Cushing's Syndrome: Recognizing and Treating Excess Cortisol

What Is Cushing’s Syndrome?

Cushing’s syndrome is a hormonal disorder caused by prolonged exposure to abnormally high levels of cortisol — the body’s primary stress hormone. Cortisol is produced by the adrenal glands (small glands above each kidney) and is regulated by the pituitary gland in the brain.

While cortisol is essential for life — regulating blood sugar, blood pressure, immune function, and stress response — too much cortisol wreaks havoc on nearly every organ system.

Cushing’s syndrome is relatively rare, affecting approximately 2–3 per million people per year, but its effects are devastating if undiagnosed. It is one of the most challenging diagnoses in endocrinology because symptoms develop gradually and overlap with many common conditions.

What Causes Cushing’s Syndrome?

1. Exogenous (External) Cushing’s — The Most Common Cause

Prolonged use of glucocorticoid medications:

• Oral steroids (prednisolone, dexamethasone)
• Injected steroids (joint injections, epidural injections)
• Inhaled steroids (high doses)
• Topical steroids (potent formulations used extensively)
• Ayurvedic/herbal preparations containing hidden steroids

This is the most common cause by far and should always be considered first.

2. Endogenous (Internal) Cushing’s

The body itself produces excess cortisol:

ACTH-Dependent (80% of endogenous cases):

• Cushing’s Disease — a benign pituitary tumor (adenoma) that produces excess ACTH, which stimulates the adrenal glands (most common endogenous cause — 60–70%)
• Ectopic ACTH Syndrome — ACTH produced by a tumor outside the pituitary, typically in the lung (small cell carcinoma, carcinoid), thymus, or pancreas (10–15%)

ACTH-Independent (20% of endogenous cases):

• Adrenal adenoma — benign cortisol-producing adrenal tumor
• Adrenal carcinoma — malignant adrenal tumor (rare)
• Bilateral adrenal hyperplasia — bilateral macronodular or micronodular adrenal disease

Signs and Symptoms of Cushing’s Syndrome

Cushing’s syndrome affects virtually every organ system. The classic features include:

Body Composition Changes

• Central obesity — fat accumulation in the abdomen, face, and upper back
• Moon face (round, plethoric face)
• Buffalo hump (fat pad between the shoulders)
• Supraclavicular fat pads
• Thin arms and legs — due to muscle wasting (proximal myopathy)

Skin Changes

• Purple/violaceous striae — wide (> 1 cm) stretch marks on the abdomen, thighs, breasts, and arms — a key distinguishing feature from obesity
• Easy bruising — even with minor trauma
• Thin, fragile skin — paper-thin, transparent
• Poor wound healing
• Acne and hirsutism (in women)
• Facial plethora — red, flushed face

Metabolic Effects

• Diabetes or glucose intolerance — cortisol raises blood sugar
• Hypertension — often resistant to standard treatment
• Dyslipidemia
• Hypokalemia (low potassium) — especially in ectopic ACTH syndrome
• Osteoporosis and fractures — cortisol weakens bones

Reproductive Effects

• Menstrual irregularity in women
• Erectile dysfunction and low libido in men
• Infertility

Neuropsychiatric Effects

• Depression — present in up to 70% of patients
• Anxiety and emotional lability
• Cognitive impairment — poor memory, difficulty concentrating
• Insomnia
• Psychosis (in severe cases)

Immune Effects

• Increased susceptibility to infections
• Opportunistic infections (fungal, tuberculosis)

Musculoskeletal Effects

• Proximal muscle weakness — difficulty climbing stairs, rising from a chair
• Osteoporosis — vertebral compression fractures
• Avascular necrosis of the hip

How Is Cushing’s Syndrome Diagnosed?

Diagnosis is a multi-step process and one of the most complex in endocrinology:

Step 1: Clinical Suspicion

Cushing’s should be suspected in patients with:

• Multiple features listed above, especially if progressive
• Young patients with osteoporosis, hypertension, or diabetes
• Incidental adrenal or pituitary masses with suggestive symptoms

Step 2: Confirm Cortisol Excess (First-Line Screening Tests)

At least two positive tests are required for diagnosis:

Test	How It Works	Positive Result
24-hour Urinary Free Cortisol (UFC)	Measures total cortisol excreted in urine over 24 hours	> 3x upper limit of normal
Late-Night Salivary Cortisol	Measures cortisol at midnight (normally at its lowest)	Elevated on 2 occasions
1 mg Overnight Dexamethasone Suppression Test (ONDST)	Take 1 mg dexamethasone at 11 PM; check morning cortisol	Cortisol > 1.8 mcg/dL (50 nmol/L)

Step 3: Determine the Cause (ACTH-Dependent vs Independent)

• Plasma ACTH levels:
  • ACTH suppressed (< 5 pg/mL) → Adrenal cause
  • ACTH normal or elevated (> 20 pg/mL) → Pituitary or ectopic cause

Step 4: Localize the Source

If ACTH-dependent:

• MRI Pituitary (with dynamic contrast) — look for pituitary adenoma
• High-dose Dexamethasone Suppression Test (HDDST) — helps differentiate pituitary from ectopic
• Inferior Petrosal Sinus Sampling (IPSS) — gold standard for confirming pituitary source when MRI is equivocal

If ACTH-independent:

• CT Adrenal glands — identify adenoma, carcinoma, or bilateral hyperplasia

Treatment of Cushing’s Syndrome

1. Stop Exogenous Steroids (If Applicable)

• Gradual taper under medical supervision (never stop abruptly — risk of adrenal crisis)
• Switch to steroid-sparing alternatives when possible

2. Surgery (First-Line for Endogenous Cushing’s)

Cushing’s Disease (Pituitary):

• Transsphenoidal surgery — removal of the pituitary adenoma through the nose
• Success rate: 65–90% for microadenomas
• Performed by experienced neurosurgeons

Adrenal Tumors:

• Adrenalectomy — surgical removal of the adrenal tumor (laparoscopic or open)
• Curative for benign adenomas
• Bilateral adrenalectomy for bilateral disease

Ectopic ACTH:

• Removal of the ACTH-producing tumor (if localized)

3. Medical Therapy

Used when surgery is not possible, has failed, or as a bridge:

• Steroidogenesis inhibitors:
  • Ketoconazole — blocks cortisol production
  • Metyrapone — inhibits cortisol synthesis
  • Osilodrostat — newer, effective option
• Pituitary-directed:
  • Pasireotide — somatostatin analogue for Cushing’s disease
  • Cabergoline — dopamine agonist (effective in some cases)
• Glucocorticoid receptor blocker:
  • Mifepristone — blocks cortisol action at the receptor level

4. Radiation Therapy

• Stereotactic radiosurgery (Gamma Knife) or conventional radiotherapy
• Used after failed pituitary surgery
• Effects are gradual (months to years)
• Risk of hypopituitarism

Recovery After Treatment

After successful surgery for Cushing’s:

• Adrenal insufficiency is expected — the normal adrenal gland has been suppressed by excess cortisol and needs time to recover
• Glucocorticoid replacement (hydrocortisone) is needed for months to sometimes years
• Recovery of the HPA axis can take 6–18 months or longer
• Weight loss, improvement in diabetes, hypertension, and mood occur gradually
• Bone density improves over 1–2 years
• Some features (striae, skin changes) may not fully reverse

The Bottom Line

Cushing’s syndrome is a serious but treatable condition. The challenge lies in early recognition and accurate diagnosis. If you have progressive weight gain with muscle weakness, unexplained diabetes or hypertension, wide purple stretch marks, or are taking long-term steroids, seek an endocrine evaluation.

“Cushing’s syndrome is the great mimicker in endocrinology — it looks like many common conditions. The key is thinking of it in the right clinical context.”

If you suspect cortisol excess or have been found to have an adrenal or pituitary mass, consult an endocrinologist for a systematic diagnostic workup and management plan.