An adrenal gland sits above each kidney, just below the middle of your back. Functionally and anatomically, each adrenal gland consists of a gland within a gland (Figure 40.16). The core, or adrenal medulla, produces epinephrine and, to a lesser degree, norepinephrine. The medulla develops from nervous tissue and is under the control of the nervous system. Surrounding the medulla is the adrenal cortex, which produces steroid hormones. The cortex is under hormonal control, largely by a tropic hormone produced by cells in the anterior pituitary.

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THE ADRENAL CORTEX The cells of the adrenal cortex use cholesterol to produce three classes of steroid hormones (see Figure 40.2B), collectively called corticosteroids:

In adult humans, the adrenal cortex secretes only negligible amounts of sex steroids. The major producers of sex steroids are the gonads, as we saw in Key Concept 40.3.

Aldosterone, the primary mineralocorticoid, stimulates the kidneys to conserve sodium and excrete potassium, as we will discuss in Chapter 51. If the adrenal glands are removed from an animal, sodium must be added to its diet, or its sodium will be depleted and it will die.

The main glucocorticoid in humans is cortisol, which is critical for mediating the body’s metabolic responses to stress. Within minutes of a stressful stimulus (one provoking fear or anger, for example), blood cortisol levels begin to rise. This response is much slower than the neurally mediated epinephrine and norepinephrine response to stress, but it lasts longer. Whereas epinephrine and norepinephrine cause sudden increases in blood pressure, cortisol causes a sustained increase in blood pressure. Cortisol stimulates tissues that are not critical for escaping the danger or threat to switch from using blood glucose for energy to using fats and proteins. This action preserves circulating glucose to fuel the actions of the nervous system and skeletal muscles necessary to meet the threat. Cortisol also raises blood pressure, to increase delivery of oxygen to the muscles to prepare them for flight or fight, and inhibits the immune system. Dealing with the immediate stressor is more important than feeling sick, having allergic reactions, or healing wounds. This explains why cortisol and drugs that mimic its action are useful for reducing inflammation and allergic responses. Cortisol decreases activity of the gut and reproductive systems—you can digest lunch and reproduce later if you escape the threat. You can see that actions of cortisol are adaptive in responding to acute stress, but they can cause problems if sustained over time, as sometimes occurs in modern society due to social, economic, and job-related stressors.

Cortisol release is controlled by adrenocorticotropic hormone (ACTH) from the anterior pituitary. ACTH release is controlled in turn by corticotropin-releasing hormone (CRH) from the hypothalamus (see Figure 40.7) . The action of ACTH on the adrenal cortex is to stimulate the synthesis of cortisol. Like other steroid hormones, cortisol is not stored in vesicles and therefore is available for immediate release. As cortisol or other steroid hormones diffuse into the blood, they combine with carrier proteins, and their release from these proteins can have a long time course, thus stretching out their actions. Also, many of their actions stimulate gene expression in target cells, which also takes time but has a long-lasting effect.

Turning off the stress responses activated by cortisol is as important as turning them on. A study of stress in rats showed that old rats could turn on these stress responses as effectively as young rats, but they had lost the ability to turn them off as rapidly. As a result, they suffered from the well-known consequences of stress seen in humans: digestive system problems, cardiovascular problems, strokes, impaired immune system function, and increased susceptibility to cancers and other diseases. Acute stress responses are turned off by negative feedback from cortisol on both the ACTH-secreting cells of the anterior pituitary and the CRH-secreting cells of the hypothalamus. With chronic or prolonged stress, these control mechanisms become insufficient and cortisol must exert negative feedback through another brain region, the hippocampus. Prolonged exposure to cortisol, however, causes trauma to and loss of hippocampal cells, resulting in the decreased ability to turn off the stress response.

Loss of adrenal cortical function results in Addison’s disease, which is characterized by fatigue, muscle weakness, digestive problems, low blood sodium (hyponatremia), low blood pressure, and salt hunger. Without replacement hormone treatment, death is likely. An interesting symptom of Addison’s disease is darkening of many skin areas that normally are not exposed to the sun—for instance, the lining of the cheeks. You can understand the cause of this symptom by thinking about the source of ACTH and the control of its secretion. In the hypothalamic–pituitary–endocrine gland axis (see Figure 40.7), an end hormone (in this case cortisol) frequently serves as a negative feedback signal to the pituitary and also the hypothalamus. If the hormones of the adrenal cortex are absent, the negative feedback is also gone, and the system will call for more ACTH. The production of ACTH by pituitary cells involves the expression of a polypeptide called proopiomelanocortin which is then cleaved to produce multiple peptide hormones. These include ACTH, MSH, endorphins, and enkephalins. The excess production of MSH is the cause of the skin darkening in Addison’s disease.

THE ADRENAL MEDULLA Stress causes the adrenal medulla to release epinephrine and norepinephrine that arouse the body to action. As we saw earlier in this chapter, epinephrine and norepinephrine increase heart rate and blood pressure and divert blood flow to active muscles and away from the gut and skin. Only about one-fifth as much norepinephrine is secreted from the adrenal medulla as epinephrine, but it has similar functions. Norepinephrine is also used by the nervous system as a neurotransmitter, and it is involved in controlling many physiological processes.

Epinephrine and norepinephrine are both water-soluble, and both bind to the same set of receptors on the surfaces of target cells. These adrenergic receptors are of two general types, α-adrenergic and β-adrenergic. The α-adrenergic receptors respond more strongly to norepinephrine than to epinephrine, whereas β-adrenergic receptors respond about equally to both epinephrine and norepinephrine. Because of this difference in receptor affinities, it is possible for drugs to blunt the flight-or-fight responses without disrupting physiological regulatory processes. Such drugs are called “beta blockers” because, by inhibiting β-adrenergic receptors, they can reduce the fight-or-flight response to epinephrine without disrupting the physiological regulatory functions of norepinephrine mediated through the α-adrenergic receptors. Beta blockers are commonly prescribed to reduce symptoms of anxiety such as dry mouth and elevated heart rate (palpitations).