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Further Experiments on Cortico-Adrenal Extract: Its Efficacy by Mouth

By S. W. Britton and H. Silvette

A rapidly accumulating mass of evidence indicates that extracts of the adrenal cortex which have recently been developed are markedly potent in both experimental and clinical cases of adrenal insufficiency. The methods of Hartman and his associates¹ and Swingle and Pfiffner² have been widely used. In experiments reported from this laboratory full support, has been given to the observations of the Princeton workers. We have employed a slightly modified Swingle-Pfiffner technique as described.³

Cortico-adrenal extract maintains completely adrenalectomized animals in good health for indefinitely long periods. It readily abolishes the severe symptoms of adrenal insufficiency when allowed to develop, and concurrently restores the blood sugar and non-protein nitrogen levels to normal.

Augmentation of the blood sugar to the normal value occurs in adrenalectomized cats showing symptoms within one to three hours after the extract is given. The increase is approximately proportional to the amount of the material injected; it is produced consistently and repeatedly when potent extracts are used. We have observed the effect at least five times within about ten days in the same adrenalectomized animal.

Cats with severe symptoms of adrenal insufficiency invariably show low blood sugar values. In over thirty cases in our experience, cortico-adrenal extract has raised the blood sugar percentage to within normal limits or higher. Notable increments in blood sugar also occur in unoperated cats, particularly if young animals are used. Biological assay of the extract based on the observed blood sugar effects is suggested from these results.⁴

The decreases in blood non-protein nitrogen, following extract injection, have not been so characteristic in our experiments. They usually occur more slowly than the glycemic changes, and sometimes are long delayed. These differences are possibly referable to the renal condition (damage?) in the different animals, and also to the fluid content of the tissues. In some cases there is considerable urination following extract administration.

Intraperitoneal injections of pituitrin, ephedrine and ergotamine solutions, known to influence the blood sugar in insulin hypoglycemia and other conditions, do not affect significantly the low blood sugar levels or the symptoms of adrenal insufficiency. The administration of cortico-adrenal extract has been tested by mouth in a series of animals. The large doses which were found to be necessary, and the relatively small supplies of the extract available as well as the considerable expense of the material, has somewhat curtailed our observations. Cats have been kept alive by oral treatment, however, for two weeks after severe symptoms (convulsions) of adrenal insufficiency became evident. Death rapidly followed withdrawal of the extract. Complete recovery from the convulsions which usually immediately preceded death, was readily brought about, in several cases in the same animal.

The low blood sugar, high non-protein nitrogen and increased blood cell volume are restored to within normal limits when the extract is given by mouth. All the effects which were produced by oral administration were in keeping, indeed, with those which resulted from intraperitoneal injection of the material. Approximately three to five times the intraperitoneal dosage was necessary to produce comparable results. It is definitely clear from the experiments, however, that the effective hormone of the adrenal cortex is not wholly, if at all, destroyed in its passage through the gastro-intestinal mucous membrane.

Numerous attempts to maintain the lives of adrenalectomized cats by feeding whole and demedullated adrenal glands have not to date been successful. The animals do not readily eat the glandular tissue; if they are forcibly fed, vomiting often follows.

Adrenaline given by mouth in similar concentration to that present in the cortical extract which was used had no noteworthy influence on adrenal insufficiency. Glucose solutions given orally were also without significant effect.

The development of a method by which potent extracts of the adrenal cortex can be consistently produced suggested that tests of extracts of other tissues be made. Knowledge that specific chemical agents or hormones may be separated from widely different body tissues, and also that certain characteristics of the adrenal cortex find a resemblance in other extra-adrenal tissues (e.g. the brain and testes), gave some hope of success in these experiments. Extracts were made of the following tissues: testes, brain, liver, spleen and heart muscle. The method of preparation of these extracts was in all details similar to that used concurrently in making potent preparations of the adrenal cortex. When the tissue extracts were tested on adrenalectomized cats showing different degrees of adrenal insufficiency, however, the results were in all cases wholly negative. No effects were observed on the muscular weakness or other symptoms, or on the length of survival after operation.

In a recent report⁵ the striking influence of cortico-adrenal extract in bringing about precocious sexual maturation in rats has been pointed out. Maintenance of the lives of adrenalectomized animals and the effects on sexual maturity—two apparently widely-separated functions—which are brought about by cortico-adrenal extract indicate the presence in the material of two distinct chemical agents or hormones.
It is suggested that the primary action of the life-preserving hormone of the adrenal cortex, which is effective in conditions of adrenal insufficiency, is concerned with preservation of the normal carbohydrate balance in the body.

Observation that animals from which the adrenal glands have been completely removed may be kept alive with extracts of the cortex indicate the dispensability but not the inutility of adrenal medullary secretion.

SUMMARY

Increase of the blood sugar which invariably follows administration of cortico-adrenal extract to adrenalectomized cats with symptoms of insufficiency, is a reliable index of potency and affords a means of bio-assay of the material. Cortico-adrenal extract is effective when given by mouth. The lives of adrenalectomized animals are prolonged and all the signs and symptoms of severe insufficiency are rapidly abolished by oral administration of large doses of the extract.

Extracts which have been prepared similarly to cortico-adrenal extract from many different (extra-adrenal) body tissues have no influence on the symptoms of adrenal insufficiency.
The existence of two hormones in cortico-adrenal extract is postulated.

References:

1. F. A. Hartman, K. A. Brownell and W. E. Hartman, Amer. J. Physiol., 95: 670, 1930
2. W.W. Swingle and J.J. Pfiffner, Amer. J. Physiol., 96: 153, 1931.
3. S.W. Britton and H. Silvette, Science, 73: p322, March 20, 1931; Ibid., p. 373, April 3, 1931: Amer. J. Physiol., 97.
4. S. W. Britton and H. Silvette, Amer. J. Physio., in press.
5. E. L. Corey and S. W Britton, Science, 74: 101-102, July 24, 1931

SIDEBAR: THE ADRENAL GLAND

The adrenal gland is a small gland that sits like a hat on top of our kidneys, hence its original name of suprarenal gland (above the kidney). It is the size of a large walnut and encased in fat. The gland has two distinct sections, the adrenal medulla (middle), which makes adrenaline and its derivatives; and the adrenal cortex, which makes cortisone and its relatives—glucocorticoids, which regulate sugar metabolism and inflammation; mineralocorticoids, which regulate salt balance; precursors to the sex hormones like testosterone and estrogen; and many other regulatory hormones.

An important aspect of optimal adrenal function is the balance between the adrenal medulla with its output of stimulating adrenaline and the adrenal cortex with its output of healing cortisoid or steroid hormones. Adrenaline revs up the body to make the fight or flight response when we find ourselves under stress or in danger. Sugar, caffeine and other stimulants work by causing the adrenal medulla to produce more adrenaline. In contrast the adrenal cortex products help regulate metabolism, fluids and chemical balances. Adrenaline is used in emergencies while the products of the adrenal cortex nourish and repair. If the adrenal medulla is under constant stimulation, the adrenal cortex may become exhausted and unable to produce sufficient amounts of its balancing, healing hormones.

The use of synthetic cortisones is one of the cornerstones of modern medicine. Prednisone and similar drugs are used for practically all of our modern medical conditions including poison ivy; asthma; eczema, psoriasis and many other skin rashes; ulcerative colitis and other inflammatory bowel diseases; arthritis, bursitis and tendonitis; and even cancer. Since cortisone and its derivatives are all hormonal products made by the adrenal cortex, one might ask whether in all these diverse illnesses, the underlying cause is a problem with the adrenal gland. After all, if one gave thyroid hormone to a patient, one would expect therapeutic benefits only for patients with thyroid disorders. A treatment with thyroid hormone extract will not help a person with constipation or dry skin unless the cause of these problems is a thyroid disorder. According to the same logic, a treatment with cortisone will help a person with some sort of inflammation (skin inflammation as eczema, lung inflammation as asthma, bowel inflammation as colitis) only if the cause of these problems is an adrenal cortex disorder.

The phenomenon called modern life has resulted in a situation in which most people experience chronic stress, and something like half our population suffers from conditions that require adrenal cortex support. However, a reliance on synthetic cortisone or its derivatives can have serious side effects and does not serve to heal the underlying cause. True relief from fatigue, asthma, allergies and other symptoms of adrenal insufficiency can only be achieved by rebuilding the gland with proper nutrition, by removal of stimulating substances from the diet and by reestablishing the balance of the adrenal system through various activities that help the patient deal with stress.

—Tom Cowan, MD

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