Secondary hypertension, or high blood pressure caused by an identifiable medical condition, affects approximately 5–15% of individuals with hypertension. Among its causes, Cushing’s syndrome (CS) represents a rare but critical disorder marked by chronic exposure to excess cortisol. Although uncommon, CS is associated with substantial cardiovascular morbidity and mortality, making early recognition essential. The main clinical challenge lies in determining which hypertensive patients should undergo screening for endogenous hypercortisolism, as universal testing is neither practical nor cost-effective.
Understanding Cushing’s Syndrome
Cushing’s syndrome results from prolonged exposure to high levels of cortisol, an important stress hormone produced by the adrenal glands. The disorder may arise from different mechanisms. The majority of cases (around 70%) are ACTH-dependent, most often due to a pituitary adenoma—a condition known as Cushing’s disease. Less commonly, ectopic production of ACTH by tumors outside the pituitary gland accounts for about 10% of cases. The remaining 20% are ACTH-independent, caused by cortisol-secreting adrenal tumors, either benign or malignant.
Although the general prevalence of CS is low—about 40 cases per million people—its clinical implications are significant. Nearly 80% of patients with Cushing’s syndrome develop hypertension, regardless of sex or whether the disease is pituitary or adrenal in origin. Studies, including data from the European Cushing’s Syndrome Registry, consistently identify high blood pressure as one of the most common early features of the disease.
Mechanisms Linking Cortisol and Blood Pressure
The development of hypertension in CS is complex and multifactorial. Cortisol influences blood pressure regulation both directly and indirectly:
- Mineralocorticoid activity: Normally, the enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) converts cortisol to its inactive form, cortisone. When cortisol levels exceed the enzyme’s capacity, cortisol binds to mineralocorticoid receptors, promoting sodium and water retention, increased plasma volume, and potassium loss. This mimics the effects of primary aldosteronism and leads to elevated blood pressure.
- Renin-angiotensin system: Excess cortisol enhances the vascular response to angiotensin II by upregulating its receptors, further increasing vascular resistance.
- Sympathetic nervous system: Cortisol heightens sensitivity to catecholamines and vasoconstrictors, contributing to persistent hypertension.
- Indirect effects: Metabolic complications like obesity, insulin resistance, and sleep apnea—common in CS—further worsen blood pressure control.
Interestingly, even after successful treatment and remission of CS, hypertension often persists, reflecting long-term vascular damage from sustained hypercortisolism.
Study Methodology
A systematic review was conducted according to PRISMA guidelines, with the most recent literature search completed in June 2023. The authors examined English-language studies that evaluated the prevalence of Cushing’s syndrome in hypertensive populations. Eight studies published between 1977 and 2020 met the inclusion criteria, encompassing 11,504 patients. Information about study populations, diagnostic criteria, screening tests, and prevalence rates was extracted and analyzed.
Results and Prevalence
The studies revealed considerable variability in the prevalence of CS among hypertensive patients, ranging from 0% to 7.7%. The prevalence of Cushing’s disease specifically varied between 0% and 1.2%. The highest rates were found in younger patients (under 40 years) and in those with adrenal masses detected incidentally on imaging—groups in which prevalence reached 6.2% and 7.7%, respectively.
The 1 mg overnight dexamethasone suppression test (DST) was the most frequently used screening tool, though cutoff levels varied among studies. Other diagnostic tests, such as late-night salivary cortisol (LNSC) and 24-hour urinary free cortisol (UFC), were also recommended, depending on test availability.
Clinical Implications and Recommendations
Clinicians should be particularly alert for CS in hypertensive patients who are young, have rapidly worsening blood pressure, or exhibit adrenal or pituitary abnormalities. In such cases, targeted screening is advised. Among available diagnostic options, LNSC is considered highly discriminatory and often preferred when accessible. For patients with adrenal incidentalomas, the 1 mg DST remains the standard initial screening method.
Conclusion
Although rare, Cushing’s syndrome represents a vital yet underrecognized cause of secondary hypertension. Early detection among select patient groups can prevent serious cardiovascular complications. Physicians should therefore maintain a high index of suspicion in younger hypertensive individuals or those with adrenal or pituitary lesions, ensuring timely diagnosis and management through appropriate hormonal screening.