Adrenal glands

Paired organs of the endocrine system

Embryology

Cortex arises from the coelomic mesodermal tissue near the cephalic end of the mesonephros during the fourth to fifth week of gestation. Biosynthetic activity can be detected from week 7. Cortical cell mass dominates the fetal adrenal gland at 4 months of development, and steroidogenesis is maximum during the third trimester.
Medulla arises from ectodermal tissues of the embryonal neural crest. Develops in parallel with CNS from 5th to 6th week. Starts off adjacent to the neural tube, and migrates ventrally to assume a para-aortic position near the cortex. Once there, these cells differentiate into chromaffin cells that make up the adrenal medulla.
- This migration explains why phaeochromocytomas can be found at extra-adrenal sites ('paragangliomas')

Gross anatomy

Paired mustard-coloured structures (bright yellow compared to fat)
Superior and slightly medial to the kidneys, in the retroperitoneal space
Right: pyramidal. Higher position than left.
Left: crescent-shaped
Weight about 4g each
Contain a cortex and medulla, which in most respects can be considered two completely distinct organs, that happen to co-localise during development
Each gland is enveloped by a capsule, in addition to sharing Gerota fascia with the kidneys. Adrenal capsules are immediately associated with the perirenal fat

Relations

Anterosuperior to the upper part of each kidney
- If kidneys are in abnormal position, the adrenals don't follow them - position determined more by relationship to great vessels
- Anatomical variations unusual apart from in blood supply
Right
- Diaphragm posteriorly
- IVC anteromedially (adrenal is slightly posterior plane to IVC)
- Bare area of liver anteriorosuperiorly
  - Inferior leaf of coronary ligament crosses it, so that the lower surface is covered by peritoneum, and the upper surface in the bare area
- Right kidney inferolaterally
Left
- Lies with left crus of diaphragm posteriorly
- Between left kidney and aorta
- Inferior limb extends farther caudad towards the renal hilum than the right side
- Tail of pancreas and splenic hilum anteriorly
Layers
- Adrenal gland
- Adrenal capsule
- Separate compartment of renal fascia

Blood supply

Among the most highly-perfused organs in the body (2L/kg/min of blood)
Both glands receive blood from three sources. Generally, all the arteries are small (<2mm) and can be safely ligated with an energy device. They don't particularly enter at the hilum. There can occasionally be a single larger artery, especially from renal artery side.
- Superior adrenal artery from the inferior phrenic artery
- (Small) middle adrenal artery from juxtacoeliac aorta
- Inferior adrenal artery from renal arteries (most prominent)
Arteries arborise extensively before entering the capsule and forming a subcapsular plexus. Blood flows centripetally through capillaries in ZG and ZF before forming a deep plexus in ZR. Then the cortisol-enriched blood moves into the medulla, where cortisol catalyses the production of phenylethanolamine N-methyltransferase, which converts noradrenaline to adrenaline.

Venous drainage

Usually a single adrenal vein
- Right: only 5mm long, enters IVC 'as short as it is wide'
  - In 20% right adrenal vein may drain into an accessory right hepatic vein or into IVC at or near the confluence of such a vein
- Left: longer, about 2cm, enters renal vein after joining inferior phrenic vein

Lymphatic drainage

To para-aortic nodes

Innervation

Preganglionic sympathetic fibres from the splanchnic nerves (via aortic and renal plexuses) - synapse directly with medullary cells
Blood vessels receive usual postganglionic sympathetic supply
Cortical control is not neural but by ACTH from the anterior pituitary

Variant anatomy

Pancake adrenal - takes on a flattened appearance, often in the presence of pelvic kidney or renal agenesis
Adrenal hypoplasia or agenesis
Accessory adrenal rests - often near adrenal glands but may be found anywhere in the abdomen, pelvis or scrotum
Variant venous anatomy

Cellular structure

Cortex
- 2mm thick, with >80% of the mass of the gland
- Zones
  - Zona glomerulosa
    - Thin layer of relatively small cells with moderately eosinophilic, lipid-poor cytoplasm
    - Undulating inner border, usually not forming a complete circumferential layer
  - Zona fasciculata
    - Largest layer
    - Long radial columns of large, clear, lipid-laden cells
  - Zona reticularis
    - Small nests of compact, eosinophilic cells
Medulla
- Clusters and short cords of chromaffin cells, which are large, polyhedral and packed with basophilic secretory granules
- Catecholamines within those granules yield a brown reaction when treated with chromium salts, giving them their name
- Medulla is richly-endowed with autonomic nerve fibres and ganglion cells. SNS fibres synapse directly with the chromaffin cells.

Steroid hormones

Synthesis - produced in cortex
- Transport of cholesterol to inner mitochondrial membrane of cells, which then undergoes a series of oxidative reactions catalysed by cytochrome P450 (CYP) enzymes
- Cleavage of cholesterol side chain yields pregnenolone, which is the inactive precursor of all the adrenal steroid hormones. Further reactions occur in regions of the cortex:
  - Zona glomerulosa: aldosterone
  - Zona fasciculata: cortisol
  - Zona reticularis: major adrenal sex steroids DHEA and androstenedione
    - (Additional steps in the gonads generate testosterone, oestrone, and oestradiol from androstenedione - see 'reproductive physiology' under 'O+G')
    - Testosterone is produced almost exclusively in the testes from androstenedione, with about 5% produced in adrenals

Function
- General steroid hormones
  - Low-molecular-weight, lipophilic signalling molecules
  - Enter cells and bind to intra-cellular receptors, causing altered gene expression
  - Largely bound to highly specific binding proteins in circulation
  - Serum levels of free hormones are changed by physiologic and disease states including pregnancy, nephrotic syndrome, and cirrhosis
  - Metabolism occurs in the level followed by urinary excretion
  - Vitamin D, retinoids and thyroid hormone are also steroid hormones, but not produced in adrenal
- Glucocorticoids
  - Regulation
    - ACRH from hypothalamus
    - ACTH from anterior pituitary - released in a pulsatile fashion that normally displays a circadian rhythm. Highest levels of ACTH (and thus, of cortisol) are seen on waking, and gradually decline throughout the day to a nadir in the early evening.
    - Glucocorticoid secretion from adrenocortical cells in zona fasciculata
  - Function
    - Broad-ranging effects on almost all organ systems
    - As a rule, generates a catabolic state - the stress response - which increases BSL
      - Hepatic gluconeogenesis
      - Inhibited peripheral glucose uptake
      - Stimulate lipolysis
      - Protein catabolism
      - Increased catecholamine concentrations and sensitised arterial smooth muscle
      - Anti-inflammatory and immuno-suppressive agents, but neutrophils counts are increased
- Mineralocorticoids
  - Regulation
    - Renin-angiotensin-aldosterone axis (RAAS) is responsive to sodium delivery to the distal convoluted tubule of the kidney - low sodium delivery (hypovolaemia, shock, renal artery vasoconstriction, and hyponatraemia) stimulates release of renin from juxtaglomerular apparatus
    - Renin cleaves angiotensinogen to angiotensin I (inactive)
    - Further cleavage to angiotensin II by angiotensin-converting enzyme in lungs and elsewhere - this is a potent vasoconstrictor and stimulator of aldosterone release
    - Hypokalaemia reduces aldosterone release by suppressing renin secretion and also by acting directly at zona glomerulosa; hyperkalaemia has the opposite effect
  - Function
    - Aldosterone regulates circulating fluid volume and electrolytes balance
    - Promotes sodium and chloride retention in the distal tubule
    - Acutely, extracellular fluid volume expands and BP rises
    - Negative feedback occurs through a subsequent increase in sodium delivery to the distal tubule, switching off the renin
- Adrenal sex steroids
  - ACTH and other (incompletely understood) mechanisms regulate secretion of androstenedione and DHEA
  - The physiological effects of adrenal sex steroids are generally weak compared to gonadal sex steroids, especially in men

Catecholamines

Synthesis (medulla)
- Hydroxylation of tyrosine leads to dopamine
- Beta-hydroxylation of dopamine forms noradrenaline
- Phenylethanolamine N-methyltransferase then produces adrenaline in chromaffin cells
- Sympathetic stimulation of the medulla results in release of stored catecholamines
Function
- Tissue response is mediated by alpha and beta-adrenergic receptors
- Alpha-adrenergic receptors have greater affinity for NA - vasoconstriction in skin, GIT
- Beta-adrenegic is more adrenaline - myocardium to increase HR and contracitlity, smooth muscle relaxation in uterus, bronchi, and skeletal muscle arterioles
Metabolism
- Catecholamines are potent and short-acting compounds, with a plasma half-life of 1 minute
- NA and adrenaline are inactivated by one or both of the enzymes monoamine oxidase and catechol-0-methyltransferase to produce metanephrine and normetanephrine, which can be detected in plasma and urine at more stable levels than the fluctuations in actual catecholamines. The final product is vanillymandelic acid, which is excreted in the urine.