The Spectrum of Dysregulated Aldosterone Production: An International Human Physiology Study.

CONTEXT: Primary aldosteronism is a form of low-renin hypertension characterized by dysregulated aldosterone production. OBJECTIVE: To investigate the contributions of renin-independent aldosteronism, and ACTH-mediated aldosteronism, in individuals with a low-renin phenotype representing the entire continuum of blood pressure. . DESIGN/PARTICIPANTS: Human physiology study of 348 participants with a low-renin phenotype with severe and/or resistant hypertension, hypertension with hypokalemia, elevated blood pressure and stage I/II hypertension, and normal blood pressure. SETTING: 4 international centers. . INTERVENTIONS/MAIN OUTCOME MEASURES: Saline suppression test (SST) to quantify the magnitude of renin-independent aldosteronism; dexamethasone suppression and ACTH-stimulation tests to quantify the magnitude of ACTH-mediated aldosteronism; adrenal venous sampling to determine lateralization. RESULTS: There was a continuum of non-suppressible and renin-independent aldosterone production following SST that paralleled the magnitude of the blood pressure continuum and transcended conventional diagnostic thresholds. In parallel, there was a full continuum of ACTH-mediated aldosteronism wherein post-SST aldosterone levels were strongly correlated with ACTH-stimulated aldosterone production (r = 0.75, P < 0.0001) and non-suppressible aldosterone production post-dexamethasone (r = 0.40, P < 0.0001). Beyond participants who met criteria for primary aldosteronism (post-SST aldosterone of ≥10 ng/dL or ≥277 pmol/L), the continuum of non-suppressible and renin-independent aldosterone production persisted below this diagnostic threshold, wherein 15% still had lateralizing aldosteronism amenable to surgical adrenalectomy, and the remainder were treated with mineralocorticoid receptor antagonists. CONCLUSIONS: In the context of a low-renin phenotype, there is a continuum of dysregulated aldosterone production that is prominently influenced by ACTH. A large proportion of individuals with low-renin have dysregulated aldosterone production and may benefit from aldosterone-directed therapy.

Multifocal, Asymmetric Bilateral Primary Aldosteronism Cannot be Excluded by Strong Adrenal Vein Sampling Lateralization: An International Retrospective Cohort Study.

BACKGROUND: Primary aldosteronism (PA) has been broadly dichotomized into unilateral and bilateral forms. Adrenal vein sampling (AVS) lateralization indices (LI) ≥2 to 4 are the standard-of-care to recommend unilateral adrenalectomy for presumed unilateral PA. We aimed to assess the rates and characteristics of residual PA after AVS-guided adrenalectomy. METHODS: We conducted an international, retrospective, cohort study of patients with PA from 7 referral centers who underwent unilateral adrenalectomy based on LI≥4 on baseline and/or cosyntropin-stimulated AVS. Aldosterone synthase (CYP11B2) immunohistochemistry and next generation sequencing were performed on available formalin-fixed paraffin-embedded adrenal tissue. RESULTS: The cohort included 283 patients who underwent AVS-guided adrenalectomy, followed for a median of 326 days postoperatively. Lack of PA cure was observed in 16% of consecutive patients, and in 22 patients with lateralized PA on both baseline and cosyntropin-stimulated AVS. Among patients with residual PA postoperatively, 73% had multiple CYP11B2 positive areas within the resected adrenal tissue (versus 23% in those cured), wherein CACNA1D mutations were most prevalent (63% versus 33% in those cured). In adjusted regression models, independent predictors of postoperative residual PA included Black versus White race (odds ratio, 5.10 [95% CI, 1.45-17.86]), AVS lateralization only at baseline (odds ratio, 8.93 [95% CI 3.00-26.32] versus both at baseline and after cosyntropin stimulation), and CT-AVS disagreement (odds ratio, 2.75 [95% CI, 1.20-6.31]). CONCLUSIONS: Multifocal, asymmetrical bilateral PA is relatively common, and it cannot be excluded by robust AVS lateralization. Long-term postoperative monitoring should be routinely pursued, to identify residual PA and afford timely initiation of targeted medical therapy.

Evaluation of a Best-Practice Advisory for Primary Aldosteronism Screening.

Importance: Primary aldosteronism (PA) is a common cause of secondary hypertension and an independent risk factor for cardiovascular morbidity and mortality. Fewer than 2% to 4% of patients at risk are evaluated for PA. Objective: To develop and evaluate an electronic health record best-practice advisory (BPA) that assists with PA screening. Design, Setting, and Participants: This prospective quality improvement study was conducted at academic center outpatient clinics. Data analysis was performed between February and June 2023 and included adults with hypertension and at least 1 of the following: 4 or more current antihypertensive medications; hypokalemia; age younger than 35 years; or adrenal nodule(s). Patients previously tested for PA were excluded. Exposure: A noninterruptive BPA was developed to trigger for PA screening candidates seen in outpatient setting by clinicians who treat hypertension. The BPA included an order set for PA screening and a link to results interpretation guidance. Main Outcomes and Measures: (1) The number of PA screening candidates identified by the BPA between October 1, 2021, and December 31, 2022; (2) the rates of PA screening; and (3) the BPA use patterns, stratified by physician specialty were assessed. Results: Over 15 months, the BPA identified 14 603 unique candidates (mean [SD] age, 65.5 [16.9] years; 7300 women [49.9%]; 371 [2.5%] Asian, 2383 [16.3%] Black, and 11 225 [76.9%] White individuals) for PA screening, including 7028 (48.1%) with treatment-resistant hypertension, 6351 (43.5%) with hypokalemia, 1537 (10.5%) younger than 35 years, and 445 (3.1%) with adrenal nodule(s). In total, 2040 patients (14.0%) received orders for PA screening. Of these, 1439 patients (70.5%) completed the recommended screening within the system, and 250 (17.4%) had positive screening results. Most screening orders were placed by internists (40.0%) and family medicine physicians (28.1%). Family practitioners (80.3%) and internists (68.9%) placed most orders via the embedded order set, while specialists placed most orders (83.0%-95.4%) outside the BPA. Patients who received screening were younger and included more women and Black patients than those not screened. The likelihood of screening was higher among patients with obesity and dyslipidemia and lower in those with chronic kidney disease and established cardiovascular complications. Conclusions and Relevance: The study results suggest that noninterruptive BPAs are potentially promising PA screening-assistance tools, particularly among primary care physicians. Combined with artificial intelligence algorithms that optimize the detection yield, refined BPAs may contribute to personalized hypertension care.

Biomarkers to Guide Medical Therapy in Primary Aldosteronism.

Primary aldosteronism (PA) is an endocrinopathy characterized by dysregulated aldosterone production that occurs despite suppression of renin and angiotensin II, and that is non-suppressible by volume and sodium loading. The effectiveness of surgical adrenalectomy for patients with lateralizing PA is characterized by the attenuation of excess aldosterone production leading to blood pressure reduction, correction of hypokalemia, and increases in renin-biomarkers that collectively indicate a reversal of PA pathophysiology and restoration of normal physiology. Even though the vast majority of patients with PA will ultimately be treated medically rather than surgically, there is a lack of guidance on how to optimize medical therapy and on key metrics of success. Herein, we review the evidence justifying approaches to medical management of PA and biomarkers that reflect endocrine principles of restoring normal physiology. We review the current arsenal of medical therapies, including dietary sodium restriction, steroidal and nonsteroidal mineralocorticoid receptor antagonists, epithelial sodium channel inhibitors, and aldosterone synthase inhibitors. It is crucial that clinicians recognize that multimodal medical treatment for PA can be highly effective at reducing the risk for adverse cardiovascular and kidney outcomes when titrated with intention. The key biomarkers reflective of optimized medical therapy are unsurprisingly similar to the physiologic expectations following surgical adrenalectomy: control of blood pressure with the fewest number of antihypertensive agents, normalization of serum potassium without supplementation, and a rise in renin. Pragmatic approaches to achieve these objectives while mitigating adverse effects are reviewed.

Somatic SLC30A1 mutations altering zinc transporter ZnT1 cause aldosterone-producing adenomas and primary aldosteronism.

Primary aldosteronism (PA) is the most common form of endocrine hypertension and is characterized by inappropriately elevated aldosterone production via a renin-independent mechanism. Driver somatic mutations for aldosterone excess have been found in approximately 90% of aldosterone-producing adenomas (APAs). Other causes of lateralized adrenal PA include aldosterone-producing nodules (APNs). Using next-generation sequencing, we identified recurrent in-frame deletions in SLC30A1 in four APAs and one APN (p.L51_A57del, n = 3; p.L49_L55del, n = 2). SLC30A1 encodes the ubiquitous zinc efflux transporter ZnT1 (zinc transporter 1). The identified SLC30A1 variants are situated close to the zinc-binding site (His43 and Asp47) in transmembrane domain II and probably cause abnormal ion transport. Cases of PA with SLC30A1 mutations showed male dominance and demonstrated increased aldosterone and 18-oxocortisol concentrations. Functional studies of the SLC30A151_57del variant in a doxycycline-inducible adrenal cell system revealed pathological Na+ influx. An aberrant Na+ current led to depolarization of the resting membrane potential and, thus, to the opening of voltage-gated calcium (Ca2+) channels. This resulted in an increase in cytosolic Ca2+ activity, which stimulated CYP11B2 mRNA expression and aldosterone production. Collectively, these data implicate zinc transporter alterations as a dominant driver of aldosterone excess in PA.

Long-term efficacy and safety of osilodrostat in patients with Cushing's disease: results from the LINC 4 study extension.

Objective: To evaluate the long-term efficacy and safety of osilodrostat in patients with Cushing's disease. Methods: The multicenter, 48-week, Phase III LINC 4 clinical trial had an optional extension period that was initially intended to continue to week 96. Patients could continue in the extension until a managed-access program or alternative treatment became available locally, or until a protocol amendment was approved at their site that specified that patients should come for an end-of-treatment visit within 4 weeks or by week 96, whichever occurred first. Study outcomes assessed in the extension included: mean urinary free cortisol (mUFC) response rates; changes in mUFC, serum cortisol and late-night salivary cortisol (LNSC); changes in cardiovascular and metabolic-related parameters; blood pressure, waist circumference and weight; changes in physical manifestations of Cushing's disease; changes in patient-reported outcomes for health-related quality of life; changes in tumor volume; and adverse events. Results were analyzed descriptively; no formal statistical testing was performed. Results: Of 60 patients who entered, 53 completed the extension, with 29 patients receiving osilodrostat for more than 96 weeks (median osilodrostat duration: 87.1 weeks). The proportion of patients with normalized mUFC observed in the core period was maintained throughout the extension. At their end-of-trial visit, 72.4% of patients had achieved normal mUFC. Substantial reductions in serum cortisol and LNSC were also observed. Improvements in most cardiovascular and metabolic-related parameters, as well as physical manifestations of Cushing's disease, observed in the core period were maintained or continued to improve in the extension. Osilodrostat was generally well tolerated; the safety profile was consistent with previous reports. Conclusion: Osilodrostat provided long-term control of cortisol secretion that was associated with sustained improvements in clinical signs and physical manifestations of hypercortisolism. Osilodrostat is an effective long-term treatment for patients with Cushing's disease. Clinical trial registration: ClinicalTrials.gov, identifier NCT02180217.

Primary Aldosteronism in Chronic Kidney Disease: Blood Pressure Control and Kidney and Cardiovascular Outcomes After Surgical Versus Medical Management.

BACKGROUND: Diagnosis and treatment of primary aldosteronism (PA) in chronic kidney disease (CKD) may be deferred due to limited evidence supporting safety and efficacy of treatment. Our goal was to assess clinical outcomes in patients with PA and CKD who received surgical or medical management. METHODS: We conducted a multicenter, retrospective cohort study of patients with PA and CKD who underwent adrenal vein sampling from 2009-2019. We characterized clinical outcomes and evaluated differences by surgical versus medical management. Primary outcomes were systolic blood pressure and number of antihypertensive medications. Secondary outcomes were diastolic blood pressure, serum potassium, estimated glomerular filtration rate (eGFR), and kidney and cardiovascular events. Analyses were adjusted for age, sex, race, cardiovascular disease, diabetes, and eGFR. RESULTS: Of 239 participants with PA and CKD, 158 (66%) underwent adrenalectomy, and 81 (34%) were treated medically. Mean age was 57±10 years, 67% were female, mean eGFR was 45±12 mL/min per 1.73 m2, and 49% were on potassium supplementation. At 5 years, mean blood pressure decreased from 149±22/85±14 to 131±28/78±16 mm Hg and mean number of antihypertensive medications decreased from 4.0±1.5 to 2.4±1.4. Adrenalectomy, compared to medical management, was associated with similar systolic blood pressure (-0.90 mm Hg [95% CI, -6.99 to 5.07]) but fewer medications (1.7 [95% CI, -2.24 to -1.10]), and no difference in potassium levels or kidney or cardiovascular outcomes. CONCLUSIONS: Patients with PA and CKD are likely to benefit from either surgical adrenalectomy or medical management. Detection and treatment of PA may help to reduce blood pressure and medication burden in patients with CKD.

High prevalence of frailty in patients with adrenal adenomas and adrenocortical hormone excess: a cross-sectional multi-centre study with prospective enrolment.

OBJECTIVE: Frailty, characterized by multi-system decline, increases vulnerability to adverse health outcomes and can be measured using Frailty Index (FI). We aimed to assess the prevalence of frailty in patients with adrenal disorders (based on hormonal sub-type) and examine association between FI and performance-based measures of physical function. DESIGN: Multi-centre, cross-sectional study (March 2019-August 2022). METHODS: Adult patients with adrenal disorders (non-functioning adrenal adenomas [NFA], mild autonomous cortisol secretion [MACS], Cushing syndrome [CS], primary aldosteronism [PA]) and referent subjects without adrenal disorders completed a questionnaire encompassing 47 health variables (comorbidities, symptoms, daily living activities). FI was calculated as the average score of all variables and frailty defined as FI ≥ 0.25. Physical function was assessed with hand grip, timed up-and-go test, chair rising test, 6-minute walk test, and gait speed. RESULTS: Compared to referent subjects (n = 89), patients with adrenal disorders (n = 520) showed increased age, sex, and body mass index-adjusted prevalence of frailty (CS [odds ratio-OR 19.2, 95% confidence interval-CI 6.7-70], MACS [OR 12.5, 95% CI 4.8-42.9], PA [OR 8.4, 95% CI 2.9-30.4], NFA [OR 4.5, 95% CI 1.7-15.9]). Prevalence of frailty was similar to referent subjects when post-dexamethasone cortisol was <28 nmol/L and was higher when post-dexamethasone cortisol was 28-50 nmol/L (OR 4.6, 95% CI 1.7-16.5). FI correlated with all measures of physical function (P < .001). CONCLUSIONS: Whilst frailty prevalence was highest in patients with adrenocortical hormone excess, even patients with NFA demonstrated an increased prevalence compared to the referent population. Future longitudinal studies are needed to evaluate the impact of various management strategies on frailty.

Interplay of Cortisol, Testosterone, and Abdominal Fat Mass in Normal-weight Women With Polycystic Ovary Syndrome.

Context: Ovarian and adrenal steroidogenesis underlie endocrine-metabolic dysfunction in polycystic ovary syndrome (PCOS). Adipocytes express aldo-keto reductase 1C3 and type 1 11ß-hydroxysteroid dehydrogenase, which modulate peripheral androgen and cortisol production. Objectives: To compare serum adrenal steroids, including 11-oxygenated androgens (11-oxyandrogens), cortisol, and cortisone between normal-weight women with PCOS and body mass index- and age-matched ovulatory women with normal-androgenic profiles (controls), and assess whether adrenal steroids associate with abdominal adipose deposition. Design: Prospective, cross-sectional, cohort study. Setting: Academic medical center. Patients: Twenty normal-weight women with PCOS and 20 body mass index-/age-matched controls. Interventions: Blood sampling, IV glucose tolerance testing, and total-body dual-energy x-ray absorptiometry. Main Outcome Measures: Clinical characteristics, hormonal concentrations, and body fat distribution. Results: Women with PCOS had higher serum total/free testosterone (T) and androstenedione (A4) levels and a greater android/gynoid fat mass than controls (androgens P < .001; android/gynoid fat mass ratio, P = .026). Serum total/free T and A4 levels correlated positively with android/gynoid fat mass ratio in all women combined (P < .025, all values). Serum 11ß-hydroxyA4, 11-ketoA4, 11ß-hydroxyT, 11-ketoT, cortisol, and cortisone levels were comparable between female types and unrelated to body fat distribution. Serum 11-oxyandrogens correlated negatively with % total body fat, but lost significance adjusting for cortisol. Serum cortisol levels, however, correlated inversely with android fat mass (P = .021), with a trend toward reduced serum cortisol to cortisone ratio in women with PCOS vs controls (P = .075), suggesting diminished 11ß-hydroxysteroid dehydrogenase activity. Conclusion: Reduced cortisol may protect against preferential abdominal fat mass in normal-weight PCOS women with normal serum 11-oxyandrogens.

Primary Aldosteronism Prevalence - An Unfolding Story.

Primary aldosteronism (PA) is characterized by dysregulated, renin-independent aldosterone excess. Long perceived as rare, PA has emerged as one of the most common causes of secondary hypertension. Failure to recognize and treat PA results in cardiovascular and renal complications, through processes mediated by both direct target tissue insults and indirectly, by hypertension. PA spans a continuum of dysregulated aldosterone secretion, which is typically recognized in late stages after treatment-resistant hypertension and cardiovascular and/or renal complications develop. Determining the precise disease burden remains challenging due to heterogeneity in testing, arbitrary thresholds, and populations studied. This review summarizes the reports on PA prevalence among the general population and in specific high-risk subgroups, highlighting the impact of rigid versus permissive criteria on PA prevalence perception.

Adrenal disorders in pregnancy.

Progress in our understanding of adrenal disorders affecting pregnant women has been hindered by three major hurdles: the phenotypical and biochemical overlap between pregnancy and adrenal pathology, the infrequent presentation of adrenal disorders during pregnancy, and the scarcity of human studies that include pregnant women. Pregnancy-specific adrenal hormone calibrations are lacking. Thus, the evaluation and management of adrenal disorders presenting during pregnancy are challenging. In this thematic issue, prominent experts in adrenal physiology and pathology have joined forces to offer a comprehensive collection of articles covering the current knowledge on adrenal disorders affecting reproductive-age women. This superb collection of reviews makes the perfect clinical companion on pregnancy-related adrenal pathology for a broad range of healthcare providers, from primary care physicians and internists to endocrinologists and gynecologist-obstetricians, regardless of career stage or practice setting.

11-Oxygenated Androgen Metabolite Concentrations Are Affected by Pubertal Progression and Obesity.

INTRODUCTION: 11-oxygenated C19 steroids (11-oxyandrogens) have been shown to rise during adrenarche and remain higher throughout adulthood than in early childhood. The patterns of circulating 11-oxyandrogens throughout normal puberty have not yet been described. METHODS: We conducted a secondary analysis of healthy youth participants, both males and females, enrolled in six prior endocrine studies (N = 249). Participants were classified according to Tanner stage and body mass index (BMI). Concentrations of three adrenal-specific 11-oxygenated androgens, 11ß-hydroxyandrostenedione (11OHA4), 11ß-hydroxytestosterone (11OHT), and 11-ketotestosterone (11KT), were measured in fasting serum samples. RESULTS: 11OHA4 and 11OHT increased modestly between early and late puberty in youth with normal weight (p < 0.05), whereas increases in 11KT did not reach statistical significance (p < 0.06). 11KT levels differed between sexes throughout puberty (p < 0.01), and changes in 11-oxyandrogens were small compared to the marked increases for estradiol in girls or testosterone in boys. The trajectories of 11KT and 11OHA4 changes throughout puberty differed by BMI category (p < 0.05). CONCLUSION: Beyond adrenarche, 11-oxyandrogens continue to rise during pubertal development. The differences in 11KT trajectories in males and females are small compared to changes in testosterone for males and estradiol for females during puberty. Obesity appears to influence the trajectories of 11-oxyandrogens during puberty.

Personalized Treatment of Patients With Primary Aldosteronism.

Primary aldosteronism (PA) is a highly prevalent yet underdiagnosed secondary cause of hypertension. PA is associated with increased cardiovascular and renal morbidity compared with patients with primary hypertension. Thus, prompt identification and targeted therapy of PA are essential to reduce cardiovascular and renal morbidity and mortality in a large population with hypertension. Unilateral adrenalectomy is preferred for lateralized PA as the only potentially curative therapy. Surgery also mitigates the risk of cardiovascular and renal complications associated with PA. Targeted medical therapy, commonly including a mineralocorticoid receptor antagonist, is offered to patients with bilateral PA and those who are not surgical candidates. Novel therapies, including nonsteroidal mineralocorticoid receptor antagonists and aldosterone synthase inhibitors, are being developed as alternative options for PA treatment. In this review article, we discuss how to best individualize therapy for patients with PA.

Primary Aldosteronism and the Role of Mineralocorticoid Receptor Antagonists for the Heart and Kidneys.

Primary aldosteronism (PA) is the most common cause of secondary hypertension but is frequently underrecognized and undertreated. Patients with PA are at a markedly increased risk for target organ damage to the heart and kidneys. While patients with unilateral PA can be treated surgically, many patients with PA are not eligible or willing to undergo surgery. Steroidal mineralocorticoid receptor antagonists (MRAs) are highly effective for treating PA and reducing the risk of target organ damage. However, steroidal MRAs are often underprescribed and can be poorly tolerated by some patients due to side effects. Nonsteroidal MRAs reduce adverse renal and cardiovascular outcomes among patients with diabetic kidney disease and are bettertolerated than steroidal MRAs. While their blood pressure-lowering effects remain unclear, these agents may have a potential role in reducing target organ damage in patients with PA.

Rates of Pheochromocytoma/Paraganglioma Screening in At-Risk Populations.

CONTEXT: Pheochromocytomas and paragangliomas (PPGL) are rare causes of secondary hypertension, but when unrecognized, they can lead to serious complications. Data regarding PPGL screening are lacking. OBJECTIVE: This study aimed to assess the rates and patterns of PPGL screening among eligible patients. METHODS: We conducted a retrospective review of adults with hypertension seen in outpatient clinics of a large academic center between January 1, 2017, and June 30, 2020. We included patients with treatment-resistant hypertension, hypertension at age < 35 years, and/or adrenal mass(es). RESULTS: Of 203 535 patients with hypertension identified, 71 088 (35%) met ≥ 1 inclusion criteria, and 2013 (2.83%) were screened for PPGL. Patients screened were younger (56.2 ± 17.4 vs 64.0 ± 17.1 years), more often women (54.1% vs 44.2%), and never-smokers (54.6% vs 47.5%, P < 0.001 for all). The rate of screening was highest in patients with hypertension and adrenal mass(es) (51.7%, vs 3.9% in patients with early-onset hypertension, and 2.4% in those with treatment-resistant hypertension). Multivariable logistic regression showed higher odds ratio (OR) of PPGL screening in women (OR [95% CI]: 1.48 [1.34-1.63]); Black vs White patients (1.35 [1.19-1.53]); patients with adrenal mass(es) (55.1 [44.53-68.15]), stroke (1.34 [1.16-1.54]), dyslipidemia (1.41 [1.26-1.58]), chronic kidney disease (1.40 [1.26-1.56]), and obstructive sleep apnea (1.96 [1.76-2.19]). CONCLUSION: PPGL screening is pursued in roughly half of patients with adrenal nodules and hypertension, but rarely in patients with treatment-resistant or early-onset hypertension. Similar to screening for other forms of secondary hypertension, PPGL screening occurs more often after serious complications develop.

Primary aldosteronism - a multidimensional syndrome.

Primary aldosteronism is a common cause of hypertension and is a risk factor for cardiovascular and renal morbidity and mortality, via mechanisms mediated by both hypertension and direct insults to target organs. Despite its high prevalence and associated complications, primary aldosteronism remains largely under-recognized, with less than 2% of people in at-risk populations ever tested. Fundamental progress made over the past decade has transformed our understanding of the pathogenesis of primary aldosteronism and of its clinical phenotypes. The dichotomous paradigm of primary aldosteronism diagnosis and subtyping is being redefined into a multidimensional spectrum of disease, which spans subclinical stages to florid primary aldosteronism, and from single-focal or multifocal to diffuse aldosterone-producing areas, which can affect one or both adrenal glands. This Review discusses how redefining the primary aldosteronism syndrome as a multidimensional spectrum will affect the approach to the diagnosis and subtyping of primary aldosteronism.

Primary Aldosteronism Screening Rates Differ with Sex, Race, and Comorbidities.

Background Primary aldosteronism (PA) is a common but under-recognized cause of secondary hypertension. Data directly comparing screening rates across single and overlapping indications are lacking. Methods and Results We conducted a retrospective review of adults with hypertension seen in outpatient clinics at a tertiary referral academic center between January 1, 2017, and June 30, 2020. We included patients with hypertension plus at least one of the following: resistant hypertension; age<35 years; obstructive sleep apnea; hypokalemia; or an adrenal mass. We excluded patients with adrenal insufficiency, severe renal disease, or heart failure, and renovascular hypertension. Of 203 535 patients with hypertension, 86044 (42.3%) met at least 1 PA screening criterion, and of these, 2898 (3.4%) were screened for PA. Screening occurred in 2.7% of patients with resistant hypertension; 4.2% of those with obstructive sleep apnea; 5.1% of those <35 years; 10.0% of those with hypokalemia; and 47.3% of patients with an adrenal mass. Screening rates were higher in patients with multiple risk factors: 16.8% for ≥3, 5.7% for 2, and 2.5% for 1 criterion. Multiple logistic regression showed that the odds of PA screening were higher in patients with hypokalemia: odds ratio (95% CI): 3.0 (2.7-3.3); women: 1.3 (1.2-1.4); Black versus White: 1.5 (1.4-1.7); those with obstructive sleep apnea, chronic renal disease, stroke, and dyslipidemia. Conclusions Consideration for PA is given in a small subset of at-risk patients, and typically after comorbidities have developed.