Function of the Adrenal Glands

The two parts of the adrenal glands have quite distinct and separate functions and release different hormones. The outer cortex makes up 85% of the gland and the inner central medulla 15%. Each of these are discussed separately below.

Adrenals - The Cortex

The cortex is a region rich in enzymatic activity, where cholesterol is converted into the main steroid hormones. These are cortisol, aldosterone and the sex steroids (principally the androgens androstenedione and dehydroepiandrosterone sulphate, DHEAS). Each layer produces one of these, although all the layers produce small amounts of the remaining hormones.

The principal sites of production of each hormone are:

Aldosterone

Fig.1: Renin-angiotensin-aldosterone systemThis is a 'mineralocorticoid' (a cortical hormone that regulates salt balance) which acts principally to maintain blood pressure. Its specific actions are:

1. Retention of sodium and water by the kidney, resulting in a rise in blood pressure.
2. Excretion of potassium and hydrogen ions by the kidney.

Aldosterone is produced in the last step of a pathway initiated by a fall in blood pressure. This system is known as the renin-angiotensin-aldosterone system. Low blood pressure causes a release of the enzyme renin from the juxtaglomerular apparatus of the kidney. Renin splits angiotensinogen, a large protein circulating in the blood, into pieces, one of which is angiotensin I.

Angiotensin converting enzyme (ACE) converts angiotensin I to angiotensin II in the lung. Angiotensin II (a far more active hormone than angiotensin I) causes the muscular walls of small arteries (arterioles) to constrict, increasing blood pressure. Angiotensin II also triggers the release of the hormone aldosterone from the adrenal glands and antidiuretic hormone from the pituitary gland. In the adrenal cortex, aldosterone is released from the zona glomerulosa, which also acts to increase blood pressure by causing salt retention in the kidney (Fig. 1).

Aldosterone release is also stimulated by high potassium levels and to a more limited extent, by ACTH from the pituitary.

Cortisol

Cortisol is a 'glucocorticoid' (a cortical hormone that increases blood glucose levels). It acts on a wide range of tissues and organs eliciting a wide range of effects. The main ones are:

• Increasing glucose levels in the blood when fasting by:
            Increasing production of glucose in the liver (gluconeogenesis)
            Decreasing utilisation of glucose by the tissues
• Break down of tissues, such as muscle, skin and bone, to release amino acids, some of which can also be used to produce more glucose
• Break down of fat into fatty acids and glycerol
• Modulation of the immune system by:
           Cortisol is released in response to infection or injury   
           Excess cortisol causes decreased white blood cell production and activity resulting in an impaired ability to fight infection and heal wounds
• It acts like aldosterone to raise blood pressure, but the effect is limited by the inactivation of cortisol to cortisone by a specific enzyme

It also has several poorly understood effects such as increased appetite, increased acid production by the stomach and effects in the mental state (e.g. euphoria or mania).

Fig.2: Control of cortisol synthesisCortisol production and release is controlled by the hypothalamus and pituitary, forming the hypothalamopituitary-adrenal axis (Fig. 2). Cortisol is released in response to stress, which can be emotional (e.g. anxiety) or physiological (e.g. fluid deprivation or injury). Stressors cause a release of Corticotrophin Releasing Hormone (CRH). This travels in the portal system of the hypothalamus to the anterior pituitary (the adenohypophysis).

There, it stimulates the cleavage of Pro-opiomelanocortin (POMC) into several molecules including melanocyte stimulating hormone (MSH) and Adrenocorticotrophic Hormone (ACTH). ACTH travels in the bloodstream to the adrenal cortex stimulating the production and release of cortisol. Cortisol then travels to the tissues where it exerts its effects.

Cortisol inhibits the release of CRH and ACTH from the hypothalamus and pituitary gland respectively, preventing further cortisol release. Cortisol is inactivated in the liver to inactive cortisone.

A daily pattern (circadian rhythm) is also seen, with cortisol being at its lowest concentration at midnight, rising to a peak between 6am and 8am, falling throughout the rest of the day.

Sex steroids

Sex steroids are hormones produced mainly by the testes in men and the ovaries in women. They are responsible for producing the male and female primary sexual characteristics (the genitalia) and secondary sexual characteristics (body hair distribution, voice pitch, breast development etc.). The adrenals also play a small role in producing mainly virilising hormones (hormones which induce male developmental characteristics) such as Dehydroepiandrosterone Sulphate (DHEAS) and androstenedione.

Their function is not entirely clear in the healthy state. These small amounts of sex steroid are of relatively little significance except in two situations.

Firstly, in postmenopausal women when the ovaries fail and the adrenals become the main source of sex steroids. This fact can be exploited in the hormonal treatment of postmenopausal women who develop breast cancer. Inhibition of the aromatase enzymes that convert these sex steroids into oestrogen can be achieved by certain drugs.

Secondly, adrenal sex steroids become relevant when there are disorders of the synthesis of enzymes (usually 21 and 11 hydroxylase) responsible for converting sex steroids in the adrenal gland. This leads to increased levels of certain active metabolites in parts of the steroid pathway that can produce clinical problems.

Adrenals - The Medulla

Catecholamines

The chromaffin cells of the adrenal medulla secrete small, non-steroid hormones called catecholamines. These are adrenaline and noradrenaline, secreted in a 4:1 ratio respectively. Other hormones are produced (e.g. leu-enkephalin and met-enkephalin) but their function is not clear.

Adrenaline and noradrenaline, when released into the bloodstream, act on a wide range of tissues such as the heart, lungs, gut and eyes to produce the following effects:

The release of noradrenaline and adrenaline from the chromaffin cells is under the control of the sympathetic nervous system. This part of the nervous system is not under voluntary control and is activated in situations of sudden stress, such as conflict or fear (the so-called 'fight or flight' response).

Adrenaline and noradrenaline are rapidly broken down to inactive molecules.

Adrenomedullin

In 1993, scientists isolated a peptide in a phaeochromocytoma, a tumour of the adrenal medulla, and named it 'adrenomedullin' (ADM or AM). In humans AM is encoded by the ADM gene on chromosome 11.

Research has shown that this peptide is expressed in a multitude of tissues in the body and is also found in the circulation. Initially it was identified as a vasodilator because of its presence in high concentrations in blood. Some argued that it was the most potent endogenous vasodilatory peptide found in the body.

Other physiological effects include stimulation of the growth of new blood vessels (angiogenesis), and increasing the tolerance of cells to hypoxia. It seems to have a positive effect therefore in hypertension, chronic obstructive pulmonary disease (COPD) and myocardial infarction (heart attack) when hypoxia of the tissues can occur. Conversely, it can have an adverse effect if it encourages the growth of new blood supply for cancer cells.

It is thought that adrenomedullin is also a regulatory peptide that affects the secretory activity of the adrenal cortex. Adrenomedullin is also thought to inhibit ACTH production from the pituitary.