Adrenal gland

The adrenal glands are paired endocrine organs located above the kidneys. They play a vital role in maintaining homeostasis by producing steroid hormones and catecholamines essential for metabolism, stress response, and electrolyte balance. Understanding their anatomy and physiology is crucial in medicine due to their involvement in a variety of disorders.

Gross Anatomy of the Adrenal Glands

Location and Relations

The adrenal glands are situated in the retroperitoneum, resting on the superior poles of the kidneys. Each gland is embedded within the perirenal fat and enclosed by the renal fascia. The right adrenal gland lies posterior to the inferior vena cava and liver, while the left adrenal gland is related to the spleen, stomach, and pancreas.

Size, Shape, and Dimensions

Typically, each adrenal gland measures about 4–6 cm in length, 2–3 cm in width, and weighs approximately 4–5 grams in adults. The right adrenal gland is pyramidal in shape, while the left is crescent-shaped, adapting to the contours of adjacent organs.

Surrounding Structures

• Right adrenal gland: In contact with the diaphragm, liver, and inferior vena cava.
• Left adrenal gland: Related to the left kidney, pancreas, splenic vessels, and diaphragm.

Histology and Microanatomy

Cortex and Its Zones

The adrenal cortex forms the outer portion of the gland and accounts for nearly 80–90% of its mass. It is divided into three distinct zones, each responsible for the synthesis of different classes of steroid hormones.

• Zona glomerulosa: The outermost layer, composed of small columnar cells arranged in clusters. It primarily produces mineralocorticoids, such as aldosterone.
• Zona fasciculata: The thickest zone, consisting of large cells arranged in radial cords. It secretes glucocorticoids, mainly cortisol.
• Zona reticularis: The innermost cortical layer, characterized by a network-like arrangement of cells. It produces adrenal androgens such as dehydroepiandrosterone (DHEA).

Medulla

The adrenal medulla occupies the central region of the gland and is derived from neural crest cells. It functions as part of the sympathetic nervous system by releasing catecholamines in response to stress.

• Chromaffin cells: Specialized neuroendocrine cells that secrete epinephrine and norepinephrine.
• Sympathetic innervation: Direct stimulation via preganglionic sympathetic fibers allows rapid hormone release into the bloodstream.

Blood Supply and Lymphatic Drainage

Arterial Supply

The adrenal glands receive a rich arterial supply from multiple sources. Each gland is supplied by three main groups of arteries:

• Superior suprarenal arteries: Branches of the inferior phrenic arteries.
• Middle suprarenal arteries: Direct branches of the abdominal aorta.
• Inferior suprarenal arteries: Branches of the renal arteries.

This extensive arterial network ensures continuous blood flow, which is essential for rapid hormone secretion into circulation.

Venous Drainage

The venous drainage of the adrenal glands is more limited, typically consisting of a single large vein from each gland:

• Right suprarenal vein: Drains directly into the inferior vena cava.
• Left suprarenal vein: Empties into the left renal vein, often after receiving the left inferior phrenic vein.

Lymphatic Pathways

Lymph from the adrenal glands drains primarily into the lateral aortic and renal hilar lymph nodes, contributing to the systemic lymphatic circulation.

Nerve Supply

The adrenal glands are richly innervated by sympathetic fibers. Preganglionic fibers reach the adrenal medulla without synapsing, allowing direct stimulation of chromaffin cells for rapid catecholamine release. The cortex has sparse innervation but responds mainly to hormonal signals rather than neural input.

Physiology of the Adrenal Cortex

Mineralocorticoids

Mineralocorticoids regulate electrolyte and fluid balance. The primary hormone is aldosterone, secreted by the zona glomerulosa. Its release is controlled by the renin-angiotensin-aldosterone system and serum potassium levels.

• Aldosterone synthesis: Derived from cholesterol through enzymatic pathways involving aldosterone synthase.
• Renin-angiotensin-aldosterone system: Renin release from the kidney leads to angiotensin II formation, stimulating aldosterone secretion, which promotes sodium retention and potassium excretion.

Glucocorticoids

Glucocorticoids, primarily cortisol, are produced by the zona fasciculata. They influence carbohydrate, protein, and fat metabolism while also modulating immune and inflammatory responses.

• Cortisol synthesis: Follows a circadian rhythm, with peak secretion in the early morning.
• Hypothalamic-pituitary-adrenal axis: Cortisol release is regulated by corticotropin-releasing hormone (CRH) from the hypothalamus and adrenocorticotropic hormone (ACTH) from the pituitary gland.

Androgens

Adrenal androgens are secreted mainly by the zona reticularis. Though weaker than gonadal androgens, they contribute to pubertal development and secondary sexual characteristics, particularly in females.

• Dehydroepiandrosterone (DHEA): A precursor that can be converted into more potent androgens or estrogens.
• Clinical role: Adrenal androgens are significant in conditions such as congenital adrenal hyperplasia where their production is altered.

Physiology of the Adrenal Medulla

Catecholamine Synthesis

The adrenal medulla synthesizes catecholamines, primarily epinephrine and norepinephrine, which play an essential role in the fight-or-flight response. The biosynthesis begins with the amino acid tyrosine and proceeds through a series of enzymatic steps:

1. Tyrosine is converted to DOPA by tyrosine hydroxylase.
2. DOPA is decarboxylated to dopamine by DOPA decarboxylase.
3. Dopamine is hydroxylated to norepinephrine by dopamine β-hydroxylase.
4. In the presence of phenylethanolamine N-methyltransferase (PNMT), norepinephrine is methylated to epinephrine.

Regulation of Secretion

Catecholamine release is regulated by direct sympathetic innervation. Preganglionic sympathetic fibers release acetylcholine, which stimulates chromaffin cells to release stored catecholamines into circulation during stress, exercise, or hypoglycemia.

Physiological Effects of Catecholamines

• Cardiovascular system: Increases heart rate, contractility, and blood pressure.
• Metabolism: Promotes glycogenolysis, lipolysis, and glucose mobilization for rapid energy supply.
• Respiratory system: Causes bronchodilation to improve oxygen delivery.
• Other effects: Dilates pupils, decreases gastrointestinal motility, and enhances alertness.

Development and Embryology

Origin of Cortex

The adrenal cortex is derived from mesodermal cells of the coelomic epithelium. Initially, a primitive fetal cortex forms, which is later replaced by the definitive cortex composed of the three distinct zones: glomerulosa, fasciculata, and reticularis.

Origin of Medulla

The adrenal medulla originates from neural crest cells, which migrate into the developing cortex. These cells differentiate into chromaffin cells, giving the medulla its neuroendocrine function.

Developmental Changes and Differentiation

During fetal life, the adrenal glands are disproportionately large, mainly due to the hypertrophied fetal cortex. After birth, the fetal cortex regresses and the definitive cortex expands, establishing normal adrenal architecture. The medulla also matures postnatally, achieving full catecholamine-secreting capacity in early childhood.

Clinical Correlations and Disorders

Adrenal Cortex Disorders

• Addison’s disease: A primary adrenal insufficiency caused by autoimmune destruction, infections, or other factors. Symptoms include fatigue, weight loss, hyperpigmentation, and hypotension.
• Cushing’s syndrome: Results from prolonged exposure to high levels of cortisol. It may arise from pituitary adenomas, adrenal tumors, or exogenous steroid use. Clinical features include moon face, truncal obesity, purple striae, and hypertension.
• Congenital adrenal hyperplasia (CAH): A group of inherited enzyme deficiencies affecting steroid biosynthesis. The most common is 21-hydroxylase deficiency, leading to cortisol deficiency and androgen excess.
• Hyperaldosteronism: Excessive aldosterone secretion, often due to adrenal adenomas (Conn’s syndrome) or bilateral adrenal hyperplasia. It manifests as hypertension, hypokalemia, and metabolic alkalosis.

Adrenal Medulla Disorders

• Pheochromocytoma: A catecholamine-secreting tumor of chromaffin cells. It leads to episodic headaches, sweating, palpitations, and paroxysmal hypertension.
• Paragangliomas: Extra-adrenal tumors arising from sympathetic or parasympathetic paraganglia. Some may secrete catecholamines and mimic pheochromocytoma.

Adrenal Incidentalomas and Tumors

Incidentalomas are adrenal masses discovered unintentionally during imaging for other conditions. They require evaluation to determine hormonal activity or malignancy risk. Malignant tumors include adrenocortical carcinoma and metastatic lesions.

Diagnostic Evaluation

Clinical Examination

Assessment begins with a detailed clinical history and physical examination. Features such as blood pressure changes, skin pigmentation, body fat distribution, and muscle weakness provide important diagnostic clues.

Hormonal Assays

Laboratory investigations help confirm adrenal dysfunction:

• Cortisol levels and ACTH stimulation tests for adrenal insufficiency.
• Dexamethasone suppression tests for Cushing’s syndrome.
• Plasma renin and aldosterone measurements for hyperaldosteronism.
• Plasma and urinary catecholamines or metanephrines for pheochromocytoma.

Imaging Modalities

Radiological studies are crucial for identifying adrenal pathology:

• Ultrasound: Useful for detecting large adrenal masses but limited in resolution.
• CT scan: Commonly used for evaluating adrenal size, density, and tumors.
• MRI: Provides better soft tissue contrast and helps differentiate adenomas from carcinomas.
• Functional imaging: Techniques such as MIBG scintigraphy and PET scans assist in locating catecholamine-secreting tumors.

Treatment and Management

Medical Management

Pharmacological therapy is often the first step in managing adrenal disorders. Treatment varies depending on the specific condition:

• Addison’s disease: Lifelong hormone replacement with glucocorticoids (e.g., hydrocortisone) and mineralocorticoids (e.g., fludrocortisone).
• Cushing’s syndrome: Medical therapy may include drugs such as ketoconazole, metyrapone, or mitotane to suppress cortisol production.
• Hyperaldosteronism: Spironolactone or eplerenone, which are aldosterone antagonists, can help control blood pressure and correct hypokalemia.
• Pheochromocytoma: Alpha-adrenergic blockers (e.g., phenoxybenzamine) are given before surgery to prevent hypertensive crises. Beta-blockers may be added after alpha-blockade to control tachycardia.

Surgical Approaches

Surgery remains the definitive treatment for many adrenal disorders. Laparoscopic adrenalectomy is the standard procedure for most adrenal tumors. Indications include:

• Adrenal adenomas causing hormone excess.
• Pheochromocytomas and paragangliomas.
• Adrenocortical carcinomas and large incidentalomas with suspicious features.

Preoperative preparation, particularly for pheochromocytoma, is crucial to avoid perioperative cardiovascular complications.

Hormone Replacement Therapy

Patients who undergo bilateral adrenalectomy or have adrenal insufficiency require lifelong replacement therapy. Treatment includes glucocorticoids and mineralocorticoids, adjusted according to stress conditions such as surgery or illness.

References

1. Young WF. Clinical practice. The incidentally discovered adrenal mass. N Engl J Med. 2007;356(6):601-610.
2. Williams GH, Dluhy RG. Diseases of the adrenal cortex. In: Jameson JL, De Groot LJ, editors. Endocrinology. 7th ed. Philadelphia: Elsevier Saunders; 2016. p. 493-540.
3. Bornstein SR, Allolio B, Arlt W, Barthel A, Don-Wauchope A, Hammer GD, et al. Diagnosis and treatment of primary adrenal insufficiency: An Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2016;101(2):364-389.
4. Kumar V, Abbas AK, Aster JC. Robbins and Cotran Pathologic Basis of Disease. 10th ed. Philadelphia: Elsevier; 2021. p. 1062-1074.
5. Stewart PM. The adrenal cortex. In: Melmed S, Polonsky KS, Larsen PR, Kronenberg HM, editors. Williams Textbook of Endocrinology. 14th ed. Philadelphia: Elsevier; 2020. p. 490-555.
6. Lenders JW, Duh QY, Eisenhofer G, Gimenez-Roqueplo AP, Grebe SK, Murad MH, et al. Pheochromocytoma and paraganglioma: An Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2014;99(6):1915-1942.
7. Else T, Kim AC, Sabolch A, Raymond VM, Kandathil A, Caoili EM, et al. Adrenocortical carcinoma. Endocr Rev. 2014;35(2):282-326.
8. McDonald J, Matthay KK, London WB, et al. Current perspectives on adrenal medullary tumors in children. Cancer. 2017;123(12):2107-2116.
9. Reznik Y. Adrenal incidentalomas: Management and follow-up. Rev Endocr Metab Disord. 2021;22(1):131-140.
10. Anderson JR, Ross EJ. The adrenal gland. In: Gray’s Anatomy: The Anatomical Basis of Clinical Practice. 42nd ed. London: Elsevier; 2020. p. 1230-1238.