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Endocrine Unit, Department of Medicine, New York University School of Medicine

Intravenous administration of thyrotrophin-releasing hormone (T.R.H.) induces a prompt rise in immunoassayable thyroidstimulating hormone (T.S.H.) and triiodothyronine (T3) in normal man. Basal T.S.H. levels are high in primary hypothyroidism and rise dramatically after T.R.H. In patients with hypothyroidism secondary to pituitary disease basal T.S.H. levels are low and show no increase with T.R.H. In contrast, 2 patients with hypothalamic hypothyroidism had nil basal levels of T.S.H., which rose normally after T.R.H. administration. Basal T3 levels were low in all forms of hypothyroidism and did not rise after T.R.H. administration. The failure of T3 to increase normally after T.R.H. in the 2 patients with hypothalamic hypothyroidism in the face of a normal T.S.H. stimulation test suggests a diminished thyroidal reserve in these patients. Intravenous T.R.H. administration may prove of value in the simultaneous assessment of pituitary and thyroidal reserve.



INTRAVENOUS administration of synthetic thyrotrophin-releasing factor or hormone (T.R.H.) in man causes prompt release of thyrotrophin (thyroidstimulating hormone, T.S.H.) from the pituitary. 1,2 This T.S.H. response has been suggested as a means of assessing pituitary reserve for T.s.H. and of distinguishing between primary hypothyroidism, hypothyroidism secondary to pituitary disease, and hypothalamic 4

hypothyroidism. 3,4 We have lately demonstrated that intravenous T.R.H. results not only in a prompt rise in serum-T.S.H. but also a rise in triiodothyronine (T3).5 This rapid rise

function and growth-hormone abnormality in sodium balance. The latter patient had no corpus callosum-a finding associated with hypothalamic hypothyroidism.6 Both which had low basal radioiodine were patients uptakes stimulated after exogenous T.s.H. After an overnight fast, the subjects were allowed to rest quietly in bed for half an hour. An intravenous cannula was inserted in the antecubital fossa for administration of T.R.H. and withdrawal of blood-samples. 400 g. of synthetic T.R.H. (Abbott Laboratories) was administered as a bolus, and blood was collected at 10, 20, 30, 40, 60, 120, and 180 minutes. The blood was immediately separated into cells and plasma, and the plasma was frozen until assay. T.S.H.7.8and T3 9.1° were measured by radioimmunoassay. T4 was measured by competitive-protein-binding analysis.ll Radioiodine uptake was determined by standard techniques.



reserve, and the other had


The normal subjects showed a prompt rise in T.s.H. and T3 after intravenous administration of T.R.H. (fig. 1). Basal T.S.H. values were 1-3±0-3 1. per ml. and reached a maximum of 9.1±0.8 U per ml. at 20 minutes, returning to basal levels by 120 minutes. Basal T3 values were 112±111 g. per 100 ml. and rose to a plateau of 164 12 .g. per 100 ml. at 120 minutes, remaining elevated for the duration of the test.

Subjects with primary hypothyroidism (fig. 2) had elevated basal levels of T.S.H. (20-135 zU per ml.). After administration of T.R.H., T.S.H. values in this group rose dramatically. The absolute values achieved in the patients with primary hypothyroidism were much higher than those in the normal subjects, even though the percentage rise was not as great. In contrast to T.S.H., T3 values were low and did not rise in response to T.R.H.

The 2 subjects with hypopituitarism (fig. 3) had low basal levels of T.s.H., which did not rise after T.R.H. administration. Baseline T3 levels were low and also did not rise after T.R.H. The 2 subjects with hypothalamic hypothyroidism (fig. 3) had normal basal levels of T.S.H. After administration of T.R.H., T.S.H.

of both T3 and T.S.H. should allow the simultaneous assessment of thyroidal and pituitary reserve in the evaluation of dysfunction of the pituitary/thyroidal axis. Methods and Subjects 10 normal subjects, 5 patients with primary hypothyroidism, 2 with hypothyroidism secondary to pituitary disease, and 2 with hypothalamic hypothyroidism were studied. The normal subjects, aged 28 to 54, had no evidence of endocrine abnormalities. The patients with primary hypothyroidism (3 men and 2 women, aged 36 to 56) all had low total thyroxine (T4) values and low radioiodine uptakes which were not responsive to exogenous bovine T.s.H. The 2 patients with pituitary disease were men aged 38 and 41; 1 had a chromophobe adenoma and the other idiopathic hypopituitarism. Both had low basal radioiodine uptakes which increased after administration of T.s.H. The 2 subjects with hypothalamic hypothyroidism had evidence of other endocrine deficits : 1 had

Fig. 1-T3 and T.S.H.

responses in 10 normal


to 400 .g.

of T.R.H.

Each point depicts the mean ± standard error of mean. T3 values rise promptly and reach a plateau at 120 minutes. T.s.H. levels reach a peak at 20 minutes.


T3, presumably first inhibiting and then causing

Fig. 2-T3 and T.S.H. responses in 5 patients with primary hypothyroidism. The corresponding T3 and T.S.H. response for a given patient Note the two breaks in the are depicted by the same symbol. vertical axis of the T.s.H. plot. The exaggerated T.s.H. response contrasts with the lack of a change in the T3 levels.

Fig. 3-T.S.H.

responses to T.R.H. in hypothalamic hypothyroidism (closed circles and open triangles) and hypopituitarism (open circles and closed triangles).

The lack of response in the patients with hypopituitarism sharply with the clearcut rise in T.S.H. in the 2 patients with hypothalamic hypothyroidism. contrasts

levels rose to a similar degree as in the normal subjects. T3 values, low initially, did not rise significantly after T.R.H. administration. In 1 of these subjects T3 was measured after 10 units of intramuscular T.s.H. and was found to rise from basal levels of 86 ng. per 100 ml. to 148 ng. per 100 ml. at 180 minutes. Discussion

Previous attempts to assess pituitary reserve for T.S.H., based on measuring an increase in radioiodine in response to various stimuli, were indirect and gave very variable results. Studer et al.12 described a test for estimating T.s.H. reserve based on the assumption that T.s.H. secretion increases if thyroid-hormone synthesis is blocked by antithyroid drugs. Ikkos 13


to measure T.s.H. reserve

by giving patients


rebound increase in T.S.H. In contrast to these indirect measures of an increase in radioiodine uptake, measurement of T.s.H. by radioimmunoassay after T.R.H. administration provides a direct means of assessing pituitary T.S.H. reserve. It clearly identifies patients with diminished or absent pituitary T.S.H. reserves and readily separates them from patients with primary hypothyroidism. Patients with hypothyroidism caused by pituitary disease have low or absent basal T.S.H. levels. 3,4 Furthermore, T.S.H. levels do not rise after T.R.H. administration. On the other hand, patients with primary hypothyroidism have high basal T.S.H. levels 14,15 which rise to even higher levels after T.R.H. infusion.3,4,16 In addition, the T.s.H. response to T.R.H. permits identification of patients with hypothyroidism caused by hypothalamic dysfunction. These patients have normal basal levels of T.S.H. which, after T.R.H. administration, rise to the same degree as in normal subjects.3,4 The concomitant rise in T3 in response to T.R.H. adds another dimension to this test and may allow for simultaneous evaluation of thyroidal reserve. The rise in T3 is probably mediated by the T.R.H.-induced rise in endogenous T.S.H. Unlike the T.S.H. rise produced by intramuscular administration of bovine T.S.H. during a standard T.S.H. stimulation test, the rise in endogenous T.s.H. after T.R.H. administration is short-lived. In most cases, T.s.H. levels fell to normal by 120 minutes. This probably accounts for the fact that patients with hypothalamic hypothyroidism show an increase in radioiodine uptake after exogenous bovine T.s.H., yet show no rise of T3 after T.R.H. administration. The T.R.H.-induced rise in T.s.H. did not evoke a thyroidal response in these patients, whereas intramuscular administration did raise T3 in the 1 patient in whom it was studied. The demonstration of a diminished thyroidal response to T.R.H. may prove to be a useful means of uncovering early or mild cases of diminished thyroidal reserve, perhaps too mild to be clinically apparent or to be demonstrable by administration of exogenous T.s.H. The patient who shows an unequivocal rise of T.S.H. after T.R.H. administration, but does not demonstrate the expected increase in circulating T3, probably has impaired thyroidal reserve. It remains to be seen whether this test will be useful as a means of detecting early forms of thyroiditis or of predicting which patients will go on to develop frank hypothyroidism. The authors express their thanks to Dr. Michael Anderson for providing the thyrotrophin-releasing hormone and to Colette Thaw, Harriet Nadel, and John Colucci for expert technical assistance. This work was supported by U.S.P.H.S. grants 1 FO 3-AAt 5156-01, 2 R01-AM 14314-02, 03, and Fr 96. Requests for reprints should be addressed to L. S., Endocrine Unit, Department of Medicine, New York School of Medicine, 550 First Avenue, New York, New York 10016, U.S.A. REFERENCES

Bowers, C. Y., Schallv, A. V., Schalch, D. S., Gual, C., Kastin, A. J., Folkers, K. Biochem. biophys. Res. Commun. 1970, 39, 352. 2. Hershman, J. M., Pittman, J. A., Jr. J. clin. Endocr. Metab. 1970 4, 480. 3. Hollander, C. S., Mitsuma, T., Shenkman, L., Woolf, P., Gershengorn, M. C. 47th Meeting American Thyroid Assoc. Inc. 1971. 1.

113 known bleeding tendency, a history of peptic ulcer, surgery within the preceding week, hypertension requiring treatment, a history of cerebral haemorrhage or any apparent cerebrovascular accident in the preceding week, pregnancy and symptoms of deep-vein thrombosis for more than one week. Verbal consent was obtained from all the patients who entered the trial after details of the study had been explained to them.






Departments of Radiology, Hœmatology, and Medicine, Radcliffe Infirmary, Oxford

Diagnostic Criteria A clinical diagnosis

was accepted if the patient had deep tenderness of the calf or thigh with an increase in circumference of either calf or thigh of more than 2 cm. when measured from a fixed point compared with the normal leg. Whenever possible, the diagnosis was confirmed by venography, carried out by the following technique: a one-way stretch elastic bandage was applied at the level of the malleolus as tightly as the patient could tolerate and then progressively loosened to knee level, in order to reduce filling of superficial veins. The patient was tilted on a fluoroscopic table to 20-30° from the vertical, and a vein on the lateral aspect of the dorsum of the foot was cannulated percutaneously with a short-bevel needle. Contrast medium (diatrizoate,’Hypaque 30%’) was injected rapidly and films taken under fluoroscopic control. Recent clot was considered to be present if a persistent filling defect, with the typical " ground glass " appearance, outlined by a thin layer of contrast, was seen in two or more films. Non-filling of veins was not accepted as evidence of thrombosis, unless part of the clot was outlined. The diagnosis was accepted only when there was clear evidence of intravenous clot as judged by the radiologist who conducted the investigation at the time and on " blind " review of the films later. 1251-labelled fibrinogen techniques7 were not used because of the potential risk of serum hepatitis from the preparations available at the time.

Ancrod allocated

(’Arvin’) or heparin was Summary randomly to thirty patients with established deep-vein thrombosis of the leg, and treatment was given intravenously by a doubleblind technique for 4 days. In twenty-two patients, the diagnosis was confirmed by venography. Venograms were repeated in nineteen patients and clinical assessment carried out in all, without knowledge of which treatment had been given. There was no significant change in the amount of thrombus present in any of the patients reassessed with venography, and more than half the patients in each treatment group had residual signs and symptoms 3 months after treatment. There were no serious side-effects. It seems that neither therapy has a significant effect on the resolution of the thrombosis in the deep leg veins. Introduction

ANTICOAGULANT therapy is the most widely accepted for thrombosis of the deep veins of the leg. Conventionally, either heparin or coumarin anticoagulants are used separately or together, heparin usually being used to start treatment. 1,2 The coagulant enzyme ancrod (‘ Arvin ’), developed from the venom of the Malayan pit-viper (Agkistrodon rhodostomct),3 has shown promise as an anticoagulant .4,5 As these studies and those of Kakkar et al. suggested that ancrod might have advantages over heparin,6a trial was designed to compare ancrod with heparin in a series of patients with deep-vein thrombosis of the lower limb, by a double-blind technique.


Allocation of Treatment Patients were divided into two groups. In the first, the diagnosis was made on clinical grounds alone; in the second, it was confirmed by venography. Therapy with either heparin or ancrod was then allocated at random to each group. Anticoagulant solutions were provided by the hoematology laboratory, made up in identical bottles and identified only by a sealed envelope which could be opened in emergency. The alternative schedules were: ancrod 140 units in 12 hours, then 70 units 12-hourly, or heparin 2500 units hourly. Treatment was given for 96 hours as a constant-flow intravenous infusion of 20 ml. hourly, using a pump (Watson-Marlow MHRE 88), and the dosage was adjusted as necessary to maintain the defined level of anticoagulant effect. After 84 hours, treatment with warfarin was started and continued for 3 months.

Patients and Methods

Selection of Patients The patients Those in the

inpatients at the Radcliffe Infirmary. following categories were excluded: a


* Present address: Royal Postgraduate Medical Hospital, London W.12.

School, Hammersmith

Anticoagulant Control was taken before treatment and daily during intratherapy, and the following tests were performed: whole-blood clotting-times,aplasma thrombin clottingtime (0.1 ml. thrombin 25 units per ml., Diagnostic Reagents Ltd., added to 0-5 ml. platelet-free citrated plasma), fibrinogen titre,9 protamine-sulphate titration of heparin,9 fibrin-fibrinogen degradation products,lo and full blood-




Hershman, J. M., Pittman, J. A. New Engl. J. Med. 1971, 285, 997. Hollander, C. S., Mitsuma, T., Shenkman, L., Woolf, P., Gershengorn, M. C. Science (in the press). 6. Kaplan, S. L., Grumbach, M. M., Hoyt, W. F. Pediat. Res. 1970, 4, 480. 7. Utiger, R. D. J. clin. Invest. 1965, 44, 1277. 8. Odell, W. D., Wilber, J. F., Utiger, R. D. Rec. Prog. Horm. Res. 1967, 23, 47. 9. Mitsuma, T., Gershengorn, M. C., Colucci, J., Hollander, C. S J. clin. Endocr. Metab. 1971, 33, 364. 10. Mitsuma, T., Nihei, N., Gershengorn, M. C., Hollander, C. S J. clin. Invest. 1971, 50, 2679. 11. Murphy, B. E., Pattee, C. J. J. clin. Endocr. Metab. 1964, 24, 187 12. Studer, H., Wyss, F., Jff, H. W. ibid. p. 965. 13. Ikkos, D. G., Lakka-Papadodima, E., Dalles, K. ibid. 1970, 31, 98. 14. Reichlin, S., Utiger, R. D. ibid. 1967, 27, 251. 15. Hershman, J. M., Pittman, J. A., Jr. Ann. intern. Med. 1971, 74, 481 16. Ormston, B. J., Garry, R., Cryer, R. J., Besser, G. M., Hall, R. Lancet 1971, ii, 10. 5.

using a Coulter S automated counter. The results were recorded and kept available for inspection, but not reported to the clinical assessor or the physician in charge of the case. The level of anticoagulation was considered adequate if, in patients treated with ancrod, the fibrinogen titre was 1/2 or less, confirmed by observation of miniclot in Lee and White tubes,5 or, in those treated with heparin, the plasma-thrombin clottingtime was shortened by the equivalent concentration of 2 mg. protamine sulphate per 100 ml. and not by the 1 mg. If a higher concentration of protamine concentration.