Adrenal Glands - Cortex, Medulla & Clinical Disorders

Anatomy Overview

Each adrenal gland is composed of two functionally distinct regions that differ in embryological origin, structure, and hormone output:

• Adrenal cortex (outer ~80-90%) - derived from mesoderm; produces steroid hormones (mineralocorticoids, glucocorticoids, androgens)
• Adrenal medulla (inner ~10-20%) - derived from neural crest ectoderm; functions as a modified sympathetic ganglion producing catecholamines

The right adrenal gland is triangular and sits just above the right kidney, closely associated with the inferior vena cava. The left adrenal gland is more crescent-shaped and is positioned medial to the upper pole of the left kidney. Both glands receive a rich arterial supply from three sources - the superior suprarenal arteries (from the inferior phrenic artery), the middle suprarenal artery (from the aorta), and the inferior suprarenal arteries (from the renal artery).

The Three Zones of the Adrenal Cortex

The adrenal cortex is organized into three concentric zones, each producing a distinct class of steroid hormones. All cortical hormones are synthesized from cholesterol. The classic mnemonic for the zones from outer to inner is "GFR" (Glomerulosa, Fasciculata, Reticularis), and for their products: "Salt, Sugar, Sex" - or the alternative "Goes, Find, Rex - the deeper you go, the sweeter it gets".

Zona Glomerulosa - Aldosterone & the RAAS

The outermost zone produces aldosterone, the principal mineralocorticoid. Aldosterone acts on the distal convoluted tubule and collecting duct of the nephron to promote sodium (Na+) reabsorption and potassium (K+) secretion. Water follows sodium, so aldosterone effectively increases blood volume and blood pressure.

Aldosterone release is primarily regulated by the renin-angiotensin-aldosterone system (RAAS):

1. Low blood pressure or low Na+ detected by juxtaglomerular cells in the kidney
2. Renin is released into the blood, cleaving angiotensinogen (from the liver) to angiotensin I
3. ACE (angiotensin-converting enzyme, mainly in the lungs) converts angiotensin I to angiotensin II
4. Angiotensin II stimulates the zona glomerulosa to secrete aldosterone; it also causes vasoconstriction and stimulates ADH release
5. Aldosterone increases Na+ and water reabsorption, raising blood pressure - completing the negative feedback loop

Aldosterone secretion is also stimulated by elevated plasma K+ levels (hyperkalemia) and, to a lesser extent, by ACTH.

Zona Fasciculata - Cortisol

The middle and largest zone produces cortisol, the body's principal glucocorticoid. Cortisol has wide-ranging effects on virtually every organ system:

Cortisol follows a diurnal (circadian) rhythm - levels peak in the early morning (6-8 AM) and reach their nadir around midnight. This rhythm is important for diagnostic testing; morning cortisol and late-night salivary cortisol are standard screening tests.

In the blood, approximately 90% of cortisol is bound to cortisol-binding globulin (CBG, transcortin), with only the free fraction being biologically active. Cortisol is metabolized in the liver and excreted by the kidneys - a 24-hour urinary free cortisol measurement is another key diagnostic tool.

Zona Reticularis - Adrenal Androgens

The innermost cortical zone produces weak androgens, primarily dehydroepiandrosterone (DHEA), DHEA-sulfate (DHEA-S), and androstenedione. These are converted peripherally to more potent androgens (testosterone) and estrogens.

In males, adrenal androgens contribute minimally compared to testicular testosterone. However, in females, adrenal androgens are the primary source of androgens and play roles in:

• Development of axillary and pubic hair (adrenarche)
• Libido and general well-being
• Serving as precursors to estrogen in postmenopausal women (peripheral conversion in adipose tissue)

Adrenal Medulla - Catecholamines & Fight-or-Flight

The adrenal medulla is functionally part of the sympathetic nervous system. Its chromaffin cells are modified postganglionic sympathetic neurons that release hormones directly into the bloodstream instead of across a synapse. The medulla produces:

Catecholamine synthesis follows the pathway: tyrosine → DOPA → dopamine → norepinephrine → epinephrine. The final conversion of norepinephrine to epinephrine requires the enzyme PNMT (phenylethanolamine N-methyltransferase), which is induced by cortisol from the overlying cortex - this is why the cortex surrounds the medulla anatomically.

Catecholamines are metabolized by two enzymes: MAO (monoamine oxidase) and COMT (catechol-O-methyltransferase). Their metabolic end products - metanephrines and vanillylmandelic acid (VMA) - are measured in urine to diagnose pheochromocytoma.

The Hypothalamic-Pituitary-Adrenal (HPA) Axis

Cortisol secretion is tightly regulated by a three-tier neuroendocrine cascade with negative feedback:

Stress (physical, emotional, or physiological) activates the hypothalamus to release CRH, which travels via the hypothalamic-hypophyseal portal system to the anterior pituitary. CRH stimulates corticotrophs to secrete ACTH, which in turn stimulates the zona fasciculata to synthesize and release cortisol.

ACTH is cleaved from the precursor molecule pro-opiomelanocortin (POMC), which also yields melanocyte-stimulating hormone (MSH). This shared precursor explains why excess ACTH (as in Addison disease) causes skin hyperpigmentation - elevated POMC processing produces excess MSH.

When cortisol levels rise sufficiently, cortisol exerts negative feedback at both the hypothalamus (suppressing CRH) and the anterior pituitary (suppressing ACTH), completing the regulatory loop. Exogenous glucocorticoid therapy also suppresses this axis, which is why abrupt withdrawal can precipitate adrenal crisis.

Clinical Correlations - Adrenal Pathology

Adrenal disorders generally fall into two categories - hormone excess or hormone deficiency. The clinical presentation depends on which hormones are affected and whether the pathology is at the adrenal, pituitary, or hypothalamic level.

Cushing Syndrome - Distinguishing the Cause

The most common cause of Cushing syndrome overall is iatrogenic - exogenous glucocorticoid administration (e.g., prednisone). Among endogenous causes, the most common is Cushing disease (pituitary adenoma). The diagnostic workup involves:

1. Screening - 24-hour urinary free cortisol, late-night salivary cortisol, or overnight low-dose dexamethasone suppression test
2. Confirm endogenous source - measure plasma ACTH: suppressed ACTH suggests an adrenal tumor; elevated ACTH suggests pituitary or ectopic source
3. Localize - high-dose dexamethasone suppression test (pituitary adenomas typically suppress; ectopic sources do not); MRI of pituitary; CT of adrenals

Addison Disease - Acute Adrenal Crisis

Chronic adrenal insufficiency can decompensate into an acute adrenal crisis - a life-threatening emergency triggered by physiological stress (infection, surgery, trauma) in a patient with insufficient adrenal reserve. Features include severe hypotension/shock, altered consciousness, hypoglycemia, and hyperkalemia. Treatment is immediate IV hydrocortisone and fluid resuscitation.

Patients on chronic glucocorticoid therapy must not abruptly discontinue their medication, as prolonged exogenous steroids suppress the HPA axis. Doses should be tapered gradually to allow the axis to recover. Patients should also carry a steroid emergency card and receive stress-dose steroids during illness or surgery.

Congenital Adrenal Hyperplasia (CAH)

CAH is a group of autosomal recessive disorders caused by enzyme deficiencies in the cortisol biosynthesis pathway. The most common form - accounting for over 90% of cases - is 21-hydroxylase deficiency.

Because cortisol cannot be adequately synthesized, negative feedback on the pituitary is lost, leading to elevated ACTH and subsequent adrenal hyperplasia. The accumulated steroid precursors are shunted into the androgen pathway (since androgen synthesis does not require 21-hydroxylase), causing:

• Female neonates - ambiguous genitalia at birth (virilization) due to excess androgens
• Males - may present later with precocious puberty
• Salt-wasting crisis - in severe forms, aldosterone production is also impaired (21-hydroxylase is also needed for aldosterone synthesis), leading to hyponatremia, hyperkalemia, and potentially fatal dehydration in the first weeks of life

Diagnosis relies on elevated serum 17-hydroxyprogesterone (the substrate that accumulates proximal to the enzymatic block). Treatment includes glucocorticoid replacement (to suppress ACTH and excess androgen production) and mineralocorticoid replacement in salt-wasting forms. Newborn screening programs in many countries test for 17-hydroxyprogesterone to enable early detection.

Summary - Adrenal Hormones at a Glance