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Home , Adrenal insufficiency, Adrenal medulla, Thyroid, Thyroid adenoma, Thyroid hormones, Triiodothyronine

med. J. (May 1968) 44, 377-384.

Postgrad. Postgrad Med J: first published as 10.1136/pgmj.44.511.377 on 1 May 1968. Downloaded from

Thyroid and adrenal relationships VICTOR PARSONS IAN RAMSAY D.M., M.R.C.P. M.D., M.R.C.P., M.R.C.P.E. Senior Lecturer in Lecturer in Medicine Department of Medicine, King's College Hospital Medical School, Denmark Hill, London, S.E.5 Summary of this relationship in various disease states such A brief review of the actions of adrenal as hypo- and . medullary and is presented Over the last 10 years more light has been and the ways in which they interact are examined. shed on this problem and the aim of this re- It is concluded that thyroid produces view is to concentrate on the cellular mechanisms the necessary intracellular environment without which seem to provide a more logical explan- which the steady state and emergency actions ation for the interaction of the hormones from of cathecholamines would be vitiated. In hyper- the two different (Ellis, 1956; Harrison, thyroidism the increased concentration of thy- 1964; Waldstein, 1966; Svedmyr, 1966). Follow- roid hormones results in a lowering of the thres- ing on from this hypothesis come the therapeutic hold for action. For this reason opportunities offered by the adrenergic block- Protected by copyright. it is possible to alleviate many of the symptoms ing which have been proved so useful in of thyrotoxicosis by means of drugs which block the early management of thyrotoxicosis. ,3-adrenergic receptors. Attention is also drawn to the simultaneous The mode of action of occurrence of thyroid and adrenal disease, in Catecholamines have a variety of effects. They the hope that this will encourage the search for act as in adrenergic , further links in this field of . have direct effects upon cardiac contraction and produce metabolic changes in , and Introduction muscle cells (Fig. 1). The relationship between the thyroid and the adrenal glands has interested surgeons, physi- catecholamines cians and pharmacologists for many years. The effect subject can be examined under two broad head- calorigenlcca_origenic actionacti adenyl cyclase I/inotropic http://pmj.bmj.com/ ings; first, the relationship between the hor- increased 02uptake 1 c mones of the and the thyroid, cyclic-3'5-'AMP/ contraction/relaxation and secondly, the coincidence of separate thy- roid and adrenal disease. lipase acivation phosphorylase activation ycogennthesase lpolyss lyoolys acivation Adrenal medullary and thyroid relationships Patients with often phaeochromocytoma pre- I l on September 28, 2021 by guest. sent with symptoms which are almost identical FFA mobilization lactate production to those of hyperthyroidism, namely , heat intolerance, sweating, , anxiety FIG. 1. Some consequences of catecholamine action. and tremor (Gifford et al., 1964). Hyperthyroid patients, on the other hand, may sometimes In 1948 Ahlquist proposed that the difference show acute psychiatric features which mimic the in the action of catecholamines on various tissues toxic catecholamine effects of monoamine oxi- could be explained by the presence of two sep- dase inhibiting drugs (Dewhurst, 1965). These arate types of , a and /3 (Ahlquist, 1967; similarities have led to the formation of many Furchgott, 1967). a-Receptors, which respond in hypotheses about the relationship between the diminishing order to , noradrenaline, adrenal medullary and . The phenylephine and isoproterenol and produce difficulty in reconciling and in amalgamating the effects such as arteriolar constriction, can be different theories lies in the probable variability blocked by ergot and phentolamine. /8-Receptors, Victor Parsons and Ian 378 Ramsay Postgrad Med J: first published as 10.1136/pgmj.44.511.377 on 1 May 1968. Downloaded from on the other hand, respond primarily to . It has been shown that the isoproterenol, followed by adrenaline, nor- release of free fatty acids from myocardial adrenaline and phenylephrine. Ergot and phento- triglyceride occurs quite independently of the tolamine have little, if any, effect upon /-recep- mechanical activity of the (Challoner & tor responses (e.g. bronchial muscle relaxa- Steinberg, 1965). Thus, in addition to the regula- tion), but these can be blocked by a different tion of and lipid by series of agents such as pronethalol, and other hormones, there appears to be and dichloroisoproterenol. Ahlquist's rather tidy an adrenergic control which can be rapidly original concept has unfortunately had to be called into play during periods of increased de- modified by the finding of both types of recep- mand. As a consequence of the fluxes of glu- tor is smooth muscle and it is possible that cose and FFA which it produces, insulin secre- there is more than one kind of 8/-receptor (Furch- tion is reduced and further glycogen and gott, 1967). triglyceride storage is prevented (Himms-Hagen, In recent years the importance of adenosine- 1967). 3',5'-phosphate (cyclic-3',5'-AMP) as an intracel- Studies of the effects of adrenaline on the lular trigger mechanism activated by catechola- perfused rat heart have shown a rise in cyclic- mines has been emphasized (Sutherland & Robi- 3',5'-AMP at the start of inotropic contraction, son, 1966). The concentration of this potent sub- before the concentration of phosphorylase A and stance depends on the activity of adenyl cyclase of other breakdown products of glycogenolytic for its formation and of phosphodiesterase for metabolism rises (Williamson, 1966). its inactivation. Thyroid hormone increases the The actions of /-adrenergic blocking agents formation of adenyl cyclase and catecholamines on the metabolic effects of catecholamines have have an activating effect on the so that not only helped to clarify the role of adrenergic either of them, or both, can cause an increase mechanisms, but have also proved useful inProtected by copyright. in the amount of cyclic-3',5'-AMP (Brodie et al., certain clinical situations characterized by cate- 1966). A sudden increase in activity of adenyl cholamine overactivity. These /3-blocking drugs cyclase triggers off a metabolic cascade (Fig. 2) decrease cardiac contractile force, cardiac phos- which, by activating liver and muscle phosphory- phorylase activation, muscle and liver glycogeno- lase, causes the production of -l-phosphate lysis and adipose tissue lipolysis, though it is from glycogen (Bowness, 1966) and by activating possible that not all the effects are mediated adipose tissue lipase results in the breakdown of through the adrenergic receptors (Mayer, Wil- triglycerides to free (FFA) and glycerol liams & Smith, 1967). The /3-blockers give addi- (Rizack, 1964; Brodie et al., 1966). tional evidence that the inotropic effect of catecholamines on the heart is mediated via cyclic- OTHER HORMONES 3',5'-AMP. Pronethalol, in a concentration which ACTH by itself produced no metabolic in the T METHYL NICOTINIC changes GLUCAGN AEE ACID both the rise http://pmj.bmj.com/ receptor'[XANTHINIESj heart, prevented cyclic-3',5'-AMP THYROID?1wm block and the when adrenaline was HORMONE' -?"]^^Sblocker4 inotropic response D ADENYL CYCLASE PHOSPHODIESTERASE added (Sutherland & Robison, 1966). The effect C-synthesis- STEROIDT+ ? HORMONE AT P upon the inotropic response may be mediated CYCLIC-3'5AM P 5-A M P by alterations in the movement of calcium ions +ATP ATP (Koch-Weser & Blinks, 1963), or by a local anaesthetic property of /-blockers which reduces " INACTIVE ACTIVE the increase of conductance IINASE KINASE explosive on September 28, 2021 by guest. INACTIVE ACT YE across the membrane at the time of de- LIPASE UPASE LPAE PHOSPHORYASE PIOSPINORLASE polarization (Morales-Aguilera & Vaughan Wil- B. A liams, 1965). TRIOLYCERIDES FFA GLYCOEN GLUCOSE IP. The mode of action of thyroid hormones 'Investigating the mechanism of action of the FIG. 2. The actions of catecholamines, other hormones thyroid hormones is like peeling an onion. Not and various drugs on carbohydrate and fat metabolism. only may it bring tears to the eyes, but, after such successful step, one is left with the layer It is now known that triglycerides as well as beneath' (Wolff & Wolff, 1964). glycogen are stored in skeletal (Brodie et al., The thyrotoxic state demonstrates admirably 1966) and cardiac muscle and that they are sub- the protean actions of the thyroid hormones, for ject to the same regulatory mechanisms as in no tissue is spared and the symptoms emanate Thyroid and adrenal relationships 379 Postgrad Med J: first published as 10.1136/pgmj.44.511.377 on 1 May 1968. Downloaded from from every in the body. Thus, there is thyrotoxicosis has been demonstrated by the weight loss and heat intolerance, palpitations and finding of loose coupling in the muscle mito- breathlessness, muscular weakness, anxiety and chondria of these patients (Hoch, 1962). More- looseness of the bowels. Investigations show a over, the muscles which display the greatest de- raised , decreased glucose gree of wasting and weakness in thyrotoxicosis tolerance and raised plasma FFA, decreased are those which contain the greatest number of but raised phosphate levels and an mitochondria (Hoch, 1962; Ramsay, 1966). The increase in the urinary excretion of hydroxypro- uncoupling theory is attractive, but thyroid hor- line, indicating that there is hardly a single mone may have some other important actions. metabolic process which is not affected by excess For instance there may be an alteration in en- thyroid hormone. zyme activity, such as the increase in adenyl Thyroid hormone may act on several of the cyclase in adipose tissue (Brodie et al., 1966), cell's control mechanisms and these vary from and structural changes which produce swelling tissue to tissue. The supply of substrate may be in the mitochondria. On the other hand, Tata changed by alterations in membrane perme- and his colleagues (1963) have shown that the ability and intracellular transport mechanisms. thyroxine-induced incorporation of amino acids The substrate is then subject to any modifica- can take place even in tissues where no depres- tions in the concentration of , their in- sion of the P:O ratio can be demonstrated. hibitors and facilitators, working in the presence These rapid and toxic effects on the mito- of nucleotides, cofactors and ions; the cellular chondria are produced by very high levels of processes may also be affected by the removal thyroid hormone. Slower changes also take place of the products of metabolism by oxidative phos- through the control of the rate of synthesis of cellular constituents. Tata work-

phorylation (Racker, 1965). specific (1964), Protected by copyright. By examining substrate and enzyme concen- ing on the cellular changes induced by the intro- trations under steady conditions some idea can duction of thyroid hormones in thyroidectomized be gained as to the critical 'throttle steps' in rats and the induction of in cellular metabolism, and it is these points amphibia, has shown the sequential stimulation which have attracted particular attention in the of ribonucleic acid (RNA) and synthesis search for the mode of action of thyroid hor- in various key tissues. The first change noted mones. The control systems are so interconnected was an increase in the synthesis of nuclear RNA, that it is difficult to determine any primary site followed by magnesium-activated RNA poly- of action. Interest has ranged from a study of merase, leading to an accumulation of newly transport changes, uncoupling of oxidative phos- formed ribosomes and polysomes which turn out phorylation, chelation of ions and synthesis of freshly labelled protein from labelled amino enzyme (Tapley, 1964). acids. These changes were also associated with Hoch (1962, 1968) postulated that, because the aggregation and synthesis of the

phospho- http://pmj.bmj.com/ the oxidation of so many substrates is stimulated lipid matrix of newly formed ribosomes (Tata, in thyrotoxicosis, the final common pathway for 1967). Thus thyroid hormones seem to act in a the action of thyroid hormones must lie within similar fashion to and testo- the mitochondria. It is in the mitochondria that sterone, in that there is an increased prolifer- three (ATP) molecules are ation of microsomal membranes at the same formed for each of oxygen utilized, giving time as hormone-induced increases in cytoplasmic a phosphate: oxygen (P:O) ratio of 3. When RNA and protein synthetic activity in vivo. A

this occurs the system is said to be 'tightly summary of the possible sites of thyroid hor- on September 28, 2021 by guest. coupled'. If less ATP is produced for each atom mone action is shown in Fig. 3. of oxygen consumed, the system is regarded, As has been mentioned already, it is difficult according to degree, as 'loosely coupled' or 'un- to disentangle the normal actions of the thyroid coupled'. Thyroxine in various concentrations hormones from those that occur during thyro- has been shown to produce both loose coupling toxicosis. In the latter situation, toxic effects may and uncoupling. The sites of action are mainly override normal control function; for example, at the adenosine diphosphate (ADP), ATP and the transport of glucose into cells is increased Pi-ATP exchange points and also at the first (Danoff & Laster, 1962), intestinal mobility is phosphorylation site (flavoprotein-diphosphopy- affected (Johansson, 1966), sodium transport is ridine nucleotide), which has been shown to be heightened (Green & Matty, 1963), the renal very sensitive to inhibition by thyroxine (Chance handling of water and phosphate is altered (Par- & Hollunger, 1963). The possibility that an effect sons & Anderson, 1964) and there is a change on oxidative phosphorylation is important in in the cellular response to, and fixation of, di- 380 Victor Parsons and Ian Ramsay Postgrad Med J: first published as 10.1136/pgmj.44.511.377 on 1 May 1968. Downloaded from goxin (Doherty & Perkins, 1966). Whether these of catecholamines in the plasma have not re- and many other metabolic changes are linked vealed abnormal amounts in uncontrolled hyper- to altered protein synthesis, to mitochondrial thyroidism, but increased concentrations may be swelling or to uncoupled oxidation, it is im- recorded in the same patients during the severe possible to say on present evidence. of a thyrotoxic crisis (Maddock, Pedersen & Coller, 1937). Alterations in catecholamine destruction. The possibility must be raised that the observed potentiation of the calorigenic effects of infused catecholamines could be due to a decrease in their inactivation by monoamine oxidase (MOA) or by catechol-ortho-methyl transferase (COMT). However, a study of the disposal of infused catecholamines in euthyroid and - treated individuals revealed no difference be- tween the two groups; and a study of 3H-labelled adrenaline and metadrenaline in the tissues of normal and thyroxine-treated rats showed simi- lar concentrations in both (Svedmyr, 1966). It therefore appears that the potentiation of cer- tain effects of catecholamines after the admini- stration of thyroid hormones must be due to changes in the cell, rather than to re- receptor Protected by copyright. duced uptake or breakdown of catecholamines locally. Possible intracellular potentiating mechanisms. Rats whose adrenergic responses have been blocked behave in a similar fashion to adrenalec- tomized animals when faced with external stimuli which demand an increased expenditure of energy (Brodie et al., 1966). Their metabolism under basal conditions is virtually normal, but if exposed to cold or muscular work neither of FIG. 3. Composite hypothesis for the possible sites of the two groups of rats can bring about pilo- action ofthyroid hormones. (A) Ion transport via ATPase erection, or shivering, nor can alteration. (B) Mitochondrial permeability actions. (C) they produce the normal or

lipolytic glyco- http://pmj.bmj.com/ Uncoupling of oxidative phosphorylation. (D) Enhance- to ment of lipolytic enzymes. (E) and (F) Alterations in genolytic responses adrenaline (Bray & Good- protein synthesis via changes in RNA and ribosomal man, 1965; Bray, 1966). All these changes are structural synthesis. (I) Inhibitory sites of action of partly restored by the administration of aldo- citrate and FFA on the Embden-Meyerhof pathway. sterone as well as and it is, there- fore, thought that normal ionic concentrations in Catecholamine and thyroid hormone interactions sympathetic receptors are important for proper in hyper- and function. Alterations in catecholamine release and pro- The experimental situation in these rats is on September 28, 2021 by guest. duction. Investigations into the possibility of an very similar to that of patients in myxoedema increase in the production and release of cate- coma who are unable to conserve or generate cholamines in the hyperthyroid state have been heat. Studies show that adipose tissue from hypo- carried out, but have been generally negative thyroid rats has a poor lipolytic response to the (Wiswell et al., 1963; Harrison et al., 1967). action of adrenaline, while the converse is true Reflex stimuli, such as hypoglycaemia and of tissue from hyperthyroid animals (Debons & abrupt postural changes, which normally release Schwartz, 1961; Felt et al., 1962). Because thy- adrenaline and noradrenaline respectively, have roid hormones increase the amount of adenyl not been shown to increase the output of these cyclase in adipose tissue (Brodie et al., 1966), hormones in either hyper- or hypothyroidism a normal quantity of circulating catecholamines (Harrison, 1961) and it has been suggested that is capable of enhancing the production of cyclic- in both situations the adrenal medulla may be 3',5'-AMP. Likewise it has been shown (Horn- under-reactive (Leak et al., 1963). Estimations brook, Quinn & Siegel, 1965) that thyroid ad- and adrenal 381

Thyroid relationships Postgrad Med J: first published as 10.1136/pgmj.44.511.377 on 1 May 1968. Downloaded from ministration potentiates the catecholamines' effect which is especially liable to occur in a thyrotoxic on myocardial glycogenolysis, though it does not patient with dilated peripheral vessels seem to produce any changes in haemodynamic (Leak, 1963). Reserpine has also been used responses (Aoki et al., 1965). (Canary et al., 1957; Wayne, 1960). It depletes A summary of possible relationships is shown both central and peripheral nervous tissue of in Fig. 4. catecholamines, but it tends to produce depres- sion and several features of the carcinoid syn- drome have been reported following its use in high dosage (Blumenthal, Davis & Doe, 1965). More recently attention has been drawn to blockade of the 8f-adrenergic receptors with pro- nethalol (now withdrawn) and propranalol. Many of the symptoms of thyrotoxicosis can be ameliorated by this means. Tachycardia dim- inishes and occasionally arrhythmias are abolished (Turner, Granville-Grossman & Smart, 1965; Robillard, Klotz & Perrault, 1967), tremor is reduced (Marsden et al., 1968) and features of anxiety and even psychosis may be eliminated (Parsons & Jewitt, 1967). Some workers, on the other hand, have been unable to show that pro- pranalol had any significant effect on haemo- dynamic responses to and amyl nitrate administration in experimental hyperthy- Protected by copyright. roidism (Wilson et al., 1966). One can never be certain, however, that the experimental condi- tions match those exactly of the disease. The major disadvantages of the use of propranalol are its tendency to cause cardiac failure in those with diseased and broncho-constriction in FIG. 4. The triggering action of catecholamines on patients with asthma or chronic bronchitis. How- thyroxine-prepared cycles. mRNA= Messenger ribo- ever, if proper care is taken, propranalol is of nucleic acid. great value in the treatment of severe thyro- toxicosis and crisis, and for the relief of symp- Therapeutic applications toms until anti-thyroid drugs begin to have a Most of the evidence points to an enhancing therapeutic effect. effect by thyroid hormone in thyrotoxicosis on http://pmj.bmj.com/ normal amounts of circulating catecholamines, The association of thyroid with adrenal disease Certainly many of the symptoms of the disease Primary adrenal disease has been associated are explicable on this basis and this has lead to in three different ways with thyroid disorders. the use of adrenergic blockade in treatment. They are: Knight (1945) observed the effects of sym- 1. Thyroid and (Schmidt's pathetic blockade, obtained by spinal anaesthesia, syndrome). on thyrotoxic crisis. He noted prompt and 2. Hyperthyroidism and adrenal insufficiency. dramatic relief of the tachycardia, high oxygen 3. Medullary of the thyroid and on September 28, 2021 by guest. consumption and the hyperthermia. Later others phaeochromocytoma. have tried various sympatholytic drugs in the treatment of thyrotoxicosis. Guanethidine, which Thyroid and adrenal insufficiency (Schmidt's syn- depletes noradrenaline stores in peripheral ad- drome) renergic endings, has been shown to re- Schmidt (1926) was the first to describe two duce the tachycardia without altering the serum patients with Addison's disease and lymphocytic protein-bound concentration (Gaffney, infiltration of the thyroid. Carpenter and his Braunwald & Kahler, 1961; De Groot et al., colleagues have recently (1964) reviewed the lit- 1961; Lee, Bronsky & Waldstein, 1962; Leak, erature on associated thyroid and adrenal failure 1963) and to diminish the eye signs of lid-lag and added a further fifteen cases of their own. and retraction (Sneddon & Turner, 1966). One The connection can probably best be explained of its disadvantages is postural , on an autoimmune basis. It is now generally 382 Victor Parsons and Ian Ramsay Postgrad Med J: first published as 10.1136/pgmj.44.511.377 on 1 May 1968. Downloaded from accepted that the thyroid in thyroi- Urbanski (1967) noted that of the twenty-nine ditis are (Roitt & Doniach, 1960). cases of thyroid carcinoma and phaeochromo- Recently two groups of workers (Blizzard, Chee cytoma he reviewed, the carcinoma was of the & Davis, 1967; Irvine, Stewart & Scarth, 1967) medullary type in twenty. There was a family have demonstrated that a majority of female history of thyroid carcinoma in eight and of patients with idiopathic Addison's disease have familial phaeochromocytoma in eleven. Although antibodies to adrenal tissue; the association was only 11 % of sporadic phaeochromocytomas are not nearly so strong in male patients. Thyroid bilateral (Graham, 1951), the tumours are mul- antibodies were also found in over half Irvine tiple in 46% of familial cases (Nourok, 1964) et al.'s (1967) Addisonian patients, and in a fifth and when associated with thyroid carcinoma as of those of Blizzard et al. (1967). Thus there is many as 76% are bilateral. now some laboratory basis for the previously The association between phaeochromocytoma noted clinical association, but it should be noted and von Recklinghausen's disease is well known that although serological evidence of thyroidities (Glushien, Mansuy & Litman, 1953) and Wil- is common in patients with the con- liams (1965) explains this on the basis of the verse is much rarer (Blizzard et al., 1967; Irvine neuroectodermal origins of both disorders. He et al., 1967). thinks that there is little evidence that medullary carcinoma arises from thyroid epithelial cells and Hyperthyroidism and adrenal insufficiency postulates that its origin, too, may be neuro- Burke & Feldman (1965) reviewed twenty-six ectodermal. The evidence for this is strengthened previously reported cases of hyperthyrodism by his report of two cases of multiple mucosal associated with Addison's disease and added a neuromas in association with medullary thyroid further case of their own, in which they demon- carcinoma and phaeochromocytoma (Williams & strated the presence of anti-adrenal and anti- Pollock, 1966). Urbanski (1967) noted that bothProtected by copyright. thyroid antibodies. Frederickson (1951) dis- thyroid medullary carcinoma and phaeochromo- covered that the incidence of hyperthyroidism cytoma appeared to be inherited as an autosomal in patients with Addison's disease was 4-4 % dominant. which is about ten times higher than would be Williams (1965) warned against confusing the expected in the general population. association of thyroid medullary carcinoma and Once again it seems likely that ultimately the phaeochromocytoma with the better-known mul- connection will be found to lie in the all-embrac- tiple endocrine syndrome; the two ap- ing term of '', for it is now peared to be quite distinct. thought (Lancet, 1967) that long-acting thyroid stimulator, which is a e-globulin, is probably the Acknowledgments cause of thyrotoxicosis and that it behaves as We are grateful to Professor J. Anderson for his encourage- an (Kabir et al., 1966) It is interesting ment and to the National Lending Library for Science and Technology, Boston Spa, Yorkshire, for a Medlars search. to note in this context that two of the patients http://pmj.bmj.com/ in a recent survey of thyroid and adrenal failure had (Carpenter et al., References originally hyperthyroidism AHLQUIST, R.P. (1967) Development of the concept of alpha 1964). and beta adrenotrophic receptors. Ann. N. Y. Acad. Sci. 139, 549. Medullary carcinoma of the thyroid and phaeo- AOKI, V.S., WILSON, W.R., THEILEN, E.O., LUKENSMEYER, W.W. & LEAVERTON, P.E. (1965) Effects of triiodothyron- chromocytoma ine on the haemodynamic response to epinephrine in The association of carcinoma of the thyroid normal subjects. Clin. Res. 13, 398. and phaeochromocytoma has recently been re- BLIZZARD, R.M., CHEE, D. & DAVIs, W. (1967) The incidence on September 28, 2021 by guest. viewed by Williams (1965, 1967) and Urbanski of adrenal and other antibodies in the sera of patients with Williams found that out of the idiopathic adrenal insufficiency (Addison's Disease). Clin. (1967). (1967) exp. Immunol. 2, 19. thirty-five cases published, twenty-six had a car- BLUMENTHAL, M., DAVIS, R. & DOE, R.P. (1965) Carcinoid cinoma of the medullary type. This is normally syndrome following reserpine in thyrotoxicosis. a rare tumour, forming only 6.5 % of all thy- Arch. intern. Med. 116, 819. roid et al., 1961). Histo- BowNEss, J.M. (1966) Epinephrine: cascade reactions and (Woolner glycogenolytic effect. Science, 152, 1370. logically it is solid, not follicular, and is char- BRAY, G.A. (1966) Studies on the sensitivity to catecho- acterized by islands of regular cells with an lamines after . Endocrinology, 79, 554. abundant granular and varying BRAY, G.A. & GOODMAN, H.M. 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