1. Endocrinology Introduction Dynamic function tests
Hypothalamus and pituitary function tests
Adrenal function
Thyroid function tests
Other glands

2. Adrenal glands Cortisol Adrenal androgens Aldosterone
Congenital adrenal hyperplasia (CAH)
Hypofunction of the adrenal cortex
Hyperfunction of the adrenal cortex

3. Case 1
A 40 year old man was investigated for severe skeletal muscle pains. The following biochemical results in a serum sample were unexpected:
Sodium 130 mmol/L
Potassium 6.1 mmol/L
Chloride 90 mmol/L
Bicarbonate 17 mmol/L
Urea mmol/L
Creatinine 150 umol/L less than 150
Suggest a likely diagnosis?
Why is the urea raised?
Why is the bicarbonate low?
What other biochemical tests may be useful?
Explain the muscle pain?
Adrenocortical insufficiency: hyponatremia and hyperkalemia.
Pre-renal ureamia.
Bicarbonate low: acidosis, hypovolemia and reduced tissue perfusion.
Timed random cortisol. Short syncathen test.
The CK should be measured as muscle pain is present. Part of the hyperkalemia may be the potassium released from damaged muscles.

4. Adrenal glands
The hormones of adrenal glands are essential for survival.
The adrenal cortex is the source of two important hormones, aldosterone and cortisol.
The adrenal medulla is histologically distinct from the cortex and is part of the sympathetic nervous system. Medullary cells synthesize, store and secrete adrenaline, along with noradrenaline and dopamine.

5. Cortisol
Cortisol is produced in the adrenal cortex, the end product of a cascade of hormones that make up the hypothalamic-pituitary-adrenocortical axis.
Corticotrophin releasing hormone (CRH) is secreted by the hypothalamus under the influence of cerebral factors.
ACTH is secreted by the anterior pituitary under the control of CRH to stimulate the secretion of cortisol from the adrenal cortex.
Hypothalamic secretion of CRH and pituitary secretion of ACTH are modulated by cortisol in negative feedback loops.

7. Synthesis of cortisol
Adrenal cortex cells have many LDL receptors on their surface. This enables them to take up cholesterol rapidly, from which the adrenal steroidal hormones are synthesized.
The conversion of cholesterol to pregnenolone is the rate-limiting step in the biosynthesis of cortisol; this conversion is stimulated by ACTH.
Cortisol biosynthesis from pregnenolone involves the action of specific reductase/isomerase and three separate hydroxylase enzymes. Inherited defects of all these enzymes have been characterized.
Cortisol is an important hormone with effects on many tissues in the body.
It plays a major role in metabolism by promoting protein break down in muscle and connective tissues and the release of glycerol and free fatty acids from adipose tissue. Thus, cortisol provides the substrates necessary for gluconeogenesis, which it promote in the liver.
Cortisol is the most important glucocorticoids.

8. Biosynthesis of adrenal steroid hormones.
Cortisol and the androgens are synthesized in the adrenal cortex.
Aldosterone is also synthesized in the adrenal cortex.
Androstenedione can be converted to testosterone in peripheral tissues, but in adult males, adrenal androgens and the testosterone derived from them make only a minor contribution to total androgenic activity.

9. Plasma cortisol concentrations show a diurnal variation, being highest in the morning and lowest at night. Single serum measurements are of limited value in clinical practice.
Cortisol is secreted in response to stress, mediated through ACTH, and thus stress must be kept to a minimum if results are to be interpreted correctly. Investigations of adrenal hypo- or hyperfunction often involve measurement of cortisol after attempting to stimulate or suppress its secretion (DFTs).

10. Adrenal androgens
The adrenal cortex also produce compounds such as androgens-androstenedione, DHA (dehydroepiandrosterone) and DHA sulphate.
These compounds owe their androgenic activity to peripheral conversion to testosterone.
In females the adrenal cortex is an important source of androgens, but in adult male this source is insignificant compared with testosterone made by the testes.
These stimulate libido and the development of pubic and axillary hair in females.
Measurements of adrenal androgens are of value in the diagnosis and management of congenital adrenal hyperplasia and in the investigation of virilization in women.

11. Aldosterone
The most important mineralocorticoid is aldosterone.
This is secreted in response to angiotensin II, produced as a result of the activation of the renin-angiotensin system by a decrease in renal blood flow and other indicators of decreased extracellular fluid (ECF) volume.
Secretion of aldosterone is also directly stimulated by hyperkalaemia.
The main action of aldosterone is to stimulate the reabsorption of sodium and the excretion of potassium and hydrogen ions in the distal convoluted tubules of the kidneys; its effect on sodium results in its having a central role in the determination of the ECF volume.
ACTH does not have a major physiological role in aldosterone secretion although it has a role in its synthesis.

12. Congenital adrenal hyperplasia (CAH)
CAH is the result of an inherited enzyme defect in corticosteroid biosynthesis.
The adrenal can not secrete cortisol and electrolyte disturbances may involve severe hyponatremia and hyperkalemia if aldosterone biosynthesis is also affected.
If the condition is not diagnosed quickly the infant may die.
Because of the lack of cortisol, negative feedback to the pituitary is absent and ACTH secretion continues to derive steroid biosynthesis. Cortisol precursors are secreted in large amounts, their nature depends which enzyme is lacking.
The 21-hydroxylase is the deficient enzyme in 95% of cases of CAH. Here large amounts of 17-hydroxyprogesterone are secreted.
Elevated plasma concentrations are diagnostic as early as 2 days after birth. Increased stimulation of adrenal androgen production can cause virilization in baby girls, and precocious puberty in boys.
One variant of the condition, the late onset form, presents as menstrual irregularity and hirsutism in young women. This is presumably the result of a partial enzyme defect.
Precocious means prematurely developed

14. Hypofunction of the adrenal cortex
Adrenal insufficiency
Acute adrenal insufficiency is rare and potentially fatal.
It is relatively simple to treat once the diagnosis has been made, the patient can lead a normal life.
In areas where TB is endemic, adrenal gland destruction may be due to TB.
In developed countries autoimmune disease is now the main cause of primary adrenal failure. Both cortisol and aldosterone may be affected.
Secondary failure to produce cortisol is more common. Frequently, this is due to suppression of the hypothalamic-pituitary-adrenocortical axis from therapeutic administration of corticosteroids.

17. Biochemical features
In addition to the clinical observations, a number of biochemical results may point towards adrenocortical insufficiency. These are hyponatremia, hyperkalemia and elevated serum urea, and may be seen in many patients with Addison's Disease.
Amyloidosis is a rare and serious disease caused by accumulation of proteins in the form of abnormal, insoluble fibres, known as amyloid fibrils, within the extracellular space in the tissues of the body

18. In primary adrenal insufficiency, patients become hyponatremic for two reasons:
The lack of aldosterone leads to pathological sodium loss by the kidney that results in a contraction of the extracellular fluid volume, causing hypotension and pre-renal uraemia.
Patients may develop life threatening sodium depletion and potassium retention due to aldosterone deficiency. The hypovolemia and hypotension stimulate ADH secretion, thus causing water retention. The kidneys' ability to excrete a water load is impaired, thus leading to hyponatremia. Overall, however, the total body water is reduced and this is reflected by the increase in the serum urea.
Lack of negative feedback of cortisol on the anterior pituitary results in an excessive secretion of ACTH. The structure of this hormone contains part of the amino acid sequence of melanocyte-stimulating hormone. Where excessive ACTH secretion occurs, patients may show darkening of the skin and mucous membranes.

19. Diagnosis and treatment
If a patient is suspected to be suffering from adrenal insufficiency, it is essential to ensure that they have an adequate sodium intake whilst investigations proceed.
It is important to remember that patients with adrenal insufficiency are not able to retain sodium effectively, so sodium requirements may be higher than normal.
Random cortisol
The sample should always be timed.
A very low or a very high random cortisol result is most useful.
Synacthen tests
Formal diagnosis or exclusion of adrenal insufficiency requires short synacthen test (SST).
The basis of therapy is maintenance of sodium intake and appropriate hormone replacement.

20. Hyperfunction of the adrenal cortex
Hyperfunction of the adrenal cortex can be conveniently discussed in terms of the overproduction of the three main products:
Cortisol
Adrenal androgens
Aldosterone

21. Cortisol excess
Prolonged exposure of body tissues to cortisol and other glucocorticoids gives rise to the clinical features that collectively are known as Cushing’s syndrome.
It most often results from prolonged use of steroid medication (iatrogenic).
Much less frequently it is caused by tumors that secrete either cortisol or ACTH.
In any investigation of Cushing’s syndrome the clinician should ask two questions:
‘Does the patient actually have Cushing’s syndrome?’ the possibility that a patient may have Cushing’s syndrome frequently arises because they are obese or hypertensive, conditions frequently encountered in the population at large.
Once diagnosis is established, then a second question may be asked: ‘what is the cause of excess cortisol?’. Tests used in the differential diagnosis are different from those used to confirm the presence of cortisol overproduction.

22. Gynecomastia is a common disorder of the endocrine system in which there is a non-cancerous increase in the size of male breast tissue

23. Confirming the diagnosis
Iatrogenic Cushing's syndrome is usually obvious-the patient is on steroid medications. The steroid may have been taken orally, inhaled or applied topically.
Cortisol, secreted in excess by the adrenal cortex, will rapidly exceed the available capacity of the plasma binding protein, cortisol binding globulin. Unbound cortisol is filtered readily into the urine. 'Urinary free cortisol' in a 24 h collection, or assessed as a cortisol:creatinine ratio in an early morning urine sample, is the initial screening test in a patient suspected of adrenocortical hyperfunction. The latter measurement can be made on a small aliquot of urine.
Repeatedly high early morning urine cortisol:creatinine ratios are evidence enough to proceed with further investigations of the patient. If the test is negative on three occasions, Cushing's syndrome may be excluded from the differential diagnosis.

24. Confirming the diagnosis
Cortisol concentrations measured at 08:00 and 22:00 normally show a circadian rhythm with the evening sample having a lower value than that in the morning. This difference is usually not apparent in the patient with Cushing's syndrome. It is essential that the patients are not stressed when such measurements are made.

25. Failure of 1 mg of dexamethasone taken at 23:00 to suppress the serum cortisol level at 08:00 the following morning, or failure to suppress urinary cortisol secretion overnight (as measured by an early morning urine cortisol:creatinine ratio) is another pointer towards the presence of Cushing's syndrome.
Failure of the serum cortiosol rise after insulin-induced hypoglycaemia is also a characteristic feature of Cushing's syndrome.
Since patients with cortisol overproduction will be insulin-resistant, adequate hypoglycaemia may not be achieved with low doses of insulin. A higher dose may have to be used.

26. Determining the cause
The possible causes of Cushing's syndrome include:
Pituitary adenoma.
Ectopic ACTH.
Adrenal adenoma.
Adrenal carcinoma.
Classically, ACTH is not detectable in the plasma of patients with adrenal tumors.
In patients with pituitary-dependent Cushing's syndrome the plasma ACTH may be within the reference range or modestly elevated.
The plasma ACTH level is often very high in patients with ectopic ACTH production.
In patients with pituitary-dependent Cushing's disease the serum or urinary cortisol will be partially suppressed after two days of dexamethasone, 2.0 mg q.i.d. Failure to suppress suggests either ectopic ACTH production or the secretion of cortisol by an adrenal tumor.

27. Carcinoma is defined as an abnormal proliferation of cells which begin in the epithelial tissues, lining various internal structures and cavities in the body. This pathological condition develops when there is a disruption to the cell growth and balance inside the body. Carcinomas are rare before the age of adolescence and genetic factors, radiation, UV rays exposure, chemicals like Benzene, smoking, tobacco, viruses, etc. are known to be some common causes for various cancers developing in the body.
Adenoma is defined as non-cancerous tumors, growing on various glands. These can grow on any gland in the body including ones in the colon, breasts, lungs, and throat. Some adenomas can rarely progress into cancers which will then be called as Adenocarcinomas.

28. Androgen excess
Adrenocortical tumors, particularly adrenal carcinomas, may produce excess androgens causing hirsutism and/or virilisation in females.
Patients with congenital adrenal hyperplasia may also present with signs or increased androgen production.

29. Aldosterone excess
Primary hyperaldosteronism (Conn' s syndrome) is rare. In most cases, the disease is due to a single adrenocortical adenoma.
Patients may present with polydipsia and polyuria, symptoms of neuromuscular abnormalities such as weakness, paresthesiae and tetany, and hypertension.
All symptoms other than hypertension are attributable to potassium depletion.

30. Aldosterone excess
The diagnosis or hyperaldosteronism may be made in the hypokalaemia patient if the serum aldosterone level exceeds the upper limit of normal or if the level is persistently inappropriate to the serum potassium.
In primary hyperaldosteronism, where the excess aldosterone arises from an adrenal adenoma, the levels or plasma renin will be low.
Secondary hyperaldosteronism is common and is associated with renal, heart or liver disease.

31. Phaeochromocytoma A tumor of the adrenal medulla.
It is considered as a secondary cause of hypertension due to the increased production of catecholamines (adrenaline and noradrenaline), which can cause vasoconstriction.
VMA: a urinary catecholamine metabolite, which can reflect the body production of epinephrine and norepinephrine.
The measurement of urinary VMA can be used diagnose phaeochromocytoma.

32. The End