If Selye's hypothesis as to the etiology of the "adaptation diseases" is correct, it should be possible to cause diseases by the exposure of experimental animals to naturally occurring forms of stress under naturally occurring conditions. It has not been shown that this is true. According to Selye, the sensitized rat exposed to cold may develop hypertension and nephrosclerosis. Other stresses were relatively ineffective.

Pathologic changes in the hearts and kidneys of sensitized rats exposed to cold (100).-Rats of the Sprague-Dawley strain were sensitized by removal of one kidney and the feeding of a diet containing 4 per cent sodium chloride.

In Experiments I and 2, immature female rats developed severe renal damage and mild myocardial changes when exposed to cold for sixty days. The food intake of the cold-exposed rats was gready increased above the amounts eaten by similar rats kept at room temperature. In Experiment 3, immature female rats were sensitized, and all were given equal amounts of the 4 per cent sodium chloride diet to eat. The cold-exposed rats were permitted to meet their extra caloric needs by eating sucrose. Under these conditions the cold-exposed rats showed somewhat greater renal damage than did similar rats at room temperature, but the damage was mild as compared to the pathology of similar cold-exposed rats eating the high-salt diet ad libitum. In Experiment 4, mature sensitized male rats were permitted to eat the 4 per cent sodium chloride diet; similar rats at room temperature ate a 10 per cent sodium chloride diet. The total renal and myocardial damage was mild as compared to the severe damage among the cold-exposed rats. One of the rats had a cerebral hemorrhage during exposure to cold. The principal renal lesions were inflammatory in nature. Nephrosclerosis was seen in a few instances.

It is concluded that the pathologic changes which appear in the sensitized rat exposed to cold are dependent in part upon the increase in food intake, especially of sodium chloride.

Pathologic changes in adrenalectomized and non-adrenalectomized rats exposed to cold (7).-Sexually mature male rats of the Sprague-Dawley strain were sensitized by removal of one kidney and fed a diet containing 4 per cent sodium chloride. Adrenalectomized rats were treated with 4 ml. of aqueous adrenal cortical extract per rat per day. Groups of adrenalectomized and non-adrenalectomized rats were each subdivided into groups which were adapted to low temperature and kept at 3°-5° for sixty days, and similar groups were kept at room temperature for the same period of time. An additional group of non-adrenalectomized sensitized rats was adapted to the overfeeding of the high-salt diet by stomach tube. The amount of fluid diet represented approximately as much dry diet as was eaten ad libitum by the cold-exposed rats. The following points were established:

1. The rats exposed to cold ate much more food but gained less weight than did rats kept at room temperature. The rats which were overfed at room temperature became overweight.

2. The adrenalectomized rats treated with adrenal cortical extract at room temperature developed more microscopic damage to the hearts and kidneys than did non-adrenalectomized rats at room temperature, but there was no significant difference in organ weights or in the ratings of gross pathology. It was postulated that the adrenal cortices may modify their secretion of hormones in order to facilitate the excretion of a high-salt load. Adrenalectomized rats on a fixed intake of replacement therapy may be at a disadvantage in this situation.

3. When the rats were exposed to cold, the gross and microscopic damage to hearts and kidneys was equally marked in adrenalectomized and in non-adrenalectomized rats. There was hypertrophy of the hearts and of the kidneys in all rats exposed to cold.

4. Rats which were overfed at room temperature showed microscopic damage to hearts and kidneys almost as severe as that seen in the rats exposed to cold.

5. The role of the adrenal glands in causing the pathology which occurred in the cold-exposed rats is uncertain for two reasons. Food intake was not constant. The amount of adrenal cortical extract used as replacement therapy in the adrenalectomized rats was associated with more damage than occurred in the non-adrenalectomized rats when the comparison was made at room temperature.

Pathologic changes in sensitized rats exposed to stress (8).- Male rats of the Sprague-Dawley strain were subjected to unilateral nephrectomy and were given a high-sodium chloride diet to eat ad libitum. These sensitized rats were exposed to various stressors (limb ligation once each week, surgery once each week, hemorrhage twice each week, a burn once each week, a fracture once each week, or an injection of 1 per cent formaldehyde twice each day) for eight weeks. It should be emphasized that each form of stress was near the maximum severity which could be tolerated by the rats. Some pathology occurred in the kidneys of non-stressed sensitized rats and was aggravated by exposure to some of the stressors. Three of the stressed rats had elevated blood pressures. Myocardial changes were seen in only a few of the stressed animals. The pathology caused by these stressors was less severe than that seen in sensitized rats overdosed with hormones and sensitized rats exposed to cold in other experiments. In no case was pathology indicative of hypertensive vascular disease observed. The hearts and kidneys did not increase in size when the animals were exposed to various stressors; the weights of the thymus glands were moderately decreased, and weights of adrenal glands were moderately increased.

Pathologic changes in adrenalectomized, sensitized rats treated with adrenal cortex extract (11).-Male rats of the Sprague-Dawley strain were adrenalectomized and unilaterally nephrectomized. The rats were adapted to the tube-feeding of a medium carbohydrate diet which contained additional NaCl amounting to 4 per cent of the dry weight. The following doses of adrenal cortex extract were given by subcutaneous injection for fifty-six days: 0.0, 0.1, 0.2, 0.5, 1.0, 2.0, 4.0, and 8.0 ml. per rat per day. When the dose of adrenal cortex extract was 1.0 ml. per day or greater, the blood pressure was elevated in proportion to the dose. Doses of 4 and 8 ml. of adrenal cortex extract per rat per day caused an increase in the amount of renal and myocardial pathology. Arteriosclerosis was not seen in any animal of the present study but has been seen in other experiments in a small number of sensitized rats given large doses of adrenal cortex extract.

Pathologic changes in sensitized rats treated with methylandrostenediol and with growth hormone (10).-The chronic administration of large doses of 7α-methyl-5-androstene-3 0, 17β-diol (methylandrostenediol) to the sensitized rat (unilateral nephrectomy and a 4 per cent sodium chloride diet) causes hypertension as well as renal and cardiovascular pathology. In the present study, methylandrostenediol was administered to non-adrenalectomized, sensitized rats and to adrenalectomized, sensitized rats treated with adrenal cortex extract. The control groups did not receive the steroid. Experiments 1 and 2 involved rats eating ad libitum. The dose of methylandrostenediol was 10 mg. per rat per day for fifty-six days; the adrenalectomized rats were each given 2 ml. of adrenal cortex extract per day. The rats given methylandrostenediol developed hypertension and renal and cardiovascular pathology in both the presence and absence of the adrenal glands. In Experiment 3, force-fed rats were given 20 mg. of methylandrostenediol per rat per day; the adrenalectomized rats were each given 1 ml. of adrenal cortex extract per day. The duration of the experiment was forty-two days. Hypertension and renal and cardiovascular changes were more severe in the non-adrenalectomized rats. It is concluded that the damaging effects of large doses of methylandrostenediol can occur in the absence of the adrenal glands but that the presence of adrenal cortical hormones is required.

In Experiment 4, a highly active preparation of growth hormone was given to sensitized rats eating ad libitum. There was an increase in body weight and in food intake. All the rats given growth hormone developed a polydipsia, but elevation in blood pressure and renal and cardiovascular pathology were minimal.

Discussion Of The Role Of The Adrenal Glands In The Etiology Of Disease

The first weakness of the Selye concept is that most supporting evidence is derived from conditions which do not occur naturally. The second weakness is the absence of convincing evidence that naturally occurring stressors can cause "adaptation diseases" under naturally occurring conditions. In our studies, exposure to stress never produced hypertensive vascular disease, tumors, diabetes, or any other disease entity. Adrenal cortical insufficiency does affect the genesis and rate of development of certain diseases, just as adrenal cortical insufficiency modifies normal growth and metabolism. Treatment of the adrenalectomized animal with normalizing doses of adrenal cortex extract permits extra-adrenal pathogens to display their full-blown effects.

The experiments of David Ingle show that at least some symptoms of cortisone overdosage can be ameliorated by stressors. These observations do not fit the Selye concept, but they could be explained by the assumption that severe stress increases the requirements for corticoids so that amounts of corticosteroids causing symptoms of hypercorticalism under resting conditions might suffice only to sustain eucorticalism during severe stress.

None of our experiments exclude the possibility that certain hormone-dependent cancers have a special dependence upon certain steroids (possibly abnormal individual steroids or an imbalance of natural steroids) in the adrenal cortex. However, we consider it possible, even probable, that the general relationship of the corticoids to disease is permissive.