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 Medicine 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 hyperthyroidism. medullary and thyroid hormones 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 hormone 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 glands (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 catecholamine action. For this reason opportunities offered by the adrenergic block- Protected by copyright. it is possible to alleviate many of the symptoms ing drugs 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 catecholamines 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 neurotransmitters in adrenergic nerves, further links in this field of endocrinology. have direct effects upon cardiac contraction and produce metabolic changes in fat, liver 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 adrenal medulla 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 lipolysis glycogenolysis 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 weight loss, heat intolerance, sweating, palpitations, 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 receptor, 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 adrenaline, noradrenaline, adrenal medullary and thyroid hormones. 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 adipose tissue. 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 heart (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 carbohydrate and lipid metabolism by series of agents such as pronethalol, propranolol insulin 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 enzyme 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 glucose-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 fatty acid (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 sodium conductance IINASE KINASE explosive on September 28, 2021 by guest. INACTIVE ACT YE across the cell 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 organ 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 basal metabolic rate, decreased glucose gree of wasting and weakness in thyrotoxicosis tolerance and raised plasma FFA, decreased are those which contain the greatest number of cholesterol but raised phosphate levels and an mitochondria (Hoch, 1962; Ramsay, 1966). The