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The Pharmacology of Cortisone, Cortisol (Hydrocortisone)And Their New

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The Pharmacology of Cortisone, Cortisol (Hydrocortisone)And Their New 300 Postgrad Med J: first published as 10.1136/pgmj.34.392.300 on 1 June 1958. Downloaded from THE PHARMACOLOGY OF CORTISONE, CORTISOL (HYDROCORTISONE) AND THEIR NEW ANALOGUES By OLIVER GARROD, M.D., M.R.C.P. Physician, Barnet General Hospital; late Research Fellow, Middlesex Hospital In man the essential functions of the adrenal corticosterone (Compound.B). Though it is the cortex stem from at least two hormones, cortisol predominant glucocorticoid in a number of (hydrocortisone) and aldosterone, these differing mammalian species, in man it is of little importance in their quality of action, mode of secretory for only small amounts are secreted (about i mg. regulation, and probable site of production within a day) (Migeon et al., 1956). the gland. The adrenal sex hormones are of re- latively minor physiological importance and will The Secretion and Metabolism of Cortisol not be considered here. The rate of cortisol secretion is governed by The new synthetic analogues of cortisol are best the level of circulating corticotrophin. Under assessed in relation to the essential duality of quiescent conditions the pituitary corticotrophin function of the adrenal cortex as revealed by the output varies inversely with the concentration of actions of its two principal hormones. The first cortisol in the blood, resulting in a fairly steady function is concerned with a number of homoeo- rate of cortisol secretion from day to day. Over-copyright. static processes and with resistance to stress and riding this basal ' feedback' regulation is the is served by the secretion of cortisol. In the body stress reaction whereby additional corticotrophin cortisol is reversibly interconvertible with corti- is released, probably in response to stimulating sone and is probably the active form of the hor- neurohormones emanating from the hypothalamus mone. Cortisol and cortisone, with their almost and reaching the adenohypophysis by portal identical actions, are called glucocorticoids for venous pathways. Under such extreme stimu- their effects on carbohydrate metabolism. Though lation cortisol secretion may rise to about 250 mg. Ingle (1950) has likened use of the word gluco- a day. corticoid for these steroids to describing an The capacity to suppress corticotrophin secre-' http://pmj.bmj.com/ elephant by the shape of its tail, yet it remains a tion is common to all known glucocorticoids, useful generic term to cover all those diverse natural and synthetic, when given in doses which actions of cortisol and its analogues which seem to 'equal or exceed in equivalence the normal cortisol be inseparably linked with their carbohydrate secretion of about 20 mg. a day. By only partially effects. suppressing corticotrophin secretion smaller doses The second or mineralocorticoid function of the than these merely replace an equivalent amount of adrenal cortex is concerned with the regulation of endogenous cortisol; hence they are usually in- sodium and potassium balance, and depends effective therapeutically in patients with intact on October 1, 2021 by guest. Protected largely on the secretion of aldosterone. A similar adrenal function. In effective doses they cause but less potent mineralocorticoid is desoxycorti- reversible atrophy of the zona fasciculata, whence costerone (DOC) which, though easily synthesized cortisol is mainly derived, which lasts for and used therapeutically as the acetate (DOCA), is many days after treatment has been stopped; secreted only in small amounts by the adrenal hence the importance of slowly tapering off the cortex. Further to their glucocorticoid properties, dose over one to several weeks according to the cortisol and cortisone also have a weak mineralo- duration of the preceeding treatment. If this corticoid activity, which assumes an increasing precaution be neglected the patient is exposed to importance when they are being produced in the risks of an acute adrenal crisis when faced excess as in Cushing's syndrome, or administered during this period with severe stress, such as in large doses pneumonia or surgical trauma. Intermediate in quality of action between Likewise, during even moderately intensive cortisolVand aldosterone, but much less potent, is glucocorticoid therapy the patient cannot step up Yune 1958 GARROD: Pharmacology of Cortisone, Cortisol and their New Analogues 301 Postgrad Med J: first published as 10.1136/pgmj.34.392.300 on 1 June 1958. Downloaded from his cortisol secretion in emergency, and must then Biochemically these steroids influence the be protected by raising the dosage, if needs beto metabolism of protein, fat, carbohydrate, purines, the equivalent of 200 mg. of cortisone a day. electrolytes and water, and exert a direct calori- Independent of corticotrophic control there are genic action (Evans et al., 1957). In excess they wide diurnal variations in the rate of cortisol inhibit tissue healing and body growth, influence secretion which falls to low levels in the early the local and general response to infection, and morning hours before rising to a sustained peak at raise the body's resistance to stress; they help in around 5 or 6 a.m. Whether this phenomenon maintaining normal functions of the brain, heart should be allowed to influence the timing and dis- and circulation, and stimulate the gastric tribution of dosage when steroids are being given secretions. in small amounts has yet to be decided. Radioisotope studies have been of great value in Metabolic Effects elucidating the metabolism of cortisol (Migeon et al., 1956; Peterson and Wyngaarden, I955 and Glucocorticoids stimulate protein katabolism, 1956). Within the body the free steroid has a thereby increasing nitrogen output and glucose half life of about I.4 hours, and is reduced to formation (gluconeogenesis). In excess this leads derivatives such as tetrahydrocortisol, tetra- to muscle wasting, weakening of connective and hydrocortisone, and allotetrahydrocortisol (Bush vascular tissue, osteoporosis and the formation of and Willoughby, 1957), which combine in the wide purple striae. Aminoacid, creatine and uric liver with glycuronic acid to form glucuronides. acid excretion are increased. This last effect may Together these metabolites account for about 36 per be useful when treating acute gout, if not neu- cent. ofthe secreted hormone and are excreted in the tralised by increased uric acid formation. urine where they can be measured as 17-hydroxy- The complex actions of glucocorticoids on car- corticoids (Reddy, I954), or, together with the bohydrate metabolism can be only partly accounted cortol and cortolone derivatives, as I7-ketogenic for by increased gluconeogenesis, for these steroids (Norymberski et al., 1953). Only about steroids also antagonize insulin, promote glycogen 4 per cent. of the metabolites of cortisol can be storage, and lower the renal glucose threshold (Fourman et al., 1950). Large doses diminish accounted for as i7-ketosteroids, and about O.I5 copyright. per cent. of the hormone is excreted in the free glucose tolerance and cause mild glycosuria. state (Wade and Kellie, 1957). Impaired liver Frank diabetes seldom results (less than i per cent. function and myxoedema retard the conjugation, treated cases), and when it does is usually un- and renal failure the excretion, of these meta- accompanied by ketonuria (Brookman et al., bolites, hyperthyroidism having the opposite effect 1953). Fat mobilization and ketone combustion (Peterson et al., 1955). By means of radio-isotope are accelerated, and starvation ketosis inhibited studies it has been shown that the high plasma (Kinsell et al., 195I). A centripetal redistribution i7-hydroxycorticoid levels of late pregnancy are of body fat contributes towards the Cushingoid due to delayed metabolism, and not increased habitus which is a feature of steroid overdosage. http://pmj.bmj.com/ secretion, of cortisol (Migeon et al., 1957). Water and Electrolytes Physiological and Pharmacological Actions The complicated actions of cortisol and corti- of Cortisol sone on water and electrolyte metabolism, though Despite the protean activities of cortisol, little is mainly located within the kidney, are not confined known about the biochemical processes which to this organ, for these steroids have been shown to mediate these effects within the cells, though there increase the extracellular fluid volume inde- on October 1, 2021 by guest. Protected is evidence that a number of enzyme systems are pendently of changes in, external water and involved (Ingle, I950). To quote Ingle (I950): electrolyte balance (Levitt and Bader, 195I). They ' The consequences of cortical hormone action also diminish the sodium : potassium ratio in spread through the organism in a manner re- sweat and saliva (Conn and Fajans, 1952). miniscent of the waves caused by the impact of a Acting as weak mineralocorticoids, cortisol and stone in a pool of water, but the point of impact of cortisone increase the renal tubular reabsorption the hormone remains unknown for the present.' of sodium, resulting in fluid retention. Often this In most instances cortisol would seem to assist effect is only transient and followed by diuresis; rather than initiate the processes which it affects frank oedema seldom follows unless other factors (Sayers, 1950). Except for the electrolyte effects, are present. Paradoxically, and notably in the actions of cortisol are common to all the Addisonian patients receiving DOCA, these known glucocorticoids, whether natural or syn- steroids may initially increase sodium excretion, thetic,
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