Zona Fasciculata

The zona fasciculata is the middle and largest layer of the adrenal cortex. It primarily synthesizes and secretes glucocorticoids, most notably cortisol, which plays a key role in glucose metabolism, immune regulation, inflammation control, and stress response. The zona fasciculata occupies about 65–80% of the total cortical volume and is highly vascularized to allow rapid hormonal diffusion into circulation.

Histological Features

The zona fasciculata is readily identifiable under the microscope due to its broad layer and characteristic appearance:

• Cell arrangement: Long, straight cords (or “fascicles”) of cells oriented perpendicularly to the gland’s surface
• Cell type: Large polyhedral cells with pale, foamy cytoplasm rich in lipid droplets
• Nuclei: Round to oval, centrally located
• Appearance: Spongy or vacuolated look due to cholesterol and lipid content (hence the term “spongiocytes”)

The zona fasciculata lies deep to the zona glomerulosa and superficial to the zona reticularis. It is surrounded by sinusoids through which blood flows centripetally from the capsule to the medulla, allowing efficient hormone release.

Hormone Production

The primary hormone produced by the zona fasciculata is cortisol in humans (or corticosterone in some other species). It also produces small amounts of corticosterone and weak androgens. Cortisol is a potent steroid hormone critical for maintaining metabolic and cardiovascular stability.

Cortisol Functions:

• Glucose metabolism: Stimulates gluconeogenesis in the liver, inhibits glucose uptake in muscle and fat (hyperglycemic effect)
• Protein catabolism: Increases protein breakdown in muscle to provide substrates for gluconeogenesis
• Lipid metabolism: Promotes lipolysis in some tissues but lipogenesis in others (especially in chronic stress)
• Anti-inflammatory and immunosuppressive: Inhibits cytokines, leukocyte migration, and T-cell function
• Cardiovascular support: Maintains vascular tone and sensitivity to catecholamines
• Bone metabolism: Inhibits osteoblast activity and calcium absorption, contributing to osteoporosis in excess

Regulation

Hypothalamic–Pituitary–Adrenal (HPA) Axis:

1. Hypothalamus secretes corticotropin-releasing hormone (CRH)
2. CRH stimulates the anterior pituitary to release adrenocorticotropic hormone (ACTH)
3. ACTH binds to melanocortin 2 receptors (MC2R) on zona fasciculata cells → activates adenylate cyclase → ↑ cAMP → activates steroidogenic enzymes
4. Cortisol is secreted into the bloodstream and provides negative feedback to both the hypothalamus and pituitary

Diurnal Rhythm:

• Cortisol secretion follows a circadian rhythm — highest in the early morning (~6–8 AM) and lowest around midnight
• This rhythm is regulated by the suprachiasmatic nucleus (SCN) of the hypothalamus

Stress Response:

• Physical, emotional, or metabolic stress rapidly increases CRH and ACTH, leading to elevated cortisol production

Enzymes Involved in Cortisol Synthesis

Cortisol is synthesized from cholesterol through a series of enzymatic steps:

• CYP11A1: Converts cholesterol → pregnenolone
• CYP17A1 (17α-hydroxylase): Converts pregnenolone → 17-hydroxypregnenolone
• 3β-HSD: Converts 17-hydroxypregnenolone → 17-hydroxyprogesterone
• CYP21A2 (21-hydroxylase): Converts to 11-deoxycortisol
• CYP11B1 (11β-hydroxylase): Final step → cortisol

Clinical Significance

Cushing's Syndrome

• Characterized by excess cortisol production
• Causes: ACTH-secreting pituitary adenoma (Cushing’s disease), adrenal adenoma/carcinoma, or exogenous corticosteroids
• Symptoms: Moon face, central obesity, abdominal striae, muscle wasting, osteoporosis, hypertension, glucose intolerance
• Diagnosis: Dexamethasone suppression test, 24-hour urinary cortisol, ACTH levels

Adrenal Insufficiency

• Primary (Addison’s disease): Destruction of adrenal cortex → ↓ cortisol and aldosterone
• Secondary: Pituitary failure → ↓ ACTH → ↓ cortisol (aldosterone spared)
• Symptoms: Fatigue, weight loss, hypotension, hypoglycemia, hyperpigmentation (in primary)

Congenital Adrenal Hyperplasia (CAH)

• Most commonly due to 21-hydroxylase deficiency (↓ cortisol and aldosterone, ↑ ACTH, ↑ androgen precursors)
• Causes adrenal hyperplasia and excessive androgen production

Pharmacological Relevance

• Glucocorticoids (e.g., prednisone, dexamethasone): Used for inflammation, autoimmune diseases, transplant rejection prevention
• Long-term use: Can suppress HPA axis → adrenal atrophy → risk of crisis if withdrawn suddenly

Pathology and Imaging

• Adrenal adenomas: Often arise from the zona fasciculata; may be cortisol-producing (functional) or silent (incidentaloma)
• Adrenal carcinomas: Rare, aggressive tumors that can produce cortisol or other steroids
• Adrenal imaging: CT and MRI used to evaluate masses and cortical thickness; functional imaging (e.g., PET, NP-59 scintigraphy) can assess hormone-producing lesions

Additional Notes

• Glucocorticoid receptor (GR): Cortisol acts via intracellular receptors widely expressed in most tissues
• 11β-HSD enzymes: Regulate local cortisol activity; type 1 converts cortisone → cortisol (activating), type 2 does the reverse (inactivating)
• Fetal adrenal cortex: Lacks a well-defined fasciculata but produces DHEA for placental estrogen synthesis