The adrenal glands are paired organs that sit atop either kidney. The adrenal gland is composed of two distinct structures, an outer cortex and an inner medulla, both of which produce hormones. The cortex secretes a variety of steroid hormones, including cortisol, aldosterone and androgens. The medulla produces primarily epinephrine (80%) and norepinephrine (20%) and embryologically is an extension of the sympathetic nervous system. We will not address the adrenal medulla since it was covered with the autonomic nervous system in Module 10 of BIO 264. However, you are still responsible to know the hormonal effects of epinephrine and norepinephrine.

• A great introduction video to the Adrenal Hormones by Janux can be viewed at https://youtu.be/iEJlwb0Syvo.

The adrenal cortex produces various hormones, all of which are derived from cholesterol. Collectively these hormones are referred to as adrenal steroids. The adrenal cortex can be subdivided into three zones or layers. Starting from the outside and moving in, these zones are called the zona glomerulosa, the zona fasciculata, and the zona reticularis. The zona glomerulosa produces a number of hormones that are collectively known as mineralocorticoids, the most common is aldosterone. The production of aldosterone is controlled by angiotensin II and/or extracellular potassium. The actions of aldosterone are discussed in unit 7 on the kidneys. The zona fasciculata produces the glucocorticoids. The most common glucocorticoid in humans is cortisol. The zona reticularis produces androgens such as DHEA and androstenedione, which contribute to the male secondary sex characteristics. (androgens will be discussed in the unit on reproduction).

Cortisol plays a role in mobilization or breakdown of carbohydrates (hence the name glucocorticoid), fats, and proteins. Cortisol production is stimulated by adrenocorticotropic hormone (ACTH) from the anterior pituitary gland. Like growth hormone, it is secreted in a circadian pattern with highest levels occurring in the early morning. Other factors that stimulate cortisol secretion include hypoglycemia and stress. The control of cortisol release by adrenocorticotropic hormone is through a pathway called the hypothalamic-pituitary-adrenal pathway and is categorized as a classical negative feedback pathway. The pathway begins with the release of CRH from the hypothalamus in response to physiological stress or hypoglycemia. CRH enters the pituitary portal system and induces the release of ACTH which acts to increase the synthesis and release of cortisol by cells in the zona fasciculata of the adrenal cortex. Cortisol diffuses out of the cell and is immediately bound by the carrier protein corticosteroid-binding globulin. Cortisol interacts with cytoplasmic receptors on target tissue. Cortisol acts in a negative feedback fashion to decrease ACTH secretion. Cortisol is anabolic in the liver and catabolic towards other tissues. The effects of cortisol are listed below:

1. Gluconeogenesis: cortisol stimulates glucose production by the liver from other sources such as amino acids or glycerol. Some of this glucose is released into the blood and some of it is stored as glycogen.

2. Protein catabolism: cortisol stimulates the breakdown of protein to amino acids in skeletal muscle, mainly to provide amino acids for glucose production by the liver.

3. Hyperglycemia: As explained above, cortisol stimulated gluconeogenesis increases blood sugar. Cortisol also diminishes the ability of insulin to lower blood sugar. It does this by making cells more resistant to insulin receptor activation. Cortisol can also reduce insulin production by beta cells of the pancreas. The increased sugar production (gluconeogenesis) and the decreased sugar absorption by cells (reduced insulin quantity and effectiveness) cause hyperglycemia.
4. Lipid catabolism: Cortisol stimulates the breakdown of fat into glycerol and fatty acids. Fatty acids will be used as energy and glycerol as a substrate for the liver. Sounds like a good weight loss idea? Actually, probably not, as cortisol favors the breakdown of fat from arms and legs but deposits fat in the torso.

5. Immuno-suppressant: Cortisol suppresses inflammation by decreasing antibody production, decreasing white blood cell migration and decreasing pro-inflammatory signaling from immune cells. Hence the logic behind a cortisol injection into an inflamed joint.

6. Brain function: Cortisol can cause mood changes and memory alterations. As may be evident, cortisol is a hormone that is essential for life; however, abnormal levels can cause problems. Excessive cortisol production results in hypercortisolism whereas low levels of cortisol results in hypocortisolism.

Hypercortisolism

Excessive cortisol release can result from a tumor in the adrenal cortex which would result in excessive cortisol secretion. It could result from a tumor in the pituitary gland that would produce excessive amounts of ACTH or a tumor in the hypothalamus that would produce excessive amounts of CRH. In either event the adrenal gland would secrete excessive amounts of cortisol (Cushing's syndrome). The most common cause of Cushing's syndrome is the over-administration of glucocorticoids prescribed to treat some other condition such as an autoimmune disorder like rheumatoid arthritis or as an immunosuppressant after organ transplant. Looking at the actions of cortisol from above then you might be able to predict what excessive cortisol might do: hyperglycemia (too much glucose), muscle breakdown, fat breakdown and re-deposition in the face and trunk, depression and learning difficulties.

Hypocortisolism

Loss of cortisol production is usually accompanied by a total loss in the function of all the layers of the adrenal cortex. The condition is known as Addison' disease and although rare is usually due to an autoimmune disease that destroys the adrenal cortex. Patients usually suffer from problems not necessarily associated with cortisol like hyperkalemia (excess potassium) or hyponatremia (low sodium) due to the loss of aldosterone. However, other symptoms associated with loss of cortisol may also be present. These include: fatigue, muscle weakness, fever, and difficulty standing up, diarrhea, sweating, mood changes and muscle pains. The adrenal insufficiency can also result in increased ACTH production since the normal negative feedback control is lost. The excess ACTH is associated with increased skin pigmentation due to the cross reactivity of ACTH with receptors for melanocyte stimulating hormone.