Objectives:
The aim of this lecture is that, by its end, you should understandThe structure and function of the steroid hormone,
How its condition is assessed and
How adrenal cortex function is altered in common diseases.
The adrenal medulla
Nervous tissueCells are post-ganglionic nerve cells of the sympathetic branch of the autonomic nervous system
Innervated by pre-ganglionic nerves from the thoraco-lumbar region of the spinal cord
Hormones produced by neurosecretion
Hormone of the adrenal medulla
Cells secrete Adrenaline
Amino acid derivative
From tyrosine
Catecholamine
Synthesis of adrenaline
Tyrosine converted to dopa
Then to dopamine
Then to noradrenaline
Secreted by other post ganglionic sympathetic nerves
Then to adrenaline by methylation
Release of adrenaline
Stored in vesicles
Released by nervous stimulation of cells
Rising calcium concentration in cells stimulates exocytosis
Adrenoreceptors
Adrenaline does not cross cell membranes
Binds to adrenoreceptor on outside of cell
Second messengers affect cell activity
Actions of adrenaline
Metabolic
Mobilises fuel resources
Increased breakdown of glycogen and triacylglycerols
Reduced insulin secretion
Cardiovascular: Increase heart rate and force of contraction
Respiratory : Bronchodilation
Disorders of adrenal medulla
Hyposecretion: Of no great consequence. Sympathetic nerves can have much the same effect as adrenal medulla
Can get tumours which over-secrete adrenaline episodically e.g. Pheochromocytoma. Symptoms of excessive sympathetic activity are sweating, pallor, chest pain , panic
Adrenal cortex:-
The adrenal cortex is part of the hypothalamic-pituitary-adrenal adrenal axis [which consists of 3 layers called zona granulosa which produces mineralocorticoids, for example aldosterone. The inner 2 layers are zona fasiculata and zona reticularis which are responsible for production of two types of hormones, glucocorticoids (e.g. cortisol) and androgens (e.g. dehydroepiandrosteroneDHEA)].Biosynthesis of Steroid Hormones (Steroidogenesis):-
Steroid hormones, bile salts and vitamin D all are derived from cholesterol that's why the steroid-producing tissues are all rich in cholesterol.
Cholesterol is a 27C molecule; its derivative steroids contain either of 18, 19 or 21C molecules according to its type:
21C-progesterone, glucocorticoids and mineralocorticoids
19C-androgens
18C-oestrogens
The rate-limiting step is the first step which is the conversion of cholesterol to pregnenolone, the final products are cortisol, aldosterone, oestrogen (oestrone) and androgensDHEA.
The pituitary hormone ACTH is stimulator of the inner two layers but not on the outer layer; therefore it stimulates production of cortisol and androgen. The outer layer of this gland is controlled by another system in the body called renin-angiotensin system which stimulates production of aldosterone (mineralocorticoid derivative).
Classification of Adrenal hormones:
There are 3 classes depending on their physiologic function:Glucocorticoids: cortisol which among other steroids, it is the only one involved in adrenal gland secretion through HPA axis.
Mineralocorticoids: the most important hormone is aldosterone
Androgens: such as dehydroepiandrosterone (DHEA)
Cortisol functions:
Metabolic function: like other stress hormones, cortisol antagonizes the activity of insulin (inhibits cellular glucose uptake), and also increases protein breakdown and lipolysis, therefore increases the activity of gluconeogenesis. That's why called diabetogenic agents.Electrolyte control: Cortisol involved in retention of water and electrolytes from renal tubules to ECF (blood and interstitial compartment). This explains why deficiency of this hormone results in hypotension, while excess amounts results in hypertension.
Immunosuppressant & anti-inflammatory Agent: because it decreases the number of leucocytes and also their migration and inhibits phospholipase A2, which is important for production of inflammatory molecules (prostaglandins and leukotrienes). For this reason, this hormone is used as a drug in the treatment of inflammatory conditions such as allergy and rheumatic diseases and to suppress immunity in tissue transplantation and cancer patients.
Circulating cortisol level
In blood, 95 per cent of cortisol is bound to cortisol-binding protein (CBP), commonly globulin (CBG). The other 5 per cent of hormone is unbound to protein (free).
High CBG due to genetic causes, pregnancy or contraceptive pills, the total [but not free] cortisol in serum is "high ". In opposite, conditions lead to low CBG, like nephritic syndrome, androgen therapy or genetic defect, the total [but not free] cortisol in serum is "low", due to a decrease in the bound form only, in both cases the patient is asymptomatic).
The hormone is inactivated by liver cells through conjugation with sulphate or glucoronate to be water soluble (not toxic) and can be excreted in urine.
Q: Why serum cortisol levels increased more than normal?
Increased serum cortisol level is due to several causes, such as:Excess ACTH (common): is part of a syndrome due to pituitary adenoma (Cushing's disease). It is either caused by non-pituitary carcinoma or by ACTH therapy. In this case, both ACTH & cortisol levels are high.
Excess Cortisol: due to tumour in adrenal cortex, in this case there is low ACTH , again it is either of two; adrenal tumours or by cortisol therapy as a drug.
Q: What occur if serum cortisol levels increased more than normal?
This causes a pathological condition called Cushing's syndromeQ: If Cushing's syndrome occurs, what are the metabolic consequences of high cortisol levels?
As it is insulin antagonist, high cortisol results in hyperglycemia and glucosuria (diabetes mellitus or glucose intolerance).
Protein breakdown causes negative nitrogen balance (with muscle weakness), breakdown in collagen (i.e. loss of bone matrix) results in osteoporosis. Also, protein breakdown results in muscle wasting and thin skin with bruising. (striae atrophicae).
At Higher levels cortisol acts like aldosterone, it enhances sodium ion reabsorption (hypernatraemia) in exchange to hydrogen and potassium ions in the renal tubules. This means increased loss in urine of potassium (hypokalaemia) and hydrogen (alkalosis = pH＞7.45).
If the cause of Cushing's syndrome is excess ACTH, this hormone will stimulate both androgen & cortisol production. This causes hirsutism, virilism and menstrual disturbances in female patients.
Q: what Laboratory tests we should do to investigate a suspected case of Cushing's syndrome?
Serum cortisol: (both morning and evening levels) to see if there is any defect in circadian rhythm which lost in this case. However, the presence of significantly high serum cortisol levels in the evening sample is also diagnostic.
Urine free cortisol: in 24hr urine samples is diagnostic when it is at very high levels.
Tests for HPA axis: by checking both serum cortisol and ACTH, in order to know the cause of disease (primary or secondary). If both are increased, this indicates secondary. If only cortisol is high while ACTH is very low, this indicates primary disease. If both are low, it indicates drug therapy. (explain how)
Good Luck