In addition to genetic factors, there are many external factors that influence our individual vulnerability to stress, including childhood trauma, early environmental factors, major life events or physical illness. These factors can influence the intensity and duration of our stress reaction, in many cases producing long-lasting effects. The stress caused by traumatic events may cause chronic stress syndromes such as PTSD, promote the onset of physical disease or worsen existing conditions, including rheumatoid arthritis, chronic pain, fibromyalgia, and multiple sclerosis, among others.
However, while individuals vary greatly in their ability to respond adequately to stressful situations, every human body is programmed and equipped to respond to the initial stressor in the same biochemical way. Among the principal structures that are immediately mobilized in the event of a physical or psychological threat is the hypothalamic-pituitary-adrenal axis (HPA). The HPA consists of three elements connected by blood vessels: the hypothalamus, the pituitary gland, and the adrenal glands. Their functioning depends almost entirely on a sequence of cascading chemical signals.
The HPA Structures and Their Chemical Output
The paraventricular nucleus (PVN) of the hypothalamus is a heterogeneous collection of specialized neurons that, when activated by stress, release corticotrophin releasing hormone(CRH) in the bloodstream. The hippocampus is an important component of the negative-feedback regulation of the neuroendocrine stress response.
The pituitary gland or hypophysis is a very small gland (one-third of an inch in diameter and one twentieth of an ounce in weight) located in a bony cavity at the base of the brain, and connected to the hypothalamus by the pituitary stalk. The pituitary two main components are the neurohypophysis that grows from the floor of the hypothalamus, and the adenohypophysis which releases adrenocorticotropic hormone (ACTH). The hormones released by the pituitary exert strong regulatory control over a wide range of bodily functions, including behavior, growth and development, metabolism, salt and water balance, reproduction and immunity. Stress influences the neuroendocrine regulation of a number of pituitary hormones including ACTH, prolactin, growth hormone, luteinizing hormone, thyrotrophin, vasopressin and oxytocin.
The adrenal glands are located in an area that lies dorsal to the kidney and release the glucocorticoid cortisol or corticosterone.
The HPA’s Starring Role in Stress Regulation
The appropriate functioning of the HPA axis is absolutely vital for species survival in humans and in all vertebrates. The HPA axis functions as a closed-loop system involving tight negative-feedback control regulated by the glucocorticoids. Automatic regulation of the HPA axis is essential for ensuring that the stress reaction is terminated after the stressor subsides, thus preventing continuous excessive activation and a healthy return to internal homeostasis.
How the HPA Responds to Acute and Chronic Stress
Most stressors affecting human life can be classified as either systemic or neurogenic stressors. Systemic stressors include all physical stressors that are a challenge to physical well-being and integrity of the body. Neurogenic stressors include those stressful stimuli that have a predominantly emotional or psychological component, such as fear or anxiety.
Exposure to acute stressors produces an immediate and intense activation of the HPA axis which results in enhanced secretion of ACTH and glucocorticoids. The HPA axis responds to the intensity of each individual stressor, in such a way that repeated or intensified stress results in increased secretion of the stress hormones. Regardless of the type of stimuli that cause an acute stress reaction, the removal of the stressor produces the return of HPA-axis activity to baseline or homeostasis.
In chronic or long-lasting stress, the exact mechanisms that produce long-term activity of the HPA axis and the near-continuous secretion of stress hormones remain largely unknown. However, numerous studies have revealed that the de-activating sequences essential to the maintenance of HPA axis integrity, including negative-feedback control, become dysregulated by prolonged stress stimulation.
Most researchers agree on the hypothesis that a defective over-activation of the HPA axis and the associated excessive secretion of powerful glucocorticoids can cause prolonged suppression of the immune system and dysregulation of immune cells, ultimately predisposing the chronically stressed individual to autoimmune disease. On the other side of the equation, the under-activation of the HPA axis has significant implications for our ability to recognize threats and be able to react to them accordingly.