What is the pathophysiology of the adrenal glands, including their role in stress response, electrolyte balance, and blood pressure regulation, and how do disorders such as Cushing's syndrome and Addison's disease affect the body?

Adrenal Gland Pathophysiology

Overview of Adrenal Function

The adrenal glands are paired endocrine organs that maintain homeostasis through three distinct functional zones: the zona glomerulosa produces mineralocorticoids (aldosterone) for blood pressure and electrolyte regulation, the zona fasciculata produces glucocorticoids (cortisol) for stress response and metabolism, and the zona reticularis produces androgens, while the inner medulla secretes catecholamines (epinephrine, norepinephrine) under sympathetic control. 1

Cortex Hormone Production and Function

• Mineralocorticoids (Aldosterone): The zona glomerulosa produces aldosterone, which is vital for maintaining blood pressure and water-electrolyte homeostasis by regulating sodium retention and potassium excretion in the kidneys 2

• Glucocorticoids (Cortisol): The zona fasciculata produces cortisol, which has profound metabolic effects including regulation of glucose and protein metabolism, and modifies the body's immune responses to diverse stimuli 3, 4

• Adrenal Androgens: The zona reticularis produces dehydroepiandrosterone (DHEA), which contributes to androgen levels, particularly important in females 2

Medulla Catecholamine Production

• The adrenal medulla secretes epinephrine (adrenaline), norepinephrine, and dopamine under sympathetic nervous system control, providing rapid responses to acute stress 1, 4

Stress Response Mechanisms

Adrenal responses to stress involve concurrent activation of the hypothalamic-pituitary-adrenocortical (HPA) axis and the adrenomedullary hormonal system, with different stressors eliciting different patterns of autonomic responses rather than a uniform "fight or flight" reaction. 5

• The HPA axis increases cortisol production during physiological stress, trauma, surgery, or illness to maintain homeostasis 3, 6

• Adrenomedullary catecholamine release is more closely tied to adrenocortical responses than to sympathetic noradrenergic activity, representing integrated neuroendocrine activation during distress 5

• Proper stress adaptation is essential, as dysregulation causes obesity, depression, Parkinson's disease, and post-traumatic stress disorder 6, 4

Electrolyte Balance Regulation

Mineralocorticoids maintain sodium and water homeostasis through direct renal effects, with aldosterone stimulating sodium retention and potassium excretion to regulate blood volume and blood pressure. 2

• During normal pregnancy, the renin-angiotensin-aldosterone system (RAAS) becomes activated by the end of the first trimester, with plasma renin activity and aldosterone remaining elevated to increase plasma volume by 40-50% above baseline 2

• Fludrocortisone (synthetic mineralocorticoid) at 50-200 µg daily maintains blood pressure and prevents salt craving, orthostatic hypotension, and electrolyte disturbances in adrenal insufficiency 2

Blood Pressure Regulation

• Aldosterone directly increases blood pressure through sodium and fluid retention, expanding plasma volume 2, 1

• Cortisol in average to large doses causes elevation of blood pressure, salt and water retention, and increased potassium excretion 3

• The RAAS system, with angiotensin II-mediated aldosterone production, is a crucial regulator of blood pressure and fluid-electrolyte balance 2

Addison's Disease (Primary Adrenal Insufficiency) Pathophysiology

Addison's disease results from destruction of all three zones of the adrenal cortex, causing deficiency of glucocorticoids, mineralocorticoids, and adrenal androgens, leading to life-threatening inability to maintain blood pressure, electrolyte balance, and metabolic homeostasis. 2, 7

Clinical Manifestations

• Glucocorticoid deficiency causes impaired glucose metabolism, decreased protein synthesis, inability to respond to stress, fatigue, weight loss, and hypoglycemia (especially in children) 2, 7

• Mineralocorticoid deficiency causes hyponatremia, hyperkalemia, volume depletion, orthostatic hypotension, salt craving, and prerenal renal failure 2

• Adrenal androgen deficiency in females causes decreased libido and low energy levels due to severe androgen deficiency 2

Adrenal Crisis Pathophysiology

• Acute adrenal crisis represents complete failure of cortisol and aldosterone production during stress, causing severe hyponatremia, hyperkalemia, hypotension progressing to shock, impaired cognitive function, confusion, loss of consciousness, and coma 2

• Typical laboratory findings include hyponatremia, hyperkalemia, increased creatinine from prerenal failure, hypoglycemia in children, and sometimes mild hypercalcemia 2

• Immediate treatment requires hydrocortisone 100 mg IV to saturate 11β-hydroxysteroid dehydrogenase type 2 for mineralocorticoid effect, plus rapid 0.9% saline infusion (1 L over one hour) 2, 8

Cushing's Syndrome Pathophysiology

Cushing's syndrome results from chronic excessive cortisol exposure, either from ACTH-dependent sources (pituitary adenomas or ectopic ACTH-producing tumors) or ACTH-independent sources (adrenal adenomas, carcinomas, or bilateral hyperplasia), causing profound metabolic, cardiovascular, and immunologic dysfunction. 2, 7

Metabolic Effects

• Excessive glucocorticoids cause hyperglycemia and manifestations of latent diabetes mellitus through increased gluconeogenesis and insulin resistance 3

• Negative nitrogen balance occurs from protein catabolism, leading to muscle atrophy and weakness 2, 3

• Increased calcium excretion and bone resorption lead to osteoporosis 3

Cardiovascular and Electrolyte Effects

• Cortisol excess causes hypertension through salt and water retention and increased potassium excretion 3

• Patients require treatment for hypertension, hyperglycemia, and hypokalemia for symptom palliation 2

Immunologic and Dermatologic Effects

• Corticosteroids mask signs of infection, decrease resistance to infection, and impair wound healing 3

• Skin manifestations include thin fragile skin, petechiae, ecchymoses, facial erythema, and increased sweating 3

Endocrine Effects

• Chronic hypercortisolism suppresses the HPA axis, causing secondary adrenocortical and pituitary unresponsiveness, particularly dangerous during stress, trauma, surgery, or illness 3

• Menstrual irregularities occur from disrupted gonadotropin secretion 3

Neurologic and Ophthalmic Effects

• Increased intracranial pressure with papilledema (pseudotumor cerebri), convulsions, vertigo, and headache can develop 3

• Posterior subcapsular cataracts, increased intraocular pressure, glaucoma with optic nerve damage, and exophthalmos occur with prolonged use 3

Critical Pathophysiologic Principles

• The adrenal gland demonstrates remarkable cellular plasticity and adaptation to physiological stress, with proper adaptation essential for human health 6

• Dysregulation of either excess or deficiency of adrenal hormones creates serious pathologies requiring clinical laboratory detection and lifelong management 7, 4

• Knowledge deficits related to adrenal disease management may cause patients to become critically ill or die, making ongoing patient education crucial 7