You may have heard of anabolic steroids, which can have harmful effects. But there's another type of steroid - sometimes called a corticosteroid - that treats a variety of problems. These steroids are similar to hormones that your adrenal glands make to fight stress associated with illnesses and injuries. They reduce inflammation and affect the immune system.

You may need to take corticosteroids to treat

• Arthritis
• Asthma
• Autoimmune diseases such as lupus and multiple sclerosis
• Skin conditions such as eczema and rashes
• Some kinds of cancer

Steroids are strong medicines, and they can have side effects, including weakened bones and cataracts. Because of this, you usually take them for as short a time as possible.

Steroid

Any of a group of lipids (fats) that have a certain chemical structure. Steroids occur naturally in plants and animals or they may be made in the laboratory. Examples of steroids include sex hormones, cholesterol, bile acids, and some drugs.

Steroid cream

A skin cream containing a type of drug that relieves swelling, itching, and inflammation.

Steroid drug

A type of drug used to relieve swelling and inflammation. Some steroid drugs may also have antitumor effects.

Steroid metabolism gene

A type of gene that helps the body build up or break down steroids. Steroids may be made by the body (such as hormones and cholesterol) or made in a laboratory (such as drugs). A steroid metabolism gene called CYP17 is being studied in breast, ovarian, and uterine cancers.

Steroid therapy

Treatment with corticosteroid drugs to reduce swelling, pain, and other symptoms of inflammation.

Any steroid hormone made in the adrenal cortex (the outer part of the adrenal gland). They are also made in the laboratory. Corticosteroids have many different effects in the body, and are used to treat many different conditions. They may be used as hormone replacement, to suppress the immune system, and to treat some side effects of cancer and its treatment. Corticosteroids are also used to treat certain lymphomas and lymphoid leukemias.

A compound that belongs to the family of compounds called corticosteroids (steroids). Glucocorticoids affect metabolism and have anti-inflammatory and immunosuppressive effects. They may be naturally produced (hormones) or synthetic (drugs).

Lipids also are sources of energy that power cellular processes. Like carbohydrates, lipids are composed of carbon, hydrogen, and oxygen, but these atoms are arranged differently. Most lipids are nonpolar and hydrophobic. Major types include fats and oils, waxes, phospholipids, and steroids. A typical fat consists of three fatty acids bonded to one molecule of glycerol, forming triglycerides or triacylglycerols. The fatty acids may be saturated or unsaturated, depending on the presence or absence of double bonds in the hydrocarbon chain; a saturated fatty acid has the maximum number of hydrogen atoms bonded to carbon and, thus, only single bonds. In general, fats that are liquid at room temperature (e.g., canola oil) tend to be more unsaturated than fats that are solid at room temperature. In the food industry, oils are artificially hydrogenated to make them chemically more appropriate for use in processed foods. During this hydrogenation process, double bonds in the cis- conformation in the hydrocarbon chain may be converted to double bonds in the trans- conformation; unfortunately, trans fats have been shown to contribute to heart disease. Phospholipids are a special type of lipid associated with cell membranes and typically have a glycerol (or sphingosine) backbone to which two fatty acid chains and a phosphate-containing group are attached. As a result, phospholipids are considered amphipathic because they have both hydrophobic and hydrophilic components. (In Chapters 4 and 5 we will explore in more detail how the amphipathic nature of phospholipids in plasma cell membranes helps regulate the passage of substances into and out of the cell.) Although the molecular structures of steroids differ from that of triglycerides and phospholipids, steroids are classified as lipids based on their hydrophobic properties. Cholesterol is a type of steroid in animal cells’ plasma membrane. Cholesterol is also the precursor of steroid hormones such as testosterone.

Fats and Oils

Lipids include a diverse group of compounds that are largely nonpolar in nature. This is because they are hydrocarbons that include mostly nonpolar carbon–carbon or carbon–hydrogen bonds. Non-polar molecules are hydrophobic (“water fearing”), or insoluble in water. Lipids perform many different functions in a cell. Cells store energy for long-term use in the form of fats. Lipids also provide insulation from the environment for plants and animals (Figure 3.13). For example, their water-repellant hydrophobic nature can help keep aquatic birds and mammals dry by forming a protective layer over fur or feathers. Lipids are also the building blocks of many hormones and an important constituent of all cellular membranes. Lipids include fats, waxes, phospholipids, and steroids.

Figure 3.13 Hydrophobic lipids in the fur of aquatic mammals, such as this river otter, protect them from the elements. (credit: Ken Bosma)

A fat molecule consists of two main components—glycerol and fatty acids. Glycerol is an organic compound (alcohol) with three carbons, five hydrogens, and three hydroxyl (OH) groups. Fatty acids have a long chain of hydrocarbons to which a carboxyl group is attached, hence the name “fatty acid.” The number of carbons in the fatty acid may range from 4 to 36; most common are those containing 12–18 carbons. In a fat molecule, the fatty acids are attached to each of the three carbons of the glycerol molecule with an ester bond through an oxygen atom (Figure 3.14).

Figure 3.14 Triacylglycerol is formed by the joining of three fatty acids to a glycerol backbone in a dehydration reaction. Three molecules of water are released in the process.

During this ester bond formation, three water molecules are released. The three fatty acids in the triacylglycerol may be similar or dissimilar. Fats are also called triacylglycerols or triglycerides because of their chemical structure. Some fatty acids have common names that specify their origin. For example, palmitic acid, a saturated fatty acid, is derived from the palm tree. Arachidic acid is derived from Arachis hypogea, the scientific name for groundnuts or peanuts.

Fatty acids may be saturated or unsaturated. In a fatty acid chain, if there are only single bonds between neighboring carbons in the hydrocarbon chain, the fatty acid is said to be saturated. Saturated fatty acids are saturated with hydrogen; in other words, the number of hydrogen atoms attached to the carbon skeleton is maximized. Stearic acid is an example of a saturated fatty acid (Figure 3.15)

Figure 3.15 Stearic acid is a common saturated fatty acid.

When the hydrocarbon chain contains a double bond, the fatty acid is said to be unsaturated. Oleic acid is an example of an unsaturated fatty acid (Figure 3.16).

Figure 3.16 Oleic acid is a common unsaturated fatty acid.

Most unsaturated fats are liquid at room temperature and are called oils. If there is one double bond in the molecule, then it is known as a monounsaturated fat (e.g., olive oil), and if there is more than one double bond, then it is known as a polyunsaturated fat (e.g., canola oil).

When a fatty acid has no double bonds, it is known as a saturated fatty acid because no more hydrogen may be added to the carbon atoms of the chain. A fat may contain similar or different fatty acids attached to glycerol. Long straight fatty acids with single bonds tend to get packed tightly and are solid at room temperature. Animal fats with stearic acid and palmitic acid (common in meat) and the fat with butyric acid (common in butter) are examples of saturated fats. Mammals store fats in specialized cells called adipocytes, where globules of fat occupy most of the cell’s volume. In plants, fat or oil is stored in many seeds and is used as a source of energy during seedling development. Unsaturated fats or oils are usually of plant origin and contain cis unsaturated fatty acids. Cis and trans indicate the configuration of the molecule around the double bond. If hydrogens are present in the same plane, it is referred to as a cis fat; if the hydrogen atoms are on two different planes, it is referred to as a trans fat. The cis double bond causes a bend or a “kink” that prevents the fatty acids from packing tightly, keeping them liquid at room temperature (Figure 3.17). Olive oil, corn oil, canola oil, and cod liver oil are examples of unsaturated fats. Unsaturated fats help to lower blood cholesterol levels whereas saturated fats contribute to plaque formation in the arteries.

Figure 3.17 Saturated fatty acids have hydrocarbon chains connected by single bonds only. Unsaturated fatty acids have one or more double bonds. Each double bond may be in a cis or trans configuration. In the cis configuration, both hydrogens are on the same side of the hydrocarbon chain. In the trans configuration, the hydrogens are on opposite sides. A cis double bond causes a kink in the chain.

Trans Fats

In the food industry, oils are artificially hydrogenated to make them semi-solid and of a consistency desirable for many processed food products. Simply speaking, hydrogen gas is bubbled through oils to solidify them. During this hydrogenation process, double bonds of the cis- conformation in the hydrocarbon chain may be converted to double bonds in the trans- conformation.

Margarine, some types of peanut butter, and shortening are examples of artificially hydrogenated trans fats. Recent studies have shown that an increase in trans fats in the human diet may lead to an increase in levels of low-density lipoproteins (LDL), or “bad” cholesterol, which in turn may lead to plaque deposition in the arteries, resulting in heart disease. Many fast food restaurants have recently banned the use of trans fats, and food labels are required to display the trans fat content.

Omega Fatty Acids

Essential fatty acids are fatty acids required but not synthesized by the human body. Consequently, they have to be supplemented through ingestion via the diet. Omega-3 fatty acids (like that shown in Figure 3.18) fall into this category and are one of only two known for humans (the other being omega-6 fatty acid). These are polyunsaturated fatty acids and are called omega-3 because the third carbon from the end of the hydrocarbon chain is connected to its neighboring carbon by a double bond.

Figure 3.18 Alpha-linolenic acid is an example of an omega-3 fatty acid. It has three cis double bonds and, as a result, a curved shape. For clarity, the carbons are not shown. Each singly bonded carbon has two hydrogens associated with it, also not shown.

The farthest carbon away from the carboxyl group is numbered as the omega (ω) carbon, and if the double bond is between the third and fourth carbon from that end, it is known as an omega-3 fatty acid. Nutritionally important because the body does not make them, omega-3 fatty acids include alpha-linoleic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), all of which are polyunsaturated. Salmon, trout, and tuna are good sources of omega-3 fatty acids. Research indicates that omega-3 fatty acids reduce the risk of sudden death from heart attacks, reduce triglycerides in the blood, lower blood pressure, and prevent thrombosis by inhibiting blood clotting. They also reduce inflammation, and may help reduce the risk of some cancers in animals.

Like carbohydrates, fats have received a lot of bad publicity. It is true that eating an excess of fried foods and other “fatty” foods leads to weight gain. However, fats do have important functions. Many vitamins are fat soluble, and fats serve as a long-term storage form of fatty acids: a source of energy. They also provide insulation for the body. Therefore, “healthy” fats in moderate amounts should be consumed on a regular basis.

Phospholipids

Phospholipids are major constituents of the plasma membrane, the outermost layer of all living cells. Like fats, they are composed of fatty acid chains attached to a glycerol or sphingosine backbone. Instead of three fatty acids attached as in triglycerides, however, there are two fatty acids forming diacylglycerol, and the third carbon of the glycerol backbone is occupied by a modified phosphate group (Figure 3.20). A phosphate group alone attached to a diacylglycerol does not qualify as a phospholipid; it is phosphatidate (diacylglycerol 3-phosphate), the precursor of phospholipids. The phosphate group is modified by an alcohol. Phosphatidylcholine and phosphatidylserine are two important phospholipids that are found in plasma membranes.

Figure 3.20 A phospholipid is a molecule with two fatty acids and a modified phosphate group attached to a glycerol backbone. The phosphate may be modified by the addition of charged or polar chemical groups.

A phospholipid is an amphipathic molecule, meaning it has a hydrophobic and a hydrophilic part. The fatty acid chains are hydrophobic and cannot interact with water, whereas the phosphate-containing group is hydrophilic and interacts with water (Figure 3.21).

Figure 3.21 The phospholipid bilayer is the major component of all cellular membranes. The hydrophilic head groups of the phospholipids face the aqueous solution. The hydrophobic tails are sequestered in the middle of the bilayer.

The head is the hydrophilic part, and the tail contains the hydrophobic fatty acids. In a membrane, a bilayer of phospholipids forms the matrix of the structure, the fatty acid tails of phospholipids face inside, away from water, whereas the phosphate group faces the outside, aqueous side (Figure 3.21).

Phospholipids are responsible for the dynamic nature of the plasma membrane. If a drop of phospholipids is placed in water, it spontaneously forms a structure known as a micelle, where the hydrophilic phosphate heads face the outside and the fatty acids face the interior of this structure.

EVERYDAY CONNECTION FOR AP® COURSES

Fats are amphiphilic molecules. In other words, the long hydrocarbon tail is hydrophobic, and the glycerol part of the molecule is hydrophilic. When in water, fats will arrange themselves into a ball called a micelle so that the hydrophilic “heads” are on the outer surface, and the hydrophobic “tails” are on the inside where they are protected from the surrounding water.

Figure 3.22

Steroids

Unlike the phospholipids and fats that we discussed earlier, steroids have a fused ring structure. Although they do not resemble the other lipids, scientists group them with them because they are also hydrophobic and insoluble in water. All steroids have four linked carbon rings and several of them, like cholesterol, have a short tail (Figure 3.21). Many steroids also have the –OH functional group, which puts them in the alcohol classification (sterols).

Figure 3.21 Four fused hydrocarbon rings comprise steroids such as cholesterol and cortisol.

Cholesterol is the most common steroid. The liver synthesizes cholesterol and is the precursor to many steroid hormones such as testosterone and estradiol, which gonads and endocrine glands secrete. It is also the precursor to Vitamin D. Cholesterol is also the precursor of bile salts, which help emulsifying fats and their subsequent absorption by cells. Although lay people often speak negatively about cholesterol, it is necessary for the body's proper functioning. Sterols (cholesterol in animal cells, phytosterol in plants) are components of the plasma membrane of cells and are found within the phospholipid bilayer.

A natural steroid hormone produced in the adrenal gland. It can also be made in the laboratory. Cortisone reduces swelling and can suppress immune responses.

When a threat or danger is perceived, the body responds by releasing hormones that will ready it for the “fight-or-flight” response. The effects of this response are familiar to anyone who has been in a stressful situation: increased heart rate, dry mouth, and hair standing up.

Fight-or-Flight Response

Interactions of the endocrine hormones have evolved to ensure the body’s internal environment remains stable. Stressors are stimuli that disrupt homeostasis. The sympathetic division of the vertebrate autonomic nervous system has evolved the fight-or-flight response to counter stress-induced disruptions of homeostasis. In the initial alarm phase, the sympathetic nervous system stimulates an increase in energy levels through increased blood glucose levels. This prepares the body for physical activity that may be required to respond to stress: to either fight for survival or to flee from danger.

However, some stresses, such as illness or injury, can last for a long time. Glycogen reserves, which provide energy in the short-term response to stress, are exhausted after several hours and cannot meet long-term energy needs. If glycogen reserves were the only energy source available, neural functioning could not be maintained once the reserves became depleted due to the nervous system’s high requirement for glucose. In this situation, the body has evolved a response to counter long-term stress through the actions of the glucocorticoids, which ensure that long-term energy requirements can be met. The glucocorticoids mobilize lipid and protein reserves, stimulate gluconeogenesis, conserve glucose for use by neural tissue, and stimulate the conservation of salts and water. The mechanisms to maintain homeostasis that are described here are those observed in the human body. However, the fight-or-flight response exists in some form in all vertebrates.

The sympathetic nervous system regulates the stress response via the hypothalamus. Stressful stimuli cause the hypothalamus to signal the adrenal medulla (which mediates short-term stress responses) via nerve impulses, and the adrenal cortex, which mediates long-term stress responses, via the hormone adrenocorticotropic hormone (ACTH), which is produced by the anterior pituitary.

Long-term Stress Response

Long-term stress response differs from short-term stress response. The body cannot sustain the bursts of energy mediated by epinephrine and norepinephrine for long times. Instead, other hormones come into play. In a long-term stress response, the hypothalamus triggers the release of ACTH from the anterior pituitary gland. The adrenal cortex is stimulated by ACTH to release steroid hormones called corticosteroids. Corticosteroids turn on transcription of certain genes in the nuclei of target cells. They change enzyme concentrations in the cytoplasm and affect cellular metabolism. There are two main corticosteroids: glucocorticoids such as cortisol, and mineralocorticoids such as aldosterone. These hormones target the breakdown of fat into fatty acids in the adipose tissue. The fatty acids are released into the bloodstream for other tissues to use for ATP production. The glucocorticoidsprimarily affect glucose metabolism by stimulating glucose synthesis. Glucocorticoids also have anti-inflammatory properties through inhibition of the immune system. For example, cortisone is used as an anti-inflammatory medication; however, it cannot be used long term as it increases susceptibility to disease due to its immune-suppressing effects.

Mineralocorticoids function to regulate ion and water balance of the body. The hormone aldosterone stimulates the reabsorption of water and sodium ions in the kidney, which results in increased blood pressure and volume.

Hypersecretion of glucocorticoids can cause a condition known as Cushing’s disease, characterized by a shifting of fat storage areas of the body. This can cause the accumulation of adipose tissue in the face and neck, and excessive glucose in the blood. Hyposecretion of the corticosteroids can cause Addison’s disease, which may result in bronzing of the skin, hypoglycemia, and low electrolyte levels in the blood.

Long-term stress response differs from short-term stress response. The body cannot sustain the bursts of energy mediated by epinephrine and norepinephrine for long times. Instead, other hormones come into play. In a long-term stress response, the hypothalamus triggers the release of ACTH from the anterior pituitary gland. The adrenal cortex is stimulated by ACTH to release steroid hormones called corticosteroids. Corticosteroids turn on transcription of certain genes in the nuclei of target cells. They change enzyme concentrations in the cytoplasm and affect cellular metabolism. There are two main corticosteroids: glucocorticoids such as cortisol, and mineralocorticoids such as aldosterone. These hormones target the breakdown of fat into fatty acids in the adipose tissue. The fatty acids are released into the bloodstream for other tissues to use for ATP production. The glucocorticoids primarily affect glucose metabolism by stimulating glucose synthesis. Glucocorticoids also have anti-inflammatory properties through inhibition of the immune system. For example, cortisone is used as an anti-inflammatory medication; however, it cannot be used long term as it increases susceptibility to disease due to its immune-suppressing effects.

Mineralocorticoids function to regulate ion and water balance of the body. The hormone aldosterone stimulates the reabsorption of water and sodium ions in the kidney, which results in increased blood pressure and volume.

Hypersecretion of glucocorticoids can cause a condition known as Cushing’s disease, characterized by a shifting of fat storage areas of the body. This can cause the accumulation of adipose tissue in the face and neck, and excessive glucose in the blood. Hyposecretion of the corticosteroids can cause Addison’s disease, which may result in bronzing of the skin, hypoglycemia, and low electrolyte levels in the blood.

Indications

Corticosteroids are hormone mediators produced by the cortex of adrenal glands that are further categorized into glucocorticoids (major glucocorticoid produced by the body is cortisol), mineralocorticoids (major mineralocorticoid produced in the body is aldosterone), and androgenic sex hormones. Endogenous cortisone was first isolated in 1935 and synthesized in 1944. In 1948, Dr. Philip S Hench published administered cortisone (called Compound E at that time) to a 29-year-old woman who was bed-ridden secondary to active rheumatoid arthritis. The patient was able to walk after three days of treatment. This case was published in 1949, and in 1950, Philip S. Hench, Edward C. Kendall, and Tadeusz Reichstein were awarded the Nobel Prize in Physiology or Medicine "for their discoveries relating to the hormones of the adrenal cortex, their structure, and biological effects."

Glucocorticoids (GCs) are a group of drugs structurally and pharmacologically similar to the endogenous hormone cortisol with various functions like anti-inflammatory, immunosuppressive, anti-proliferative, and vaso-constrictive effects. Their actions are used medically for the treatment of various conditions indicated below. The list of indications of glucocorticoids is extremely long. We have categorized and mentioned the most important and broad-spectrum indication below.

As a Replacement Therapy

• Adrenocortical insufficiency (Addison disease)

• Congenital adrenal hyperplasia (CAH)

Systemic Symptomatic Treatment

Acute

• Allergic reactions and anaphylactic shock (vasoconstrictive effects)

• Asthma (bronchodilatory effects)

• Antiemetic treatment, for example, nausea due to chemotherapy)

• Toxic pulmonary edema

• Acute exacerbation of autoimmune diseases such as multiple sclerosis, vitiligo, uveitis, rheumatoid arthritis, SLE, etc.

• Acute exacerbation of chronic obstructive pulmonary disease (COPD)

• Cerebral edema: Recommended only in specific conditions like elevated intracranial pressure due to the neoplasm or central nervous system (CNS) infection; generally avoided in moderate to severe brain injury

Long-Term

• Chronic, inflammatory diseases (asthma, chronic obstructive pulmonary disease, inflammatory bowel disease)

• Rheumatic diseases (sarcoidosis, Sjogren syndrome, SLE)

• Graves' ophthalmopathy

• Local symptomatic treatment: anterior uveitis, steroid-responsive dermatoses (SRD), tenosynovitis, and osteoarthritis or juvenile idiopathic arthritis

Prophylactic

• Organ transplant (to prevent rejection due to their immunosuppressive action)

• Preterm delivery (to allow fetal lung maturity)

Mineralocorticoids are primarily involved in the regulation of electrolyte and water balance by modulating ion transport in the epithelial cells of the collecting ducts of the kidney. The use of mineralocorticoid drugs is limited to their replacement therapy in acute adrenal crisis and Addison disease.

Due to several roles played by corticosteroids in the human body, they see extensive use in medical practice for the treatment of various diseases. As a result, their side-effects, have, in turn, become another significant medical issue requiring special attention.

Mechanism of Action

ANTI-INFLAMMATORY and IMMUNOSUPPRESSIVE EFFECTS

The anti-inflammatory and immunosuppressive effects of glucocorticoids are dose-dependent, with immunosuppressive effects seen mostly at higher doses. The pharmacological anti-inflammatory and immunosuppressive effects of glucocorticoids are extensive and can be the genomic or non-genomic mechanisms. Most effects of glucocorticoids are via the genomic mechanisms, which takes time, while immediate effects via the non-genomic mechanisms can occur with high doses of glucocorticoids (such as pulse therapy). Clinically, it is not possible to separate these effects.

Genomic mechanisms

Being small, lipophilic substances, glucocorticoids readily pass the cell membrane by diffusion and enter the cytoplasm of the target cells, where most of their action is mediated by binding to the intra-cytoplasmic glucocorticoid receptors. Glucocorticoid receptors have two isoforms, α, and β. Glucocorticoids bind to the α-isoform only. Glucocorticoid resistance in some patients has been partly attributed to higher levels of the β-isoform in these patients. Binding of the glucocorticoid to the glucocorticoid receptor results in shedding of heat-shock proteins, which are otherwise bound to the glucocorticoid receptor, and this results in the formation of the activated glucocorticoid receptor-glucocorticoid complex which easily translocates to the nucleus. In the nucleus of the target cells, this complex reversibly binds to several specific DNA sites resulting in stimulation (transactivation) and suppression (transrepression) of a large variety of gene transcription. Tranpression of transcription factors such as nuclear factor-κB [NF-κB], activator protein-1 and interferon regulatory factor-3 results in suppression of synthesis of pro-inflammatory cytokines such as IL-1, IL-2, IL-6, IL-8, TNF, IFN-gamma, Cox-2, VEGF, and prostaglandins. Transactivation of transcription factors, including glucocorticoid response elements (GREs), leads to activation of synthesis of anti-inflammatory cytokines such as IL-10, NF-κB inhibitor, and lipocortin-1.

Non-Genomic mechanisms

The immediate effects of high dose-glucocorticoids are mediated via non-genomic mechanisms. At high doses, glucocorticoids bind the membrane-associated glucocorticoid receptors on target cells such as T-lymphocytes, resulting in impairment of receptor signaling and immune response of the T lymphocytes. High dose glucocorticoids also interact with the cycling of calcium and sodium across the cell membrane resulting in a rapid decrease in inflammation.

By altering the cytokine production via the genomic and non-genomic mechanisms, glucocorticoids lead to suppression of the immune system and decreased inflammation. They target a wide variety of cells, including T-lymphocytes, macrophages, fibroblasts, neutrophils, eosinophils, and basophils. Notably, glucocorticoids have almost no effect on B-cell function and immunoglobulin production. The downstream effects of glucocorticoids are summarized below:

• Inhibition of neutrophil adhesion to endothelial cells, and demargination of neutrophils from the marginal pool of blood vessels causing neutrophilic leukocytosis

• A decrease in the number of lymphocytes, macrophages, monocytes, eosinophils, and basophils (decreased myelopoiesis and release from bone marrow, and increased apoptosis)

• Decreased proliferation of fibroblasts

• Decreased MHC-Class II and Fc receptor expression on macrophages and monocytes

• Decreased phagocytosis and antigen presentation by macrophages

• Decreased cytokine production by macrophages and lymphocytes

• Decreased proliferation of fibroblasts.

• Reduction in the formation of arachidonic acid derivatives by the promotion of synthesis of lipocortin-A that inhibits phospholipase A2

• Inhibition of metalloproteinases collagenase and stromelysin which are otherwise responsible for cartilage degradation

EFFECTS ON HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS

Glucocorticoids exert negative feedback effects on the HPA axis. They directly suppress adrenocorticotropic hormone (ACTH) and corticotropin-releasing hormone (CRH) secretion. Additionally, by suppressing the release of pro-inflammatory cytokines that stimulate ACTH and CRP secretion, glucocorticoids further suppress ACTH and CRH secretion indirectly in inflammatory diseases. Chronic HPA axis suppression by glucocorticoids leads to functional adrenal atrophy (sparing the mineralocorticoid producing outer adrenal cortex that is functionally independent of ACTH). The risk of this functional adrenal atrophy and insufficiency is challenging to predict, and varies from patient to patient but is largely dependant on the dose and duration of glucocorticoid therapy. The adrenal function generally recovers by slow tapering of glucocorticoids.

MINERALOCORTICOID EFFECTS

Glucocorticoids bind to mineralocorticoid receptors (MRs) and produce their mineralocorticoid effect (i.e., increasing sodium and decreasing potassium), but only when used at the high dose and for the extended period.

Administration

Several preparations of glucocorticoids are available, each with varying efficacy. Dexamethasone and betamethasone are long-acting with the highest glucocorticoid efficacy with a biological half-life of 36 to 54 hours. Cortisone and cortisol are short-acting with a biological half-life of under 12 hours, and not frequently used. Prednisone, prednisolone, methylprednisolone, and triamcinolone are intermediate-acting with a biological half-life of 18 to 36 hours. The glucocorticoid and mineralocorticoid effects of each available preparation varies, with cortisol and cortisone having almost 1 to 1 glucocorticoid and mineralocorticoid effects while all others with almost no mineralocorticoid effects. Equivalent glucocorticoid doses can be calculated for these various preparations. 5 mg of prednisone is equivalent in its glucocorticoid effects to 5 mg of prednisolone, 4 mg of methylprednisolone, 4 mg of triamcinolone, 0.75 mg of dexamethasone, 0.60 mg of betamethasone, 20 mg of cortisol and 25 mg of cortisone.

Intravenous Administration

Parenteral intravenous administration of high doses of glucocorticoids may be warranted in emergencies, such as septic shock, COPD exacerbation, and severe acute asthma. Pulse therapy of glucocorticoids (1000 mg intravenous methylprednisolone divided over 3 to 4 daily doses) for several days has been studied in several rheumatological conditions and is recommended only for organ-threatening or life-threatening situations including lupus nephritis (Class III or IV), giant cell arteritis with vision loss, ANCA-associated vasculitis, etc. Americal College of Rheumatology also recommends using intravenous glucocorticoids in patients with acute gout who are unable to take medications orally.

Oral Administration

Oral preparations are usually useful in both acute and chronic indications. For acute exacerbations of underlying chronic illness (such as asthma, COPD, gout, pseudogout, rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), etc.), short duration of moderate to high doses of oral corticosteroids is usually efficacious in treating the flare. Tapering dose packs starting at high dose and tapering daily over 7 to 9 days are commercially available and can be used in these situations as well. Long term oral corticosteroid therapy may be necessary for chronic illnesses such as polymyalgia rheumatica, SLE, RA, vasculitis, myositis, IgG4-related disease, chronic myelogenous leukemia (CML), lymphoma, leukemia, multiple sclerosis, organ transplantation, etc. Clinicians must make every effort to use the glucocorticoids at the lowest possible dose and for the shortest possible duration in these cases. A slow taper shall be attempted in patients with prolonged exposure to glucocorticoids to prevent adrenal crisis.

Local Administration

Glucocorticoid administration can be via several non-systemic routes, including intra-articular joint injections for joint inflammation, inhalational for asthma, topical for dermatological problems, ocular drops for eye conditions, and intra-nasal for seasonal rhinitis. Clinicians generally avoid intramuscular (IM) glucocorticoids due to the risk of local muscle atrophy due to depot effect and the only indications for intramuscular glucocorticoids are for IM triamcinolone acetonide for specific inflammatory disorders and IM injection of betamethasone to a pregnant mother less than 37 weeks of gestation to stimulate fetal lung maturity. When appropriate, a non-systemic route is preferable to the systemic route of administration to minimize systemic adverse effects.

Adverse Effects

Factors influencing the adverse effects of glucocorticoids

Given the diversity in the mechanism of action of glucocorticoids, they can cause a wide array of adverse effects ranging from mild to severe, some of which are unavoidable. Of all the factors influencing the adverse effects of glucocorticoids, dose, and duration of therapy are the most important independent and well-documented risk factors. It is usually at “supra-physiologic” doses of corticosteroid administration where multiple and especially severe adverse effects of glucocorticoids occur, ranging from mild suppression of hypothalamic-pituitary axis to severe, life-threatening infections. However, long term use of low to moderate doses of glucocorticoids can lead to several serious adverse effects as well. Adverse effects of corticosteroids are both dose and time-dependent. Some adverse effects follow a linear dose-response pattern where the incidence increases with an increase in the dose (ecchymosis, cushingoid features, parchment-like skin, leg edema, and sleep disturbance). Other adverse effects may follow a threshold dose-response pattern with an elevated frequency of events beyond a specific threshold value (weight gain and epistaxis at prednisone dose greater than 5 mg daily, glaucoma, depression, hypertension at prednisone dose greater than 7.5 mg daily, etc.).

Several other factors may influence the adverse effects of glucocorticoids. Older age, comorbid conditions (such as diabetes mellitus), concomitant use of other immunosuppressive agents, severity, and nature of the underlying disease and poor nutritional status can all influence the occurrence and magnitude of side-effects.

Musculoskeletal adverse effects

Glucocorticoids induced Osteoporosis is one of the well-known and devastating adverse effects of long-term use of glucocorticoids. Up to 40% of patients on long-term glucocorticoids develop bone loss leading to fractures. Several mechanisms play a role, including osteoclast activation by promoting RANK-ligand as well as a decrease in function and number of osteoblasts and osteocytes. The trabecular bone is initially affected, with cortical bone loss seen with longer-term use. The loss of trabecular bone can occur within the first 6 to 12 months of therapy.

Steroid-induced myopathy, which is a reversible painless myopathy and is a direct result of muscle breakdown, can occur in both the upper and lower extremities, usually with high-dose long-term use of glucocorticoids. Muscle enzymes (CK and Aldolase) are typically normal, and findings on electromyography are non-specific. Muscle biopsy reveals Type-II fiber atrophy without inflammation. Withdrawal of glucocorticoids and exercises usually results in resolution of the myopathy. “Critical illness myopathy” may also develop in patients admitted in the intensive care unit (ICU) requiring large doses of IV glucocorticoids and neuromuscular blocking agents. It characteristically presents with a severe, diffuse, proximal, and distal weakness that develops over several days. Although it is usually reversible, critical illness myopathy can lead to prolonged ICU admissions, increased length of hospital stays, severe necrotizing myopathy, and increased mortality.

Osteonecrosis can be seen especially with long-term use of prednisone more than 20 mg daily. Patients with SLE and children are at higher risk. Hips and knees are the most commonly involved joints with less common involvement of shoulders and ankles. Pain is the initial feature, which may eventually become severe and debilitating. Magnetic resonance imaging is the most sensitive test, especially for early detection. Plain radiographs may be negative initially but can be useful for follow-up. Treatment is by decreased weight-bearing and immobilization initially, but if severe, surgery and/or joint replacement may be necessary.

Metabolic and endocrine adverse effects

Systemic glucocorticoids cause a dose-dependent increase in fasting glucose levels and a more significant increase in postprandial values in patients without preexisting diabetes mellitus, but the development of de novo diabetes in a patient with initially normal glucose tolerance is uncommon. Risk factors for new-onset hyperglycemia during glucocorticoid therapy appear to be the same as those for other patients. However, patients with diabetes mellitus or glucose intolerance exhibit higher blood glucose levels while taking glucocorticoids, leading to increased difficulty with glycemic control.

The development of cushingoid features (redistribution of body fat with truncal obesity, buffalo hump, and moon face) and weight gain are dose and duration-dependent and can develop early. Cushingoid features showed a linear increase in frequency with dosing. Glucocorticoid therapy is the most common cause of Cushing syndrome. The clinical presentation in the pediatric population is similar to that in adults and includes truncal obesity, skin changes, and hypertension. In children, growth deceleration is also a feature.

Administration of glucocorticoids can suppress the hypothalamic-pituitary-adrenal (HPA) axis decreasing corticotropin-releasing hormone (CRH) from the hypothalamus, adrenocorticotropic hormone (ACTH) from the anterior pituitary gland and endogenous cortisol. Prolonged ACTH suppression cause atrophy of adrenal glands, and abrupt cessation or rapid withdrawal of Glucocorticoids in such patients may cause symptoms of adrenal insufficiency. The clinical presentation of adrenal suppression is variable. Many of the signs and symptoms are non-specific and can be mistaken for symptoms of intercurrent illness or the underlying condition that is receiving treatment (weakness/fatigue, malaise, nausea, vomiting, diarrhea, abdominal pain, headache usually in the morning, fever, anorexia/weight loss, myalgia, arthralgia, psychiatric symptoms, poor growth and weight gain in children). Adrenal suppression is the most common cause of adrenal insufficiency in children and is associated with higher mortality in the pediatric population. In adults, the symptoms of adrenal suppression are non-specific; therefore, the condition may go unrecognized until exposure to physiological stress (illness, surgery, or injury), resulting in an adrenal crisis. Children with adrenal crisis secondary to adrenal suppression may present with hypotension, shock, decreased consciousness, lethargy, unexplained hypoglycemia, seizures, and even death.

The impairment of growth in young children and delay in puberty commonly presents in children receiving glucocorticoids for chronic illnesses like nephrotic syndrome and asthma. The effect is most pronounced with daily therapy, and less marked with an alternate-day regimen and can also occur with inhaled glucocorticoids. Although growth impairment can be an independent adverse effect of corticosteroid therapy, it can also be a sign of adrenal suppression.

Infections

Moderate to high dose use of glucocorticoids poses a significant risk of infections, including common mild infections as well as serious life-threatening infections. There is a linear increase in the risk with dose and duration of therapy, especially with common bacterial, viral, and fungal pathogens. Concomitant use of other immunosuppressive agents and the elderly age further increases the risk of infections. Prednisone dose of less than 10 mg daily pose minimal to no risk of infection. Patients taking glucocorticoids may not manifest common signs and symptoms of infection as clearly, due to the inhibition of cytokine release and the associated reduction in inflammatory and febrile responses leading to a failure in early recognition of infection.

Cardiovascular adverse effects

Mineralocorticoid effects, especially as seen with cortisol and cortisone, can lead to fluid retention, edema, weight gain, hypertension, and arrhythmias by increasing renal excretion of potassium, calcium, and phosphate. Hypertension usually occurs with higher doses only. Long-term use of medium-high dose glucocorticoids has implications in premature atherosclerosis in a dose-dependent pattern.

Dermatologic adverse effects

Several cutaneous adverse effects can occur even at a low dose use of glucocorticoids, although the risk increases linearly with the increasing dose and duration of glucocorticoid therapy. Although cutaneous adverse effects appear to be clinically significant by physicians, they are usually of most concern to the patients. These adverse effects include ecchymosis, skin thinning and atrophy, acne, mild hirsutism, facial erythema, stria, impaired wound healing, thinning of hair, and perioral dermatitis.

Ophthalmologic adverse effects

The risk of cataract is significantly high in patients taking prednisone more than 10 mg daily for more than one year, with a dose-dependence in a linear fashion. However, an increased risk of cataracts has been reported even with low-dose glucocorticoids. Cataracts are usually bilateral and slowly progressing. Increased intraocular pressure, especially in patients with a family history of open-angle glaucoma, is seen in patients receiving intraocular glucocorticoids, and high dose systemic glucocorticoids. Glaucoma is often painless and can lead to visual field loss, optic disc cupping, and optic nerve atrophy. After the discontinuation of systemic therapy, the elevation in intraocular pressure usually resolves within a few weeks, but the damage to the optic nerve is often permanent. A rare adverse effect of systemic or even topical use of glucocorticoids is central serous chorioretinopathy; this leads to the formation of subretinal fluid in the macular region, which leads to separation of the retina from its underlying photoreceptors. This condition manifests as central visual blur and reduced visual acuity.

Gastrointestinal (GI) adverse effects

Glucocorticoids increase the risk of adverse GI effects, such as gastritis, gastric ulcer formation, and GI bleeding. The use of NSAIDs and glucocorticoids is associated with a 4-fold increased risk of a GI adverse effect compared with the use of either drug alone. Other complications associated with glucocorticoid use include pancreatitis, visceral perforation, and hepatic steatosis (fatty liver) that can rarely lead to systemic fat embolism or cirrhosis.

Neuropsychiatric adverse effects

Patients receiving glucocorticoids often experience an improved sense of well-being within several days of starting the medications; mild euphoria or anxiety may also occur. Hypomanic reactions and activated states are more common early in the therapy than depression, but the prevalence of depression is greater in patients on more longstanding therapy. Psychosis can occur but does so almost exclusively at doses of prednisone above 20 mg per day given for a prolonged period. Disturbances in sleep are reported, especially with split doses that may interfere with the normal pattern of diurnal cortisol production. Akathisia (motor restlessness) is a common glucocorticoid side effect. The risk of developing a given neuropsychiatric disorder following glucocorticoid therapy may increase among patients with a history of the condition. Rare cases of pseudotumor cerebri have also correlated with glucocorticoid use.

There is specific documentation of neuropsychiatric adverse effects with glucocorticoid therapy in children with acute lymphoblastic leukemia (ALL) receiving dexamethasone or prednisone for the induction and maintenance of treatment. The risk is higher in preschool-age children, and the symptoms typically present during the first week of glucocorticoid therapy. Glucocorticoid-induced acute neuropsychiatric impairment may present with a wide variety of behavioral symptoms, including euphoria, aggression, insomnia, mood fluctuations, depression, manic behavior, and even frank psychosis. Although these psychiatric disturbances tend to wear off with time on cessation of glucocorticoid therapy, a small minority of the patients may experience persistent symptoms even after discontinuation of the drug.

Contraindications

General contraindications include hypersensitivity.

Systemic

• Systemic fungal infections

• Intrathecal administration

• Cerebral malaria

• Concomitant live or live attenuated virus vaccination (if using glucocorticoids in immunosuppressive doses)

• Idiopathic thrombocytopenic purpura (IM administration)

• Use in premature infants (formulations containing benzyl alcohol)

Topical

• Dermatological: Bacterial, viral, or fungal infection of the mouth or throat (triamcinolone)

• Ophthalmic: Acute untreated purulent ocular infections, fungal or mycobacterial ocular infections, viral conjunctivitis, or keratitis

Clinicians can administer live virus vaccines to patients who are on:

• Prednisone or it

• s equivalent in doses of less than 20 mg per day for 14 days or less

• Glucocorticoids used for long-term physiologic replacement

• Glucocorticoids administered topically, by aerosol, or by intra-articular or bursal injection, provided that there is no clinical or laboratory evidence of immunosuppression

Monitoring

Baseline assessment and monitoring

Preexisting conditions that should be assessed for and treated when starting glucocorticoids include:

• Diabetes mellitus

• Poorly controlled hypertension

• Heart failure and peripheral edema

• Cataract or glaucoma

• Peptic ulcer disease

• Presence of infection

• Low bone density or osteoporosis

• Psychiatric illness

Before initiating long-term systemic glucocorticoid therapy, the clinician should perform a thorough history and physical examination to assess for risk factors or preexisting conditions that may potentially be exacerbated by glucocorticoid therapy, such as above.

Baseline measures of body weight, height, blood pressure, BMD (bone mineral density) via DEXA scan, and ophthalmological examination should be obtained along with laboratory assessments that include a complete blood count (CBC), blood glucose values (Fasting blood sugar, 2-hour OGTT, Hb1Ac), and lipid profile (LDL-C, HDL-C, TC, non-HDL-C, TG). In children, the clinician should also examine nutritional and pubertal status.

Subsequent monitoring

Assessment of Bone Health

American College of Rheumatology has published specific guidelines addressing this issue to help prevent and manage GiOp.

• All adults receiving prednisone 2.5 mg or more daily for more than three months shall be encouraged to optimize calcium and vitamin D intake, and shall be counseled to quit smoking, have a balanced diet and be engaged in regular weight-bearing exercises, and limit alcohol intake to 1 to 2 alcoholic beverages in a day.

• Clinical fracture risk reassessment shall be performed at baseline and every 12 months in patients receiving long term glucocorticoids.

• Bone mineral density (BMD) measurement via DEXA scan shall be performed ideally before, or within six months after the initiation of glucocorticoid therapy in all adults 40 years of age or more, and in adults younger than 40 years of age if there is a history of osteoporotic fractures or other risk factors for osteoporosis.

• In adults 40 years of age or more, the 10-year fracture risk assessment is necessary using the FRAX tool (a diagnostic tool that incorporates clinical factors and bone mineral density at the femoral neck).

• Based on the above data, in addition to the dose and duration of glucocorticoid therapy, patients fall into three fracture risk categories: low risk, moderate risk, and high risk. Their fracture risk category shall dictate further management.

• Bisphosphonates, teriparatide or denosumab shall be recommended in patients less than 40 years of age but in the moderate or high fracture risk category.

• Bisphosphonates, teriparatide, denosumab, or raloxifene shall be recommended in patients 40 years of age or more in the moderate or high fracture risk category.

• Oral bisphosphonates are preferred in all these patients.

• Lateral spine X-ray shall be considered in adults 65 years of age or older to evaluate for vertebral fractures.

• Consider referral to endocrinologist/rheumatologist if fracture risk is high and/or BMD is declining.

Assessment of Hypothalamic: Pituitary-Adrenal (HPA) Function

The HPA axis should undergo assessment if the patient has received systemic corticosteroids for more than two consecutive weeks or more than three cumulative weeks in the last six months or if the patient has persistent symptoms of adrenal suppression. Screening is by measuring early morning salivary cortisol after tapering off the dose of cortisol. If morning cortisol is normal, but the patient has symptoms of adrenal suppression, perform a low-dose ACTH stimulation test to confirm the diagnosis. Consider endocrinology referral for confirmation of diagnosis.

Assessment of Growth (Children and Adolescents)

Growth in children and adolescents on chronic glucocorticoid therapy shall be monitored every six months and plotted on a growth curve.

Assessment of Dyslipidemia and Cardiovascular Risk (Adults)

Lipid profile shall be monitored one month after glucocorticoid initiation, and then every 6 to 12 months. Glycemic control requires assessment via screening for classic symptoms at every visit: polyuria, polydipsia, weight loss. Monitor glucose parameters for at least 48 hours after glucocorticoids initiation, then every 3 to 6 months for the first year and annually afterward. In children, an annual oral glucose tolerance test merits consideration if the child is obese or has risk factors for diabetes.

Assessment of Ophthalmological Complications

An annual ophthalmological examination shall be considered, especially for those with symptoms of cataracts, and early referral for intraocular pressure assessment should take place if there is personal or family history of open-angle glaucoma, diabetes mellitus, or high myopia.

Prevention of adverse effects

Although some adverse effects of glucocorticoids are unavoidable, some can be prevented by:

• Use of the lowest dose of glucocorticoids for the shortest period needed to achieve the treatment goals

• Management of preexisting comorbid conditions

• Monitoring of patients under treatment for adverse effects

Patients who also require concomitant treatment with non-steroidal anti-inflammatory drugs (NSAIDs) or anticoagulants shall receive therapy with proton pump inhibitors (PPI). There is no consensus on PPI treatment of patients on glucocorticoids alone without NSAIDs and no other risk factors for peptic complications

Patients who require an extended course of glucocorticoids, especially high doses, shall receive appropriate immunizations before the institution of therapy. Prophylaxis for opportunistic infection with Pneumocystis jirovecii pneumonia (PCP) is also a recommendation in patients receiving prednisone at a dose of 20 mg or more for more than two weeks. The prophylaxis can stop once the dose of prednisone is below 20 mg daily dose. Symptoms of and/or exposure to serious infections should also be assessed as corticosteroids are relatively contraindicated in patients with untreated systemic infections. Concomitant use of other medications also merits attention before initiating therapy as significant drug interactions exist between glucocorticoids and several drug classes.

Withdrawal of glucocorticoid therapy

Abrupt cessation of chronic glucocorticoid therapy can be dangerous as there is a risk of HPA axis suppression. Withdrawal of glucocorticoid therapy needs tapering over the period. In general, patients who are given acute corticosteroid therapy for less than 14 to 21 days do not develop HPA axis suppression, and treatment can stop with no need for any tapering regime in them. If the therapy has been ongoing for greater than three weeks, tapering is needed (e.g., over two months), but there is no universally accepted optimal regimen.

Toxicity

Acute psychosis can develop in patients receiving high-dose glucocorticoids. Immediate cessation of the drug on the appearance of symptoms is the first step. Although many drugs, including antipsychotics, antidepressants, benzodiazepines, and hydrocortisone have been tried with variable success, currently there is no consensus on the ideal therapeutic remedy to stop and reverse the corticosteroid-induced neuropsychiatric adverse effects in adults or children. Their specific adverse effects further limit the use of the medications mentioned above. The outcome of limited interventional trials has shown a decrease in corticosteroid-induced neuropsychiatric symptoms with chlorpromazine and lorazepam, albeit at the cost of drowsiness, orthostatic hypotension, and paradoxical agitation. Physiologic doses of hydrocortisone have shown to improve mild to moderate psychosocial disturbances and insomnia experienced by children who developed severe behavioral problems with dexamethasone-based treatment regime administered to treat ALL. Recently, oral potassium chloride (KCl) administered at a median dose of 0.5 mEq/kg/ day in two divided doses per day reportedly was to be moderately effective in reducing corticosteroid-induced psychiatric events in the majority of children with ALL. No adverse effects were found with oral KCl supplementation.

Enhancing Healthcare Team Outcomes

Glucocorticoids are widely used to manage many acute and chronic inflammatory disorders. The adverse effects of glucocorticoids are extensive and can involve many organ systems. While short-term use of corticosteroids is associated with mild side effects, long-term use can result in several severe adverse effects, some of which are irreversible. Physicians shall consider adverse effects and patients' underlying comorbidities before prescribing glucocorticoids and use glucocorticoids judiciously. The clinician should use the lowest possible dose for the shortest possible. Patient education is vital in recognizing the adverse effects early. Children are particularly vulnerable to the side effects of corticosteroids, and parents need to understand the benefits and adverse effects of glucocorticoids. Pharmacists shall alert physicians about possible drug interactions. The nursing team can play a crucial role in communication with the patient and early detection of adverse effects and to ensure regular monitoring. Close communication with other health professionals is necessary to ensure that the patient is not left unmonitored.

The adrenal, or suprarenal, gland is paired with one gland located near the upper portion of each kidney. Each gland is divided into an outer cortex and an inner medulla. The cortex and medulla of the adrenal gland, like the anterior and posterior lobes of the pituitary, develop from different embryonic tissues and secrete different hormones. The adrenal cortex is essential to life, but the medulla may be removed with no life-threatening effects.

The hypothalamus of the brain influences both portions of the adrenal gland but by different mechanisms. The adrenal cortex is regulated by negative feedback involving the hypothalamus and adrenocorticotropic hormone; the medulla is regulated by nerve impulses from the hypothalamus.

Hormones of the Adrenal Cortex

The adrenal cortex consists of three different regions, with each region producing a different group or type of hormones. Chemically, all the cortical hormones are steroid.

Mineralocorticoids are secreted by the outermost region of the adrenal cortex. The principal mineralocorticoid is aldosterone, which acts to conserve sodium ions and water in the body. Glucocorticoids are secreted by the middle region of the adrenal cortex. The principal glucocorticoid is cortisol, which increases blood glucose levels.

The third group of steroids secreted by the adrenal cortex is the gonadocorticoids, or sex hormones. These are secreted by the innermost region. Male hormones, androgens, and female hormones, estrogens, are secreted in minimal amounts in both sexes by the adrenal cortex, but their effect is usually masked by the hormones from the testes and ovaries. In females, the masculinization effect of androgen secretion may become evident after menopause, when estrogen levels from the ovaries decrease.

Hormones of the Adrenal Medulla

The adrenal medulla develops from neural tissue and secretes two hormones, epinephrine and norepinephrine. These two hormones are secreted in response to stimulation by sympathetic nerve, particularly during stressful situations. A lack of hormones from the adrenal medulla produces no significant effects. Hypersecretion, usually from a tumor, causes prolonged or continual sympathetic responses.

Hormones of the Zona Fasciculata

The intermediate region of the adrenal cortex is the zona fasciculata, named as such because the cells form small fascicles (bundles) separated by tiny blood vessels. The cells of the zona fasciculata produce hormones called glucocorticoids because of their role in glucose metabolism. The most important of these is cortisol, some of which the liver converts to cortisone. A glucocorticoid produced in much smaller amounts is corticosterone. In response to long-term stressors, the hypothalamus secretes CRH, which in turn triggers the release of ACTH by the anterior pituitary. ACTH triggers the release of the glucocorticoids. Their overall effect is to inhibit tissue building while stimulating the breakdown of stored nutrients to maintain adequate fuel supplies. In conditions of long-term stress, for example, cortisol promotes the catabolism of glycogen to glucose, the catabolism of stored triglycerides into fatty acids and glycerol, and the catabolism of muscle proteins into amino acids. These raw materials can then be used to synthesize additional glucose and ketones for use as body fuels. The hippocampus, which is part of the temporal lobe of the cerebral cortices and important in memory formation, is highly sensitive to stress levels because of its many glucocorticoid receptors.

You are probably familiar with prescription and over-the-counter medications containing glucocorticoids, such as cortisone injections into inflamed joints, prednisone tablets and steroid-based inhalers used to manage severe asthma, and hydrocortisone creams applied to relieve itchy skin rashes. These drugs reflect another role of cortisol—the downregulation of the immune system, which inhibits the inflammatory response.

Hormones of the Zona Reticularis

The deepest region of the adrenal cortex is the zona reticularis, which produces small amounts of a class of steroid sex hormones called androgens. During puberty and most of adulthood, androgens are produced in the gonads. The androgens produced in the zona reticularis supplement the gonadal androgens. They are produced in response to ACTH from the anterior pituitary and are converted in the tissues to testosterone or estrogens. In adult women, they may contribute to the sex drive, but their function in adult men is not well understood. In post-menopausal women, as the functions of the ovaries decline, the main source of estrogens becomes the androgens produced by the zona reticularis.

Adrenal Medulla

As noted earlier, the adrenal cortex releases glucocorticoids in response to long-term stress such as severe illness. In contrast, the adrenal medulla releases its hormones in response to acute, short-term stress mediated by the sympathetic nervous system (SNS).

The medullary tissue is composed of unique postganglionic SNS neurons called chromaffin cells, which are large and irregularly shaped, and produce the neurotransmitters epinephrine (also called adrenaline) and norepinephrine (or noradrenaline). Epinephrine is produced in greater quantities—approximately a 4 to 1 ratio with norepinephrine—and is the more powerful hormone. Because the chromaffin cells release epinephrine and norepinephrine into the systemic circulation, where they travel widely and exert effects on distant cells, they are considered hormones. Derived from the amino acid tyrosine, they are chemically classified as catecholamines.

The secretion of medullary epinephrine and norepinephrine is controlled by a neural pathway that originates from the hypothalamus in response to danger or stress (the SAM pathway). Both epinephrine and norepinephrine signal the liver and skeletal muscle cells to convert glycogen into glucose, resulting in increased blood glucose levels. These hormones increase the heart rate, pulse, and blood pressure to prepare the body to fight the perceived threat or flee from it. In addition, the pathway dilates the airways, raising blood oxygen levels. It also prompts vasodilation, further increasing the oxygenation of important organs such as the lungs, brain, heart, and skeletal muscle. At the same time, it triggers vasoconstriction to blood vessels serving less essential organs such as the gastrointestinal tract, kidneys, and skin, and downregulates some components of the immune system. Other effects include a dry mouth, loss of appetite, pupil dilation, and a loss of peripheral vision. The major hormones of the adrenal glands are summarized in Table 17.5.

Hormones of the Adrenal Glands

Table17.5

Disorders Involving the Adrenal Glands

Several disorders are caused by the dysregulation of the hormones produced by the adrenal glands. For example, Cushing’s disease is a disorder characterized by high blood glucose levels and the accumulation of lipid deposits on the face and neck. It is caused by hypersecretion of cortisol. The most common source of Cushing’s disease is a pituitary tumor that secretes cortisol or ACTH in abnormally high amounts. Other common signs of Cushing’s disease include the development of a moon-shaped face, a buffalo hump on the back of the neck, rapid weight gain, and hair loss. Chronically elevated glucose levels are also associated with an elevated risk of developing type 2 diabetes. In addition to hyperglycemia, chronically elevated glucocorticoids compromise immunity, resistance to infection, and memory, and can result in rapid weight gain and hair loss.

In contrast, the hyposecretion of corticosteroids can result in Addison’s disease, a rare disorder that causes low blood glucose levels and low blood sodium levels. The signs and symptoms of Addison’s disease are vague and are typical of other disorders as well, making diagnosis difficult. They may include general weakness, abdominal pain, weight loss, nausea, vomiting, sweating, and cravings for salty food.