Treatment of primary aldosteronism

INTRODUCTION — Primary and nonsuppressible hypersecretion of aldosterone is an increasingly recognized, but still underdiagnosed, cause of hypertension. The classic presenting signs of primary aldosteronism are hypertension and hypokalemia, but potassium levels are frequently normal in current series of primary aldosteronism.

The overall treatment goal in patients with primary aldosteronism is to prevent the adverse outcomes associated with excess aldosterone, including hypertension, hypokalemia, renal toxicity, and cardiovascular damage. The subtype-directed treatment of primary aldosteronism will be reviewed here and in this algorithm (algorithm 1). The pathophysiology, clinical manifestations, and diagnosis of this disorder and other less common causes of mineralocorticoid excess are discussed separately. (See "Pathophysiology and clinical features of primary aldosteronism" and "Diagnosis of primary aldosteronism" and "Familial hyperaldosteronism".)

OVERVIEW

Subtypes of primary aldosteronism — Renin-independent, incompletely suppressible (primary) hypersecretion of aldosterone is an increasingly recognized, but still underdiagnosed, cause of hypertension [1-3]; it is estimated to be responsible up to 10 percent of hypertension in humans [3,4]. Many subtypes of primary aldosteronism have been described since Conn's original report of the aldosterone-producing adenoma (APA) in 1954 [5-8].

The subtypes of primary aldosteronism include:

●Bilateral idiopathic hyperaldosteronism (or idiopathic adrenal hyperplasia [IHA], 60 to 70 percent). The underlying pathophysiology of the zona glomerulosa autonomy in patients with IHA is unknown. Forms of bilateral hyperplasia include multiple aldosterone-producing nodules and diffuse hyperplasia [9]. (See 'Idiopathic adrenal hyperplasia' below.)

●In 30 to 40 percent of patients, hyperaldosteronism is unilateral and due to APAs (≥10 mm) and aldosterone-producing nodules (<10 mm) [9]. Somatic mutations in KCNJ5 or other ion channels appear to be present in most patients with APAs and aldosterone-producing nodules. (See "Pathophysiology and clinical features of primary aldosteronism", section on 'Mutations in aldosterone-producing adenomas'.)

●Unilateral hyperplasia or primary adrenal hyperplasia (PAH), caused by micronodular or macronodular hyperplasia of the zona glomerulosa of predominantly one adrenal gland (approximately 3 percent) [8]. While less common, the clinical presentation and outcome of these patients is similar to those with APAs [10]. (See 'Patients with unilateral adenoma or hyperplasia' below.)

This topic reviews only the treatment of the above subtypes of primary aldosteronism. Other causes are reviewed elsewhere:

●Familial hyperaldosteronism type I (glucocorticoid-remediable aldosteronism [GRA]), type II (the familial occurrence of APA or bilateral IHA or both), type III (germline mutations in the KCNJ5 potassium channel), and type IV (mutations in the CACNA1H gene, which encodes the alpha subunit of an L-type, voltage-gated calcium channel, Cav3.2). The four types of familial hyperaldosteronism and their treatment are reviewed in detail separately. (See "Familial hyperaldosteronism".)

●Pure aldosterone-producing adrenocortical carcinomas and ectopic aldosterone-secreting tumors (eg, neoplasms in the ovary or kidney). Patients with these disorders are reviewed separately. (See "Clinical presentation and evaluation of adrenocortical tumors", section on 'Adrenocortical carcinoma'.)

Treatment goals — The overall treatment goal in patients with primary aldosteronism is to prevent the morbidity and mortality associated with hypertension, hypokalemia, renal toxicity, and cardiovascular damage. Excessive secretion of aldosterone is associated with an increased risk of cardiovascular events (which are independent of hypokalemia), including an increase in left ventricular (LV) mass measurements, stroke, myocardial infarction, heart failure, and atrial fibrillation [7,8,11-14]. The excess cardiovascular risk resolves after appropriate treatment of the mineralocorticoid excess.

Therefore, the goals of therapy for primary aldosteronism due to either unilateral or bilateral adrenal disease are the same and include:

●Reversal of the adverse cardiovascular effects of hyperaldosteronism

●Normalization of the serum potassium in patients with hypokalemia

●Normalization of the blood pressure

Determination of the correct subtype diagnosis is essential since the treatment of primary aldosteronism is based upon the cause (algorithm 1). (See "Diagnosis of primary aldosteronism", section on 'Subtype classification'.)

Once the correct subtype diagnosis is confirmed, the approach to management includes the following:

●For patients with unilateral disease (APAs, aldosterone-producing nodules, or unilateral hyperplasia), we suggest laparoscopic adrenalectomy. Surgery is curative only in patients with unilateral disease. Although surgery is the preferred approach, mineralocorticoid receptor antagonists (MRAs), when given at an appropriate dosage, are an alternative in patients who are not candidates for or who decline surgery. (See 'Patients with unilateral adenoma or hyperplasia' below.)

●For patients with bilateral idiopathic hyperaldosteronism, we suggest MRA therapy (spironolactone or eplerenone). (See 'First line: Mineralocorticoid receptor antagonists' below.)

•Amiloride, a potassium-sparing diuretic, is an alternative for patients intolerant of both spironolactone and eplerenone. (See 'Second line: Potassium-sparing diuretics' below.)

•In general, we suggest not performing total adrenalectomy in these patients. However, some patients may be candidates for unilateral adrenalectomy to debulk their disease (algorithm 1). (See 'Role of unilateral adrenalectomy' below.)

Our approach follows that of the 2016 Endocrine Society clinical practice guidelines for the diagnosis and treatment of primary aldosteronism [15]. (See "Diagnosis of primary aldosteronism", section on 'Case detection'.)

PATIENTS WITH UNILATERAL ADENOMA OR HYPERPLASIA

Laparoscopic adrenalectomy — Surgery is the preferred treatment for patients with unilateral disease (aldosterone-producing adenomas [APAs], aldosterone-producing nodules, or unilateral hyperplasia) (algorithm 1). Unilateral adrenalectomy in these patients induces a marked reduction in aldosterone secretion and correction of the hypokalemia in almost all patients [8,16,17]. Hypertension is improved in all and is cured in approximately 35 to 60 percent of patients [8,16-20].

We suggest laparoscopic adrenalectomy (by an experienced endocrine surgeon) over open adrenalectomy because it is associated with shorter hospital stays and fewer complications [21-23].

We also suggest resection of the entire affected adrenal gland rather than a laparoscopic partial adrenalectomy (removal of an adenoma, leaving the remaining gland intact). Partial adrenalectomy has been tried as a strategy to further reduce surgical morbidity, but it is an inadequate procedure in many cases [24]. This was illustrated in a series of 92 patients with primary aldosteronism undergoing laparoscopic adrenalectomy [25]. Postoperatively, all 63 patients with total adrenalectomy had improved blood pressure and normal plasma aldosterone, while 2 of 29 with partial adrenalectomy had persistent hypertension and high plasma aldosterone. Of the 63 removed adrenal glands, 17 (27 percent) contained multiple nodules along with what was thought to be the hypersecretory adenoma. Using sensitive pathologic methods, zona glomerulosa hyperplasia and nodules were observed adjacent to the resected aldosteronoma in 17 of 25 (68 percent) of cases studied [26].

These findings were further confirmed in a study of 55 patients with primary aldosteronism who underwent adrenalectomy; three (5.5 percent) had persistent hyperaldosteronism postoperatively [27]. All three patients had undergone partial adrenalectomy to remove a computed tomography (CT)-detected nodule present on the same side with adrenal vein sampling (AVS) lateralization. However, in the two cases with available data, immunohistochemistry showed a CYP11B2-negative nodule [27]. Thus, CT-detected adrenal nodules are not always a source of aldosterone excess, even when ipsilateral with AVS lateralization [24].

Preoperative management — Preoperatively, hypertension should be controlled, and hypokalemia should be corrected with potassium supplementation or a mineralocorticoid receptor antagonist (MRA) (eg, spironolactone or eplerenone) [2]. The blood pressure response to spironolactone preoperatively often predicts the blood pressure response to unilateral adrenalectomy in patients with APAs. (See 'First line: Mineralocorticoid receptor antagonists' below.)

Postoperative management — Postoperative management after unilateral adrenalectomy should include the following [1,7]:

●Plasma aldosterone should be measured the day after surgery to assess for cure (algorithm 1). This should be a morning venipuncture, just as is done for the initial evaluation. An undetectable plasma aldosterone concentration confirms correct preoperative subtype assignment and long-term cure (analogous to a low serum cortisol the day after pituitary surgery for Cushing syndrome, which predicts a long-term cure). However, if the postoperative plasma aldosterone concentration is >5 ng/dL, the patient should be followed closely by monitoring daily home blood pressure measurements and weekly serum potassium concentrations. Re-evaluation for persistent hyperaldosteronism is indicated in those patients with either persistent hypokalemia or lack of blood pressure improvement postoperatively.

●Potassium supplements and MRA (eg, spironolactone or eplerenone) should be discontinued in all patients, and, if possible, antihypertensive therapy should be decreased. When patients are treated with multiple antihypertensive agents prior to surgery, postoperatively we either discontinue or decrease the doses of those drugs that may predispose to hyperkalemia (eg, angiotensin-converting enzyme [ACE] inhibitors and angiotensin II receptor blockers [ARBs]) and, if needed for blood pressure control, continue those that are potassium neutral (eg, calcium channel blockers).

●Patients should be monitored closely for hyperkalemia, which may result from transient hypoaldosteronism due to chronic suppression of renal renin release and contralateral adrenal gland aldosterone secretion.

Serum potassium should be measured during the hospitalization and, subsequently as an outpatient, once weekly for four weeks. In a retrospective study of 192 patients with surgically treated primary aldosteronism, 12 (6.3 percent) developed hyperkalemia (median serum potassium 5.5 mmol/L), with a median time to onset of 13.5 days (range 7 to 55 days) [28]. Four patients received mineralocorticoid replacement therapy with fludrocortisone. On univariate analysis, hyperkalemic patients had slightly greater preoperative serum creatinine levels (1.2 versus 1 mg/dL), higher postoperative creatinine (1.3 versus 1 mg/dL), lesser median contralateral suppression index (0.14 versus 0.27), and larger adenomas (1.9 versus 1.4 cm). On multivariable logistic regression, the contralateral aldosterone suppression index remained the only significant predictor of postoperative hyperkalemia with an optimal cutoff of <0.47 [28].

In another retrospective study of 110 patients with APA who were treated with unilateral adrenalectomy, 12 (11 percent) developed transient postoperative hyperkalemia [29]. Prolonged hyperkalemia was observed in six patients (5 percent), and these patients required mineralocorticoid replacement therapy for 11 to 46 months. Preoperative decreased glomerular filtration rate (GFR) and increased serum creatinine, as well as increased postoperative creatinine and microalbuminuria, were significant predictors of hyperkalemia.

●Serum creatinine should be monitored for at least three to six months following surgery in all patients, including those without preoperative evidence of kidney dysfunction. Primary aldosteronism has been associated with kidney damage [30-33]. Although treatment of primary aldosteronism improves long-term kidney function [15,34], the postoperative reduction in aldosterone corrects renal hyperfiltration and may unmask preexisting kidney impairment in patients with a normal preoperative GFR. For example, in a cohort of 213 patients with primary aldosteronism, the prevalence of chronic kidney disease increased by approximately 20 percent after surgical or medical treatment [33]. Similarly, treatment of primary aldosteronism may reveal more severe kidney dysfunction in patients with known kidney impairment. In a long-term study that included 50 patients with primary aldosteronism and 100 patients with primary hypertension (formerly called "essential" hypertension), during 30 to 90 days after surgical or medical intervention, the mean GFR decreased in patients with primary aldosteronism by 13.6 mL/min/1.73 m² but only by 2.1 mL/min/1.73 m² in patients with primary hypertension despite similar blood pressure values [30]. Observational studies have found that GFR stabilizes within three to six months after surgical or medical treatment, and preoperative metrics of disease severity (eg, lower serum potassium, albuminuria, higher serum aldosterone) may predict the early posttreatment decline in GFR [33,35].

●The preferred intravenous fluid after surgery is isotonic saline without potassium (unless the patient is still hypokalemic), and a sodium-rich diet should be considered before and after discharge [7].

Outcomes

Hypertension — Although hypertension is cured in some patients, a lesser degree of hypertension persists in as many as 40 to 65 percent of cases [16-20,36,37]. A number of clinical features help to identify patients who are more likely to experience complete resolution of their hypertension after adrenalectomy, including [16]:

●Lack of family history of hypertension

●Shorter duration of hypertension

●Preoperative use of two or fewer antihypertensive agents

●Younger age

●Higher preoperative ratio of plasma aldosterone concentration to plasma renin activity

●Higher urine aldosterone level

Persistent hypertension may be related to underlying primary hypertension and/or the development of nephrosclerosis after a prolonged period of uncontrolled hypertension [19,38]. It is also possible that an error in subtype assignment has been made and that the patient has bilateral adrenal hyperplasia, a disorder that usually should be treated medically, not with unilateral adrenalectomy. If the patient has persistent primary aldosteronism after surgery, it should be treated with an MRA (eg, spironolactone or eplerenone). As many as one-third of patients thought to have a unilateral lesion on imaging studies have bilateral adrenal hyperplasia on AVS. (See "Diagnosis of primary aldosteronism", section on 'Adrenal vein sampling'.)

Biochemical outcomes — As indicated, if the preoperative subtype assignment was correct (ie, unilateral hyperaldosteronism), the immediate postoperative plasma aldosterone concentration should be low. In most patients, aldosterone secretion from the remaining adrenal gland recovers over a couple of weeks as renal renin release recovers from chronic suppression. If preoperative hypokalemia was present, it should resolve in a matter of days. The concern in the first several weeks after surgery is for hyporeninemic hypoaldosteronism and resultant hyperkalemia. (See 'Postoperative management' above.)

Patients who have recurrent hypokalemia at any point following surgery and those who experience limited hypertension improvement should undergo formal reevaluation with case-detection testing for recurrent primary aldosteronism.

Left ventricular mass — Although it has been suggested that adrenalectomy is more effective than MRA therapy for reduction of left ventricular (LV) mass [39], a meta-analysis of four studies including 355 patients reported that while adrenalectomy was more effective than medical therapy for blood pressure reduction, both treatments had a similar effect on LV mass change [40,41].

Quality of life — Quality of life is low in patients with unilateral disease (APAs, aldosterone-producing nodules, or unilateral hyperplasia) when compared with healthy individuals but improves to normal within 3 to 12 months of unilateral adrenalectomy [42,43]. The improvement appears to be maintained at six months. Quality of life is also improved by medical therapy, but not to the level found in the general population [43,44]. (See 'Efficacy' below.)

Nonsurgical candidates — The goals of medical therapy in patients with unilateral disease who refuse or are not candidates for surgery are the same as those with bilateral disease receiving mineralocorticoid receptor antagonists (MRAs): correction of hypokalemia, restoration of normal blood pressure, and reversal of the effects of hyperaldosteronism on the heart. (See 'Medical therapy' below.)

Pharmacologic therapy — Although laparoscopic adrenalectomy is more cost effective over time [45], the administration of an MRA is a reasonable alternative in patients who refuse or are not candidates for surgery [46-49]. The efficacy of this approach was illustrated in a study of 24 patients with adenomas who were treated medically for at least five years [47]. The following results were reported:

●Systolic and diastolic blood pressures decreased from 175/106 to 129/79 mmHg

●The serum potassium concentration increased from 3.0 to 4.3 mEq/L

●Five tumors had increased in size by at least 0.5 cm (as determined by CT scan), but there was no evidence of malignant transformation in any patient

However, one study suggests that patients with primary aldosteronism treated with MRAs (if renin activity remains suppressed) have a higher rate of cardiovascular events than patients with essential hypertension, independent of blood pressure control. However, patients on higher doses of MRAs with unsuppressed renin have no excess cardiovascular risk [50]. This was illustrated in a cohort study of 602 patients with primary aldosteronism treated with MRAs and 41,853 age-matched patients with essential hypertension. The incidence of cardiovascular events was higher in patients with primary aldosteronism on MRAs than in patients with essential hypertension (56.3 versus 26.6 events per 1000 person-years, adjusted hazard ratio [HR] 1.91, 95% CI 1.63-2.25). Patients with primary aldosteronism also had higher adjusted risks for incident mortality (HR 1.34, 95% CI 1.06-1.71), diabetes (HR 1.26, 95% CI 1.01-1.57), and atrial fibrillation (HR 1.93, 95% CI 1.54-2.42).

The excess risks of cardiovascular events were independent of blood pressure control and were limited to patients with primary aldosteronism whose renin activity remained suppressed on MRAs (<1 microgram/L per hour) (adjusted HRs 2.83, 95% CI 2.11-3.80), whereas patients who were treated with higher MRA doses and had unsuppressed renin (≥1 microgram/L per hour) had no significant excess risk [50].

Not recommended: Ablative procedures — Although published data are limited, some centers have advocated percutaneous ablative therapy for unilateral adrenal adenomas, including percutaneous acetic acid injection and thermal ablation [51-53]. However, we advise against this approach.

There are no prospective treatment trials comparing thermal ablation with unilateral adrenalectomy. Unilateral hyperaldosteronism is frequently due to more than one aldosterone-producing nodule [24]; thus, targeting a single adrenal nodule with thermal ablation is associated with low cure primary aldosteronism rates compared with surgery. In one report of 34 patients with primary aldosteronism (24 in the laparoscopic adrenalectomy group and 10 in the ablation group) [54]. Hypertensive crisis occurred in 7 of 10 patients (70 percent) of patients in the ablation group versus 1 of 24 (4 percent) in the surgical group. At a median follow-up of 46 months, the surgical group had more patients with cured hypertension (29 versus 0 percent), better blood pressure control rate (96 versus 50 percent), less frequent use of MRAs (42 versus 90 percent), and possibly fewer blood pressure medications (1.8 versus 3, p = 0.054) [54].

In addition, thermal ablation has associated risk for adjacent organ injury (eg, pneumothorax, hemorrhage, visceral perforation, and vascular thrombosis). The pain associated with thermal ablation requires general anesthesia or deep conscious sedation.

Given the limited experience, uncertain success rate, and potential complications, we cannot recommend adrenal percutaneous ablative therapy.

PATIENTS WITH BILATERAL DISEASE — There are four forms of primary aldosteronism due to bilateral adrenal zona glomerulosa hyperplasia: idiopathic adrenal hyperplasia (IHA); the rare glucocorticoid-remediable aldosteronism (GRA), which responds to the administration of exogenous glucocorticoid; type III familial hyperaldosteronism due to germline KCNJ5 potassium channel mutations; and type IV due to mutations in the CACNA1H gene. As noted above, GRA and type III and IV familial hyperaldosteronism are reviewed in detail separately. (See "Familial hyperaldosteronism", section on 'Familial hyperaldosteronism type I (FH type I) or glucocorticoid-remediable aldosteronism (GRA)' and "Familial hyperaldosteronism", section on 'Familial hyperaldosteronism type III (FH type III)'.)

Idiopathic adrenal hyperplasia — IHA is generally a milder disease than adrenal adenoma, with less hypersecretion of aldosterone and less hypokalemia. Such patients should be treated with a mineralocorticoid receptor antagonist (MRA). However, in patients with severe primary aldosteronism (spontaneous hypokalemia and serum aldosterone concentration >30 ng/dL) and who have marked asymmetry on adrenal venous sampling (AVS) (aldosterone lateralization ratio between 3 and 4), unilateral laparoscopic adrenalectomy can be considered (algorithm 1) [55].

Medical therapy — We recommend that patients with bilateral adrenal hyperplasia be treated with medical therapy and not adrenalectomy because:

●Blood pressure control is often inadequate with unilateral adrenalectomy in patients with bilateral disease

●The risks associated with bilateral adrenalectomy (including the need for lifelong glucocorticoid and mineralocorticoid replacement) outweigh the potential benefits

First line: Mineralocorticoid receptor antagonists — Optimal treatment of IHA consists of mineralocorticoid receptor blockade with spironolactone or eplerenone. Spironolactone has long been the drug of choice; eplerenone, although shorter-acting, is more specific for the aldosterone receptor and is associated with fewer side effects.

The goals of therapy are: raising serum potassium into the high-normal range, normalization of the blood pressure, and reversal of the effects of hyperaldosteronism on the heart and kidneys. (See 'Treatment goals' above.)

Choice of MRA — Our current approach is to start with the mineralocorticoid receptor antagonist (MRA) spironolactone and, if endocrine side effects are limiting, switch to eplerenone. Eplerenone is now available as a generic, but it remains substantially more expensive than spironolactone.

Efficacy — One open-label study suggested that spironolactone and eplerenone have a similar effect on blood pressure in patients with primary aldosteronism [56]. However, a randomized, clinical trial in patients with primary aldosteronism reported that spironolactone was more effective for hypertension than eplerenone [57].

Dietary sodium restriction (<100 mEq/day), maintenance of ideal body weight, avoidance of alcohol, and regular aerobic exercise contribute to the success of pharmacologic therapy in almost any patient with hypertension [8].

In patients with bilateral adrenal hyperplasia, quality of life, as measured by the validated Medical Outcomes Study Short Form 36 General Health Survey (SF-36), improves during treatment with MRAs [44]. However, the improvement appears to be more modest and occurs more slowly when compared with historical control patients undergoing unilateral adrenalectomy for unilateral adrenal adenoma [43,44].

Dosing and monitoring — When using spironolactone or, if not tolerated, eplerenone, we suggest the following regimen, which is consistent with the 2016 Endocrine Society guidelines [15].

●Spironolactone (or eplerenone) is titrated upward to a mid- to high-normal serum potassium concentration without the aid of potassium supplements. The spironolactone starting dose is 12.5 to 25 mg daily with food, which increases drug absorption [1]. The dose can be increased every two weeks until the target serum potassium of 4.5 mEq/L is reached. The typical maximum dose is between 100 to 400 mg daily.

The starting dose of eplerenone, which has 50 percent less mg per mg potency than spironolactone, is 25 mg twice daily (total of 50 mg/day). The maximum eplerenone dose approved by the US Food and Drug Administration (FDA) for hypertension is 100 mg daily. However, to effectively treat primary aldosteronism, higher doses are frequently required [57].

The target of a mid- to high-normal serum potassium concentration without the aid of potassium supplements reflects the goal of blocking the mineralocorticoid receptor from excess aldosterone effect. Another approach is to monitor plasma renin activity with the goal level higher than 1 ng/mL/hour [50].

●The blood pressure goal is often difficult to achieve with monotherapy because of concomitant essential hypertension [16-18]. (See 'Outcomes' above and 'Patients with persistent hypertension' below.)

●With each medication change, it is important to monitor the effect on both blood pressure and serum potassium. Serum potassium, creatinine, and blood pressure should be monitored frequently during the first four to six weeks of medical therapy (especially in patients with renal insufficiency or diabetes mellitus). Clinical course and circumstances dictate the frequency of monitoring thereafter.

Precautions and side effects

●Spironolactone – There are some precautions with the use of spironolactone:

•Serum potassium and creatinine should be monitored frequently during the first four to six weeks of therapy, especially in patients with renal insufficiency or diabetes mellitus. The clinical course and circumstances dictate the frequency of subsequent monitoring.

•Concomitant therapy with salicylates or nonsteroidal antiinflammatory drugs (NSAIDs) may interfere with the antihypertensive efficacy of spironolactone (and other antihypertensive medications).

Spironolactone is also a progesterone receptor agonist and androgen receptor antagonist, resulting in side effects such as breast tenderness and menstrual irregularities in women and impotence, decreased libido, and gynecomastia in men [47,48]. In a review of 699 patients with primary aldosteronism treated with spironolactone, the incidence of gynecomastia was dose dependent: 6.9 percent at doses below 50 mg/day and 52 percent at doses above 150 mg/day [47]. Spironolactone may also be associated with minor gastrointestinal symptoms. (See "Clinical features, diagnosis, and evaluation of gynecomastia in adults".)

●Eplerenone – As noted, eplerenone may be less effective than spironolactone for hypertension, but it has fewer side effects. Eplerenone is a highly selective MRA.

In a multicenter trial, 141 patients were randomized to treatment with spironolactone (75 to 225 mg once daily) or eplerenone (100 to 300 mg once daily) [57]. Changes from baseline in diastolic blood pressure were less on eplerenone (-5.6±1.3 SEM mmHg) than spironolactone (-12.5±1.3 SEM mmHg).

Compared with spironolactone, eplerenone has 0.1 percent of the binding affinity to androgen receptors and less than 1 percent of the binding affinity to progesterone receptors, properties that are favorable for minimizing side effects. In the multicenter trial above, eplerenone was associated with a lower incidence of endocrine side effects when compared with spironolactone. The overall incidence of side effects was similar, but more patients receiving spironolactone developed gynecomastia or, in women, mastodynia (21.1 versus 0 percent).

Because of its short half-life, eplerenone is more effective if given twice daily. Thus, until more data become available, it is reasonable to start with spironolactone and, if endocrine side effects are limiting, switch to eplerenone.

Patients with persistent hypertension — If hypertension persists, we add another antihypertensive drug (eg, 12.5 to 25 mg of hydrochlorothiazide or chlorthalidone daily) or an angiotensin-converting enzyme (ACE) inhibitor (eg, lisinopril 5 to 10 mg daily). The efficacy of an ACE inhibitor in the low plasma renin state may, in part, reflect the role of low concentrations of angiotensin II as an aldosterone secretagogue in adrenal hyperplasia.

Second line: Potassium-sparing diuretics — Potassium-sparing diuretics are an alternative for patients intolerant of both spironolactone and eplerenone [58].

These drugs (amiloride, triamterene) block the aldosterone-sensitive sodium channel in the collecting tubules, lowering the blood pressure and raising the serum potassium concentration [58,59]. However, these drugs are not recommended for first-line therapy, because of persistence of the effect of the hyperaldosteronism at the mineralocorticoid receptor, with its possible deleterious cardiovascular effects. (See "Mechanism of action of diuretics", section on 'Potassium-sparing diuretics'.)

Amiloride dosing may be started at 5 mg twice daily and increased to the dose needed to correct the hypokalemia. If the hypertension persists, a second-step drug should be added. Low doses of a thiazide diuretic (eg, 12.5 to 25 mg of hydrochlorothiazide or chlorthalidone daily) are preferred because hypervolemia is a major reason for resistance to amiloride [47,48].

Role of unilateral adrenalectomy — Unilateral adrenalectomy in patients with bilateral adrenal disease has been tried in patients with IHA, but only a minority of patients have a clinically significant hypotensive response [60]. However, unilateral adrenalectomy in patients with bilateral adrenal hyperplasia does have the potential to effectively "debulk" the amount of adrenal tissue responsible for aldosterone hypersecretion and may, in selected patients, provide improved blood pressure control (algorithm 1) [55]. However, the risk of long-term morbidity from mild hyperaldosteronism from the remaining gland has not been defined.

PREGNANCY — Primary aldosteronism is uncommon in pregnancy, with fewer than 60 patients reported in the medical literature; most patients have had aldosterone-producing adenomas (APA) [61-65]. Primary aldosteronism can lead to intrauterine growth retardation, preterm delivery, intrauterine fetal demise, preeclampsia, and placental abruption [66,67].

An unusual feature of primary aldosteronism during pregnancy is that the degree of disease may be either improved or aggravated. In some women with primary aldosteronism, the high blood levels of pregnancy-related progesterone are antagonistic at the mineralocorticoid receptor and partially block the action of aldosterone; these patients have an improvement in the manifestations of primary aldosteronism during pregnancy [68,69]. In other pregnant women, increased expression of luteinizing hormone choriogonadotropin receptor (LHCGR) has been documented in APAs harboring beta-catenin mutations, and the degree of hyperaldosteronism is aggravated by the increased pregnancy-related blood levels of human chorionic gonadotropin [70,71].

The type of treatment for primary aldosteronism in pregnancy depends on how difficult it is to manage the hypertension and hypokalemia. If the patient is in the subset of patients who have a remission in the degree of primary aldosteronism, then surgery or treatment with a mineralocorticoid receptor antagonist (MRA) can be avoided until after delivery. However, if hypertension and hypokalemia are marked, then surgical and/or medical intervention is indicated. Unilateral laparoscopic adrenalectomy during the second trimester can be considered in those women with confirmed primary aldosteronism and a clear-cut unilateral adrenal macroadenoma (>10 mm). (See 'Laparoscopic adrenalectomy' above.)

There are concerns about spironolactone use during pregnancy because it crosses the placenta and has been associated with feminization of newborn male rats. However, there is only one human case in the medical literature where treatment with spironolactone in pregnancy led to ambiguous genitalia in a male infant; this occurred in a woman treated with spironolactone for polycystic ovary syndrome (PCOS) prepregnancy and through the fifth week of gestation [72].

There are some concerns about eplerenone as well. Therefore, for pregnant women who will be managed medically, the hypertension should be treated with standard antihypertensive drugs approved for use during pregnancy rather than mineralocorticoid receptor antagonists (MRAs). Hypokalemia, if present, should be treated with oral potassium supplements. For those patients with refractory hypertension and/or hypokalemia, the addition of eplerenone may be cautiously considered [61,65,73]. (See "Treatment of hypertension in pregnant and postpartum patients", section on 'Overview of antihypertensive drugs used in pregnancy'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Primary aldosteronism".)

SUMMARY AND RECOMMENDATIONS

●Major forms of primary aldosteronism – From a treatment perspective, the two major forms of primary aldosteronism are unilateral adrenal aldosterone hypersecretion (eg, adenoma, nodule, unilateral hyperplasia, or carcinoma) and bilateral aldosterone hypersecretion (eg, idiopathic adrenal hyperplasia [IHA]). (See 'Patients with unilateral adenoma or hyperplasia' above and 'Patients with bilateral disease' above.)

●Treatment

•Goals – The goals of therapy for primary aldosteronism due to either unilateral or bilateral adrenal disease are the same and include: normalization of serum potassium in hypokalemic patients; reversal of the adverse cardiovascular effects of hyperaldosteronism; and normalization of blood pressure (although hypertension often persists after correction of the hyperaldosteronism). (See 'Treatment goals' above.)

•Surgery for unilateral disease – For most patients with confirmed unilateral aldosterone hypersecretion (eg, adrenal adenoma, unilateral nodule, or unilateral adrenal hyperplasia), we suggest unilateral adrenalectomy over medical therapy (Grade 2B). We also suggest resection of the entire affected adrenal gland rather than a laparoscopic partial adrenalectomy (removal of an adenoma, leaving the remaining gland intact). (algorithm 1). (See 'Laparoscopic adrenalectomy' above.)

-Surgical approach – For patients with unilateral disease, we suggest laparoscopic adrenalectomy rather than open laparotomy (Grade 2C), because of the reduction in postoperative morbidity, hospital stay, and expense. Plasma aldosterone should be measured the day after adrenal surgery to assess for cure. (See 'Laparoscopic adrenalectomy' above and 'Postoperative management' above.)

-Nonsurgical candidates – For patients with confirmed unilateral adrenal aldosterone hypersecretion (who refuse or are not candidates for surgery), we use medical therapy with a mineralocorticoid receptor antagonist (MRA; eg, spironolactone or eplerenone). (See 'First line: Mineralocorticoid receptor antagonists' above.)

•Bilateral adrenal hyperplasia – For patients with bilateral adrenal hyperplasia, we suggest treatment with medical therapy rather than surgery (Grade 2C) (algorithm 1). Blood pressure control is often inadequate with subtotal adrenalectomy, and the risks associated with bilateral adrenalectomy (including the need for lifelong glucocorticoid and mineralocorticoid replacement) outweigh the potential benefits. (See 'Patients with bilateral disease' above.)

-Approach to medical therapy – We suggest mineralocorticoid receptor antagonists over other potassium-sparing diuretics (eg, amiloride, triamterene) (Grade 2C). Potassium-sparing diuretics are not considered first-line because the effect of the hyperaldosteronism at the mineralocorticoid receptor persists, with its possible deleterious cardiovascular effects.

Of the MRAs, we suggest spironolactone as the first-line drug (Grade 2C) and switch to eplerenone if side effects are limiting. Eplerenone is a more selective MRA than spironolactone and is associated with fewer side effects; however, when administered once daily and compared with spironolactone, eplerenone is a less effective antihypertensive agent. (See 'Choice of MRA' above.)

-Monitoring – Serum potassium, creatinine, and blood pressure should be monitored frequently during the first four to six weeks of medical therapy (especially in patients with renal insufficiency or diabetes mellitus). Clinical course and circumstances dictate the frequency of monitoring thereafter. (See 'Dosing and monitoring' above.)

-Patients who cannot tolerate MRAs – For patients who do not tolerate the MRAs spironolactone or eplerenone, we switch to a potassium-sparing diuretic such as amiloride. (See 'Second line: Potassium-sparing diuretics' above.)

●Pregnancy – The type of treatment for primary aldosteronism in pregnancy depends on how difficult it is to manage the hypertension and hypokalemia. If the patient is in the subset of patients who have a remission in the degree of primary aldosteronism, then surgery or treatment with an MRA can be avoided until after delivery. However, if hypertension and hypokalemia are marked, then surgical and/or medical intervention is indicated. (See 'Pregnancy' above.)

ACKNOWLEDGMENTS — The views expressed in this topic are those of the author(s) and do not reflect the official views or policy of the United States Government or its components.

The UpToDate editorial staff acknowledges Norman M Kaplan, MD, who contributed to earlier versions of this topic review.