Anatomy of the Adrenal Glands

The Adrenal Glands

• The adrenal glands are flattened, roughly pyramidal (right) or crescent-shaped (left) structures, typically weighing 4 g each, positioned superior and slightly medial to the kidneys in the retroperitoneal space
• The adrenal glands are highly perfused, receiving 2000 mL/kg/min of blood, second only to the kidney and thyroid

Distinct Regions

• The adrenal cortex and medulla can be considered two completely distinct organs
• The primordial cortex arises from coelomic mesodermal tissue by the 4th to 5th week of gestation with biosynthetic activity detectable as early as the 7th week
• The adrenal medulla emerges from ectodermal tissues of the embryonic neural crest
• The adrenal medulla develops in parallel with the sympathetic nervous system beginning in the fifth to sixth week of gestation, differentiating into chromaffin cells, which make up the adrenal medulla

Surgically Relevant Sequelae

• Both cortical and medullary tissues can populate extra-adrenal locations
• The potential sites are wider for chromaffin tissue than for cortical tissue
• Pheochromocytomas may originate in extra-adrenal sites more commonly than previously believed, referred to as paragangliomas

Adrenal Gland Relations

• Right Adrenal Gland: The posterolateral surface of the retrohepatic vena cava abuts it. The right adrenal fossa borders inferolaterally on the right kidney, posteriorly on the diaphragm, anterosuperiorly on the bear area of the liver
• Left Adrenal Gland: Between the left kidney and aorta, with its inferior limb extending further caudally toward the renal hilum. The posterior borders are the diaphragm and the anterior is the tail of the pancreas and splenic hilum
• The adrenal capsules are immediately associated with the perirenal fat

Vasculature Supply and Drainage

• Macroscopic vascular anatomy knowledge is vital for surgical management
• Arterial supply is diffuse, venous drainage is usually solitary
• Arterial feed emerges from 3 separate vessels which include the superior adrenal arteries (from the inferior phrenic arteries), the small middle adrenal arteries (from the juxtaceliac aorta), and inferior adrenal arteries (from the renal arteries)
• The inferior is the most prominent of the three, commonly a single identifiable vessel
• The left adrenal vein is approximately 2 cm long, drains into left renal vein after joining inferior phrenic vein
• The right adrenal vein is typically as short as it is wide (0.5 cm) and drains directly into the vena cava
• The right adrenal vein may drain into an accessory right hepatic vein/vena cava, at or near the confluence of such a vein ( up to 20% of individuals)

Normal Histopathology

• The cortex is approximately 2 mm thick, comprises over 80% of the gland mass
• Has 3 layers with the outer zone glomerulosa being a thin layer of relatively small cells with moderately eosinophilic, lipid-poor cytoplasm that undulates but does not form a circumferential layer, with the zone fasciculata being the middle layer consisting of long radial columns of large, clear, lipid-laden cells
• The inner zone reticularis consists of small nests of compact, eosinophilic cells
• The adrenal medulla is richly endowed with autonomic nerve fibers and ganglion cells, and consists of clusters and short cords of chromaffin cells, large, polyhedral, packed with basophilic secretory granules
• Sympathetic fibers synapse directly with the chromaffin cells, constituting an interface between the nervous and endocrine systems

Microvasculature

• Microvasculature functionally unifies the cortex and medulla
• Adrenal arteries arborize extensively before entering capsule → subcapsular plexus
• Blood flows centripetally through capillaries in the zona glomerulosa and zona fasciculata, creating a deep plexus within the zona reticularis, enabling steroid-enriched postcapillary blood to enter the medulla
• Cortisol drives the expression of phenylethanolamine N-methyltransferase responsible for the conversion of norepinephrine to epinephrine
• This arrangement is essentially a portal system between the cortex and medulla

Adrenal Steroid Biosynthesis

• Biosynthesis starts with the transport of cholesterol, in the inner mitochondrial membrane, by the steroidogenic acute regulatory protein
• Cholesterol undertakes serial oxidation catalyzed predominantly by membrane-associated enzymes with cytochrome P450 family
• Side chain cleavage yields the hormonally inactive compound pregnenolone, or the immediate precursor to the adrenal steroid hormones
• Serial oxidation by CYP17 converts pregnenolone/progesterone into dehydroepiandrosterone (DHEA)/androstenedione
• Additional enzymatic steps confined to the gonads generate testosterone, estrone, and estradiol from androstenedione
• Aldosterone is generated by the oxidation of corticosterone by CYP11B2 in the zona glomerulosa while oxidation of 17-hydroxypregnenolone by 3β-hydroxysteroid dehydrogenase, followed by action of CYP21A2 and CYP11B1 yields cortisol

Steroid Hormone Physiology and Metabolism

• Steroid hormones belong to general class of signaling molecules acting by entering cells, binding to intracellular receptors, and altering gene expression
• Hormone binding = gene alteration with delayed, prolonged response
• Endogenous steroid hormones, in circulation, are largely bound to highly specific binding globulins
• Metabolism of endogenous and pharmacologic steroids proceeds through hydroxylation, sulfonation, or conjugation to glucuronic acid in the liver, followed by urinary excretion

Glucocorticoids

• Corticotropin-releasing factor release results in adrenocorticotropic hormone (ACTH) secretion
• ACTH binds to a G protein–coupled receptor, stimulating glucocorticoid secretion.
• Cholesterol transport/pregnenolone synthesis is upregulated by increased steroidogenic acute regulatory protein
• ACTH is released in a pulsatile fashion displaying a circadian rhythm.
• The highest ACTH/cortisol levels are detected on waking, with gradually declining levels throughout the day to reach a nadir in the early evening

Glucocorticoid Action

• Broad-ranging effects on almost all organ systems
• Generates/characterizes the body’s response to stress (catabolic state)
• Net effect increases blood glucose concentrations via hepatic glucose output (upregulation of gluconeogenesis and net glycogen deposition), peripheral tissue uptake is also directly inhibited
• Glucocorticoids stimulate lipolysis with a release of free fatty acids, inducing a general state of insulin resistance by causing protein catabolism with fatty acids and amino acids (energy sources and substrates for gluconeogenesis)

Cardiovascular Role of Glucocorticoids

• They are a permissive enhancer of catecholamine signaling by sensitizing arterial smooth muscle cells to β-adrenergic and increasing catecholamine concentrations in neuromuscular junctions
• Cardiac contractility/peripheral vascular tone maintained, explaining improvement of acute adrenal insufficiency

Glucocorticoid Anti-inflammatory/Immunosuppressive Roles

• Reduces lymphocyte/eosinophil counts, increases neutrophil counts
• Promotes Lymphocyte apoptosis while decreasing cytokine/immunoglobulin production
• Suppresses histamine release/ reduces prostaglandin synthesis through inhibition of phospholipase A2

Mineralocorticoids

• Aldosterone release from the zona glomerulosa is regulated Angiotensin II/blood potassium level
• The renin-angiotensin-aldosterone axis is responsive to sodium distal convoluted tubule of kidney delivery
• Low sodium delivery stimulates renin release from the juxtaglomerular apparatus
• The liver converts prohormone angiotensinogen to inactive angiotensin I by renin
• Angiotensin-converting enzyme converts angiotensin I to angiotensin II in the lungs, leading to vasoconstriction and aldosterone release
• Hypokalemia reduces aldosterone release, hyperkalemia has opposite effect

Actions of Aldosterone

• Regulates circulating fluid volume/electrolyte balance promoting sodium/chloride retention in the distal tubule
• Potassium/hydrogen ions are secreted into the urine
• Expansion of extracellular fluid and elevated blood pressure occurs after aldosterone infusion
• Negative feedback occurs through elevated sodium delivery to the distal tubule, suppressing renin release

Adrenal Sex Steroids

• Androstenedione, DHEA, and DHEA-S secretion is regulated by ACTH
• Androstenedione quantities are produced the least
• Sex steroids' physiologic effects are weak, particularly in males
• Functions are generally weak in comparison to gonadal sex steroids
• DHEA/DHEA-S peripheral conversion to more potent androgens (androstenedione, testosterone, dihydrotestosterone) supports normal pubic/axillary hair growth maintaining libido

Catecholamine Synthesis

• Occurs in adrenal medulla
• Rate-limiting step is tyrosine hydroxylation that generates dihydroxyphenylalanine (L-dopa) in the cytosol
• L-dopa decarboxylation generates dopamine, then becomes β-hydroxylated, creating norepinephrine
• Epinephrine is made by phenylethanolamine N-methyltransferase in the zone medulla
• Sympathetic stimulation of the adrenal medulla results in release of stored catecholamines (up to a 50x increase)

Catecholamine Action

• Target tissue responses are mediated by α-/β-adrenergic receptors
• α-Adrenergic receptors have greater affinity for norepinephrine compared with epinephrine (opposite is true for β-adrenergic receptors)
• β1-Adrenergic receptors stimulate the myocardium increasing heart rate/contractility which occurs by smooth muscle relaxation in the uterus, bronchi, and skeletal muscle arterioles
• α1-Adrenergic receptors mediate vasoconstriction in the skin and gastrointestinal tract
• α2-Adrenergic receptors in the central nervous system attenuate sympathetic outflow
• Results in augmented blood flow and brain, heart, and skeletal muscle oxygen delivery at expense of other organ systems