THERAPY OF ENDOCRINE DISEASE: Medical treatment of primary aldosteronism

in European Journal of Endocrinology

Correspondence should be addressed to M Reincke; Email: martin.reincke@med.uni-muenchen.de

In patients with primary aldosteronism, specific treatment provides prognostic benefit over optimal antihypertensive therapy and is therefore crucial to reduce mortality and morbidity in this subgroup of patients with hypertension. Prognostic relevance has been shown for adrenalectomy in unilateral disease and for medical treatment with mineralocorticoid receptor antagonists in bilateral adrenal hyperplasia. Collectively, evidence points to the superiority of surgical treatment compared to medical treatment. The causal approach of removing the mineralocorticoid excess, as well as the often-accompanying glucocorticoid excess, might provide one biologically plausible explanation for the observation of slightly better outcomes with surgical therapy. However, in patients living with primary aldosteronism, medical treatment is often insufficient for three major reasons. First and foremost, no marker of sufficient aldosterone blockade has yet been established and therefore adequate treatment of the aldosterone excess is often dismissed as a treatment goal. Second, side effects often limit patient compliance. Third, as recommendations differ from other indications like heart failure, drug dosing is often inadequate. The aim of this review is first to provide an overview over medical treatment options and second to review potential markers for treatment surveillance in patients with primary aldosteronism.

Abstract

In patients with primary aldosteronism, specific treatment provides prognostic benefit over optimal antihypertensive therapy and is therefore crucial to reduce mortality and morbidity in this subgroup of patients with hypertension. Prognostic relevance has been shown for adrenalectomy in unilateral disease and for medical treatment with mineralocorticoid receptor antagonists in bilateral adrenal hyperplasia. Collectively, evidence points to the superiority of surgical treatment compared to medical treatment. The causal approach of removing the mineralocorticoid excess, as well as the often-accompanying glucocorticoid excess, might provide one biologically plausible explanation for the observation of slightly better outcomes with surgical therapy. However, in patients living with primary aldosteronism, medical treatment is often insufficient for three major reasons. First and foremost, no marker of sufficient aldosterone blockade has yet been established and therefore adequate treatment of the aldosterone excess is often dismissed as a treatment goal. Second, side effects often limit patient compliance. Third, as recommendations differ from other indications like heart failure, drug dosing is often inadequate. The aim of this review is first to provide an overview over medical treatment options and second to review potential markers for treatment surveillance in patients with primary aldosteronism.

Invited Author’s profile

Martin Heinrich Reincke is Professor of Endocrinology and Chair of Medical Department IV, Ludwig-Maximilians University in Munich. His research specialities include endocrine hypertension, mineralocorticoid and glucocorticoid action and stress research. Professor Reincke is heading a research team specifically exploring the prevalence and relevance of mineralocorticoid excess in resistant hypertension on the epidemiological, clinical, genetic and molecular levels. Prof. Reincke won the prestigious European Research Council Advanced Grant Award (2.5 Mio €) in 2016 and is the president-elect of the European Society of Endocrinology.

Introduction

Primary aldosteronism is the most common cause of surgically curable secondary hypertension. The estimated prevalence is 4–6% in patients living with hypertension in primary care, around 10% in specialized hypertensive clinics, and reaches 20% in patients with refractory hypertension (1). Primary aldosteronism is characterized by inappropriately high plasma aldosterone concentrations relative to suppressed plasma renin activity (2). A growing body of sound evidence suggests that the aldosterone excess poses a significantly increased risk of cardiometabolic disease via activation of the mineralocorticoid receptor (1, 3). This provides biologic plausibility for the observation that several studies have shown higher morbidity rates in patients with primary aldosteronism compared to matched patients with essential hypertension (4, 5, 6, 7, 8).

Early specific medical or surgical treatment decreases the risk associated with primary aldosteronism and therefore has the potential to impact prognosis (9, 10).

Of note, recent data suggest that in patients with resistant hypertension, despite the exclusion of primary aldosteronism, spironolactone and amiloride are superior to other antihypertensive medication in lowering blood pressure (11). This has been explained by their potential to counteract the increased salt retention in resistant hypertension, which is likely due to mild inappropriate aldosterone secretion.

Types of primary aldosteronism and treatment options

Primary aldosteronism is classified into unilateral and bilateral forms of the disease. These conditions must be distinguished because of different treatment approaches (1). While in unilateral disease, surgical treatment via adrenalectomy is considered the gold standard, in bilateral disease, medical treatment with mineralocorticoid receptor antagonists is the therapy of choice (1).

Although there is controversy over whether adrenalectomy is superior to adequate medical treatment with regard to cardiovascular outcomes, lines of recent evidence from observational studies speak to the superiority of surgical treatment in unilateral disease (9, 12, 13, 14, 15, 16). For example, Rossi et al. showed a higher risk of atrial fibrillation in medically treated versus adrenalectomized PA patients (17) and in a study done by Strauch et al. arterial stiffness was reduced significantly by adrenalectomy but not after 1 year of spironolactone treatment (14). Moreover, a nationwide survey in Japan showed greater improvement of hypertension and hypokalemia in surgically treated PA patients compared to medical treatment with spironolactone (13). In the prospective SPARTACUS trial, which compared adrenal vein sampling with CT scan to determine treatment in primary aldosteronism, blood pressure was similar in surgically versus medically treated patients. However, patients who underwent adrenalectomy needed less (non-MRA) antihypertensive medication after 6 and 12 months and showed higher quality of life compared to medically treated patients (18, 19). Of note, adrenalectomy results in clinical blood pressure remission in 17–62% and in biochemical remission of aldosterone excess in 93–100% (1, 15). Another layer of complexity is added by the emerging evidence that glucocorticoid co-secretion is very common in aldosterone producing adenomas as well as in bilateral hyperplasia (20, 21). This has been linked to the increased cardiovascular morbidity and mortality in primary aldosteronism and could provide a biologically plausible explanation for the observation that adrenalectomy, which removes the glucocorticoid and aldosterone excess, has shown more favorable outcomes than medical treatment (9, 13, 14). Glucocorticoid co-secretion is associated with BMI, insulin resistance (20), left ventricular hypertrophy (21) and impaired glucose tolerance (22).

Of note, surgical candidates with primary aldosteronism have a higher rate of persistent hypertension after adrenalectomy if preoperative plasma renin levels are not suppressed (23). This clinically unfavorable escape of renin from suppression by excess aldosterone has been explained by more severe renal damage and altered intra-glomerular hemodynamics leading to less favorable outcomes after treatment. It could be, however, also due to a wrong diagnosis of PA. Other factors that predict clinical success after adrenalectomy are known duration of hypertension, sex, antihypertensive medication dosage, BMI, target organ damage and size of the largest nodule as depicted by imaging (15).

Noteworthy, a recently published study by Hundemer et al. sheds new light on the treatment with mineralocorticoid receptor antagonists (3). In this retrospective analysis the authors compared data of 602 medically treated patients with primary aldosteronism with 41,853 essential hypertension patients. Data were sourced from the Brigham and Women’s, the Massachusetts General and affiliate partner hospitals and included patients seen over a 25-year period (1991–2016). Patients whose baseline laboratory data were inconsistent with the diagnosis of primary aldosteronism (defined as aldosterone-to-renin ratio <555 pmol/L per µg/L per h or plasma renin activity ≥1 µg/L per h or negative confirmatory testing) as well as patients with primary aldosteronism who underwent adrenalectomy, had a previous cardiovascular event or were not treated with MR antagonists were excluded from the analysis. The groups were matched by decade of age at study entry. Mean age (58 years in the PA group, 57 years in the essential hypertension group) and BMI values (31.1 kg/m2 in the PA group, 29.8 kg/m2 in the essential hypertension) were quite high and the sex balance was fairly even (45% female in the PA group, 51% in the essential hypertension group).

The results show an almost doubled incidence of cardiovascular events in patients with primary aldosteronism compared to the essential hypertension group during a follow-up of 7 years for patients with PA and 8.8 years for those with essential hypertension. Of note, in a subgroup analysis of 201 primary aldosteronism patients in whom plasma renin was measured at least 1 month after starting MR antagonists, there was a strong correlation between plasma renin activity and cardiovascular outcomes: those 67 patients with unsuppressed plasma renin activity (≥1 µg/L per h) showed an identical risk profile as the essential hypertension group, whereas those 134 patients with suppressed plasma renin activity had a risk profile almost three times higher, despite the fact that mean blood pressure did not differ between the groups (3, 24). The authors thus concluded that plasma renin activity might be a predictor of cardiovascular outcomes and may serve as a secondary marker for treatment response.

However, as John W Funder pointed out in an accompanying editorial, there are several limitations that should provide caution against oversimplified inference (24). First, sodium plays a major role in renin regulation. With dietary sodium restriction, renin tends to rise, whereas with sodium excess, renin is suppressed. This may be a confounder, because dietary sodium restriction has been linked to more favorable cardiovascular outcomes in PA (25), a parameter which was not available in the aforementioned study. Second, non-compliance, which leads to suppressed renin activity, is very common, particularly in men treated with spironolactone. Therefore, it may be hypothesized that non-compliance was overrepresented in the suppressed renin activity group (24). Another reason for non-suppressed renin levels could be simply a sloppy diagnosis of primary aldosteronism. It is worth mentioning that the aldosterone-to-renin ratio as a screening test is notoriously imprecise (26). The diagnostic criteria for primary aldosteronism used in this study were rather loose (3, 24), since confirmatory testing was only performed in 72%, and adrenal vein sampling in only 55%. In such a scenario, non-suppressed renin levels could also indicate the presence of essential hypertension, which would explain the better cardiovascular long-term outcome.

Advantages and disadvantages of different drugs

Medical treatment options for PA are very limited. Treatment of choice is mineralocorticoid receptor antagonists, the most commonly used agents being spironolactone and eplerenone. In case of contraindications against MRA therapy, potassium-sparing diuretics like amiloride or triamterene are recommended, which are less effective (1, 27).

In many countries including Germany, only spironolactone, a non-selective MR antagonist which has been clinically applied since the early 1960s, has been approved for the therapy of primary aldosteronism (28). Upon administration spironolactone is rapidly dethioacetylated to its principal pharmacologically active metabolite canrenone. Recent data suggest that spironolactone as well as canrenone undergo further metabolization by adrenal enzymes (CYP11B1 and CYP11B2) into hydroxylation products with different pharmacological properties (28). Due to the extended metabolization and high affinity to bind to plasma proteins (>90%), the biological effects of spironolactone are long lasting (24–58 h) (29). Therefore, a one-time per day or even every other day administration has proven to be efficacious. Of note, severe hepatic cirrhosis (Child C) and impaired kidney function increase half-life and biological effects of spironolactone. Ingestion with a high-fat meal has shown to enhance oral bioavailability of spironolactone significantly (up to 90%) (29).

An important downside to be considered with spironolactone is its antiandrogenic action due to its affinity to the androgen receptor. This causes a variety of dose-dependent adverse effects, especially in men, which include painful and oversensitive nipples, painful gynecomastia and erectile dysfunction. Severe side effects might be one of the explanations for the commonly observed non-compliance (30). In the SPARTACUS trial the authors observed a high rate of antiandrogenic adverse events in both sexes: gynecomastia, mastopathy, menstrual disturbances, erectile dysfunction and decreased libido were present in 1% of the adrenalectomy group, but in 57% of the spironolactone group. In consequence, 34% of patients were switched to eplerenone.

The more selective MR-antagonist eplerenone, which at the right dose, has been proven to be equally efficacious as spironolactone, is approved for treatment of hypertension including PA in Japan and USA (maximal dose 100 mg/day), but not in European countries and Australia where it has to be administered in terms of compassionate use. However, its common use in heart failure makes it easily available and off-label use is common. The advantage of eplerenone over spironolactone is its relative selectiveness on the mineralocorticoid receptor, with no adverse antiandrogenic effects (30). In this context, eplerenone is a viable option to consider in patients with antiandrogenic complications under spironolactone treatment. In contrast to spironolactone, eplerenone is not converted into active metabolites and has a lower plasma protein-binding affinity (28). Therefore, its biological effects are much shorter lasting (3–6 h) (31). This requires a twice-daily administration (30).

Moreover, this pharmacological agent is hepatically eliminated by CYP3A4, and therefore, prone to interact with other pharmacological and non-pharmacological agents. In clinical practice, eplerenone is administered at higher doses than spironolactone, since it has been shown to be inferior in lowering blood pressure in primary aldosteronism in a randomized head-to-head comparison (32) (Table 1). As opposed to spironolactone, food intake does not affect the bioavailability of eplerenone (31). The use of eplerenone is contraindicated in patients with severe hepatic impairment (Child C) because in this subgroup of patients, its pharmacokinetics has not yet been investigated. In renal impairment and moderate hepatic impairment, no dose adjustment is needed (31). However, potassium levels need to be closely monitored in patients with impaired renal function.

Table 1

Comparison of the pharmacological profiles of MR antagonists.

SpironolactoneEplerenone
Approved for PA treatmentYesNo*
Duration of biological effect (h)24–583–6
Changes in bioavailability with food intakeYes (increased absorption up to 90%) No
Active metabolitesYesNo
Hepatic elimination NoYes (CYP3A4)
Drug interactionsNone• Elevates levels of Digoxin

• Interacts with pharmaceuticals that induce or inhibit CYP3A4
Contraindications• Hyperkalemia

• Addison’s disease

• Concomitant use with eplerenone
• Severe hepatic cirrhosis (Child C)

• Hyperkalemia

• Combination with strong CYP3A inhibitors
Administration1×/day2–3×/day
Starting dose25 mg – 0 – 0 25 mg – 0 – 25 mg
Maximal approved dose400 mg/day100 mg/day
Maximal dose used in studies400 mg/day300 mg/day
Antiandrogenic side effectsYes (painful gynecomastia, painful and oversensitive nipples, erectile dysfunction, loss of libido, menstrual irregularities)No

*Status is country-dependent (only approved for hypertension including PA in USA and Japan).

Drug titration in medically treated PA patients

Optimal medical therapy is crucial to prevent the complications of PA. As there is not a ‘one size fits all’ therapy regimen in PA, individualized treatment is key for optimal patient benefit. In addition to normotensive blood pressure, causally targeting the aldosterone excess by pharmacological MR receptor blockade constitutes an important treatment goal and conveys prognostic superiority over optimal blood pressure control in PA (1).

For optimal disease control, regular follow-up visits, including blood pressure monitoring and surveillance of serum potassium levels are of utmost importance (Fig. 1). MR antagonists should be administered at a low starting dose (e.g. 25 mg spironolactone per day) with a slow uptitration according to blood pressure (1).

Figure 1
Figure 1

MRA dose titration. *In case of severe hyperkalemia (>5.2 mmol/L) MRA reduction must be considered. **According to the 2018 ESC/ESH Guidelines for the management of arterial hypertension.

Citation: European Journal of Endocrinology 181, 4; 10.1530/EJE-19-0215

In our outpatient clinic, we re-evaluate the patients after 4 weeks to amend the spironolactone dose. Although hyperkalemia rarely limits uptitration because of the underlying hyperaldosteronism favoring hypokalemia, serum potassium levels should be monitored frequently in the beginning. In our experience, efficient MR blockade is achieved in the majority of patients (>90%) with 50 mg spironolactone, using potassium as the read-out. Higher doses are usually not well tolerated, particularly in males because of the antiandrogenic actions leading to painful gynecomastia, erectile dysfunction and loss of libido (31). Nevertheless, in some rare cases, higher doses are required for optimal treatment. Those patients have excessive plasma aldosterone levels and quite low pre-treatment potassium levels. While some studies investigated doses up to 400 mg/day of spironolactone, the Endocrine Society guidelines recommend not to exceed 100 mg/day (1). In males with insufficient treatment response under 50 mg spironolactone, we often add amiloride to potentiate the nephron blockade. In females, spironolactone is usually tolerated in higher doses, but ingesting above 100 mg/day often induces breast pain and menstrual irregularities (32).

In case of antiandrogenic side effects, dose reduction of spironolactone or switching the medication to eplerenone must be considered (1). In our outpatient clinic, in case of antiandrogenic side effects, we first and foremost reduce the dose of spironolactone. This is often sufficient for symptom control. In the long run, we always try to switch the medication to eplerenone.

If eplerenone is used for PA treatment, an important consideration is the significantly shorter half-life compared to spironolactone (31). For an adequate aldosterone antagonism administration at least twice daily is necessary. In case of an insufficient response, a three times per day administration should be considered. In general, eplerenone must be dosed twice as high as spironolactone for therapeutic equivalence (30).

In our experience, 25 mg eplerenone twice daily are generally a good dosage to start. Most of our patients achieve sufficient aldosterone blockade with 50 mg twice daily. In those who do not respond adequately, we switch to a three times per day regimen. Doses up to 300 mg/day have been used in studies, but the maximal approved dosage is 100 mg/day (30).

In patients with severe hepatic or renal impairment, MRA titration must be monitored very carefully because of reduced drug clearance and enhanced risk of hyperkalemia.

If blood pressure control is suboptimal despite maximum tolerated MRA dose, adding further antihypertensive drugs should be considered (1).

Plasma renin activity might constitute an additional marker to evaluate successful aldosterone blockade (3). In case of persistent renin suppression, increasing the MRA dose should be considered, provided that there are no contraindications (e.g. antiandrogen side effects, elevated serum potassium levels or hypotension). Another alternative, or adjunct, might be dietary sodium restriction (24). In our experience, primary aldosteronism patients tend to spontaneously consume a very high salt diet often exceeding 10 g per day, potentially because of a shift in the sensory salt perception (Adolf et al., manuscript under review).

In case of poor blood pressure control, low serum potassium and suppressed renin activity despite high doses of MRA medication, non-compliance must be considered (1).

Future directions in medical treatment of PA

Future studies should address by a prospective design whether uptitration using renin levels is superior in managing PA treatment. Such a study could use surrogate parameters such as pro-BNP, microalbuminuria or high-sensitive CRP as endpoints. As an additional clinically relevant endpoint 24-h blood pressure profiles with restoration of night-time dipping could be employed. In a pilot study, flow-mediated vasodilatation could be used to demonstrate the superiority of ‘normalized’ renin levels on endothelial function. Finally, only long-term randomized studies involving appropriate numbers of patients to evaluate cardiovascular endpoints will answer the question whether uptitration of MRA toward normalized renin levels is superior.

Conclusion

Early diagnosis, and specific treatment, has prognostic relevance in primary aldosteronism. In unilateral disease, the standard of care remains surgical treatment via adrenalectomy. This causally addresses aldosterone excess, as well as potentially accompanying hypercortisolemia.

In bilateral disease, medical treatment with MR antagonists is the gold standard. Slow drug titration under regular supervision improves adherence and disease control. Primary markers of adequate treatment are potassium levels in the upper normal range and optimal blood pressure control. Plasma renin activity has been suggested as an adjunct marker that might provide additional information. In case of persistently suppressed plasma renin activity, adjustment of the MRA therapy should be considered, provided the absence of contraindications. It is important to not draw precipitous conclusions from one single study. More data from larger populations is needed to confirm these results, especially in the context of salt consumption and compliance.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this review.

Funding

This work was supported by the Else Kröner-Fresenius Stiftung in support of the German Conns Registry-Else-Kröner Hyperaldosteronism Registry (2013_A182 and 2015_A171 to M R), the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement No (694913) to M R), by the Deutsche Forschungsgemeinschaft (DFG) (within the CRC/Transregio 205/1 ‘The Adrenal: Central Relay in Health and Disease’ to A R, F B and M R).

Author contribution statement

All authors contributed to the review. Benjamin Lechner did the literature search and drafted the manuscript. Martin Reincke and the other authors reviewed and edited the manuscript. All authors approved the final version of the manuscript.

Acknowledgments

The authors would like to thank Celso Gomez-Sanchez, Michael Stowasser, Hide Naruse and Paolo Mulatero for sharing their experience and expertise regarding the use of eplerenone in PA treatment.

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    SeferovicPMPellicciaFZivkovicIRisticALalicNSeferovicJSimeunovicDMilinkovicIRosanoG. Mineralocorticoid receptor antagonists, a class beyond spironolactone – focus on the special pharmacologic properties of eplerenone. International Journal of Cardiology 2015 37. (https://doi.org/10.1016/j.ijcard.2015.02.096)

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  • 32

    ParthasarathyHKMenardJWhiteWBYoungWFJrWilliamsGHWilliamsBRuilopeLMMcInnesGTConnellJMMacDonaldTM. A double-blind, randomized study comparing the antihypertensive effect of eplerenone and spironolactone in patients with hypertension and evidence of primary aldosteronism. Journal of Hypertension 2011 980990. (https://doi.org/10.1097/HJH.0b013e3283455ca5)

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    MRA dose titration. *In case of severe hyperkalemia (>5.2 mmol/L) MRA reduction must be considered. **According to the 2018 ESC/ESH Guidelines for the management of arterial hypertension.

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    MulateroPMonticoneSBertelloCViolaATizzaniDIannacconeACrudoVBurrelloJMilanARabbiaF et al. Long-term cardio- and cerebrovascular events in patients with primary aldosteronism. Journal of Clinical Endocrinology and Metabolism 2013 48264833. (https://doi.org/10.1210/jc.2013-2805)

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    WilliamsTAReinckeM. MANAGEMENT of ENDOCRINE DISEASE: Diagnosis and management of primary aldosteronism: the Endocrine Society guideline 2016 revisited. European Journal of Endocrinology 2018 R19R29. (https://doi.org/10.1530/EJE-17-0990)

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    CatenaCColussiGLapennaRNadaliniEChiuchAGianfagnaPSechiLA. Long-term cardiac effects of adrenalectomy or mineralocorticoid antagonists in patients with primary aldosteronism. Hypertension 2007 911918. (https://doi.org/10.1161/HYPERTENSIONAHA.107.095448)

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    WilliamsBMacDonaldTMMorantSVWebbDJSeverPMcInnesGTFordICruickshankJKCaulfieldMJPadmanabhanS et al. Endocrine and haemodynamic changes in resistant hypertension, and blood pressure responses to spironolactone or amiloride: the PATHWAY-2 mechanisms substudies. Lancet: Diabetes and Endocrinology 2018 464475. (https://doi.org/10.1016/S2213-8587(18)30071-8)

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    RossiGPBolognesiMRizzoniDSecciaTMPivaAPorteriETiberioGAGiuliniSMAgabiti-RoseiEPessinaAC. Vascular remodeling and duration of hypertension predict outcome of adrenalectomy in primary aldosteronism patients. Hypertension 2008 13661371. (https://doi.org/10.1161/HYPERTENSIONAHA.108.111369)

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    MiyakeYTanakaKNishikawaTNaruseMTakayanagiRSasanoHTakedaYShibataHSoneMSatohF et al. Prognosis of primary aldosteronism in Japan: results from a nationwide epidemiological study. Endocrine Journal 2014 3540. (https://doi.org/10.1507/endocrj.EJ13-0353)

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    StrauchBPetrakOZelinkaTWichterleDHolajRKasalickyMSafarikLRosaJWidimskyJJr. Adrenalectomy improves arterial stiffness in primary aldosteronism. American Journal of Hypertension 2008 10861092. (https://doi.org/10.1038/ajh.2008.243)

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    WilliamsTALendersJWMMulateroPBurrelloJRottenkolberMAdolfCSatohFAmarLQuinklerMDeinumJ et al. Outcomes after adrenalectomy for unilateral primary aldosteronism: an international consensus on outcome measures and analysis of remission rates in an international cohort. Lancet: Diabetes and Endocrinology 2017 689699. (https://doi.org/10.1016/S2213-8587(17)30135-3)

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    CalhounDA. Medical versus surgical treatment of primary aldosteronism. Hypertension 2018 566568. (https://doi.org/10.1161/HYPERTENSIONAHA.118.10759)

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    RossiGPMaiolinoGFlegoABelfioreABerniniGFabrisBFerriCGiacchettiGLetiziaCMaccarioM et al. Adrenalectomy lowers incident atrial fibrillation in primary aldosteronism patients at long term. Hypertension 2018 585591. (https://doi.org/10.1161/HYPERTENSIONAHA.117.10596)

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    ReinckeM. Anxiety, depression, and impaired quality of life in primary aldosteronism: why we shouldn't ignore it! Journal of Clinical Endocrinology and Metabolism 2018 14. (https://doi.org/10.1210/jc.2017-02141)

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    VelemaMDekkersTHermusATimmersHLendersJGroenewoudHSchultze KoolLLangenhuijsenJPrejbiszAvan der WiltGJ et al. Quality of life in primary aldosteronism: a comparative effectiveness study of adrenalectomy and medical treatment. Journal of Clinical Endocrinology and Metabolism 2018 1624. (https://doi.org/10.1210/jc.2017-01442)

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    ArltWLangKSitchAJDietzASRhayemYBancosIFeuchtingerAChortisVGilliganLCLudwigP et al. Steroid metabolome analysis reveals prevalent glucocorticoid excess in primary aldosteronism. JCI Insight 2017 93136. (https://doi.org/10.1172/jci.insight.93136)

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    AdolfCKohlerAFrankeALangKRiesterALowAHeinrichDABidlingmaierMTreitlMLadurnerR et al. Cortisol excess in patients with primary aldosteronism impacts left ventricular hypertrophy. Journal of Clinical Endocrinology and Metabolism 2018 45434552. (https://doi.org/10.1210/jc.2018-00617)

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    GerardsJHeinrichDAAdolfCMeisingerCRathmannWSturmLNirschlNBidlingmaierMBeuschleinFThorandB et al. Impaired glucose metabolism in primary aldosteronism is associated with cortisol co-secretion. Journal of Clinical Endocrinology and Metabolism 2019 31923202. (https://doi.org/10.1210/jc.2019-00299)

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    CatenaCColussiGNadaliniEChiuchABaroselliSLapennaRSechiLA. Relationships of plasma renin levels with renal function in patients with primary aldosteronism. Clinical Journal of the American Society of Nephrology 2007 722731. (https://doi.org/10.2215/CJN.00050107)

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    SeferovicPMPellicciaFZivkovicIRisticALalicNSeferovicJSimeunovicDMilinkovicIRosanoG. Mineralocorticoid receptor antagonists, a class beyond spironolactone – focus on the special pharmacologic properties of eplerenone. International Journal of Cardiology 2015 37. (https://doi.org/10.1016/j.ijcard.2015.02.096)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 32

    ParthasarathyHKMenardJWhiteWBYoungWFJrWilliamsGHWilliamsBRuilopeLMMcInnesGTConnellJMMacDonaldTM. A double-blind, randomized study comparing the antihypertensive effect of eplerenone and spironolactone in patients with hypertension and evidence of primary aldosteronism. Journal of Hypertension 2011 980990. (https://doi.org/10.1097/HJH.0b013e3283455ca5)

    • PubMed
    • Search Google Scholar
    • Export Citation