ADAPTIVE STEROIDS: RETROSPECT AND PROSPECT HANS SELYE* The important role of steroid hormones in the regulation of growth, reproduction, and general metabolism has long been recognized; yet it is only during the last thirty years or so that we became aware oftheir participation in diverse nonspecific adaptive reactions, and particularly in the maintenance ofthe body's resistance to stress. This review attempts to give (i) a briefintroductory outline ofwhat we believe to be a natural basis for the classification ofadaptive steroids, (2) a survey ofthe historic development ofthis topic with special reference to the recently characterized "catatoxic" steroids, and (3) an outlook assessing the future possibilities ofresearch along these lines. Classification It has been found convenient to classify these adaptive hormones and their derivatives into two main groups which control essentially different defensive processes [1]: A. The syntoxic steroids (e.g., Cortisol, triamcinolone, aldosterone, desoxycorticosterone) initiate changes which permit life under stress without directly attacking the damaging agent. They create conditions for coexistence with the aggressor either through passive indolence to it (e.g., antiphlogistics) or by actively stimulating the formation of a * Institut de Médecine et de Chirurgie expérimentales, Université de Montréal, Montreal, Canada. This work was supported by theMinistèrede la Santé, Québec, and the Medical Research Council ofCanada (Block Term grant MT-1829). I wish to thank the following companies for kindly supplying the compounds used in these experiments: E. R. Squibb & Sons Ltd., G. D. Searle Sc Co., Lederle Laboratories, Merck & Co. Inc., Organon Inc., Schering Corporation Inc., Schieffelin & Co., Smith, Kline & French Laboratories, Sterling-Winthrop Research Institute, Syntex Research, and the Upjohn Co. 343 granulomatous barricade, which tends to isolate the irritant from the surrounding tissue (e.g., prophlogistics). Through similar mechanisms, the syntoxic steroids also promote repair (e.g., cicatrization, anabolism) or help to eliminate the pathogen (e.g., evacuation through the formation ofa perforating abscess), but they do not destroy it. The systemic action of the syntoxic steroids is mainly of the "lifemaintaining corticoid" type; it is highly efficient in restoring the nonspecific stress resistance of adrenal-deficient organisms to normal, but then a plateau is reached above which tolerance cannot be raised easily. Only in some instances (e.g., damage due to endotoxins, inflammatory irritants, immune reactions, lathyrogenic compounds) do syntoxic steroids increase tolerance far above normal, because here "disease" is primarily due to active morbid reactions of the tissues, not to direct tissue damage by the exogenous aggressor. Thus, endotoxin shock is thought to be caused mainly by the liberation of enzymes normally sequestered in lysosomes, whereas inflammation, various pathogenic immune reactions (allergies, anaphylaxis, homograft rejection), and osteolathyrism represent excessive responses of the body to different types of irritation. Finally, it must be remembered that some protective actions are based on specific pharmacologic antagonisms between steroids and toxic substances (e.g., mineralocorticoid-induced potassium tolerance, glucocorticoid -induced insulin tolerance). Here again, homeostasis is achieved by adjusting the body's reaction to the damaging agent, not by destroying the latter. B. The catatoxic steroids (e.g., ethylestrenol, spironolactone) act primarily by inducing aggressive reactions which inactivate toxic substances (e.g., by accelerating their metabolic degradation). They not only restore a deficient resistance to normal (as do the glucocorticoids after adrenalectomy ), but are capable ofraising it far above the norm. Sometimes this reaction defeats its purpose, because the products ofmetabolic degradation are more toxic than the original poison which was to be inactivated. Yet the response is still catatoxic since it attacks the toxic aggressor. For similar reasons we speak of allergy and anaphylaxis as "immune reactions ," although they actually produce damage. There are many overlaps between syntoxic and catatoxic steroid actions. Thus, stimulation ofinflammation may lead to topical degradation ofthe 344 Hans Selye · Adaptive Steroids Perspectives in Biology and Medicine · Spring 1970 irritant by enzyme activation in the inflammatory focus; furthermore, under certain circumstances the primarily syntoxic glucocorticoids may enhance the hepatic detoxification of barbiturates. Yet, the distinction between these two categories appears to be as justified as, say, the distinction between glucocorticoids and mineralocorticoids, because as a rule individual steroids act predominantly by eliciting one or the other reaction form. Furthermore, available evidence suggests that the two types ofdefense are...