The Adrenal Glands
And Stress
The adrenal glands are located just above each
kidney (hence the name; Fig. 49a)
and consist of two endocrine tissues of distinct developmental origins. The
inner core (the adrenal medulla) releases the catecholamine hormones adrenaline
(epinephrine) and noradrenaline (norepinephrine). It develops from
neuronal tissue and is functionally part of the sympathetic nervous system
(Chapter 7). The outer layers of the gland (the adrenal cortex)
originate from mesodermal tissue and secrete steroid hormones, primarily under
the control of the anterior pituitary gland (Chapter 44). Removal of the
adrenal glands in animals results in death within a few days, which is thought
to result from the loss of the ability to cope with stress.
The adrenal medulla
The chromaffin cells of the
adrenal medulla manufacture and secrete noradrenaline (20%) and adrenaline
(80%). These catecholamine hormones are derived from tyrosine by a series
of steps catalysed by specific enzymes (Fig. 49b). The production of the
rate-limiting enzyme, phenylethanolamine-N-methyl transferase, is
stimulated by cortisol, providing a direct link between the functioning
of the medulla and cortex. The secretion of catecholamines is stimulated by
sympathetic preganglionic neurones located in the spinal cord (Chapter 7), so
that the adrenal medulla functions in concert with the sympathetic nervous
system, of which noradrenaline is the main neurotransmitter. Catecholamine
release contributes to normal physiological functions, but is enhanced by
stress (see below). Adrenaline and noradrenaline act through guanosine
triphosphate-binding protein (G-protein)-coupled adrenoceptors. These
are classified as α1, α2 and β1–β3. The
hormones have the same effects in tissues as the stimulation of sympathetic
nerves, with important stress-related responses being vasoconstriction (α1),
increased cardiac output (β1) and increased glycolysis and lipolysis (β2,
β3). These actions support increased physical activity.
Noradrenaline has equal potency at all adrenoceptors, but adrenaline, at normal
plasma concentrations, will only activate β-receptors (NB: higher levels do
stimulate α-receptors). Phaeochromocytoma is a tumour of the adrenal
medulla that leads to the excess production of catecholamines, with high blood
pressure as the most immediately threatening symptom. It is treated by
α-adrenoceptor antagonists and/or surgery.
The adrenal cortex
The cortex is made up of three
zones of tissue: the outer zona glomerulosa, which releases aldosterone;
the zona fasciculata, which produces cortisol and several related
but less important hormones; and the inner zona reticularis, which
secretes the androgen dehydroepiandrosterone (DHEA). All of these
secretions are steroids (Fig. 49c). Aldosterone is referred to as a mineralocorticoid
as it controls the reabsorption of Na+ and K+ ions in the kidney (Chapter
35), whereas DHEA and its metabolite, androstenedione, provide an
important source of androgens for females, contributing to hair growth and
libido (Chapter 50). Cortisol and its analogues (such as cortisone) have
powerful effects on glucose metabolism and are collectively classified as glucocorticoids,
although they do have some mineralocorticoid actions. The release of cortisol and DHEA is stimulated by adrenocorticotrophic
hormone (ACTH) liberated from the pituitary gland (Chapter 44; Fig.
49d), whereas the secretion of aldosterone is stimulated by angiotensin II
(Chapter 35). The effects of cortisol are mediated by intracellular receptors
that translocate to the cell nucleus after binding the hormone. The
cortisol–receptor complex binds to glucocorticoid response elements on
deoxyribonucleic acid (DNA) to initiate gene transcription.
Cortisol is released during the
course of normal physiological activity. The pattern of secretion is pulsatile,
driven by activity in corticotrophin-releasing hormone (CRH) neurones of the
hypothalamus (Chapter 44). There is usually a surge in cortisol release in the
hour after waking. The primary stimulus for the increased release of
glucocorticoids is stress, which is the result of exposure to adverse
situations. The stress response is driven by the amygdala, part
of the forebrain that stimulates: (i) activity in hypothalamic CRH neurones;
(ii) activity in the sympathetic nervous
system; (iii) activity in the parasympathetic nerves that cause acid secretion
in the stomach (Chapter 38); and (iv) the feeling of fear (Fig. 49d). The
stress response evolved to cope with immediate threats, such as predators, to
which the appropriate physiological reaction is to prepare for physical activity.
The actions of the two parts of the adrenal gland are complementary in this
respect. Catecholamines are released from the medulla to produce a rapid
increase in cardiac output and the mobilization of metabolic fuels.
Corticosteroids produce a slower, more sustained response, increasing the
amount of glucose in the plasma (Chapter 43) by: (i) increasing glycolysis and gluconeogenesis
in the liver (Chapter 40); (ii) reducing glucose transport into storage
tissues; (iii) increasing protein catabolism with a consequent release of amino
acids from all tissues other than the liver; and (iv) increasing the
mobilization of lipids from adipose tissue. High levels of glucocorticoids also
suppress the activity of immune cells to produce an anti-inflammatory effect,
and can mimic the actions of aldosterone on the kidney to retain Na+
and lose K+ ions. The stress response is appropriate as long as the
stress is relieved promptly. Unfortunately, modern life places many of us in
positions in which stress is prolonged. This can lead to chronic hypertension,
gastric ulceration, immunosuppression and depression (Fig. 49d). Glucocorticoid
derivatives, such as dexamethasone, are widely used as anti-inflammatory
agents in conditions such as arthritis and asthma. Chronically high levels of
glucocorticoids eventually cause weakening of the skin, muscle wasting,
reduction in bone strength, increased rates of infection due to immunosuppression,
and can damage nerve cells in the hippocampus that are part of a
feedback circuit controlling responses to stress (Fig. 49d). Thus, the
long-term therapeutic use of steroids must be very carefully monitored,
especially in the young where normal growth may be affected. Diseases of the
adrenal cortex include Cushing’s syndrome, which results from the
excessive release of glucocorticoids and has a range of symptoms similar to
those described above, and Addison’s disease, which is the result of
adrenocortical hypoactivity and is characterized by symptoms of hypoglycaemia,
weight loss and skin pigmentation.
