Module 5 Section 4 (Adrenocortical Steroids)

Question 1

What are adrenocortical steroids?

Answer 1

Adrenocortical steroids are hormones produced by the adrenal cortex of the adrenal glands.

Some of these hormones have profound anti-inflammatory and immunosuppressive qualities, making them useful for a number of conditions unrelated to adrenal cortex function.

Question 2

True or false: Conditions in which the function of the adrenal cortex is altered can result in deficient or excess levels of adrenocortical steroids. As a result, natural and synthetic therapies exist for these conditions.

Answer 2

True

Question 3

The adrenocortical hormones are divided into three main categories. What are they?

Answer 3

1) Mineralocorticoids: a class of corticosteroids produced in the adrenal cortex. These hormones influence the salt/water balance in the body.
2) Sex hormones: a class of hormones that affect sexual development and reproduction.
3) Glucocorticoids: a class of corticosteroids that have important effects on metabolism and immune function.

Question 4

Discuss what occurs during the regulatory process of the hypothalamic-pituitary-adrenal axis.

Answer 4

1) In general, adrenocortical steroids are controlled by the hypothalamic hormone known as corticotropin-releasing hormone (CRH).
2) Once released from the hypothalamus, CRH stimulates the pituitary gland to release adrenocorticotropic hormone (ACTH; also known as corticotropin).
3) In turn, ACTH causes an increase in the production and secretion of adrenocortical steroids.
4) Negative feedback regulation occurs within the system, where increased levels of glucocorticoids inhibit CRH secretion, thereby decreasing the secretion of ACTH.

Question 5

Describe the hormones involved with the hypothalamic-pituitary-adrenal axis and the organ that releases each hormone.

Answer 5

The 3 hormones are corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH), and corticosteroids. These are released by the hypothalamus, pituitary gland, and adrenal cortex, respectively.

Question 6

What are mineralocorticoids?

Answer 6

Mineralocorticoids are a class of adrenocortical steroids that primarily affect salt-retaining activity.  
- The prototypical mineralocorticoid is aldosterone.

Question 7

What effect does aldosterone have in the renal tubules?

Answer 7

Aldosterone stimulates the renal tubules to retain sodium and water, and excrete potassium.

• This results in an increase in blood volume and hence an increase in blood pressure.
• Both the renin-angiotensin system and ACTH can stimulate aldosterone secretion.

Question 8

What is the role of sex hormones produced by the adrenal cortex?

Answer 8

Sex hormones have primarily estrogenic or androgenic activity.
- The adrenal cortex secretes large amounts of dehydroepiandrosterone (DHEA; an intermediate in the synthesis of androgen and estrogen sex steroids), and smaller amounts of androstenedione and testosterone.

While thought to contribute to normal maturation, the sex hormones produced by the adrenal cortex are not thought to support major androgen-dependent pubertal changes in humans.

Question 9

Glucocorticoids have important effects on metabolism and immune function. The major glucocorticoid in humans is cortisol. Discuss the role of cortisol.

Answer 9

Cortisol exerts a wide range of physiologic effects, including regulation of metabolism, cardiovascular function, growth, and immunity.

Question 10

How is cortisol synthesized? How are its secretions regulated?

Answer 10

Cortisol is synthesized from cholesterol and its secretion is tightly regulated by the CNS (i.e. hypothalamus and pituitary gland), which is very sensitive to negative feedback by circulating cortisol levels as well as synthetic glucocorticoids.

Question 11

What occurs when cortisol is used as a medication?

Answer 11

When cortisol is used as a medication, it is termed hydrocortisone.

Hydrocortisone can be administered orally, topically, or by injection. Synthetic corticosteroids have also been developed, such asprednisone, an oral medication commonly used to suppress the immune system.

Question 12

True or false: the majority of the effects of glucocorticoids are due to binding to and activating glucocorticoid receptors.

Answer 12

True

These receptors are widely distributed throughout the body, and are members of the superfamily of nuclear receptors, which are intracellular receptors.

Question 13

In a few sentences, describe how intracellular receptors exert their effects. Hint: recall your discussion on intracellular receptors from Module 1.

Answer 13

Once activated, the ligand-bound receptor complex is transported into the nucleus, where it interacts with DNA and nuclear proteins, regulating gene expression and protein synthesis.

Question 14

True or false: in general, approximately 10% to 20% of all expressed genes in a cell are regulated by glucocorticoids.

Answer 14

True

Question 15

True or false: Glucocorticoid preparations differ with respect to relative anti-inflammatory and mineralocorticoid effect, duration of action, cost, and dosage forms available.

Answer 15

True

Question 16

Discuss the metabolic effects of Glucocorticoids.

Answer 16

1) Carbohydrate metabolism: stimulates gluconeogenesis (formation of glucose), leading to an increase in blood glucose levels, followed by release of insulin and hence inhibition of glucose uptake by muscle cells
2) Protein metabolism: increases muscle catabolism (breakdown), leading to the release of amino acids from proteins
3) Lipid metabolism: the increased insulin as a result of glucocorticoid-initiated gluconeogenesis stimulates lipogenesis (conversion of acetyl-CoA into fatty acids), increasing fat deposition and release of fatty acids into the blood

Question 17

Discuss the catabolic and anti-anabolic effects of Glucocorticoids.

Answer 17

1) Catabolic and anti-anabolic effects occur in connective tissue, muscle, peripheral fat, and skin.
- Therefore, increased amounts of glucocorticoids can result in decreased bone mass, decreased muscle mass, weakness, and thinning of the skin

2) Reduces growth in children

Question 18

Discuss the anti-inflammatory and immunosuppressive effects of Glucocorticoids.

Answer 18

1) Dramatically reduces inflammation
2) Suppresses inflammatory cytokines, chemokines and other mediators of inflammation
3) Reduces circulating leukocytes (white blood cells) by moving leukocytes from blood into lymphoid tissue
4) Reduces expression of cyclooxygenase-2 in inflammatory cells, reducing production of prostaglandins

Question 19

Discuss the CNS effects of Glucocorticoids.

Answer 19

Altered glucocorticoid levels can produce behavioural disturbances (e.g. insomnia, euphoria, depression)

Question 20

Discuss the mineralocorticoids-like action of Glucocorticoids.

Answer 20

Some of the effects of glucocorticoids are due to their binding to mineralocorticoid receptors, as these receptors bind aldosterone and cortisol with similar affinity. Not all glucocorticoids have this effect, but some have a similar effect to aldosterone -increasing sodium and water retention and potassium excretion, which results in an increase in blood volume and blood pressure.

Question 21

Compare the short and long term effects of systemic administration of glucocorticoids.

Answer 21

Short-Term Use: systemic short term use of glucocorticoids (less than two weeks) is not commonly associated with serious adverse effects, even with moderately large doses.

• However, insomnia, behavioural changes, and acute peptic ulcers can occur even after only a few days of treatment.
• A rare but serious adverse effect of high-dose glucocorticoids is acute pancreatitis.

Long-Term Use: the majority of patients on 100 mg of hydrocortisone (or equivalent synthetic steroid) or more for longer than two weeks undergo a series of metabolic changes callediatrogenic Cushing’s syndrome.

• The symptoms of iatrogenic Cushing’s syndrome include a round, puffy face, redistribution of fat from the extremities to the trunk and back of the neck, steroid-induced acne, and insomnia.
• These changes may require cessation of therapy, however, in dangerous or disabling disorders where other treatment options are not available, treatment will be continued.
• With continued treatment, patients will eventually develop osteoporosis and diabetes.

Question 22

What are some other complications associated with systemic glucocorticoid use?

Answer 22

• Peptic ulcers
• Severe myopathy (more frequent with long-acting glucocorticoids)
• Hypomania or acute psychosis
• Adrenal suppression may occur (if administered > 2 weeks).

Question 23

True or false: when a patient’s dose of glucocorticoid is to be decreased or stopped, the dose should be tapered slowly.

Answer 23

True

It can take anywhere from 2 to 12 months for the hypothalamic-pituitary-adrenal axis to begin functioning properly again without the exogenous source of glucocorticoids, and cortisol levels may not return to normal for another 6 to 9 months.

Question 24

Using your knowledge of withdrawal from Module 02, predict what would happen if the dosage of glucocorticoids is reduced too rapidly.

Answer 24

If the dosage of glucocorticoids is reduced too rapidly, then the symptoms of the disorder may reappear or increase in intensity.

Patients without an underlying disorder can go into adrenal crisis as a result of rapid reductions in glucocorticoids.
- In this case, the body is not able to produce sufficient amounts of adrenocortical steroids, resulting in symptoms such asnausea, vomiting, weight loss, lethargy, headache, fever, joint or muscle pain, and postural hypotension.

Question 25

The most common clinical use of glucocorticoids is as an anti-inflammatory agent, as they dramatically decrease inflammation. However, glucocorticoids have a multitude of other clinical indications. What are they?

Answer 25

• Adrenal hypofunction (replacement therapy)
• Allergic reactions (simple such as eczema or severe such as anaphylaxis)
• Asthma
• Autoimmune diseases (e.g. rheumatoid arthritis)
• Organ transplantation (immunosuppressive to inhibit rejection)
• Malignancies (e.g. acute leukemia)
• Other inflammatory conditions (e.g. inflammatory bowel disease, inflammatory dermatoses)
• Development of the fetal lungs in premature infants
• Diagnostic purposes (e.g. diagnosing Cushing’s Syndrome)

Question 26

The clinical use of glucocorticoids can be divided into two categories. What are they?

Answer 26

1) Therapy for disturbed adrenal function
2) Therapy unrelated to adrenal function
- The immunosuppressive and anti-inflammatory properties of glucocorticoids account for their beneficial effects in diseases like rheumatoid arthritis and asthma.
- They are also first-line immunosuppressive therapy for organ transplants.

Question 27

What are some disorders characterized by disturbed adrenal function that are treated with glucocorticoids?

Answer 27

Addison’s disease: chronic adrenocortical insufficiency is known as Addison’s disease, which can be caused by an adrenal gland disorder (primary adrenal insufficiency), or a pituitary gland disorder (secondary adrenal insufficiency).

• Clinical manifestations include fatigue and muscle weakness, weight loss, and hypotension (can be fatal).
• Treatment for primary adrenal insufficiency involves hydrocortisone and a mineralocorticoid, such as fludrocortisone.

Cushing’s Syndrome: it’s characterized by an increase in the secretion of glucocorticoids due to an ACTH-secreting pituitary tumour or adrenal gland tumour.
- The clinical manifestations are those associated with chronic presence of excessive glucocorticoids, including:
• Obesity (moon face)
• Myopathy
• Hypertension
• Hyperglycemia (diabetes mellitus)
• Recurrent infections
• Thin atrophic skin with bruises
• Osteoporosis
• Psychosis
- Treatment includes surgical removal or irradiation of the tumour, followed by hydrocortisone therapy (since the body will no longer be able to produce its own cortisol if part of the adrenal cortex was removed).

Question 28

What are some disorders unrelated to disturbed adrenal function that are treated with glucocorticoids?

Answer 28

1)Organ Transplant

Rheumatic Disorders: glucocorticoids are widely used in the treatment of the more serious inflammatory rheumatic diseases, such as systemic lupus erythematosus.
- Glucocorticoids are just one component of the treatment, as they are often used in conjunction with other immunosuppressive agents, providing better long-term control than occurs with steroids alone.

When first introduced, glucocorticoids were the first line-treatment for inflammatory arthritis.

• Over time, however, treatments for inflammatory arthritis with less toxicities than glucocorticoids have been developed, and are used when possible.
• Despite this, glucocorticoids continue to have a significant role in the long-term treatment of arthritis.
• Additionally, patients with major symptoms that are confined to a few joints may be treated with intra-articular glucocorticoid injections.

Question 29

Discuss the role of glucocorticoids in organ transplants.

Answer 29

Glucocorticoids are administered post-transplant and are able to reduce antigen expression from grafted tissue, delay revascularization, and interfere with the sensitization of cytotoxic T lymphocytes and the generation of primary antibody-forming cells.

Question 30

Discuss the role of glucocorticoids in rheumatic disorders.

Answer 30

Glucocorticoids are widely used in the treatment of the more serious inflammatory rheumatic diseases, such as systemic lupus erythematosus.
- Glucocorticoids are just one component of the treatment, as they are often used in conjunction with other immunosuppressive agents,
providing better long-term control than occurs with steroids alone.

Glucocorticoids continue to have a significant role in the long-term treatment of arthritis. Additionally, patients with major symptoms that are confined to a few joints may be treated with intra-articular glucocorticoid injections.

Question 31

Discuss the role of glucocorticoids in inflammatory dermatoses.

Answer 31

Inflammatory dermatoses refer to inflammation of the skin.
- Topical glucocorticoids exhibit great efficacy in the treatment of inflammatory dermatoses, based primarily on their anti-inflammatory activity.
- Many synthetic analogs of hydrocortisone have been developed for topical preparations, and these synthetic analogs vary based on potency.
- Examples of inflammatory dermatoses include:
● Atopic dermatitis, also known as eczema
● Psoriasis
● Contact dermatitis

In general, glucocorticoids are minimally absorbed following application to the skin.

• However, regional anatomic variation exists (e.g. topical glucocorticoids are absorbed 6 times as well through the forehead than through the forearm).
• Absorption and penetration of topical glucocorticoids is increased several-fold in inflamed skin (e.g. atopic dermatitis), and even more so in severe exfoliative diseases in which little barrier to absorption and penetration exists.
• Topical glucocorticoids can be found as ointments, creams, or lotions.
• Ointment bases tend to result in better absorption than do creams or lotions.
• Dermatologic disorders that are very responsive to topical steroids include atopic dermatitis, psoriasis, and the later phase of allergic contact or irritant dermatitis.

Adverse effects:
- All topical glucocorticoids possess the potential to suppress the pituitary-adrenal axis via negative inhibition.
- Chronic use of topical glucocorticoids in large quantities can result in Cushing’s syndrome.
- In addition, the likelihood of systemic effects resulting from topical application increases when glucocorticoids are applied to extensive areas of the body for prolonged periods of time.
- There is the potential for growth restriction in children.
• Adverse local effects include:
• Atrophy (wrinkled appearing skin)
• Perioral dermatitis
• Steroid acne
• Alterations of cutaneous infections
• Hypopigmentation

Question 32

Inflammatory bowel disease encompasses two distinct disorders. What are they?

Answer 32

1) Ulcerative colitis: a chronic condition that causes inflammation of the gastrointestinal tract that occurs in the colon (large intestine) or rectum
2) Crohn’s disease: a chronic condition that causes inflammation of the gastrointestinal tract anywhere from the mouth to the anus

Question 33

Discuss the role of glucocorticoids in inflammatory bowel disease.

Answer 33

Patients with moderate to severe active inflammatory bowel disease are commonly treated with glucocorticoids, such as oral prednisone.

• In severely ill patients, the drugs can be administered intravenously.
• Prednisone and prednisolone are the most commonly used oral glucocorticoids in gastrointestinal practice.
• However, for active inflammatory disease in the rectum and sigmoid colon, topical treatment with hydrocortisone is preferred in order to localize the drug’s effects in the colon tissue and to minimize the potential for systemic absorption.

Glucocorticoids are only useful for active inflammatory bowel disease – they are not useful for maintaining disease remission.
- The adverse effects observed are the same as those described for systemic and local glucocorticoids.

Question 34

An individual with an inflammatory dermatosis, such as atopic dermatitis, is likely to be given a corticosteroid by which route of administration?

a) Oral
b) Inhalation
c) Intra-muscular
d) Topical

Answer 34

d) Topical

Question 35

Which one of the statements regarding glucocorticoids is correct?

a) Glucocorticoids have few therapeutic applications
b) The major human glucocorticoid is cortisol
c) Glucocorticoids increase inflammation
d) Systemic, long-term administration of glucocorticoids is free of any major adverse effect

Answer 35

b) The major human glucocorticoid is cortisol