Glucocorticoids and the immune system

BACKGROUND

Steroids are natural or synthetic fatty substances that contain four carbon rings, including the sex hormones. Corticosteroids are steroid hormones that are naturally produced (endogenous) in the adrenal glands. They suppress the immune response and decrease inflammation. There are two types of corticosteroids - glucocorticoids and mineralocorticoids. Technically, the term corticosteroid refers to both steroids, but it is often used as a synonym for glucocorticoids.

The most abundant type of glucocorticoid is cortisol (also called hydrocortisone). It is involved in the functioning of proper glucose metabolism, as well as the regulation of blood pressure, insulin release for blood sugar maintenance and the inflammatory response.

More than 50 years ago, synthetic glucocorticoids were developed in laboratories for pharmaceutical purposes. These drugs have similar effects to the natural steroid hormones produced by the adrenal cortex. Glucocorticoid drugs are used to treat many different inflammatory conditions, including arthritis and dermatitis. They are also used as adjunctive therapy for conditions like autoimmune diseases and asthma, as well as to prevent the rejection of transplanted organs.

While glucocorticoid drugs are steroids, they are not the same as anabolic steroids, which are sometimes taken to enhance physical performance in athletes, or to help rebuild tissues that have become weak because of serious injury or illness. Instead glucocorticoids are catabolic steroids, which break down tissue.

HOW THEY WORK

Glucocorticoids (both natural and synthetic) inhibit the immune response, thus preventing inflammation from occurring.

Transcription is a set of processes in which DNA is converted into messenger RNA (mRNA), a ribonucleic acid molecule that directs protein production. Once mRNA is formed, it is transported into the cytoplasm (contents of the cell, expect the nucleus), where it is used to help build a protein molecule. The process by which the protein molecule is formed from the mRNA blueprint is called translation.

Glucocorticoids regulate transcription factors (proteins that bind to regulatory regions and control gene expression). They bind to the intracellular glucocorticoid receptors (GRs) of inflammatory cells to form a glucocorticoid-GR complex. This complex then enters the cell's nucleus and acts as a transcription factor.

Once the glucocorticoid-GR complex enters the nucleus, it causes changes in the production of mRNA from the DNA molecule, which subsequently changes the production of the protein molecules. Glucocorticoids can cause an increase or decrease in the production of certain proteins by binding to key sites in the gene and either enhancing or suppressing their transcription into mRNA. Glucocorticoids can also cause changes in the mRNA molecule itself, which can further alter the production of proteins in the cell.

In addition to interfering with the transcription of enzymes involved in inflammation, glucocorticoids also suppress inflammation by activating enzymes called lipocortins. Lipocortins slow the action of phospholipase A2 (PLA2), an important enzyme involved in the release of arachidonic acid (AA) from the cell membrane.

Arachidonic acid, a type of omega-6 fatty acid, is incorporated into cell membranes. When a cell is damaged or under attack by foreign substances, arachidonic acid is released from the cell membrane, and it is converted into substances that mediate inflammation (like prostaglandins). Free arachidonic acid is converted into inflammatory prostaglandins cyclooxygenase-2 (COX-2).

In order for arachidonic acid to be released, the PLA2 enzyme must be activated. Lipocortins inhibit PLA2 activity. Therefore, when the glucocorticoids activate lipocortins, they cause the inhibition of PLA2 and subsequent inhibition of arachidonic acid and inhibition of prostaglandin production. Since lower amounts of inflammatory prostaglandins are produced, inflammation is suppressed.

Glucocorticoids can also inhibit COX-2 enzymes directly.

USES

Glucocorticoids are used to suppress many types of allergic, inflammatory and autoimmune disorders. They are also used in transplant recipients to prevent acute transplant rejection and graft-versus-host disease. However, since they suppress the body's immune system, which fights off foreign substances that enter the body, these drugs do no prevent an infection or disease. In fact, individuals who are taking glucocorticoids are more susceptible to infection or diseases than those who are not.

The most commonly prescribed glucocorticoids are prednisone and prednisolone. The liver converts prednisone into prednisolone. Prednisolone may be administered in tablet or liquid form. While these medications are often considered to be interchangeable, the dosing may be different.

Oral glucocorticoids have been used to treat such conditions as Addison's disease, acquired hemolytic anemia (red blood cells are destroyed prematurely), acute mountain sickness, allergic reactions, antiemetic asthma, chronic obstructive pulmonary disease (COPD), inflammatory bowel disease (Crohn's disease and ulcerative colitis), collagen diseases, congenital hypoplastic anemia (low levels of red blood cells due to dysfunctional bone marrow), dermatologic disorders, drug hypersensitivity reaction, Graves ophthalmopathy, exfoliative dermatitis, hepatitis, hirsutism, hypercalcemia, leukemias, lymphomas, muscular dystrophy, multiple sclerosis, organ transplant, pemphigus (skin disease that causes chronic blistering), adrenal cortical insufficiency and rheumatic disorders.

Inhaled glucocorticoids (like Aerobid©, Azmacort©, Beclovent©, Flovent©, Pulmicort© or Vanceril©) have been used to treat asthma.

Nasal inhaled glucocorticoids like fluticasone (Flonase©), mometasone (Nasonex©) and triamcinolone (Nasacort©), have been used to treat allergic rhinitis, non-allergic (vasomotor) rhinitis and nasal polyps.

Ocular glucocorticoids (eye drops/cream) have been used to treat allergic conjunctivitis, allergic corneal marginal ulcers, corneal injury, cyclitis (inflammation of the middle part of the eye), posterior uveitis (inflammation of the layer of the eye between the sclera and the retina) and choroiditis (inflammation of the layer of the eye beneath the retina), iritis, keratitis (inflammation of the cornea), keratoplasty (surgical replacement of the cornea), nonspecific superficial keratitis, optic neuritis (inflammation of the optic nerve) and superficial punctate keratitis (cell death of the surface of the cornea).

Topical glucocorticoids have been used to treat allergic contact dermatitis, anogenital pruritus, atopic dermatitis (eczema), burns, insect bite reactions, lichen simplex chronicus (skin disorder characterized by chronic itching and scratching), psoriasis, seborrheic dermatitis (dandruff) and xerosis (dry mouth, eye or skin).

Intravenous glucocorticoids have been used to treat acute spinal cord injury, allergic reactions, anemias, bacterial meningitis, cerebral edema, idiopathic thrombocytopenia purpura in adults, Pneumocystis jiroveci pneumonia (formerly called Pneumocystis carinii pneumonia), septic shock and hives.

Rectal glucocorticoids (such as enemas) have been used to treat cryptitis, factitial proctitis, hemorrhoids and ulcerative colitis.

SIDE EFFECTS

General: Since glucocorticoids suppress the body's immune system, individuals who are taking glucocorticoids are more susceptible to infection or diseases than those who are not. Glucocorticoids can cause serious side effects like diabetes or osteoporosis. Patients taking long-term medication need to gradually taper off the medication to avoid serious side effects. Patients should consult their healthcare providers to discuss the risks and benefits of glucocorticoid steroid therapy. Patients should tell their doctors if they are taking any drugs (prescription or over-the-counter), herbs or supplements.

Infection: Corticosteroids may lower the patient's resistance to infections. Also, if the patient develops an infection it may be difficult to treat because the patient's immune system is weakened. Patients should consult their healthcare providers if they notice signs of possible infections, such as sore throat, fever, sneezing or coughing.

Long-term side effects: Glucocorticoids have been found to increase blood glucose levels as well as suppress calcium absorption through their various metabolic affects. Severe side effects such as diabetes or osteoporosis have been reported. Even short-term glucocorticoid therapy tends to cause the patient to become temporarily insulin-resistant. Long-term side effects may include abdominal pain or burning, acne, bloody or black stools, changes in vision, eye pain, swollen face, headache, arrhythmia (irregular heartbeat) menstrual problems, muscle cramps or pain, muscle weakness, nausea, pitting or depression of skin at injection site, reddish purple lines on the skin (especially the arms, face, groin, legs or trunk), redness of eyes, eye sensitivity to light, stunting of growth (in children), swelling of feet or lower legs, tearing of eyes, thin or shiny skin, difficulty sleeping, unusual bruising, unusual increase in hair growth, unusual tiredness or weakness, vomiting, rapid weight gain (due to increased appetite), wounds that will not heal or pain in arms, back, hips, legs, ribs, or shoulders. Glucocorticoids may also cause Cushing's syndrome, which is characterized by a moon face (round face) and buffalo hump (accumulation of fat around the abdomen and the upper back).

Uncommon side effects: Less common side effects may include decreased or blurred vision, frequent urination and increased thirst. Rare side effects may include blindness (sudden, when injected into the head or neck area), burning, numbness, confusion, excitement, hallucinations, mental depression, mistaken feelings of self-importance or being mistreated, mood swings, redness or swelling at injection site, restlessness, skin rash, hives or pain or tingling at the site of injection.

Unneeded treatment: Patients who take corticosteroids, but do not need treatment often experience side effects such as increased appetite, indigestion, loss of appetite, nervousness or restlessness. Some patients may experience darkening or lightening of skin color, dizziness or lightheadedness, flushing of face or cheeks, hiccups, increased joint pain (after injection into a joint), increased sweating, nosebleeds (after injection into the nose) or sensation of spinning.

Early withdrawal: Patients who receive long-term treatment with glucocorticoids must be slowly tapered off the medication when discontinuing therapy to avoid side effects. Patients who do not taper off the medication appropriately may experience abdominal pain, back pain, dizziness, fainting, fever, loss of appetite, muscle or joint pain, nausea, reappearance of disease symptoms, shortness of breath, unexplained headaches (frequent or continual), unusual tiredness or weakness, vomiting or rapid weight loss.

ADRENAL SUPPRESSION AND WITHDRAWAL

Glucocorticoids can begin to suppress the adrenal glands after long-term use or after high-dose administration for periods longer than one week. Glucocorticoids suppress the hypothalamic corticotropin releasing hormone (CRH) and the adrenocorticotropic hormone (ACTH). CRH stimulates ACTH, which then stimulates the adrenal glands to release glucocorticoid hormones.

Prolonged suppression of the adrenal glands can lead to atrophy (shrinkage) and may take several weeks to months for the patient to recover to full function after the drug is discontinued. During this recovery time, the patient is predisposed to experience adrenal insufficiency.

The dose necessary to cause adrenal suppression and the recovery time vary significantly among patients. There are many variations of clinical guidelines that have been developed to estimate the potential for adrenal suppression and recovery. Patients should take medication exactly as prescribed by their doctors, and they should not discontinue treatment without first consulting their doctors.

INTEGRATIVE THERAPIES

Bromelain: Several preliminary studies suggest that when taken by mouth, bromelain can reduce inflammation or pain caused by inflammation. Better quality studies are needed to confirm these results.

Avoid if allergic to bromelain, pineapple, honeybee, venom, latex, birth pollen, carrots, celery, fennel, cypress pollen, grass pollen, papain, rye flour, wheat flour or other members of the Bromeliaceae family. Use cautiously with history of bleeding disorders, stomach ulcers, heart disease, liver disease or kidney disease. Use cautiously before dental or surgical procedures or while driving or operating machinery. Avoid if pregnant or breastfeeding due to insufficient scientific evidence of safety. Bromelain may cause abnormal uterine bleeding.

Comfrey: In vitro studies have found that comfrey may have anti-inflammatory effects. Clinical trials investigating topical application of comfrey-containing creams have found significant reductions in inflammation and pain associated with sprains and muscle injuries. Overall, these studies have been well designed, although some improvements in reporting are needed.

Avoid if allergic or hypersensitive to comfrey, its constituents, or members of the Boraginaceae family. Avoid oral comfrey due to hepatotoxic (liver toxicity) and carcinogenic (cancer-causing) pyrrolizidine alkaloids. Oral use has caused death. Avoid topical comfrey on broken skin due to hepatotoxic and carcinogenic pyrrolizidine alkaloids. Avoid topical comfrey in individuals who have or at risk of developing hepatic disorders, cancer or immune disorders. Use topical creams containing comfrey cautiously if taking anti-inflammatory medications or cytochrome P450 3A4-inducing agents. Use extreme caution when using topical creams containing comfrey for extended periods. Avoid topical comfrey in pregnant or lactating patients due to potential for absorption of toxic compounds.

Cat's claw: Several laboratory and animal studies suggest that cat's claw may reduce inflammation, and this has led to research of cat's claw for conditions such as rheumatoid arthritis. Large, high-quality human studies that compare the effects of cat's claw alone vs. placebo are needed before a conclusion can be drawn.

Coleus: There is a lack of sufficient data to recommend for or against the use of coleus in patients who are recovering after cardiopulmonary bypass for its anti-inflammatory effects. Randomized, clinical trials are warranted.

Cordyceps: Two studies using combination herbal treatments that included cordyceps indicate that these combinations suppressed the immune system in kidney transplant recipients and lupus nephritis patients. However, as these treatments used combination products, the effect of cordyceps cannot be defined. More studies with cordyceps as a monotherapy are needed.

Dandelion: Research in laboratory animals suggests that dandelion root may possess anti-inflammatory properties. There are no well-conducted human studies currently available in this area.

Euphorbia: Euphorbia balsamifera has been studied in patients with acute dental pulpitis (inflammation of the nerve in the innermost layer of the tooth), and may be comparable to that of pulpal nerve caustics. Additional study is necessary before a firm conclusion can be made.

Eyebright: Limited evidence from animal research suggests that several iridoid glycosides isolated from eyebright, particularly aucubin, possess anti-inflammatory properties comparable to those of indomethacin. The mechanism of action may the inhibition of thromboxane-synthase. The clinical relevance in humans is unclear, and there are no known human clinical observations or controlled trials in this area. Therefore, there is currently insufficient evidence to recommend for or against eyebright as an anti-inflammatory agent.

Shark cartilage: Based on laboratory studies, shark cartilage may reduce inflammation. However, it is unclear if shark cartilage is a safe or helpful treatment for pain in humans.

Turmeric: Laboratory and animal studies show anti-inflammatory activity of turmeric and its constituent curcumin. Reliable human research is lacking.

AUTHOR INFORMATION

This information has been edited and peer-reviewed by contributors to the Natural Standard Research Collaboration (www.naturalstandard.com).

• Colorado State University. Glucocorticoids. http://www.vivo.colostate.edu/hbooks/pathphys/endocrine/adrenal/gluco.html. Accessed March 16, 2007.
• Huntington's Outreach Project for Education, at Stanford. http://www.stanford.edu/group/hopes/treatmts/antinflm/i3.html. Accessed March 16, 2007.
• Natural Standard: The Authority on Integrative Medicine. http://www.naturalstandard.com. Copyright © 2007. Accessed March 16, 2007.