The HPA axis, which has traditionally been seen as the body's "stress system", and which ultimately controls levels of cortisol and other important stress related hormones, is generally underactive in people suffering from CFS and burnout. New research is beginning to show that the HPA axis should instead be thought of as the body's energy regulator, as it is ultimately responsible for controlling virtually all of the hormones, nervous system activity and energy expenditure in the human body, as well as modulating the immune system. In CFS and burnout the HPA axis becomes suppressed, resulting in the various physical and mental symptoms associated with these conditions.
Any stress lasting longer than a few minutes results in increased levels of cortisol being released from the adrenal cortex. The release of cortisol is controlled by the paraventricular nucleus (PVN) of the hypothalamus, where corticotropin-releasing hormone (CRH) is released in response to the stress. CRH then acts on the pituitary gland, causing it to release adrenocorticotrophic hormone (ACTH), which in turn causes the adrenal cortex to release cortisol. CRH and ACTH are released in short pulses, each of which causes a (roughly) 15 minute sustained release of cortisol from the adrenal cortex, which then has a half-life of 100 minutes in the blood. Prolonged release of ACTH causes the adrenal cortex to increase in size (presumably to cope with a greater need for cortisol production), whereas long-term ACTH deficiency causes it to shrink. The combined system of CRH-ACTH-cortisol release is referred to as the hypothalamic-pituitary-adrenal axis (or HPA axis). Positive and negative feedback occurs at various sites in the brain to ensure that cortisol production stays within certain bounds, depending on current requirements and stress levels.
Figure: Overview of the HPA axis
Another important hormone released by the pituitary along with ACTH is beta-endorphin, a morphine-like hormone. Both ACTH and beta-endorphin are similar in structure, and are released together in response to CRH stimulation by the hypothalamus. Endorphins are thought to be important in reducing pain during times of stress.
In addition to cortisol, the adrenal cortex also releases DHEA, a precursor to the sex hormones testosterone and oestrogen, and aldosterone, a mineralocorticoid that maintains blood volume and pressure by controlling the sodium/potassium balance of the blood. Both DHEA and cortisol are released in response to ACTH stimulation, but aldosterone is relatively independent of HPA axis stimulation.
The ratio of cortisol to DHEA depends on a number of factors. During acute stress and illness, the balance shifts towards cortisol and away from DHEA. Interestingly, mental attitude has been shown to influence the DHEA/cortisol ratio, with high DHEA-to-cortisol ratios corresponding to feelings of warm-heartedness, and low ratios corresponding to feelings of being stressed. Studies show that when people are trained to eliminate negative emotions and thought processes, their DHEA-to-cortisol ratio also increases.
During normal, non-stress situations, a certain level of cortisol is maintained in the bloodstream. There is a circadian rhythm of ACTH and cortisol release, with the highest levels occurring around 8-10am in the morning and the lowest levels around midnight. Other hormones released by the hypothalamus also follow a circadian rhythm, although not necessarily peaking at the same time. For example, growth hormone release peaks during sleep, and melatonin is released at night.
The circadian pattern of cortisol release is controlled by the suprachiasmatic nucleus (SCN) of the hypothalamus, also known as the body clock. Nerve signals from the SCN cause the paraventricular nucleus (PVN) of the hypothalamus to release pulses of CRH roughly once per hour, resulting in HPA axis activation and cortisol release. There are also direct links between the SCN and the adrenal gland itself (bypassing the HPA axis) through sympathetic nerve fibres, causing the adrenal gland to become more sensitive to ACTH stimulation during the morning, further adding to the circadian pattern of cortisol release throughout the day.
Both the amplitude and frequency of CRH pulses can vary to change the overall pattern of HPA axis activation.
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