That cortisol plays a role in homoeostasis is evident by the disordered metabolism of Addison's disease, many facets of which can be corrected only by cortisol. However, little direct knowledge of the physiological role of cortisol is available. Much of the research on the effects of cortisol on various para-meters has been done in animals under conditions, and using amounts of cortisol or related compounds, which can scarcely be described as physiological. Larger doses of cortisol in man or of cortisol or corticosterone in the mouse result in loss of body nitrogen; but negative nitrogen balance is certainly not the normal state for man or mouse, for these, by definition, must have "normal" amounts of circulating adrenocortical steroid. On the other hand, it would be folly to deny that the classic experiments of Loeb, Atchley, Benedict & Leland (1933) on adrenalectomized dogs made a very real contribution to the understanding, and more rational treatment, of some of the basic disorders associated with adrenal insufficiency in man. The history of physiology is punctuated with numerous examples of the major contribution made by "unphysio-logical" experiments in the evolution of our understanding of normal human physiology. It is for this reason that this paper includes data obtained in experiments in several animal species as well as from studies in man, although in many instances it is not as yet entirely clear where the results invoked fit into the pattern of homoeostasis.
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The occurrence of hypoglycaemia in Addison's disease implies that cortisol influences mechanisms of carbohydrate metabolism on which maintenance of normal blood sugar is dependent. Cortisol deficiency leads to hypoglycaemia on fasting or on a low-carbohydrate diet, as well as after a glucose load, whether administered orally or intravenously. In addition there is an increase in sensitivity to exogenous insulin, an elevation in the respiratory quotient and a marked decrease in hepatic glycogen reserves.
Long & Lukens (1936) first showed an increase in urinary nitrogen excretion when cortisone reversed the fasting hypo-glycaemia of the adrenalectomized animal, and suggested that the mechanism involved gluconeogenesis from protein catabolism. Ingle & Thorn (1941) in similar studies showed that the production of glucose was in excess of that derived by gluconeogenesis and suggested that glucocorticoids also inhibit the peripheral utilization of glucose, but recent evidence suggests that this inhibition is a relatively minor physiological effect (de Bodo & Altszuler, 1958).
The phenomenon of unresponsiveness to hypoglycaemia wasfirst recognized in patients with cortisol deficiency (Fraser, Albright & Smith, 1941). Recent re-study of this phenomenon by Fajans (1961) and Fajans, Schneider, Schteingart & Conn (1961) in adrenalectomized subjects, using either exogenous insulin or sodium tolbutamide, has failed to demonstrate significant differences from normal. These workers have suggested that the decreased nutritional intake in untreated adrenal insufficiency is primarily responsible for the increased insulin sensitivity and unresponsiveness to hypoglycaemia. This supports the interpretation of Long, Katzin & Fry (1940) that in the experimental animal decreased glycogenesis is the primary defect.
Cortisol excess produces fasting hyperglycaemia, an impaired glucose tolerance, glycosuria, an increased resistance to insulin and an increase in liver glycogen. The apparent "resistance" of the normal animal or human subject to this hyperglycaemic effect may be related to the pancreatic (i-cell response, in contrast to the response observed in the diabetic subject (Wilson, Frawley, Forsham & Thorn, 1950; Bastenie, Conard & Franckson, 1954; Conn & Fajans, 1956).
The influence of cortisol in accelerating gluconeogenesis is well established (Long et al. 1940; Welt, Stetten, Ingle & Morley, 1952; de Bodo & Altszuler, 1958; Froesch, Winegrad, Renold & Thorn, 1958). The alteration in urinary nitrogen, however, cannot alone explain the impairment in carbo-hydrate tolerance with increased amounts of cortisol (Conn, Louis & Wheeler, 1948; Conn, Louis & Johnston, 1949). It has also been suggested that the early effects on carbohydrate metabolism precede protein catabolism (Long, Fry & Bonny-castle, 1960). Studies of the intermediates in the Krebs cycle in patients with Cushing's syndrome have demonstrated elevation of the fasting blood pyruvate and lactate, and depression of the blood citrate (Frawley, 1955; Henneman & Bunker, 1957; Hennes, Wajchenberg, Fajans & Conn, 1957; Henneman & Henneman, 1958; Fajans, 1961). Similar changes have been shown to occur with glucocorticoid administration, and in addition no effect on a-ketoglutarate levels was observed. Glucose administration results in both more rapid and greater increases in blood pyruvate levels after corticosteroid administration. This suggests an inhibition of some phase of glucose utilization and can perhaps best be explained by postulating an inhibition of the utilization of pyruvate. Further support for this hypothesis has come from a number of investigations. Frawley & Shelley (1961) have shown a reduced disappearance rate of injected pyruvate during corticosteroid therapy. Glenn, Bowman, Bayer & Meyer (1961) have observed a decreased rate of oxidation of exogenous glucose after cortisol administration to adrenal-ectomized rats, and indicate that the inhibiting effect occurred at the pyruvate level of glucose metabolism. Fajans (1961)
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infused sodium pyruvate into normal subjects before and during the administration of prednisone, and found that the steroid inhibited the ensuing rise in blood citrate in spite of the fact that the fasting blood glucose and pyruvate were elevated. Yielding & Tomkins (1959), Yielding, Tomkins & Munday (1960) found that corticosteroids inhibit the oxidation of reduced diphosphopyridine nucleotide (DPNH) in vitro, thus reducing the availability of DPN, which is essential for the oxidative decarboxylation of pyruvic acid to acetyl coenzyme A. Thorn, Renold & Cahill (1959) observed increased hepatic synthesis of glucose from pyruvate under the influence of cortisol. It would thus appear that corti-costeroid-induced hyperglycaemia is in part due to an inhibition of pyruvate catabolism, with a resultant increased availability of pyruvate for re-synthesis of glucose. Increases in hepatic glucose 6-phosphatase and fructose diphosphatase during corticosteroid administration may be associated with the increased availability of pyruvate (Mokrasch, Davidson & McGilvery, 1956; Weber, Allard, de Lamirande & Cantero, 1956; Kvam & Parks, 1960).
Plasma inorganic phosphorus concentrations fall when cortisol is administered intravenously (Mills, Thomas & Williamson, 1960). Studies on arteriovenous differences have shown that the decrease occurs during the passage of blood through muscle, but not through liver. The connexion of this change with other metabolic activities is entirely unknown at present.
The "catabolic" effects of cortisol have already been discussed in the previous section. The response to glucocorticoid excess is variable and in part dependent upon dose, dietary intake and the general metabolic state of the organism. These effects on protein metabolism are best demonstrated in patients with either spontaneous or iatrogenic Cushing's syndrome. The negative nitrogen balance is accompanied by retardation or cessation of growth, muscle wasting, thinning of the skin, osteoporosis and reduction in lymphoid tissue.
The effects of corticosteroids on protein synthesis, the so-called "anti-anabolic" action (Albright, 1943), have been less well documented until recently. Wool & Weinshelbaum (1959, 1960) and Wool (1960) have shown that the incorporation of 14C from glucose, carboxylic acids and bicarbonate into proteins of rat diaphragm was facilitated by adrenalectomy and decreased by cortisone. In large doses cortisone produced a marked reduction of incorporation of amino acids into the diaphragm of both intact and adrenalectomized rats. Adrenalectomy increased incorporation of amino acids. The high concentration of corticosteroid required to produce these effects raises the question of whether anti-anabolism is a physiological phenomenon.
A review of some of the experimental studies may serve to shed light on the possible mechanisms involved. Ingle, Prestrud & Nezamis (1948) demonstrated that glucocorticoids increased plasma amino-acid levels in the adrenalectomized, hepatectomized rats. Adrenocorticotropic hormone (ACTH) and cortisol increase plasma levels of amino acids in both man and the experimental animal (Bergenstal, Landau, Kirsner & Lugibihl, 1951; Bondy, Ingle & Meeks, 1954). Noall, Riggs, Walker & Christensen (1957) have shown that glucocorticoids facilitate the liver's ability to concentrate amino acids. This led to the suggestion that the corticosteroid-induced " trapping " of amino acids by liver might serve as the stimulus, not only for peripheral protein catabolism but also for the degradation of amino acids by the liver. This hypothesis has received support through the recent observations of Rosen, Roberts, Budnick & Nichol (1958). They have shown that cortisol markedly increases hepatic glutamic-pyruvic transaminase activity, thus increasing the transamination of alanine to pyruvate. It might be postulated that the cortisol-controlled hepatic levels of this enzyme could serve as the mechanism which in turn regulates gluconeogenesis. Nichol (1961) has recently cautioned against this interpretation, in view of the delayed response of this enzyme activity to cortisol.
Lipid metabolism is undoubtedly influenced by cortisol as is well demonstrated in patients with Cushing's syndrome or in patients receiving pharmacological amounts of glucocorticoids. The redistribution of body fat under these circumstances, with an increase in centripetal fat at the expense of fat in the extremities, suggests both lipolysis and lipogenesis. However, information as to the mechanisms involved is very limited. Brady, Lukens & Gurin (1951) demonstrated decreased hepatic synthesis of long-chain fatty acids in cortisone-treated rats.
Glucocorticoids are ketogenic in the adrenalectomized depancreatized animal (Scow, Chernick & Guarco, 1959). Similarly, administration of glucocorticoid to subjects of Addison's disease, with concomitant diabetes, results in severe ketosis (Conn & Fajans, 1956). Scow et al. (1959) have suggested that ketosis is produced by mobilization of fat to the liver and an increased rate of ketogenesis.
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Corticosteroid administration to intact rats or guinea-pigs increases peripheral lipogenesis, which is probably mediated by the associated increase in insulin release (Jeanrenaud & Renold, 1960). In contrast, cortisol when added in vitro fails to influence lipogenesis of rat adipose tissue, but actually increases the net release of free fatty acids (Hausberger, 1958). Cortisol has been shown both in vivo and in vitro to potentiate the free fatty acid release from adipose tissue induced by epinephrine (Reshef & Shapiro, 1960; Shafrir & Steinberg, 1960).
Electrolyte and Water Metabolism
The electrolyte and water disturbances associated with adrenal insufficiency were first described by Loeb et al. (1933) and have been studied extensively since that time by numerous investigators. The abnormalities include excessive renal and extrarenal loss of sodium, potassium retention, decreased serum sodium, increased serum potassium, metabolic acidosis, decreased intracellular sodium and increased intracellular potassium. Some disagreement has existed with respect to alterations in distribution of body fluids (Mendelsohn & Pearson, 1955), but the weight of evidence would support the following changes: an increase in total body-water, a reduction of extracellular fluid volume (inulin space), a fall in plasma volume, a decrease in glomerular filtration rate (GFR) and loss of the diurnal rhythm of water excretion and the ability to handle a water load (Hills, Chalmers, Webster & Rosenthal, 1953;Nabarro, 1960).
The relative roles of cortisol and aldosterone (or any mineralocorticoid) in correcting these defects in the distribution of electrolytes and water is highly controversial. At one extreme are those who feel that the diminished diuretic response is the only facet which is cortisol-dependent, while at the other are those who consider the main physiological action of cortisol to reside in this sphere. A number of examples serving to high-light this controversy may be cited. Hepps, Hartman & Brownell (1959) studied the " K uptake of various tissues of the rat. The uptake of "K by tissues was significantly less in the adrenalectomized than in the control group, although the quantity of potassium per gram of body-weight was similar. Cortisone, with minimal sodium-retaining effects in the doses used, restored the reduced 4fK uptake to normal, whereas a mineralocorticoid was without effect. However, in no instance has "K uptake been related to either glucose or amino-acid uptake. Arons, Nusimovich, Vanderlinde & Thorn (1958) measured the effects of large doses of cortisol and of 11-deoxycorticosterone (DOQ on exchangeable sodium and potassium in normal man. In " acute studies " the cortisol failed to influence the exchangeability of body sodium and potassium, in contrast to the effect of the DOC. Swingle, Da Vanzo, Glenister, Crossfield & Wagle (1959) reported that a glucocorticoid (prednisolone) maintained vigour and normal activity in the adrenalectomized dog, despite low serum sodium and chloride concentrations, elevated blood urea level and, inconstantly, reduced plasma volume. In the dog, aldosterone, whether administered in small or large doses, increased the serum sodium and chloride concentrations, but plasma volume and blood pressure continued to fall. These workers suggest, on this basis, that mineralocorticoids act on the kidney only to maintain external electrolyte balance, while glucocorticoids influence the internal distribution of fluid and electrolyte between the intracellular and extracellular compartments.
The deficient diuretic response to water, characteristic of adrenal insufficiency, can be rapidly corrected by a glucocorti-coid (Oleesky & Stanbury, 1951; Slessor, 1951; Garrod & Burston, 1952; Garrod, Davies & CahilL 1955; Kleeman, Maxwell & Rockney, 1958). In pharmacological doses glucocorticoids have been shown to increase water diuresis in normal subjects (Gaunt, Birnie & Eversole, 1949; Raisz, McNeely, Saxon & Rosenbaum, 1957). Glucocorticoids appear to be specific in this regard and a wide range of other steroids have been repeatedly shown to be ineffective. The mechanism of this action of glucocorticoids appears to be undergoing some clarification. It had been suggested that they antagonize the action of antidiuretic hormone (Gaunt et al. 1949; Lloyd & Lobotsky, 1950; Slessor, 1951), but recently reported observations of Lindeman, Van Buren & Raisz (1961) would seem to make this claim untenable, as they found that cortisol did not alter the sensitivity of the renal tubule to vasopressin. It seems more likely that its effect is associated with a specific action on the diluting segment of the nephron, a suggestion supported by the following data: aminophyUine and mercuhydrin, by increasing GFR or solute excretion, or both, can in part correct the abnormality in water excretion, but not nearly as effectively as cortisol (Kleeman et al. 1958). A glucocorticoid, 6a-methylprednisolone, also improved water diuresis, although this compound has little effect on renal haemodynamics or sodium reabsorption (Kkeman, Koplowitz & Maxwell, 1959). These observations would therefore tend to eliminate changes in GFR or re-distribution of solute reabsorption between proximal and distal tubules as main explanations for this physiological action of cortisol.
Almost universal agreement exists with respect to the predominant role of aldosterone in the control of electrolytes by the kidneys. As was alluded to in the preceding section, one of the difficulties in interpretation has been the separation of primary effects on renal function from those occurring secondarily as a result of changes induced elsewhere in the organism by corticosteroids. Direct infusion of corticosteroids into the renal artery has in part circumvented this problem (Barger, Berlin & Tulenko, 1958; Ganong & Mulrow, 1958).
Adrenocortical insufficiency in dogs and man results in a moderate reduction in GFR, effective renal plasma flow (ERPF), and in maximal tubular excretion of />-aminohippuric acid (Tin PAH) or diodrast (Tm diodrast) (Talbott, Pecora, Melville & Consolazio, 1942; White, Heinbecker & Rolf, 1947; Waterhouse & Keutmann, 1948; Gaudino & Levitt, 1949; Luft & Sjogren, 1950; Skillern, Corcoran & ScherbeL 1956). These conditions are restored to normal by glucocorticoid administration (Burnett, 1950; Ingbar, Relman, Burrows, Kass, Sisson & Burnett, 1950; Alexander, Pellegrino, Farber & Earle, 1951; Ingbar, Kass, Burnett, Relman, Burrows & Sisson, 1951; Laidlaw, Dingman, Arons, Finkenstaedt & Thorn, 1955; Huffman, Wilson, Clark & Smyth, 1956; Raisz et al. 1957; Dingman, Finkenstaedt, Laidlaw, Renold, Jenkins, Merrill & Thorn, 1958; Froesch et al. 1958). Cortisol infusion raises the GFR and, to a lesser extent, ERPF, resulting in an increased filtration fraction. Little, if any, increase in the Tm PAH or Tm glucose occurs. Cortisol, particularly in small doses, usually increased sodium output, an effect most likely related to the rise in GFR (Dingman et al. 1958; Slater, Mestitz, Walker & Nabarro, 1961). In those circumstances where the glucocorticoids fail to stimulate GFR they clearly facilitate renal tubular sodium chloride reabsorption and decrease urinary sodium chloride excretion. All corticosteroids increase potassium excretion. The extent to which the changes induced by cortisol are dependent upon alterations in circulating blood volume, arterial blood pressure and vascular reactivity is unknown, but may be considerable. It would appear that its main effect is exerted through an alteration in renal haemodynamics. The influence of cortisol upon the renal regulation of water has already been discussed in a previous section.
Maintenance of Blood Pressure
It has been suggested that the disturbances in cardiovascular function seen in adrenocortical insufficiency may in part be due to inadequacy of myocardial function (Brown & Remington, 1955; Sayers & Solomon, 1960), to poor vaso-motor tone of the arterioles (Ramey, Goldstein & Levine, 1950), and to an alteration in permeability of the capillaries (Zweifach, Shorr & Black, 1953). The interdependence of the autonomic and adrenocortical systems has been emphasized by a number of investigators (Ingle, 1956; Ramey & Gold-stein, 1957). Ramey, Goldstein & Levine (1951) showed that the hypertensive response to norepinephrine in the dog was greatly reduced after adrenalectomy, and continued administration of norepinephrine resulted in exhaustion of the vasopressor responses. Infusion of adrenocortical extract to the adrenalectomized dogs resulted in a normal vasopressor response to norepinephrine, while DOC failed to affect the response. Fritz &Levine (1951) observed mesenteric arterioles directly in normal and adrenalectomized rats. Under these conditions, the blood vessels of the adrenalectomized animals became refractory to the topical application of norepinephrine, whereas the normal vascular response could be restored by the topical application of adrenocortical extract. It has been suggested (Friedman, Friedman & Nakashima, 1957) that cationic shifts in the arteriolar smooth-muscle cell play a vital part in determining the integrity of the vascular response to norepinephrine and other pressor agents. The relative importance of cortisol and aldosterone under these conditions remains to be elucidated. Attempts to apply these experimental observations in the clinical management of circulatory collapse in man have been largely unsuccessful (Smith, Hamlin, Walker & Moore, 1959).
Role in Infection, Inflammation and Trauma The clinical observation of increased susceptibility to infection in Addison's disease and Cushing's syndrome focused attention on the role of the adrenal in defensive responses to bacterial invasion, and various aspects of the host response to infection have been studied. Since corticosteroids cause dissolution of lymphatic tissue, which is established as the site of antibody synthesis (Coons, Leduc & Connolly, 1955), it is not surprising that a good deal of work has been done on the effect of corticosteroids on antibody production.1 Antibody production is increased in the adrenalectomized rabbit (Murphy & Sturm, 1947), and it is now clear that in the rat, the mouse and the rabbit (Bjeraeboe, Fischel & Stoerk, 1951; Germuth, Oyama & Ottinger, 1951; Dews & Code, 1953; Darrach, 1959) antibody formation can be suppressed with large doses of cortisone or corticosterone. The degree of suppression varies directly with the dose of steroid and inversely with the amount of antigen given. Thus Darrach (1959) showed that, in the mouse, antibody formation could be completely suppressed if the animal received 2 mg. of cortisone daily. Increasing the antigen up to 100 times that of the standard immnni7ing dose resulted in production of substantial amounts of antibody, although the serum levels achieved were much lower than those of the controls. It has been shown that the depression of antibody formation occurs very early in the course of antibody synthesis (Berglund, 1956) and that, if the steroid is discontinued while there is still circulating antigen, antibody will be formed although its appearance will be delayed (Ward & Johnson, 1959).
Suppression of antibody production is limited to the primary response, the anamnestic reaction being unaltered (Blumer, Richter, Cua-Lim & Rose, 1962) or partially suppressed (Ward & Johnson, 1959). There is no detectable alteration in the metabolism of antibody passively transferred to cortisone-treated animals (Fischel, Stoerk & BjOTneboe, 1951; Germuth et al. 1951). TTiose species in which antibody formation is suppressed also show a fall in serum Y-globulin (Werder, Hardin & Morgan, 1957), although there is no change in the concentration of other serum globulin fractions or in serum albumin.
In contrast to the well-established effect on antibody production in mice, rats and rabbits, no effect of cortisone or cortisol on the response to immunization in man (de Vries, 1950; Mirick, 1951; Friedman, 1953) or monkey (Shewell & Long, 1956) has been demonstrated. While, in man, the dose of steroid or ACTH used has been in general proportionately less than that in rodents, Shewell & Long (1956) were unable 1 Much of tbii h u been recently revtarcd (McMuter & Franzl, 1961).
to show any effect on antibody production in rhesus monkeys receiving 50 mg./kg./day of cortisone, although such a dose effectively suppressed antibody production in a parallel experiment in mice. They suggested that, whereas the rodent loses weight on steroid treatment and Y-globulin production is decreased, man and monkey maintain their body-weight and show little change in serum Y-globulin concentration; and therefore inhibition of antibody production in rodents may be associated with failure to maintain Y-globulin synthesis.
The therapeutic efficacy of glucocorticoids in allergic states stimulated studies of the mechanism of this effect which have recently been reviewed (Rose, 1959). Manifestations of delayed hypersensitivity such as the Arthus phenomenon, the tuberculin reaction, vasculitis and serum sickness are sup-pressed, as are acute reactions associated with serotonin release, e.g., anaphylaxis in the mouse. While there is no clear correlation between histamine release or metabolism and the response to glucocorticoids, in general the acute reactions associated with histamine release, such as anaphylaxis in the guinea-pig and the immediate skin reaction in man, are not alleviated (Rose, 1959).
Studies of other effects which might be concerned with resistance and wound healing have not been so numerous. Ebert & Wissler (1951) observed the action of cortisone on inflammatory changes induced by horse serum in intact rabbits, by the ear chamber technique. In cortisone-treated animals vascular tone and endothelial integrity were better maintained; there was marked diminution in diapedesis of leucocytes and in exudate. Non-specific mechanisms involved in the response to bacterial invasion have recently been carefully studied in the rabbit (Hirsch & Church, 1961). Polymorphonuclear leucocytes harvested from peritoneal exudates of rabbits receiving cortisone showed no differences from controls in numbers, in morphology or in content of non-specific antimicrobial agents (lysozyme, "phagocytin",' histone), nor were there any detectable changes in the activity of serum bacteriocidins (P lysins and complement-antibody) or of opsonins. Whether or not corticosteroids inhibit phagocytosis by reticulo-endothelial cells is still a matter of controversy (Kaplan & Jandl, 1961). Dougherty has recently reviewed contributions from his laboratory (Dougherty, Berliner & Berliner, 1961). The suggestion was made that cortisone may produce anti-inflammatory effects by influencing fibroblastic activities and inhibiting fibroblastic proliferation and destruction, as well as by deposition of collagen and polysaccharides. Dorfman & Schiller (1958) have also shown that cortisone depresses the metabolism of mucopolysaccharide in skin.
The role of cortisol in wound healing is not dear. It may be noted that no difficulty in wound healing was found in two large groups of patients on long-term therapy with anti-inflammatory steroids (Rose, McGarry & Knight, 1959; Savage, 1959). The metabolic changes which have been re-ported to occur with trauma, such as negative nitrogen and potassium balance, were attributed by Abbott, Levey & Krieger (1959) to decreased nitrogen intake. The only differ-ence that could be determined between starved normal controls and surgical patients was an increase in urinary 17-hydroxycorticoids. However, in severe trauma nitrogen balance may be negative, even on high protein intakes (Browne, 1944).
sodium and potassium might occur, which are not detected in 9. Other Effects of Cortisol over-all nitrogen balances. The effects of cortisol on intermediary metabolism of carbohydrate, protein and fat have already been dealt with and almost certainly play a role in the metabolic response to injury.
With regard to susceptibility to infection, Wagner, Bennett, Lasagna, Cluff, Rosenthal & Mirick (1956) studied the effect of cortisol on pneumococcal infections in man. There was more rapid return of the temperature to normal, but no other clinical or laboratory difference could be demonstrated between the cortisol-treated group (52 patients) and the controls (61 patients). Similar results were reported by Kirby, Polis & Romansky(1960).
Effects on the Central Nervous System Emotional aberrations are seen in both adrenocortical hypofunctional and hyperfunctional states in man. These range from symptoms compatible with a chronic anxiety state to severe psychotic episodes. Patients with Addison's disease frequently complain of inability to concentrate, of restlessness and insomnia, and show a slowed frequency in the electroencephalogram. These changes are completely reversed only with a glucocorticoid such as cortisol (Thorn, Forsham, Bennett, Roche, Reiss, Slessor, Flink & Somerville, 1949). Patients with Cushing's syndrome often show euphoria and increased mental and motor excitability, and reversal of these findings is usually seen with a return of the adrenocortical function to normal. In an analysis of the endocrinological aspects of tumours in and about the region of the sella turcica, Rasmussen, Morgen and Beck (unpublished work, 1957) showed that the "protective" effect of cortisone or cortisol during operative procedures in this area seemed equally dramatic, whether hypopituitarism was present or absent pre-operatively. The beneficial effect of a glucocorticoid in reducing the mortality and morbidity of patients operated upon in this region is clearly established (Ingraham, Matson & McLaurin, 1952; Raaf, Stainsby & Larson, 1954; Gurdjian, Webster, Latimer, Klein & Lofstrom, 1955; Tytus, Seltzer & Kahn, 1955; Troen & Rynearson, 1956; Gurdjian & Webster, 1958). It has been suggested that one of the possible explanations for these findings lies in the influence of the corticosteroids in reducing cerebral oedema. Further clinical support for this suggestion comes from observations of marked improvement in neurological defects associated with cerebrovascular accidents (Russek, Russek & Zohman, 1955; Roberts, 1958), intracerebral metastases (Kofman, Garvin, Nagamani & Taylor, 1957), primary brain tumours (Saeker & Rust, 1959; Galicich & French, 1961; Galicich, French & Melby, 1961), severe head injuries and a variety of neurosurgical procedures, with the administration of glucocorticoids (Rasmussen and Gulati, personal communication, 1961). Evidence for an action of glucocorticoids on experimental cerebral oedema is more fragmentary. Prados, Strowger & Feindel (1945a, 1945b) concluded that adrenocortical extract and corticotropin prevented or minimized the swelling of the brain, the changes in permeability of cerebral capillaries and the electroencephalographic alterations which follow exposure of the cat brain to air. Confirmation of these observations has been reported by Grenell & McCawley (1947) and Grenell & Mendelsohn (1954). It would appear that a further exploration of the influences of cortisol on the metabolism and function of tissue in the central nervous system would be fruitful.
Alterations in function of striated muscle related to changes in adrenocortical activity have been used by Ingle (1944) in a muscle work test. Reduction in muscle function occurs in the absence of corticosteroids, and physiological doses of cortisol or cortisone will reverse this defect. The relative glucocorticoid potencies of steroids have been assayed, using this technique.
Recent evidence by Sayers & Solomon (1960) would suggest that the inadequacy of cardiovascular function seen in adrenocortical insufficiency is at least in part due to a failure of the myocardium. The left ventricular work index of a carefully standardized preparation of the rat heart-lung has been shown to be exquisitely sensitive to minute amounts of corticosterone, cortisol and aldosterone, with aldosterone as the most potent. The application of this to the bio-assay of corticosteroids with "cardiotonic" activity appears feasible.
Adrenocortical insufficiency is usually associated with eosinophilia, lymphocytosis, neutropenia and anaemia, abnormalities which can be corrected only with cortisol or its analogues. In similar vein, Cushing's syndrome, whether of the iatrogenic or spontaneously occurring variety, is associated with eosinopenia, lymphopenia, a neutrophilic leucocytosis and increased erythropoiesis associated with increased red-cell mass. The exact mode of action of cortisol on bone-marrow remains an enigma.
Skeletal dynamics in man and the experimental animal have been measured, using 46Ca, *'Ca, various isotopes of strontium and non-radioactive strontium as tracers. This technique has been used to study the osteoporosis associated with excessive glucocorticoid activity. These studies suggest that increased bone dissolution is responsible for the demineralization (Eisenberg & Gordan, 1961). Increased bone deposition is often seen in the early phases, which is apparently an attempt at correcting the bone dissolution (Eisenberg, 1960). The importance of physiological levels of cortisol in maintenance of the skeleton remains unclear.
An attempt has been made toreview some of the high lights of the physiological influences of hydrocortisone. There must of necessity be gaps, and perhaps the most outstanding in this instance concern the importance of cortisol in pregnancy and lactation.
The most important physiological actions of cortisol appear to be concerned with the distribution of body-water and electrolyte, maintenance of blood pressure and GFR, and the renal regulation of water excretion. At present it would seem that the term glucocorticoid is a misnomer, since the evidence available suggests that the role of cortisol in carbohydrate metabolism is arelatively minor one. The apparent specificity of tissue response raises the question of whether only certain tissues possess the necessary enzyme systems "permitting" a physiological response to occur. In spite of all the research that has been done in the field of adrenal physiology, it is abundantly clear that great advances in knowledge still lie ahead.
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