CORTICOSTEROID

The adrenal cortex releases several steroid hormones into the circulation.
They are divided by their actions into two classes:
1 Mineralocorticoids, mainly aldosterone in humans; have saltretaining
activity and are synthesized in the cells of the zona
glomerulosa.
2 Glucocorticoids, mainly cortisol (hydrocortisone) in humans;
affect carbohydrate and protein metabolism, but also have significant
mineralocorticoid activity. They are synthesized in the cells of the zona
fasciculata and zona reticularis.
The release of cortisol is controlled by a negative feedback mechanism
involving the hypothalamus and anterior pituitary (upper figure,
). Low plasma cortisol levels result in the release of corticotrophin
(adrenocorticotrophic hormone, ACTH), which stimulates cortisol
synthesis and release by activating adenylyl cyclase. Cyclic adenosine
monophosphate (cAMP) then activates protein kinase A, which phosphorylates
and increases the activity of cholesterylester hydrolase, the
rate-limiting step in steroid synthesis. Aldosterone release is affected
by ACTH, but other factors (e.g. renin–angiotensin system, plasma
potassium) are more important.
The steroids are examples of gene-active hormones. The steroid
diffuses into the cells (lower figure, S ) where it binds to cytoplasmic
glucocorticoid receptors ( R ). In the absence of cortisol, the receptor
is inactivated by a heat-shock protein ( hsp90 ). Cortisol triggers the
release of hsp90 and the activated receptor ( S R ) enters the nucleus
where it stimulates (or inhibits) the synthesis of proteins, which then
produce the characteristic actions of the hormone (middle bottom).
The steroid hormones (hydrocortisone or cortisone) are given
with a synthetic mineralocorticoid, usually fludrocortisone (top
right), for replacement therapy in patients with adrenal insufficiency
(e.g. in Addison’s disease). For most therapeutic uses, synthetic glucocorticoids
(top middle) have replaced the natural hormones, mainly
because they have little or no salt-retaining activity.
Glucocorticoids (often prednisolone) are used to suppress
inflammation, allergy and immune responses. Anti-inflammatory
therapy is used in many diseases (e.g. rheumatoid arthritis, ulcerative
colitis, bronchial asthma, severe inflammatory conditions of the eye
and skin). Suppression of the immune system is of value in preventing
rejection following tissue transplantation. Steroids are also used
to suppress lymphopoiesis in patients with certain leukaemias and
lymphomas.
Steroids can produce striking improvement in certain diseases, but
high doses and prolonged use may cause severe adverse effects (right,
). These are usually predictable from the known actions of the
drugs.

polypeptide whose action is enhanced by arginine vasopressin (antidiuretic

hormone, ADH). It is produced in the hypothalamus and
reaches the adenohypophysis in the hypothalamo–hypophysial portal
system, where it stimulates the release of corticotrophin.
Corticotrophin (ACTH) is processed from a large-molecularweight
precursor, pro-opiomelanocortin (POMC), present in corticotroph
cells of the adenohypophysis; its main action is to stimulate the
synthesis and release of cortisol (hydrocortisone). POMC also contains
the sequences for β-lipotropin (β-LPH) and β-endorphin, which
are concomitantly released into the blood. Corticotrophin is also
believed to sensitize the zona glomerulosa to other stimuli that
cause aldosterone release (i.e. low plasma Na+, high plasma K+, angiotensin
II).
Glucocorticoids
Mechanisms of action
Cortisol (and synthetic glucocorticoids) diffuses into target cells and
binds to a cytoplasmic glucocorticoid receptor belonging to the superfamily
of steroid, thyroid (Chapter 35) and retinoid receptors. The
activated receptor–glucocorticoid complex enters the nucleus and
binds to steroid response elements on target DNA molecules. This
either induces the synthesis of specific mRNA or represses genes by
inhibiting transcription factors, e.g. nuclear factor κB (NFκB). For
most clinical purposes, synthetic glucocorticoids are used because
they have a higher affinity for the receptor, are less rapidly inactivated
and have little or no salt-retaining properties.
Hydrocortisone is used (i) orally for replacement therapy; (ii) intravenously
in shock and status asthmaticus; and (iii) topically (e.g.
ointments in eczema, enemas in ulcerative colitis).
Prednisolone is the drug most widely given orally in inflammatory
and allergic diseases.
Betamethasone and dexamethasone are very potent and have no
salt-retaining actions. This makes them especially useful for high-dose
therapy in conditions, such as cerebral oedema, where water retention
would be a disadvantage.
Beclometasone dipropionate and budesonide pass membranes
poorly and are more active topically than when given orally. They are
used in asthma (as an aerosol) and topically in severe eczema to provide
a local anti-inflammatory action with minimal systemic effects.
Triamcinolone is used in severe asthma and by intra-articular injection
for local inflammation of joints.
Effects
Glucocorticoids influence most cells in the body.
Metabolic effects Glucocorticoids are essential for life, their most
important action being to facilitate the conversion of protein to glycogen.
Glucocorticoids inhibit protein synthesis and stimulate protein
catabolism to amino acids. Gluconeogenesis, glycogen deposition and
glucose release from the liver are stimulated, but peripheral glucose
uptake is inhibited. During fasting, glucocorticoids are vital to prevent
(possibly fatal) hypoglycaemia.
Anti-inflammatory and immunosuppressive effects Corticosteroids
have profound anti-inflammatory effects and are widely used for this
purpose. They suppress all phases of the inflammatory response,
including the early swelling, redness and pain, and the later proliferative
changes seen in chronic inflammation. Inflammation is suppressed
by several mechanisms. Circulating immunocompetent cells and macrophages
are reduced and the formation of pro-inflammatory mediators,
such as prostaglandins, leucotrienes and platelet activating factor
(PAF), is inhibited. Steroids produce these latter effects by stimulating
the synthesis in leucocytes of a protein (annexin-1) that inhibits phospholipase
A2. This enzyme, located in the cell membrane, is activated
in damaged cells and is responsible for the formation of arachidonic
acid, the precursor of many inflammatory mediators (Chapter 32).
Corticosteroids also suppress the genes encoding phospholipase A2,
cyclo-oxygenase-2 (COX-2) and the interleukin-2 (IL-2) receptor.
These genes are normally switched on by NFκB, but steroids induce
the synthesis of IκB, which binds to NFκB and inhibits it by preventing
its entry into the nucleus.
Glucocorticoids depress monocyte/macrophage function and
decrease circulating thymus-derived lymphocytes (T-cells), especially
helper T4 lymphocytes. The release of IL-1 and IL-2 (necessary to
activate and stimulate lymphocyte proliferation) is inhibited. The
transport of lymphocytes to the site of antigenic stimulation and the
production of antibody are also inhibited.
Adverse effects
Glucocorticoids produce many adverse effects, especially with the high
doses required for anti-inflammatory activity. (Similar effects are produced
by the excess corticosteroids secreted in Cushing’s syndrome.)
Metabolic effects High doses quickly cause a rounded, plethoric face
(moon face), and fat is redistributed from the extremities to the trunk and
face. Purple striae and a tendency to bruise develop. Disturbed carbohydrate
metabolism leads to hyperglycaemia and occasionally diabetes.
Protein loss from skeletal muscles causes wasting and weakness.
This cannot be remedied by dietary protein because protein synthesis is
inhibited. An increase in bone catabolism may cause osteoporosis.
Bisphosphonates (e.g. etidronate, alendronate) are incorporated into
the bone matrix and accumulate in the osteoclasts when they resorb
bone. This results in inhibition and apoptosis of the osteoclasts and
reduction of bone resorption. Bisphosphonates can be used for the
prevention and treatment of corticosteroid-induced osteoporosis and
to treat osteoporosis in postmenopausal women (Chapter 34).
Fluid retention, hypokalaemia and hypertension These may occur
with compounds that have significant mineralocorticoid activity. Thus,
hydrocortisone (and cortisone) are generally used only for replacement
therapy in adrenal insufficiency.
Adrenal suppression Steroid therapy suppresses corticotrophin secretion
and this eventually leads to adrenal atrophy. It may take 6–12
months for normal adrenal function to recover once therapy is stopped.
Because the patient’s response to stress is suppressed, additional
steroid must be administered in times of severe stress (e.g. surgery,
infection). Steroid therapy must be withdrawn very gradually, because
abrupt withdrawal causes adrenal insufficiency.
Infections There is increased susceptibility to infections, which may
progress unrecognized because the natural indicators of infection are
inhibited.
Other complications These include psychosis, cataracts, glaucoma,
peptic ulceration and the reactivation of nascent infections (e.g.
tuberculosis).
Mineralocorticoids
Fludrocortisone is given with hydrocortisone in adrenal insufficiency
(e.g. Addison’s disease or following adrenalectomy) because the latter
drug does not possess sufficient salt-retaining activity.