Cushing Syndrome: Clinical Features, Screening Tests, and When to Refer

Cushing syndrome, or endogenous hypercortisolism, is uncommon but clinically important, with an estimated prevalence of 2–3 million persons affected per year for overt disease.

Despite its rarity, primary care clinicians play a critical role in early recognition, as subtle metabolic, cardiovascular, musculoskeletal, and neuropsychiatric changes often precede diagnosis. Delayed or missed diagnosis can lead to significant morbidity, including diabetes, hypertension, osteoporosis, thromboembolic events, infections, and neurocognitive impairment, and increases long-term mortality risk. Timely identification and referral for confirmatory testing and treatment can substantially improve patient outcomes, making awareness of key signs and symptom clusters essential in routine practice.

At a Glance

What: Endogenous Cushing syndrome = chronic cortisol excess from pituitary (Cushing disease), adrenal, or ectopic adrenocorticotropic hormone (ACTH) sources (eg, adenomas). Iatrogenic (exogenous glucocorticoids) is the most common overall cause.
Prevalence: 2–3 cases per million annually for overt disease, but likely underdiagnosed.
Why it matters: Untreated hypercortisolism increases cardiometabolic risk, infections, fractures, neuropsychiatric morbidity, and mortality.
When to suspect: Clusters of new/worsening metabolic disease (resistant hypertension, new diabetes), characteristic physical signs (centripetal obesity, purple striae, easy bruising), or unexplained osteoporosis. [1–3]

1. When to Consider Screening

Guidelines recommend screening for Cushing syndrome when you see several of the following without an alternative explanation, especially if changes are rapid or disproportionate to lifestyle/age:

• New or worsening resistant hypertension (on 3 or more agents)

• New-onset diabetes or worsening glycemia despite therapy

• Rapid, unexplained central weight gain with facial fullness (moon facies) and dorsocervical fat pad

• Purple, wide (>1 cm) striae, easy bruising, proximal muscle weakness

• Early osteoporosis or multiple low-trauma fractures

• Hypokalemia with hypertension (consider ectopic ACTH)

• Adrenal incidentaloma with metabolic syndrome features

Use clinical clustering (2 or more findings, preferably 3+) rather than single signs—no one feature is diagnostic.1-3

2. First-Line Screening Tests (Choose 1, Confirm Positives)

The Endocrine Society recommends any 1 of these first-line tests for most patients:

• 1-mg overnight dexamethasone suppression test (1-mg DST): Morning cortisol greater than 1.8 μg/dL (50 nmol/L) is abnormal and suggests Cushing syndrome.
• Late-night salivary cortisol (2 samples): Abnormal when elevated relative to lab reference ranges.
• 24-hour urinary free cortisol (UFC): Useful with repeated collections for suspected cyclic or more severe disease.

Choosing your test: The 1-mg DST is most convenient for most patients; late-night salivary cortisol is best for shift workers or suspected cyclic disease; 24-hr UFC when compliance with collection is assured.

Select the test while being mindful of interfering medications, the impact of shift work, estrogens, and reduced renal function. If clinical suspicion remains high but results are borderline or inconsistent, repeat testing or use a different modality.1,2

3. Positive Screen → Next Steps (Do Not Image First)

Refer to endocrinology for confirmatory testing and localization unless the cause is clearly exogenous.

Typical confirmatory/localization workflow after a positive screen: measure plasma ACTH to distinguish ACTH-dependent vs independent disease, then targeted imaging (pituitary MRI, adrenal CT) and specialist tests (inferior petrosal sinus sampling when needed).

Do not obtain adrenal or pituitary imaging before biochemical confirmation except in specific contexts (eg, adrenal incidentaloma already identified).1,3

4. Immediate Primary-Care Management Priorities

While definitive therapy (usually surgery) is arranged, address comorbidities and optimize treatment:

• Cardiometabolic: Tighten BP and glycemic control, treat dyslipidemia, assess thrombotic risk.
• Bone health: Screen for osteoporosis; consider calcium/vitamin D and antiresorptive therapy as indicated.
• Infection risk & perioperative planning: Ensure vaccinations and infection surveillance; coordinate with specialists about perioperative glucocorticoid coverage and adrenal insufficiency risk.
• Psychiatric support: Screen and treat depression/anxiety; consider early social supports.2,3

5. Definitive Treatment (Brief)

First-line: Surgical removal of the causative lesion when feasible (transsphenoidal pituitary surgery for Cushing disease; adrenalectomy for unilateral adrenal cortisol-producing tumors).

Medical therapy: Indicated when surgery is not possible, as bridging therapy, or for persistent/recurrent disease. Approved and investigational agents target steroidogenesis, cortisol receptor antagonism, or pituitary tumor control. (Clinical selection and monitoring are specialist tasks.)2,3

6. Practical Primary-Care Tips & Pitfalls

DON'T assume obesity, depression, or aging account for all features—look for clustering and rapid onset.

DON'T order imaging before biochemical confirmation—this can mislead diagnosis.

DO think about Cushing's in patients with adrenal incidentalomas or unexplained osteoporosis.

DO beware of interfering drugs (eg, estrogen, carbamazepine, rifampin) and physiologic states (pregnancy, critical illness) that alter cortisol testing—coordinate with endocrinology for complex cases.

If tests are negative but suspicion remains (cyclical disease), repeat testing or refer early.1,2

7. Brief Note on Evolving Therapies

Advances in molecular insights and a more comprehensive understanding of pathophysiology have supported development of potential therapeutic targets that could control ACTH and cortisol secretion or even reduce tumour cell proliferation. At the pituitary level, pasireotide is an approved somatostatin receptor ligand, and compounds targeting cell cycle regulation, cell signalling and epigenetics are now under investigation. Levoketoconazole and osilodrostat are novel steroid inhibitors, and relacorilant, an investigational selective glucocorticoid receptor modulator overcomes the adverse effects of mifepristone. Adrenal ACTH receptor blockage and immunotherapy could also play a role.4

8. Quick Reference Checklist

✓ Suspect Cushing's if 2 or more of: resistant HTN, new/worsening DM, purple striae, easy bruising, proximal muscle weakness, unexplained osteoporosis.

✓ First-line screen: 1-mg DST OR late-night salivary cortisol OR 24-hr UFC.

✓ If positive → measure ACTH → endocrinology referral for localization and treatment planning.1-3

Bottom Line: Think Cushing's when you see unexplained metabolic disease clusters. Screen biochemically first, then refer to endocrinology. Early recognition prevents serious morbidity and reduces mortality risk.

References

1. Nieman LK, Biller BMK, Findling JW, et al. The Diagnosis of Cushing's Syndrome: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2008;93(5):1526–1540.
2. Nieman LK, Biller BMK, Findling JW, et al. Treatment of Cushing's Syndrome: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2015;100(8):2807–2831.
3. Fleseriu M, Biller BMK, Findling JW, et al. Consensus on Diagnosis and Management of Cushing's Disease. Pituitary. 2021;24(2):145–165.
4. Violetis O, Alexandraki K. New trends in treating Cushing's disease. touchREV Endocrinol. 2024;20(2):10–15. doi:10.17925/EE.2024.20.2.3