Regulation of Cortisol Secretion by Adrenocorticotropic Hormone from the Pituitary Gland

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ACTH Stimulates Cortisol Secretion. Unlike aldosterone secretion by the zona glomerulosa, which is controlled mainly by potassium and angiotensin acting directly on the adrenocortical cells, almost no stimuli have direct control effects on the adrenal cells that secrete cortisol. Instead, secretion of cortisol is controlled almost entirely by ACTH secreted by the anterior pituitary gland. This hormone, also called corticotropin or adrenocorticotropin, also enhances the production of adrenal androgens.

Chemistry of ACTH. ACTH has been isolated in pure form from the anterior pituitary. It is a large polypep-tide, having a chain length of 39 amino acids. A smaller polypeptide, a digested product of ACTH having a chain length of 24 amino acids, has all the effects of the total molecule.

ACTH Secretion Is Controlled by Corticotropin-Releasing Factor from the Hypothalamus. In the same way that other pituitary hormones are controlled by releasing factors from the hypothalamus, an important releasing factor also controls ACTH secretion. This is called corti-cotropin-releasing factor (CRF). It is secreted into the primary capillary plexus of the hypophysial portal system in the median eminence of the hypothalamus and then carried to the anterior pituitary gland, where it induces ACTH secretion. CRF is a peptide composed of 41 amino acids. The cell bodies of the neurons that secrete CRF are located mainly in the paraven-tricular nucleus of the hypothalamus. This nucleus in turn receives many nervous connections from the limbic system and lower brain stem.

The anterior pituitary gland can secrete only minute quantities of ACTH in the absence of CRF. Instead, most conditions that cause high ACTH secretory rates initiate this secretion by signals that begin in the basal regions of the brain, including the hypothalamus, and are then transmitted by CRF to the anterior pituitary gland.

ACTH Activates Adrenocortical Cells to Produce Steroids by Increasing Cyclic Adenosine Monophosphate (cAMP). The principal effect of ACTH on the adrenocortical cells is to activate adenylyl cyclase in the cell membrane. This then induces the formation of cAMP in the cell cytoplasm, reaching its maximal effect in about 3 minutes. The cAMP in turn activates the intracellular enzymes that cause formation of the adrenocortical hormones.

This is another example of cAMP as a second messenger signal system.

The most important of all the ACTH-stimulated steps for controlling adrenocortical secretion is activation of the enzyme protein kinase A, which causes initial conversion of cholesterol to pregnenolone. This initial conversion is the "rate-limiting" step for all the adrenocortical hormones, which explains why ACTH normally is necessary for any adrenocortical hormones to be formed. Long-term stimulation of the adrenal cortex by ACTH not only increases secretory activity but also causes hypertrophy and proliferation of the adrenocortical cells, especially in the zona fasciculata and zona reticularis, where cortisol and the androgens are secreted.

Physiologic Stress Increases ACTH and Adrenocortical Secretion

As pointed out earlier in the chapter, almost any type of physical or mental stress can lead within minutes to greatly enhanced secretion of ACTH and consequently cortisol as well, often increasing cortisol secretion as much as 20-fold. This effect was demonstrated by the rapid and strong adrenocortical secretory responses after trauma shown in Figure 77-5.

Pain stimuli caused by physical stress or tissue damage are transmitted first upward through the brain stem and eventually to the median eminence of the hypothalamus, as shown in Figure 77-6. Here CRF is secreted into the hypophysial portal system. Within minutes the entire control sequence leads to large quantities of cortisol in the blood.

Mental stress can cause an equally rapid increase in ACTH secretion. This is believed to result from increased activity in the limbic system, especially in the region of the amygdala and hippocampus, both of which then transmit signals to the posterior medial hypothalamus.

Inhibitory Effect of Cortisol on the Hypothalamus and on the Anterior Pituitary to Decrease ACTH Secretion. Cortisol has direct negative feedback effects on (1) the hypothalamus to decrease the formation of CRF and (2) the anterior pituitary gland to decrease the formation of ACTH. Both of these feedbacks help regulate the plasma concentration of cortisol. That is, whenever the cortisol concentration becomes too great, the feedbacks automatically reduce the ACTH toward a normal control level.

Summary of the Cortisol Control System

Figure 77-6 shows the overall system for control of cortisol secretion. The key to this control is the excitation of the hypothalamus by different types of stress. Stress stimuli activate the entire system to cause rapid release of cortisol, and the cortisol in turn initiates a series of metabolic effects directed toward relieving the damaging nature of the stressful state.

There is also direct feedback of the cortisol to both the hypothalamus and the anterior pituitary gland to decrease the concentration of cortisol in the plasma at times when the body is not experiencing stress.

Adrenocorticotropic Hormone

Figure 77-6

Mechanism for regulation of glucocorticoid secretion. ACTH, adrenocorticotropic hormone; CRF, corticotropin-releasing factor.

Figure 77-6

Mechanism for regulation of glucocorticoid secretion. ACTH, adrenocorticotropic hormone; CRF, corticotropin-releasing factor.

However, the stress stimuli are the prepotent ones; they can always break through this direct inhibitory feedback of cortisol, causing either periodic exacerbations of cortisol secretion at multiple times during the day (Figure 77-7) or prolonged cortisol secretion in times of chronic stress.

Circadian Rhythm of Glucocorticoid Secretion. The secretory rates of CRF, ACTH, and cortisol are high in the early morning but low in the late evening, as shown in Figure 77-7; the plasma cortisol level ranges between a high of about 20 mg/dl an hour before arising in the morning and a low of about 5 mg/dl around midnight. This effect results from a 24-hour cyclical alteration in the signals from the hypothalamus that cause cortisol secretion. When a person changes daily sleeping habits, the cycle changes correspondingly. Therefore, measurements of blood cortisol levels are meaningful only when expressed in terms of the time in the cycle at which the measurements are made.

Synthesis and Secretion of ACTH in Association with Melanocyte-Stimulating Hormone, Lipotropin, and Endorphin

When ACTH is secreted by the anterior pituitary gland, several other hormones that have similar chemical structures are secreted simultaneously. The reason for this is that the gene that is transcribed to form the RNA molecule that causes ACTH synthesis initially causes the formation of a considerably larger protein, a preprohormone called proopiomelanocortin (POMC), which is the precursor of ACTH as well as several other peptides, including melanocyte-

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