Maudsley Hospital, London

Transcription

1 29 J. Physiol. (I954) I26, 29-4 THE EFFECT OF EMOTIONAL AND PHYSICAL STRESS ON THYROID ACTIVITY IN THE RABBIT By K. BROWN-GRANT, G. W. HARRIS AND S. REICHLIN From the Department of Neuroendocrinology, Institute of Psychiatry, Maudsley Hospital, London (Received 28 January 1954) Many workers have shown that thyroid activity is altered by physical damage. However, there is no direct evidence that such stress affects the rate of release of thyroid hormone from the gland. As part of a study on the functional relationship between the central nervous system, anterior pituitary gland and thyroid gland a method has been devised for studying the rate of output of thyroid hormone in conscious rabbits (Brown-Grant, von Euler, Harris & Reichlin, 1954). In the experiments to be described the effects of both emotional and physical stress on the rate of release of thyroid hormone in the rabbit have been studied. METHODS The technique used for studying thyroid activity in unanaesthetied rabbits has been described previously (Brown-Grant, von Euler, Harris & Reichlin, 1954). As in the previous work the animals were maintained on a standard diet and at a constant environmental temperature. Emotional stress has been produced by: (1) applying brief subcutaneous electric shocks (faradism) at approximately 1 min intervals. During the period of stimulation the animals were partially immobilied by placing them in small wire cages. The intensity of the stimulus was just sufficient to cause signs of fright. (2) Restraining the animals, either by confining them in a small cage, or by tying the back legs to the side of the cage with wide gaue bandages. In most experiments the two types of restraint were used alternately for periods from 24 to 72 hr, since the effect of any one procedure tended to wear off. (3) Subjecting the animals to abrupt changes in lighting, either from the normal day/night alternation to continuous darkness, or from continuous illumination to continuous darkness, or from continuous darkness to continuous illumination. All stresses were continued for at least 24 hr as it was noted that measurable changes in thyroid activity do not occur within shorter periods. Physical stress has been produced by: (1) removing 2 % of the estimated blood volume from the marginal vein of the ear on either a single occasion or on two consecutive days. (2) Subjecting the animal to laparotomy under ether anaesthesia, and (3) giving an intraperitoneal injection of 1- ml. turpentine (which produced no visible signs of pain or discomfort). Operations The anaesthetics used were the same as in a previous study (Brown-Grant, von Euler, Harris & Reichlin, 1954). The thyroid gland was denervated by removing the stellate ganglia and the lower part of the cervical sympathetic chains. The completeness of operation was checked by careful

2 3 K. BROWN-GRANT, G. W. HARRIS AND S. REICHLIN post-mortem dissection under a binocular microscope. Adrenalectomy was performed in two stages. In the first stage, performed through a mid-line abdominal incision, the right adrenal was exposed by reflecting the right kidney and dissected as free as possible from the inferior vena cava to which it is closely adherent. By pulling and twisting the adrenal a false pedicle of vein wall was formed, which was then clamped and tied. The second stage was performed 7-1 days later, the left adrenal being rapidly removed through a small lumbar incision. Five milligrams of cortisone acetate was injected immediately after the second operation, and 4 mg and 2 mg on the succeeding postoperative days. Following this a maintenance dose of *4-1-2 mg of cortisone/ day (in two doses) was administered. Larger doses of cortisone (1 mg/day) appeared to delay wound healing and to increase the incidence of wound infections. The completeness of adrenalectomy and the absence of accessory adrenal tissue was verified in all rabbits by careful postmortem dissection of the retroperitoneal area and the broad ligament. After all operations, penicillin (1, U/day) either alone, or more generally together with streptomycin (125 mg/ day) was given for 3 days. RESULTS A. Effects of emotional stress (1) Subcutaneous faradism Five rabbits were subjected, in six experiments, to subcutaneous faradism for hr. Four of the rabbits showed a prompt inhibition of release of thyroidal 131I (Fig. 1). The fifth rabbit showed no change on the first occasion, but when the experiment was repeated an inhibition of the release of radioiodine from the thyroid was observed. 15 _ Rabbit 498, Restraint and release curve, s.c. faradism 2itc 1311, 3. iii. 53 Ec 1 ~~~~~~~~ %;~~ ~ X 5_ Soo~~~~~ Q Time (hr) Fig. 1. The effect of alternating periods of restraint and subcutaneous faradism on the release of L31I from the thyroid gland of the rabbit. (2) Restraint Nineteen rabbits in twenty-three experiments have been subjected to restraint. In twenty-one of the twenty-three experiments a prompt reduction in the rate of release of 131I from the thyroid gland was observed. The one rabbit that failed to show an inhibition on two occasions when its legs were tied showed a response when placed in a small cage on the third trial, so that

3 STRESS AND THYROID ACTIVITY 313 every rabbit tested responded to restraint at some time. In five of the twenty-one experiments almost complete cessation of 1311 release from the thyroid was seen. The other cases, however, showed partial inhibition. The latent period of the inhibitory response was found to be short. A rough estimate, obtained by extrapolation, indicated a value of less than 3 hr. In nine experiments the inhibition lasted for as long as the restraint was applied, but in twelve 'escape' occurred after hr. Two animals that adapted to one of the procedures after a 24 hr inhibition of thyroidal release of 1311 showed a second 24 hr inhibition when another type of stress stimulus was applied. After the period of inhibition all the rabbits returned to approximately the initial rate of release. (3) Changes in lighting Nine rabbits were subjected to an abrupt change in conditions of illumination on twenty-three occasions. In none of the rabbits did the change result in a maintained difference in the rate of 131I release from the thyroid, which indicates that there is no sustained effect of illumination on thyroid activity in the rabbit. However, in seven experiments on three rabbits an inhibitory response lasting for 1-55 hr followed a change in lighting conditions (in four cases the change was from permanent light to darkness, and in three cases a change from darkness to light). In ten experiments on five rabbits no change in the rate of release of thyroidal 1311 was observed, and in six experiments on six rabbits the responses were of doubtful significance. B. Effects of physical stress (1) Haemorrhacge Six experiments have been performed on 6 rabbits. All animals showed an inhibition of the release of 131J from the thyroid gland, lasting hr (Fig. 2). (2) Anaesthesia Four animals were anaesthetied (open ether, together with intravenous chloralose and urethane). In two, no inhibition, in the other two a partial inhibition only, was observed over the subsequent 1-2 days. (3) Laparotomy Four rabbits were subjected to laparotomy under ether anaesthesia, the intestines being exposed for 15, 25, 25, and 35 min respectively. Each animal showed a complete inhibition of 131I release from the thyroid lasting from hr (Fig. 3). (4) Intraperitoneal injection of turpentine 1 ml. of turpentine was injected intraperitoneally in 4 rabbits. All four showed complete inhibition of the release of 131I lasting from 17 to 63 hr (Fig. 4).

4 32 K. BROWN-GRANT, G. W. HARRIS AND S. REICHLIN (5) Subcutaneou,s abscess During the course of an experiment a rabbit developed a large subcutaneous abscess at the site of injection of arachis oil. The release of thyroidal 15 1 _- Haemorrhage Rabbit.591, release curve, 2,uc I'l, 22. vi. 53 C 4) 5 _- Fig. 2. I I fi I Time (hr) The effect of haemorrhage (removal of blood, 15 ml./kg body weight) on the release of 131I from the thyroid gland of the rabbit. ūe 2 I- Rabbit 455, release curve, 21c "'I, 9. iii S- Laparotomy u 1 t 5 I I (, Time (hr) Fig. 3. The effect of surgical trauma (laparotomy) on the release of 1311 from the thyroid gland of the rabbit was inhibited at the time that the abscess became prominent, and remained inhibited for 8- days. Two days after surgical drainage of the abscess the previous rate of release of radio-iodine was resumed (Fig. 5).

5 STRESS AND THYROID ACTIVITY 33 C. Experiments on wild rabbits Kracht & Kracht (1952) have reported that wild rabbits brought into captivity develop a state of hyperthyroidism (exophthalmos, weight loss and muscular weakness) and die within 3 weeks. In view of the.se results experi- 5 Rabbit 642, release curve,.e E 4i C m U 4 F- 3 H- 1 ml. turpentine ip. I\ -he u v 2 1- I Time (hr) Fig. 4. The effect of an intraperitoneal injection of 1 ml. turpentine on the release of 131I from the thyroid gland of the rabbit. *- Abscess.E 1 Abscess drained Rabbit 553, release curve, 2iLc I'll, 9. vi Body weight (kg) '73 1F82 3 I Time (hr). Fig. 5. The effect of surgical drainage of an abscess on the rate of release of 1311 from the thyroid gland, and on the body weight, of a rabbit. ments were conducted on five wild rabbits. The animals, two male and three female, were ferreted and captured in nets near Dorking, Surrey, during the month of July. After transport to the laboratory they were maintained under 3 PHYSIO. CXXVI

6 34 K. BROWN-GRANT, G. W. HARRIS AND S. REICHLIN conditions similar to those of the tame rabbits. All five animals lost weight during the first week of captivity, but during the succeeding 6 weeks four out of the five maintained or increased their body weight. No exophthalmos or muscular weakness ascribable to a hyperthyroid state was observed, although the transient widening of the palpebral fissure and proptosis, similar to that which occurs during fright in tame rabbits, was noticed when the animals were handled or disturbed. The fact that wild rabbits will live for long periods in captivity, though not breed, has been noticed by previous workers (J. Hammond senr., personal communication). Three of the five rabbits were injected, on one or more occasions, with radioiodine and the rate of release of 131J from the thyroid gland measured as for the tame animals. During the course of four such experiments the animals were subjected to restraint and an inhibition of the rate of release of thyroidal 131I was observed to follow the restraint stimulus on three occasions. During the fifth experiment an animal was placed for 46 hr in close proximity to a ferret (separated only by a wire mesh). No effect on the release of 131I from the thyroid gland was seen. D. Mechanism of thyroid inhibition by stress stimuli (1) Cervical sympathectomy Although there is good evidence that the thyroid gland is not supplied by secretomotor fibres (see Harris, 1948) the possible role of the nerve supply to the blood vessels of the thyroid gland in the emotionally induced thyroid inhibition was investigated. Two rabbits were subjected to the usual restraint 2-3 weeks after stellate ganglionectomy and avulsion of a portion of the cervical sympathetic chain. The inhibitory response of these animals was in every way typical of normal rabbits (Fig. 6). (2) The adrenal gland The procedures found to give inhibition of thyroid activity are those which, in all probability, lead to an increased secretion of adrenaline and of adrenal cortical hormones. Since there are data in the literature that injection of adrenaline or adrenal cortical steroids influences thyroid activity it became necessary to determine, first, the effect of these substances on the rate of release of 131I from the thyroid gland of the normal rabbit, and secondly the effect of stress stimuli on the rate of release of thyroidal radio-iodine in the adrenalectomied rabbit. Injection of adrenaline. Nine experiments have been performed on eight rabbits in which adrenaline ['Hyperduric Adrenaline', (adrenaline in the form of the salt of mucic acid), Allen and Hanburys Ltd., London] was injected subcutaneously in divided doses of 5-1,ug/day for 2-6 days while the release of 1311 from the thyroid gland was observed. In four cases control

7 STRESS AND THYROID ACTIVITY 35 injections of the diluent were administered twice daily for 1 or 2 days preceding and following the period during which adrenaline was injected. In no case did the control injections alter the rate of release of thyroidal iodine, but in every case the injection of adrenaline was seen to result in inhibition in the release of In seven of the nine experiments, however, the inhibitory effect was maintained for only hr, although injection of adrenaline was continued for periods up to 131 hr \ Rabbit 513, release curvve, Restraint ~stellate removedganjglia 4. iv uc "II, 19. iv.53 3 o ~~~~ 2 1 \ Fig. 6. I I I I II 4 8 Time (hr) The effect of restraint on the release of 131I from the thyroid gland of a rabbit 19 days after removal of the stellate ganglia. Injection of adrenocorticotrophic hormone (ACTH) or adrenal cortical steroids. Subcutaneous injection of ACTH or 11-dehydro-17-hydroxycorticosterone (cortisone) has been shown to inhibit the release of thyroidal 131I (Brown- Grant, Harris & Reichlin, 1954). Adrenalectomied rabbits. Ten adrenalectomied rabbits, maintained by administration of constant doses of cortisone (-2-.6 mg subcutaneously, twice daily), were subjected to restraint or subcutaneous faradism while the rate of release of 131I from the thyroid gland was studied. Nine rabbits showed a definite inhibition of the release of thyroidal radio-iodine, lasting from 29 to 58 hr, on at least one occasion (Fig. 7). The inhibition of 1311 release was, however, less constantly elicited by stress stimuli in the adrenalectomied rabbits than in normal rabbits. One adrenalectomied animal failed to respond on two occasions, and two others failed to respond on one occasion. 3-2

8 36 K. BROWN-GRANT, G. W. HARRIS AND S. REICHLIN The inhibition of 131I release from the thyroid gland of the adrenalectomied rabbit following emotional stress was otherwise identical with the responses in the normal. -6 mg cortisone twice daily 15 Restraint Rabbit 477, adrenalectomied, 23. iii. 53. N ~~~~~~~~~Releasecurve,.' 4Lc 1311, 13. vi. 53 vc 1 5 l Time (hr) Fig. 7. The effect of restraint on the release of a3"i from the thyroid gland of a rabbit 3 months after adrenalectomy, and while on constant maintenance therapy with cortisone. DISCUSSION The present results demonstrate that the rate of release of 131I from the thyroid gland of the rabbit is inhibited by stress stimuli. The question arises as to whether the decreased rate of release observed could be explained on the grounds of increased reaccumulation of 131I derived from degraded hormone, or whether it represents a true decrease in thyroid activity (decreased rate of loss of 131I-labelled hormone). It would seem valid to interpret the observed change in terms of decreased thyroid secretion for the following reasons. (i) In normal rabbits only 1% of the 131I leaving the gland as radioactive hormone is reaccumulated (Brown-Grant, von Euler, Harris & Reichlin, 1954). (ii) In many experiments stress stimuli resulted in complete inhibition of the loss of thyroid It is very unlikely that this can be explained in terms of a changed rate of reaccumulation alone. (iii) The protein-bound 1311 in the blood of the rabbit is decreased by both physical and emotional stress stimuli (Brown-Grant, unpublished data). (iv) There is much evidence in the literature that conditions of stress are in fact associated with a decrease of 131I uptake by the thyroid, which would tend to reduce the reaccumulation of 131I (see below).

9 STRESS AND THYROID ACTIVITY 37 The fact that emotional stimuli influence thyroid activity indicates that the central nervous system exerts a regulating influence on the thyroid gland. The latent period of the response following emotional stress (less than 3 hr) is of the same order of magnitude as that seen following thyroxine or TSH administration, or exposure to a cold environment (Brown-Grant, von Euler, Harris & Reichlin, 1954). Complete or partial inhibition of the release of thyroidal 131J was observed to follow emotional stress stimuli. It is of interest that the rate of release of 131J from the thyroid often showed a return to that of the initial control period before the cessation of the stress. This 'escape' is most likely due to the animals becoming 'accustomed' to the stressing procedure, since the overt behaviour of the animals change, suggesting that the procedures had become less disturbing. Furthermore, it was found that alternation of two different stress stimuli would prolong the inhibitory effect on the thyroid as compared with the effect produced by one constant stimulus. Although abrupt changes in the conditions of lighting are followed by a temporary reduction in the rate of release of 131I from the thyroid gland, it is clear that it is the change in the lighting, rather than light or darkness per se, which affects thyroid activity. The rate of release of L311 from the thyroid eventually returned to the same level whether the animals were kept in permanent light or in almost permanent darkness. These findings are contrary to those of Puntriano & Meites (1951) who reported that continuous darkness for 28 days increased thyroid activity in the mouse. The depression of thyroid activity caused by emotional stress in the rabbit appears to be one of several responses to such stimuli in this species. Apart from the well-known activation of the sympathetic nervous system and adrenal medulla, restraint and other emotional stimuli have been shown to result in hypothermia (Grant, 195), inhibition of a water diuresis (Brod & Sirota, 1949) and an increased discharge of adrenocorticotrophic hormone (Colfer, de Groot & Harris, 195) in the rabbit. The observation in the present work that emotional stress results in decreased thyroid activity in the rabbit is contrary to the findings of Kracht & Kracht (1952). Their conclusion that a state of hyperthyroidism develops in wild rabbits under conditions of captivity is based on indirect and histological criteria rather than actual measurement of thyroid activity. A small group of wild rabbits captured and kept in this laboratory have failed to show maiifestations similar to those described by these authors. Also they responded to the emotional stimulus of restraint in the same way as the domestic rabbit, that is with a decreased rate of release of 13II-labelled hormone from the thyroid. The effect of physical trauma or stress on thyroid activity in the rabbit is very similar to that elicited by emotional stress. Following laparotomy, haemorrhage or intraperitoneal injection of turpentine a definite inhibition in

10 38 K. BROWN-GRANT, G. W. HARRIS AND S. REICHLIN the rate of release of 131J from the thyroid gland was observed in all fourteen experiments. The latent period of the inhibitory response was short, being less than 3 hr, and the duration in ten cases out of the fourteen was between 24 and 48 hr. Most previous workers have reported that physical stress of various types reduces 1311 uptake by the thyroid. Injection of typhoid vaccine, trauma, fasting, cold, heat (Williams, Jaffe & Kemp, 1949), injection of formalin (Paschkis, Cantarow, Eberhard & Boyle, 195), injection of formalin, cordotomy (Bogoroch & Timiras, 1951), anoxia, starvation, vitamin deficiency, nephrectomy (van Middlesworth & Berry, 1951), tourniquet shock (Hamolsky, Gierlach & Jensen, 1951) have all been reported to decrease the uptake of 131I by the thyroid gland of the rat. However, measurements of 131I uptake by the thyroid under conditions of stress do not necessarily give a specific index of thyroid activity, since stress (Bogoroch & Timiras, 1951) and the injection of cortisone (see Ingbar, 1953) lead to an increased renal clearance of iodide. The amount of 1311 present in the thyroid gland at a given time after injection will also depend on the turn-over rate, and this factor may have to be considered in interpreting some of the data in the literature (e.g. that of Wase & Repplinger, 1953). In the present study large daily doses of adrenaline were found to decrease the rate of secretion of '311-labelled thyroid hormone in the rabbit. Much contradictory evidence exists in the literature regarding the effect of adrenaline on thyroid activity. Soffer, Volterra, Gabrilove, Pollack & Jacobs (1947) found hyperplasia of the thyroid following adrenaline injections in the dog. Soffer, Gabrilove & Jailer (1949) described a decrease in the 24 hr uptake of radio-iodine in rats following adrenaline, whereas Williams, Jaffe & Kemp (1949) found that the 24 hr uptake of 131I in rats was increased by adrenaline, although the 1 and 2 hr uptake and the serum protein-bound 1311 were decreased. Botkin & Jensen (1952) similarly report a decrease in the 131I uptake and serum protein-bound radio-iodine in rats. Reiss (1953) also describes a reduced 131I uptake by the thyroid in rabbits following adrenaline administration, although Reiss, Forsham & Thorn (1949) have shown that the 1311 uptake of the human thyroid is increased by this hormone. It is impossible at the moment to harmonie these findings, though the bulk of the evidence suggests that adrenaline exerts an inhibitory effect on thyroid activity. The mechanism by which conditions of stress lead to decreased activity of the thyroid gland in the rabbit has been investigated. The fact that interruption of the cervical sympathetic nerves did not abolish this response makes it seem unlikely that the effect is mediated by a direct nerve supply to the thyroid gland. Since both the adrenal medulla and adrenal cortex are well known to be activated by stresses, and since injections of ACTH or cortisone (Brown-Grant, Harris & Reichlin, 1954) and adrenaline result in decreased secretion of thyroid hormone in the rabbit, the possibility existed that the

11 STRESS AND THYROID ACTIVITY 39 effect of stress on the thyroid gland was secondary to increased secretion by the adrenal. However adrenalectomy did not abolish the inhibitory response of the thyroid to stress stimuli. This finding is in harmony with that of Hamolsky et al. (1951) who found that depression of 131J uptake occurs in the adrenalectomied, as well as the normal, rat in response to stress. Since neither denervation of the thyroid (stellate ganglionectomy) nor adrenalectomy prevents the response of the thyroid gland to emotional stress, the most likely hypothesis is that such responses are due to reduction in the secretion of thyrotrophic hormone from the anterior pituitary gland. SUMMARY 1. Emotional stress produced in rabbits by subcutaneous faradism, restraint, or abrupt changes in environmental lighting induces a prompt inhibition of 1-2 days' duration in the release of 131I-labelled hormone from the thyroid gland. 2. Similar effects on thyroid activity are also produced by physical traumata (haemorrhage, surgical operations, injection of turpentine). 3. Neither denervation of the thyroid gland (stellate ganglionectomy) nor adrenalectomy prevents the inhibition of release of thyroid hormone that follows emotional stress. 4. These findings support the view that the central nervous system can influence thyroid activity, and that this influence is mediated through alterations in the secretion of thyrotrophic hormone from the anterior pituitary gland. Our gratitude is due to Mr W. Piper and Mr G. J. Christofinis for their valuable technical assistance. We should also like to acknowledge the help given by Mr H. V. Thompson and his staff of the Ministry of Agriculture and Fisheries in obtaining wild rabbits. The expenses of this research were in part defrayed by grants (to G. W. H.) from the Medical Research Council and from the Foulerton Gift Fund of the Royal Society. Grateful acknowledgements are also due to the Medical Research Council for the grant of a Research Studentship (to K. B.-G.), and to the Commonwealth Fund for the grant of a Fellowship (to S. R.) during the tenure of which this work was carried out. REFERENCES BOGoRocH, R. & TIMIRAS, P. (1951). The response of the thyroid gland of the rat to severe stress. Endocrinology, 49, BOTKIN, A. L. & JENSEN, H. (1952). The effect of epinephrine and thyrotropin on thyroid function in rats. Endocrinology, 5, BROD, J. & SIROTA, J. (1949). Effects of emotional disturbance on water diuresis and renal blood flow in the rabbit. Amer. J. Phy8iol. 157, BROWN-GRANT, K., von EULER, C., HARRIS, G. W. & REICHLIN, S. (1954). The measurement and experimental modification of thyroid activity in the rabbit. J. Physiol. 126, BROWN-GRANT, K., HARRIS, G. W. & REIcHLIw, S. (1954). The influence of the adrenal cortex on thyroid activity in the rabbit. J. Phy8iol. 126, COLFER, H. F., DE GROOT, J. & HARRIS, G. W. (195). Pituitary gland and blood lymphocytes. J. Phy8iol. I11, GRANT, R. (195). Emotional hypothermia in rabbits. Amer. J. Phy8iol. 16,

12 4 K. BROWN-GRANT, G. W. HARRIS AND S. REICHLIN HAMOLSKY, M. W., GIERLACH, Z. S. & JENSEN, H. (1951). Uptake and conversion of radioactive iodine ('3'I) by thyroid gland in vivo and in vitro in tourniquet shock in rats. Amer. J. Physiol. 164, HARRIS, G. W. (1948). Neural control of the pituitary gland. Physiol. Rev. 28, INGBAR, S. H. (1953). The effect of cortisone on the thyroidal and renal metabolism of iodine. Endocrinology, 53, KRACHT, J. & KRACHT, U. (1952). Zur Histopathologie und therapie der Schreckthyreotoxikose des Wildkaninchens. Virchows. Arch. 321, VAN MIDDLESWORTH, L. & BERRY, M. M. (1951). Iodide metabolism during anoxia, nephrectomy, trauma, avitaminoses and starvation in the rat. Amer. J. Physiol. 167, PASCHKIS, K. E., CANTAROW, A. H., EBERHARD, T. & BOYLE, D. (195). Thyroid function in the alarm reaction. Proc. Soc. exp. Biol., N. Y., 73, PUNTRIANO, G. & MEITES, J. (1951). The effects of continuous light or darkness on thyroid function in mice. Endocrinology, 48, REISS, M. (1953). Untersuchungen iiber Psycho-Endokrinologie. Schwei. Arch. Neurol. Psychiat. 71, REISS, R., FORSHAM, P. H. & THORN, G. W. (1949). Studies on the inter-relationship of adrenal and thyroid function. J. clin. Endocr. 9, 659. SOFFER, L. J., GABRILOVE, J. L. & JAILER, J. W. (1949). Role of adrenalin uptake of 131I by the thyroid following parenteral administration of epinephrine. Proc. Soc. exp. Biol., N. Y., 71, SOFFER, L. J., VOLTERRA, M., GABRILOVE, J. L., POLLACK, A. & JACOBS, M. (1947). Effect of iodine and adrenalin on thyrotropin in Graves' disease and in normal and thyroidectomied dogs. Proc. Soc. exp. Biol., N. Y., 64, WASE, A. W. & REPPLINGER, E. (1953). The effect of thermal burns on the thyroid activity of the rat. Endocrinology, 53, WILLIAMS, R. H., JAFFE, H. & KEMP, C. (1949). Effect of severe stress upon thyroid function. Amer. J. Physiol. 159,