The adrenal gland produces numerous hormones.  The most important of these are the glucocorticoids (GC), mineralocorticoids (MC), and small amounts of sex hormones.  Adrenal production of sex hormones are especially important during fœtal development to differentiate gender and also as the primary source of œstrogens and androgens post menopause.  The actions of these hormones have been discussed in the previous section.  The primary glucocorticoid in humans in hydrocortisone (cortisol) and the primary mineralocorticoid is aldosterone.  As their classification implies, these hormones are intimately associated with regulating glucose and mineral utilisation respectively.  Both hormones are synthesised and released from the adrenal cortex in response to ACTH.  ACTH and GC are released cyclically throughout the day (peaking at meals and approximately 1 hr prior to waking.  ACTH release and subsequent GC release is also stimulated in response to "stress" situations such as trauma, infection, insult, or injury.

Mechanism of Action -- Cortisol acts by at least two different mechanisms.  It will combine with a typical cellular steroid receptor to cause increased synthesis of proteins.  However, the mechanism of its binding and effect are slightly different than those of the sex hormones or aldosterone.  The GC receptor is bound to a heat shock protein (HSP) that prevents it from binding with DNA (the other hormonal receptors will not bind to DNA because their binding site is hidden and only revealed with the conformational change in shape caused by ligand interaction).  When GC binds to the receptor, the HSP dissociates from the receptor, allowing the GC-R complex to interact with DNA to cause increase transcription, translation, and protein synthesis.  The GC-R complex then dissociates, the GC is metabolised and the R binds with the HSP, so that the HSP-R complex prevents activity until bound with another GC.

It is also thought to act directly on cells by some mechanism(s) as yet unknown.  This is due to the fact that many of the effects of GC occur too rapidly to be the result of protein synthesis.

Pharmacodynamic Effects of GC -- the physiologic responses to cortisol may be the result of 1) the direct receptor-mediated or cellular effects of the hormone, 2) the result of an intermediary hormone such as insulin or glucagon, or 3) a permissive effect that does not occur due to the action of the GC but is rather allowed to happen due to the presence of the GC. (As an example, noradrenaline-mediated bronchodilatation is much less pronounced in the absence of normal levels of CG.  Cortisol does not cause the adrenergic action but it does enhance it.  Similarly, some lipid effects and growth hormone action is accentuated in the present of GC even though cortisol does not directly cause the action.)  The effects of cortisol may be loosely categorised as

Metabolic effects -- the goal of GC is to increase energy sources, by increasing plasma glucose and
increasing gluconeogenesis which is mediated by increased uptake of amino acids by the liver.  This will result in higher levels of plasma glucose (by the increased de novo synthesis and decreased utilisation of dietary glucose).  The source of amino acids is predominately muscle proteins.

increase glycogen deposition (by increasing the synthase pathways of carrier proteins)

increase plasma glucose (as described above) resulting in increased insulin release (this in turn causes increase lipogenesis)

decreased glucose uptake by fat which causes increased lipolysis (note that there are opposing effects here, increased fat formation and increased fat breakdown, the net effect of glucocorticoids is fat deposition)

Catabolic effects -- primary effect is to provide the sources for glucose utilisation described above
breakdown of tissues in lymphatics, connective tissue (minor), muscle (major and may lead to muscle wasting), fat (as described above), skin (may lead to "brittle" skin and easy bruising), and bone (may lead to osteoporosis).

Anti-inflammatory/Immunosuppressive effects

decrease the adhesion of leukocytes in inflamed areas (decrease T and B lymphocytes, monocytes, eosinophils, basophils which are shifted to lymphoid tissue)

decrease the function of leukocytes and macrophages (decreased responsiveness to antigens and mitogens) to decrease the release of interferon, interleukin, pyrogens, collagenase, elastase, tumour necrosis factor, and plasminogen activator, stabilise lysosomal membranes to decrease the release of proteolytic enzymes

decrease the action of phospholipase A₂, to decrease the formation of arachidonic acid, thus inhibiting the synthesis of PG, TX, LT

decrease the genetic expression of COX II (inflammatory isozyme) to decrease the synthesis of PG, TX

inhibit the actions of kinins and decrease histamine release (both of which are vasodilatatory), causing vasoconstriction and thus reducing blood flow to inflamed areas

Other Effects
CNS
decrease seizure threshold (increase incidence of seizures)
behavioural changes characterised as psychotic episodes, paranoia, aggression, irritability
increase intracranial pressure (pseudotumour cerebri)  -- dexamethasone has the least likelihood of causing this and is paradoxically sometimes used in the treatment of cerebral œdema
Gastrointestinal
increase acid and pepsin production, causing gastric and duodenal ulcers
increase dietary fat absorption
decrease vitamin D-mediated calcium absorption
Blood -- increase number of platelets and red blood cells
Term -- immediately before delivery, GC release in the mother will increase the synthesis of pulmonary surfactant in the fœtus, preparing it for breathing upon birth.  Without the surfactant, the neonate will be in respiratory distress.

Replacement Therapy
Chronic Adrenal Insufficiency (Addison's Disease) -- occurs when the adrenal glands are not able to produce adequate amounts of GC or MC.  Patients will present with hyperpigmentation, weakness, fatigue, weight loss, hypotension, and decreased fasting glucose.  They will respond poorly to stress and may expire as a result of the insufficiency during stress.  Treatment requires daily dosing with 20 to 30 mg of cortisol (or appropriate doses of other GC) and higher doses during periods of stress.

Acute Adrenal Insufficiency -- most often occurs in adrenal-compromised patients under physical stress.  The state is potentially lethal.  Treatment is aggressive with 100 mg of cortisol q 6-8 hr until the patient is stabilised.  Fluids and electrolytes must often accompany GC therapy.

Congenital Adrenal Hyperplasia -- infants that are born with an inability to synthesis GC will exhibit increase ACTH release.  This continuous stimulation of an unresponsive adrenal gland will result in an enlarged (hyperplastic) gland that is ineffective.  The specific enzyme deficiency may be diagnosed with challenge doses of ACTH or GC.  Treatment is with GC replacement.

Cushing's Disease (pituitary) and Cushing's Syndrome (adrenal) -- This condition represents the physiologic opposite of Addison's disease.  It may result from an adrenal tumour, an ectopic tumour with adrenal activity, or from over secretion of ACTH.  Patients present with a round, full "moon" face, trunk obesity, muscle wasting and protein loss, thinning and easily bruised skin, poor wound healing, osteoporosis, mental disturbances, hypertension, diabetes mellitus, and peptic ulcer (all effects of GC and/or MC).  Treatment typically involves either irradiation of the adrenal gland or its removal.  Either form of adrenalectomy results in a state of adrenal insufficiency that must be supplemented.

Other Uses of GC
These agents are administered to premature infants to increase the synthesis of surfactant, to reduce complications from respiratory distress.

These agents are also used for their immunosuppressant and anti-inflammatory effects in a number of conditions (arthritis, asthma, allergy, graft rejection) discussed previously.

Adverse Reactions -- The side effects seen with GC therapy can be quite severe and extensive.  The effects are essentially the same as those seen with Cushing's syndrome (see above).

Clinical Considerations -- Due to the diverse and potentially dangerous effects of GC, patients should be closely monitored during therapy.  Additionally, following chronic therapy (or even high dose short-term therapy) feedback mechanisms may shut down adrenal production of GC and MC.  Abrupt discontinuation of the exogenous source of these hormones will precipitate a state of acute adrenal insufficiency, placing the patient at risk.  Therefore, patients should be slowly withdrawn from therapy, allowing the adrenal gland time to recover.  This effect may be minimised by using the lowest effective dose and alternate day therapy.

Hyperaldosteronism presents as hypertension, polyuria, polydipsia, weakness, tetany, and alkalosis.  The treatment is spironolactone, an aldosterone antagonist.

Hypoaldosteronism is characterised by decreased urine output, hyponatræmia and hyperkalæmia.  Treatment is with either desoxycorticosterone (rarely used) or fludrocortisone, which has some GC and extensive MC activity.  Adverse effects of fludrocortisone are essentially the same effects as hyperaldosteronism.

Mechanism of Action -- inhibition of 11-hydroxylase, thus inhibiting the synthesis of cortisol.

Use -- It is used primarily as a short-term treatment in Cushing's patients while the proper course of therapy (radiation or surgery) is chosen.  It is not effective for chronic treatment of these patients.

Adverse Effects -- Occur as a result of a shift in the biosynthetic pathway, causing increases in MC and Androgen synthesis -- salt and water retention, hirsutism.

Mechanism of Action -- inhibits the conversion of cholesterol to pregnenolone, thus inhibiting the synthesis of ALL steroid hormones

Use -- Treatment of œstrogen-dependent breast cancer, Cushing's disease/syndrome

Adverse Effects -- lethargy, rash, drowsiness

Mechanism of Action -- inhibition of 3-beta 17 dehydrogenase, decreasing cortisol production

Use -- similar to aminoglutethimide

Adverse Effects -- gastrointestinal