The concept of permissive hormone action was first used in an attempt to explain those experimental and clinical situations in which a biologic response or the overt signs of a disease disappeared or were ameliorated by removal of the adrenal glands but reappeared when the animal or patient was treated with normalizing amounts of adrenal cortical hormones. Herein, the response could not be dependent on an absolute increase in the secretory activity of the adrenal cortices. It would still appear when these glands were out although the presence of cortical hormones was required. It was supposed that a biochemical function of the hormone was needed to maintain the functional integrity and biologic responsiveness of the tissues to extra-adrenal stimuli. It is still believed by me and some other protagonists of the concept of permissiveness that this is a valid although admittedly superficial explanation for some causal relationships. But it is probable that the general concept of permissiveness covers other kinds of causal relationships.

A lubricant has a passive sort of permissive relationship to the operation of a machine. All homeostatic mechanisms which operate to maintain a constant internal environment have a permissive relationship to other processes which are dependent on a constant internal environment. The kidney, lungs and buffering systems of the blood contribute to the maintenance of acid-base balance and electrolyte balance, permitting man to walk, run, speak, think, etc.-all independent functions of muscle and brain.

And so the concept of permissiveness is not limited to the adrenal cortex. Many causal relationships in the physical and biologic world can be described as permissive until we gain greater insight into the mechanisms involved.

But how can a substance needed for life and health also permit the development of a disease? Possibly because the diseases in question represent active biochemical processes. Arteriosclerosis is such a disease. Hypertension may well represent greater than normal use of energy to sustain a high pressure in the vascular tree. Diabetes is due in part to overproduction of glucose. Cancer represents growth. This rationalization does not represent a very high order of insight into the relationship between adrenal cortical physiology and the processes of disease, but it may contain elements of truth.

If a severe stress causes increased secretion of corticoids, should not hypercorticalism ensue? We do not understand why increased titers of steroid in the body fluids of the stressed individual are needed to maintain homeostasis; we do not know why hypercorticalism is not a consequence of prolonged exposure to stress. This is the way things are. When stress is severe, the animal or patient needs more corticoids in order to survive the stress. Cushing's disease is not an outcome.

The concept that these adaptive mechanisms can go awry during exposure to stress and cause disease has been and still is a heuristic concept. I cannot deny that much more information on the metabolism of steroids and on the responsiveness of tissues to steroids is needed before we can appraise the part that these hormones play in disease processes. But to this moment, I have sought in vain for published data and for evidence from my own experiments which provide direct support for the view that the adrenal cortex is commonly the villain in pathogeneses.

References

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3 Skelton, F. R.: Adrenal regeneration and adrenal-regeneration hypertension. Physiol. Rev. 39: 162, 1959.

4 Ingle, D. J.: Effect of endocrine glands on normal muscle work. Am. J. Med. H: 724, 1955.

5 Selye, H.: The chemical prevention of cardiac necroses. New York, Ronald Press, 1958.

6 Wilgram, G. F., and Ingle, D. J.: Pathology of aging female breeder rats. Arch. Path., in press.

7 Wexlek, B. C., and Miller, B. F.: Severe arteriosclerosis and other diseases in the rat produced by corticotropin. Science. 197: 590. 1958.

8 Crane, W. 8. J., and Ingle, D. J.: Pathologic changes in sensitized rats exposed to stress. Endocrinology 6S: 474. 1958.

9 Meneely, G. R., Tucker, R. G., Darby, W. J., and Auerbach, S. H.: Chronic sodium chloride toxicity in the albino rat.

10. Occurrence of hypertension and of a syndrome of edema and renal failure. J. Exper. Med. 98: 1. 1953. 10 Crane, W. A. J., Porter, R. E., and Ingle, D. J.: Pathologic changes in adrenalectomized sensitized rats treated with adrenal cortex extract. Enodocrinology 64: 215. 1959.

11 - Baker, B. L., and Ingle, D. J.: Pathologic changes in adrenalectomized and non-adrenalectomized rats exposed to cold. Endocrinology 62: 216. 1958.

12, Porter, R. E., and Ingle, D. J.: Pathologic changes in sensitized rats treated with methylandrostenediol and with growth hormone. Endocrinology 63: 43. 1958.

13 Grollman, A.: A unitary concept of experimental and clinical hypertensive cardiovascular disease. Perspectives Biol. & Med. 208, 1959.