Chiara Sabbadin

Polycystic ovary syndrome: Implications of measurement of plasma aldosterone, renin activity and progesterone.

A positive correlation between aldosterone, inflammatory parameters, blood pressure and metabolic abnormalities in polycystic ovary syndrome (PCOS) has been reported in the early estrogenic phase. The aim of the study was to measure plasma aldosterone, plasma renin activity (PRA) and progesterone on the 21st day of the cycle, in women with PCOS and to consider the interrelationships between these hormones. Sixty-six consecutive normal BMI women with PCOS (median age 24 years, range 21-28 years) and 53 age- and body mass index-matched healthy controls were enrolled in the study. Aldosterone, aldosterone/PRA ratio (ARR) and Homeostasis Model Assessment (HOMA) index were significantly higher (p<0.0001) in PCOS women than controls. Positive correlations were found in PCOS but not in controls between (i) progesterone and aldosterone, (ii) aldosterone and PRA, (iii) PRA and progesterone. Mean blood pressures were within the normal range but significantly higher in PCOS than controls. The increase of plasma aldosterone, ARR and blood pressure in PCOS compared with controls is consistent with an increased mineralocorticoid effector mechanism in PCOS; prolonged therapy with spironolactone could counteract both the hyperandrogenism and reduce future cardiovascular risk.

Aldosterone receptor blockers spironolactone and canrenone: two multivalent drugs

Canrenone is a derivative of spironolactone with lower antiandrogen activity. The drug is used only in few countries and can block all the side effects of aldosterone (ALDO). The drug is effective even in the presence of normal concentrations of ALDO. Mineralcorticoid receptor antagonists block the inflammatory activity of ALDO at the level of target tissues as heart, vessels and mononuclear leukocytes. Canrenone reduces the progression of insulin resistance and of microalbuminuria in type 2 diabetes and other related diseases. Both canrenone and hydrochlorothiazide can enhance the effect of treatment with ACE inhibitors and angiotensin II receptor blockers on microalbuminuria, but ALDO receptor blockers are more active. This different action is due to the fact that only canrenone blocks mineralocorticoid receptors. Serum potassium and renal function should be monitored before and during the treatment. ALDO receptor blockers are recommended in addition to polytherapy for resistant hypertension, but there are no studies on the effect of the drug as first-choice therapy.

Human Red Blood Cells Alterations in Primary Aldosteronism

CONTEXT Aldosterone (Aldo) effects include NADPH oxidase activation involved in Aldo-related oxidative stress. Red blood cells (RBCs) are particularly sensitive to oxidative assault, and both the formation of high molecular weight aggregates (HMWAs) and the diamide-induced Tyr phosphorylation (Tyr-P) level of membrane band 3 can be used to monitor their redox status. OBJECTIVE The Aldo-related alterations in erythrocytes were evaluated by comparing in vitro evidence. DESIGN This was a multicenter comparative study. STUDY PARTICIPANTS The study included 12 patients affected by primary aldosteronism (PA) and 6 healthy control subjects (HCs), whose RBCs were compared with those of patients with PA. For in vitro experiments, RBCs from HCs were incubated with increasing Aldo concentrations. MAIN OUTCOME MEASURES The Tyr-P level, band 3 HMWA formation, and autologous IgG binding were evaluated. RESULTS In patients with PA, both Tyr-P levels and band 3 HMWAs were higher than those in HCs. RBCs from HCs were treated with increasing Aldo concentrations in both platelet-poor plasma (PPP) and charcoal-stripped (CS)-PPP. Results showed that Aldo had dose- and time-dependent effects on band 3 Tyr-P and HMWA formation in CS-PPP more than in PPP. These effects were almost completely prevented by canrenone or cortisol. Aldo-related membrane alterations led to increased autologous IgG binding. CONCLUSIONS Erythrocytes from patients with PA show oxidative-like stress evidenced by increased HMWA content and diamide-induced band 3 Tyr-P level. Aldo effects are mediated by the mineralocorticoid receptor, as suggested by the inhibitory effects of canrenone, an antagonist of Aldo. In CS-PPP, in which Aldo induces remarkable membrane alterations leading to IgG binding, Aldo may be responsible for premature RBC removal from circulation.

Astaxanthin Improves Human Sperm Capacitation by Inducing Lyn Displacement and Activation

Astaxanthin (Asta), a photo-protective red pigment of the carotenoid family, is known for its multiple beneficial properties. In this study, the effects of Asta on isolated human sperm were evaluated. Capacitation involves a series of transformations to let sperm acquire the correct features for potential oocyte fertilization, including the generation of a controlled amount of reactive oxygen species (ROS), cholesterol depletion of the sperm outer membrane, and protein tyrosine phosphorylation (Tyr-P) process in the head region. Volunteers, with normal spermiogram values, were divided in two separate groups on the basis of their ability to generate the correct content of endogenous ROS. Both patient group (PG) and control group (CG) were analysed for Tyr-phosphorylation (Tyr-P) pattern and percentages of acrosome-reacted cells (ARC) and non-viable cells (NVC), in the presence or absence of Asta. In addition, the involvement of ROS on membrane reorganization and the presence of Lyn, a Src family kinase associated with lipid rafts, were investigated. Results show that Lyn is present in the membranes of human sperm, mainly confined in midpiece in resting conditions. Following capacitation, Lyn translocated to the head concomitantly with raft relocation, thus allowing the Tyr-P of head proteins. Asta succeeded to trigger Lyn translocation in PG sperm thus bypassing the impaired ROS-related mechanism for rafts and Lyn translocation. In this study, we showed an interdependence between ROS generation and lipid rafts and Lyn relocation leading the cells to undergo the successive acrosome reaction (AR). Asta, by ameliorating PG sperm functioning, may be utilised to decrease male idiopathic infertility.

Considerations for the Assessment of Salt Intake by Urinary Sodium Excretion in Hypertensive Patients

Do and colleagues have evaluated the effectiveness of the Eat Less Salt intervention in a Vietnamese population, collecting spot urine samples for estimation of 24hour sodium excretion before and after informed reduction of sodium intake. It is well-known that hypertension has important implications both on the expense of health and on the future risk of illness. A major factor involved in hypertension is salt intake associated with genetic predisposing factors. Increased dietary sodium intake is a modifiable risk factor for cardiovascular disease. The monitoring of population sodium intake is a key part of any salt reduction intervention. However, the extent and methods used for assessment of sodium intake in Southeast Asia is currently unclear. Dietary data suggest that sodium intake in most Southeast Asian countries exceeded the World Health Organization recommendation of 2 g/d, and even healthy patients have frequently lower renin values compared with those in western countries, as a result of different sodium intake. The greatest proportion of dietary sodium comes from salt added in home cooking, soy sauce, and commercially processed foods. The results of the study by Do and colleagues show a correlation between reduced sodium intake and sodium excretion using spot urine samples. Moreover, they demonstrated that a community-based intervention on salt reduction behavior can reduce the risk related to high sodium intake. Collection of 24-hour urine is widely considered the best method for assessment of sodium intake. It is known that about 90% of ingested sodium is excreted in the urine in 24 hours. The remaining 10% is excreted through sweat and feces, which could play an important role in situations of hot climates, increased physical activity, diarrhea, and vomiting. Assessment of completeness of 24-hour urine collection is more precise measuring urinary creatinine or administering paraaminobenzoic acid. This latter method may be challenging for patients because it requires administration several times during the 24-hour collection. Recently, many authors have tried to demonstrate that 24-hour sodium excretion can be estimated using spot urine samples, which are easily collected and cannot account for inaccuracy of collection and losses. Sodium concentration in spot urine represents the sodium intake in the short period preceding the collection; for that reason, the sodium excretion can vary during the day depending on sodium intake. Spot urine samples, however, have increased individual variability depending not only on sodium ingestion in the previous hours but also water ingestion and regulation of hormonal and nonhormonal factors involved in sodium concentration. The determination should be standardized by collecting urine samples at the same period of the day to compare the excretion in the same patient. The estimation of sodium intake from measurement of sodium excretion is feasible in the general population, in particular in studies aimed to investigate a sample of patients before and after a dietetic intervention, considering that all the factors involved in the sodium regulation do not change over a short period of time. In hypertensive patients, the estimation of sodium intake from spot urine could be misleading and should be associated with the measurement of plasma renin and aldosterone, plasma, and urinary osmolality to exclude plasma dilution caused by increased water intake or treatments that change sodium excretion. It is also known that renin and aldosterone are dependent on the standing or lying position and therefore these factors should also be considered.

Hypothesis on a relationship between hyperaldosteronism, inflammation, somatic mutations, and autoimmunity

After the description of the adaption syndrome, Selye hypothesized in 1949 that desoxycorticosterone (DOC), the first mineralocorticoid to be discovered, could induce an inflammatory effect. This hypothesis was based on the effect of DOC in worsening the symptoms of rheumatoid arthritis and inducing a strong inflammatory effect in animal models.1 Similar activity was also supposed for aldosterone, when it was discovered in 1953. Edith Glàz and Paul Vecsei in 1971 reported in their book on aldosterone that “Relying upon the fundamental concept of Selye, maybe it will be possible in the future to demonstrate that DOC, which has recently been shown to be secreted in significant amounts in the human adrenal vein, plays an important part in the pathogenesis of inflammatory diseases. No observations that might exclude this possibility have been made so far.”2 This concept was later abandoned for several decades and mineralocorticoids were only studied for their sodium and waterretaining activity and related hypertension. The inflammatory effect of aldosterone was later revisited in cardiovascular diseases, in particular, by Pitt and colleagues,3,4 who pointed out the importance of aldosterone receptor blockers to prevent the relapse of cardiovascular or heart accidents even in patients with normal aldosterone values. In 1985, we characterized mineralocorticoid receptors (MRs) in human mononuclear leukocytes,5 where aldosterone regulates intracellular electrolytes6 and volume.7 Subsequently, we demonstrated that incubation of mononuclear leukocytes with aldosterone increases the expression of two specific markers of inflammation, and this effect is blocked by coincubation with the MR antagonist canrenone.8 Nongenomic effects of aldosterone were also evaluated in mononuclear leukocytes and recently in erythrocytes.9 Both leukocytes and erythrocytes can interplay and contribute to the local inflammatory reaction, bringing their MRs in the site of inflammation, and this process could be modulated by canrenone, emphasizing a possible role of classical MRs in the genomic and nongenomic effects of aldosterone. Inflammation and autoimmunity are strictly linked and recent studies are focusing on the relationship between aldosterone and autoimmune disorders. In particular, Herrada and coworkers10 demonstrated a direct action of aldosterone in promoting the induction of Thelper 17 polarization of CD4+ T cells, which have been associated with the promotion of many organspecific autoimmune diseases. Recently, we also reported an increased association of Hashimoto thyroiditis in patients with primary aldosteronism (PA).11 From these studies it could be hypothesized that MR blockers could also modulate the onset and/ or evolution of some autoimmune disorders, suggesting new therapeutic targets for MR antagonists.

Vertebral fractures assessed with dual-energy X-ray absorptiometry in patients with Addison’s disease on glucocorticoid and mineralocorticoid replacement therapy

Purposeto assess bone damage and metabolic abnormalities in patients with Addison’s disease given replacement doses of glucocorticoids and mineralocorticoids.MethodsA total of 87 patients and 81 age-matched and sex-matched healthy controls were studied. The following parameters were measured: urinary cortisol, serum calcium, phosphorus, creatinine, 24-h urinary calcium excretion, bone alkaline phosphatase, parathyroid hormone, serum CrossLaps, 25 hydroxyvitamin D, and 1,25 dihydroxyvitamin D. Clear vertebral images were obtained with dual-energy X-ray absorptiometry in 61 Addison’s disease patients and 47 controls and assessed using Genant’s classification.ResultsNineteen Addison’s disease patients (31.1%) had at least one morphometric vertebral fracture, as opposed to six controls (12.8%, odds ratio 3.09, 95% confidence interval 1.12–8.52). There were no significant differences in bone mineral density parameters at any site between patients and controls. In Addison’s disease patients, there was a positive correlation between urinary cortisol and urinary calcium excretion. Patients with fractures had a longer history of disease than those without fractures. Patients taking fludrocortisone had a higher bone mineral density than untreated patients at all sites except the lumbar spine.ConclusionsAddison’s disease patients have more fragile bones irrespective of any decrease in bone mineral density. Supra-physiological doses of glucocorticoids and longer-standing disease (with a consequently higher glucocorticoid intake) might be the main causes behind patients’ increased bone fragility. Associated mineralocorticoid treatment seems to have a protective effect on bone mineral density.

Syndromes that Mimic an Excess of Mineralocorticoids

Pseudohyperaldosteronism is characterized by a clinical picture of hyperaldosteronism with suppression of renin and aldosterone. It can be due to endogenous or exogenous substances that mimic the effector mechanisms of aldosterone, leading not only to alterations of electrolytes and hypertension, but also to an increased inflammatory reaction in several tissues. Enzymatic defects of adrenal steroidogenesis (deficiency of 17α-hydroxylase and 11β-hydroxylase), mutations of mineralocorticoid receptor (MR) and alterations of expression or saturation of 11-hydroxysteroid dehydrogenase type 2 (apparent mineralocorticoid excess syndrome, Cushing’s syndrome, excessive intake of licorice, grapefruits or carbenoxolone) are the main causes of pseudohyperaldosteronism. In these cases treatment with dexamethasone and/or MR-blockers is useful not only to normalize blood pressure and electrolytes, but also to prevent the deleterious effects of prolonged over-activation of MR in epithelial and non-epithelial tissues. Genetic alterations of the sodium channel (Liddle’s syndrome) or of the sodium-chloride co-transporter (Gordon’s syndrome) cause abnormal sodium and water reabsorption in the distal renal tubules and hypertension. Treatment with amiloride and thiazide diuretics can respectively reverse the clinical picture and the renin aldosterone system. Finally, many other more common situations can lead to an acquired pseudohyperaldosteronism, like the expansion of volume due to exaggerated water and/or sodium intake, and the use of drugs, as contraceptives, corticosteroids, β-adrenergic agonists and FANS. In conclusion, syndromes or situations that mimic aldosterone excess are not rare and an accurate personal and pharmacological history is mandatory for a correct diagnosis and avoiding unnecessary tests and mistreatments.

Maternal and Fetal Outcomes in Preeclampsia: Interrelations Between Insulin Resistance, Aldosterone, Metabolic Syndrome, and Polycystic Ovary Syndrome

Cicero and colleagues have reported an interesting study on the independent determinants of maternal and fetal outcomes in a group of pregnant patients with different forms of hypertension. The diagnosis of preeclampsia (PE) and increased serum acid uric level have been found to be associated with negative maternal outcomes, while diagnosis of PE and pre-pregnancy maternal body mass index (BMI) were associated with negative fetal outcome. In both cases, the effective treatment of hypertension both during pregnancy and at delivery was a protective factor. Hypertension in pregnancy is a major risk factor for adverse outcomes both for the mother and for the fetus, and early therapeutic management is necessary not only to optimize blood pressure (BP) values but also to monitor and prevent the related complications such as metabolic syndrome, microalbuminuria, BMI, and gestational diabetes. Many studies recommend pre-pregnancy planning, therapeutic adjustments, and adequate care during and after pregnancy in women with chronic hypertension. The increase in BP in the first trimester of pregnancy, as well as the finding of an increase in BP before pregnancy, require immediate treatment and monitoring. The early management in these patients reduces the rate of complications during pregnancy and could explain the reason why only PE was found to be associated with negative outcome in the study by Cicero and colleagues. PE is the most severe form of hypertension in pregnancy, characterized by proteinuria and edema in the third trimester of pregnancy. Its pathogenesis is still debated and involves different hormonal, inflammatory, and immunologic mechanisms. PE is a characteristic complication of pregnancy, which is usually reversed after delivery and can relapse in a subsequent pregnancy. An abnormal invasion of miometrium by trophoblast is an evident alteration, but the initial cause is still unknown. The evidence of early alterations of the placental vasculature suggests that the disease has a preclinical period with few symptoms and is often not treated because BP is normal. The pathogenesis of PE is promoted by genetic and epigenetic factors and is likely related to the release into the circulation of placental factors that can activate the immune cells in an inappropriate manner. A supporting feature to this hypothesis is the development of PE in patients with hydatidiform mole in the absence of a fetus. The onset of the disease in the third trimester is sometimes dramatic and frequently associated with liver, kidney, heart, coagulation, and neurological complications, which need full treatment, careful monitoring, and often an urgent cesarean section to avoid maternal and fetal complications.

Association of primary aldosteronism with chronic thyroiditis.

Primary aldosteronism (PA) is associated with an increased risk of cardioand cerebro-vascular events, mediated not only by its hypertensive effect but also by its proinflammatory action [1]. Recent studies suggest a role of aldosterone in the development and/or progression of autoimmune disorders: aldosteronism is associated with an activation of circulating immune cells, which is attenuated by mineralocorticoid receptor (MR)-antagonists [2]. We previously characterized MR in circulating mononuclear leukocytes (MNL) and found an increased protein expression of PAI-1 and p22(phox) after incubation of MNL with aldosterone, this effect being reversed by coincubation with canrenone [3, 4]. Aldosterone can directly increase the capacity of dendritic cells to activate CD8T cells and induce Th17 polarization of CD4T cells, which have been associated with many autoimmune diseases, and a recent study has found an increased expression of Th17-related factors in autoimmune thyroiditis (AIT) [5, 6]. PA can be associated with AIT and surgical removal of an aldosterone-producing adrenal adenoma (APA) improved thyroid function and decreased thyroid autoimmunity in a case report of a female with PA and AIT [7–9]. We previously found a high prevalence of thyroid morphological alterations in patients affected by PA compared to general population [10]. Another study confirmed a significant increase of thyroid ultrasonographic abnormalities in PA compared with patients affected by essential hypertension, while the prevalence of thyroid dysfunction and anti-thyroid antibodies was similar [11]. We here report a study on the prevalence of the association of PA and chronic thyroiditis, according to functional, immunological, and/or sonographic criteria.