Medical Hypotheses 13: 31-44, 1984

STRESS, CORTISOL, INTERFERON AND "STRESS" DISEASES

I. CORTISOL AS THE CAUSE OF "STRESS" DISEASES

Alfred T. Sapse, 802 N. Venetian Drive, Miami, Florida 33139, U.S.A.

ABSTRACT

An attempt is made to define a biochemical formula for stress, as an overproduction of cortisol + impaired interferon response. -

The behavior Type A individual under stress, would exhibit

elevated levels of cortisol with normal interferon response,

whereas the Type C individual, would exhibit elevated levels of

cortisol and impaired interferon responses.

Evidence is presented that elevated levels of cortisol manufac- tured chronically under the affect of stress, and regardless of the type of individual affected, are a cause or the cause of chronic diseases, and not the result of same.

This evidence would show that:

1.

2.

3.

4.

Elevated levels of cortisol precede certain diseases, and do not follow them, when cortisol is checked out for this purpose in pre-disease conditions.

When elevations of cortisol levels are induced through long-term corticosteroids therapy, in patients suffering of diseases requiring this type of treatment, conditions mimicking chronic diseases, would appear.

When corticosteroids therapy would be discontinued, the "chronic diseasesu mentioned above would dis-

appear.

When pharmaceuticals with potential cortisol an- tagonistic capabilities, were used in diseases totally unrelated, but having in common, elevated levels of cortisol, alleviation of symptoms and/ or diseases would occur.

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Key Words: stress, cortisol, hydrocortisone, interferon, chronic diseases.

INTRODUCTION

STRESS

Stress has been defined by Selye (1) as a nonspecific response to stimuli, internal and external. He introduced the concept of Gen- eral Adaptation Syndrome (GAS), which is induced by stress and consists of an alarm reaction followed by a stage of resistance eventually leading to the state of exhaustion.

The first phase, the alarm reaction is the “call to arms” of the or- ganism’s defense forces characterized by a sudden, massive and tran- sitory production of corticoids with its prime hormone: cortisol. The stage of resistance is characterized by a chronic release of corticoids. Finally the stage of exhaustion is followed by death when corticoid production is depressed to nil.

It is the second phase of GAS, the state of resistance, and what Selye calls “Diseases of Adaptation” that we are addressing ourselves in this paper. These diseases generally known as “chronic diseases”, embrace the whole spectrum of medicine, with every sinnle medical speciality involved from internal medicine, dermatology, psychiatry, neurology, gynecology, etc., etc., to cancer aging.

If stress is the common denominator of so many diseases, should have a biochemical common denominator as well. I this common denominator is an elevated level of cortisol colism, alone as in stress behavior Type A or associated paired interferon response as in stress behavior Type C.

virology, and premature

then they submit that or hypercorti- with an im-

Stress behaviors have been categorized as Type A, B and C. The Type A is the aggressive, ambitious, impatient type, who is said to be prone to hypertension, ulcers, heart attack, strokes, depression and others. (2) The Type C is the quiet, introvert, self destructive, that exhibits low resistance to colds, other viral diseases and cancer.

Finally the type B is the one that controls stress and benefits from it. (3)

Stress control techniques and other means were developed that would try to transform Types A and C into Type B. (Biofeedback, transcen- dental medication, other relaxation and psychological procedures, nutrition, etc. 1.

From the cortisol standpoint, the Type A is reported to correspond to individuals exhibiting more elevated levels of cortisol than Type B, under stressful conditions. (4) The Type C, as it will be documented would correspond to individuals that under stress exhibit more elevated levels of cortisol than Type B, but associated with an impaired inter- feron response.

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As such, a biochemical formula might explain why the Type A de- veloped heart attacks, strokes, depression whereas Type C develops low resistance to colds, other viruses and cancer.

CORTISOL

1. Cortisol (Hydrocortisone, 17-hydroxy corticosteriod, 17-OHCS) is a hormone secreted by the adrenal cortex.

The raw material for cortisol is cholesterol; the exogenous choles- terol, in normal conditions accounts for 80% of the total cortisol production, 20% being synthesized by the adrenal cortex. The total amount of cortisol produced in normal conditions is about 20 mg/day. In man, its levels in peripheral plasma range from lo-20 ug/day with a mean value of 14 ug + 6, on samples taken at 8:00 AM and 4-10 ug% with a mean value of 7 ug + 3 at 5:00 P.M. Other methods of measure- ment provide different figures, but the one presented above is com- mercially used by medical laboratories using a radio-immuno assay technique. Cortisol or total cortisol in peripheral blood exists in three forms. About 80% is bound to a special binding protein named corticosteriod binding globulin (CBG),or transcortin, 10% is bound to serum albumin and the remaining 10% travels as free cortisol. (5) Most researchers agree that the free cortisol is metabolically active (6) but there is some evidence that the protein bound cortisol is also exerting a biological effect. (7) When the 1 evels of total cortisol are elevated, these elevations refer mainly to free cortisol and albumin bound cortisol with little change in the levels of cortico- steroid binding globulin. The implication is that under stress, the rise in the cortisol levels refers mainly to biologically active free cortisol and albumin bound cortisol.

Murray et a,l (8) in a study comparing “bound” versus “free cortisol” in health, stresss and at death, states that stressful situations in man, regardless of the outcome, are associated with increased plasma levels of biologically active “free cortisol”. ,

Some cortisol values comparing normal, sick and dead are very impressive; we have compiled some from Murray’s paper.

Total Cortisol and Free Cortisol Levels

Subject Total Cortisol Free Cortisol

Normal Subject

Surgery

Burns

12 + 6 ug/dl 1.0 + 0.8 ug/dl

24 - 48 0.6 - 9.3

39 - 133 7.6 - 38

Infections 63 - 99 16 - 33

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Death After Long- Standing Illness

90 + 15 35 + 7

Death Preceded By 137 + 19 57 + 7 Prolonged Period of Hypertension with Peripheral Cirtula- tory Failure

Notice the cortisol values, for free cortisol, after death in the last two groups. The samples of blood were taken, 2-4 hours after death.

Yet this message coming from beyond the grave is difficult to in- terpret. Is this elevated cortisol a witness of tremendous anxiety or terror before death? Or is it because of high levels of cortisol associated with a long illness that the death has occured? It is of interest to mention that Sandberg et al (9) had noticed a sudden in- crease in plasma cortisol 2-7 days before death. Regardless of this hypothetical question, numerous diseases are associated with elevated levels of cortisol. Among them depression (101 cancers of all types (111 hypertension (121 ulcers (131 myocardial infarction (14) diabetes (15) infections (16) alcoholism (171 obestity (18) chronic painful diseases, organic; arthritis and other (19) or psychological (20) cerebral vascular accidents -CVA- (211 psychosis of the aging (22) skin diseases; psoriasis (231 acne (24) eczema (25) and others. Parkinson’s disease (261 multiple sclerosis (27) myastenia gravis (281 are associated with stress. Even Alzheimer’s disease (291 is suspected to be associated with elevated levels of cortisol. Diseases of adaptation, are not limited to individuals living on earth only. Astronauts plagued by symptoms of Space Adaptaiton Syndrome, one of them being Bill Lenoir during the fifth Columbia shuttle, are as exposed to stress, elevations of cortisol, and disruption of its cir- cadian rhythm, as anybody down on earth. Hale and Williams and Leach et al have found disrupted and/or elevated levels of adrenocortical responses during simulated orbital flight (30) and on Apollo 17 crew members (31).

INTERFERON

Cortisol can affect profoundly the immune resistance of the body. It fully qualified to be a potential powerful immunosuppressor.

Cortisol lyses lymphoid tissues in thymus and lymph nodes (32). It affects selectively T-lymphocytes sub-populations. It reduces the level of T-helper cells (33) increases the level of T-suppressor cells (34) and inhibits production of cells with natural killer (NK) capa- bilities (35). Fibroblast growth is also inhibited (36).

Since T-lymphocytes and fibroblasts are major producers of interferon; immune and beta (37) there may be some cause/effect relation between stress and diminished immune resistance to viral infections and cancer. Cortisol acts not only on interferon producers but on interferon itself.

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Chang and Rasmussen (38) documented the stress induced suppression of interferon in experimental animals. Mendelson et al (39) and Solomon, Merigan and Levine (40) showed that cortisol and other corticoids exert a direct action in vitro and in experimental animals in preventing interferon synthesis.

While there is substantial evidence to document that chronic diseases are indeed associated with elevated levels of cortisol, some associated with diminished interferon response, the unanswered key question is: Are elevated levels of cortisol the result of chronic diseases, or is a chronically elevated level of cortisol manufactured under continuous stress, a cause, or the cause of chronic diseases?

If the answer is that “high” cortisol is the result of chronic di- seases, there is nothing new to it. But if the answer is that cortisol is a cause or the cause of chronic diseases, then some conclusions with major consequences will have to be drawn.

CORTISOL AS A CAUSE OF “STRESS” DISEASES

I submit that the second answer is correct. Cortisol is a cause or the cause of chronic diseases. While cortisol levels can be elevated tempo- rarily because of acute stress, in its alarm phase, if continuously manufactured under chronic stress, cortisol will become a cause or the cause of chronic diseases. Three types of evidence will be provided to substantiate this claim:

1. Elevated levels of cortisol precede certain diseases and do not follow them.

Cancer. In vivo studies carried out by Walker, et al. show that in two groups of mice treated with low and high doses of cortisol, on a long term basis, 56% of the mice died of sarcomas in the low cortisol group, whereas 76% died of sarcomas in the high cortisol reeimen group.

In humans, in a paper entitled “Does Endogenous Cortisol Play a Role in the Development of Cancer?” Klein (42) had shown that human lymphocytes are capable of metabolizing cortisol, an immuno suppressor, into meta- bolites devoid of immunosuppressive capabilities. This cortisol meta- bolizing action is enhanced by a lymphocytic - cortisol - metabolism - enhancing factor (LCMEF) that KIein had identified in the plasma. Through elegant experiments, Klein was able to show that cortisol in- duced lymphopenia, and disappearance of the LCMEF precedes appearance of cancer. He concludes that the destruction by cortisol of these two immunoresistance agents opens the way for malignant cells to proliferate and form tumors.

Elevated levels of cortisol have been found in all types of cancers (11-12)

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Recurring Herpes Genitalis In an epiemiological report on 375 patients with recurrent herpes genitalis, Bierman (43) reported that emotional stress, induced a reactivation of genital recurrences in 86% of the cases. He suggested that these recurrences were triggered by elevated levels of cortisone, associated with emotional stress.

Diabetes, Diabetic Retinopathy One of the side effects of adrenocortical steroid therapy, in patients needing this type of treatment is diabetes. In clinical practice Inga and Thorn, since 1940, had reported cortisol to be the “causation of the diabetes”, and very recently (19831, Bhatia et al. (44) had found elevated levels of cortisol in early as well as in advanced stages of diabetic retinopathy. They conclude that: “These findings suggest that increased plasma cortisol levels may take some part in the production of diabetic retinopathy.”

2. When elevation of cortisol levels is induced through the use of corticosteroids, in patients suffering diseases requiring this type of treatment, conditions mimicking chronic diseases would appear. When this therapy would be discontinued, these “chronic diseases” would disappear. Information regarding this has been provided by Goodman and Gilman’s Pharmacology (45) and the Physicians Desk Reference, (PDR) 1980 (46) in chapters dealing with side effects of corticosteriod therapy. Side effects as quoted in Goodman and and Gilman’s:

Carbohydrate Metabolism: Prolonged exposure to large doses of glucocorticoids induces: Diabetes-like state, hypoglocemia in the fasting subject.

Lipids : Dramatic redistribution of fat that occurs in the hypercorticoid state, in deposits of the back of the neck (buffalo hump) and”moon face”.

Electrolytes and Water Balance: Cortisol induces sodium reten- tion and postassium excretion, leading to hypertension.

Central Nervous System: Anxiety, depression, psychotic reactions.

Side effects of long-term corticoid therapy as quoted by Physicians Desk Reference (PDR).

Hypertension, congestive heart failure in susceptible patients, osteoporosis, vertebral compression, fractures, peptic ulcers with possible perforation and hemorrhage, pancreatitis, increased intracranial pressure with papilledema, convulsions, vertigo headaches, manifestation of latent diabetes mellitus, psychotic manifestations, insomnia, mood swings, personality changes, severe depression to frank psychotic manifestations.

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All these corticoid induced side effects are practically undis- tinguishable from “chronic diseases” as they are seen in the every day medical practice.

A case in point is Cushing’s syndrome, regardless of whether exo- genous or endogenous corticoid induced. The cause and the symptoms are the same in both situations. By definition Cushing’s syndrome occurs whenever cortisol in excessive quantities is chronically avail- able to peripheral tissues (47). Its clinical manifestations are: obesity, moon face, hypertension, acne, backache (osteporosis), transient diabetes, depression (48) with its symptoms of decreased concentration and memory, decreased libido, insomnia, fatigue (49).

It is of interest to reproduce a comment made in Goodman’s and Gilman’s pharmacology. “A smaller but significant percentage of patients treated with high doses of cortisol become anxious or depressed and a still smaller percentage exhibit incidence of neuroses and psychoses among patients with Cushing’s syndrome. The abnormali- ties of behavior usually disappear when the corticosteroids are with- drawn or the Cushing’s syndrome is effectively treated.”

This refers also to cortisol levels and physical appearance both re- turning to normal. (49)

3. Cortisol lowering pharmaceuticals in the treatment of “chronic diseases”.

A number of pharmaceutical products have been shown to induce unexpected, beneficial, sometimes dramatic results, when used in various chronic diseases, which were totally unrelated, but all having in common elevated levels of cortisol. All these phar- maceuticals have been shown to have some cortisol lowering capabilities.

a. Phenytoin (Dilantin, Diphenylhydantoin, DPH) is a product approved by FDA, for the treatment of epilepsy.

A book authored by Jack Dreyfus “A Remarkable Medicine Had Been Overlooked” is bringing abundant evidence, that Dilantin induces beneficial results in a wide range of diseases from depression, hypertension, ulcers, migraine headaches to many others. A check of references, revealed that Dilantin has cortisol antagonistic capabilities, when tested in tissue cultures (50), experimental animals (511, and in clinical use including in Cushing’s syndrome. (52)

b. Procaine (Gerovital H3) Procaine is able to prevent experimental ulcers induced by stress in animals, (53)

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C. Vitamin C (Ascorbic Acid) advocated by Linus Pauling as effective in viral diseases, cancers, etc., has an inhibi- ting effect on cortisol, following adrenal stimulation (541, and elevates blood concentration of salicylates (55).

d. Salicylates (Aspirin, etc.) have cortisol lowering capabi- lities even when cortisol levels are normal (56). Aspirin prevents release of prostaglandins from spleen and platelets and prevents synthesis of proetaglandins from arachidonic acid (57). It is known that prostaglandins El and F’s increase the concentration of cortisol by a direct action on the adrenals (58).

e. Cimetidine, a histamine HZ-receptor inhibitor, was able to prevent development of gastric ulcers, induced in rats by chronic administration of predisolone and hydrocortisone (59).

f. Lidocaine (KRONOS) - While the products mentioned above were found incidentally to have cortisol lowering capabilities, Kronos (60) is a product that was developed specifically with’ the cortisol theory in mind.

Results obtained so far with this product look very promising. Kronos seems to be a forerunner in a new class of pharmaceuti- cals the “cortisol antagonists”.

CONCLUSION

An attempt is being made to define a biochemical formula for stress, as an overproduction of cortisol + an impaired interferon response. When this “formula” is present for extended periods of time, chronic diseases appear, diseases similar to those induced by extended periods of cortisol/cortisone therapy. Elevated levels of cortisol precede certain diseases, and do not follow them.

When pharmaceuticals with cortisol lowering capabilities are used in chronic diseases, but all having in common elevated levels of cortisol, alleviation of symptoms and/or diseases, would occur. The “Stress formula” mentioned above, has potential applications in the field of diagnostic, therapy and prevention.

In the therapy of diseases of unknown origin (Alzheimer’s, MS, ALS, Coma) where cortisol is suspected to play a role, a cortisol-lowering therapy might be considered, if no other forms of treatment are available.

Stress and its biochemical counterpart cortisol in terms of elevated levels or disturbances of its circadian rhythm, might eventually be shown to play a role not only in “old” stress diseases ranging from depression to cancer, but in “new” civilization stress diseases, ranging from mild ones like jet lag and Space Adaptation Syndrome to more serious ones from increased recurrences of herpes genitalis to acquired immune deficiency syndrome (AIDS).

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In preventive medicine, elevated levels of cortisol can be a useful

predictor of suicide (61) and when checked in the cord blood of new-

borns, can provide important clues on the role of genetics vs future

resistance of individuals to stress and stress diseases (62).

Gold (47) in his description of symptoms of Cushing's syndrome states: "The lack of any single manifestation unique to Cushing's syndrome creates serious and long recognized clinical problems. One such

problem reflects the commonplace futures of the syndrome that if sur- veyed individually, could encompass perhaps half the adult U.S. popu-

lation". That does not mean that one hundred and ten million Americans

are suffering from Cushing's syndrome, but they are experiencing one

or more symptoms of elevated cortisol level.

A measurement of cortisol of these individuals might reveal figures that are still in the normal range, but bordering superior limit.

These individuals might experience the first symptoms of stress or stress diseases namely unexplained fatigue, mild depression,

impairment of sex life, memory problems, and yet if laboratory tests

would be checked, all tests would be "normal".

In these individuals, cortisol lowering means including pharmaceuti-

cals, might prevent these "stress" symptoms from becoming "stress"

diseases.

This would be an effective way to do preventive medicine, that is

said to be the medicine of the future.

Acknowledgement

Excellent secretarial work by Tina Weyman, is greatly appreciated.

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