GREGORY PINCUS 



well-known dosage-response curve. In intact organisms this 

 may be reflective of quantitative variations in hormone-in- 

 activating systems; but one may observe this variability in 

 response in isolated tissues or cells, e.g., in the glycogenolytic 

 action of glucagon or epinephrine on liver cells in vitro, in the 

 effects of insulin on glycogenesis of the isolated diaphragm. 

 What is the basis of this variable effectiveness, which in certain 

 instances may amount to nearly complete ineffectiveness? One 

 may of course postulate hormone-inactivating mechanisms of 

 varying efficiency present in the end organs themselves. An- 

 other possibility inheres in the quantitative variations of sub- 

 strates or cofactors of the hormone-labile systems. A third, and 

 most intriguing, possibility is the existence in the end-organ 

 tissue of native hormone analogues as inhibitors. I may cite 

 as an example the recent demonstration by Velardo and his 

 collaborators (16) of the pacemaking action of estriol. When 

 estradiol, which is a much more potent uterus-stimulating es- 

 trogen than estriol, is administered along with estriol, the degree 

 of stimulation over a considerable dosage range is determined by 

 the estriol, not by estradiol. It is as if estriol has an estradiol- 

 displacing action at the effector sites. Is it possible that for 

 many, most, or even all of the hormones endogenous antagonists 

 are produced either as extraglandular metabolites of the active 

 compounds or by the secretory tissues themselves? One of the 

 most interesting phases of the adaptation syndrome is the so- 

 called stage of adaptation. Effects characteristic of the initial 

 stage of alarm cannot be duplicated at this time by identical 

 stresses. May not the stage of adaptation be characterized by a 

 shift to secretion of, for example, corticoid antagonistic sub- 

 stances which saturate the sites of action at the end organs and 

 render the corticoids ineffective. 



Thus far in attempting a broad look at the future of the 

 hormones we have apparently been occupied in asking questions. 

 But I feel that these questions are keys to the future. In the case 

 of any individual hormone we must continue to ask our five 

 leading questions. But this is not the limit of our inquiry. We 



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