Effects of Adrenocortical Hormones

Although the secretions of the adrenal cortex are known to influence the metabolism of lipids in the intact mammal (Welt and Wilhelmi, 1950 Lukens, 1953 Folley, 1953 Engel, 1957 Hausberger, 1958 Hausberger and Hausberger, 1958b), until recently a direct influence on the metabolism of adipose tissue has been difficult to demonstrate. Many of the studies related to this problem were carried out in the intact animal and cannot be evaluated with certainty because of the possibility that the effects observed might result from secondary hormonal adjustments, particularly altered insulin secretion, or from differences in dietary intake and activity. Welt and Wilhelmi (1950) studied the uptake of deuterium into the liver and carcass fats of adrenalectomized rats and found that 

Rict-Correa el al. (1960) found that the subcutaneous injection of cortisone acetate into normal fed rats over a 3.5-day period markedly reduces the stimulation of glucose uptake and CO2 production (measured a,s net gas exchange) that is produced by the addition of insulin m vitro to epididymal adipose tissue, removed from these animals. These inhibitory effects were most marked at low insulin concentrations. 

Jeanrenaud and Renold (1960) reported no significant effect of adrenalectomy on C 02 production from uniformly labeled gluctose by adipose, tissue from alloxan diabetic rats. They also concluded that adrenalectomy did not affect the incorporation of glucose carbon into long-chain fatty 

At variance with the decrea.sed release of free fatty acid by mesenteric and epididymal adipose tissue from fasted or semifasted adrenalectomized rats (Reshef and Shapiro, 1960 Schotz et cd., 1959) and the in vitro effects of adrenocortical steroids (Jeanrenaud and Renold, 1960) is the report of Levy and Ramey (1959). These workers measured the extractable lipid in the epididymal fat pads of rats before and after a 12-hour fast they reported that the loss of lipid from the adipose ti.ssue stores of adrenalectomized rats exceeds that from normal rats. They further observed that the prior 

Rashef and Shapiro (1960) reported that pretreatment of adrenalecto-mizc d rats with either epinephrine or eortisone inereased the depressed rate of free fatty acid release by their mesenteric adipose tissue in vitro however, maximal effects were, obtained only when both were given. It was further pointed out that epinephrine alone was highly effective in restorii the depressed rate of free fatty acid release by tissue from adrenal demedul-lated rats. Reshef and Shapiro (1960) also observed that pretreatment of starved intact rats with cortisone had little effect on the release of free fatty acid by mesenteric adipose tissue. Such treatment, however, inereased and prolonged the response of tissue removed from rats injected with epinephrine (sec Section VI, A). These results may reflect in part the effects of glucocorticoid administration on the adipose tissue stores of the intact animal, but the interesting relation between the effects of epinephrine and adrenocortical steroids on the release of free fatty acids deserves further study. 

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In patients with longstanding hypothyroidism and those with ischemic heart disease, rapid correction of hypothyroidism may precipitate angina, cardiac arrhythmias, or other adverse effects. For these patients, replacement therapy should be started at low initial doses, followed by slow titration to full replacement as tolerated over several months. If hypothyroidism and some degree of adrenal insufficiency coexist, an appropriate adjustment of the corticosteroid replacement must be initiated prior to thyroid hormone replacement therapy. This prevents acute adrenocortical insufficiency that could otherwise arise from a thyroid hormone-induced increase in the metabolic clearance rate of adrenocortical hormones. 

Hench P S et al 1949 The effect of a hormone of the adrenal cortex (17-hydroxy-ll-dehydrocorticosterone Compound E) and of pituitary adrenocorticotrophic hormone on rheumatoid arthritis. Proceedings of the Staff Meetings of the Mayo Clinic 24 181,277 (acute rheumatism). The classic studies of the first clinical use of an adrenocortical steroid in inflammatory disease. See also page 298 for an account by E C Kendall of the biochemical and pharmaceutical background to the clinical studies. Kendall writes of his collaboration with Hench, he can now say "17-hydroxy-ll-dehydrocorticosterone" and in turn I can say "the arthritis of lupus erythematosus". In sophisticated circles, however, I prefer to say, "the arthritis of L.E. ". 

The evidence in favour of a relationship between non-steroidal antirheumatic activity and the pituitary-adrenal system is based mainly on experiments involving salicylates and phenylbutazone. No attempt will be made to discuss these problems in detail since they have been adequately reviewed by Smith and Done for salicylates, and by Rechenburg for phenylbutazone. Smith argued persuasively that the available experimental evidence on salicylates does not support the view that they either mimic or reinforce the actions of the natural adrenocortical hormones, and that the similar clinical effects of salicylates and these steroids in rheumatic diseases must therefore be produced by different mechanisms. Done, on the other hand, suggests that the concept cannot be prematurely dismissed and believes that the possibility that salicylate simultaneously affects the production and disposition of adrenocortical hormones deserves further consideration. He emphasizes that the antirheumatic effects of salicylates are not dependent on the maintenance of elevated circulating levels of corticoids. 

The question of the effect of ascorbic acid on adrenocortical hormone production has proved hard enough (see Section XI) the question of the influence of adrenocortical hormones on ascorbic acid metabolism seems likely to be still more difficult. 

Any changes in the urinary excretion of ascorbic acid following the administration of cortisone or ACTH cannot be interpreted in terms of adrenocortical function until the probable effect of these hormones on the renal threshold for ascorbic acid has been more thoroughly... 

Anatomical Considerations 458 Histophysiology 459 Adrenocortical Hormones 460 Steroid Hormone Biosynthesis Metabolic Effects of Corticoid Hormones Properties of ACTH Cushing s Syndrome... 

The hexokinase theory originated from experiments by Colowick, Cori, and Slein [128]. The combined effects of three hormones—an anterior pituitary extract, an adrenocortical extract, and insulin— were studied on crude or purified hexokinase preparations obtained from kidney, brain, liver, and heart of normal and alloxan-diabetic rats. We shall first present the results obtained on normal rats, and then those obtained on diabetic rats. 

Biologic Significance of the Adrenal Cortex. The adrenocortical hormones constitute some of the most vital substances. Extirpation of the adrenal gland in experimental animals is followed by most serious disturbances and, in a few days, by death. Among other things, the metabolism of electrolytes is unbalanced (increased Na+ excretion). This effect can be reversed by administration of adrenocortical hormones, some of which (especially aldosterone) effect the retention of sodium and excretion of potassium (cf. Chapt. XXI-5). 

Effect of glucocorticoid administration on adrenocortical cortisol production (A). Release of cortisol depends on stimulation by hypophyseal ACTH, which in turn is controlled by hypothalamic corticotropin-releasing hormone (CRH). In both the hypophysis and hypothalamus there are cortisol receptors through which cortisol can exert a feedback inhibition of ACTH or CRH release. 

Mitotane, or o,p -DDD, is an oral medication used in the treatment of adrenocortical carcinoma. Chemically it is an isomere of DDT. Following its metabolism in the adrenal cortex to a reactive acyl chloride intermediate, mitotane covalently binds to adrenal proteins, specitically inhibiting adrenal cortical hormone production. The drug accumulates in fat tissue. It is eliminated mainly by the kidneys with a half-life of 18-159 days. Common side effects include anorexia, nausea, lethargy, sleepiness and skin problems. 

Secretion of adrenocortical steroids is controlled by the pituitary release of corticotropin (ACTH). Secretion of the salt-retaining hormone aldosterone is primarily under the influence of angiotensin. Corticotropin has some actions that do not depend on its effect on adrenocortical secretion. However, its pharmacologic value as an anti-inflammatory agent and its use in testing adrenal function depend on its secretory action. Its pharmacology is discussed in Chapter 37 and is reviewed only briefly here. 

Even a single dose of corticotropin can cause inhibition of thyrotrophic hormone secretion (19), although the effect is brief. Conversely, thyroid hormones increase the sensitivity of adrenocortical cells in vitro to corticotropin (20) and hyperthyroidism increases sensitivity to corticotropin (21,22). 

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