Zona Glomerulosa

The zona glomerulosa is the outermost layer of the adrenal cortex and is responsible for the production of mineralocorticoids, primarily aldosterone. These hormones are essential for the regulation of electrolyte balance, blood pressure, and extracellular fluid volume. Despite its thinness compared to the deeper layers of the adrenal cortex, the zona glomerulosa plays a critical role in homeostasis and cardiovascular regulation.

Histological Features

Under light microscopy, the zona glomerulosa appears as a narrow, densely packed layer just beneath the adrenal capsule. Its cells are arranged in rounded or arched clusters (glomeruli-like structures), which is the origin of its name.

• Cell shape: Small, columnar or pyramidal cells
• Cytoplasm: Eosinophilic with few lipid droplets (unlike the foamy appearance of zona fasciculata)
• Nuclei: Round, centrally placed
• Vascularity: Highly vascular, surrounded by sinusoidal capillaries allowing direct hormone secretion into the bloodstream

Hormone Production

The zona glomerulosa synthesizes and secretes aldosterone, the principal mineralocorticoid in humans. Aldosterone regulates sodium and potassium levels in the body, influencing fluid retention and blood pressure.

Aldosterone – Mechanism of Action

• Acts on the distal convoluted tubules and collecting ducts of the nephron
• Promotes sodium reabsorption and potassium excretion
• Increases water retention → expands blood volume → raises blood pressure

Additional Mineralocorticoids:

Other weak mineralocorticoids like deoxycorticosterone may be secreted in small amounts but are clinically less significant compared to aldosterone.

Regulation

Unlike the inner adrenal zones, the zona glomerulosa is primarily regulated by the renin–angiotensin–aldosterone system (RAAS) and serum potassium levels, rather than ACTH.

Renin–Angiotensin–Aldosterone System (RAAS):

1. ↓ Blood pressure or ↓ Na⁺ → juxtaglomerular cells in kidneys release renin
2. Renin converts angiotensinogen → angiotensin I
3. ACE (angiotensin-converting enzyme) converts angiotensin I → angiotensin II
4. Angiotensin II stimulates the zona glomerulosa to release aldosterone

Potassium Levels:

• ↑ Serum potassium directly stimulates aldosterone secretion
• This helps lower potassium through renal excretion

ACTH:

Adrenocorticotropic hormone (ACTH) has only a transient and minor effect on aldosterone secretion, unlike its strong influence on cortisol and androgen production in the deeper cortical layers.

Enzymes Involved in Aldosterone Synthesis

The biosynthesis of aldosterone from cholesterol requires a cascade of enzymatic reactions, notably:

• Cholesterol side-chain cleavage enzyme (CYP11A1): Converts cholesterol to pregnenolone
• 21-hydroxylase (CYP21A2): Converts progesterone to 11-deoxycorticosterone
• Aldosterone synthase (CYP11B2): Converts corticosterone to aldosterone (highly specific to zona glomerulosa)

Note: The expression of CYP11B2 is a key feature that distinguishes zona glomerulosa from other adrenal cortical zones.

Clinical Significance

Hyperaldosteronism

• Primary (Conn’s syndrome): Caused by aldosterone-secreting adrenal adenoma or bilateral adrenal hyperplasia
• Leads to hypertension, hypokalemia, metabolic alkalosis, muscle weakness
• Diagnosis: Plasma aldosterone-renin ratio (ARR), salt-loading test
• Treatment: Surgical removal (if adenoma) or mineralocorticoid receptor blockers (e.g., spironolactone)

Secondary Hyperaldosteronism

• Due to increased renin from renal artery stenosis, heart failure, or liver cirrhosis
• Results in elevated aldosterone but with elevated renin levels as well

Hypoaldosteronism

• Can result from adrenal insufficiency (e.g., Addison’s disease), ACE inhibitors, or diabetic nephropathy
• Leads to hyperkalemia, hyponatremia, hypotension

Congenital Adrenal Hyperplasia (CAH)

• 21-hydroxylase deficiency impairs aldosterone synthesis → salt-wasting form of CAH
• Can present with dehydration, low sodium, high potassium in neonates

Pharmacological Relevance

• Mineralocorticoid receptor antagonists: Spironolactone, eplerenone are used in hyperaldosteronism, resistant hypertension, and heart failure
• ACE inhibitors / ARBs: Indirectly reduce aldosterone levels by inhibiting RAAS
• Licorice ingestion: Contains glycyrrhizic acid, which can mimic hyperaldosteronism by inhibiting 11β-HSD2 (pseudo-hyperaldosteronism)

Imaging and Pathology

• Adrenal adenomas: Benign tumors may arise in the zona glomerulosa and overproduce aldosterone
• Adrenal venous sampling: Used to localize unilateral vs bilateral aldosterone secretion before surgery
• Immunohistochemistry: CYP11B2 staining helps pathologists identify glomerulosa-derived adenomas