- Email: [email protected]
Stress, adrenals, and vitamin C
Medical Hypotheses 17: 399-402, 1985
STRESS, ADRENALS, AND VITAMIN C J. Richardson. Department of Biology, Old Dominion University, Norfolk, Virginia, 23508 ABSTRACT Large daily doses of vitamin C maintained high levels of corticosteroids in the blood of stressed mice. Of these corticosteroids, glucocorticoid is known to suppress the immune response. It is hypothesized that large doses of vitamin C may reduce the organism's immunity to disease when stress is present. INTRODUCTION Selye (1) was the first to describe the role of glucocorticoids in resistance to stress. Later research showed that glucocorticoids generally suppressed immune responses as well as inflammatory reactions (2). Current research proposes that stress-induced increases in glucocorticoid levels is to protect not against the source of stress itself but against the normal defense reactions that are activated by stress and this is accomplished by turning off those reactions which themselves would threaten homeostasis. The suppressive influence on the immune system by glucocorticoids is sufficiently delayed to the initial stress stimulus to allow the defense mechanism to be activated. This delay is measured in hours (3). The physiological function of the delayed rise in glucocorticoid levels during the primary immune response may be to preserve the antigenic specificity of the response by preventing lymphocytes with little affinity for the antigen from proliferating unrestrictedly which could lead to autoimmunity (b-7). Glucocorticoid effects are not actions on their target cells but are secondary effects carried by a network of intercellular mediators such as prostaglandins and lymphokines which are under glucocorticoid control (8,9). However, once the primary defense reactions have coped with a stress-induced disturbance and glucocorticoids have suppressed the defense reactions, the most important physiological need is to reduce the levels of glucocorticoids to release the immune system from their control. This occurs through a negative feedback system through ACTH. As corticoid levels increase ACTH secretion decreases which in turn reduces corticoid blood levels (10). The adrenal cortex is unable to increase its rate of secretion of glucocorticoids without first receiving an increased 399
quantity of ACTH secreted by the anterior lobe of the pituitary. It appears that stress increases ACTH secretion because the anterior pituitary responds to a decrease in concentration of corticoid hormone in the body fluids (11). Another factor in corticosteroid release is ascorbic acid. Steroid release has never preceded ascorbic acid release from the adrenals nor has ascorbic acid release occurred in the absence of steroid release. ACTH secretion during stress releases ascorbic acid from the adrenals and corticoid secretion then follows. As corticoid blood levels increase, ascorbic acid level falls back to normal (12). Perhaps the effect of ACTH on corticoids is not direct but is a secondary effect through ascorbic acid. METHOD In this study 30 male CFW mice were used. All 30 were born in our laboratory and weaned 24 to 28 days after birth. Four males were randomly selected from each litter and placed in pairs in 18 x 25 x 3Ocm Wahmann cages. Cotton nesting material from their parent's cages was placed with each pair. The control room was kept at 20C + 2C with a 12 hour photoperiod and extended from 0700 to 1900 hours. Water and Purina laboratory chow were supplied in unlimited quantities. Extraneous odors were kept from the control room by an exhaust fan in an adjacent room. Only one person fed and watered the animals during the study. At 70 days of age 20 mice were removed from the control room to a room for stressing. Ten control animals remained undisturbed in the control room. Ten of the experimental animals received daily intraperitoneal injections of one mg of sodium ascorbate for five days. The other 10 animals received daily placebo injections of one mg of sodium bicarbonate for five days. Stressing of experimental animals consisted of daily submersion in water for one minute. On the fifth day two animals from each group were sacrificed by cervical fracture at zero, two, four, six, and eight hours after stressing. Blood was collected by rapidly opening the abdominal cavity and cutting the vena cava directly above the adrenal glands. The serum was analyzed for corticosterone after the method of Zenker and Bernstein (13) using a Coleman 12C flourometer. The blood of each group was pooled for analysis. CONCLUSIONS An advocate of vitamin C therapy (14) states that cancer patients exhibit a decreased effectiveness of their immune system and that the simplest and safest way to enhance immunocompetence in these patients is to increase the intake of vitamin C. However, cancer patients probably have a higher stress level than do non-cancer patients because of the
400
severity of the disease. The results of our research with stressed mice have shown that large daily doses of vitamin C maintained significantly higher levels of adrenal cortical hormones (Table I) which in turn may reduce rather than improve immunocompetence. When tonic stress was present in rats (15) ascorbic acid fell dramatically to the point of near depletion after 3 hours. Perhaps this is the organism's way of adapting to stress by reducing ascorbic acid levels in the blood thus releasing the immune system from corticoid suppression. TABLE I Mean Values for Corticosterone Levels in Serum (&lOOml) for Each of Three Groups of Mice Over Eight Hours Groups
Control Stressed Stressed & Vitamin C
Sample Size
Corticosterone4Levelz (Hours) 2 0 8
(n=lO) (n=lO) 19':; 1,':: 12:: (n=lO) 20.1 19.4 19.6
125:: 1;":
19.1
1818 -
Significant difference between the three groups at p<.O5 by ANOVA REFERENCES 1. Selye H. The general adaptation syndrome and the diseases of adaptation. Journal of Clinical Endocrine Metabolism 6: 117, 1946.
2. Munck A, Leung K. Glucocorticoid receptors and mechanisms of action. Receptors and Mechanism of Action of Steroid Hormones Part II: 311, Marcel Dekker, New York, 1977. 3. Munck A, Guyx PM. Physiological Functions of Glucocorticoids in Stress and Their Relation to Pharmacological Actions. Endocrine Reviews 5: 25-44, 1984. 4. Besedovsky H, Sorkin E. Network of immune-neuroendocrine interactions. Clinical Experiments in Immunology 27: 1, 1977.
5. Besedovsky HO, de1 Ray A, Sorkin E. Antigenic competition between horse and sheep red blood cells as a hormone-dependent phenomenon. Clinical Experiments in Immundogy
371 106, 1979.
401
6. Besedovsky HO, de1 Ray A, Sorkin E. Lymphokine-containing supernatants from Con A-stimulated cells increase corticosterone blood levels. Journal of Immunology 1261 385, 1981. 7. Besedovsky HO, de1 Ray A, Sorkin E. Neuroendocrine immunoregulation. Immunoregulation, 315, Plenum, New York, 1983. 8. Guyre PM, Bodwell J, Holbrook NJ, Jeffries M, Munck A. Glucocorticoids and the immune system: activation of glucocorticoid-receptor complexes in thymus cellsl modulation of FC-receptors of phagocytic cells. Progress in Research and Clinical Applications of Corticosteroids, 14, 1982. 9. Hadden JW, Stewart WE II. The Lymphokines. Humana Press, Clifton, New Jersey, 1981. 10. Vale W, Rivier C, Yang L, Minick S, Guillemin R. Effects of purified hypothalamic corticotropin-releasing factor and other substances on the secretion of adrenocorticotropin and,8-endorphin-like immunoactivities in vitro. Endocrinology 1031 1910, 1978. 11. Goldberg ND, Haddox MK, Hartle DK, Hadden JW. The biological role of cyclic 3', 5'-guanosine monophosphate, pharmacology and the future of man. Proceedings of the Fifth International Congress of Pharmacology 5: 146-169, 1972. 12. Lipscomb H, Nelson D. Dynamic changes in ascorbic acid and corticosteroids in adrenal vein blood after ACTH. Endocrinology 668 144-146, 1960, 13. Zenker N, Bernstein DE..The estimation of small amounts of corticosterone in rat plasma. Journal of Biological Chemistry 231% 695-701, 1958. 14. Pauling L. Cancer and Vitamin C, 108-111, WWNorton Co., New York, 1979. 15. Long CN. Recent progress in hormone research. 11 99, 1947.
402
STRESS, ADRENALS, AND VITAMIN C J. Richardson. Department of Biology, Old Dominion University, Norfolk, Virginia, 23508 ABSTRACT Large daily doses of vitamin C maintained high levels of corticosteroids in the blood of stressed mice. Of these corticosteroids, glucocorticoid is known to suppress the immune response. It is hypothesized that large doses of vitamin C may reduce the organism's immunity to disease when stress is present. INTRODUCTION Selye (1) was the first to describe the role of glucocorticoids in resistance to stress. Later research showed that glucocorticoids generally suppressed immune responses as well as inflammatory reactions (2). Current research proposes that stress-induced increases in glucocorticoid levels is to protect not against the source of stress itself but against the normal defense reactions that are activated by stress and this is accomplished by turning off those reactions which themselves would threaten homeostasis. The suppressive influence on the immune system by glucocorticoids is sufficiently delayed to the initial stress stimulus to allow the defense mechanism to be activated. This delay is measured in hours (3). The physiological function of the delayed rise in glucocorticoid levels during the primary immune response may be to preserve the antigenic specificity of the response by preventing lymphocytes with little affinity for the antigen from proliferating unrestrictedly which could lead to autoimmunity (b-7). Glucocorticoid effects are not actions on their target cells but are secondary effects carried by a network of intercellular mediators such as prostaglandins and lymphokines which are under glucocorticoid control (8,9). However, once the primary defense reactions have coped with a stress-induced disturbance and glucocorticoids have suppressed the defense reactions, the most important physiological need is to reduce the levels of glucocorticoids to release the immune system from their control. This occurs through a negative feedback system through ACTH. As corticoid levels increase ACTH secretion decreases which in turn reduces corticoid blood levels (10). The adrenal cortex is unable to increase its rate of secretion of glucocorticoids without first receiving an increased 399
quantity of ACTH secreted by the anterior lobe of the pituitary. It appears that stress increases ACTH secretion because the anterior pituitary responds to a decrease in concentration of corticoid hormone in the body fluids (11). Another factor in corticosteroid release is ascorbic acid. Steroid release has never preceded ascorbic acid release from the adrenals nor has ascorbic acid release occurred in the absence of steroid release. ACTH secretion during stress releases ascorbic acid from the adrenals and corticoid secretion then follows. As corticoid blood levels increase, ascorbic acid level falls back to normal (12). Perhaps the effect of ACTH on corticoids is not direct but is a secondary effect through ascorbic acid. METHOD In this study 30 male CFW mice were used. All 30 were born in our laboratory and weaned 24 to 28 days after birth. Four males were randomly selected from each litter and placed in pairs in 18 x 25 x 3Ocm Wahmann cages. Cotton nesting material from their parent's cages was placed with each pair. The control room was kept at 20C + 2C with a 12 hour photoperiod and extended from 0700 to 1900 hours. Water and Purina laboratory chow were supplied in unlimited quantities. Extraneous odors were kept from the control room by an exhaust fan in an adjacent room. Only one person fed and watered the animals during the study. At 70 days of age 20 mice were removed from the control room to a room for stressing. Ten control animals remained undisturbed in the control room. Ten of the experimental animals received daily intraperitoneal injections of one mg of sodium ascorbate for five days. The other 10 animals received daily placebo injections of one mg of sodium bicarbonate for five days. Stressing of experimental animals consisted of daily submersion in water for one minute. On the fifth day two animals from each group were sacrificed by cervical fracture at zero, two, four, six, and eight hours after stressing. Blood was collected by rapidly opening the abdominal cavity and cutting the vena cava directly above the adrenal glands. The serum was analyzed for corticosterone after the method of Zenker and Bernstein (13) using a Coleman 12C flourometer. The blood of each group was pooled for analysis. CONCLUSIONS An advocate of vitamin C therapy (14) states that cancer patients exhibit a decreased effectiveness of their immune system and that the simplest and safest way to enhance immunocompetence in these patients is to increase the intake of vitamin C. However, cancer patients probably have a higher stress level than do non-cancer patients because of the
400
severity of the disease. The results of our research with stressed mice have shown that large daily doses of vitamin C maintained significantly higher levels of adrenal cortical hormones (Table I) which in turn may reduce rather than improve immunocompetence. When tonic stress was present in rats (15) ascorbic acid fell dramatically to the point of near depletion after 3 hours. Perhaps this is the organism's way of adapting to stress by reducing ascorbic acid levels in the blood thus releasing the immune system from corticoid suppression. TABLE I Mean Values for Corticosterone Levels in Serum (&lOOml) for Each of Three Groups of Mice Over Eight Hours Groups
Control Stressed Stressed & Vitamin C
Sample Size
Corticosterone4Levelz (Hours) 2 0 8
(n=lO) (n=lO) 19':; 1,':: 12:: (n=lO) 20.1 19.4 19.6
125:: 1;":
19.1
1818 -
Significant difference between the three groups at p<.O5 by ANOVA REFERENCES 1. Selye H. The general adaptation syndrome and the diseases of adaptation. Journal of Clinical Endocrine Metabolism 6: 117, 1946.
2. Munck A, Leung K. Glucocorticoid receptors and mechanisms of action. Receptors and Mechanism of Action of Steroid Hormones Part II: 311, Marcel Dekker, New York, 1977. 3. Munck A, Guyx PM. Physiological Functions of Glucocorticoids in Stress and Their Relation to Pharmacological Actions. Endocrine Reviews 5: 25-44, 1984. 4. Besedovsky H, Sorkin E. Network of immune-neuroendocrine interactions. Clinical Experiments in Immunology 27: 1, 1977.
5. Besedovsky HO, de1 Ray A, Sorkin E. Antigenic competition between horse and sheep red blood cells as a hormone-dependent phenomenon. Clinical Experiments in Immundogy
371 106, 1979.
401
6. Besedovsky HO, de1 Ray A, Sorkin E. Lymphokine-containing supernatants from Con A-stimulated cells increase corticosterone blood levels. Journal of Immunology 1261 385, 1981. 7. Besedovsky HO, de1 Ray A, Sorkin E. Neuroendocrine immunoregulation. Immunoregulation, 315, Plenum, New York, 1983. 8. Guyre PM, Bodwell J, Holbrook NJ, Jeffries M, Munck A. Glucocorticoids and the immune system: activation of glucocorticoid-receptor complexes in thymus cellsl modulation of FC-receptors of phagocytic cells. Progress in Research and Clinical Applications of Corticosteroids, 14, 1982. 9. Hadden JW, Stewart WE II. The Lymphokines. Humana Press, Clifton, New Jersey, 1981. 10. Vale W, Rivier C, Yang L, Minick S, Guillemin R. Effects of purified hypothalamic corticotropin-releasing factor and other substances on the secretion of adrenocorticotropin and,8-endorphin-like immunoactivities in vitro. Endocrinology 1031 1910, 1978. 11. Goldberg ND, Haddox MK, Hartle DK, Hadden JW. The biological role of cyclic 3', 5'-guanosine monophosphate, pharmacology and the future of man. Proceedings of the Fifth International Congress of Pharmacology 5: 146-169, 1972. 12. Lipscomb H, Nelson D. Dynamic changes in ascorbic acid and corticosteroids in adrenal vein blood after ACTH. Endocrinology 668 144-146, 1960, 13. Zenker N, Bernstein DE..The estimation of small amounts of corticosterone in rat plasma. Journal of Biological Chemistry 231% 695-701, 1958. 14. Pauling L. Cancer and Vitamin C, 108-111, WWNorton Co., New York, 1979. 15. Long CN. Recent progress in hormone research. 11 99, 1947.
402