potassium was well maintained throughout treatment. This regimen of treatment was clinically effective and simple to follow.     

Red Cell Sodium in Hyperthyroidism

A simple method of measuring red cell sodium has shown that about 90% of thyrotoxic patients have values above the upper limit of the normal range. Patients taking 0·3 mg of L-thyroxine daily were found to have a significantly higher mean value for red cell sodium than that of the normal controls. It is suggested that patients taking this amount of thyroxine may be hypermetabolic. The determination of red cell sodium may prove useful as a measure of the peripheral action of thyroid hormone.     

Studies on the congenitally goitrous sheep. The iodinated compounds of serum, and circulating thyroid-stimulating hormone

1. A group of normal and congenitally goitrous Merino sheep were investigated to identify the metabolic defect present in the abnormal animals. 2. Protein-bound iodine concentrations of serum from goitrous animals (average 5·7μg./100ml.) were higher than normal (average 4·2μg./100ml.; P 0·001), but the hormonal iodine measured as butanol-extractable ¹³¹I was low in the serum of goitrous (average 40·3% of protein-bound ¹³¹I) compared with that of normal (84·2%; P 0·02) sheep. The non-hormonal iodine of the serum of goitrous sheep appeared to include iodotyrosines and iodinated protein. 3. Starch-gel-electrophoretic separations of sera from normal and goitrous sheep after ¹³¹I injection (100–500μc) showed no qualitative differences in the radioactivity of protein components. No significant differences in thyroxine-binding in vitro by serum proteins of normal and goitrous sheep were observed. 4. The clearance rates of ¹³¹I-labelled iodotyrosines (t_½ 1·2–2·9hr.) and iodothyronines (t_½ 33·5–47·4hr.) were similar in normal and goitrous sheep. 5. The concentration of circulating thyroid-stimulating hormone was significantly higher (P<0·01 in three sheep, P<0·05 in one sheep) in goitrous sheep. 6. The congenital goitre appears to be due to compensatory hypertrophy of the gland resulting from an inability to synthesize an adequate supply of thyroid hormone.     

Double-blind Evaluation of Verapamil,Propranolol, and Isosorbide Dinitrate against a Placebo in the Treatment of Angina Pectoris

In the treatment of angina pectoris a double-blind evaluation of verapamil (Cordilox) at two dose levels—namely, 80 mg thrice daily and 120 mg thrice daily—propranolol (Inderal) 100 mg thrice daily, and isosorbide dinitrate (Vascardin) 20 mg thrice daily has been made against a placebo. The assessment was based on relief from daily attacks of angina on effort and the response to a whole-body exercise test. We can find no statistically significant difference between the effects of verapamil (120 mg three times a day) and propranolol (100 mg three times a day) in the treatment of angina of effort. Both of these preparations are more effective than a placebo both in the reduction of daily attacks (P < 0·01) and in the prolongation of exercise test (P < 0·05). Isosorbide dinitrate (20 mg three times a day) appears to be no more effective than a placebo in the treatment of angina on effort, but 14 out of 32 patients experienced headache of such severity that even when the dose was reduced to 10 mg thrice daily this drug therapy had to be withdrawn. Both propranolol (100 mg three times a day) and verapamil (120 mg three times a day) had a significant lowering effect on the diastolic blood pressure as measured with the patient standing (P < 0·01).     

Raised plasma intact parathyroid hormone concentrations in young people with mildly raised blood pressure

To study the role of parathyroid gland activity in early primary hypertension plasma concentrations of intact parathyroid hormone were measured in 90 untreated young subjects, aged 16-29, with stable mildly raised blood pressure and in 40 normotensive control subjects selected from the same population in Zoetermeer, The Netherlands. Intact parathyroid hormone concentration was significantly higher in the hypertensive than the normotensive group (2.34 (SE 0.11) pmol/l v 1·47 (0·13)pmol/l, respectively; difference 0·87 pmol/l; 95% confidence interval 0·55 to 1·21; p<0·0001). Serum total calcium concentration was 2·36 (0·01) mmol/l in the hypertensive group and 2·42 (0·01) mmol/l in the normotensive group (difference 0·06 mmol/l; 95% confidence interval 0·02 to 0·09; p=0·02). Urinary calcium excretion over 24 hours did not differ significantly between the two groups (4·17 (0·28) mmol/24 h in the hypertensive group and 3·89 (0·39) mmol/24 h in the normotensive group; difference 0·28 mmol/24 h; 95% confidence interval -0·66 to 1·22). In the hypertensive group both systolic and diastolic blood pressures increased slightly though significantly with intact parathyroid hormone concentrations. No obvious associations between serum calcium concentration and blood pressure were observed.These findings support the view that enhanced activity of the parathyroid gland may play a part in the early stage of primary hypertension.     

Additive antianginal effect of verapamil in patients receiving propranolol

Ten men with stable angina pectoris not fully relieved by optimal doses of propranolol (mean 218 mg daily) were given a single oral dose of 120 mg verapamil or a placebo on alternate mornings; the order of treatment was double blind. Patients had trained in a protocol that precipitated angina after three to six minutes of exercise on a bicycle ergometer. On test days, and with continued propranolol treatment, bicycle exercise was performed just before the administration of verapamil or placebo and hourly thereafter for eight hours. Mean exercise tolerance was 118 seconds greater one hour after verapamil than one hour after placebo (p <0·001), and a significant though somewhat diminished difference of 66 seconds was still present at six hours (p <0·01). Verapamil lowered resting systolic blood pressure by 12 mm Hg (p <0·01) without changing heart rate. None of the 10 patients showed adverse effects from the verapamil-propranolol combination.The results of this study suggest that verapamil is a highly effective antianginal supplement to propranolol.     

High Dosage Metolazone in Chronic Renal Failure

Metolazone is a modified quinazolinesulphonamide and in a dose of between 4 and 7·5 mg is an effective diuretic in man with normal renal function. Fourteen patients with non-oedematous stable chronic renal failure (creatinine clearance ranging from 1·2 to 12 ml/min) were given metolazone in doses ranging from 20-150 mg. A noticeable increase in urine flow and sodium excretion occurred, free water clearance increased, and there was a small but significant increase in potassium excretion. No side effects were noted.     

Variations in the serum levels of thyroid hormones and TSH after intake of a dose of L-thyroxine in euthyroid subjects and in adequately-treated hypothyroid patients

The aim of the present study was to determine whether the temporary variations in blood thyroid hormone levels secondary to a therapeutic dose administration of L-thyroxine observed in adequately treated hypothyroid patients also occur in spontaneously euthyroid subjects under analogous conditions. Serum levels of T3, T4, FT3, FT4 and TSH were measured over 6 hours following a single oral administration of L-thyroxine (dosage 85 mcg/mq body surface area) in a group of 18 euthyroid volunteers and 8 hypothyroid patients adequately compensated with replacement therapy. In the euthyroid subjects there was a significant increase in T4 and a significant fall in TSH values at 60', while a significant decrease in FT3 and FT4 as compared to initial values was observed at 120'. In the treated hypothyroid patients serum T3 and T4 increased at 120', while FT4 concentrations, already significantly higher at 120', still remained higher than initial levels at 360'. The different behaviour of the hypothyroid patients, in spite of being compensated with therapeutic doses of L-thyroxine, reflects the persistence of a thyroid-metabolic condition substantially different to the physiological feature, which appears to be realized by means of a reduced iodothyronine clearance and a lower sensitivity in TSH feedback.     

Genetic Variants Associated with Serum Thyroid Stimulating Hormone (TSH) Levels in European Americans and African Americans from the eMERGE Network

Thyroid stimulating hormone (TSH) hormone levels are normally tightly regulated within an individual; thus, relatively small variations may indicate thyroid disease. Genome-wide association studies (GWAS) have identified variants in PDE8B and FOXE1 that are associated with TSH levels. However, prior studies lacked racial/ethnic diversity, limiting the generalization of these findings to individuals of non-European ethnicities. The Electronic Medical Records and Genomics (eMERGE) Network is a collaboration across institutions with biobanks linked to electronic medical records (EMRs). The eMERGE Network uses EMR-derived phenotypes to perform GWAS in diverse populations for a variety of phenotypes. In this report, we identified serum TSH levels from 4,501 European American and 351 African American euthyroid individuals in the eMERGE Network with existing GWAS data. Tests of association were performed using linear regression and adjusted for age, sex, body mass index (BMI), and principal components, assuming an additive genetic model. Our results replicate the known association of PDE8B with serum TSH levels in European Americans (rs2046045 p = 1.85×10⁻¹⁷, β = 0.09). FOXE1 variants, associated with hypothyroidism, were not genome-wide significant (rs10759944: p = 1.08×10⁻⁶, β = −0.05). No SNPs reached genome-wide significance in African Americans. However, multiple known associations with TSH levels in European ancestry were nominally significant in African Americans, including PDE8B (rs2046045 p = 0.03, β = −0.09), VEGFA (rs11755845 p = 0.01, β = −0.13), and NFIA (rs334699 p = 1.50×10⁻³, β = −0.17). We found little evidence that SNPs previously associated with other thyroid-related disorders were associated with serum TSH levels in this study. These results support the previously reported association between PDE8B and serum TSH levels in European Americans and emphasize the need for additional genetic studies in more diverse populations.