ENDOCRINOLOGY LECTURE 3

The adrenal glands Located superior to kidneys Retroperitoneal

Objectives At the end of this lecture we should know about adrenal Hormones the following: Where does it come from? What is its chemical nature? How is it made? What causes its release? How is it transported in the blood stream? What is and where is the receptor on the target cell? How does its binding interact with the metabolism of the target cell? What effects does it have? How can the system go wrong?

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 O HO CH(OH)-CH2-NH(CH3)

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 (cAMP) affect cell activity

Actions of adrenaline Metabolic Cardiovascular Respiratory 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

Disorders of adrenal medulla Can get tumours which over-secrete adrenaline episodically Pheomochromocytoma Symptoms of excessive sympathetic activity Sweating, pallor, chest pain , panic Lab high plasma metanephrin & urine VMA

Adrenal Cortex It is part of the HP- adrenal axis Producing mineralocorticoids (aldosterone) glucocorticoids (cortisol) and androgens (DHEA). Note: Steroid hormones, bile salts and vitamin D all are derived from cholesterol that's why the steroid-producing tissues are rich in cholesterol.

The pituitary 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 renin-angiotensin system which stimulates production of aldosterone (mineralocorticoid).

Steroidogenesis Synthesis of adrenal steroids Cholesterol ester Cholesterol (C27) Progesterone (C21) Mineralocorticoids (C21) Glucocorticoids (C21) Androgens (C19)

Classification of Adrenal hormones: 3 classes depending on their physiologic function: Glucocorticoids: cortisol which is the only one involved in adrenal gland secretion through HPA axis. Mineralocorticoids: the most important is aldosterone (Na-K-H metabolism) Androgens: such as dehydroepiandrosterone (DHEA)

Regulation of cortisol secretion

Feedback control Hypothalamus CRH Anterior Pituitary -ve ACTH Cortisol Adrenal Gland

Circadian rhythms Cortisol shows marked daily (circadian) rhythm Highest in morning (9 AM) Lowest in middle of night (11 PM)

Stimuli to CRH release Stress Shock Hypoglycaemia Infection Exercise Cold exposure Emotional stress Shock Haemorrhage Burns Trauma

Cortisol functions Metabolic function: stress hormones, cortisol antagonizes the activity of insulin by: inhibits cellular glucose uptake, increases protein breakdown & lipolysis, (i.e. increases the activity of gluconeogenesis. [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 enzyme results in hypotension, while excess amounts results in hypertension.

Immunosuppressant & anti-inflammatory Agent: because it decreases the No. of leucocytes and also their migration and inhibits phospholipase A2, which is important for production of inflammatory molecules (prostaglandins and leukotrienes). For this reason, cortisol 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 CBP, The other 5 per cent of hormone is free. High CBG due to genetic causes, pregnancy or contraceptive pills, the total [but not free] cortisol in serum is "high ".

The opposite is true in conditions lead to low CBG, like nephritic syndrome, androgen therapy or genetic defect, in both cases the patient is asymptomatic. The hormone is inactivated by liver cells and excreted in urine.

Q: Why serum cortisol levels increased more than normal? 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. Both ACTH & cortisol high. Excess Cortisol: due to tumours in adrenal cortex or cortisol therapy. High cortisol & low ACTH Q: In Cushing’s we use dexamethazone but not other steroids as dynemic Tests. Why?)

Q: What occur if serum cortisol levels increased more than normal? causes Cushing's syndrome

Q: If Cushing's syndrome occurs, what are the metabolic consequences of high cortisol levels? As it is insulin antagonist, cortisol results in hyperglycemia and glucosuria (diabetes mellitus or glucose intolerance).

Protein breakdown causes negative nitrogen balance (with muscle weakness), breakdown in collagen results in osteoporosis. Also, protein breakdown results in muscle wasting and thin skin with bruising. (striae atrophicae).

Higher cortisol acts like aldosterone, enhances Na reabsorption (hypernatraemia) in exchange to H & K ions in the renal tubules. This means increased loss in urine of K (hypokalaemia) and H (alkalosis = pH＞7.45). If the cause of Cushing's syndrome is excess ACTH, this hormone will stimulate both androgen & cortisol production. Androgen causes hirsutism, virilism and menstrual disturbances in female patients.

Differential Diagnosis Alcoholism Anorexia nervosa (high urine free cortisol) Familial cortisol resistance Familial partial lipodystrophy type I

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. 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 & ACTH, to know the cause of disease If both are increased, this secondary. If only cortisol is high while ACTH is very low, this primary disease. If both are low, it indicates drug therapy. (explain how?)

Screening Test Overnight dexamethasone suppression test (1 mg at 11 pm, cortisol measured at 8 am) – normal <2 micrograms/dL Or 24 hour urine free cortisol (>140 nmol/day)