Adrenal gland (suprarenal gland)
ADRENOCORTICAL FUNCTION
The hypothalamus is in overall control of adrenocortical function by producing factors that
stimulate die pituitary to release adrenocorticotrophic hormone (ACTH or corticotrophin).
The adrenal cortex produces a series of corticosteroids, mainly the glucocorticoids cortisol
(hydrocortisone) and corticosterone, and the mineralocorticoid, aldosterone. Glucocorticoid
production by the adrenal glands is stimulated by adrenocorticotropic hormone (ACTH:
corticotropin) from the anterior pituitary gland, and cortisol exerts a negative feedback on
the pituitary and hypothalamus.
Adrenocorticotropic hormone arises from a precursor, pro-opiomelanocortin (POMC), and is
released in response to hypothalamic corticotropin releasing hormone (CRH), with a diurnal
rhythm (peak early morning, nadir on retiring).
Corticosteroids are an essential part of the body's response to stresses such as trauma,
infection, general anaesthesia or operation, pain, stress, fever, burns, and hypoglycaemia. At
such times there is normally raised adrenal corticosteroid production and the size of the
response is related to the degree of stress.
Circulating corticosteroids have a negative feedback control on hypothalamic activity and
ACTH production. There is thus a hypothalamic-pituitary-adrenocortical axis (HPA).
Mineralocorticoid (aldosterone) production is regulated mainly by the renin-angiotensin
system, renal blood pressure and sodium and potassium levels. Renin, an enzyme that
converts angiotensinogen to angiotensin 1, is produced by the renal juxta-glomerular
apparatus, in response to low sodium or renal perfusion. Angiotensin 1 is converted by
angiotensin-converting enzyme in the lung parenchyma to the active angiotensin 2, which
stimulates aldosterone release.
Aldosterone acts on the kidney to promote sodium retention, potassium excretion and fluid
retention, and causes vaso-constriction and thirst.
Atrial natriuretic peptide (ANP), synthesized by myocytes in the right atrium and ventricles,
causes sodium loss, and thus counters the effect of aldosterone.
Adrenocortical hyperfunction may lead to release of excessive:
 glucocorticoids (Cushing's disease)
 mineralocorticoids (Conn's syndrome or hyperaldosteronism)
 androgens (congenital adrenal hyperplasia).
ADRENOCORTICAL HYPERFUNCTION
CUSHING'S DISEASE
General aspects
Cushing's disease is due to sustained overproduction of cortisol. A similar clinical picture is
produced by systemic corticosteroid therapy and, rarely, by the multiple endocrine adenoma
syndromes.
Cushing's disease is caused by excess glucocorticoid production by adrenal hyperplasia
secondary to excess ACTH production by pituitary basophil adenomas. It is occasionally
caused by ectopic ACTH from adrenal or other tumours such as small-cell lung carcinomas
or carcinoid tumours. A similar clinical picture results where there is ectopic production by a
tumour (usually a bronchial carcinoid tumour) of corticotrophin-releasing hormone (CRH).
Cushing's syndrome is clinically similar but caused by primary adrenal disease (adenoma or
rarely carcinoma or micronodular bilateral hyperplasia). However, most cases of Cushing's
syndrome have been found to be due to microadenomas of the pituitary, so that the terms
Cushing's disease and Cushing's syndrome are in effect synonymous.
Clinical features
The most obvious features of Cushing's disease are:
1. central obesity, affecting particularly the face (moon face), interscapular region
(buffalo hump) and trunk, but with relative sparing of the limbs
2. hypertension
3. breakdown of proteins with conversion to glucose (gluconeogenesis). This leads to
hyperglycaemia and diabetes mellitus.
4. osteoporosis
5. muscle weakness
6. thinning of the skin, purpura and purplish skin striae
7. hirsutism and acne
8. oligomenorrhoea
9. infections
10.psychoses.
General management
Facial photographs from the past and more recently may show the development of a moon
face. The main differential diagnoses are from severe depression and alcoholism.
Cushing's disease is confirmed by the following:
1) The plasma cortisol levels are often raised, but it is better to look for absence of the
normal diurnal variation in cortisol levels, normally highest in the morning around
08.00a.m., and lowest at midnight.
2) Another useful screening test is the low-dose overnight dexamethasone suppression
test to measure plasma cortisol at 8.00-9.00 a.m. after giving 1 mg dexamethasone
orally at midnight to suppress the adrenals temporarily when normally cortisol levels
fall but, in Cushing's syndrome, there is no such fall.
3) Other special dexamethasone tests or sampling from the inferior pctrosal sinus arc
needed to distinguish pituitary from adrenal causes of Cushing's syndrome.
Localization of the cause of Cushing's disease as adrenal, pituitary or ectopic tumour relies
on:
 corticotrophin-releasing hormone (CRH) stimulation test. This depends on the fact
that the pituitary responds to CRH, whereas adrenal tumours and other tumours
producing ectopic ACTH do not. Baseline ACTH and cortisol levels are first obtained
CRH is then given and an exaggerated rise in plasma ACTH and cortisol levels is given
by patients with pituitary Cushing's, but not by patients with other types of Cushing's
syndrome. ^ ACTH levels, dexamethasone suppression, effect of metyrapone on 11deoxycortisol and petrosal sinus ACTH levels.
 Pituitary MRJ, tomography of the sella turcica
 abdominal CT
 adrenal ultrasound scans.
In Cushing's disease, the pituitary tumour is treated by trans-sphenoidal microadenectomy
and then by pituitary irradiation or an yttrium implant for those not cured. Cyproheptadine or
sodium valproate are sometimes used where surgery is inappropriate.
In Cushing's syndrome, the adrenal gland responsible is usually irradiated or excised, though
medical treatment with ketoconazole, mitotane, aminoglutethimide or metyrapone can also
be effective. About 10% of patients subjected to bilateral adrenalectomy develop pituitary
ACTH-producing adenomas with hyperpigmentation and symptoms related to the pituitary
tumour (Nelson's syndrome). Cushing's syndrome secondary to carcinoma of the bronchus is
not controllable by surgery but metapyrone, an inhibitor of hydroxylation in the adrenal
cortex, can relieve symptoms.
Steroid replacement is subsequently necessary in treated Cushing's disease/syndrome.
Dental aspects
Local anaesthesia is preferred for pain control.
Conscious sedation can be given, preferably with nitrous oxide and oxygen. General
anaesthesia must be carried out in hospital.
Management complications may include:
 need for corticosteroid cover. Patients, once treated, are maintained on corticosteroid
replacement therapy and then are at risk from an adrenal crisis if subjected to
operation, anaesthesia or trauma.
 hypertension
 cardiovascular disease
 diabetes mellitus
 psychosis
 vertebral collapse or myopathy causing limited mobility
 multiple endocrine adenomatosis.
There are no specific oral manifestations of Cushing's disease, but, though it may be hard to
believe, patients have been referred for a suspected dental cause of the swollen face.
Subacute adrenal insufficiency (corticosteroid withdrawal syndrome)
Subacute adrenal insufficiency develops if corticosteroid dosage is reduced too quickly after
replacement therapy in postsurgical patients with Cushing's syndrome.
Features include lethargy, abdominal pain, hypotension and psychological disturbances.
Scaly desquamation of the facial skin, particularly of the forehead, is a characteristic sign.
Hydrocortisone replacement needs to be increased if there are signs of adrenal insufficiency.
Clinical features of hyper- and hypoadrenocorticis
HYPERALDOSTERONISM
General aspects
Primary hyperaldosteronism (Conn's syndrome) arises from a rare benign tumour or
hyperplasia of the adrenal cortex.
Secondary hyperaldosteronism arises as a result of activation of the renin-angiotensin
system, which may be seen in cirrhosis, nephrotic syndrome, severe cardiac failure or renal
artery stenosis.
Clinical features
 High aldosterone secretion leads to potassium loss and sodium retention. Hypokalaemia
often causes muscle weakness and cramps, paraesthesia, polyuria and polydipsia, and,
since it is associated with a metabolic alkalosis, may lead to tetany.
 Sodium retention leads to hypertension but rarely to oedema.
General management
Amiloride, or the aldosterone antagonist spironolactone, is given until the affected adrenal
gland can be excised.
Dental aspects
Local anaesthesia is used for pain control. Conscious sedation may be helpful, especially if
there is hypertension. General anaesthesia must always be carried out in hospital,
particularly to deal with the metabolic abnormalities. Competitive muscle relaxants may be
dangerous, as they can cause profound paralysis.
In the untreated patient, hypertension and muscle weakness are the main complications.
If bilateral adrenalectomy has been carried out, the patient is at risk from collapse during
dental treatment and therefore requires corticosteroid cover.
ADRENOCORTICAL HYPOFUNCTION
Adrenocortical hypofunction can lead to hypotension, shock and death if the individual is
stressed, for example, by operation, infection or trauma. H Most commonly, adreno-cortical
hypofunction is due to adrenocorticotrophic hormone (ACTH; corticotrophin) deficiency
caused by the suppression of adrenocortical function following the use of systemic
corticosteroids (secondary hypoadrenocorticism). H Occasionally, adrenocortical
hypofunction is caused by acquired adrenal disease (primary hypoadrenocorticism). ^
Rarely, adrenocortical hypofunction may be due to a congenital defect in the biosynthesis of
corticosteroids (congenital adrenal hyperplasia).
PRIMARY HYPOADRENOCORTICISM (ADDISON'S DISEASE)
General aspects
Primary hypoadrenocorticism is a rare autoimmune disease, caused by circulating
autoantibodies to the adrenal cortex, characterized by atrophy of the adrenal cortices and
failure of secretion of cortisol (hydrocortisone) and aldosterone. Patients also have a higher
incidence of other endocrine deficiencies, vitiligo and, occasionally, chronic mucocutaneous
candidosis.
Primary hypoadrenocorticism occasionally has other causes, such as:
 adrenal tuberculosis
 histoplasmosis (particularly, secondary to HIV infection)
 malignancy
 haemorrhage
 sarcoidosis
 amyloidosis or adrenalectomy for metastatic breast
Clinical features
Lack of cortisol predisposes to hypotension and hypoglycaemia.
The low serum cortisol stimulates the hypothalamopituitary axis causing release of proopiomelanocortin, which has ACTH and melanocyte-stimulating hormone (MSH) activity
and can cause hyperpigmentation.
Lack of aldosterone leads to sodium depletion, reduced extracellular fluid volume and
hypotension.
The lack of adrenocortical reserve makes patients vulnerable to any stress such as infection,
trauma, surgery or anaesthesia, though they may be asymptomatic otherwise.
An acute adrenal crisis (Addisonian crisis or shock) is characterized by collapse,
bradycardia, hypotension, profound weakness, hypoglycaemia, vomiting and dehydration.
Patients with hypoadrenocorticism also suffer from:
a. fatigue and weakness
b. lethargy
c. anorexia
d. nausea, vomiting and diarrhoea
e. weight loss
f. hyperpigmentation
g. dizziness and postural hypotension
General management
Diagnosis of hypoadrenocorticism is confirmed by finding:
 hypotension
 low plasma cortisol levels. Blood for plasma cortisol estimation (10ml in lithium
heparin tube, or plain tube) should be taken at 8.00 or 9.00a.m. In
hypoadrenocorticism the basal plasma cortisol level is usually lower than 6mg/100ml
(170nmol/l), often lower than 100nmol/l.
 In early hypoadrenocorticism, the cortisol levels may still be in the low normal range
and, therefore, a short ACTH stimulation test is indicated. Depressed cortisol
responses to ACTH stimulation. Plasma is collected before and 30 min after 250 mg
of tetracosactrin (synthetic ACTH: Synacthen) is injected intramuscularly or
intravenously. In health, the plasma cortisol level normally doubles from at least 200
nmol/1 to more than 500 nmol/1 after tetracosactrin. In hypoadrenocorticism the basal
cortisol level is low and does not rise by more than 200 nmol/1 after tetracosactrin is
given.
 Estimation of serum ACTH levels differentiates primary (ACTH raised, usually above
200 ng/1) from secondary (ACTH low or normal) hypoadrenocorticism.
 Plasma electrolytes should be assayed but in many cases are normal, unless a crisis is
imminent, when the plasma sodium level may be low and the potassium raised. There
is often also hypoglycaemia.
 Serum should be tested for autoantibodies to various tissues, especially endocrine
glands.
 Other investigations may be needed, including radiography or CT or MRI scans of the
skull (for pituitary abnormalities), chest (for tuberculosis) or abdomen (for adrenal
calcification suggestive of tuberculosis or a mycosis).
Most patients are treated with oral hydrocortisone and fludrocortisone.
Dental aspects
The risk of precipitating hypotensive collapse is such that corticosteroids must be given
preoperatively. Conscious sedation should generally be avoided unless the patient has had
corticosteroid cover. General anaesthesia is obviously a matter for the expert anaesthetist in
hospital. Brown or black pigmentation of the mucosa is seen in over 75% of patients with
Addison's disease, but is not a feature of corticosteroid-induced hypoadrenocorticism or of
hypoadrenocorticism secondary to hypothalamopituitary disease. Hyperpigmentation is
related to high levels of MSH and affects particularly areas normally pigmented or exposed
to trauma (for example in the buccal mucosa at the occlusal line, or the tongue, but also the
gingivae). Other causes of oral pigmentation (especially racial pigmentation) are far more
common and need to be differentiated. Addison's disease is a rare cause but must be
considered, particularly if there is hypotension, weakness, weight loss, anorexia, nausea,
vomiting or abdominal pain.
Acute adrenal insufficiency has several causes and is managed as follows:
A. Lay the patient flat with the legs raised.
B. Give 200 mg hydro-cortisone intravenously.
C.
D.
E.
F.
G.
Summon medical assistance.
Take blood for glucose and electrolyte estimation.
Give glucose if there is hypoglycaemia (25 g orally or intravenously).
Put up an i.v. infusion of normal saline or glucose-saline.
Give 11 over 2 h together with 200 mg hydrocortisone sodium succinate, repeating
this at 4-6-hourly intervals as required and monitor the blood pressure.
H. Determine and deal with the underlying cause when the blood pressure has been
stabilized. Control of pain and infection are particularly important and steroid
supplementation must be continued for at least 3 days after the blood pressure has
returned to normal.
The causes of adrenal insufficiency
SYSTEMIC CORTICOSTEROID THERAPY
General aspects
Steroids have different potencies.
Corticosteroids have a negative feedback control on hypothalamic activity and ACTH
production and there is, thus, supression of the hypothalamic-pituitary-adrenocortical axis
(HPA) and the adrenals may become unable to produce a steroid response to stress.
Corticosteroids are an essential part of the body's response to stresses such as trauma,
infection, general anaesthesia or operation.
At such times there is normally an enhanced adrenal corticosteroid response related to the
degree of stress.
In patients given exogenous steroids, the enhanced adrenal corticosteroid response may not
follow. When the adrenal cortex is unable to produce the necessary steroid response to
stress, acute adrenal insufficiency (adrenal crisis) can result, with rapidly developing
hypotension, collapse and possibly death.
Suppression of the HPA axis becomes deeper if corticosteroid treatment has been prolonged
and/or the dose of steroids exceeds physiological levels (more than about 7.5 mg/day of
prednisolone). Adrenal suppression is less when the exogenous steroid is given on alternate
days or as a single morning dose (rather than as divided doses through the day).
Corticotrophin (ACTH) has been used in the hope of reducing adrenal suppression, but the
response is variable and unpredictable, and wanes with time. However, adrenal function may
even be suppressed for up to 1 week after cessation of steroid treatment lasting only 5 days.
If steroid treatment is for longer periods, adrenal function may be suppressed for at least 30
days and perhaps for 2-24 months after the cessation of treatment.
Patients on, or who have been on, corticosteroid therapy within the past 30 days may be at
risk from adrenal crisis, and those who have been on them during the previous 24 months
may also be at risk, if they are not given supplementary corticosteroids before and during
periods of stress such as operation, general anaesthesia, infection or trauma. Patients who
have used systemic corticosteroids should be warned of the danger and should carry a steroid
card indicating the dosage and the responsible physician.
However, the frequency and extent of the adrenocortical suppression (and the need for
supplementary corticosteroids before and during periods of stress) is unclear and has been
questioned.
Although the evidence for the need for steroid cover may be questionable, medicolegal and
other considerations suggest that one should act on the side of caution and:
 fully inform and discuss with the patient
 take medical advice in any case of doubt
 give a steroid cover unless confident that collapse is unlikely.
Therapeutic uses of systemic corticosteroid
Clinical features
Long-term systemic use of corticoeteroids can cause many other adverse effects, often
beginning soon after the start of treatment and can cause significant morbidity or mortality,
including:
 Cushingoid weight gain around the face (moon face) and upper back (buffalo hump),
and hirsutism are the most immediately obvious effects
 growth retardation in children
 diabetes
 hypertension








infections
perforated or bleeding peptic ulcers
mood changes or psychoses
cataracts
muscle weakness
skin striae
osteoporosis
malignant tumours if given long term.
The above complications may be reduced, but not abolished, if steroids are given on
alternate days. Thus, once the desired therapeutic effect of the steroid is achieved by daily
administration, there should be a transition to giving the entire 48-h dose as a single early
morning dose on alternate days.
Patients on systemic steroids, in order to minimize the above effects, are usually also given:
ranitidine, calcitriol or didronel.
Complications of systemic corticosteroid therapy
General management
Corticosteroids should be prescribed under the following conditions:
o There should be no contraindications such as hypertension
o Bone density, blood pressure and Neoplasms
blood glucose baseline measures should be taken and these parameters monitored. The
smallest effective steroid dose should be given. The steroid is best given in the morning on
alternate days. The patient must be given a warning card and told of the dangers of
withdrawal, and side effects. There should never be abrupt withdrawal of the steroid. The
dose should be raised if there is illness, infection, trauma, or operation. Systemic
corticosteroids cause the greatest risk of adrenocortical suppression. Topical steroids should
always be used in preference to systemic steroids provided that the desired therapeutic effect
is achievable. However, there can also be adrenocortical suppression from extensive
application of steroid skin preparations, particularly if occlusive dressings are used. Patients
who are to be put on systemic steroids should, therefore, have baseline evaluations of their:
weight, blood pressure, chest radiograph, blood glucose, and bone densitometry.
Dental aspects
Adrenocortical function may be suppressed if:
1. the patient is currently on daily systemic corticosteroids at doses above 7.5 mg
prednisolone
2. corticosteroids have been taken regularly during the previous 30 days
3. corticosteroids have been taken for more than 1 month during the past year.
During intercurrent illness or infection, after trauma, or before operation or anaesthesia,
these patients may require a higher steroid dosage. Although the evidence for this may be
questionable, medicolegal and other considerations suggest that one should act on the side of
caution and give steroid cover unless confident that collapse is unlikely.
The blood pressure must be carefully watched during surgery and especially during
recovery, and steroid supplementation given immediately if the blood pressure starts to fall.
Dentoalveolar or maxillofacial surgery may result in stress and a cortisol response, but most
other forms of dental treatment cause little response.
Minor operations under local anaesthesia may be covered by giving the usual oral steroid
dose in morning and giving oral steroids 2-4 h pre- and postoperatively (25-50 mg
hydrocortisone or 20 mg prednisolone or 4 mg dexamethasone) or by giving i.v. 25-50 mg
hydrocortisone immediately before operation. Intravenous hydrocortisone must be
immediately available for use if the blood pressure falls or the patient collapses.
Cover for major operations can be provided by giving at least 25-50 mg hydrocortisone
sodium succinate intramuscularly or intravenously (with the premedication) and then 6hourly for a further 24-72 h. Corticosteroids given by intramuscular injection are more
slowly absorbed and reach lower plasma levels than when given intravenously or orally.
Drugs, especially sedatives and general anaesthetics, are a hazard and it is extremely
important to avoid hypoxia, hypotension or haemorrhage. Patients may also require special
management as a result of diabetes, hypertension, poor wound healing, or infections.
Aspirin and other non-steroidal anti-inflammatory agents should be avoided as they may
increase the risk of peptic ulceration.
Osteoporosis introduces the danger of fractures when handling the patient.
Topical corticosteroids for use in the mouth are unlikely to have any systemic effect but
predispose to oral candidosis. Susceptibility to infection is increased by systemic steroid use
and there is a predisposition to herpes virus infections (particularly herpes simplex).
Chickenpox is an especial hazard to those who are not immune and fulminant disease can
result. Passive immunization with varicella zoster immunoglobulin is indicated for nonimmune patients on systemic corticosteroids (or who have been on them within the previous
3 months) if exposed to chickenpox or zoster. Immunization should be given within 3 days
of exposure.
Candidosis and bacterial infections also tend to be more frequent and severe.
Wound healing is impaired and wound infections are more frequent. In addition to careful
aseptic surgery, prophylactic antimicrobials may be indicated.
Long-term and profound immunosuppression may lead to the appearance of hairy
leukoplakia, Kaposi's sarcoma, lymphomas,. lip cancer or oral keratosis or other oral
complications. Corticosteroids can also mask the presence of many serious diseases that may
influence dental care as well as causing suppression of the adrenocortical response to stress.
ADRENAL MEDULLA
The adrenal medulla secretes the catecholamines norepinephrine and epinephrine, which are
normally released in response to hypotension, hypoglycaemia and other stress, their release
being regulated by the central nervous system.
PHAEOCHROMOCYTOMA
General aspects
Phaeochromocytomas are rare, usually benign, tumours producing excessive
catecholamines. Phaeochromocytomas most commonly form in the adrenal medulla
(produce epinephrine) but others arise in other neuroectodermal tissues such as paraganglia
or the sympathetic chain and produce norepinephrine or dopamine. ^ Ten per cent of phaeochromocytomas are familial, 10% are bilateral, 10% are outside the adrenals and 10% are
malignant. Phaeochromocytomas may occasionally be associated with other tumours:
 neurofibromatosis
 endocrine tumours, particularly medullary carcinoma of the thyroid and
hyperparathyroidism
 von Hippel-Lindau disease (cerebelloretinal haemangioblastomatosis)
 gastric leiomyosarcoma
 pulmonary chondroma
 testicular tumours (Carney's triad).
Clinical features
Typical features of phaeochromocytoma are episodes of: anxiety, headache epigastric
discomfort, palpitations, tachycardia, dysrhythmias, sweating, pyrexia and flushing,
hypertension, glycosuria.
General management
Diagnosis of a phaeochromocytoma is supported by finding excessive urinary
catecholamines and metabolites such as vanillylmandelic acid (VMA) or metanephrines.
Plasma catecholamines (collected at rest in the supine position) may also be raised but are
less reliable than urinary assays.
The site of the tumour is localized by imaging techniques such as CT, MRI, venous
cathetcrization, arteriography, ultra-sonography and radionuclide scanning such as MIBG
(m- 131I -L-benzylguanidine).
The tumour is excised after the blood pressure has been controlled with an alpha-blocking
agent, such as phenoxybenzamine, and a beta blocker.
Dental aspects
Local anaesthesia is generally safe and epinephrine in modest amounts is unlikely to have
any significant adverse effect. Conscious sedation may be desirable to control anxiety and
endogenous epinephrine production. A general anaesthetic must only be given in hospital.
Neuroleptanalgesia using a combination such as droperidol, fentanyl and midazolam may be
the most satisfactory choice. Acute hypertension and dysrhythmias are likely to complicate
dental treatment. Elective treatment should, therefore, be deferred until after surgical
treatment of the phaeochromocytoma. If emergency care is required, the blood pressure
should first be controlled with alpha- (such as phenoxybenzamine or prazosin) and then
beta-adrenergic (such as propanolol) blockers. Patients who have had adrenal surgery may
suffer from hypoadrenocorticism, since the adrenal cortex is inevitably damaged at
operation. These patients therefore require steroid cover at operation.
Suggested management of patients with a history of systemic corticosteroid therapy