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The hypothalamic-pituitary-adrenal axis (HPA) is a complex set of interactions and feedback mechanisms between the hypothalamus, the pituitary gland and the adrenal glands. These interactions of the HPA axis plays a major role in the neuroendocrine system which controls stress and regulates processes such as; thermoregulation, digestion, and immune response (Rey et al, 2008). As this process involves the glands, hormones and the midbrain, it is a system which can be found in a variety of species not only in humans.
The HPA axis responds to stress to maintain a stable diurnal rhythm of circulating glucocorticoids during basal conditions. In a normal basal condition, the HPA axis works seamlessly in a cascade of interactions, producing peptides (Vasopressin (VP)/Corticotropin Releasing Hormone (CRH)), which release hormones (Adreno-corticotropic Hormone (ACTH)) which in turn acts on other hormones (Cortisol (CORT) - in humans corticosterone in mice) which either act on various tissues in the body or acts as a negative feedback system on the hypothalamus and pituitary to inhibit the secretion of further peptides (CRH/VP).
Figure 1 - The HPA Axis (Herman et al, 2003)Figure 1 shows a schematic view of the HPA axis. The para-ventricular nucleus of the hypothalamus (PVN) contains two types of neurons: magnocellular and parocellular.
The magnocellular neurons produce peptides: vasopressin (VP) and oxytoxcin (OT), when secreted these peptides transported for release to act on the posterior pituitary. The parocellular neurons project to the median eminence, where it releases peptides such as; CRH and VP into the portal blood vessels which acts on the anterior pituitary regulating the cleavage of proopiomelanocortin (POMC) into ACTH, Î²-endorphin and Î±- melanocyte stimulating hormone. Once POMC is cleaved secretion of ACTH from the corticotrope cells can occur. ACTH is transported by the blood to the adrenal gland, where it synthesises cortisol from cholesterol (Herman et al, 2003).
Stress has been described as the "state of disharmony or of threatened homeostasis, evoking physiologically and behaviourally adaptive responses that can be specific to the stressor or generalised and non-specific" (Chrous and Gold, 1992). It challenges homeostasis via different signal pathways as stressors have more than one component.
Cortisol is a major component in stress, this hormone which is secreted in precise amount to meet the body's daily needs effects many tissues in the body, too much or too little can lead to disruption of the system (ref). In basal conditions cortisol has a circadian and a diurnal rhythm (Smyth et al, 1997). In the brain, cortisol acts via - mineralocorticoid receptors and glucocorticoid receptors expressed by many different types of neurons. Glucocorticoids is a major target it this process as it controls the HPA axis by inhibiting the secretion of CRH and VP - negative feedback. Cortisol also can elicit a positive feedback system, its local effects in the adrenal medulla synthesises epinephrine and norepinephrine (adrenaline/ noradrenaline), which stimulates the pituitary to increase ACTH synthesis.
In rats, chronic stress alters the amount of seretonergic receptors in the cerebral cortex and hippocampus, which leads to depressive behaviours (e.g. giving up in forced swim tests). This same change has been observed in humans who have committed suicide or suffered from diseases that cause hypersecretion of glucocorticoids. However, the mind and how we cope with diseases can influence the immune system (Greer et al, 1979). This hypothesis when repeated in patients with malignant melanomas who have been given intense psychoscoial interventions, were found to have decreased distress and metastasis and an increase immune system and survival rate compared to those who did not have such an intervention (Fawzy et al, 1993). After 10 years Fawzy et al (2003) conducted a follow up study on these patients, which showed that the intervention group had a longer disease free period and a higher survival rate, even though there was no support given after the initial study period.
The HPA can be influenced by a variety of factors such as; type of stressor (acute or chronic) intensity and duration of the stressor, genetics, immune factors, age, gender, coping skills, support systems and previous experience of stress (Turner-Cobb, 2005). All of which can affect the synthesis, transport and secretion of peptides and hormones, disrupting HPA axis activity and regulation via different pathways. Usually, in a healthy individual the axis will monitor and modify the process if hormone or peptide levels are increasing or decreasing too much, however, if something goes wrong within the HPA axis either in the regulating switches in the pituitary gland, hypothalamus or adrenal gland it can go awry.
Defects in HPA axis activity
Cushing's disease is a hormone disorder, the endocrine system is defected in this syndrome. It develops due to prolonged exposure to high levels of cortisol circulating in the blood and present in tissues, usually due to an adenoma in the pituitary gland which produces ACTH that elevates cortisol levels (Cushing, 1932). However, it can also occur due to the use of glucocorticoids medicinally (e.g. prednisone for asthma), which is a steroid hormone similar to cortisol. As noted before the HPA axis is not only found in humans and the defects of this system are also found in other species (e.g. dogs and horses) (Kemppainen and Peterson, 1994).
The symptoms of this disorder include; upper body obesity, a rounded face, increased fat around the neck, fragile and thin skin, weak bones, excess hair growth and many more symptoms.
One of the causes of Cushing's disease is an adenoma which elevates cortisol levels in the blood normally the negative feedback on the pituitary would cause ACTH levels to decrease. However in Cushing's disease there is also an excess production of ACTH from a pituitary adenoma. This causes ACTH levels to increase along with cortisol. The ACTH levels remain high because the adenoma results in a non-responsive pituitary to the negative feedback from high cortisol levels.
Helseth et al (1992) developed transgenic mice which had ACTH secreting pituitary tumour, similar to Cushing's disease. They were generated by linking a polyoma promoter to a cDNA encoding polyoma large T antigen. The adenoma started to develop around 9 months of age. The adrenal glands of these mice were larger in weight, hyperplasic and plasma ACTH levels were significantly higher.
The treatment of this disease is dependent upon the cause. If it is an adenoma it can be treated by surgical removal, however, it may cause damage to other parts of the pituitary gland dysregulating other hormone production and sometimes there may be residual activity of the adenoma cells. Other treatments can be weaning off and eventually ceasing glucocorticoid medication that have been taken. Canine Cushing's disease may serve as another animal model. However, there are some distinct differences compared with human Cushing's Disease that need to be considered when using this animal model to evaluate new treatments for potential use in humans. A study by Bruin et al (2009) studied a case report of an 8-year-old female dog that developed Cushing's disease due to an ACTH secreting pituitary adenoma. The dog underwent surgery to remove pituitary adenoma and has remained in complete remission in the 3.5 years since surgery.
Addison's disease was first discovered in 1849 by Thomas Addison in tuberculosis (TB) patients. It is the opposite of Cushing's disease in that there is an insufficient production of cortisol (Nieman and Chanco Turner, 2006).
The causes of this disease can vary; it can be due to autoimmune disorders, where the immune system attacks the body's own tissues destroying the adrenal cortex; by TB which also destroys the adrenal glands (Munver and Volfson, 2006) but due to improved TB treatment this is becoming very rare these are termed adrenal destruction. This disease can also occur due to adrenal dysgenesis, where the adrenal glands did not form properly in development or due to the gland simply not being able to synthesis cortisol. This is generally due to genetic mutations.
Addison patients tend to have hyperpigmentation due to low levels of cortisol elevating ACTH levels to try and the release of glucocorticoids, which in turn increases the amount of Î±-melanocyte stimulating hormone making the skin darker.
If this disease is left untreated it can be fatal as it can lead to symptoms such as an adrenal haemorrhage. Treatment of adrenal insufficiency involves replacing, or substituting, the hormones that the adrenal glands are not making in a similar rhythm acquired naturally in the HPA axis system.
This is not a condition which can be defined as a result of a defect in the HPA axis or a factor which has altered the way the axis works as a consequence of the disease. As it can be caused by the immune system attacking the HPA axis at one region or another, by an immature adrenal gland not producing cortisol as it should but it can also be a combination of those factors; if there is an immature adrenal gland which is working just enough to make the system work efficiently and the immune system challenges it during an illness it can reduce the immature adrenal gland synthesis of cortisol.
This condition is an inflammatory disorder which usually attack the synovitis fluid in the joints, making it an extremely disabling condition. This condition promotes T-helper 1 cells which are pro inflammatory, in turn this promotion increases CORT and ACTH levels which exaggerates the disease. There is a loss of pulsitile CORT as it remains highly sustained, due to this the HPA axis switches from CRH mRNA to VP which maintains the HPA axis responsiveness. There is no known cure for this condition however there are treatments to elevate the pain and swelling.
The circadian and cortisol awakening response is normal in rheumatoid arthritis patients, however, studies tend to focus on the diurnal rhythms of this condition and it is evident from many studies that this condition is worse in the morning but that should provoke the question that the problem may lie in the night time rhythms of cortisol, if it is low it may not be able to sufficiently reduce inflammation (Marti and Scheinberg, 2009). Buttgereit et al (2009) conducted a trial testing a new modified release tablet prednisone to take at bed time which has a delay release to top up cortisol in the night relieving early morning stiffness. Which was the case it reduced IL-6 production, from this Marti and Scheinberg (2009) have been developing a possible treatment for this condition which blocks IL-6, this is an interesting approach as this cytokine tends to rise early in the morning promoting inflammation.
A well known animal model for rheumatoid arthritis is the adjuvant arthritis rat, this model is frequently used to study aspects of rheumatoid arthritis (Edan et al, 2001). It is developed by injecting various bacterial walls into the hind leg which then travels throughout the body mimicking the effects of rheumatoid arthritis in humans. As noted before genetics can play a role in susceptibility to the disease and it is shown in this condition as different rat strains such as the dark agouti (DA) rat is more susceptible to developing arthritis, more so than the Lewis rat (Edan et al, 2001).
The HPA axis in this condition is defected as there is an increase in ACTH and CORT which results in an increased activity of the system. Although the system is highly activated to attempt to reduces CRH and VP synthesis in the hypothalamus it is not sufficient to switch off the increase of pro-inflammatory cytokines such as IL-1, IL-6 and TNFÎ±, therefore making it unable to cope with inflammation. Another HPA defect is the increased amount of 11-Î² hydroxysteroid dehydrogenase type 1 and 2 activity in inflamed tissue, instead of cholesterol to cortisol there is a conversion to the inactive cortisone which cannot reduce inflammation.
Previous experiences of stress early in life has been shown to be associated with a poor outcome in response to stress in adults. It was thought by Videlock et al (2009) that early stresses predispose individuals to a range of chronic illnesses by negatively modifying the HPA axis, so that when a stressor is presented in later life the response may be hindered.
A stressful early life experience is maternal separation, Gunner et al (1992) conducted episodes of maternal separation in healthy 9 month old children and it was found that it activated the HPA axis when an unfamiliar sitter only responded if the child cried. A further study by Nicolson (2004) looked at parental loss during childhood (12 years old) and found that the HPA axis activation was linked to a higher diurnal cortisol level when they were adults indicating an the long term effects of early life experiences. However it must be said that these effects may differ from child to child depending on age, sex, and type of stress/trauma and the duration of stress/trauma. Even so most studies in this area show a dysregualtion in the HPA axis.
In an animal model of neonatal programming, if a rat is injected with a lipopolysaccharide (LPS) on day 3 and 5 after birth, when neogenesis is most active it will effect methylation in development. When you investigate these rats as adults you would find that they have an increased CORT level during the day and night, a prolonged stress response which can predispose it to various conditions if there is a chronic activation of the HPA axis.
Early life experiences have an enormous effect on your stress response, there is not much difference evident in basal condition but when a stressor is applied there is a significant change in response and HPA activity.
From the above information, it seems evident that a lot of aspects can impinge upon the HPA axis and effect its functioning in stress, inflammation and in the immune and endocrine system. However, the question begs to be asked whether you are predisposed to a particular disease or condition by having a defect in the HPA axis to begin with or if an external factor such as a drug (i.e. glucocorticoids) modified the HPA axis in a negative way so it does not function accordingly anymore. A lot more need to be explored in this area as asking if these defects are a cause or consequence need to be explored longitudinally looking at the individual before the disease onset to identify if he/she is predisposed to the disease however this is very difficult since most patients come into clinics with symptoms which may mask the underlying causes of the development of the condition/disease.
Most of the studies in this area only extend to a 1 or 2 year period, it does not tend to look at pre-existing factors prior to the disease onset. Programmes like the Avon Longitudinal Study of Parents and Children (ALSPAC - "children of the 90's") is a great way to look at predisposing factors of such chronic illnesses. It is a long term health research project which includes 14,000 mothers who were pregnant in 1991 and 1992. These families have provided genetic and environmental information such as Array et al (2009), this study looked at the early life effects of maternal depression on pre-adolescent children. They found a slight interaction between stressful life events and genotype development. Being able to identify subtle changes and modest anomalies in systems such as slight diurnal rhythmic changes in the HPA axis, could help identify the onset of various disorders or diseases. Unravelling the genetic and environmental pathways that predispose children and adults to the development chronic disorders, is will be helpful in the development of preventative drug treatments and assessing the role of environment and life stresses.
Variations in studies in the literature, which look at defects of the HPA axis in chronic diseases may be due to the various influencing factors mentioned before. Everyone deals with stress differently and the way our stress response processes has a large part to play in that. It is possible that a pre existing defect in the HPA axis may trigger a disease onset, however, it is also possible that the disease or stressor may have a role in disrupting the HPA axis pathway.
Prolonged chronic stress also seems to alter the response of receptors and to have harmful effects on people's mental equilibrium, especially when social or family supports are absent. Under these conditions, the glucocorticoid response becomes maladaptive. It is unclear how a defect in the HPA axis can be important but in identifying a defect you can look for associations and whether that identified defect was the cause or a consequence of the condition.
Psychological interventions such as cognitive behavioural therapy and cognitive behavioural stress management, during a disease or following a traumatic operation, can improve survival rates, give good coping skills and can normalise cortisol and T cell levels (Turner-Cobb et al, 2005; McGregor and Antoni, 2009) but it does not benefit everyone. Social support can influence treatment outcome but the drug is important too, a combination of treatments and interventions may give the patient the best outcome as it will target both pre existing or consequential defects in the HPA axis and the how the individual copes and deals with the condition.
In conclusion it is important to outline whether a defect in the HPA axis is a pre-existing problem as it may hold the key to determining genetic risks and targeting for early interventions. Large longitudinal studies are required to investigate causative systems which may underlie mechanisms in diseases.