ENDO 05: Adrenal Disorders

1. Overview of the Adrenal Glands

• Your adrenal glands sit on top of your kidneys and are very important for life because they regulate hormones essential for survival.

• They have two major parts:

  • Adrenal Cortex (outer layer) → Makes steroid hormones (corticosteroids)

  • Adrenal Medulla (inner part) → Makes catecholamines (epinephrine, norepinephrine)

Adrenal Cortex: Three Layers & Their Functions

Think of it as three layers, each making a different type of hormone:

⭐ Mnemonic: "Salt, Sugar, Sex – the deeper you go, the sweeter it gets!"

2. Aldosterone (Mineralocorticoid - Zona Glomerulosa)

• Main function: Maintains extracellular fluid & electrolyte balance

• Acts on the kidneys:

  • Increases Na+ reabsorption (water follows → increases blood pressure)

  • Increases K+ excretion

Why does this happen?

• Sodium (Na⁺) is key for blood pressure:

  • When aldosterone tells the kidneys to reabsorb more sodium, water follows by osmosis.

  • This increases blood volume → raises blood pressure.

• Potassium (K⁺) needs to be excreted properly:

  • The body must keep Na⁺ and K⁺ in balance.

  • So, when sodium is reabsorbed, potassium gets excreted in exchange.

Control System:

• Aldosterone is mostly controlled by the Renin-Angiotensin-Aldosterone System (RAAS), NOT the HPA axis.

• Key triggers for aldosterone release:

  • High K+ (serum potassium)

  • Angiotensin II (from RAAS system, activated when BP is low)

When is aldosterone released?

• When blood pressure is low (RAAS activation)

• When potassium levels are high (to prevent hyperkalemia)

Why is aldosterone important?

• Keeps blood pressure stable

• Prevents dehydration

• Regulates potassium balance

3. Cortisol (Glucocorticoid - Zona Fasciculata)

Cortisol is the "stress hormone" and has many effects on the body:

Stimulatory Effects (What it Increases)

• Blood sugar (glucose production = gluconeogenesis) → Can cause hyperglycemia

• Leukocytosis (temporary increase in white blood cells)

• Vascular tone (keeps blood vessels from leaking → helps maintain blood pressure)

• Fluid retention

Inhibitory Effects (What it Suppresses)

• Immune system (anti-inflammatory effect)

• Fibroblast activity (slows wound healing)

• Bone metabolism (can lead to osteoporosis with long-term use)

• Reproductive axis (can disrupt fertility & sex hormone balance)

🔹 Why do we use cortisol (or synthetic glucocorticoids like prednisone) as medication?

• To suppress inflammation (e.g., asthma, autoimmune diseases)

• To prevent organ transplant rejection

• To boost blood pressure in adrenal insufficiency

🔹 Why does it have side effects?

• If we give too much, we can see hyperglycemia, osteoporosis, fluid retention, and immune suppression

4. Androgens (Zona Reticularis)

• The adrenal glands are a major source of androgens (especially as people age).

• DHEA (dehydroepiandrosterone) is the main adrenal androgen and affects:

  • Mood

  • Libido (sex drive)

  • Energy levels

Even though sex hormones (testosterone, estrogen) mostly come from the gonads, the adrenals become an important source later in life.

5. Hypothalamic-Pituitary-Adrenal (HPA) Axis

The HPA axis controls cortisol release through negative feedback:

1⃣ Stress (physical or emotional) signals the hypothalamus
2⃣ Hypothalamus releases CRH (Corticotropin-Releasing Hormone) + Vasopressin
3⃣ CRH stimulates the pituitary gland to release ACTH (Adrenocorticotropic Hormone)
4⃣ ACTH tells the adrenal cortex to release Cortisol, Aldosterone, and DHEA

🔹 Negative feedback:

• When cortisol levels are high, the hypothalamus & pituitary slow down CRH and ACTH release to prevent overproduction.

‼ Note: The HPA axis does NOT control aldosterone much (RAAS does!)

6. Circadian Rhythm & Cortisol

• Cortisol follows a daily rhythm:

  • Morning peak → Highest cortisol levels (helps wake you up)

  • Afternoon surge → Small boost in the afternoon

  • Midnight nadir → Lowest levels (prepares for sleep)

🌙 This cycle depends on having a regular day-night sleep pattern. If sleep is disrupted (e.g., night shifts, stress), cortisol rhythms can get out of sync.

Final Takeaways

• The adrenal glands make essential hormones for survival:

  • Aldosterone (Salt) → Blood pressure & fluid balance

  • Cortisol (Sugar) → Stress, metabolism, immune function

  • DHEA (Sex) → Androgen production, mood, energy

• Cortisol release is controlled by the HPA axis (stress response)

• Aldosterone is controlled by RAAS (blood pressure & electrolyte balance)

• Cortisol follows a daily rhythm, peaking in the morning and lowest at midnight

1. What Are Glucocorticoids?

Glucocorticoids are steroid hormones that mimic cortisol, which is naturally produced by the adrenal glands. They bind to glucocorticoid receptors (GRs) and alter gene transcription, leading to changes in metabolism, immune function, and inflammation.

💊 Why do we use them as drugs?

• To replace cortisol if the body isn’t making enough (e.g., adrenal insufficiency)

• To suppress inflammation and the immune system (e.g., autoimmune diseases, asthma, organ transplants)

2. Mechanism of Action (MOA)

🛠 How do they work?

• They bind to glucocorticoid receptors (GRs) inside cells.

• This changes gene expression → Increases or decreases the production of certain proteins.

• The effects depend on the target tissue (immune cells, liver, bones, etc.).

Key Effects

✅ Increase:

• Blood sugar (gluconeogenesis in the liver) → risk of hyperglycemia

• Blood pressure (by increasing vascular tone & sodium retention)

• Breakdown of muscle & fat (to provide energy during stress)

❌ Decrease:

• Inflammation (suppresses immune cells, cytokines, and histamine release)

• Bone formation (risk of osteoporosis with long-term use)

• Fibroblast activity (slower wound healing & skin thinning)

3. Important Pharmacokinetics (PK)

• Prednisone and cortisone are prodrugs → They must be activated in the liver:

  • Prednisone → Prednisolone

  • Cortisone → Hydrocortisone

• Different glucocorticoids have varying half-lives due to differences in protein binding and chemical structure.

4. Adverse Effects (CUSHINGOID)

Too much glucocorticoid activity mimics Cushing’s syndrome, so we use the CUSHINGOID mnemonic to remember side effects:

⚠ Key Takeaway: Long-term glucocorticoid use can cause serious metabolic, cardiovascular, and immune-related side effects.

5. Comparison of Different Corticosteroids

Not all corticosteroids are the same! Some have more glucocorticoid activity (anti-inflammatory effects), while others have more mineralocorticoid activity (salt & water balance).

Key Takeaways from This Table

• Hydrocortisone and cortisone are closest to natural cortisol (equal glucocorticoid & mineralocorticoid activity).

• Prednisone, prednisolone, and methylprednisolone are more potent than hydrocortisone for inflammation, but have less mineralocorticoid effect.

• Dexamethasone is extremely potent (30x stronger than cortisol) and lasts a long time (36-72 hours).

• Fludrocortisone is mostly used for its mineralocorticoid (salt-retaining) effects, not glucocorticoid effects.

Final Takeaways

• Glucocorticoids mimic cortisol and work by altering gene transcription.

• Prednisone & cortisone are prodrugs that require activation in the liver.

• Long-term use has serious side effects (CUSHINGOID mnemonic).

• Different glucocorticoids vary in potency, half-life, and mineralocorticoid effects.

Adrenal Enzyme Inhibitors

These drugs work by blocking enzymes needed for steroid production in the adrenal cortex, leading to reduced cortisol (and sometimes aldosterone or androgens).

1. Ketoconazole (Antifungal)

• MOA: Inhibits multiple steps in steroid production:

  • Blocks CYP11B1, stopping conversion of 11-deoxycortisol → cortisol

  • Inhibits CYP11A1, blocking cholesterol from converting to pregnenolone (first step in steroid synthesis)

• PK:

  • Needs acidic environment for absorption (avoid antacids, PPIs, H2RAs)

  • Strong CYP3A4, 2C9, 1A2 inhibitor → significant drug interactions

• AE:

  • Hepatotoxicity

  • ↓ Cortisol effects → fatigue, headache, low BP (orthostatic hypotension)

  • ↓ Testosterone effects → gynecomastia, ↓ libido, impotence

• Key Note: Only affects HPA axis when taken orally → No concern with topical ketoconazole

2. Metyrapone

• MOA:

  • Blocks CYP11B1, preventing 11-deoxycortisol → cortisol

  • Also blocks aldosterone synthase, leading to buildup of another mineralocorticoid

• PK:

  • Fast onset → within 24 hours

• AE:

  • GI upset (N/V)

  • Adrenal insufficiency (too little cortisol)

  • Acne/hirsutism in females (due to androgen buildup)

  • Rare: Hypokalemia, hypertension

• Drug Interactions:

  • Phenytoin & phenobarbital → Increase metyrapone metabolism

  • Estrogen → Decreases metyrapone metabolism

Adrenolytics (Mitotane)

These drugs destroy adrenal cortex cells, reducing cortisol production.

Mitotane

• MOA:

  • Adrenolytic → Metabolite disrupts adrenal mitochondria, leading to adrenal cell death

  • Steroidogenic inhibition:

    • Blocks CYP11A1, stopping cholesterol from converting to pregnenolone

    • Blocks CYP11B1, preventing 11-deoxycortisol → cortisol

• PK:

  • Highly lipophilic

  • Long half-life (18-159 days!)

• AE:

  • CNS: Lethargy, drowsiness, dizziness

  • CVS: High cholesterol

  • GI: N/V/D, anorexia, primary adrenal insufficiency

  • Endocrine: ↓ T4, gynecomastia

  • Derm: Rash

  • Teratogenic → Avoid pregnancy for years after stopping!

• Drug Interactions: CYP3A4 inducer

ACTH Release Inhibitors

These drugs work higher up in the HPA axis by blocking ACTH release from the pituitary, leading to less stimulation of the adrenal glands.

1. Cabergoline

• MOA:

  • Dopamine receptor agonist → Reduces ACTH secretion from pituitary tumors

• PK:

  • Metabolized by hepatic hydrolysis (minimal CYP involvement)

• AE:

  • CNS: Headache, dizziness, fatigue, drowsiness

  • CVS: Orthostatic hypotension

  • GI: Nausea, constipation, abdominal pain

• Drug Interactions:

  • Additive effects with other dopamine agonists (caution in Parkinson’s)

2. Pasireotide

• MOA:

  • Somatostatin receptor agonist → Blocks ACTH release from corticotroph tumors

• PK:

  • High Vd (>100L) (widely distributed)

  • Highly protein-bound

  • Biliary excretion as unchanged drug

• AE:

  • CNS: Headache, fatigue, dizziness, insomnia

  • CVS: HTN, bradycardia, peripheral edema

  • GI: Diarrhea, nausea, cholelithiasis, ↑ LFTs

• Drug Interactions:

  • Avoid with ceritinib

  • Potential bradycardia, QTc-prolonging effects

Glucocorticoid Receptor Antagonists

These drugs block the effects of cortisol at the receptor level.

Mifepristone

• MOA:

  • Antagonizes glucocorticoid receptors

  • Also blocks progesterone receptors (why it’s used as an abortifacient)

• PK:

  • Highly protein-bound (98%)

  • Metabolized by CYP3A4

• AE:

  • CNS: Fatigue, headache, dizziness

  • CVS: HTN, edema

  • Respiratory: Dyspnea

  • GI: N/V, abdominal cramps, ↓ appetite

  • MSK: Arthralgia, myalgia

  • Endo: Hypokalemia, abnormal TSH

  • Possible QTc prolongation

• Drug Interactions:

  • CYP3A4 substrate

Key Takeaways

• Adrenal Enzyme Inhibitors (Ketoconazole, Metyrapone): Block cortisol synthesis

• Adrenolytics (Mitotane): Destroys adrenal cells → long-lasting effect

• ACTH Release Inhibitors (Cabergoline, Pasireotide): Block ACTH secretion → Less cortisol production

• Glucocorticoid Receptor Antagonists (Mifepristone): Blocks cortisol at receptor level

Adrenal Insufficiency (Too Little Hormone)

When the adrenal glands don’t make enough cortisol (and sometimes aldosterone).

Types:

1. Primary Adrenal Insufficiency (Addison’s Disease)

   • Problem with adrenal glands themselves

   • ↓ Cortisol & ↓ Aldosterone

   • Causes: Autoimmune destruction, infections (TB, HIV), cancer, hemorrhage

2. Secondary Adrenal Insufficiency

   • Problem higher up in the HPA axis (pituitary) → low ACTH → low cortisol

   • Aldosterone remains normal (regulated by RAAS, not ACTH)

   • Causes: Chronic glucocorticoid use (causing adrenal atrophy), pituitary tumor, head trauma

3. Acute Adrenal Insufficiency (Adrenal Crisis)

   • Medical emergency! Rapid cortisol ± aldosterone deficiency

   • Causes:

     • Sudden withdrawal of steroids (most common)

     • Adrenal gland damage (infection, hemorrhage)

     • Severe stress (infection, surgery) in someone with adrenal insufficiency

   • Requires immediate treatment!

Hypercortisolism (Too Much Hormone) = Cushing’s Syndrome

Excess cortisol from exogenous or endogenous sources.

Causes:

1. Exogenous Cushing’s Syndrome

   • Most common cause → Long-term steroid use (iatrogenic)

2. Endogenous Cushing’s Syndrome (Body overproduces cortisol)

   • ACTH-Dependent (ACTH is high → adrenal glands make too much cortisol)

     • Ectopic ACTH-producing tumor (e.g., small cell lung cancer)

     • Pituitary adenoma (Cushing’s disease – most common endogenous cause)

   • ACTH-Independent (Adrenal glands secrete cortisol without ACTH)

     • Adrenal adenoma (benign tumor)

     • Adrenal carcinoma (malignant tumor)

Key Takeaways

• Adrenal Insufficiency = Too little cortisol (± aldosterone)

  • Primary → Problem with adrenal glands (↓ cortisol & aldosterone)

  • Secondary → Problem with pituitary (↓ ACTH → ↓ cortisol, but normal aldosterone)

  • Acute → Emergency! Needs rapid treatment

• Cushing’s Syndrome = Too much cortisol

  • Exogenous → Steroid use

  • Endogenous

    • ACTH-Dependent (ectopic tumor or pituitary adenoma → high ACTH)

    • ACTH-Independent (adrenal adenoma/carcinoma → high cortisol despite low ACTH)

Types of Adrenal Insufficiency

Normal HPA Axis Function

1. Hypothalamus → releases CRH

2. Pituitary → releases ACTH

3. Adrenal Cortex → produces cortisol (+ aldosterone & androgens)

Primary Adrenal Insufficiency (Addison’s Disease)

• Problem: Adrenal cortex doesn't respond → low cortisol, aldosterone, DHEA

• HPA Axis:

  • High ACTH (pituitary keeps trying to stimulate adrenals)

  • High CRH (hypothalamus trying to compensate)

  • Low cortisol (adrenals don’t produce it)

Secondary Adrenal Insufficiency

• Problem: Pituitary doesn’t release ACTH → adrenals aren’t stimulated → low cortisol

• HPA Axis:

  • Low ACTH (pituitary isn’t sending the signal)

  • High CRH (hypothalamus trying to compensate)

  • Low cortisol

  • Aldosterone is normal (controlled by RAAS, not ACTH)

Etiology (Causes) – “VITAMIN C” Mnemonic

• Vascular → Adrenal hemorrhage, necrosis

• Infection → TB, fungal infections, HIV

• Trauma → Physical injury to adrenal glands

• Autoimmune → APS Type 1 & Type 2 (most common cause in developed countries)

• Metabolic → Rare enzyme deficiencies

• Iatrogenic/Idiopathic → Drugs (anticoagulants, adrenal enzyme inhibitors, phenytoin, carbamazepine, rifampin)

• Neoplasm → Cancer infiltrating the adrenal glands

• Congenital → Congenital Adrenal Hyperplasia (CAH)

Clinical Presentation

• General Symptoms:

  • Fatigue, weakness, low mood, low libido

  • Nausea, vomiting, diarrhea, abdominal pain, weight loss, anorexia

  • Orthostatic hypotension (dizzy when standing up)

  • Headache

• Key Signs of Primary Adrenal Insufficiency:

  • Salt craving (low aldosterone → sodium loss)

  • Vitiligo, hyperpigmentation (↑ ACTH stimulates melanin)

  • Adrenal calcification

  • ↑ Potassium (hyperkalemia), ↓ Sodium (hyponatremia) (low aldosterone → electrolyte imbalance)

Diagnosis

1. Clinical suspicion → Measure morning cortisol (should normally be high)

   • If low, check ACTH levels

   • High ACTH + Low Cortisol → Primary AI

   • Low ACTH + Low Cortisol → Secondary AI

2. ACTH Stimulation Test (Gold Standard)

   • Synthetic ACTH is given → cortisol levels should increase

   • No response = adrenal insufficiency (problem with adrenals themselves)

   • If cortisol rises → likely secondary (pituitary problem)

3. Imaging (if needed)

   • Adrenal imaging for primary AI (tumors, hemorrhage)

   • Pituitary MRI for secondary AI

Complications

• Acute Adrenal Insufficiency (Adrenal Crisis)

  • Life-threatening → needs emergency treatment!

  • Sudden worsening of symptoms (shock, coma, death) if not treated

  • Usually triggered by stress, infection, surgery, or stopping steroids too quickly

• Corticosteroid Over-Treatment (If Given Too Much)

  • Adrenal suppression → body stops making its own steroids

  • Cushingoid side effects → weight gain, high blood pressure, high blood sugar, osteoporosis