Oral T.R.H. for evaluation of patients with impaired response to intravenous T.R.H.
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Biomedical subjects
Publications and source records attributed to J J Staub.
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Plasma ACTH levels in response to metyrapone and insulin hypoglycaemia were compared in subjects with normal pituitary-adrenal function. After a single dose of 2 g of metyrapone given with a snack at midnight, the ACTH level was 468 ng/l +/- 66 )SEM) at 07.30 h the next morning (mean increment approximately nine fold over normal morning values). After insulin-hypoglycaemia the peak ACTH level was 369 ng/l +/- 31 (SEM). Peak ACTH levels greater than 200 ng/l were achieved in twenty of twenty-one (95%) subjects after metyrapone and twenty of twenty-four (83%) after insulin. No major side effects were noted after metyrapone. It is concluded that the short single-dose metyrapone test produces at least as strong and consistent a stimulus to ACTH release as the standard insulin-hypoglycaemia test in normal subjects. A direct assay of ACTH avoids misinterpretations which are inherent in a judgement based on compound S increase only. The short test has significant practical advantages over the classical metyrapone test, and provides a convenient and sensitive method of assessing the negative feedback ACTH control mechanism. It may be particularly useful in detecting minor degrees of pituitary suppression. The value of this test in clinical practice for the investigation of patients with hypothalamic-pituitary diseases in comparison to the classical tests of ACTH stimulation has yet to be demonstrated.
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After years of progress, there appear to be few new developments in the treatment of breast cancer at the present time. Aspects of breast cancer are discussed which might offer new therapeutic possibilities. The rather schematic management of the patient with breast cancer is less than well matched with the variable biology and the multitude of factors influencing risk and prognosis. Epidemiological, hereditary, and environmental, as well as endocrinological, immunological, and psychoneurological variables are believed to determine the spontaneous course of the disease and the therapeutic results. One way of improving treatment results is better evaluation of such biological factors in a given patient and variation of treatment plans according to individual needs.
SHBG (sex hormone binding globulin) is a carrier protein for the sex hormones testosterone and estradiol with a molecular weight of about 95000 dalton. It can be used as a metabolic test of thyroid function. SHBG was measured by the adsorption method of Mickelson and Petra; the SHBG contained in serum is incubated with 3H-5alpha-dihydrotestosterone and adsorbed to a cellulose filter. Thirty-eight female patients with hyperthyroidism before treatment had markedly elevated levels of SHBG (x +/- SD: 4.85 +/- 2.4 microgram DHT/100 ml) compared with normal controls (1.50 +/- 0.57; p is less than 0.001). A good correlation between the thyroid hormones and SHBG could be domonstrated which was better for T3 than for T4:r =0.76 (p is less than 0.001) for T3 and r= 0.65 (p is less than 0.001) for T4. This agrees with the clinical finding that the circulating T3 level is a better index of the metabolic severity of thyrotoxicosis than T4. After radioiodine treatment SHBG returns to normal values in euthyroid patients (1.38 +/- 0.8; n = 15) and remains elevated in persistent hyperthyroidism (3.99 +/-1,6; n = 67). Even in patients with persistent biochemical hyperthyroidism who are completely euthyroid on clinical examination, SHBG remains high. Despite lack of evidence of clinical hyperthyroidism, this metabolic test demonstrates the biologic significance of merely biochemical hyperthyroidism. Estimation of SHBG as a metabolic thyroid function test in vitro is of special value for the evaluation of patients showing discrepancies between the clinical and biochemical states and for borderline hyperthyroidism.
TSH, T3 and T4 response to stimulation with thyrotropin releasing hormone (TRH) has been investigated in 24 young healthy adults after intravenous injection and in 25 young healthy adults upon oral application of 40 mg of TRH. After intravenous injection the TSH concentration raises from a mean of 1.6 to a mean maximum of 11.7 muU/ml. A statistically significant sex difference could not be found. T3 shows a statistically significant increase which is however too small to be of diagnostic value in an individual test. After oral stimulation with 40 mg of TRH, TSH rises to a slightly higher maximum of 13.2 muU/ml after 3 h. The T3 increase from 1.5 to 2.19 ng/ml is significant and considerably higher than after intravenous stimulation. The thyroxin increase is statistically significant. The present results compare well with previously published data for intravenous stimulation. The oral route of TRH application has not yet been widely used and the present series establishes the normal response in young healthy adults. Repetitive stimulation with three times 40 mg of TRH leads to a decrease in TSH stimulation which reaches 5.8 muU/ml 3 h after the third dose. This is in contrast to a comparable increase in plasma T3.
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Cyproteroneacetate, an antiandrogenic and gonadotropin-inhibiting steroid, has a marked ACTH suppressive effect. In rats, adrenal atrophy and severe impairment of ACTH and corticosterone responses to stress are induced by a 10-day treatment with 3-0.75 mg/100 g BW cyproteroneacetate/day. Two weeks after cessation of treatment, the ACTH adrenal system has not yet recovered. The ACTH suppression is evident 6 h after a single dose. In 25 human volunteers, a single dose of 200 mg cyproteroneacetate impaired their ACTH and 11-deoxycorticosteroid response to 1 g metyrapone. A similar impairment was seen in 12 women on sequential treatment with cyproteroneacetate and ethinyl estradiol. In 4 out of 11 children treated for precocious puberty, random plasma ACTH and cortisol measurements, cortisol responses to ACTH, and ACTH and cortisol responses to insulin-induced hypoglycemia revealed severely impaired ACTH adrenal function. Questionable impairment was found in 2 out of 11 and normal function in 5 out of 11 children. In 10 patients with endogenous elevated plasma ACTH, 10 days of treatment with cyproteroneacetate, in addition to the steroid substitution, diminished the morning plasma ACTH levels. It is concluded that cyproteroneactate has a pronounced ACTH-suppressive effect. The individual susceptibility of treated patients varies and the effect is dose dependent. A cortisol-like effect must be assumed, because cyproteroneacetate-treated animals and patients under therapy can withstand stress situations without signs of adrenal insufficiency. ACTH adrenal function must, however, be closely watched in treated patients and steroid cover must be considered in conditions of stress. Great care has to be taken when the drug, with its own "stress-protective" effect, is withdrawn. The recovery of ACTH adrenal function may take several months.
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A comparative study of thyroid uptake and PB131I in two groups of 20 euthyroid persons each was performed. In one group 131I was administered in the form of capsules and in the other as a solution. The application of 131I in capsule form showed no significant decrease of thyroid uptake at 2, 24 and 48 hr but a significant diminishment of PB131I 48 hr after capsule ingestion (p less than 0,05). In 3 patients the scintiscans of the abdomen 24 hr after administration of three 131I capsules (90 muCi) revealed no circumscribed areas of activity. Because the iodine metabolism is dependent upon the kind of carrier, we conclude that for thyroid uptake measurements and the following 131I therapy the same 131I preparation should be used.
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The suppressibility of the TSH-thyroid axis one week after a single dose of 3000 microgram L-thyroxine was studied in 21 euthyroid subjects. In all cases the normal thyroid function was proven by euthyroid values for thyroxine (T4), free thyroxine index (FT4-I), triiodothyronine (T3), radioiodine uptake, PBI-131, a normal scintiscan and by a physiologic TSH response to thyrotropin-releasing hormone (TRH). Compared to the baseline values the mean suppression of radioiodine uptake at 2,24 and 48 h was 61.8% (+/- 32.9), 62.0% (+/- 15.3) and 62.1% (+/- 13.4) respectively. Because of the large variation at 2 h this value can be disregarded. If the 24 h value shows a clear suppression over 50%, no further measurement is necessary. Mean serum levels of thyroxine and free T4-index rose from 8.2 +/- 1.0 to 13.0 +/- 2.1 microgram/100 ml and from 7.7 +/- 1.9 to 15.1 +/- 3.4 respectively on the third day, to the upper limits for normal controls. Triiodothyronine increased from 1.69 +/- 0.42 to 2.08 +/- 0.38 ng/ml and remained definitely below the level of 2.60 ng/ml observed in overt thyrotoxicosis. In single subjects T4, FT4-I or T3 achieved slightly hyperthyroid levels. In view of the effectiveness of a single dose of 3000 microgram T4 with good suppression of radioiodine uptake and TSH production after stimulation with TRH without noticeable side effects, the classical T3 suppression test should be abandoned and replaced by this test, which latter can be used for the same diagnostic and therapeutic purposes.
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