Adrenal Disorders - Comprehensive Lecture Note

1. Learning Objectives

Describe the anatomy, physiology, and hormonal regulation of the adrenal gland.
Differentiate Cushing's syndrome, Cushing's disease, and adrenal insufficiency by cause and presentation.
Identify the signs, symptoms, and diagnostic approach for primary hyperaldosteronism.
Recognize the clinical features and management of pheochromocytoma.
Select glucocorticoid and mineralocorticoid replacement therapy for adrenal insufficiency.
Identify pharmacologic agents used for cortisol excess in Cushing's syndrome.
Recognize and manage adrenal crisis as a medical emergency.
Provide patient-centered counseling on glucocorticoid therapy, dosing schedules, adherence, and sick day rules.

2. Introduction to the Adrenal Gland

The adrenal glands are paired triangular endocrine glands above each kidney. Each gland has a hormonally active cortex and medulla, and disorders of either region can create major cardiovascular, metabolic, and emergency-care consequences.

Region	Hormones Produced	Primary Functions
Adrenal cortex	Glucocorticoids, mineralocorticoids, and androgens	Stress response, metabolism, electrolyte balance, blood pressure control, and secondary sex traits
Adrenal medulla	Catecholamines	Fight-or-flight signaling with higher heart rate, BP, and glucose

Hypothalamic-Pituitary-Adrenal axis regulation

Hypothalamus -> Corticotropin-Releasing Hormone (CRH)
            ↓
        Pituitary Gland
            ↓
Adrenocorticotropic Hormone (ACTH)
            ↓
        Adrenal Cortex
            ↓
            Cortisol
            ↓
Negative feedback to hypothalamus and pituitary

Clinical pearl: exogenous glucocorticoids suppress the HPA axis. Abrupt withdrawal after chronic use can produce adrenal insufficiency or adrenal crisis.

3. Disorders of Adrenal Cortical Excess

3.1. Cushing's Syndrome

Cushing's syndrome is chronic glucocorticoid excess from any cause. Exogenous steroid exposure is the most common overall cause, while pituitary ACTH excess is the most common endogenous source.

Type	Cause	Frequency Pattern
Exogenous	Long-term glucocorticoids or ACTH exposure	Most common overall
ACTH-dependent	Pituitary adenoma or ectopic ACTH production	Most endogenous cases
ACTH-independent	Adrenal adenoma, adrenal carcinoma, bilateral adrenal hyperplasia	Minority of endogenous cases

CUSHINGOID clinical pattern

Central obesity / upper body obesity: truncal fat with thin extremities and buffalo hump
Skin changes: purple striae, easy bruising, thin skin
Hypertension and hyperglycemia: cortisol drives both hemodynamic and metabolic injury
Immune, neuropsychiatric, gonadal, and bone effects: infection risk, depression, menstrual disturbance, osteoporosis
Androgen excess: hirsutism or acne, especially with adrenal tumors

Test	Finding in Cushing's Syndrome
24-hour urinary free cortisol	Elevated; classic screening test
Late-night salivary cortisol	Elevated because circadian rhythm is lost
Low-dose dexamethasone suppression	Failure to suppress cortisol
Plasma ACTH	Differentiates ACTH-dependent from ACTH-independent disease
High-dose dexamethasone suppression	Suppression suggests pituitary source
Imaging	MRI pituitary or CT adrenals/chest depending on source

3.2. Hyperaldosteronism (Primary Aldosteronism)

Primary hyperaldosteronism is aldosterone excess independent of the renin-angiotensin system. It causes resistant hypertension, hypokalemia, metabolic alkalosis, and suppressed plasma renin.

Etiology	Relative Frequency
Idiopathic bilateral adrenal hyperplasia	Most common
Aldosterone-producing adenoma (Conn's syndrome)	Second most common
Unilateral adrenal hyperplasia, familial disease, adrenal carcinoma	Rare

Clinical presentation

Resistant or severe hypertension
Hypokalemia with weakness, cramps, and fatigue
Metabolic alkalosis and mild hypernatremia
Polyuria or polydipsia from hypokalemia-induced nephrogenic DI

Diagnostic approach

Aldosterone-to-renin ratio: screening test of choice
Oral sodium loading: confirmatory if aldosterone fails to suppress
Adrenal CT: adenoma versus bilateral disease
Adrenal vein sampling: gold standard for lateralization before surgery

4. Disorders of Adrenal Cortical Insufficiency

4.1. Primary Adrenal Insufficiency (Addison's Disease)

Primary adrenal insufficiency results from adrenal cortex destruction, causing deficiency of cortisol, aldosterone, and adrenal androgens.

Cause	Clinical Note
Autoimmune adrenalitis	Most common in developed settings
Infectious disease	TB, HIV, or fungal disease remain important globally
Metastatic, hemorrhagic, infiltrative, or drug-induced injury	Think cancer, Waterhouse-Friderichsen syndrome, ketoconazole, etomidate, or mitotane

Clinical presentation

Profound chronic fatigue and weight loss
Hyperpigmentation: key feature from high ACTH
Orthostatic hypotension and salt craving
Hyponatremia, hyperkalemia, and hypoglycemia
Nausea, vomiting, abdominal pain, or diarrhea

4.2. Secondary Adrenal Insufficiency

Secondary adrenal insufficiency reflects low ACTH from pituitary or hypothalamic dysfunction. Aldosterone is usually preserved, so hyperkalemia and marked mineralocorticoid deficiency are not typical.

Most common cause: chronic exogenous glucocorticoid therapy
Other causes: pituitary tumors, surgery, radiation, Sheehan's syndrome, hypothalamic disease

Feature	Primary (Addison's)	Secondary
Hyperpigmentation	Present	Absent
Aldosterone deficiency	Yes	No
Plasma ACTH	Elevated	Low or inappropriately normal
Renin	Elevated	Usually normal

4.3. Adrenal Crisis

Adrenal crisis is acute life-threatening adrenal insufficiency, often triggered by illness, surgery, trauma, abrupt glucocorticoid withdrawal, or bilateral adrenal hemorrhage.

Emergency pattern: hypotension or shock, severe hyponatremia, hyperkalemia, hypoglycemia, vomiting, fever, and altered mental status.

Intervention	Emergency Management
IV hydrocortisone	100 mg IV bolus, then 50-100 mg IV every 6 hours or continuous infusion
IV fluids	0.9% normal saline rapidly, often liters over the first 24 hours
Glucose	D50W if hypoglycemia is present
Monitoring	Electrolytes, hemodynamics, and the precipitating cause

5. Disorders of Adrenal Medulla

5.1. Pheochromocytoma

Pheochromocytoma is a catecholamine-secreting tumor from adrenal medullary chromaffin cells. Extra-adrenal analogues are paragangliomas.

PHEO clinical picture

P: Paroxysmal hypertension
H: Headache
E: Episodic sweating
O: Ordinary triggers with palpitations, anxiety, tremor, and pallor

The classic triad is headache, palpitations, and diaphoresis.

Triggers and work-up

Stress, exertion, anesthesia, tyramine, opioids, metoclopramide, tricyclics
Plasma-free metanephrines: screening test of choice
24-hour urinary fractionated metanephrines: confirmatory support
CT/MRI and MIBG: localize adrenal or extra-adrenal disease

Critical warning: never give a beta-blocker alone in pheochromocytoma. Unopposed alpha-mediated vasoconstriction can precipitate a hypertensive crisis.

5.2. Paraganglioma

Paragangliomas are extra-adrenal catecholamine-producing tumors. They share the same diagnostic logic and perioperative alpha-first management principles as pheochromocytoma.

6. Pharmacological Management

6.1. Glucocorticoid Replacement Therapy

Agent	Dose	Clinical Note
Hydrocortisone	15-25 mg/day divided	Preferred physiologic replacement; largest dose in the morning
Prednisone	3-5 mg/day	Longer-acting alternative
Dexamethasone	0.5-0.75 mg/day	Not preferred for replacement because suppression is stronger and mineralocorticoid activity is absent

Dosing principles: largest dose at 6-8 AM, smaller dose in early afternoon, and double or triple the dose during illness, fever, trauma, or surgery.

6.2. Mineralocorticoid Replacement Therapy

Fludrocortisone 0.05-0.2 mg/day is used in primary adrenal insufficiency only. Monitor BP, sodium, potassium, and plasma renin activity.

6.3. Drugs for Cushing's Syndrome	Mechanism	Use
Ketoconazole, metyrapone, etomidate, mitotane, osilodrostat	Adrenal steroidogenesis inhibition	Pre-op control, persistent disease, or metastatic/inoperable disease
Pasireotide	Pituitary-directed ACTH suppression	Cushing's disease when surgery is not suitable or is incomplete
Mifepristone	Glucocorticoid receptor antagonism	Cushing's syndrome with hyperglycemia when surgery is not an option

6.4. Drugs for Hyperaldosteronism	Mechanism	Use
Spironolactone, eplerenone	Mineralocorticoid receptor antagonism	First-line medical therapy, especially in bilateral adrenal hyperplasia
Amiloride, triamterene	ENaC inhibition	Alternative if MRAs are not tolerated
Laparoscopic adrenalectomy	Surgical removal of adenoma	Curative for unilateral aldosterone-producing adenoma

Spironolactone adverse effects: hyperkalemia, gynecomastia, impotence, and menstrual irregularities.

6.5. Drugs for Pheochromocytoma	Dose or Sequence	Purpose
Phenoxybenzamine	Start low and titrate over 7-14 days pre-op	Alpha-blockade to control BP and prevent hypertensive crisis
Propranolol or atenolol	Add only after alpha-blockade is established	Control tachycardia
High-sodium diet / IV fluids	After alpha-blockade	Reverse vasoconstriction-induced hypovolemia
Metyrosine	Adjunct in refractory disease	Reduce catecholamine synthesis

7. Patient Counseling Points

For chronic glucocorticoid therapy

Never stop abruptly: sudden withdrawal can cause adrenal crisis.
Sick day rules: double or triple the dose during illness, fever, surgery, or trauma.
Timing matters: larger morning dose helps mimic circadian rhythm.
Bone and glucose monitoring: long-term steroids weaken bone and raise blood sugar.
Take with food: helps reduce gastric irritation.

For spironolactone or pheochromocytoma therapy

Spironolactone: avoid potassium salt substitutes and report muscle weakness or palpitations.
Gynecomastia counseling: breast tenderness or enlargement can occur; alternatives exist.
Pheochromocytoma pre-op: take alpha-blocker exactly as prescribed and avoid known triggers.
Medical alert: adrenal insufficiency patients should carry emergency steroid information.

8. Summary for Exam Preparation

Condition	Key Feature	First-Line Treatment
Cushing's Syndrome	Central obesity, striae, hypertension, hyperglycemia	Surgery when possible; steroidogenesis inhibitors if not
Primary Aldosteronism	Hypertension plus hypokalemia with suppressed renin	Spironolactone/eplerenone or adrenalectomy for adenoma
Addison's Disease	Hyperpigmentation, hyponatremia, hyperkalemia, hypotension	Hydrocortisone plus fludrocortisone
Secondary Adrenal Insufficiency	No hyperpigmentation, normal aldosterone pattern	Hydrocortisone or prednisone without fludrocortisone
Adrenal Crisis	Shock, hyponatremia, hyperkalemia, hypoglycemia	IV hydrocortisone 100 mg plus IV normal saline
Pheochromocytoma	Paroxysmal hypertension, headache, palpitations, diaphoresis	Alpha-blockade, then beta-blockade, then surgery

CUSHINGOID

Central obesity, upper body obesity, skin changes, hypertension, hyperglycemia, immune suppression, neuropsychiatric change, gonadal dysfunction, osteoporosis, and diabetes.

ADDISON

Autoimmune, dark hyperpigmentation, diarrhea, insidious onset, sodium loss, orthostatic hypotension, and negative energy balance.

PHEO

Paroxysmal hypertension, headache, episodic sweating, and ordinary triggers with palpitations.

9. Key Guidelines Links

Endocrine Society Cushing's Syndrome Guidance 2015: https://www.endocrine.org/clinical-practice-guidelines/cushings-syndrome

Endocrine Society Primary Aldosteronism Guidance 2016: https://www.endocrine.org/clinical-practice-guidelines/primary-aldosteronism

Endocrine Society Adrenal Insufficiency Guidance 2016: https://www.endocrine.org/clinical-practice-guidelines/adrenal-insufficiency

Endocrine Society Pheochromocytoma and Paraganglioma Guidance 2014: https://www.endocrine.org/clinical-practice-guidelines/pheochromocytoma-and-paraganglioma

Society for Endocrinology Emergency Adrenal Crisis Guidance 2020: https://www.endocrinology.org/clinical-practice/emergency-guidelines/