Adrenocorticosteroids

Adrenocorticosteroids

The adrenal gland consists of the cortex & the medulla. The latter secretes epinephrine, whereas the cortex synthesizes & secretes two major classes of steroid hormones: adrenocorticosteroids (glucocorticoids & mineralocorticoids ) & the adrenal androgens.
The adrenal cortex is divided into three zones that synthesize various steroids from cholesterol & then secrete them as follows:
1. Outer zona (glomerulosa) produces mineralocorticoids (eg. aldosterone). Production of aldosterone is regulated primarily by the renin-angiotensin system.
2. Middle zona (fasciculate) synthesizes glucocorticoids (eg. cortisol), which are involved with normal metabolism & resistance to stress.
3. Inner zona (reticularis) secretes adrenal androgens (eg. dehydroepiandrosterone).
• Secretion of glucocorticoids & adrenal androgens and, to some extent, the mineralocorticoids is controlled by ACTH (corticotropin).
• Glucocorticoids serve as feedback inhibitors of ACTH and CRH secretion.
• Adrenal cortex hormones are used in replacement therapy, treatment & management of asthma as well as other inflammatory diseases, such as rheumatoid arthritis; treatment of severe allergic reactions and in the treatment of some cancers.

Adrenocorticosteroids:
• Bind to specific intracellular cytoplasmic receptors.
• Glucocorticoid receptor is widely distributed throughout the body, whereas. mineralocorticoid receptor is confined mainly to excretory organs (eg. kidney, colon, and salivary and sweat glands).
• Both glucocorticoid and mineralcorticoid receptors are found in the brain.
• The receptor-hormone complex translocates into the nucleus, where it attaches to gene promoter elements and acting as a transcription factor to turn genes on (if complexed with co-activators) or off (if complexed with co-repressors), depending on the tissue.
This mechanism requires time to produce an effect, but other glucocorticoid effects, such as their interaction with catecholamines to mediate relaxation of bronchial musculature or lipolysis are immediate.


A. Glucocorticoids
Cortisol is the principal human glucocorticoid. Its production is diurnal, with a peak early in the morning (8:00 a.m.) followed by a decline and then a secondary, smaller peak in the late afternoon (1:00 a.m.). Stress and levels of the circulating steroid influence secretion. Glucocorticoids effects include:


1. Promote normal intermediary metabolism:
• Favor gluconeogenesis through increasing amino acid uptake by the liver and kidney and elevating activities of gluconeogenic enzymes.
• Stimulate protein catabolism (except in the liver) and lipolysis, thereby providing the building blocks and energy that are needed for glucose synthesis (note: glucocorticoid insufficiency may result in hypoglycemia (eg. during stressful periods or fasting).
• Glucocorticoid augmenting the action of GH on adipocytes, causing an increase in the activity of hormone-sensitive lipase enhancing lipolysis.
2. Increase resistance to stress:
• By raising plasma glucose levels, glucocorticoids provide the body with the energy it requires to combat stress caused by, eg. trauma, fright, infection, bleeding, or debilitating disease.
• Glucocorticoids enhance the vasoconstrictor action of adrenergic stimuli on small vessels result in a modest rise in BP.
3. Alter blood cell levels in plasma:
• Glucocorticoids redistribute eosinophils, basophils, monocytes and lymphocytes from the circulation to lymphoid tissue decreasing their levels in the plasma.
• Increase blood levels of Hb, erythrocytes, platelets and polymorphonuclear leukocytes.
Note: Although the decrease in circulating lymphocytes & macrophages compromises the body’s ability to fight infections, but this an important property in the treatment of leukemia.
4. Anti-inflammatory action:
• The most important therapeutic property of glucocorticoids is the dramatic reduction of the inflammatory & immunologic responses. The exact mechanism is complex and incompletely understood, it is thought to be through:
1. Lowering & inhibition of peripheral lymphocytes and macrophages.
2. Inhibition of phospholipase A2 (due to elevation of lipocortin), blocking the release of arachidonic acid from membrane-bound phospholipid.
3. Reduction of Cox-2 synthesis, lowering the availability of prostaglandins.
4. Interference with mast cell degranulation, decreasing histamine & capillary permeability.
5. Effects on endocrine system:
Elevated level of glucocorticoids cause feedback inhibition of corticotropin production, thus inhibiting further synthesis of both glucocorticoid and TSH.
6. Effects on other systems:
• Adequate cortisol levels are essential for normal glomerular filtration.
• Effects of corticosteroids on other systems are mostly associated with the adverse effects of the hormones.
• High doses of glucocorticoids stimulate gastric acid & pepsin production and may exacerbate ulcers.
• On CNS, the influence on mental status has been identified.
• Chronic glucocorticoid therapy can cause severe bone loss & myopathy.

B. Mineralocorticoids:
• They control the body’s water volume and concentration of electrolytes, especially sodium & potassium.
• Aldosterone causes reabsorption of sodium, bicarbonate and water. While it decreases reabsorption of potassium (which with H+, is then lost in the urine).
• Aldosterone also enhances sodium reabsorption in GI mucosa, sweat & salivary glands.

Note: Elevated aldosterone levels may cause alkalosis & hypokalemia, whereas retention of sodium and water leads to an increase in blood volume and BP.
• Hyperaldosteronism is treated with spironolactone (aldosterone antagonist).

Therapeutic uses of the adrenal corticosteroids:
Several semisynthetic derivatives of the glucocorticoids have been developed that vary in their anti-inflammatory potency, mineralocorticoid activity & duration of action as follows:

Duration of action
Glucocorticois
Anti-inflammatory effect Salt-retaining effect
Short acting
(1-12 hours) Hydrocortisone 1 1
Cortisone 0.8 0.8
Intermediate acting
(12-36 hours) Prednisone 4 0.8
prednisolone 5 0.8
Methylprednisolone 5 0.5
Triamcinolone 5 0
Long acting
(36-55 hours) Betamethasone 35 0
Dexamethasone 30 0
Mineralocorticoids
Fludrocortisone 10 125
Desoxycorticosterone 0 20