Primary aldosteronism is a condition that occurs when 1 or both adrenal glands produce too much aldosterone,1 a hormone that regulates sodium and potassium in the blood. It was once viewed as rare but is now recognized as the most common and treatable endocrine cause of secondary hypertension, affecting 5% to 14% of all patients with hypertension and up to 29% of those with resistant hypertension.1,2
See related editorial, page 525
The 2025 Endocrine Society clinical practice guideline1 on primary aldosteronism is a timely update that redefines case detection, diagnostic testing, and therapeutic decision-making for clinicians across specialties. Here and in Table 1, we summarize the key differences between the 20251 and the 2016 guidelines.3
Comparison of the 2016 and 2025 Endocrine Society clinical practice guidelines on primary aldosteronism
UNIVERSAL SCREENING FOR ALL PATIENTS WITH HYPERTENSION
The most striking change in the 2025 guideline1 is the recommendation that all patients with hypertension should be screened for primary aldosteronism (the Endocrine Society classifies this as conditional strength, low confidence). This is a major departure from the 2016 guideline,3 which restricted screening to patients in the following high-risk groups:
Resistant or sustained hypertension
Hypertension with hypokalemia
Hypertension with adrenal incidentaloma
Hypertension with family history of early-onset hypertension or early-onset stroke
Hypertension with family history of primary aldosteronism
Hypertension with obstructive sleep apnea.
Universal screening for primary aldosteronism eliminates uncertainty about who should be tested and could markedly increase case detection. Furthermore, early diagnosis and treatment improves clinical outcomes in patients with primary aldosteronism.
This shift toward implementing universal screening, however, might pose significant challenges. There are 1.4 billion adults worldwide with hypertension4; broad screening in primary care will increase testing volume, overall workload, and referrals to endocrinology. In addition, clinicians will need training to appropriately interpret results, manage false-positive screenings, and coordinate follow-up diagnostic testing.1 These additional challenges will likely increase the burden on health systems that are already facing workforce shortages.5
The guideline acknowledges these challenges and incorporates flexibility for local practicability. Its recommendations focus on step-by-step improvements in case detection rather than strict, one-size-fits-all standards.
SIMPLIFIED SCREENING
To support broader screening, the 2025 guideline1 simplifies screening logistics and provides a framework for clinicians (Figure 1A, steps 1–5).
Stepwise approach to the screening, diagnostic evaluation, and treatment of primary aldosteronism. Screening steps 1 to 5.
The previous guideline3 recommended discontinuing interfering antihypertensive medications such as angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, diuretics, or mineralocorticoid antagonists for several weeks before testing when possible. The 2025 guideline allows initial screening while patients remain on these agents because some patients with primary aldosteronism will test positive for the condition with low renin levels even while on medications that elevate renin. However, clinicians should interpret results with appropriate caution (see below).
This updated approach to screening reduces barriers to testing, avoids destabilizing blood pressure control, and minimizes patient burden associated with medication withdrawal. Importantly, it allows primary care clinicians to consider screening all patients with hypertension when feasible.
A simplified approach in the primary care setting is appropriate, as further testing and medication adjustments can be complex. Initial screening should be limited to minimal testing: measuring plasma aldosterone concentration, plasma renin with either plasma renin activity or direct renin concentration, and serum potassium (conditional recommendation, low confidence). (The potassium level is measured because low potassium can cause a falsely low aldosterone level, which would require potassium correction first for accurate interpretation.)
Patients should be evaluated for medication interference if screening results are discordant with clinical suspicion. For high-risk patients with a negative result or a positive result while taking strongly renin-suppressive medications like beta-blockers or centrally acting alpha-2 adrenergic agonists, referral to endocrinology for repeat testing after medication adjustment and further evaluation may be appropriate.
Low-risk patients with a negative result who are not taking renin-suppressive mediations can continue standard hypertension management.
Individualized protocols for medication withdrawal
The 2025 guideline also outlines practical testing strategies based on a patient’s medication status, including protocols for no withdrawal, minimal withdrawal, or full interfering-medication withdrawal. Suggested alternative antihypertensive agents that can be used during washout periods are given, and include nondihydropyridine calcium channel blockers, alpha-1 adrenergic blockers, hydralazine combined with a negative chronotropic agent such as verapamil to avoid reflex tachycardia, and moxonidine.
If a patient still screens positive for primary aldosteronism on an agent that negatively interferes with aldosterone such as an angiotensin II receptor blocker, then a diagnosis can be made without needing to adjust the medication. A positive screening result while taking such an agent strongly suggests primary aldosteronism since the autonomous aldosterone production has overcome the expected pharmacologic effect.
The guideline maintains that full withdrawal of interfering medications is the ideal condition for testing if clinical suspicion remains.
Assay-specific cutoff values
The guideline also provides positive screening cutoff values that account for assay differences (eg, immunoassay vs liquid chromatography–tandem mass spectrometry) and offers technical guidance on patient positioning, timing of sample collection, potassium correction, and medication effects to support accurate interpretation in clinical practice (Figure 1A, step 2).
If results show suppressed renin with elevated aldosterone and an increased aldosterone-to-renin ratio (eg, aldosterone ≥ 10 ng/dL with aldosterone-to-renin ratio > 20, using cutoff values in the guideline; see Table 2 for other laboratory-specific cutoffs, including ones used by Cleveland Clinic), patients should be referred to endocrinology for further evaluation where aldosterone suppression testing, imaging, and adrenal venous sampling can be performed when appropriate.
Aldosterone-to-renin ratios based on assays used to determine renin values and plasma aldosterone concentrations
If the screening result is negative, patients can continue standard hypertension management. The guideline recommends rescreening patients in the future if they develop any one of the following:
Unexplained worsening of hypertension or resistant hypertension
New spontaneous or diuretic-induced hypokalemia
Atrial fibrillation without underlying structural heart disease or hyperthyroidism.
REFINED APPROACH TO ALDOSTERONE SUPPRESSION TESTING AND LATERALIZATION
Aldosterone suppression testing, previously referred to as confirmatory testing, has historically been a cumbersome step in the diagnostic pathway. The 2025 guideline1 emphasizes a probability-based approach, allowing clinicians to bypass aldosterone suppression testing in patients with a strong likelihood of primary aldosteronism (eg, spontaneous hypokalemia with suppressed renin and elevated aldosterone) or when results would not change treatment plans (eg, a patient does not want to pursue surgery).
Although there is no gold standard suppression test, the seated saline infusion test (2 L of normal saline is administered intravenously over 4 hours while the patient remains seated) is commonly used due to its ease and practicality. However, any available aldosterone suppression test can be used.
The guideline clarifies when adrenal venous sampling, the definitive method for distinguishing unilateral from bilateral disease (lateralization), is not necessary. Similar to the 2016 recommendations,3 the 2025 guideline suggests proceeding directly to adrenalectomy without performing adrenal venous sampling when a patient is younger than 35 and has marked excess aldosterone levels, hypokalemia, and a clear unilateral adenoma that is larger than 1.0 cm. Adrenal venous sampling is also not recommended for individuals with bilateral adrenal disease, including familial hyperaldosteronism and bilateral macronodular adrenal hyperplasia. The guideline supports proceeding directly to medical therapy when disease is mild or bilateral or when surgical intervention is not planned. This patient-centered approach aims to balance diagnostic precision with practicality, acknowledging that adrenal venous sampling is technically demanding and not universally available.
Patients who are undergoing adrenal venous sampling and taking a mineralocorticoid receptor antagonist would ideally discontinue it 4 to 6 weeks beforehand. However, the procedure may still be performed when renin is suppressed in patients taking blood pressure medications generally known to increase renin.
We do not recommend discontinuing mineralocorticoid receptor antagonists in patients who are at risk of uncontrolled or resistant hypertension, dangerous hypokalemia, or stroke due to uncontrolled hypertension if the medication is stopped.
This refined diagnostic approach is summarized in Figure 1B, steps 6 to 10.
Stepwise approach to the screening, diagnostic evaluation, and treatment of primary aldosteronism. Diagnostic steps 6 to 9 and screening steps 10 to12.
aChronic kidney disease may also affect interpretation of results.
bPatients with significant comorbidities or elevated surgical risk may not be ideal candidates; decisions should be individualized.
Based on information from reference 1.
Mild autonomous cortisol secretion
Another key addition to the guideline is the recommendation to perform a dexamethasone suppression test to screen patients with adrenal adenomas for mild autonomous cortisol secretion (conditional recommendation, very low confidence). This reflects growing recognition of the metabolic and cardiovascular impact of aldosterone and cortisol cosecretion and its influence on surgical decision-making.6
According to a recent meta-analysis, around 22% of patients with primary aldosteronism have mild autonomous cortisol secretion.7 Its presence can confound interpretation of adrenal venous sampling and may cause postoperative adrenal insufficiency after adrenalectomy.
To perform a dexamethasone suppression test, the patient takes 1 mg of dexamethasone at bedtime (between 11 pm and 12 am), and serum cortisol and dexamethasone levels are measured the following morning between 8 am and 9 am. A serum cortisol level greater than 1.8 μg/dL (50 nmol/L) suggests mild autonomous cortisol secretion, and patients can be referred to endocrinology for further evaluation.
TREATMENT MOVES TOWARD RENIN-GUIDED THERAPY
The 2025 guideline1 reinforces that all patients with confirmed or probable primary aldosteronism should receive primary aldosteronism–specific surgical or medical therapy with an emphasis on renin-guided titration for those treated medically.
Lateralizing adrenalectomy is the preferred treatment for patients with unilateral primary aldosteronism who are surgical candidates and amenable to surgery.
Mineralocorticoid receptor antagonists are the preferred medical therapy for patients who are not surgical candidates or have bilateral disease.
Spironolactone is typically the first-line medication due to its effectiveness and low cost. The starting dose is 12.5 to 25 mg daily, which is then titrated based on the patient’s blood pressure, serum potassium level, and renin value. Spironolactone may cause antiandrogen side effects such as gynecomastia, nipple tenderness, and menstrual irregularities.
Eplerenone is a more selective mineralocorticoid receptor antagonist with fewer hormonal side effects; however, it is more expensive and usually requires a twice-daily dose of 25 to 50 mg.
Epithelial sodium-channel inhibitors such as amiloride may be used when mineralocorticoid receptor antagonists are not tolerated, though they do not directly block the mineralocorticoid receptor and may be less effective.
The approach to primary aldosteronism treatment is outlined in Figure 1B, steps 11 and 12.
Monitoring patient response
Potassium and creatinine levels should be checked within 1 week (though earlier monitoring should be considered for patients at higher risk of hyperkalemia or worsened renal function) after medication initiation or dose changes, and renin measurement should be repeated at 2 to 3 months to guide titration.
If blood pressure remains uncontrolled and renin remains suppressed, the guideline recommends titrating the mineralocorticoid receptor antagonist dose upward as potassium level, blood pressure, and renal function allow, until renin is no longer suppressed or has increased from baseline.
If blood pressure is controlled but renin remains suppressed, the guideline suggests decreasing or stopping non–mineralocorticoid receptor antagonist medications to allow the dose of mineralocorticoid receptor antagonists to be increased, with the goal of further increasing renin. Observational studies have shown better cardiovascular risk reduction when mineralocorticoid receptors are adequately blocked.8
The guideline advises that further renin monitoring is essential only if regularly monitored blood pressure or potassium becomes uncontrolled, necessitating mineralocorticoid receptor antagonist titration. Many clinicians recheck renin levels annually to individualize treatment and target the underlying pathophysiology, rather than relying only on blood pressure and potassium control.
EVIDENCE GAPS AND RESEARCH NEEDS
The 2025 guideline1 recognizes the relative lack of randomized controlled trials on primary aldosteronism. Most of the recommendations are based on expert consensus and observational data, underscoring the need for greater research investment. Considering primary aldosteronism’s high prevalence and the significant association with cardiovascular, bone, and renal sequelae, there is a disproportionate lack of funding and attention relative to its clinical impact. Future studies should aim to further define screening thresholds, evaluate cost-effectiveness of universal screening, and determine optimal treatment strategies, including renin-guided targets and long-term outcomes of medical vs surgical therapy.9
A WELCOME STEP FORWARD
Overall, the 2025 Endocrine Society guideline1 is a well-balanced advancement in the management of primary aldosteronism. It agrees with the growing evidence that primary aldosteronism is common, often missed, and treatable, while also realistically addressing the challenges of diagnosing it in daily practice. The broader screening recommendations, simplified testing protocols, and refined management strategies will likely expand detection and improve outcomes, if implementation challenges can be met.
The guideline’s success will rely on better education and training, strong system support, and more research to fill the remaining evidence gaps. With these efforts, the 2025 update moves closer to the goal of ensuring that all patients with hypertension receive appropriate screening and personalized, effective care for primary aldosteronism.
DISCLOSURES
Dr. Correa has disclosed teaching and speaking for Amryt Pharma, Ascendis Pharma, and Moderna and consulting for Moderna, Novo Nordisk, Inc, and Recordati. The other authors report no relevant financial relationships which, in the context of their contributions, could be perceived as a potential conflict of interest.
The authors disclose use of ChatGPT 5.6 Luna, Claude Opus 4.7, and OpenEvidence for research; language, wording, organization, and structure; and figures, illustrations, or tables in the development of the manuscript submission. The authors take full responsibility for the published content.
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REFERENCES
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