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Aldosterone excess may inhibit insulin secretion: A comparative study on glucose metabolism pre- and post-adrenalectomy in patients with primary aldosteronism.

Conflicting data have been published on the effects of aldosterone excess on glucose metabolism. Specifically, there are limited data on whether adrenalectomy in patients with aldosterone-producing adenomas (APA) can improve glucose metabolism. In this study we evaluated changes in glucose metabolism, before and after surgery for APA. The subjects were 61 patients treated with unilateral adrenalectomy, localized by adrenal venous sampling. A 75g-oral glucose tolerance test (OGTT) was performed before and 1 year after adrenalectomy. Patients with diabetes mellitus or a serum cortisol level >3 µg/dL after a 1 mg dexamethasone suppression test, were excluded. Using the 75g-OGTT data, insulin secretion and insulin resistance (or sensitivity) indices were calculated. The results showed that immunoreactive insulin levels during the OGTT increased significantly after adrenalectomy, whereas plasma glucose levels, before and after surgery, were comparable. The insulinogenic index significantly increased after surgery (0.5 [0.4-0.8] to 0.8 [0.4-1.1], p < 0.001). The disposition index remained largely unchanged (806.2 [489.4-1,138.9] to 686.6 [479.4-922.1], p = 0.25). The homeostatic model assessment of insulin resistance increased significantly (1.0 [0.6-1.5] to 1.5 [1.0-2.2], p < 0.001) and the ISImatsuda decreased significantly (6.9 [4.5-10.4] to 5.2 [3.4-7.9], p < 0.001). Changes in these indices were not correlated with changes in potassium and aldosterone levels before and after surgery. In conclusion, insulin secretion increased after adrenalectomy for APA, indicating that aldosterone excess inhibits insulin secretion. However, because of a parallel increase in insulin resistance, plasma glucose levels remained unchanged.

The management of primary aldosteronism: case detection, diagnosis, and treatment: an endocrine society clinical practice guideline - update information

OBJECTIVE: To develop clinical practice guidelines for the management of patients with primary aldosteronism. PARTICIPANTS: The Task Force included a chair, selected by the Clinical Guidelines Subcommittee of the Endocrine Society, six additional experts, a methodologist, and a medical writer. The guideline was cosponsored by American Heart Association, American Association of Endocrine Surgeons, European Society of Endocrinology, European Society of Hypertension, International Association of Endocrine Surgeons, International Society of Endocrinology, International Society of Hypertension, Japan Endocrine Society, and The Japanese Society of Hypertension. The Task Force received no corporate funding or remuneration. EVIDENCE: We searched for systematic reviews and primary studies to formulate the key treatment and prevention recommendations. We used the Grading of Recommendations, Assessment, Development, and Evaluation group criteria to describe both the quality of evidence and the strength of recommendations. We used ""recommend"" for strong recommendations and ""suggest"" for weak recommendations. CONSENSUS PROCESS: We achieved consensus by collecting the best available evidence and conducting one group meeting, several conference calls, and multiple e-mail communications. With the help of a medical writer, the Endocrine Society's Clinical Guidelines Subcommittee, Clinical Affairs Core Committee, and Council successfully reviewed the drafts prepared by the Task Force. We placed the version approved by the Clinical Guidelines Subcommittee and Clinical Affairs Core Committee on the Endocrine Society's website for comments by members. At each stage of review, the Task Force received written comments and incorporated necessary changes. CONCLUSIONS: For high-risk groups of hypertensive patients and those with hypokalemia, we recommend case detection of primary aldosteronism by determining the aldosterone-renin ratio under standard conditions and recommend that a commonly used confirmatory test should confirm/exclude the condition. We recommend that all patients with primary aldosteronism undergo adrenal computed tomography as the initial study in subtype testing and to exclude adrenocortical carcinoma. We recommend that an experienced radiologist should establish/exclude unilateral primary aldosteronism using bilateral adrenal venous sampling, and if confirmed, this should optimally be treated by laparoscopic adrenalectomy. We recommend that patients with bilateral adrenal hyperplasia or those unsuitable for surgery should be treated primarily with a mineralocorticoid receptor antagonist.

The Role of Aldosterone in Obesity-Related Hypertension.

Obese subjects often have hypertension and related cardiovascular and renal diseases, and this has become a serious worldwide health problem. In obese subjects, impaired renal-pressure natriuresis causes sodium retention, leading to the development of salt-sensitive hypertension. Physical compression of the kidneys by visceral fat and activation of the sympathetic nervous system, renin-angiotensin systems (RAS), and aldosterone/mineralocorticoid receptor (MR) system are involved in this mechanism. Obese subjects often exhibit hyperaldosteronism, with increased salt sensitivity of blood pressure (BP). Adipose tissue excretes aldosterone-releasing factors, thereby stimulating aldosterone secretion independently of the systemic RAS, and aldosterone/MR activation plays a key role in the development of hypertension and organ damage in obesity. In obese subjects, both salt sensitivity of BP, enhanced by obesity-related metabolic disorders including aldosterone excess, and increased dietary sodium intake are closely related to the incidence of hypertension. Some salt sensitivity-related gene variants affect the risk of obesity, and together with salt intake, its combination is possibly associated with the development of hypertension in obese subjects. With high salt levels common in modern diets, salt restriction and weight control are undoubtedly important. However, not only MR blockade but also new diagnostic modalities and therapies targeting and modifying genes that are related to salt sensitivity, obesity, or RAS regulation are expected to prevent obesity and obesity-related hypertension.

Bicarbonate-sensitive calcification and lifespan of klotho-deficient mice.

Klotho, a protein counteracting aging, is a powerful inhibitor of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] formation and regulator of mineral metabolism. In klotho hypomorphic (kl/kl) mice, excessive 1,25(OH)2D3 formation leads to hypercalcemia, hyperphosphatemia and vascular calcification, severe growth deficits, accelerated aging and early death. Kl/kl mice further suffer from extracellular volume depletion and hypotension, leading to the stimulation of antidiuretic hormone and aldosterone release. A vitamin D-deficient diet, restriction of dietary phosphate, inhibition of mineralocorticoid receptors with spironolactone, and dietary NaCl all extend the lifespan of kl/kl mice. Kl/kl mice suffer from acidosis. The present study explored whether replacement of tap drinking water by 150 mM NaHCO3 affects the growth, tissue calcification, and lifespan of kl/kl mice. As a result, NaHCO3 administration to kl/kl mice did not reverse the growth deficit but substantially decreased tissue calcification and significantly increased the average lifespan from 78 to 127 days. NaHCO3 did not significantly affect plasma concentrations of 1,25(OH)2D3 and Ca(2+) but significantly decreased plasma phosphate concentration and plasma aldosterone concentration. The present study reveals a novel effect of bicarbonate, i.e., a favorable influence on vascular calcification and early death of klotho-deficient mice.

Phase II multicenter study of abiraterone acetate plus prednisone therapy in patients with docetaxel-treated castration-resistant prostate cancer.

PURPOSE: Persistence of ligand-mediated androgen receptor signaling has been documented in castration-resistant prostate cancers (CRPCs). Abiraterone acetate (AA) is a potent and selective inhibitor of CYP17, which is required for androgen biosynthesis in the testes, adrenal glands, and prostate tissue. This trial evaluated the efficacy and safety of AA in combination with prednisone to reduce the symptoms of secondary hyperaldosteronism that can occur with AA monotherapy. PATIENTS AND METHODS: Fifty-eight men with progressive metastatic CRPC who experienced treatment failure with docetaxel-based chemotherapy received AA (1,000 mg daily) with prednisone (5 mg twice daily). Twenty-seven (47%) patients had received prior ketoconazole. The primary outcome was > or = 50% prostate-specific antigen (PSA) decline, with objective response by Response Evaluation Criteria in Solid Tumors (RECIST) criteria, and changes in Eastern Cooperative Oncology Group (ECOG) performance status (PS) and circulating tumor cell (CTC) numbers. Safety was also evaluated. RESULTS: A > or = 50% decline in PSA was confirmed in 22 (36%) patients, including 14 (45%) of 31 ketoconazole-naïve and seven (26%) of 27 ketoconazole-pretreated patients. Partial responses were seen in four (18%) of 22 patients with RECIST-evaluable target lesions. Improved ECOG PS was seen in 28% of patients. Median time to PSA progression was 169 days (95% CI, 82 to 200 days). CTC conversions with treatment from > or = 5 to < 5 were noted in 10 (34%) of 29 patients. The majority of AA-related adverse events were grade 1 to 2, and no AA-related grade 4 events were seen. CONCLUSION: AA plus prednisone was well tolerated, with encouraging antitumor activity in heavily pretreated CRPC patients. The incidence of mineralocorticoid-related toxicities (hypertension or hypokalemia) was reduced by adding low-dose prednisone. The combination of AA plus prednisone is recommended for phase III investigations.

Long-term effects of surgical correction of adrenal hyperplasia and adenoma causing primary aldosteronism.

PURPOSE: The purpose of this is to study long-time results of surgery for primary aldosteronism. MATERIALS AND METHODS: Thirty patients operated on for primary aldosteronism were followed for an average of 7 years. All but five required potassium substitution. Systolic as well as diastolic hypertension (mean 157/93 mmHg) was present necessitating one to five antihypertensive drugs daily (mean 2.33). Preoperative indications for surgery included presumed adenoma (aldosterone-producing adenoma (APA)) or in one case unilateral dominance of hyperplasia. RESULTS: Histopathology was classified into adenoma (n = 9), dominant nodule (n = 16), and general hyperplasia without dominating nodules (n = 5), demonstrating a higher frequency of hyperplasia than anticipated. Long-term results revealed well-controlled blood pressure (BP; mean 134/80 mmHg). Antihypertensive medication was reduced (average of 1.78 per day), but only 36% of the patients were taken off these drugs completely. S-Aldosterone was normalized. All but one (a recurrence) were normokalemic without potassium substitution at follow-up. The APA group needed less medication (median 0.5 vs. 1.5 and 2 per day) and more patients in this group were totally medication free (50%). Two recurrences occurred in the group with general hyperplasia without dominating nodules. CONCLUSION: Nodular hyperplasia is more common than anticipated. Hypersecretion of aldosterone may be released from a large nodule identified as an adenoma, as well as from a generally hyperplastic gland that has not been identified as such. Nevertheless, surgery for lateralized disease results in good long-term control of BP with less antihypertensive medication. However, patients with dominant nodule or general hyperplasia without dominating nodules need more postoperative treatment than patients with APA. The majority of patients do not achieve normotension without medications, but they do become normokalemic.

Suppression of surgical hyperaldosteronism by potassium canrenoate during gynecologic surgery under sevoflurane anesthesia.

BACKGROUND: Surgical hyperaldosteronism leads to sodium and water retention during surgery and often causes postoperative edema. This study investigated the effect of potassium canrenoate (PC) on pituitary adrenocortical function in lower abdominal surgery under sevoflurane anesthesia. METHODS: Twenty patients were randomized to receive 400 mg of PC (the PC group, n=10) or saline (the control group, n=10) intravenously. The following parameters were determined: plasma aldosterone, adrenocorticotropic hormone (ACTH), plasma renin activity (PRA), serum sodium and potassium, urinary sodium and potassium, and urine output. RESULTS: The aldosterone and ACTH levels showed significant increases in the control group during surgery. Plasma ACTH also increased significantly in the PC group, but plasma aldosterone levels were unchanged during surgery. The urine Na/K ratio of the PC group was significantly higher than that of the control group. CONCLUSION: The present study suggested that PC suppresses the increase of plasma aldosterone caused by surgical stress. That may prevent sodium retention and potassium excretion during surgery.

A PCR-based method of screening individuals of all ages, from neonates to the elderly, for familial hyperaldosteronism type I.

AIM: Unless specifically treated (glucocorticoids in low doses), Familial Hyperaldosteronism Type I (FH-I) may result in early death from stroke. We report the successful application of a rapid, polymerase chain reaction (PCR)-based method of detecting the 'hybrid' 11 beta-hydroxylase (11 beta-OHase)/aldosterone synthase (AS) gene as a screening test for FH-I. METHODS: 'Long-PCR' was used to amplify, concurrently, a 4 kb fragment of AS gene (both primers AS-specific) and a 4 kb fragment of the hybrid gene (5' primer 11 beta-OHase-specific, 3' primer AS-specific) from DNA extracted from blood either collected locally or transported from elsewhere. Sample collection and transport were straightforward. This 4 kb fragment contains all the currently recognised hybrid gene 'crossover' points. RESULTS: Within a single family, long-PCR identified all 21 individuals known to have FH-I. Hypertension was corrected in all 11 treated with glucocorticoids. Nine with normal blood pressure are being closely followed for development of hypertension. Long-PCR cord blood analysis excluded FH-I in three neonates born to affected individuals. Long-PCR newly identified two other affected families: (1) a female (60 years) with a personal and family history of stroke and her normotensive daughter (40 years), and (2) a female (51 years) previously treated for primary aldosteronism with amiloride, her two hypertensive sons (14 and 16 years) and her hypertensive mother (78 years). No false negative or false positive results have yet been encountered. At least seven other centres have successfully performed this test. CONCLUSION: Long-PCR is a reliable method of screening individuals of all ages for FH-I.

The usefulness of the captopril test as a simultaneous screening for primary aldosteronism and renovascular hypertension.

The usefulness of the captopril test as a simultaneous screening method for primary aldosteronism (PA) and renovascular hypertension (RVH) was evaluated in 111 patients with essential hypertension, and in 79 patients with secondary hypertension, which included 16 patients with PA and 18 with RVH. Plasma renin activity (PRA, ng/mL/h) and plasma aldosterone concentration (PAC, ng/dL) were determined before and 90 min after administration of 50 mg of captopril in the supine position on a normal NaCl diet. A cutoff point or a discriminant function in the screening was determined by discriminant analysis. A quadratic discriminant function of PRA and PAC after the captopril test identified patients with PA with a false negative rate of 6.3% (1/16), and a false positive rate of 0.6% (1/174) which was significantly lower than that of 3.4% at the basal state (P < .05). In the screening for RVH, the criterion of a postcaptopril PRA of greater than 10.6 ng/mL/h had a false negative rate of 5.6% (1/18) and a false positive rate of 15.1% (26/172). This false positive rate was also significantly lower than that using a criterion for precaptopril PRA of 2.21 ng/mL/h (P < .05). Accordingly, the captopril test was a useful method in the simultaneous screening for PA and RVH, and it may be particularly applicable in specialized hypertension clinics.

Reversal of diuretic-induced secondary hyperaldosteronism and hypokalemia by enalapril (MK-421): a new angiotensin-converting enzyme inhibitor.

The study reported here prospectively evaluated the prevention of diuretic-induced secondary hyperaldosteronism and hypokalemia by a converting enzyme inhibitor, enalapril (MK 421). Eighteen normal subjects were randomized into three groups: (1) a HCTZ group (hydrochlorothiazide (HCTZ) 50 mg/day); (2) a MK-421 group (MK-421 10 mg/day); and (3) a HCTZ + MK-421 group [HCTZ 50 mg/day plus MK-421 10 mg/day]. Following a five-day control and a 28-day treatment period, the HCTZ group demonstrated an attenuated but persistent secondary hyperaldosteronism and hypokalemia, the MK-421 group manifested a gradual decline in aldosterone secretion, and the HCTZ + MK-421 group had a delayed but effective correction of secondary hyperaldosteronism and hypokalemia at 28 days but not before. In conclusion, MK-421 reversed diuretic-induced secondary hyperaldosteronism and hypokalemia after 28 days of hydrochlorothiazide therapy. Therefore, converting enzyme inhibitors, such as enalapril, provide useful adjunctive therapy in diuretic-treated patients, but potassium supplementation may be required before the start of four weeks of combined therapy.