Adrenocorticotropic hormone (ACTH) is a hormone produced by the pituitary gland. This is a polypeptide, synthesized and secreted by the anterior part of the pituitary gland. To understand its feedback regulation mechanism, an introduction into the hypothalamic-pituitary-adrenal axis must be given.

The hypothalamic-pituitary-adrenal axis is a cascade of feedback interactions within the central nervous system and adrenal glands aimed to perform body reactions to stress by regulating numerous processes. The latter are the energy storage and activation, emotions, immune status, and digestion. Anatomically, the hypothalamic-pituitary-adrenal axis consists of the hypothalamus (a brain portion, located below the thalamus above the brain stem), the pituitary gland (its anterior lobe), and the adrenal glands (the adrenal cortex which produces glucocorticoids). Functionally, the hypothalamic-pituitary-adrenal axis acts according to the anatomical pattern described. Thus, the hypothalamus releases the corticotropin-releasing hormone, a peptide that reaches the anterior pituitary gland. ACTH is stored in the corticotrope cells of the pituitary gland and released as soon as the corticotropin-releasing hormone reaches the pituitary gland. Next, the ACTH is released and transported by the circulatory system to the adrenal glands. In the adrenal cortex, ACTH stimulates synthesis of cortisol. Cortisol is the key stress hormone, a derivate of cholesterol. Cortisol is the molecule to affect all organs within the body to achieve response to the initial stress. But what is most important in the hypothalamic-pituitary-adrenal axis is the fact that cortisol also causes effects on the hypothalamus and the pituitary gland. As for the hypothalamus, cortisol reduces the secretion of the corticotropin-releasing hormone. Thus, the lesser corticotropin-releasing hormone is excreted, the smaller amounts of ACTH are released. As for the pituitary gland, cortisol reduces the synthesis of ACTH directly by inhibiting enzymes engaged in ACTH synthesis.

In the hypothalamic-pituitary-adrenal axis there is a negative feedback mechanism of ACTH secretion. In fact, there are two negative feedback mechanisms that differ in their timing as well as manner. In the first type, the ACTH is suppressed by reducing the release of the corticotropin-releasing hormone directly by the elevated level of cortisol. The higher level of cortisol, the lower the level of corticotropin-releasing hormone, the lower concentrations of ACTH in the blood.  This mechanism works fast on the order of minutes. The second type lies in effects of cortisol to regulate the synthesis of ACTH in the pituitary gland: the cortisone suppresses peptide synthesis. The slower the synthesis rate, the lesser amounts of cortisol excreted by the gland. This negative feedback loop takes hours to days. Because the half life of ACTH is ten minutes, both the fast negative feedback and the slow loop are effective in regulating the level of ACTH secretion.

The negative feedback mechanism is a set of consequences that stands for self-regulating the system so that it reduces its activity. The negative feedback supports stability, or homeostasis within the body. The disorders in negative feedback loops lead to undesirable results, which mean the loss of homeostasis. In pituitary adenoma, the sensitive feedback mechanism is lost. The tumour produces excessive amounts of ACTH that stimulates the adrenal glands. As a result, hypercorticism or  Cushing’s disease develops. This is a disorder of elevated level of cortisol. The latter hormone in large amounts over a long period causes weakness, truncal obesity, striae (stretch marks on the skin), hypertension, psychological disarrangements and immune suppression.

In figure 1, the schematic presentation is given as it acts normally. It shows that the corticotropin-releasing hormone enhances the release of ACTH and ACTH increases cortisol (marked as ‘+’), while cortisol itself inhibits the two regulating hormones secretion (marked as ‘-‘).

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