Last updated on April 16, 2020 at 20:36
The adrenal glands are paired endocrine glands consisting of a cortex and a medulla. The cortex is comprised of three layers, each of which produce a type of hormone:
- Zona glomerulosa – produces mineralocorticoids, especially aldosterone
- Zona fasciculata – produces glucocorticoids, especially cortisol
- Zona reticularis – produces sex steroids, especially androgens
The zona fasciculata accounts for 75% of the cortex, making it much thicker than the other two layers. Mineralocorticoids can bind to glucocorticoid receptors and vice versa (spill-over), so their function may overlap slightly, especially in pathological conditions.
The adrenal medulla is comprised of chromaffin cells which synthesize and secrete catecholamines.
Adrenocortical hyperfunction can cause three different syndromes, depending on which layer of the cortex is hyperfunctioning:
- Cushing syndrome – if there is an excess of cortisol
- Conn syndrome – if there is an excess of aldosterone due to primary hyperaldosteronism
- Congenital adrenal hyperplasia – if there is an excess of androgens
Cushing syndrome is an endocrine disorder that is caused by excessive amounts of glucocorticoids, especially cortisol. We distinguish four different types:
|Pituitary Cushing syndrome (= Cushing disease)||ACTH-producing pituitary microadenoma|
|Adrenal Cushing syndrome||Cortisol-producing adrenocortical adenoma or carcinoma or adrenocortical hyperplasia|
|Ectopic Cushing syndrome||Paraneoplastic syndrome|
|Iatrogenic Cushing syndrome||Prolonged glucocorticoid therapy|
The most common cause of Cushing syndrome is the iatrogenic type, as glucocorticoid therapy is used for many conditions. Of the endogenous types pituitary Cushing syndrome, also called Cushing disease, is the most common.
Cushing disease is caused by ACTH-producing microadenomas in the anterior lobe of the pituitary. The large amount of ACTH stimulates bilateral hyperplasia of the adrenal cortex, with resulting increased production of glucocorticoids.
Adrenal Cushing syndrome is most commonly caused by adrenocortical adenoma or more rarely adrenocortical carcinoma. Only a small percentage of adrenal tumors are hormone-secreting, so adrenal Cushing syndrome is the rarest of the four types. The ACTH level is low due to negative feedback.
Ectopic Cushing syndrome occurs as a paraneoplastic syndrome where a tumor produces ACTH. This most commonly occurs in cases of small cell lung carcinoma. Like in Cushing disease the adrenal cortex is bilaterally hyperplastic.
A common diagnostic tool in suspected endogenous Cushing syndrome is giving the patient a pharmacologic glucocorticoid (dexamethasone) and later measuring the cortisol level. In normal cases the glucocorticoid will suppress ACTH secretion from the pituitary, which again decrease cortisol production from the adrenal cortex. In any type of endogenous Cushing syndrome, the cortisol level will not be decreased following administration of glucocorticoids.
The morphological changes to the Adrenal gland depend on the cause of the hypercortisolism, they include: (1) Cortical atrophy, (2) Diffuse Hyperplasia, (3) macro/micronodular hyperplasia, (4) adenoma or carcinoma.
Cortical Atrophy happens in patients that have the syndrome due to exogenous glucocorticoid administration. Diffuse hyperplasia is found in patients where there is an excess of ACTH produced.
Common symptoms of Cushing syndrome include:
- Purple stretch marks, especially on the abdomen
- Hyperpigmentation – only in those types where ACTH is elevated. Due to the effect of melanocyte stimulating hormone (MSH)
- Peripheral muscle atrophy
- Central obesity, thin extremities
- Buffalo hump
- Moon face
- Secondary hypertension
- Secondary diabetes
Conn syndrome is the same as primary hyperaldosteronism. It occurs due to increased production of aldosterone in the adrenal cortex. The most important causes are:
- Idiopathic bilateral hyperplasia
- Aldosterone-producing adrenal adenoma
- Aldosterone-producing adrenal carcinoma
Idiopathic bilateral hyperplasia is the most common cause of Conn syndrome. The symptoms in these cases are usually mild.
Aldosterone-producing adrenal adenomas are less common than the above, but the symptoms produced are more severe. Like for adrenal Cushing syndrome it’s important to keep in mind that only a small percentage of adrenal adenomas secrete hormones, including aldosterone.
Common symptoms of Conn syndrome include:
- Secondary hypertension – less severe than in Cushing syndrome
- Muscle weakness
Even though aldosterone stimulates fluid retention, no significant oedema develops in Conn syndrome. This is because of the aldosterone escape mechanism, which prevents excess amounts of aldosterone from increasing the vascular volume too much.
Congenital adrenal hyperplasia
Congenital adrenal hyperplasia (CAH), also called adrenogenital syndrome, is a group of autosomal recessive conditions characterised by defects in enzymes that are responsible for cortisol, aldosterone and androgen synthesis in the adrenal cortex. The most common subtype is the enzyme deficiency of 21-hydroxylase.
Deficiency of the 21-hydroxylase enzyme causes cortisol and aldosterone levels to decrease while the level of androgens increases. Due to decreased negative feedback, the ACTH level increases, causing adrenocortical hyperplasia. The increased levels of androgens cause:
- In females
- Clitoris hypertrophy
- Early puberty
- Virilization – the appearance of male characteristics
- Deep voice
- Facial hair
- In males
- Early puberty
Adrenal insufficiency refers to a decreased production of all adrenocortical hormones. It can be primary, in cases where the adrenal cortex itself is damaged, or secondary, when the insufficiency is due to decreased production of ACTH in the pituitary. Secondary adrenal insufficiency is more common than the primary form.
Primary adrenal insufficiency is also known as Addison disease. It can be caused by:
- Autoimmune adrenalitis – 80% of cases
- fungal infection
- Congenital adrenal hyperplasia
- Waterhouse-Friderichsen syndrome
Autoimmune adrenalitis is the most common cause of Addison disease and involves an autoimmune destruction of the steroid-producing cells of the adrenal cortex. Autoantibodies against these cells are often present. It often occurs as part of both types of a genetic syndrome called autoimmune polyendocrine syndromes.
Waterhouse-Friderichsen syndrome is a life-threatening condition characterised by acute adrenal insufficiency due to haemorrhagic necrosis of the adrenal glands. Patients develop hypotension, circulatory shock and often death due to the lack of fluid regulation due to aldosterone deficiency. Waterhouse-Friderichsen syndrome most frequently develops during meningococcal (Neisseria meningitidis) sepsis.
Tumors of the adrenal gland
Adrenocortical adenomas are small (1 – 5 cm), yellow, soft benign tumors. Only a small percentage of them are functional (hormone-secreting). Non-functional adrenocortical adenomas are usually asymptomatic and discovered incidentally, giving them the nickname adrenal incidentaloma.
Adrenocortical carcinomas are larger (up to 20 cm) and aggressive malignant tumors. They usually contain necrosis or haemorrhage. They tend to invade the adrenal veins and inferior vena cava.
Pheochromocytoma is the most important tumor of the adrenal medulla. They originate from the catecholamine-producing chromaffin cells of the adrenal medulla and therefore can produce catecholamines in most cases. They can be benign or malignant. They’re most commonly small, circumscribed lesions, but they can be large, haemorrhagic masses as well. Pheochromocytomas are considered malignant only if they’re locally aggressive or metastatic.
Pheochromocytoma is a very convenient type of tumor because it follows something called the “10 percent rule”. Here’s how it works:
- 10% of cases of pheochromocytoma occur bilaterally (90% occur unilaterally)
- 10% of cases are familiar (90% are sporadic) – as part of MEN type II or other syndromes
- 10% of cases are malignant (90% are benign)
- 10% of cases are extra-adrenal, often in sympathetic ganglia (90% are in the adrenal medulla)
- 10% of cases occur in children (90% occur in adults)
Pheochromocytomas usually only secrete catecholamines in episodes and not constantly. This causes paroxysmal hypertensive crises, with systolic pressures reaching even 300 mmHg. These episodes are characterised by throbbing headache, sweating, palpitations and anxiety. They may also cause complications such as apoplexy, rupture of aneurysms, myocardial infarct and aortic dissection.
Diagnosis of pheochromocytoma is based on the presence of high levels of catecholamines and catecholamine breakdown products like VMA and HVA in a 24-hour urine sample.
Peripheral neuroblastic tumors like neuroblastoma, ganglioneuroblastoma and ganglioneuroma are tumors that develop from neural crest cells that would develop into the sympathetic nervous system. These tumors are most frequently found in infants and young children. These tumors can occur anywhere in the sympathetic nervous system, but the majority arises from the adrenal medulla.
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