Basic Primary Prevention Review: Progress in the scientific knowledge of health and well being and the body's response to stress and the relationship to the development of chronic disease (2006-2007)
Abstract: Over recent years there has been great progress in the scientific knowledge of health and well being and the body's response to stress and the relationship to the development of chronic disease.
1 The Body and its reaction to challenge
Homeostasis is the term used which means the harmonious equilibrium of many physical and emotional factors that permit the body to maintain a steady state of health (Cannon, 1914). Stress is a departure from homeostasis.
The stress response is the body's constant effort to right any physical or mental stressor to maintain physiological, mental and emotional harmony or homeostasis. If a person is not able to re-establish homeostasis the typical consequence is disease. Activation of the chemical stress pathway (gluco-corticosteroids) tends to be associated with depression, whereas the activation of the electrical stress pathway (adrenalin) is more frequently correlated with anxiety.
A person's level of stress must reach a certain threshold before the stress syndrome develops. The stress syndrome can be produced by physical illness, chronic emotional upset, work problems, status problems, financial worries, divorce and bereavement. Memory plays a significant role in the perpetuation of stress and people can worry themselves sick and even to death.
Melatonin is the principal hormone of the pineal gland which is the major transducer of neuroendocrine information -- it transforms neural input into endocrine output. The pineal converts light, temperature, and magnetic environmental information into neuro-endocrine signals that influence the body's functions, often via melatonin.
There are changes in both the body's electrical and hormonal pathways underlying the stress syndrome.
Stressful stimuli cause the hypothalamus in the brain to secrete corticotrophin-releasing hormone (CRH) and antidiuretic hormone (ADH). CRH stimulates the release of adrenocorticotrophic hormone ACTH from the pituitary which then causes the adrenal cortex to release corticosteroids -- primarily cortisol. At the same time the autonomic nervous system initiates the adrenal medulla to release adrenaline -- which increases heart rate, blood pressure and respiratory rates -- resulting in increased arousal and anxiety.
The glucocorticoids, adrenalin and noradrenalin all can inhibit insulin secretion, and this results in the conversion of stored protein and fat to immediately useable energy for exertion. The increased depth of respiration makes more oxygen available and the blood circulation is adjusted to direct more oxygen and glucose (energy) to specific organs and muscles essential for exertion. Hormones related to functions that are not essential for immediate survival, such as reproduction, appetite and immune system function are suppressed. Endorphins, which are strong analgesics, are also released. There are strong connections between the chemical (hormonal) and electrical pathways in response to stress. For example, adrenalin stimulates the hypothalamus to produce CRH which helps to instigate the stress response of the sympathetic nervous system, stimulating the secretion of both adrenalin and nor-adrenalin (Dunn and Berridge 1990, Cuningham et al 1990). Also ADH works synergistically with CRH to stimulate ACTH, which works synergistically with CRH to stimulate ACTH, also appears to work synergistically to promote behavioural effects -- such as memory enhancement -- of the stress response (Elkaler et al, 1990, Rittmaster et al 1987).
The secretion of CRH usually stops when glucocorticoids reach a certain point by a negative feedback loop. However chronic stress can disrupt the feedback mechanism and cause a prolonged secretion of glucocorticoids, which can be very detrimental to health.
The symptoms that occur with chronic stress correlate to the changes that are induced by acute stress and which support the fight or flight response. The symptoms such as weight loss, loss of sexual drive, peptic ulcers and immune suppression are an exaggeration of this initial adaptive response.
Allostasis means the body's ability to adjust to various vital functions in order to reset itself to a steady state. It is the ability of the body to achieve stability through changing situations (McEwin 1998) with an Allostatic Load (McEwen and Stellar 1993).
There comes a point when the body can no longer handle all the stress and the person enters into a state of chronic stress accompanied by physiological breakdown -- reduction of the size and functions of the thymus, decreased blood lymphocytes and eosinophils, decrease in lymph node size, inhibition of cytokine release (essential for T and B cell maturation), suppression of natural killer cells and promotion of programmed cellular death of lymphocytes -- lymphocyte apoptosis (Hetts, 1998, Munck and Guyre 1991). In contrast the acute stress response has been shown to strengthen the immune response and proved an immunological memory (McEwen 1998).
1.3 Neurotransmitter and Hormonal influences on Stress
There are many factors that affect the stress system and the major hormones and neurotransmitters of the system are usually beneficial modulators, but they can also cause malfunction and potential serious illness.
The net effect of glucocorticoids is one of modulation. They prevent immune overactivity and adjust the magnitude and duration of immune reactions (Besedovsky et al 1975, Besedovsky and Sorkin 1977, Munck et al 1984). They suppress the immune system by decreasing the production of many factors that facilitate B- and T- cell proliferation, including cytokines, beta-endorphin, and insulin. Inhibition of these mediators reduces the proper functioning of monocytes and macrophages. In high levels glucocorticoids also reduce natural killer cell activity levels.
However, in low concentrations they have been found to actually enhance the immune system. It has been found that steroids must saturate at least 50% of the glucocorticoid receptors for a minimum of 24 hours before monocyte inhibition occurs (Munch and Guyre 1991).
The secretion of ACTH from the pituitary prompted by CRH from the hypothalamus, stimulates the adrenals to secrete glucocorticoids. During chronic stress glucocorticoids remain high but ACTH returns to normal or slightly below normal. Chromaffin cells of the adrenal medulla communicate extensively with the steroid producing cells of the adrenal cortex so as to elevate cortisol (Bornstein et all 1997, Haidan et al 1998).
When the pituitary ACTH shuts down during chronic stress, the chromaffin cells of the adrenal medulla become stimulators of adrenocortical production of corticosteroids.
CRH is released from the hypothalamus to stimulate the secretion of ACTH (Saffran and Schaly 1955, Taylor and Fishman 1988). It is a powerful hormone capable of affecting many human functions including mood, growth and reproduction (Pacak et al 1995, Pacak 2000). Nor-adrenalin and CRH are able to stimulate each other and operate differently during acute stress than during chronic stress.
Opioids are also involved in the stress response. They, as endorphins, are secreted by the adrenal medulla during the stress response and are primarily associated with the reduction of pain. Depending on the length and intensity of pain, the body responds with either an opioid or non opioid mediated form of analgesia. The opioid mediated analgesia is associated with depressed natural killer cell activity levels and a decreased tumour median survival time (Shavit et al 1985).
Graphic above Figure 1 : Interactions and interdependency between the nervous, endocrine and immune systems in response to the social environment
n an acute stress response, the hypothalamic-pituitary-adrenal (HPA) axis stimulates the immune response and arouses immunological memory for the invaders (Dhabhar and McEwen, 1996). The stress stimulus starts a process by which white blood cells -- particularly T cells and monocytes -- move from the blood stream to the walls of blood vessels, lymph nodes or bone marrow, in preparation to mount an immune response (Dhabhar et al, 1996) This results in a reduction of the number of white blood cells in the blood by half and increasing them in other areas, particularly the skin (Dhabhar and McEwen 1996, Dhabhar et al, 1996). After acute stress some of the white blood cells are retained in certain area of the skin and gamma interferon mediates an enhancement of skin immunity and fosters immunological memory (Dhabhar et al 2000). Glucocorticosteroids are the primary mediators of this leukocyte shift. This immune enhancing effect can last for around 3 -- 5 days, after which the allostatic load become too great and features of chronic stress emerge (McEwen, 1998). Chronic stress causes white blood cell function to be inhibited and causes a decrease in the redistribution of white blood cells from the blood to the immune compartments (Dhabhar and McEwen 1997, 1999).
A prolonged stress response depresses the immune system.
Studies on various types of stress, such as bereavement, depression, exams, space flight, sleep deprivation, loneliness, divorce, cancer, helplessness, all show that the body becomes more vulnerable to illness.
The HPA Axis in response to stress/challenge
Figure 2 : The hypothalamic-pituitary-adrenal (HPA) Axis
With malfunctioning of the immune system, the chronically stimulated cytokines can create systemic inflammation which can affect major organs, including those of the cardiovascular system.
Interleukin and tumour necrosis factor levels correlate with the severity of depression and higher levels of these cytokines have been linked to more serious depression.
C-reactive protein is another protein found in inflammation and it is an independent risk marker for coronary heat disease and can also indicate some cancers and some autoimmune diseases.
Neuropeptide Y has been shown to reduce the function of the immune system (Fabiene, Mackay & Herzog, 2005). It is released during periods of stress into the blood stream and inhibits the function of immune cells so that they do not seek out, recognise and destroy pathogens.
There are four main groups of factors that determine vulnerability and resilience to stress and these are genetic traits, personality, experiences during childhood and current social adversity.
The study of Twins has helped differentiate the effect of genetics from the effect of the environment/ Studies have shown:
Thus vulnerability is determined by a combination of genes predisposing a person to anxiety and other genes partially determining the personality type. This potential vulnerability may be increased by experiences which occur after birth or greatly reduced by favourable experiences.
Factors that increase the incidence rates for common mental disorders by increasing the sensitivity of the HPA axis include:
Case control studies show:
In cases of separation or divorce between parents with frequent rows, violence between parents associated with all forms of abuse, the abused child had higher rates of depression and anxiety, sexual difficulties and interpersonal problems (Mullen and Romans-Clarkson 1995). Childhood sexual abuse leads to more disturbed behaviour, higher scores on depression and anxiety, binge eating and self injury compared to matched non-abused controls (Swanson et al 1997).
Many genes manifest in life only in certain environments
Genes also partially determine personality traits, which in turn control types and number of stressful life events - people create their own environments.
This affects the way in which people view and react to possible stressful situations.
1.6 Gender differences
In the absence of androgenic stimulation, the foetal brain will develop into a female brain which is capable of supporting ovulation after puberty.
During foetal life a male foetus' testes have their first spurt of activity and will convert the brain into a male brain which is incapable of much cyclical activity and has marked cerebral laterality.
Males develop language skills slightly less well than females and become more competitive and aggressive.
Males tend to be more systematising which refers to the language used to understand systems and attention to detail, tend to have superior spatial and motor skills, mechanical and constructional skills - maths, physics and engineering skills.
Females tend to be more empathising which refers to the language used to understand intimate relationships, tend to have superior language skills, developing intimate relationships with others - self disclosure and social skills - making friendships more important.
In adolescence girls are six times more likely to be depressed if they have no close friends compared with those who have many friends, whereas boys are not more likely to be so affected.
Children with no friends or who get into arguments are more likely to be bullied than those with friends. Girls who are bullied are four times more likely to be depressed and twice as likely to be depressed a year later, but this is not so for boys (Bond et al BMJ 2001).
Reasons for gender differences:
In 2000 a US team at the University of California (Taylor et al) proposed a tend and befriend pattern in females mediated by a stress regulatory system primarily involving the secretion of oxytocin. This was based on both human and animal studies.
Other studies have shown that oxytocin causes mild sedation, decreased blood pressure, lower sensitivity to pain and decreased glucocorticoid secretion. Oxytocin levels also increase with massage and decrease with sadness.
This pattern in response is present in the mother-infant bond, and is also typical of women in a stressful situation where they seek and use socials support much more than men.
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Later US research showed that socioeconomic status was associated in a graded fashion with higher basal levels of cortisol and catecholamines. These associations occurred independent of race and were consistent with mediation by health practices and social factors. (Cohen, Sheildon et al, Psychosomatic Med. 69(3) May/Jun 06).
Sapolsky and others have shown that low-status animals have higher cortisol levels than high-status animals.95 The strength of this link between low status and cortisol varies across animal species; the more frequently low status is associated with being on the receiving end of stressful encounters the stronger the link between low status and cortisol. (Marmot M, The Lancet 2006; 368:2081-2094)
In Australia there was an estimated 50% higher mortality in the 1980s amongst the unemployed. The lower the social position, the higher the risk of heart disease, lung disease, kidney disease, cancers and HIV related disease.. There is a relationship between occupation and mortality from these diseases with persons in manual occupations having higher rates of mortality compared with profession and managerial occupations (Australias Health 2006)
n Australia, the ABS National Surveys show that persons aged 25-64 living in disadvantaged areas are more likely to assess their health as poor to fair, drink alcohol at harmful levels, smoke, be obese and have high blood pressure. They have also shown that the proportion of deaths from cardiovascular disease and stroke in adults in most disadvantaged areas has risen sharply since 1992 and is more than one and a half times higher than the least disadvantaged areas. This translates to over 3,400 deaths that may be due to social economic inequality (AIHW August 2006)
In the Report of the Chief Health Officer of Queensland The Health of Queenslanders 2006 it states that about one fifth of total death and disability is due to socioeconomic inequality. If everyone experienced the same death rates as those in most advantaged areas about 1530 deaths of people aged less that 75 years could be avoided. Socio-demographic differences are seen in death rates from cancer and specifically lung cancer, coronary heart disease, diabetes, chronic obstructive pulmonary disease and asthma, and transport injury. People in area of socioeconomic disadvantage have about 50% higher rates of avoidable deaths and hospitalisations.
A combination of smoking, plasma cholesterol, blood pressure, being overweight, and lack of physical activity accounted for under a third of the social gradient in coronary heart disease mortality in Marmot’s first Whitehall study in the United Kingdom. Smoking was found to be linked with social disadvantage in the developing world also. Similarly for obesity, particularly for women, a clear inverse association with socioeconomic position was found. This association is now also emerging in developing countries. (Marmot M, The Lancet 2006; 368:2081-2094)
Marmot in 2004 wrote: "what characterises being poor and lower in the hierarchy is the great sense of helplessness….lack of control over life circumstances”. To focus on agents of disease such as smoking and lack of exercise is to focus on the causes of ill health and not on “the causes of the causes”. “The cause of the social gradient in health are to be found in the circumstances in which we live and work; in other words in our set of social arrangements…it is not the calamities that most determine well-being, but the way we go about our daily lives, in offices, banks, factories, houses and neighbourhoods. It is about the fact that control of life circumstances and full social engagement and participation in what society has to offer are distributed unequally, and as a result health is distributed unequally". (Status Syndrome, Marmot 2004).
In 2006 he wrote: "We should focus not only on extremes of income poverty but on the opportunity, empowerment, security, and dignity that disadvantaged people want in rich and poor countries alike. We need biological understanding of disease but we need, too, understanding of how society influences biology, in order to change disease risk. This social understanding is central to the process of change to reduce the burden of disease". (Marmot M, The Lancet 2006; 368:2081-2094)
Concentrating of individual diseases ignores the complex interrelationships between illness and social context and weakens a social approach. Focussing on modifying individual behaviours will not address the powerful influences of unemployment or underemployment, low income or homelessness. [Emphasis in this past paragraph done by editor nc not author qr 2007.04.23a]
... To be continued 2007.04.24
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REFERENCES / FOOTNOTES
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Quentin Reilly, Specialist Medical Officer © 2007 Australia
Quentin Reilly, author of the above report is a content contributor, i.e.. photos and articles, to ManusIsland.com. In the 1970's Quentin worked as the medical officer for Manus and has since then formed attachments with the people of Manus. As a health consultant he has visited many Pacific islands and South East Asian countries over the past 30 years, and volunteers energy and resources in helping people at the grass-roots level to better develop their own resources.
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