Summary of Glucocorticoids
Transcript for Glucocorticoids
Content Reviewers:Ursula Florjanczyk, Samantha McBundy, Will Wei, Samantha McBundy, Anju Paul, Yifan Xiao M.D., Supriya Sreedhar, Justin Ling, MD, MS
Glucocorticoids are a group of steroid hormones, which are secreted by the two adrenal glands that sit like hats, one on top of each kidney. Each one has an inner layer called the medulla and an outer layer called the cortex.
The adrenal cortex secretes different corticosteroid hormones: like glucocorticoids under the control of adrenocorticotropic hormone, or ACTH.
Normally the hypothalamus, located at the base of the brain, secretes corticotropin releasing hormone, known as CRH, which stimulates the pituitary gland to secrete adrenocorticotropic hormone, known as ACTH.
ACTH then travels to the pair of adrenal glands and binds to the ACTH receptors on adrenocortical cells. This causes the adrenocortical cells to release the glucocorticoids from the zona fasciculata, which have powerful anti- inflammatory and metabolic effects.
These glucocorticoids have a negative feedback effect on the hypothalamo- pituitary- adrenal axis, meaning excess corticosteroids suppress the release of both CRH and ACTH into the circulation.
Now, once made, glucocorticoids enter the circulation and travel via the blood to reach the target cells.
Steroids are lipophilic molecules, so they cross the cell membrane, enter inside the cell, and bind with a cytoplasmic receptor protein, called a ‘glucocorticoid receptor’.
Now, this ‘glucocorticoid-receptor complex’ undergoes some structural changes, which allow them to enter inside the nucleus and bind with the ‘glucocorticoid response elements’ or GRE on the chromatin.
Now, this induces transcription of specific mRNA that’s used to synthesize different proteins, which in turn modifies various cell functions and metabolic effects in the body.
The most important glucocorticoid in humans is cortisol, and it’s generally released during times of stress, like during an illness or starvation.
Cortisol helps to regulate both the immune response as well as cellular metabolism like gluconeogenesis.
With regard to the immune response, cortisol promotes an overall anti- inflammatory state by inhibiting the two main products of inflammation - prostaglandins and leukotrienes - as well as inhibiting interleukin-2 production by white blood cells.
Now, for cellular metabolism, cortisol promotes overall catabolic effects on the body.
In peripheral adipose tissue, cortisol triggers lipolysis, which is the breakdown of fats into free fatty acids.
In the muscles, cortisol stimulates proteolysis, which is the breakdown of proteins into amino acids. Often these free fatty acids and amino acids serve as a substrate for gluconeogenesis - a process where the liver cells produce new glucose molecules from non-carbohydrate sources like amino acids and free fatty acids.
High cortisol levels also increase insulin resistance in tissues, which means that insulin becomes less effective at moving glucose into cells, leading to an increase in blood glucose levels. The increased glucose level also stimulates the release of more insulin. And because this is similar to what happens in people with diabetes, this effect of cortisol is called diabetogenic. The end result is we have a lot more glucose in the blood which can be used as fuel during times of stress!
Now, there are only a few pathological conditions where the corticosteroid level in the body is lower than the normal.
For example, primary adrenal insufficiency, also known as Addison’s disease. The reason it’s called “primary” is that the underlying problem is due to damage to the adrenal glands themselves.
When the cortisol levels fall, it causes a decrease in immunity which in turn leads to frequent infection and further increases the stress.
Low cortisol levels also lead to inadequate glucose levels during times of stress. This is known as Addisonian crisis or acute primary adrenal insufficiency. Left untreated, an Addisonian crisis can be fatal.
Another pathological condition with low corticosteroid levels is congenital adrenal hyperplasia. This is caused by genetic defects that prevent the synthesis of specific enzymes that make cortisol.
Now, synthetic glucocorticoids can be given to treat Addison’s disease, but they are more commonly used as anti-inflammatory agents to treat diseases like rheumatoid arthritis, and immunosuppressants to treat chronic asthma and autoimmune diseases, like systemic lupus erythematosus.
Based on the duration of action, synthetic glucocorticoids can be classified into three groups: The first group includes glucocorticoids with short duration of action.
Hydrocortisone falls under this group. It’s chemically identical to cortisol and can be taken orally, intravenously, or intramuscularly. It then enters inside the circulation, goes to the target cells, and very rapidly takes effect, but only for a short duration of time. That’s why, hydrocortisone is the drug of choice in acute adrenal insufficiency. It’s also used in topical forms to treat various inflammatory skin conditions and allergic rashes.
The second group are the glucocorticoids with intermediate duration of action.
Prednisone, prednisolone, and methylprednisolone fall under this group. These medications are given peroral or by injection into a vein or muscle.
In comparison to hydrocortisone, medications of this group are almost 4 to 5 times more potent- meaning a lesser dose is needed to produce the desired response. These medications are used as an anti-inflammatory and immunosuppressive agent to reduce the severity and extent of inflammation in certain inflammatory diseases like asthma, or to treat autoimmune conditions like rheumatoid arthritis. For example, intravenous prednisolone is the drug of choice for an acute attack of asthma.