Endocrinology 6
THE ADRENAL GLAND
H Christian
Development & Gross Anatomy
The adrenal gland comprises an inner medulla that secretes the catecholamines noradrenaline and
adrenaline and an outer cortex that secretes steroid hormones. The adrenal glands are located just
medial to the upper pole of each kidney. The adrenal cortex and the adrenal medulla develop from
different origins. The medulla develops from neural crest tissue and the cortex develops from
mesoderm close to the mesonephros. The adrenal gland is identifiable as a separate organ at 2
months gestation and is composed of a fetal zone and a definitive zone. The 'fetal zone' of the
adrenal cortex is very prominent in the fetus but it regresses after birth. The fetal zone produces
androgens which the placenta aromatizes to oestrogens (see reproduction lectures Trinity term). The
definitive zone is similar to the adult adrenal cortex.
Structure:
The adrenal medulla is made up of groups of chromaffin cells packed with
catecholamine granules which store large amounts of adrenaline and noradrenaline. The adrenal
cortex is made up of sheets of cells surrounded by capillaries and arranged in three zones: the outer
zona glomerulosa which makes aldosterone; middle zona fasciculata which makes cortisol and
inner zona reticularis which makes small amounts of androgens.
Blood supply to the adrenal
The adrenal gland is richly vascularised and receives its main arterial supply from branches of the
Inferior phrenic artery, the renal arteries and the aorta. These small arteries form an arterial plexus
beneath the capsule surrounding the adrenal and then enter a sinusoidal system that penetrates the
cortex and the medulla draining into a single central adrenal vein in each gland. The veins drain to
the inferior vena cava (R) and renal vein (L). The blood supply is not reduced in stress.
Innervation: principally to the medulla. Innervated by thoracic preganglionic sympathetic nerves
which release ACh, acts at nicotinic receptors.
THE ADRENAL MEDULLA - responses to acute stress
Synthesis of adrenaline: in the cytoplasm of chromaffin cells tyrosine is converted to DOPA by
tyrosine hydroxylase; DOPA to dopamine by DOPA decarboxylase; dopamine is then pumped into
granules and is converted to noradrenaline by dopamine  hydroxylase; noradrenaline is then stored
or pumped out of the granule for conversion to adrenaline (80% of total) by phenyl-N-methyl
transferase (PNMT) in the cytoplasm. Adrenal is then pumped into granules for storage and release.
Actions: Preparation for emergency physical activity. The adrenal medulla contributes 10% of
the total sympathetic nervous system response to stress so thus it is not vital.
What is stress? a change that disturbs or threatens to disturb homeostasis.
Receptors: Adrenaline and noradrenaline act at adrenergic receptors.
ß receptors (cAMP
coupled); ß1 (heart, fat); ß2 bronchi, blood vessels (vasodilator skeletal muscle).  receptors
(PLC coupled): 1, all blood vessels (vasoconstrictor), gut sphincters, 2 presynaptic terminals.
Relative potency of adrenaline and noradrenaline at receptors: ß1 A=NA; ß2 A>>NA;  NA>A.
See Pharmacology lectures for actions of selective drugs on the different adrenergic receptors.
Cardiovascular system, adrenaline
 increases heart rate and force of contraction via ß 1.
 stimulates vasodilation in skeletal muscle (ß 2), vasoconstriction in skin (1).
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 noradrenaline increases mean arterial pressure
Respiratory system, adrenaline acts to
 increase dilation of the bronchi and bronchioles via ß2 receptors.
 increase respiratory rate by effects in the CNS.
GI tract, adrenaline acts to cause:
 inhibition of peristalsis, relaxation of gut smooth muscle.
 contraction of gut sphincters (1).
 Vasoconstriction (1) of gut vasculature.
Metabolic substrate metabolism, adrenaline increases metabolite availability. In
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 liver: promotes glycogenolysis, gluconeogenesis, release of glucose into the circulation.
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 skeletal muscle: promotes glycogenolysis and lactic acid formation.
 fat: stimulates lipolysis to release free fatty acids and glycerol.
Central nervous system:
 causes arousal via actions in the brainstem, produces coarse tremor.
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Stimuli
Any stressfull stimuli which activate the sympathetic nervous system – e.g. low blood pressure,
haemorrhage, pain, low blood glucose, exercise, surgery, asphyxia.
Pathology
If the adrenal medulla is removed the adrenal medulla stress response is compensated for by the
remainder of the sympathetic system. Tumours of the adrenal medulla (phaeochromocytoma)
constantly secrete catecholamines causing hypertension, tremor, anxiety, forceful heartbeat.
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ADRENAL CORTEX- the maintenance of essential processes in chronic stress
General principles
The adrenal cortex produces predominantly glucocorticoid (cortisol) and mineralocorticoid
(aldosterone) hormones, but also small amounts of androgens from cholesterol.
Synthesis of adrenal steroid hormones
 Cholesterol is stored in lipid droplets as cholesterol ester in adrenal cortex cells and is mobilised
by ACTH stimulation.
 The rate-limiting step is the cleavage of the side chain of cholesterol by cytochrome P450 side
chain cleavage enzyme to yield pregnenolone.
 Enzymes which convert pregnenolone to glucocorticoids and mineralocorticoids via
intermediates are located in the mitochondria and smooth endoplasmic reticulum. Therefore
these organelles are prominent in adrenal cortex cells.
 The zona glomerulosa produces aldosterone, the zona fasciculata produces cortisol and the
zona reticularis produces small amounts of androgens.
Plasma transport of adrenal steroid hormones
Cortisol: binds to cortisol-binding globulin in plasma with high affinity and to albumin with low
affinity (albumin binds all steroids). Aldosterone: No high affinity binding protein is present in
plasma so binds weakly to albumin and has a shorter half-life than cortisol as a result.
Metabolism
The kidney filters free steroid hormone but reabsorbs ~90%. The liver converts steroid hormones to
hydrophilic metabolites by hydroxylation and conjugation reactions (liver damage e.g. cirrhosis in
alcoholics causes cortisol build up).
CORTISOL
Receptors: glucocorticoid receptors (GR) are present in almost all cells. GR are located in the
cytoplasm of cells and migrate to the nucleus to regulate gene transcription when cortisol binds.
Metabolism: cortisol is converted in the liver to the relatively inactive metabolite, cortisone, by 11 ß -
hydroxysteroid dehydrogenase.
Control of glucocorticoid output
The hypothalamus releases corticotrophin releasing factor (CRF) in response to stress (inhibited by
cortisol negative feedback). CRF acts on anterior pituitary corticotrophs to stimulate ACTH
production and release (ACTH is cleaved from the prohormone POMC – pro-opio-melanocortin).
ACTH (peptide hormone – see Pituitary lecture) stimulates the zona fasciculata cells via cyclic AMP
to stimulate cortisol production.
Actions: Provides protection of the body in prolonged stress – primarily to preserve glucose for the
brain. Exerts widespread actions on many tissues.
Metabolic substrate metabolism cortisol stimulates metabolism of:
 carbohydrates: stimulates glucose production. Opposes insulin actions.
 lipids: stimulates lipolysis and ketogenesis (results in redistribution of fat to trunk if fatty acids
are in excess).
 proteins: stimulates gluconeogenesis.
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Cardiovascular effects:
 maintains the circulation via increased myocardial contraction; increases vascular tone.
 maintains plasma volume by preventing increased vascular permeability.
Skeletal muscle: maintains ability to give sustained contractile responses.
Ion control: promotes Na+ retention and K+ excretion (actions at MR- see aldosterone, when
cortisol is high).
In the CNS: varied effects on mood and behaviour.
Haemopoiesis: increases red blood cell production so enhances oxygen carrying capacity of blood.
Inflammatory response, immune system: immunosuppressive actions.
 inhibits leukocyte translocation from blood to sites of tissue damage or infection.
 stimulates lymphocyte destruction.
 glucocorticoid selective drugs are used therapeutically to treat inflammatory diseases such as
asthma, eczema e.g. prednisone, betamethasone but have some mineralocorticoid effects.
Reproduction and lactation : inhibits, in part by inhibition of LH and PRL release from the
anterior pituitary gland (pregnancy is a non-essential metabolic drain on resources).
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Abnormal glucocorticoid function
Cortisol insufficiency - Addison's disease, cortisol excess - Cushing's syndrome. Work out the
effects of too much or too little cortisol from its actions above.
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ALDOSTERONE - mineralocorticoid regulation of body sodium & fluid volume
Receptors: Mineralocorticoid (MR) receptors are present in the nuclei of only a few cell types- kidney
collecting tubule epithelia, salivary and sweat glands. However, cortisol also binds to MR. Therefore,
in aldosterone targets cortisol is deactivated to protect MR from cortisol activation.
Actions: (see also Trinity term Kidney lectures)
In kidney aldosterone regulates ion transport in the kidney collecting tubules in order to stimulate
reabsorption of Na+ in exchange for secretion of K+, H+, NH3+. There is a 2h lag in the response to
aldosterone as MR effects are via stimulating transcription of the Na/K ATPase protein. In salivary
and sweat glands aldosterone regulates ion transport to retain sodium.
Control of aldosterone output – the renin-angiotensin system
Aldosterone secretion is stimulated by the renin-angiotensin system which in turn is stimulated by low
plasma Na+ or low renal blood pressure. Low plasma Na+ /low renal blood pressure stimulates renin
release which acts in the lung to stimulate conversion of angiotensin I to Angiotensin II (AII) by
activating angiotensin converting enzyme (ACE). AII stimulates output of aldosterone from the zona
glomerulosa of the adrenal cortex (AII also causes arteriolar constriction and drinking in response to
thirst).
Abnormal plasma concentrations of aldosterone
Hypoaldosteronism - in adrenal failure – results in sodium loss, low blood volume and low blood
pressure. Hyperaldosteronism - Conn's syndrome – results in excess sodium retention, water retention
and increased blood pressure. Spironolactone – an aldosterone antagonist is used as an antihypertensive.
ADRENAL ANDROGENS - DHEA
DHEA = dehydroepiandrosterone, is produced and released from the adrenal cortex zona reticularis.
DHEA is a weak androgen which stimulates axillary/pubic hair development at puberty, and libido.
Release of DHEA is stimulated by ACTH. At most times DHEA is a very minor component of
adrenal secretions.
Congenital adrenal hyperplasia – inability to produce adrenal steroids. It is an inherited disorder
arising from mutations in enzymes of steroid synthesis e.g. 21-hydroxylase.
Syllabus
14.4 Adrenal gland; 11.3.3 Renal tubular transport
Core learning objectives
Describe the development, gross and microscopic structure of the parts of the adrenal
Outline the basic steps in the synthesis of catecholamines and adrenal steroid hormones
Describe the stimuli which cause the release of catecholamines and adrenal steroids
Describe the principal actions of catecholamines via their various receptors
Describe the principal actions of glucocorticoids and mineralocorticoids
Describe the principal abnormalities produced by excess or lack of adrenal hormones
Suggested Textbook Reading: Rang and Dale p 416-427
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