Clinical Interactions of the Neuroendocrine-Immune System with
Hormone Disorders
Datis Kharrazian, DC, MS
The stress response is an orchestration of nervous, endocrine and immune systems.
Neurological adaptation to stress requires integrative synthesis of the hypothalamic,
neocortical, basal ganglionic and mesenchepalic activation. The coordination of these
neurological tissues in a stress response is based on activity of the
corticolenticulopallidostratiothalmalic loop, neocortical-hypothalamic modulation of the
pontomedullary reticulospinal tract and mesencephalic integration of the locus ceruleus
on ponotmedullary pools of neurons.
The immune system, via cytokines, immunokines, neurotransmitters, prostanoids,
prostaglandins, and leukotrienes transmits signals from the body to segmental and
suprasegmental structures. The expression of these cellular messengers impacts excitation
and inhibition of the central integrative state of the neuraxis and leads to phenotypic
clinical expressions of immune and hormone dysfunction seen commonly in a clinical
practice settings.
Activation of the neuroendocrine-immune system leads to the production of
cytokines that may be expressed in the body as TH-1 or TH-2 subset dominance,
suppression of natural killer cells and abnormal immune modulation. The exaggerated
expression of cellular messenger systems leads to inflammatory disorders,
hypersensitivities, suppression of hormonal feedback systems, gut mucosa dysfunction,
hindered phase I and II detoxification, etc.
Chronic expression of the neuroendocrine axis leads to central neuronal cell
death, trans-neural degeneration, global loss of mitochondria pools and far reaching
clinical expressions such as chronic fatigue syndrome, allergies, asthma, depression, etc.
The expressions of abnormal neuroendocrine dysfunction can be evaluated using
hormone profiles, cytokine testing, immune panels, VNG testing and standard physical
examination. Modulation of abnormal neuroendocrine expression may be achieved by
removing antigenic stimulation, herbal compounds, nutrition, neurological rehabilitation,
and cognitive and physical exercises.
1
rabbits. Horumon To Rinsho 197018:601-605.
Koska M, Kikui S, Fujiwara T. Kimoto T. Aciton of panathine on the adrenal cortex. Horumn ToRhinsho
1966;14:843-847.
Onuki M, Suzawa A. Effect of panthine on the function of the adrenal cortex. Clinical experience using
panatethine in cases under steroid hormone treatment. Horumon To Rhinsho 1970;18:937-940.
Bhatt HR. Antagonistic effectsof pentagastrin and cortisol on plasma level, urinary excretion and hepatic
and renal uptake of vitamin B12 after intravenous injection in the cat. J Physiol 296, 1979.
Crook TH, Petrie W, Wells C, Massari DC, Effects of phosphatidylserine in Alzheimer’s Disease.
Psychopharmacol Bull 1992;28:61-66.
Ameducci L, Crook TH, Lippi A, et al. Use of phosphatidylserine in Alzheimer’s Disease. Ann Ny Acad
Sci 1991;640:245-249.
Cenacchi T, Bertoldin T, Farina C, et al. Cognitive decline in the elderly: A double-blind, placebo
controlled multicenter study on efficacy of phosphatidylserine administration. Aging Clin Ecp Res
1993;5:123-133.
Latorraca S, Piersanti P, Tesco G, et al. Effects of phosphatidylserine on free radical susceptibility in
human diploid fibroblasts. Neurol Transm Park Dis Dement Sect 1993;6:73-77.
Maggioni M, Picotti GB, Bondiolotti GP, et al. Effects of phosphatidylserine therapy in geriatric patients
with depressive disorders. Acta Psychiatr Scand 1990;81:265-270.
Brambilli F, Magioni M. Blood levels of cytokines in elderly patients with major depressive disorder. Acta
Psychiatr Scand 1998;97:309-313.
Brambilla F, Maggioni M, Panerai AE, et al. Beta-endorphin concentration in peripheral blood
mononuclear cells of elderly depressed patients effects on phosphatidylserine therapy. Neuropsychobiology
1996;34:18-21.
Palmieri G. Double-blind controlled trial of phosphatidylserine in patients with senile mental deterioration.
Clin Trials J 1987;24:73-83.
Kidd PM, Phosphatidylserine; membrane nutrient for memory. A clinical and mechanistic assessment.
Altern Med Rev 1996;1:70-84.
Cenacchi T, Betoldin R, Farina C, et al. Cognitive decline in the elderly. A double blind, placebocontrolled multicenter study on efficacy of phosphatidylserine administration. Aging 1993;5:123-133.
Crook TH, Tinklenberg J, Yesavage J, et al. Effects of phosphatidylserine in age-associated memory
impairment. Neurology 1991;41:644-649.
Monteleone P, Mag M, Beinat, et al. Blunting of chronic phosphatidylserine administration of the stressinduced activation of the hypothalamic-pituitary-adrenal axis in healthy men. Eur J Clin Pharmacol
1992;41:385-388.
Monteleone P, Beintat L, Tanzillo C, et al. Effects of phosphatidylserine on the neuroendocrine response
to physical stress in humans. Neuroendocrinology 1990;52:243-248.
Nerozzi D, Aceti F, Melia E, et al. Early cortisol escape phenomenon reversed by phosphatidylserine in
elderly normal subjects. Clinical Trial J 1989;26:33-38.
Fahey TD, Pearl MS. The hormonal and perceptive effects of phosphatidylserine administration during
two weeks of resistive exercise-induced overtraining. Biol Sport 1998;15:135-144.
LoPresti, JS and Nicoloff, JT. Thyroid response to critical illness. Endocrinology of Critical Disease.
Human Press. Totowa. NJ. 1997. pp 157-173.
Strakis, CA and Chrousos, GP. Neuroendocrinology and Pathophysiology of the Stress System, Ann Ny
Acad Sci, Vol. 771, pp. 1-18,1995.
Stockigt, JR. Update on the Sick Euthyroid Syndrome, in Baverman, LE ed., Diseases of the Thyroid,
Humana Press, Totowa, NJ, 1997, pp. 49-68.
Van Der Pomp G., et al. Elevated basal cortisol levels and attenuated ACTH and cortisol resposes to a
behavioral challenge in women with metastatic breast cancer. Psychoneuroendocrinology, 21(4). 361374,1996.
Guhad, FA, et al. Salivary IgA as a marker of social stress in rats. Neurosci Lett, 216(2). 137-140,1996.
Cunningham-Rundies, C., et al. Proc. Nat Acada. Sci USA. 75:3387,1978.
Scott, H., et al. Scan. J. Gastroenterol. 15:81, 1980.
Daynes, R., et al. Eur J Immunol. 20:793,1990.
Maggioni M, Picotti GM, Bondiolotti GP, et al. Effects of phosphatidylserine therapy in geriatric patients
with depressive disorders. Acta Psychiatr Scan 1990;81:265-270.
2
Havel PJ. Leptin production and action: relevance to energy balance in humans. Am J Clin Nutr.
1998;67(3):355-358.
Freidman JM. Leptin, leptin receptors, and the control of body weight. Nutr Rev. 1998;56(2):S38-S46.
Brindly DN. Role of glucocorticoids and fatty acids in the impairment of lipid metabolism observed in
metabolic syndrome. Int J Obes Relat Metab Disord 1995;19(Suppl 1):S69-75.
Bergh, F.T., et al. Dysregulation of the hypothalamo-pituitary-adrenal axis is related to the clinical course
of MS. Neurology 53; 772-777,1999.
.Grimm JJ. Interaction of physical activity and diet: implications for insulin-glucose dynamics. Public
Health Nutr 1999;2:363-368.
Moore MA, et al. Implications of the hyperinsulinemia –diabetes-cancer link for preventative efforts. Eur J
Cancer Prev 1998;7:89-107
Despres JP, et al. Hyperinsulinemia as an independent risk factor for ischemic heart disease. N Eng J Med
1996;334:952-957.
Tiihonen M, Partinen M. Narvanen S. The severity of obstructive sleep apnea is associated with insulin
resistnace. J Sleep Res 1993;2:56-61.
Arthur LS, Selvakumar R, Seshardir MS. Hyperinsulinemia in polycystic ovary disese. J Reprod Med
1999;44:783-787.
Benzi L, et al. Intracellular hyperinsulinemia: a metabolic characteristic of obesity with and without type 2
diabetes: intracellular insulin in obesity and type 2 diabetes. Diabetes Res Clin Pract 1999:46:231-237.
Stoll BA. Essential fatty acids, insulin resistance and breast cancer risk. Nutr Cancer 1998;31:72-77.
Tedde R, Sechi LA, Marigliao A, Palo A, Scano L. Antihypertensive effect of insulin reduction in diabetic
hypertensive patients. Am J Hypertens 1989;2:163-170.
Randeree H, Omar MA, Motala AA, Seedet MA. Effect of insulin therapy on blood pressure in NIDDM
patients with secondary failire. Diabetes Care 1992;15:1258-1263.
Zavaroni I, Mazza S, Dall’aglio E, et al. Prevelance of hyperinsulinemia in patients with high blood
pressure. J int Med 1992;231:235-240.
Potter van Loon, et al. The cardiovascular risk factor plasminogen activator inhibitor type I is related to
insulin resistance. Metabolism 1993;42:945-949.
Juhan-Vague, et al. Fibrinolytic factors and the risk of myocardial infarction or sudden death in patients
with angina pectoris. Circulation 1996;94(9):2057-2063.
Dietschy JM, Brown MS. Effect of alterations of the specific activity of the intracellular acetyl CoA pool
apparent rates of hepatic cholesterogenesis. J Lipid Res 1974;15:508-516.
Swensen TL. The role of cholesteryl ester transfer protein in lipoprotein metabolism. Diabetes Metab Res
1991;7:139-153.
Sozen I, Arici A. Hyperinsulinism and its interaction with hyperandrogenism in polycystic ovary
syndrome. Obest Gynecol Surv 2000;55:321-328,
Nestler J. Insulin resistance effects on sex hormones and ovulation in the polycystic ovary syndrome.
In:Reaven G, Laws A, eds. Contemporary Endocrinology: Insulin Resistance. Totowa NJ: Humana Press;
1999.347-365.
Dahlgreen E, et al. Women with polycystic ovary syndrome wedge resected in 1956 to 1965: a long-term
follow-up focusing on natural history and circulating hormones. Fertil Steril 1992;57:505-513.
Oberfiled S. Metabolic lessons from the study of young adolescents with polycystic ovary syndrome, is
insulin indeed the culprit. J Clin Endocrinol Metab 2000;85:3520-3525.
Wild RA. Obesity, lipids, cardiovascular risk and androgen excess. Am J Med 1995;98:27S-32S.
Wu XK, et al. Ovarian-adrenal cross-talk in polycystic ovary syndrome: evidence of wedge reCategory.
Euro J Endocrinol 2000;143:383-388.
Singh A, et al. Effect of insulin-like growth factor-type I (IFG-1) and insulin on the secretion of sexhormone binding globulin and IGF-1 binding protein (IBP-1) by human hepatoma cells. J Endocrinol
1990;124:R1-3.
Nestle J, et al. A direct effect of hyperinsulinemia on serum sex-hormone binding globulin levels in obese
women with polycystic ovary syndrome. J Clin Endocrinol Metab 1991;72:83-89.
Ciaraldi TP, et al. Cellular mechanisms of insulin resistance in polycystic ovarian syndrome. J Clin
Endocrinol Metab 1992;75:577-583.
Peiris AN, Mueller RA, et al. Relationship of androgenic activity to splanchnic insulin metabolism and
peripheral glucose utilization in premenopausal women. J Clin Endocrinol Metab 1987;64:162-169.
3
Pasquali R, Fabbri R, et al. Effect of weight loss and antiandrogenic therapy on sex hormone blood levels
and insulin resistance in obese patients with polycystic ovaries. Am J Obstet Gynecol 1986;154:139-144.
Conway GS, Honour JW, Jacobs HS. Heterogeneity of polycystic ovary syndrome: clinical endocrine and
ultrasound features in 566 patients. Clin Endocrinol 1989;30:459-470.
Yen SS. The polycystic ovary syndrome. Clin Endocrinol 1980;12:177-207.
Wildt L, Sir-Petermann T, et al. Opiate antagonist treatment of ovarian failure. Hum Reprod 1993;8:168174.
Jenkins PJ, Grossman A. The control of gonadotrophin releasing hormone pulse generator in relation to
opiod and nutritional cues. Hum Reprod 1993;8:154-161.
Carmina E, Ditkoff EC, et al. Increased circulating levels of immunoreactive beta-endorphin in polycystic
ovary syndrome is not caused by pituitary secretion. Am J Obstet Gynecol 1992;167:1819-1824.
Velazquez E, et al. Menstrual cyclicity after metaformin therapy in polycystic ovary syndrome. Obstet
Gynecol 1997;90:392-395.
Venturoli S, et al. Ketoxonazole therapy for women with acne and/or hirstutism. J Clin Endocrinol Metab
1990;71:335-337.
Fuenmayor NM, et al. Relations between fasting serum insulin, glucose, and dehydroepiandrosteronesulfate concentrations in obese patients with hypertension: short term effects of antihypertensive drugs. J
Card Pharm 1997;30:523-527.
Nestler JE, Clore JN, Blackard WG. Dehydroepiandrosterone: the missing link between hyperinsulinemia
and atherosclerosis. FASEB 1992;9:3073-3074.
Zakrzewska KE, et al. Glucocorticoids as counterregulatory hormones of leptin: toward an understanding
of leptin resistance. Diabetes 1997;46: 717-719.
Zakrzewska, et al. Induction of obesity and hyperleptinemia by central glucocorticoid infusion in the rat.
Diabetes 1999;48:365-370.
Bermeis K, Vosmeer S, Kelly U. Effects of gluccorticoids and of growth hormone on serum leptin
concentrations in man. Eur J Endocrinol 1996;663-665.
Weiderpass E, et al. Diabetes mellitus and risk of large bowel cancer. J Natl Cancer Inst 1997;89:660-661.
Corpet D, et al. Insulin injections promote the growth of aberrant crypt foci in the colon of rats. Nutr
Cancer 1997;27:316-320.
Storlien LH, et al. Fatty acids, triglycerides and syndromes of insulin resistance. Prostaglandin Leukot
Essent Fatty Acids 1997;57(4-5):379385.
Brenner R. Nutrition and hormonal factors influencing desaturation of essential fatty acids. Prog Lipid
Res 1982;20;41-48.
Shanmugasundaram ERB, et al. Use of Gynema sylvestre leaf extract in the control of blood glucose in
insulin-dependent diabetes mellitus. J Ethanopharmacol 1990; 30: 281-294.
Persaud SJ, Al-Majed H, Raman A, Jones PM. Gymnema sylvestre stimulates insulin release in vitro by
increased membrane permeability. J Endocrinol 1999; 163(2):207-12.
Shanmugasundaram ERB, et al. Possible regeneration of the islet of Langerhans in streptozoticin-diabetic
rats given Gynema sylvestre leaf extracts. J Ethnopharmacol 1990 30; 265-279.
Shanmugasundaram KR, et al. Enzyme changes and glucose utilization in diabetic rabbits: the effect of
Gymnema sylvestre, R.Br. J Ethnopharmacol 1983;7(2):205-34.
Kaskaran K, et al. Antidiabetic effect of a leaf extract from Gymnema sylvestre in non-insulin dependent
diabetes mellitus patients. J Ethnopharmacol 1990; 30: 295-305.
Khare AK, Tondon RN, Tewari JP. Hypoglycemic activity of an indigenous drug (Gymnema sylvestre,
‘Gurmar’) in normal and diabetic persons. Indian J Physiol Pharmacol 1983;27(3):257-8.
Striffler JS, Polansky MM, Anderson RA. Overproduction of insulin in the chromium-deficient rat.
Metabolism 1999;48:1063-1068.
Striffler JS, Polansky MM, et al. Chromium improves insulin response to glucose in rats. Metabolism
1995;44:1314-1320.
Anderson RA, Polansky MM, Bryden NA, Canary JJ. Supplemental-chromium effects on glucose, insulin,
glucagon, and urinary chromium losses in subjects consuming controlled low-chromium diets. Am J Clin
Nutr 1991:54:909-916.
Offenbacher EG, Pi-Sunyer FX. Beneficial effect of chromium-rich yeast on glucose tolerance and blood
lipids in elderly subjects. Diabetes 1980;29:919-925.
Riales R, Albrink MJ. Effect of chromium chloride supplementation on glucose tolerance and serum lipids
including high-density lipoprotein of adult men. Am J Clin Nutr 1981;34:2670-2678.
4
Evans GW, Browman TD. Chromium picolinate increases membrane and rate of insulin internalization. J
Inorg Bio 1992;46:243-250.
Roeback, Jr. JR, Hla KM, Chambless, et al. Effects of chromium supplementation on serum high density
lipoprotein cholesterol levels in men taking beta-blockers. Ann Intern Med. 1991:115:917-924.
Anderson R, Cheng N, Bryden, et al. Beneficial effects of chromium for people with type II diabetes.
Diabetes. 1996;45:124A.
Anderson RA, Cheng N, Bryden NA, et al. Elevated intakes of supplemental chromium improve glucose
and insulin variables in individuals with type 2 diabetes. Diabetes 1997;46:1786-1791.
Levine R, Streeten D, Doisy R. Effect of oral chromium supplementation on the glucose tolerance of
elderly human subjects. Metabolism 1968;17:114-125.
French RJ, Jones PJ. Role of vanadium in nutrition: metabolism, essential and dietary considerations. Life
Sciences. 1992;52:339-346.
Shechter, Li Meyerovitch, et al. Insulin-like actions of vanadate are mediated in an insulin receptor
independent manner via non-receptor protein tyrosine kinases and protein phosphotyrisine phosphates. Mol
Cell Biochem. 1995;153(1-2):39-47.
Halberstm M, Cohen N, Shlimovish P, et al. Oral vanadyl sulfate improves insulin sensitivity NIDDM but
not in obese nondiabetic subjects. Diabetes. 1996;45:659-665.
Boden G, Chen X, Ruiz J, et al. Effects of vanadyl sulfate on carbohydrate and lipid metabolism in patients
with non-insulin dependent diabetes mellitus. Metabolism. 1996;45:1130-1135.
Cohen N,Halberstam M, Shlimovih P, et al. Oral vanadyl sulfate improves hepatic and peripheral insulin
insensitivity in patients with non-insulin dependent diabetes mellitus. J Clin Invest. 1995;95:2501-2509.
Goldfine AB, Simonson DC, Folli F, et al. Metabolic effects of sodium metavandate in humans with
insulin-dependent and noninsulin-dependent diabetes mellitus in vivo and vitro studies. J Clin Enco and
Meta. 1995;80(11);3311-3319.
Shang H, Osada K, Maebashi M, et al. A high biotin diet improves the impaired glucose tolerance of longterm spontaneously hyperglycemic rats with non-insulin dependent diabetes mellitus. J Nutr Sci Vitamin
1996;42:517-526.
Jacob S, Henriksen EJ, Schiemann AL, et al. Enhancment of glucose disposal in patients with Type 2
diabetes by alpha-lipoic acid. Arzneim-Rosch Drug Res 1995;45(2):872-874.
Jacob S, Streeper RS, Fogt DL, et al. The antioxidant alpha-lipoic acid enhances insulin-stimulated glucose
metabolism in insulin resistant rate skeletal muscle. Diabetes 1996;45:1024-1029.
Streeper RS, Henriksen EJ, Jacob S, et al. Differential effects of lipoic acid stereoisomers on glucose
metabolism in insulin resistant skeletal muscle. Am J Physiol 1997;273:E185-E191.
Konard T, Vicini P, Kuster K, et al. Alpha-lipoic acid treatment decreases serum lactate and pyruvate
concentrations and improves glucose effectiveness in lean and obese patients with type 2 diabetes. Diabetes
Care 1999;22(2):280-287.
Rudich A, Tirosh A, Potashinik R, Khamaisi M, Bashan N. Lipoic acid protects against oxidative stress
5