Adrenal cortex

The adrenal cortex is the outer layer of the adrenal glands and plays a crucial role in maintaining homeostasis through the production of steroid hormones. These hormones regulate metabolism, electrolyte balance, stress response, and secondary sexual characteristics. Proper functioning of the adrenal cortex is essential for overall endocrine and metabolic health.

Introduction

The adrenal cortex constitutes the outer portion of the adrenal glands, which are located atop the kidneys. It is responsible for synthesizing corticosteroids and androgens that influence various physiological processes. Understanding the anatomy, function, and regulation of the adrenal cortex is vital for diagnosing and managing endocrine disorders.

Anatomy of the Adrenal Cortex

The adrenal cortex is organized into three distinct zones, each producing specific hormones. Its vascular supply and innervation facilitate efficient hormone secretion and responsiveness to physiological signals.

Gross Structure and Location

The adrenal glands are triangular-shaped organs situated on the superior aspect of each kidney. The cortex forms the outer layer, surrounding the medulla, and constitutes approximately 80-90 percent of the gland’s mass.

Vascular Supply and Innervation

The adrenal cortex receives blood from the superior, middle, and inferior adrenal arteries. Venous drainage occurs via a single central vein. Sympathetic innervation regulates hormone secretion and local blood flow.

Zones of the Adrenal Cortex

• Zona glomerulosa: The outermost layer responsible for mineralocorticoid production.
• Zona fasciculata: The middle layer producing glucocorticoids.
• Zona reticularis: The innermost cortical layer responsible for androgen synthesis.

Histology

The adrenal cortex exhibits distinct histological features in each zone that correspond to their specific hormonal functions. Understanding these features is important for recognizing normal physiology and pathological changes.

Cell Types in Each Cortical Zone

• Zona glomerulosa: Small, columnar or pyramidal cells arranged in rounded clusters; primarily synthesize aldosterone.
• Zona fasciculata: Large, lipid-rich cells organized in straight cords; secrete glucocorticoids such as cortisol.
• Zona reticularis: Smaller, compact cells in a network of cords; produce adrenal androgens like DHEA.

Structural Features Related to Hormone Production

Cortical cells contain abundant smooth endoplasmic reticulum and mitochondria, reflecting their active steroidogenic function. Lipid droplets within cells provide substrates for steroid hormone synthesis.

Staining Characteristics and Microscopic Appearance

Hematoxylin and eosin staining reveals a pale, vacuolated appearance in the zona fasciculata due to lipid content. The zona glomerulosa stains darker and more compactly, while the zona reticularis appears as a network of smaller cells.

Hormones Produced by the Adrenal Cortex

The adrenal cortex synthesizes three major classes of steroid hormones: mineralocorticoids, glucocorticoids, and androgens. Each class has specific physiological roles and target organs.

Mineralocorticoids

The primary mineralocorticoid is aldosterone, produced by the zona glomerulosa. Aldosterone regulates sodium and potassium balance, water retention, and blood pressure by acting on the distal renal tubules.

Glucocorticoids

Glucocorticoids, primarily cortisol, are secreted by the zona fasciculata. They influence carbohydrate, protein, and fat metabolism, modulate immune responses, and help the body respond to stress.

Androgens

Adrenal androgens, including dehydroepiandrosterone (DHEA) and androstenedione, are produced by the zona reticularis. These hormones contribute to secondary sexual characteristics, serve as precursors for sex steroids, and play a minor role in anabolic processes.

Regulation of Adrenal Cortex Function

The adrenal cortex is tightly regulated by multiple endocrine pathways to ensure appropriate hormone production according to physiological needs. These regulatory mechanisms include feedback loops, stress responses, and circadian rhythms.

Hypothalamic-Pituitary-Adrenal (HPA) Axis

The HPA axis is the primary regulator of glucocorticoid secretion. The hypothalamus releases corticotropin-releasing hormone (CRH), which stimulates the anterior pituitary to secrete adrenocorticotropic hormone (ACTH). ACTH then stimulates cortisol production in the zona fasciculata.

Renin-Angiotensin-Aldosterone System (RAAS)

Aldosterone secretion by the zona glomerulosa is primarily controlled by the RAAS. Low blood pressure or sodium levels trigger renin release from the kidneys, leading to angiotensin II formation, which stimulates aldosterone synthesis and secretion.

Feedback Mechanisms

Negative feedback loops regulate hormone levels. Elevated cortisol inhibits CRH and ACTH release, while increased aldosterone and sodium levels suppress renin and angiotensin II production, maintaining homeostasis.

Stress Response and Circadian Rhythm Influence

Stress activates the HPA axis, increasing cortisol secretion to facilitate metabolic and cardiovascular responses. Cortisol also follows a circadian rhythm, peaking in the early morning and declining throughout the day.

Physiological Functions

Hormones produced by the adrenal cortex are essential for multiple physiological processes, including metabolism, electrolyte balance, immune modulation, and cardiovascular function.

Electrolyte and Water Balance

Aldosterone promotes sodium retention and potassium excretion in the kidneys, helping regulate blood volume, blood pressure, and overall fluid balance.

Metabolism of Carbohydrates, Proteins, and Fats

Glucocorticoids influence energy metabolism by stimulating gluconeogenesis, protein catabolism, and lipolysis, ensuring adequate energy supply during stress or fasting.

Immune Modulation

Cortisol modulates immune responses by suppressing inflammation, regulating cytokine production, and influencing lymphocyte activity, protecting the body from excessive immune reactions.

Influence on Cardiovascular Function

Adrenal cortical hormones contribute to vascular tone and cardiac output. Aldosterone maintains blood pressure through sodium and water retention, while glucocorticoids support myocardial function and vascular responsiveness.

Disorders of the Adrenal Cortex

Abnormalities in adrenal cortical function can lead to a range of disorders characterized by hormone excess or deficiency. These conditions significantly impact metabolism, electrolyte balance, and overall health.

Hyperfunction

• Cushing’s Syndrome: Excess cortisol production leading to obesity, hypertension, hyperglycemia, and skin changes.
• Hyperaldosteronism (Conn’s Syndrome): Excess aldosterone causing hypertension, hypokalemia, and metabolic alkalosis.
• Adrenogenital Syndrome (Congenital Adrenal Hyperplasia): Enzyme deficiencies result in excess androgen production, leading to virilization and ambiguous genitalia.

Hypofunction

• Addison’s Disease: Primary adrenal insufficiency characterized by low cortisol and aldosterone, causing fatigue, hypotension, and hyperpigmentation.
• Secondary Adrenal Insufficiency: Due to pituitary or hypothalamic dysfunction, leading to cortisol deficiency with preserved aldosterone levels.

Neoplasms

• Adrenal Cortical Adenoma: Benign tumors that may secrete hormones, potentially causing hyperfunction syndromes.
• Adrenal Cortical Carcinoma: Rare malignant tumors with aggressive growth and potential hormone overproduction.

Diagnostic Evaluation

Diagnosis of adrenal cortex disorders involves biochemical testing, imaging studies, and occasionally histopathology to confirm structural or functional abnormalities.

Biochemical Tests

• Serum cortisol, aldosterone, and adrenocorticotropic hormone (ACTH) levels
• Plasma renin activity for assessment of aldosterone regulation

Stimulation and Suppression Tests

Dynamic tests such as ACTH stimulation, dexamethasone suppression, or renin-angiotensin modulation help differentiate primary versus secondary disorders and assess adrenal responsiveness.

Imaging Studies

Computed tomography (CT) or magnetic resonance imaging (MRI) of the adrenal glands identifies structural lesions, masses, or hyperplasia contributing to dysfunction.

Histopathology

In cases of neoplasm or surgical resection, microscopic examination confirms the diagnosis and differentiates benign from malignant lesions.

Treatment and Management

Management of adrenal cortex disorders depends on the underlying cause, hormone imbalance, and severity of symptoms. Treatment may involve medical therapy, surgical intervention, and supportive care.

Medical Management

• Hormone replacement therapy for adrenal insufficiency (hydrocortisone, fludrocortisone)
• Pharmacologic agents to control hormone excess, such as ketoconazole or metyrapone for hypercortisolism
• Mineralocorticoid antagonists for hyperaldosteronism (spironolactone, eplerenone)

Surgical Interventions

• Adrenalectomy for hormone-secreting tumors or large adrenal masses
• Minimally invasive laparoscopic approaches preferred when feasible

Lifestyle and Supportive Care

• Monitoring blood pressure, electrolytes, and glucose levels
• Dietary modifications to support electrolyte balance and metabolic health
• Patient education on stress management and medication adherence

Recent Advances and Research

Ongoing research has expanded understanding of adrenal cortex physiology and pathophysiology, leading to novel diagnostic and therapeutic approaches.

Novel Pharmacologic Agents

New drugs targeting steroidogenesis, ACTH receptor signaling, and specific enzyme pathways are under investigation for the treatment of hypercortisolism and hyperaldosteronism.

Genetic and Molecular Insights

Advances in genomics and molecular biology have identified mutations and regulatory mechanisms underlying congenital adrenal hyperplasia, adrenal tumors, and other disorders, facilitating personalized medicine approaches.

Emerging Diagnostic Techniques

High-resolution imaging, functional adrenal scans, and biomarker-based assays improve early detection of adrenal lesions and assessment of hormone activity, enhancing diagnosis and monitoring of adrenal cortex disorders.

References

1. Young WF. Clinical review: Primary aldosteronism—diagnosis and treatment. J Clin Endocrinol Metab. 2007;92(8):2536-2543.
2. Funder JW, Carey RM, Mantero F, Murad MH, Reincke M, Shibata H, et al. The management of primary aldosteronism: Case detection, diagnosis, and treatment: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2016;101(5):1889-1916.
3. Nieman LK, Biller BMK, Findling JW, Murad MH, Newell-Price J, Savage MO, et al. Treatment of Cushing’s syndrome: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2015;100(8):2807-2831.
4. Speiser PW, Azziz R, Baskin LS, Ghizzoni L, Hensle TW, Merke DP, et al. Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2010;95(9):4133-4160.
5. 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.
6. Else T, Kim AC, Sabolch A, Raymond VM, Kandathil A, Caoili EM, et al. Adrenocortical carcinoma. Endocr Rev. 2014;35(2):282-326.
7. Bornstein SR. Predisposing factors for adrenal insufficiency. N Engl J Med. 2009;360(22):2328-2339.
8. Vinson GP. The adrenal cortex. In: DeGroot LJ, Jameson JL, editors. Endocrinology. 7th ed. Philadelphia: Elsevier; 2016. p. 703-723.
9. Charmandari E, Nicolaides NC, Chrousos GP. Adrenal insufficiency. Lancet. 2014;383(9935):2152-2167.