The cortex consists of 3 layers 1 st is zona granulosa - mineralocorticoids, for example aldosterone. The inner 2 layers are zona fasiculata and zona reticularis - glucocorticoids (e.g. cortisol) and androgens (e.g. dehydroepiandrosterone—DHEA). Excess or deficiency in serum level of any of these layers results in diseases.

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 and androgens— DHEA, and oestrogen (oestrone). 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).

Glucocorticoids: include cortisone and cortisol. Cortisol stimulates gluconeogenesis, lipolysis and protein breakdown (catabolic hormone) and antagonizes the action of insulin. That's why they are called diabetogenic agents. Cortisol is normally involved in retention of water and electrolytes from renal tubules to ECF. This explains why deficiency of this enzyme results in hypotension, while excess amounts results in hypertension.

Cortisol also suppresses the immune and inflammatory responses (anti- inflammatory), 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 leucotrienes). For this reason, this hormone is used as a drug in the treatment of inflammatory conditions such as allergy and rheumatic diseases in form of cortisone (Hydrocortisone™) which converts inside the body to cortisol—the active form.

In blood, 95 per cent of cortisol is bound to cortisol- binding protein (CBP). The other 5 per cent of hormone is unbound to protein (free). In CBG↑ due to genetic causes or pregnancy, or if the patient is on contraceptive pills so the total cortisol in serum is high due to high level of bound form only. In contrast, loss of CBG, like nephrotic syndrome, androgen therapy, leading to decrease in total level of hormones, due to a decrease in the bound form only, while the free form is normal in both cases (no symptoms). The hormone is inactivated by liver cells through conjugation with sulphate or glucoronate to sulphated or glucoronated hormone can be excreted in urine. cortisol is the only steroid involved in HPA axis.

Increased serum cortisol level is due to several causes, such as: ACTH↑ (common): (1) as part of a syndrome due to pituitary adenoma (Cushing's disease) (2) caused by non- pituitary carcinoma or (3) by ACTH therapy as a drug. Cortisol↑: (1) due to tumor in adrenal cortex, or (2) by cortisol therapy as a drug¹ in both there is ACTH↓.

1.high cortisol results in hyperglycaemia and glucosuria, because cortisol antagonises the activity of insulin and increases protein breakdown and lipolysis, therefore increases the activity of gluconeogenesis. [Diabetogenic] 2.Protein breakdown also causes negative nitrogen balance (increased loss of nitrogen in urine) loss of bone matrix is due to defect in collagen and this result in osteoporosis. Also, protein breakdown results in muscle wasting and thin skin with bruising. (striae atrophicae).

3.High cortisol acts like aldosterone, therefore it enhances sodium reabsorption in exchange to hydrogen and potassium ions in the renal tubules. This means it causes hypernatraemia (Na ⁺ ↑) and increased loss of potassium and hydrogen in urine, therefore results in hypokalaemia (K ⁺ ↓) and alkalosis (pH ＞ 7.45), respectively. 4.If the cause of Cushing's syndrome is increased ACTH, this hormone will stimulate androgen production as well as cortisol. This explains hirsutism and virilism in female subjects with menstrual disturbances.

Serum cortisol: we should measure this hormone in the morning and evening to see if there is any defect in circadian rhythm, which is a diagnostic feature of Cushing's syndrome. However, the presence of significantly high serum cortisol levels in the evening sample is also diagnostic. Urine cortisol: in 24hr urine samples is diagnostic when it is at very high levels. Tests for HPA axis: by checking both serum cortisol and serum ACTH, in order to differentiate the cause of disease (primary or secondary). If both are increased, this indicates secondary (explain how). If one of them (only cortisol) is high and ACTH is undetectable, this indicates primary endocrine disease. If both are low, it indicates drug therapy.