Once released from the pituitary gland, ACTH crosses the blood-brain barrier and travels in the blood stream throughout the body. ACTH-rich blood contacts cells within the adrenal cortex, where it stimulates glucocorticoid-containing and producing cells to release their stores and increase production of the hormones. (Marieb 620) �Glucocorticoids were named for their hyperglycemic effect (DeGroot 1643), and we are at least familiar with the most potent of these glucocorticoids, cortisol. When cortisol levels reach a threshold and/or as the body begins to adapt to or overcome the stressor, cortisol completes the negative feedback loop, causing decreased stimulation of the hypothalamus and to a lesser extent of the pituitary. This causes a decreased production of the predecessors to cortisol, respectively CRH and ACTH, and thus a completion of the typical cycle in which cortisol is regulated. (Wilding, DeGroot 1644)
This stress circuit influences heart rate, blood pressure, digestion, appetite, body temperature, pain perception, fertility, growth, immunity, metabolism, motivation, mood, and memory. �(A) long-term activation of the stress hormone system causes changes that put a person at higher risk for physical and psychological disorders�obesity, diabetes, heart disease, anxiety disorders, and depression.� (AMA) In addition to stimulating the adrenal cortex to release glucocorticoids, and the adrenal medulla to release epinephrine and norepinephrine, activation of this circuit and a shift in the �normal� axis causes stimulation of other areas of the brain, including the fear and anger center, the amygdala; the mood and motivation center, the limbic system; and the memory center, the hippocampus. (NIH)
History of Glucocorticoid Research
During his ground-breaking, unconventional postulation in the 1930s and early �40s, Selye suggested that �by stimulating gluconeogenesis, (glucocorticoids) supply an increased need for sugar. He also suggested that disease of adaptation like diffuse collagen disease and allergy could be attributed to the body�s adaptation to stress. White and Dougherty proposed that through lymphocytolysis, they enhance immune responses by releasing preformed antibodies.� Neither of these hypotheses stood the tests of colleagues. (DeGroot 1643) In 1949, another group of endocrinologist-researchers claimed that their evidence showed that glucocorticoids improved the condition of patients with rheumatoid arthritis, throwing glucocorticoid physiology studies into chaos. (DeGroot 1643) In the early 1950s, a foundation for a majority consensus began to be laid when researcher DJ Ingle published an article in the Journal of Endocrinology. He �formulated a protective role for glucocorticoids distinct from the regulatory (role) of high, stress-induced levels.� In this postulation, Ingle explained that glucocorticoids at basal levels exhibit permissive effects and at stress levels, they contribute to maintenance of homeostasis under extreme conditions. (DeGroot 1643) This was the beginning of �rise in therapeutic applications of these hormones and synthetic analogues�miracle drugs�without a firm base in physiology.� (DeGroot 1644)
Effects of Cortisol
Cortisol influences many different systems in many ways. As it is normally part of a constantly-regulated homeostatic balance, its levels follow a diurnal variation (DeGroot1627), lowest during the early sleeping hours and highest just after a full rest. (NIH) �Fragmentation of sleep� tends to cause higher sustained levels of cortisol. (NIH) Cortisol has a biologic half life of approximately 90 minutes. (Huether 463)
�Substantial experimental evidence indicates that when an impaired HPA axis cannot increase glucocorticoid activity in response to stress, activated but unrestrained defense mechanisms overshoot and damage or kill the organism.� (DeGroot 1650) The reason for the difference between chronic and acute reactions appears to be that glucocorticoids exert both permissive and suppressive actions, depending on an array of variables, including time of day (point of diurnal variation), mediator concentration, and receptor concentration, and level of stress. (DeGroot 1651)
Glucocorticoid production never stops in healthy individuals. Rather, it ebbs (to a permissive role) and flows (to a suppressive role) in accordance with changes basal metabolic demands, and internal and external environment. If an acute emergent stress appears, the typical HPA axis shift in a healthy individual results in a sudden increase in available glucocorticoid, which will control responses to more severe stress by a range of permission and inhibition. �In some cases, glucocorticoids permissively enhance activity of a mediator by inducing its synthesis. (This) assumes that for such a mediator, (the two different ) effects obey identical dose-response relationships, each proportional to the fraction of glucocorticoid receptors occupied by cortisol.� (DeGroot 1651) In simpler terms, the change in function of cortisol from permissive to inhibitive takes place at a midrange concentration level. Under, and up to this level, cortisol acts to enhance activity of receptors (e.g.: IL-6 receptors) by causing them to more aggressively attract the mediator (e.g.: IL-6). Levels of cortisol above and beyond a midrange concentration, however, cause a sloping decrease in receptor sensitivity/affinity for its given mediator, thus rendering the mediator ineffective to complete its task.
Glucocorticoids exert an influence over most cells in the body and are �essential for the response to stress and for survival, normally they rarely exert major control over physiological processes other than their own feedback mechanisms.� (DeGroot 1644). DeGroot continues by explaining that while glucocorticoids influence the regulation of blood glucose levels, the main regulators are insulin and glucagon. Instead of responding to a feedback mechanism of desired physiological effect, glucocorticoid release is regulated by glucocorticoid levels, indirectly.
While inhibition of glucose transport is a direct effect of cortisol, activity of cytokines, inflammatory agents, hormones and other mediators are secondary effects of increased glucocorticoid presence. �Many cells are subjected to both primary and secondary glucocorticoid effects.� (DeGroot 1644) Some body systems over which cortisol exerts its influence, and the mechanisms by which it does so, are listed below. (Greenspan 345-7; DeGroot 1741-2; NIH; AMA)