Cushing syndrome: recognising cortisol excess in general practice

Cushing syndrome is the clinical manifestation of prolonged, excessive glucocorticoid exposure. The most common cause — by a wide margin — is iatrogenic: prescribed corticosteroid medication in any formulation. Endogenous Cushing syndrome, where the body itself produces too much cortisol, is rare (incidence approximately 1.8–3.2 per million per year) but carries serious morbidity and an untreated five-year mortality of approximately 50%, predominantly from cardiovascular disease and infection (Clayton Lancet Diabetes Endocrinol 2016).

The GP’s role is pattern recognition across a non-specific clinical picture, screening with widely available tests, and timely referral to endocrinology. Early identification and treatment substantially improve outcomes. The challenge is that the individual features of Cushing syndrome are each common and each occur in many other conditions — it is their constellation that raises suspicion.

A. Core clinical — the AU general-practice framework

Who to consider screening

The Endocrine Society 2008 Clinical Practice Guideline recommends screening in patients with:

• Suggestive clinical cluster — especially in younger patients: central obesity with peripheral wasting, wide (>1 cm) violaceous striae on the abdomen, thighs, axillae, or breasts; easy bruising without significant trauma; proximal muscle weakness; facial plethora and rounding; dorsocervical and supraclavicular fat pads; new hypertension; new type 2 diabetes; osteoporosis with low-trauma fracture; persistent depression or mood instability.
• Adrenal incidentaloma — any incidentally discovered adrenal mass warrants evaluation including a 1 mg overnight dexamethasone suppression test to exclude subclinical Cushing syndrome.
• Children with weight gain and slowing height velocity — obesity in children should normally preserve or accelerate height; growth faltering alongside weight gain is a red flag.
• Iatrogenic exposure — any patient on supraphysiologic corticosteroid for more than three weeks in any formulation: oral prednisolone or dexamethasone; high-dose inhaled corticosteroids (particularly fluticasone or budesonide at higher doses); potent topical corticosteroids on extensive skin areas; repeated intra-articular or intrabursal depot injections; intranasal high-dose preparations. Some herbal creams contain undisclosed corticosteroid and can suppress the adrenal axis.

Recognising the clinical picture

History: Weight gain characteristically central — “thin arms and legs, big trunk”. Easy bruising: bruises appearing from minimal trauma or appearing without a recalled mechanism. Wide striae: purple or violaceous striae wider than 1 cm on abdomen, thighs, or axillae (compare with narrow, white striae of simple weight gain). Proximal weakness: difficulty rising from a low chair without using arms, difficulty climbing stairs. Psychiatric features — depression, anxiety, irritability, emotional lability — present in 50–80% of patients. Reproductive changes: oligomenorrhoea, amenorrhoea, erectile dysfunction, reduced libido. Recurrent infections, slow wound healing. Polyuria and polydipsia if secondary diabetes has developed.

Medication history: Ask specifically about oral, intra-articular, intrabursal, intramuscular depot, topical, intranasal, and ophthalmic steroid preparations. Ask about herbal or naturopathic products. A patient receiving intra-articular triamcinolone four-weekly for joint pain may not volunteer this unless asked directly.

Examination: Blood pressure, weight, BMI, waist circumference. Document presence or absence of: supraclavicular fat pad, dorsocervical fat pad (“buffalo hump”), moon facies (rounded face with facial plethora), skin thinning. Skin assessment — striae width and colour, bruising distribution, hyperpigmentation of palmar creases and oral mucosa (suggests ACTH-dependent disease). Proximal muscle power — sit-to-stand from a chair without using armrests (Trendelenburg test). Visual fields by confrontation if pituitary mass is suspected.

Screening tests

Per Endocrine Society 2008, at least two concordant abnormal tests are required to confirm hypercortisolism. Any one of the following can be used as a first-line screen:

Late-night salivary cortisol (×2): Collected at 11:00 pm on two separate evenings. Reflects loss of the normal diurnal cortisol rhythm — the most sensitive ambulatory test for Cushing syndrome. The patient collects saliva into a specialised tube at home. Available through commercial and hospital labs. Instruct the patient not to eat, drink, brush teeth, or smoke for 30 minutes before collection. Results above the laboratory reference range are abnormal.

1 mg overnight dexamethasone suppression test (1 mg overnight DST): Patient takes 1 mg dexamethasone at 11:00 pm. Serum cortisol measured at 8:00 am the following morning. A result below 50 nmol/L effectively excludes Cushing syndrome (sensitivity approximately 95%). A result above 50 nmol/L is abnormal and requires a second test. False positives occur with oestrogen-containing contraception or HRT (elevates cortisol-binding globulin — stop 6 weeks before if feasible), CYP3A4 inducers (phenytoin, rifampicin, carbamazepine — reduce dexamethasone levels), alcohol misuse, severe depression, and obesity.

24-hour urinary free cortisol (×2): Patient collects all urine over 24 hours into a provided container. Significant Cushing syndrome usually produces values more than three times the upper reference limit. Lower elevations are harder to interpret. Useful in confirming moderate-to-severe cases; less sensitive for mild or cyclic Cushing syndrome. Affected by collection completeness and high fluid intake.

When to stop and refer

If any screening test is abnormal, or if clinical suspicion is high with a borderline result, refer to endocrinology within four to six weeks. A florid clinical picture with severe hypertension, hypokalaemia, or new psychosis warrants semi-urgent referral within two weeks. Suspected ectopic ACTH from a lung cancer or carcinoid — characterised by rapid onset, profound hypokalaemia, skin hyperpigmentation, and often male patients — is semi-urgent.

B. Aetiology and the endocrinology workup — what happens after referral

Understanding the workup helps the GP interpret referral letters and support patients through what can be a lengthy diagnostic process.

Aetiology:

• Iatrogenic / exogenous — most common; ACTH and cortisol both suppressed biochemically.
• Endogenous ACTH-dependent (~80% of endogenous):
  • Cushing disease — pituitary corticotroph adenoma; female-to-male ratio 3–4:1; peak age 25–45; accounts for approximately 70% of endogenous cases.
  • Ectopic ACTH — small cell lung carcinoma, bronchial carcinoid, pancreatic NET, medullary thyroid cancer; typically rapid onset, severe, with profound hypokalaemia and hyperpigmentation; often male; often systemically unwell.
• Endogenous ACTH-independent (~20% of endogenous):
  • Adrenal adenoma — approximately 10%; female predominance; often smaller and well-defined on CT; laparoscopic adrenalectomy is curative.
  • Adrenal carcinoma — approximately 5%; typically larger (over 4 cm), heterogeneous on CT; often co-secretes sex steroids (androgen or oestrogen); poor prognosis; requires oncology MDT.
  • Bilateral adrenal hyperplasia — PMAH or PPNAD; rare; some associated with McCune–Albright or Carney complex syndromes.

Localisation by endocrinology:

1. Plasma ACTH at 9:00 am — low or undetectable = ACTH-independent → adrenal CT; normal or elevated = ACTH-dependent → pituitary MRI.
2. If pituitary MRI is negative or shows a lesion under 6 mm → bilateral inferior petrosal sinus sampling (IPSS) to confirm pituitary versus ectopic source.
3. CT chest and abdomen plus Ga-68 DOTATATE PET for suspected ectopic ACTH source.

Treatment by cause:

• Cushing disease → transsphenoidal pituitary surgery (remission 65–90% for microadenoma). If persistent or recurrent: medical therapy with osilodrostat (TGA-approved 2024, not yet PBS-listed; private/special access), metyrapone, or ketoconazole; pituitary radiotherapy; bilateral adrenalectomy as last resort.
• Adrenal adenoma → laparoscopic adrenalectomy; curative.
• Adrenal carcinoma → open en-bloc resection plus mitotane plus oncology MDT.
• Ectopic ACTH → resect the source plus bridging steroidogenesis inhibitor.
• Iatrogenic → taper corticosteroid as slowly as the underlying disease allows; address HPA axis suppression.

C. Complications and their GP management

Cushing syndrome is a multi-system condition. The GP coordinates comorbidity management alongside specialist care.

Hypertension — often refractory; responds well to mineralocorticoid receptor antagonists (spironolactone, eplerenone) alongside standard agents. Blood pressure typically improves substantially after treatment of the cortisol source, though may not fully normalise immediately.

Diabetes mellitus — secondary to glucocorticoid-induced insulin resistance and hepatic glucose production. Metformin first-line if renal function permits. Avoid sulfonylureas in lean patients due to hypoglycaemia risk. Insulin if severe. Typically improves after curative treatment.

Osteoporosis — high-dose chronic glucocorticoid causes rapid trabecular bone loss. Dual-energy X-ray absorptiometry (DEXA) at diagnosis. If T-score below −2.5 or prior fragility fracture, bisphosphonate therapy is indicated (see eTG Endocrine). Calcium and cholecalciferol supplementation if dietary intake is insufficient.

Mood and psychiatric disorders — depression occurs in 50–80% of patients. Anxiety, cognitive impairment, irritability, and occasionally psychosis also occur. A Mental Health Care Plan (MBS items 2715/2717) is appropriate and enables psychological support. Antidepressant medication may be needed but often improves substantially once cortisol levels are normalised.

Adrenal axis suppression post-treatment: After curative surgery, the remaining adrenal tissue (previously suppressed by excess cortisol) may take six to eighteen months to recover function. Patients require physiological hydrocortisone replacement during this period — typically 15–25 mg daily in split doses. They need written sick-day rules (double dose for minor illness; triple or IM hydrocortisone for major illness or vomiting) and a MedicAlert identification. Failure to follow this plan can result in adrenal crisis — a medical emergency. The GP is often the first point of contact for patients on replacement therapy and must be comfortable recognising early adrenal insufficiency.

Immunocompromise: Chronic hypercortisolism suppresses immune function. Ensure vaccinations are up to date per the Australian Immunisation Handbook immunocompromised schedule, including pneumococcal, influenza, COVID-19, herpes zoster (shingles), and measles-mumps-rubella review.

D. Australian operations

MBS items relevant to Cushing syndrome workup in general practice:

• Cortisol assay (serum, urine, salivary): item 66543
• ACTH: item 66518
• 24-hour urinary free cortisol: item 66628
• MRI pituitary (specialist referral): item 63491
• CT abdomen/pelvis adrenal protocol: item 56501
• Ga-68 DOTATATE PET (specialist criteria): item 61632
• DEXA bone densitometry: item 12320
• GP consultations: items 23/36/44
• GP Chronic Condition Management Plan (GPCCMP): items 965/967 (replaced 721/723 from 1 July 2025) — Cushing syndrome with multi-system comorbidities is eligible; enables allied health referral (dietitian for secondary diabetes and weight, exercise physiologist for sarcopenia and bone health, psychologist for mood disorders, diabetes educator)
• Mental Health Care Plan: items 2715/2717 — for depression and anxiety common in this condition

PBS medicines relevant to Cushing syndrome:

• Hydrocortisone tablets (4 mg, 20 mg) and IM ampoules — PBS General Schedule for adrenal replacement therapy.
• Prednisolone and dexamethasone — PBS General Schedule (used for both DST testing and as therapeutic glucocorticoids).
• Pasireotide LAR (Signifor LAR) — PBS Section 100 Highly Specialised Drug; authority required from endocrinologist for Cushing disease.
• Osilodrostat (Isturisa) — TGA-approved 2024 for endogenous Cushing syndrome; not PBS-listed at the time of writing; available via private prescription or special access scheme. Phase 3 LINC4 trial (Pivonello Lancet Diabetes Endocrinol 2022) demonstrated 86% urinary free cortisol normalisation at week 34.
• Ketoconazole — special access scheme for Cushing syndrome; not on standard PBS.
• Metyrapone — special access scheme.
• Mitotane (Lysodren) — Section 100 Highly Specialised Drug for adrenocortical carcinoma.

Specialist centres: Pituitary adenoma surgery and complex adrenal surgery are undertaken at major teaching hospitals. The Australian Pituitary Foundation provides peer support and resources for patients.

E. Special populations

Iatrogenic Cushing syndrome patients: Often overlooked because the medication is prescribed. Any patient on prednisolone equivalent greater than 5 mg daily (or equivalent dose of any corticosteroid in any route) for more than three weeks may develop adrenal axis suppression. A 9:00 am cortisol below 100 nmol/L on minimum required steroid dose suggests axis suppression; below 50 nmol/L is consistent with adrenal insufficiency requiring cortisol replacement. Written sick-day rules and patient education are mandatory for all on long-term supraphysiologic corticosteroid, not just those with confirmed Cushing syndrome.

Children: Cushing syndrome in children most commonly presents as weight gain with growth failure. A child who is gaining weight but not growing normally warrants assessment including growth velocity charting and, if the curve is flattening, appropriate investigation. The paediatric approach differs in reference ranges and screening test interpretation — paediatric endocrinology referral is appropriate.

Pseudo-Cushing states: Alcohol misuse, severe depression, poorly controlled diabetes, and morbid obesity can produce mildly abnormal cortisol suppression tests and mildly elevated urinary free cortisol, mimicking Cushing syndrome. A thorough alcohol history is essential. Resolution of biochemical abnormalities with treatment of the underlying condition (abstinence from alcohol, treatment of depression) confirms pseudo-Cushing rather than true disease. This distinction requires endocrinology expertise.

Pregnancy: Cushing syndrome in pregnancy is rare and complex, as normal pregnancy elevates cortisol and reduces suppression on the DST. Late-night salivary cortisol remains useful but reference ranges differ. Specialist obstetric endocrinology involvement is essential.

When to escalate

Refer urgently or contact on-call endocrinology when:

• Severe hypokalaemia (potassium below 2.5 mmol/L) with features of Cushing syndrome — suggests ectopic ACTH from a malignancy.
• New psychosis in a patient on corticosteroid therapy or with suspected Cushing syndrome.
• Suspected pituitary apoplexy — sudden severe headache, visual loss, and ophthalmoplegia in a known or suspected pituitary adenoma patient.
• Adrenal crisis on replacement therapy — vomiting, profound hypotension, confusion: administer IM hydrocortisone 100 mg and call 000.
• Hypertensive emergency in the context of suspected Cushing syndrome.
• Suspected adrenocortical carcinoma (large adrenal mass on imaging with heterogeneous features or sex steroid co-secretion).

What this article is and is not

This is general health information drawn from current Australian general practice guidelines and international specialist society guidelines — Therapeutic Guidelines, Australian Medicines Handbook, Endocrine Society 2008 and 2015 Clinical Practice Guidelines, Pituitary Society 2021 Consensus, and NPS MedicineWise. It is not personal medical advice and does not create a doctor–patient relationship. All decisions about investigation, diagnosis, and treatment of Cushing syndrome are made in partnership with the treating GP, endocrinologist, and relevant specialist team.

For Australian patient resources: HealthDirect — Cushing syndrome, Australian Pituitary Foundation.

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Sources cited

1. Therapeutic Guidelines (eTG) — Endocrine
2. Endocrine Society 2008 — Diagnosis of Cushing Syndrome CPG
3. Endocrine Society 2015 — Treatment of Cushing Syndrome CPG
4. Pituitary Society Consensus 2021 — Cushing Disease Update
5. Pivonello et al. LINC4 — osilodrostat. Lancet Diabetes Endocrinol 2022
6. Clayton et al. — mortality in Cushing. Lancet Diabetes Endocrinol 2016
7. Australian Medicines Handbook
8. RACGP — Endocrine clinical resources
9. NPS MedicineWise — Corticosteroids
10. Australian Immunisation Handbook — Immunocompromised schedule
11. HealthDirect — Cushing syndrome
12. Australian Pituitary Foundation