We often hear of 30-year-old marathon runners who are forced into early retirement because of recalcitrant tendonitis. Are these simply cases of poor biomechanics and faulty training plans? Or are these athletes suffering from a maladaptation syndrome in which their bodies can no longer compensate for massive levels of exogenous and endogenous stress (work, family responsibilities, exercise, etc.)? Uncontrolled stress strains the entire organism. Stress increases the metabolic rate, resulting in the mobilization of stored energy sources and the eventual breakdown of muscle protein to make up for energy shortfalls.16 In short, the body attempts to maintain homeostasis at all costs. Extended bouts of stress, such as high-volume exercise, psychologic stress, or other lifestyle challenges, lead to abnormal increases in serum cortisol levels and irregular circadian rhythm variations in cortisol secretion.17 Sustained elevated levels of cortisol may lead to reduced adrenal responsiveness to ACTH.18 This is compensated for by increases in pituitary releases of ACTH in the initial stages of overtraining. However, protracted stress causes pituitary release of ACTH to decrease and, thus, the pituitary gland becomes under-responsive to stimulation. The ultimate effects of prolonged elevated levels of cortisol are suppression of corticotropin-releasing hormone and ACTH release and atrophy of the zonae fas-ciculata and reticularis as a consequence of ACTH deficiency.19 Finally, the HPA axis fails to respond to stress and stimulation.20 This clinical measurement of suppressed endocrine function may be the defining element in the accurate identification and appropriate treatment of chronic "overstress syndrome.''21
The stress response affects many hormones. Prolactin is secreted from the pituitary, which may suppress reproduction. The pancreas is stimulated to release the hormone glucagon, which raises blood sugar levels. Antidiuretic hormone, or vasopressin, is secreted from the pituitary, which maintains fluid levels. Additional hormones, such as growth hormone, luteinizing hormone, testosterone, thyroid releasing hormone (TRH), thyroid stimulating hormone (TSH), and insulin, are suppressed.22,23
Stress has been shown to impact cardiovascular health and related morbidity and mortality. Conditions such as atherosclerosis, hypertension, stroke, and hyperlipidemia have been linked to chronic and repetitive acute stress. Stress has been shown to increase inflammation primarily through the cytokine interleukin-6 and C-reactive protein (CRP).24 Research suggests that the inflammation caused by the stress response is responsible for 40% of the atherosclerosis that occurs in patients with no other known risk factors.25 Also, epinephrine has been shown to increase coagulation. Research suggests that stimulation of adrenergic receptors is responsible for platelet activation implying that the catecholamine surge may lead to increased risk of thrombosis in individuals with atherosclerosis.26 Additional studies indicate that physiological levels of norepinephrine as seen with aerobic exercise may increase platelet reactivity and hypercoagulability as well.27 Hypertension is also associated with increased physiological reactivity in the sympathetic and HPA axis. Studies indicate that individuals at higher risk for hypertension show increased cortisol, blood pressure, and heart rate in response to a psychological stressor.28 A study with nondiabetic individuals with acute myocardial infarction has also correlated increased cortisol and glucagon with insulin resistance.29
Stress is associated with irritable bowel syndrome (IBS), peptic ulcer disease, and changes in appetite. IBS is a condition characterized by abdominal discomfort and diarrhea and=or constipation. Studies indicate that individuals with IBS have elevated cortisol as well as increased pro-inflammatory cytokines interleukin-6 and interleukin-8. Also, these patients show an exaggerated cortisol and ACTH response to infused CRH.30 A study on women with IBS demonstrated that these individuals exhibit a greater postprandial increase in systolic blood pressure and plasma norepinephrine levels. This study also showed a greater increase in postprandial granulocytes and leukocytes and decreased natural killer cells and monocytes in these women compared to controls demonstrating altered cellular immune responses to food intake, which may at least, in part, be mediated by adrenergic mechanisms.31 Additional studies correlate IBS with increased urinary norepinephrine, epinephrine, and cortisol levels.32 Studies also show that physical and psychological stressors can induce gastric and duodenal ulcers.33 Epidemiological studies have shown that an increase in self-perceived stress also increases the risk of developing peptic ulcers.34 Researchers demonstrated that young individuals with duodenal ulcers have parietal cells and sympathetic-adrenal systems that exhibit increased sensitivity to environmental stressors.35
Stress affects normal brain function as well as multiple psychological conditions. Studies indicate that cortisol and psychological stress impair memory retrieval, and particularly emotionally arousing words were most affected by this effect.36 Research also has demonstrated that stress-induced cortisol effects long-term consolidation of declarative memories.37 Stress and increased glucocorticoids have been shown to impact the size and function of the hippocampus. Hippocampal atrophy, decreased hippocampal activation with memory task, and memory deficits are associated with increased stress and particularly with posttraumatic stress disorder.38 Cognitive function is also impacted as studies indicate that higher levels of cortisol are associated with decreased cognitive performance including processing speed, eye-hand coordination, executive functioning, verbal memory and learning, and visual memory.39
Additionally, the HPA axis is hyperactive in individuals with depression, and increased vasopressin levels are associated with increased suicide risk.40 ACTH autoantibodies are correlated with conditions such as chronic fatigue syndrome, anorexia nervosa, and major depression. These autoantibodies cause a decrease in cortisol by disrupting the HPA axis.41 Studies have shown that late-in-life depression is associated with both below and above normal levels of cortisol, suggesting a sensitivity to any variation in the HPA axis.42 In addition to depression, dysregulation of the HPA axis is also found in anxiety and panic disorder.43
The release of cortisol that occurs in response to stress suppresses the immune system. Studies suggest that an elevated cortisol: DHEA ratio is a contributing factor to this reduced immunity, particularly in elderly patients.44 A study correlating perceived life stress and risk of upper respiratory infections (URI) found that those individuals with high levels of negative life events and who showed high cortisol reactivity had increased numbers of URIs. Also this study showed that during times of increased perceived stress, lower reactivity of natural killer cells and CD8 cells were also correlated with increased URIs.45
Autoimmune disease is also correlated with dysregulation of the stress response. Individuals with rheumatoid arthritis have been shown to have a decreased cortisol response to an acute stressor and elevated pro-inflammatory interleukin-6.46 Decreased HPA activity has also been demonstrated in individuals with Sjogrens syndrome showing a decrease in ACTH, cortisol, and a blunted adrenal-pituitary response to CRH.47
Endometriosis is a disease affecting reproductive age women and is characterized by ectopic endometrial tissue outside the uterus, dysmenorrhea, and infertility. Recent research indicates that the severity of endometriosis is directly correlated to elevated serum cortisol and prolactin levels.48 Infertile women undergoing in-vitro fertilization have been shown to exhibit increased cortisol and prolactin levels compared to fertile women, and elevated anxiety levels were correlated with decreased success of the procedure.49 Gonadal hormones are also affected by stress. Studies show that stress significantly decreases testosterone levels. Also, estrogen has been shown to blunt the HPA axis stress response stimulated by psychological stress. Estrogen supplementation in perimenopausal women decreases cortisol, ACTH, epinephrine, norepinephrine, and blood pressure.50
Cortisol also plays a role in weight management. Increased abdominal obesity and binge eating is associated with increased levels of cortisol.51 Studies show that glucocorticoids increases appetite and levels of leptin, a polypeptide hormone that modulates appetite.52 Also, studies show that increased perceived stress is associated with increased serum leptin concentrations.53 Leptin is an intricate factor in the HPA axis, as research shows that it is involved in the expression of CRH in the hypothalamus, the adrenal level with ACTH, and is regulated by glucocorticoids. In addition, leptin and cortisol show an inverse circadian rhythm suggestive of regulatory feedback loop.54 Furthermore, the hormone ghrelin, which stimulates increased food intake and fat mass, is increased by a stress-induced rise in cortisol.55
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