HORMONES 



suspect as responsible a combination of actions, some of them 

 tissue-specific, others nonspecific. Even in the fairly simple 

 muscle-work test, the increase of efficiency caused by Cortisol is 

 in part due to its making glucose available to the muscle, but 

 there is also a component ascribable to a direct effect of Cortisol 

 on the muscle itself. 



In considering how Cortisol exerts its characteristic effects the 

 problem we face is its biochemical mode of action. Here we are 

 confronted with a rather specific puzzle and a general dilemma. 

 The specific issue rests on the fact that Cortisol given orally 

 to men and animals is very nearly as effective as when it is given 

 by the parenteral route. In being absorbed from the gut Cor- 

 tisol passes through the liver, in which it is subjected to extraor- 

 dinarily rapid chemical transformation (6). Is it possible 

 then that one or more transformation products are the agents 

 responsible for the various effects of Cortisol, and that we must 

 search for these if we are to investigate the substance truly 

 active biochemically? May a variety of metabolites in fact be 

 the basis of the diversity of effect? A number of attempts to 

 obtain the characteristic lymphocytopenic effect of Cortisol by 

 incubating it with lymphocytes in vitro have met with failure. 

 Is this because a liver-formed metabolite is indeed the effective 

 agent? Even in those instances where direct local action has 

 been demonstrated, e.g., on direct intra-articular or intradermal 

 injection, there is evidence of rapid transformation of Cortisol to 

 subsidiary products (12). This possibility of "active" hormone 

 being something else at the site of its action applies to most if not 

 all of the hormones. 



The general dilemma is that which involves all who are 

 interested in the mechanism of hormone action. It is first of all 

 the problem of disentangling direct from indirect effects. Thus 

 Cortisol is extraordinarily potent in effecting glycogen deposition 

 in the liver of adrenalectomized animals. Yet this effect cannot 

 be obtained by incubating Cortisol in vitro with liver tissue. 

 Glycogen deposition represents the end result of a series of events 

 in which Cortisol plays a role; the best evidence available sug- 



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