NEW CONCEPTS ON THE MODE OF ACTION OF HORMONES PETER KARLSON* Itseems appropriate to begin our discussionwith a statement ofGregory Pincus [i] fromhis preface to the firstvolume ofthe well-known comprehensive treatise The Hormones: The final stage in the study ofa hormone and its activity, ifindeed the word "final" caneverbeapplied inphysiology, istheelucidationofthemechanism ofits action. . . . AU must entail enzyme systems, probably systems of which as yet we know nothing. Can a steroid function, for instance, as a coenzyme? How can the utilization ofpotassium, or calcium, be influenced by traces ofsubstances? The future ofhormone research will thus be in large part bound up with the advances in general biochemistry and physiology___ As yet it must be said, that this aspect ofthe work is scarcely begun. Nevertheless, the accumulation ofknowledge now available means that much progress along these lines is now possible. And in Volume HI we read: Seven years have passed since the appearance ofVolume I of TAe Hormones. . . . The expected emphasis upon mechanism ofaction has not yet developed to the degree expected , and the major discoveries in this direction are still probably for the future, although there have been interesting and suggestive developments___ In recentyears, many ideas on the subjecthave beenproposed and tested experimentally, and a lot ofexperimental material has accumulated; however , a clear understanding ofthe biochemical mechanism ofaction ofany ofthe well-known hormones is still lacking. Let us first consider die main lines ofthinking that prevailed in the past. I. Older Views on Mode ofAction ofHormones A. HORMONES CONTROL ENZYME ACnVITY This concept is a fairly old one and reappears from time to time. It was perhaps first introduced as a hypothesis of hormone action by D. E. * Professor ofPhysiological Chemistry, University ofMunich, Germany. 203 Green [2] in 1941. The role ofvitamins as part of coenzymes was then a surprising discovery, and there was a tendency to unify the three groups —enzymes, vitamins, and hormones—under one roof. Even a word had been coined, "Ergine" [3]. However, neither the word nor the concept has gained wide acceptance; the obvious differences in the function of enzymes, vitamins, and hormones made it impracticable to group them together. The main argument in favor ofthe hypothesis ofhormone-enzyme interaction was the fact that most hormones are active in very low concentrations . It was clear that their role was different from other metabolites, even those with regulatory functions like CO2, which influences the respiratory center, and action on the enzyme level apparently could account for the large influence ofvery small amounts ofa certain hormone. The great achievement ofexplaining the mode ofaction ofmost vitamins may also have influenced the ideas. For those who regard biochemistry as enzymology and the living cell as a complex system ofvarious enzymes, it must seem logical that hormones would exert their control by interaction with enzymes. In 1954, Martius [4] began an article on the mode ofaction of thyroxine with the statement: "The problem ofthe mechanism ofaction ofhormones, that is the way in which these factors intervene with and exert their influence and control upon enzymatic processes in the cell, is one ofthe most difficult problems of functional biochemistry. ..." And even today L. L. Engel [5] states the problem of hormone action as follows: "Unless we are to be engulfed by mysticism, we are forced to define a hormone as a substance which exerts chemical control over one or more metabolic reactions ." This is true only if"metabolic reactions" are understood to comprise all possible changes in cellularactivity; butitis apt to narrow theview to enzymatic reactions. A survey of the interaction of hormones with enzymes reveals very little positive evidence [6], In most cases there is no activity on homogenates or cell-free systems; apparently it is some part ofthe structure ofthe cell that participates in the response to hormones. The action ofthyroxine on mitochondrial metabolism—i.e., the uncoupling of oxidative phosphorylation —is now regarded as unspeclfic [7]; it may be the basis of thyreotoxicosis, but not ofnormal control ofbasic metabolism. The activation of transhydrogenases by steroid hormones, especially estradiol, is 204 Peter Karlson · Hormone Action Perspectives in Biology and Medicine · Winter 1963 well established, but there are serious doubts about the biological significance ofthis effect [8]. As for the...