Cortisol

Cortisol is produced mainly in the zona fasciculata and in small quanities in the zona reticularis of the adrenal cortex, the end product of a cascade of hormones that make up the hypothalamic–pituitary–adrenocortical axis (Fig 47.2). Corticotrophin releasing hormone (CRH) is secreted by the hypothalamus under the influence of cerebral factors. Adrenocorticotrophic hormone (corticotrophin, or simply ACTH) is secreted by the anterior pituitary under the control of CRH to maintain the fascicular and reticular zones of the adrenal cortex and to stimulate the secretion of cortisol. Hypothalamic secretion of CRH and pituitary secretion of ACTH are modulated by cortisol in negative feedback loops.

Adrenal cortex cells have many low-density lipoprotein receptors on their surface. This enables them to take up cholesterol rapidly, from which the adrenal steroid hormones are synthesized (Fig 47.3).

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 a specific reductase/isomerase and three separate hydroxylase enzymes. Inherited defects of all of 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 breakdown in muscle and connective tissue and the release of glycerol and free fatty acids from adipose tissue. Thus, cortisol provides the substrates necessary for gluconeogenesis, which it promotes in the liver.

Natural or synthetic steroids with cortisol-like effects are called glucocorticoids. Such compounds can act as anti-inflammatory or immunosuppressive agents. Synthetic glucocorticoids have found therapeutic applications in a wide range of clinical situations, e.g. asthma and connective tissue disorders.

Adrenal androgens

The adrenal androgens – androstenedione, DHA (dehydroepiandrosterone) and DHA sulphate – are produced predominantly by the zona reticularis. These compounds probably owe their androgenic activity to peripheral conversion to testosterone. In females the adrenal cortex is an important source of androgens, but in adult males this source is insignificant compared with testosterone made by the testes.

Assessing the function of the hypothalamic–pituitary–adrenocortical axis

Cortisol secretion fluctuates widely throughout the day, and single serum measurements are of limited value in clinical practice. There is a marked diurnal rhythm. Dynamic tests of cortisol production involving stimulation of the adrenal cortex by synthetic ACTH, or stimulation or suppression of the whole HPA axis, form an important part of investigations of adrenocortical hyper- or hypofunction and are discussed on the following pages.

Aldosterone

Aldosterone is produced exclusively by the zona glomerulosa and is primarily controlled by the renin–angiotensin system (p. 15). The metabolic pathway for the synthesis of aldosterone utilizes many of the same enzymes involved in cortisol biosynthesis. The zona glomerulosa lacks the 17-hydroxylase enzyme and has the additional 18-hydroxylase and 18-hydroxysteroid dehydrogenase enzymes necessary for aldosterone synthesis.

Other factors, including ACTH, are also involved in the regulation of aldosterone synthesis. Aldosterone is responsible for promoting sodium reabsorption and potassium excretion in the kidney.

A natural or synthetic steroid with aldosterone-like activity is called a mineralocorticoid. All of the 21-hydroxylated steroids have mineralocorticoid effects to varying degrees.

Congenital adrenal hyperplasia (CAH)

CAH is the result of an inherited enzyme defect in corticosteroid biosynthesis. The adrenals cannot secrete cortisol and electrolyte disturbances may involve severe hyponatraemia and hyperkalaemia if aldosterone biosynthesis is also affected. If the condition is not diagnosed quickly the afflicted infant may die.

Because of the lack of cortisol, negative feedback to the pituitary is absent and ACTH secretion continues to drive steroid biosynthesis (Fig 47.3). Cortisol precursors are secreted in large amounts, their nature depending on 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.

Relationship of adrenal cortex and medulla

For a multicellular organism to survive it is essential that the extracellular fluid bathing the tissues is continually circulating so that nutrients may be supplied to the cells and waste products removed from their environment. The adrenal medulla and the two separate hormone systems of the adrenal cortex act in harmony to ensure that this occurs. Adrenaline (epinephrine) and noradrenaline (norepinephrine) through their inotropic effects on the heart and their vasoconstrictor actions on the arterioles maintain the blood pressure and facilitate tissue perfusion. Cortisol facilitates the synthesis of adrenaline and potentiates its vasopressor effects. Cortisol is also required for the efficient excretion of water in the kidney. Aldosterone, through its action in promoting sodium reabsorption, maintains the extracellular volume.