Actions of Adrenal Steroids and Treatment of Adrenal Disorders

Question 1

Identify the main parts of the adrenal cortex, and state what each secretes.

Answer 1

Zona glomerulosa
– Produces mineralocorticoids
(Aldosterone)

• Zona fasciculata
– Produces mainly glucocorticoids
(Cortisol and Corticosterone)

• Zona reticularis
– Produces mainly androgens (DHEA and Testosterone precursors)

Question 2

What is the role of mineralocorticoids ? What is the main mineralocorticoid ?

Answer 2

• Mineralocorticoids regulate salt/electrolyte and water balance - important for Na+ retention in the kidney to maintain blood pressure.

ALDOSTERONE (main endogenous one)

Question 3

What is the role of glucocorticoid ? What is the main glucocorticoid ?

Answer 3

• The glucocorticoids have widespread actions affecting carbohydrate, protein, and lipid metabolism but also have potent effects on host defence mechanisms – largely immunosuppressive and anti-inflammatory (+ regulatory actions)
• Glucocorticoid actions are NOT completely separate from mineralocorticoid actions because equal potency for the GR and MR so can have substantial effects on water and electrolyte balance

HYDROCORTISONE (CORTISOL)

Question 4

What are the main uses of synthetic glucorticoids ? How are their effects on Mineralocorticoid receptor limited ?

Answer 4

• With the exception of replacement therapy, glucocorticoids are used most commonly for their anti-inflammatory and immunosuppressive properties
• To limit the overlapping effects, synthetic drugs have been designed that are more selective

Question 5

How are adrenal corticosteroids regulated ?

Answer 5

• Adrenals are part of the (H-P-A) axis
• CRF and ADH (vasopressin) from hypothalamus act on corticotrophs
in anterior pituitary inducing ACTH release
• ACTH stimulates the synthesis and secretion of both glucocorticoids and mineralocorticoids from the adrenal cortex.
• Renin-Angiotensin system aids ACTH to promote mineralocorticoid secretion.

Question 6

Identify the main drugs used to mimic: 
-ACTH 
-Mineralocorticoid
-Glucocorticoid
actions.

Answer 6

• ACTH: Tetracosactide (synthetic analogue) (recombinant ACTH seldom used)
• Mineralocorticoid: Fludrocortisone
• Glucocorticoid: Prednisolone

Question 7

Identify the RLS in biosynthesis of corticosteroids, mineralocorticoids and sex hormones. Identify a drug which inhibits this RLS.

Answer 7

• Conversion of cholesterol to pregnenolone is rate-limiting step (RLS) regulated by ACTH
• Aminoglutethimide inhibits RLS

Question 8

Identify drugs acting at different steps of the biosythesis of corticosteroids, mineralocorticoids and sex hormones.

Answer 8

• Trilostane blocks 3 β-dehyd - used in treating Cushing’s and primary hyperaldosteronism.
• Metapyrone prevents the β- hydroxylation of C11
• Carbenoxolone inhibits the conversion of hydrocortisone to cortisone in the kidney.

Question 9

Identify the main mechanisms of action of Glucocorticoids.

Answer 9

• GCs bind intracellular receptors migrate to the nucleus, dimerize and regulate gene transcription.
• Also rapid non-genomic effects of glucocorticoids - mediated through signalling systems in the cytosol
• Metabolic effects of glucocorticoids are mediated by enzymes such as cAMP-dependent protein kinase (PKA) but not all the target genes are known - varies between tissues

Question 10

Identify common glucocorticoid drugs used systematically. What is the main function of each ?

Answer 10

• Hydrocortisone (drug of choice for replacement therapy (cortisol))
• Prednisolone (drug of choice for systemic anti-inflammatory and immunosuppressive effects)
• Dexamethasone (anti-inflammatory and immunosuppressive, used especially when water retention is undesirable (e.g. cerebral oedema), because minimal Sodium retaining effects unlike the other two) + drug of choice for suppression of ACTH production

Question 11

What are the main physiological regulatory roles of Glucocorticoids ?

Answer 11

REGULATORY ACTIONS
• Hypothalamus and pituitary – negative feedback on CRF and ACTH leading to reduced release of endogenous glucocorticoids
• Cardiovascular – reduced vasodilation and fluid exudation.
• Musculoskeletal – decreasing osteoblast and increasing osteoclast
activity to give a tendency for osteoporosis.

Question 12

What are the main physiological metabolic roles of Glucocorticoids ?

Answer 12

METABOLIC ACTIONS
• Carbohydrates - decreased uptake and utilization of glucose accompanied by increased gluconeogenesis to cause hyperglycaemia. Also increased glycogen storage (may be the result of increased insulin secretion due to hyperglycemia).
• Proteins - increased catabolism and reduced anabolism particularly in muscle. Can lead to muscle wasting.
• Lipids – permissive effect on lipolytic hormones and a redistribution of fat as observed in Cushing’s Syndrome.

Question 13

What are the main anti-Inflammatory and immunosuppressive effects of Glucocorticoids ?

Answer 13

• Acute inflammation- decreased influx and activity of leukocytes
• Chronic inflammation- decreased activity of mononuclear cells,
decreased angiogenesis and fibrosis
• Lymphoid tissue- decreased clonal expansion of T and B cells and decreased activation of cytokine-secreting T cells. Switch from Th-1 to Th- 2 responses

ALSO
• Decreased production and action of cytokines including interleukins, TNF-α, cell adhesion factors and induced nitric oxide
• Reduced generation of eicosanoids due to decreased COX-2 expression
• Reduced generation of IgG and complement components in the blood
• Increased release of anti-inflammatory factors (IL-10 and Annexin-1)
• Overall reduction in activity of the innate and acquired immune systems

Question 14

What are the main clinical uses of glucocorticoid (drugs) ?

Answer 14

1) REPLACEMENT THERAPY for patients with adrenal failure (Addison’s disease)
2) ANTI-INFLAMMATORY/IMMUNOSUPPRESSIVE THERAPY

3) CANCER
- In combo with cytotoxic drugs in the treatment of Hodgkin’s disease and acute lymphocytic leukaemia. Reduces oedema in tumours (e.g. Dexamethasone)

Question 15

Identify pathologies glucocorticoids may be used in as anti-inflammatory/immunosuppressive therapy.

Answer 15

• Hypersensitivity states (severe allergic reactions) and Asthma
• Topically in inflammatory conditions of the skin, eye, ear or throat (eg, eczema, allergic conjunctivitis or rhinitis)
• Other diseases with inflammatory and immune components (e.g. rheumatoid arthritis and other connective tissue diseases, IBD, some forms of haemolytic anaemias, idiopathic thrombocytopaenia)
• To prevent graft-versus host disease (i.e. rejection) following organ or bone marrow transplantation

Question 16

Identify the main adverse effects of glucocorticoid drugs.

Answer 16

SEEN MAINLY AFTER PROLONGED SYSTEMIC USE BUT NOT FOLLOWING REPLACEMENT THERAPY

• Suppression of response to infection and injury.
• Opportunistic infections can be problematic.
• Oral fungal or yeast infections can occur.
• Wound healing is impaired.
• Osteoporosis.
• Hazard of fractures.
• Hyperglycaemia.
• Muscle wasting and weakness.
• Inhibition of growth in children.
• CNS effects- euphoria, depression and psychosis.
• Glaucoma.

Question 17

What is the cause of Cushing’s ?

Answer 17

• Caused by excessive exposure to glucocorticoids, which can be due to:

• Disease (e.g. pituitary or adrenal tumor)
• Prolonged administration of glucocorticoid drugs

Question 18

Describe management of Cushing’s, both iatrogenic and endogenous.

Answer 18

For iatrogenic Cushing’s: decrease or withdraw use of corticoids. BUT must be done gradually to avoid unpleasant side effects

For endogenous Cushing’s:
surgery to remove tumor usually recommended (if unsuccessful, or it is not possible to remove the tumour safely, medication can be used to counter the effects of the high cortisol levels BUT can take some time to bring symptoms under control, from weeks to years)

Question 19

What are risks of untreated Cushing’s ?

Answer 19

• Left untreated, Cushing’s syndrome can cause high blood pressure which increases the risk of heart attack and stroke.

Question 20

Describe the main actions of mineralocorticoids ?

Answer 20

1) Retention of sodium ions and water by kidneys (e.g. Aldosterone does this promoting sodium reabsorption in the collecting tubules, by stimulating synthesis of Sodium Potassium antiporter on the basolateral membrane, and by acting on the Sodium H+ exchanger on the luminal surface)
2) Increased BV and BP

Question 21

What are the main clinical uses of mineralocorticoids ?

Answer 21

• The main clinical use of mineralocorticoids is replacement therapy as in Addison’s disease where there is decreased aldosterone secretion.

Question 22

Identify the main mineralocorticoid drugs, and their indication.

Answer 22

Fludrocortisone (orally)
-Replacement therapy in Addison’s

Spironolactone

• Competitive antagonist of aldosterone, K+ sparing diuretic
• Also used to treat hyperaldosteronism, resistant hypertension, HF, and edema

Question 23

What is the mechanism of action of Fludrocortisone ?

Answer 23

• It increases Na+ reabsorption in distal tubules and increases K+ and H+
efflux
• Acts on intracellular receptors that modulate DNA transcription.

Question 24

Identify possible causes of Addison’s.

Answer 24

Dysfunctional adrenal glands.

• Mostly due to AI disease, such as AI adrenalitis. In AI Addison’s, antibodies destroy the adrenal cortex cells which make cortisol and aldosterone
• TB which usually affects lungs can also spread to and destroy adrenals
• Metastatic cancers of other parts of the body can spread to and other adrenals
• Atrophy due to prolonged steroid therapy, amyloidosis can also cause it

Question 25

What are the main symptoms of Addison’s ?

Answer 25

Symptoms will include: anorexia, nausea, vomiting, weakness, hypotension, skin pigmentation (due to ACTH), low sodium/high potassium, Chronic dehydration and sexual dysfunction.

Question 26

Describe management of Addison’s.

Answer 26

• Treatment will usually involve corticosteroid (steroid) replacement therapy for life, by replacing endogenous cortisol and aldosterone (no longer produced) by corticosteroid medication:

• In most cases, hydrocortisone is used to replace cortisol. These are easy to take, usually in tablet form, 2-3 times a day, a common treatment is 25 mg in morning and 12.5 mg in the afternoon
• Prednisolone or dexamethasone may also be used, though less commonly
• If greater mineralocorticoid effects are needed aldosterone is replaced with fludrocortisone, a more selective analogue

Question 27

How can side effects of corticosteroid medication be prevented in Addison’s ?

Answer 27

• Side-effects can be prevented by slowly increasing the dose.

Question 28

What is another name of primary hyperaldosteronism ? What are potential causes of it ?

Answer 28

Conn’s syndrome

CAUSES:

• Adrenal adenoma
• Adrenal hyperplasia (bilateral adrenal hyperplasia, adrenal cells become hyperplastic, resulting in excess secretion of aldosterone)
• Adrenal carcinoma (rare)

Question 29

Describe management of Conn’s.

Answer 29

• Medical management is used in the period prior to surgery - involves the use of aldosterone antagonists, (e.g. Spironolactone usually for 4 weeks)
• Surgical treatment involves surgical adrenalectomy, laparoscopic surgery is preferred over open surgery.

Question 30

Describe the effects of surgical removal of the adenoma in Conn’s syndrome, on hypertension.

Answer 30

• Hypertension may persist after removal of the adenoma, due to effects of the previous hypertension on vasculature

Question 31

Describe the underlying cause of congenital adrenal hyperplasia.

Answer 31

• Genetic disorder where the C-21 hydroxylase enzyme is missing.
Non-hydroxylated versions of cortisol, corticosterone and aldosterone are made.

• These lack normal activity and do not negatively feedback on the HPA axis. Hence, high levels of ACTH cause constant stimulation of production of C-19 androgens.
• Lead to genital changes and early puberty (due to increased androgens) in addition to other health problems related to decreased cortisol and aldosterone)

Question 32

How is congenital adrenal hyperplasia treated ?

Answer 32

• Treat with cortisol to replace the missing cortisol and cause negative feedback on HPA
• Replace the mineralocorticoid if needed (with fludrocortisone)