Hypothalamic Pituitary Adrenal Axis

Secretory granules

Secretory granules

Hypothalamic Pituitary Adrenal Axis

ACTH p-LPH

The main actions of corticotropin-releasing hormone (CRH) on a corticotroph. CRH

binds to membrane receptors that are coupled to adenylyl cyclase (AC) by stimulatory G proteins (Gs). Adenylyl cyclase is stimulated, and cAMP rises in the cell. cAMP activates protein kinase A (PKA), which then phosphorylates proteins (P proteins) involved in stimulating ACTH secretion and the expression of the POMC gene.

ACTH p-LPH

The main actions of corticotropin-releasing hormone (CRH) on a corticotroph. CRH

binds to membrane receptors that are coupled to adenylyl cyclase (AC) by stimulatory G proteins (Gs). Adenylyl cyclase is stimulated, and cAMP rises in the cell. cAMP activates protein kinase A (PKA), which then phosphorylates proteins (P proteins) involved in stimulating ACTH secretion and the expression of the POMC gene.

duces the rate of secretion of glucocorticoids by the adrenal cortex. If the blood glucocorticoid level begins to fall for some reason, this negative-feedback effect is reduced, stimulating ACTH secretion and restoring the blood glu-cocorticoid level. This interactive relationship is called the hypothalamic-pituitary-adrenal axis (Fig. 32.6). This control loop ensures that the level of glucocorticoids in the blood remains relatively stable in the resting state, although there is a diurnal variation in glucocorticoid secretion. As discussed later, physical and emotional stress can alter the mechanism regulating glucocorticoid secretion.

The negative-feedback effect of glucocorticoids on ACTH secretion results from actions on both the hypothalamus and the corticotroph (see Fig. 32.6). When the concentration of glucocorticoids rises in the blood, CRH secretion from the hypothalamus is inhibited. As a result, the stimulatory effect of CRH on the corticotroph is reduced and the rate of ACTH secretion falls. Glucocorti-coids act directly on parvicellular neurons to inhibit CRH release, and indirectly through neurons in the hippocampus that project to the hypothalamus, to affect the activity of parvicellular neurons. At the corticotroph, glucocorticoids inhibit the actions of CRH to stimulate ACTH secretion.

If the blood concentration of glucocorticoids remains high for a long period of time, expression of the gene for POMC is inhibited. As a result, the amount of POMC mRNA falls in the corticotroph, and gradually the produc-

Hypothalamus Pituitary Adrenal Gland

The hypothalamic-pituitary-adrenal axis. "The negative-feedback actions of glucocorticoids on the corticotroph and the hypothalamus are indicated by dashed lines.

tion of ACTH and the other POMC peptides declines as well. Since CRH stimulates POMC gene expression and glucocorticoids inhibit CRH secretion, glucocorticoids inhibit POMC gene expression, in part, by suppressing CRH secretion. Glucocorticoids also act directly in the corti-cotroph itself to suppress POMC gene expression.

The negative-feedback actions of glucocorticoids are essential for the normal operation of the hypothalamic-pitu-itary-adrenal axis. This relationship is vividly illustrated by the disturbances that occur when blood glucocorticoid levels are changed drastically by disease or glucocorticoid administration. For example, if an individual's adrenal glands have been surgically removed or damaged by disease (e.g., Addison's disease), the resulting lack of glucocorticoids allows corticotrophs to secrete large amounts of ACTH. As noted earlier, this response may result in hyperpigmenta-tion as a result of the melanocyte-stimulating activity of ACTH. Individuals with glucocorticoid deficiency caused by inherited genetic defects affecting enzymes involved in steroid hormone synthesis by the adrenal cortex have high blood ACTH levels from the absence of the lack of the negative-feedback effects of glucocorticoids on ACTH secretion. Because a high blood concentration of ACTH causes hypertrophy of the adrenal glands, these genetic diseases are collectively called congenital adrenal hyperplasia (see Chapter 34). By contrast, in individuals treated chronically with large doses of glucocorticoids, the adrenal cortex atrophies because the high level of glucocorticoids in the blood inhibits ACTH secretion, resulting in the loss of its trophic influence on the adrenal cortex.

Stress and ACTH Secretion. The hypothalamic-pitu-itary-adrenal axis is greatly influenced by stress. When an individual experiences physical or emotional stress, ACTH

secretion is increased. As a result, the blood level of gluco-corticoids rises rapidly. Regardless of the blood glucocorticoid concentration, stress stimulates the hypothalamic-pi-tuitary-adrenal axis because stress-induced neural activity generated at higher CNS levels stimulates parvicellular neurons in the paraventricular nuclei to secrete CRH at a greater rate. Thus, stress can override the normal operation of the hypothalamic-pituitary-adrenal axis. If the stress persists, the blood glucocorticoid level remains high because the glucocorticoid negative-feedback mechanism functions at a higher set point.

AVP and ACTH Secretion. Glucocorticoid deficiency and certain types of stress also increase the concentration of arginine vasopressin (AVP) in hypophyseal portal blood. The physiological significance is that AVP, like CRH, can stimulate corticotrophs to secrete ACTH. Acting along with CRH, AVP amplifies the stimulatory effect of CRH on ACTH secretion.

AVP interacts with a specific receptor on the plasma membrane of the corticotroph. These receptors are coupled to the enzyme phospholipase C (PLC) by G proteins. The interaction of AVP with its receptor activates PLC, which, in turn, hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP2) present in the plasma membrane. This generates the intracellular second messengers inositol trisphosphate (IP3) and diacylglycerol (DAG). IP3 mobilizes intracellular calcium stores and DAG activates the phospholipid- and calcium-dependent protein kinase C (PKC) to mediate the stimulatory effect of AVP on ACTH secretion.

As noted earlier, AVP and oxytocin are produced by magnocellular neurons of the supraoptic and paraventricu-lar nuclei of the hypothalamus. These neurons terminate in the posterior lobe, where they secrete AVP and oxytocin into capillaries that feed into the systemic circulation. However, parvicellular neurons in the paraventricular nuclei also produce AVP, which they secrete into hypophyseal portal blood. It appears that much of the AVP secreted by parvicellular neurons is made in the same cells that produce CRH. It is assumed that the AVP in hypophyseal portal blood comes from these cells and from a small number of AVP-producing magnocellular neurons whose axons pass through the median eminence of the hypothalamus on their way to the posterior lobe.

The Sleep-Wake Cycle and ACTH Secretion. Under normal circumstances, the hypothalamic-pituitary-adrenal axis in humans functions in a pulsatile manner, resulting in several bursts of secretory activity over a 24-hour period. This pattern appears to be due to rhythmic activity in the CNS, which causes bursts of CRH secretion and, in turn, bursts of ACTH and glucocorticoid secretion (Fig. 32.7). A diurnal oscillation in secretory activity of the axis is thought to be due to changes in the sensitivity of CRH-producing neurons to the negative-feedback action of glucocorticoids, altering their rate of CRH secretion. As a result, there is a diurnal oscillation in the rate of ACTH and glucocorticoid secretion. This circadian rhythm is reflected in the daily pattern of glucocorticoid secretion. In individuals who are awake during the day and sleep at night, the blood gluco-

Acth Secretion Hours
night

ACTH secretion and the sleep-wake cycle. Pulsatile changes in the concentrations of ACTH and glucocorticoids in the blood of a young woman over a 24-hour period. Note that the amplitude of the pulses in ACTH and glucocorticoids is lower during the evening hours and increases greatly during the early morning hours. This pattern is due to the diurnal oscillation of the hypothalamic-pitu-itary-adrenal axis. (Modified from Krieger DT. Rhythms in CRF, ACTH and corticosteroids. In: Krieger DT, ed. Endocrine Rhythms. New York: Raven, 1979.)

corticoid level begins to rise during the early morning hours, reaches a peak sometime before noon, and then falls gradually to a low level around midnight (see Fig. 32.7). This pattern is reversed in individuals who sleep during the day and are awake at night. This inherent biological rhythm is superimposed on the normal operation of the hy-pothalamic-pituitary-adrenal axis.

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  • cheyenne
    What is hypothalamic pituitary adrenal axis?
    4 years ago

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