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The Negative Spiral of Stress

The impact of HPA axis, adrenal hormones and modern lifestyle habits

By Jesse Davis, DC

Our health often moves in a spiral, advancing either in a positive or negative direction. It’s easier to work out, eat right and make good choices when we are feeling good. When we are sick, or feel tired, it is difficult to focus on health because easy, more harmful choices are often more appealing. Experiencing chronic stress is a powerful example of this spiral in action. Excess stress makes us sick – and for a variety of reasons quite possibly leads to more stress — resulting in a negative cycle of stress and poor health.

Modern stress

Modern life is producing greater and more frequent episodes of stress. Activated stress responses are commonly due to unhealthy lifestyle choices, such as limited social connections, inconsistent sleep habits, and poor nutrition among other things. While the stress system is a key adaptation to challenges , there may be a point where chronic stress becomes its own problem leading to a malfunction of the stress system itself.

This passage from the journal Metabolism in 2002, describes how stress can become a risk factor for serious illness:

The body’s principal adaptive responses to stress stimuli are mediated by an intricate stress system, which includes the hypothalamic-pituitary-adrenocortical (HPA) axis and the sympathoadrenal system (SAS). Dysregulation of the system, caused by the cumulative burden of repetitive or chronic environmental stress challenges (allostatic load) contributes to the development of a variety of illnesses including hypertension, atherosclerosis, and the insulin-resistance-dyslipidemia syndrome.”[1]

Chronic stress created by modern life not only activates the HPA axis and turns on the stress system, but also with enough stress brings about the possibility of a vicious cycle of feedback from stress and its damaging effects.

The adrenal glands are a primary effector of the body’s response to stress. The HPA axis, communication from the hypothalamus to the pituitary gland and the adrenals, allows the brain to rapidly respond to stressors of all types perceived by the brain. Activating this HPA axis releases stress hormones, such as epinephrine and cortisol throughout the body.

Causes of increased stress

Let’s examine some of the most pervasive causes of increasing chronic stress. Most people now experience one or all of the effects of disturbed sleep patterns, unhealthy diets, and even challenges from lack of social interaction.

Less than one week of disturbed sleep is enough to disrupt the function of the endocrine system. In a recent study, subjects who received only four hours of sleep for five consecutive nights showed measurable changes in hormonal activity, including an increased resistance to insulin of 25 percent, increased non-esterified fatty acid (NEFA) levels, and elevated levels of cortisol and epinephrine metabolites.[1] In fact, even a single night of sleep shortened to four hours was enough to change test subjects’ insulin sensitivity.[2]

Researchers believe that increasing fatty acid levels in the blood (an impact of increased cortisol) contributed to sleep-loss related insulin resistance.

For individuals who try to make up for lost sleep during the weekends, the picture is also bleak. A study replicating the effects of sleeping less during the workweek suggestsa disrupted interplay between the hypothalamic-pituitary-adrenal and inflammatory systems in the context of repeated exposure to sleep restriction and recovery.”[3]

Furthermore, researchers found that the subjects did not necessarily feel the changes happening. Physiologically, however, effects were noted:

“The observed dissociation between subjective and physiological responses may help explain why many individuals continue with the behavior pattern of restricting and recovering sleep over long time periods, despite a cumulative deleterious physiological effect.”[4]

cant sleepUnfortunately, for legions of people not sleeping well, this bodes poorly for their stress systems. According to the National Sleep Foundation’s inaugural Sleep Health IndexTM, “forty-five percent of Americans say that poor or insufficient sleep affected their daily activities at least once in the past seven days.”[5]

However, poor sleep is not the only widespread disturbance on the body’s HPA axis. Other impacts like our social interactions, or lack thereof, affect us profoundly as well. It has long been recognized that a lack of social support is associated with an increase in stress. According to a 2015 review in Acta Neuropathologica:

“The deleterious effects of chronic social isolation (SI) have been recognized for several decades. Isolation is a major source of psychosocial stress and is associated with an increased prevalence of vascular and neurological diseases. In addition, isolation exacerbates morbidity and mortality following acute injuries such as stroke or myocardial infarction. In contrast, affiliative social interactions can improve organismal function and health.The molecular mechanisms underlying these effects are unknown.”[6]

How prevalent is this stressor? A full 35 percent of adults over age 45 were classified as lonely in a survey commissioned by AARP. Of those, over half that were unmarried were classified as lonely.[7] In further evidence, a PLOS Medicine review of 148 studies on social interaction found that those with the strongest social interactions had a 50 percent reduction in mortality in the elderly.[8]

“These findings indicate that the influence of social relationships on the risk of death are comparable with well-established risk factors for mortality such as smoking and alcohol consumption and exceed the influence of other risk factors such as physical inactivity and obesity.”[9]

The 2015 study from Acta Neuropathologica described the impact of stress on the body through psychosocial influences, primarily through the HPA axis. “Recently, results from large epidemiological trials and pre-clinical studies have revealed several potential mediators of the detrimental effects of isolation. At least three major biological systems have been implicated: the neuroendocrine (HPA) axis, the immune system, and the autonomic nervous system.”[10]

Diet and stress

diet and healthA fascinating study of breast cancer survivors examined the effects of improving lifestyle in these patients and their future success rates. Commonly, cancer survivors may experience depression and other sequelae. In the study, a group of women were counseled on improving exercise and nutrition strategies. A distinctive part of the study was that they also measured HPA axis activity through cortisol levels. Research published in Breast Cancer Research in 2014, determined, for the first time, “that an improvement in depressive symptoms resulting from supervised exercise and healthy eating advice in the early recovery phase, three to 18 months, after breast cancer treatment is accompanied by a significant change in diurnal salivary cortisol rhythm. The increase in morning salivary cortisol at the six-month follow-up suggests a normalisation of HPA axis regulation.”[11]

And while research has associated diet quality with the majority of chronic diseases, the powerful role of the HPA axis in human physiology is being shown in relation to nutrition as well.

Damage resulting from increased chronic stress

The physical toll caused by increased levels of chronic stress can be extensive. The activation of the HPA axis changes how the body responds to short-term stress, including cortisol release, and an increase in blood glucose and free fatty acids. In a chronic fashion, these effects mount and become harmful. Consider the following from the journal Hormones in 2009:

“Chronic stress can lead to overeating, co-elevation of cortisol and insulin, and suppression of certain anabolic hormones. This state of metabolic stress in turn promotes abdominal adiposity. Both the direct stress response and the accumulation of visceral fat can promote a milieu of systemic inflammation and oxidative stress.”

“This biochemical environment appears to be conducive to several cell aging mechanisms, mainly dampening telomerase and leading to telomere length (TL) shortening and cell senescence. Immune cell telomere shortness is linked with many chronic disease states and earlier mortality.[12]

In short, researchers feel chronic stress responses can create hormonal changes that may promote obesity, chronic disease states, and even increased mortality rates.

A paper published in the journal Molecular Neurobiology in 1998 points to increasing evidence of this effect noting that “the detrimental effects of glucocorticoid (GC) hypersecretion occur by activation of the hypothalamic-pituitary-adrenal (HPA) axis in several human pathologies, including obesity, Alzheimer’s disease, AIDS, dementia, and depression.[13] The 2002 study in Metabolism discussing chronic elevated stress response via the HPA axis, describes not only obesity but also the association with pathologies such as Alzheimer’s disease and depression.“The brain’s limbic system, particularly the hippocampus and amygdala, is also intimately involved in the stress response. Chronically elevated corticosteroid levels induced by persisting stress may adversely affect hippocampal structure and function, producing deficits of both memory and cognition.” Additionally, further research shows that elevated chronic stress levels can also impair brain function.

Learn more about the effect of adrenals on nutrition and blood sugar

Cyclic damage from HPA axis dysregulation

This damage caused by chronic stress can also cause its own effect on the HPA axis and stress response overall. HPA axis dysregulation is now a popular avenue of investigation for the onset of chronic disease.

“Chronic stress, mainly through hypothalamic-pituitary-adrenal axis dysregulation, promotes the accumulation of visceral fat. Reciprocally, obesity promotes a systemic low-grade inflammation state, mediated by increased adipokine secretion, which can chronically stimulate and disturb stress system. This vicious cycle, probably initiated by visceral adipose tissue dysfunction, might be the trigger for the development of metabolic syndrome.”[14]

“Overall obesity (BMI) appears to also be related to a hyperresponsive HPA axis in many but not all studies, such as when acute reactivity is examined.”[15]

Ultimately with health, both inertia and momentum can be a powerful force. Healthy people who successfully manage stress and minimize events of excessive stress are less likely to derail their own health. On the other hand, once issues begin to mount, health can become more difficult to attain.

Strategies to minimize excess stress in our lives such as healthier sleep, nutrition and social lives are strongly needed. It is also necessary to recognize that not only is minimizing excess stress critical but also that adding strategies to handle the adverse effects of excess stress are necessary to prevent a negative spiral.

[1] Madhu NR, Neylan TC, et al. Subchronic Sleep Restriction Causes Tissue Specific Insulin Resistance. J Clin Endocrinol Metab. 2015 Apr; 100(4): 1664–1671.

[2] Donga E, van Dijk M, et al. A single night of sleep deprivation induces insulin resistance in multiple metabolic pathways in healthy subjects. J Clin Endocrinol Metab. 2010 Jun;95(6):2963-8.

[3] ibid.

[4] Simpson NS, Diolombi M, et al. Repeating patterns of sleep restriction and recovery: Do we get used to it? Brain Behav Immun. 2016 Jun 2. pii: S0889-1591(16)30150-7.

[5] Lack of Sleep is Affecting Americans, Finds the National Sleep Foundation. Dec. 2014. Accessed online at

[6] Friedler B, Crapser J et al. One is the deadliest numbers: The detrimental effects of social isolation on cerebral diseases and cognition. Acta Neuropathol. 2015 Apr;129(4):493-509.

[7] Loneliness Among Older Adults: A National Survey of Adults 45+. Conducted for AARP, the Magazine. 2010 Dec. Accessed online at

[8] Holt-Lunstad J, Smith TB et al. Social Relationships and Mortality Risk: A Meta-analytic Review. PLOS Medicine. 2010, July 27.

[9] ibid.

[10]   Ibid. Acta Neuropathologica 2015.

[11] Saxton JM, Scott EJ, et al. Effects of an Exercise and hypocaloric eating intervention on indices of psychological health status, hypothalmic-pituitary-adrenal axis regulation and immune function after early state breast cancer: a randomised controlled trial. Breast Cancer Res. 2014; 16(2): R39.

[12] Epel ES. Psychological and metabolic stress: a recipe for accelerated cellular aging. Hormones (Athens). 2009 Jan-Mar;8(1):7-22.

[13] Raber J. Detrimental effects of hypothalmic-pituitary-adrenal axis activation: From obesity to memory deficits. Mol Neurobiol. 1998 Aug;18(1):1-22.

[14] Paredes S, Ribeiro L. Cortisol: the villain in metabolic syndrome? Rev Assoc Med Bras. 2014 Jan-Feb;60(1):84-92.

[15] Incollingo Rodriquez AC, Epel ES , et al. Hypothalmic-pituitary-adrenal axis dysregulation and cortisol activity in obesity: A systematic review. Psychoneuroendocrinology. 2015 Dec;62:301-18.

[1] Vanitallie TB. Stress: a risk factor for serious illness. Metabolism. 2002 Jun;51(6 Suppl 1):40-5.


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