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

2015; Wiley; Volume: 17; Issue: 10 Linguagem: Inglês

10.1111/jch.12613

1751-7176

Decio Armanini, Chiara Sabbadin, Gabriella Donà, Alessandra Andrisani, Guido Ambrosini, Luciana Bordin,

Gestational Diabetes Research and Management

The Journal of Clinical HypertensionVolume 17, Issue 10 p. 783-785 CommentaryFree Access Maternal and Fetal Outcomes in Preeclampsia: Interrelations Between Insulin Resistance, Aldosterone, Metabolic Syndrome, and Polycystic Ovary Syndrome Decio Armanini MD, Corresponding Author Decio Armanini MD Department of Medicine – Endocrinology (DIMED), University of Padua, Padua, Italy Address for correspondence: Decio Armanini, MD, Department of Medicine – Endocrinology (DIMED), University of Padua, Via Ospedale 105, 35128 Padua, Italy E-mail:decio.armanini@unipd.itSearch for more papers by this authorChiara Sabbadin MD, Chiara Sabbadin MD Department of Medicine – Endocrinology (DIMED), University of Padua, Padua, ItalySearch for more papers by this authorGabriella Donà PhD, Gabriella Donà PhD Department of Molecular Medicine – Biological Chemistry, University of Padua, Padua, ItalySearch for more papers by this authorAlessandra Andrisani MD, Alessandra Andrisani MD Department of Women's Health–Salus Pueri, University of Padua, Padua, ItalySearch for more papers by this authorGuido Ambrosini MD, Guido Ambrosini MD Department of Women's Health–Salus Pueri, University of Padua, Padua, ItalySearch for more papers by this authorLuciana Bordin PhD, Luciana Bordin PhD Department of Molecular Medicine – Biological Chemistry, University of Padua, Padua, ItalySearch for more papers by this author Decio Armanini MD, Corresponding Author Decio Armanini MD Department of Medicine – Endocrinology (DIMED), University of Padua, Padua, Italy Address for correspondence: Decio Armanini, MD, Department of Medicine – Endocrinology (DIMED), University of Padua, Via Ospedale 105, 35128 Padua, Italy E-mail:decio.armanini@unipd.itSearch for more papers by this authorChiara Sabbadin MD, Chiara Sabbadin MD Department of Medicine – Endocrinology (DIMED), University of Padua, Padua, ItalySearch for more papers by this authorGabriella Donà PhD, Gabriella Donà PhD Department of Molecular Medicine – Biological Chemistry, University of Padua, Padua, ItalySearch for more papers by this authorAlessandra Andrisani MD, Alessandra Andrisani MD Department of Women's Health–Salus Pueri, University of Padua, Padua, ItalySearch for more papers by this authorGuido Ambrosini MD, Guido Ambrosini MD Department of Women's Health–Salus Pueri, University of Padua, Padua, ItalySearch for more papers by this authorLuciana Bordin PhD, Luciana Bordin PhD Department of Molecular Medicine – Biological Chemistry, University of Padua, Padua, ItalySearch for more papers by this author First published: 14 July 2015 https://doi.org/10.1111/jch.12613Citations: 7AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Cicero and colleagues1 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.2 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.3 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.1 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.4 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. PE: Interrelationship Between Insulin Resistance, Inflammation, Metabolic Syndrome, and PCOS Cicero and collaborators evaluated some determinants of maternal and fetal outcomes, but genetic and epigenetic factors are also involved in hypertension in pregnant women. The focus of research is to find the pathogenetic mechanisms and risk predictors. Different meta-analyses have shown that polycystic ovary syndrome (PCOS), metabolic syndrome, diabetes, insulin resistance, and inflammatory reaction are the most important factors involved in this disease, in particular, PE. Insulin resistance plays a key role in the pathogenesis of PCOS, producing the ovarian picture and hyperandrogenism. This feature is also often present in lean PCOS patients, pointing out that the focus of the question is insulin resistance and not obesity itself.5 Women with PCOS also have a significantly elevated risk for developing gestational diabetes mellitus, pregnancy-induced hypertension, PE, premature delivery and caesarean section, and other cardiovascular events during pregnancy compared with controls.6 Hypertension in pregnancy and particularly PE are frequently linked with PCOS, increase in BMI and uric acid, and cardiovascular disease, all features related to the metabolic syndrome. PE is also characterized by increased inflammatory status, which may be promoted by the altered placental perfusion leading to the release of cytotoxic factors into the circulation, increased vascular tone, and endothelial dysfunction.7 The pro-oxidative status is also present in PCOS and is involved in the increased metabolic, cardiovascular, and obstetric complications seen in the disease.8 Hormonal Regulation of Water and Solute During Pregnancy and PE Knowledge of the physiology of pregnancy is necessary to understand the differences between normal pregnancy and pregnancy complicated by hypertension. Pregnancy is associated with decreased immune reaction, volume expansion, solute dilution, and decrease in BP in the first two trimesters. It is well-known that high progesterone concentrations in pregnancy are protective against the risk for hypertension, being progesterone antagonist at level of mineralocorticoid receptor. Progesterone can have an agonist effect at the level of mineralocorticoid receptors only in cases of PE associated with a mutation of the aldosterone receptor, leading to severe hypertension and PE.9 The increase in progesterone in pregnancy could explain the physiological activation of the renin-angiotensin-aldosterone system (RAAS), but the putative diuretic effect of progesterone is not consistent with the retention of water and sodium typical of pregnancy. Important factors involved in the retention of sodium and water during pregnancy could be estradiol, which can increase the effect of antidiuretic hormone and cortisol, compensatory of the estradiol-mediated increase in corticosteroid-binding globulin. Cortisol activity may be effectively increased in PE, expanding plasma volume and reducing the activation of the RAAS as a consequence of the saturation of 11-beta-hydroxysteroid dehydrogenase type 2 (11β-HSD2) at the renal and placental site. Previous studies have reported a lower activation of the RAAS in patients with PE compared with normal pregnancy. It is worth noting that the same pattern of hypercortisolism is also found during treatment with contraceptives, which are often responsible for a significant increase in BP values. Another hypothesis involves reduced expression and activity of 11β-HSD2 at the level of the placenta in PE.10 RAAS in PE and PCOS Plasma renin and aldosterone levels are high during pregnancy and the underlying mechanism of this increase is still debated. Estrogens stimulate the secretion of angiotensinogen, activating the RAAS, which is not effective, however, and do not cause hypertension or hypokalemia in normal pregnant women. For this reason it is more likely that the activation of the system is caused by the excess of progesterone or to a reduced sensitivity to aldosterone. A possible link between PCOS and PE is the finding of activation of RAAS both in PE and in PCOS. Pregnant women with PCOS are not hypertensive but are more prone to develop hypertension later in life, and the RAAS is frequently activated even in normotensive patients, as recently reported.11 In the same study, we found that BP was normal though the values were slightly and significantly higher compared with controls. A recent paper found that patients who develop PE have a slightly higher BP in the first trimester of pregnancy compared with normal pregnant controls.3 Another interesting factor is the presence in PE of autoantibodies stimulating the receptor of angiotensin II. These antibodies have also been found in primary aldosteronism (PA), but patients with PA usually show an improvement in BP values and hypokalemia during pregnancy, probably because of the antagonism of increased progesterone at the level of mineralocorticoid receptors.12 Patients with PA usually do not have PE and this finding is consistent with a genetic factor and not hyperaldosteronism itself. Considering the regulation of BP and volume, some unknown mechanisms are involved in the onset of PE and these factors are related to the regulation of the effector mechanism of aldosterone and cortisol. We previously hypothesized the involvement of aldosterone in the pathogenesis of PE. The relative increase of aldosterone in PE is associated with its expected activity in regulating BP, while in normal pregnancy, aldosterone and progesterone levels are similarly high but BP is normal. Biological function of aldosterone was evaluated in this study by measuring the mineralocorticoid receptor number in mononuclear leukocytes and the rectal minus skin potential difference in normal pregnancy and PE. Our conclusion was that in normal pregnancy, some placental factors blunt the effect of aldosterone and this effect is lacking in PE, allowing a normal effect of aldosterone on mineralocorticoid receptors. The alternative possibility is that the hypothetical placental factors blunt the antagonist effect of progesterone at the receptor site.13 This factor has not yet been characterized. Why Evaluate the Metabolic and Hormonal Situation During Pregnancy? The importance of evaluation of pre-pregnancy risk factors of all fertile women comes from observations and studies in the literature. The early treatment of the factors linked to the metabolic syndrome could prevent complicated pregnancy and PE. Even thyroid function should be monitored since 30% of women with PCOS have Hashimoto's thyroiditis and an unrecognized thyroid abnormality could interfere with the development of fetal brain functions and predispose to PE.14 The study by Cicero and colleagues excluded patients with thyroid abnormalities and likely omitted a number of cases with PE associated with PCOS, not considering patients with PCOS and Hashimoto's thyroiditis, and therefore the difference with controls should have been more evident. Conclusions The findings by Cicero and coworkers have indirectly confirmed the predominant role of factors related to the metabolic syndrome in the negative outcome of the mother and the fetus. From this study and others, the concept of pre-pregnancy prevention must always be considered and the possible complications should be monitored early in pregnancy to start adequate treatment as soon as possible. The prevention of hypertension and PE is important both for the mother and the fetus, also avoiding cardiovascular and metabolic complications after menopause. Considering that PCOS is a lifetime disease that is present in 10% of fertile women, it is important to carefully evaluate family history and related endocrine and metabolic features during childhood by pediatricians, family doctors, cardiologists, and all doctors evaluating a fertile women. Lifestyle changes and treatment of metabolic syndrome may help avoid a number of future complications and promote the well-being of patients. Competing Interests The authors have nothing to disclose. References 1Cicero AF, Degli Esposti D, Immordino V, et al. Independent determinants of maternal and fetal outcomes in a sample of pregnant outpatients with normal blood pressure, chronic hypertension, gestational hypertension, and preeclampsia. J Clin Hypertens (Greenwich). 2015; 17: 777– 782. 2Seely EW, Ecker J. Chronic hypertension in pregnancy. N Engl J Med. 2011; 365: 439– 446. 3Macdonald-Wallis C, Lawlor DA, Fraser A, et al. Blood pressure change in normotensive, gestational hypertensive, preeclamptic, and essential hypertensive pregnancies. Hypertension. 2012; 59: 1241– 1248. 4Armanini D. Preeclampsia: the role of aldosterone in hypertension and inflammation. Hypertension. 2012; 59: 1099– 1100. 5Dunaif A, Segal KR, Futterweit W, et al. Profound peripheral insulin resistance, independent of obesity, in polycystic ovary syndrome. Diabetes. 1989; 38: 1165– 1174. 6Qin JZ, Pang LH, Li MJ, et al. Obstetric complications in women with polycystic ovary syndrome: a systematic review and meta-analysis. Reprod Biol Endocrinol. 2013; 11: 56. 7Dordević NZ, Babić GM, Marković SD, et al. Oxidative stress and changes in antioxidative defense system in erythrocytes of preeclampsia in women. Reprod Toxicol. 2008; 25: 213– 218. 8Donà G, Sabbadin C, Fiore C, et al. Inositol administration reduces oxidative stress in erythrocytes of patients with polycystic ovary syndrome. Eur J Endocrinol. 2012; 166: 703– 710. 9Geller DS, Farhi A, Pinkerton N, et al. Activating mineralocorticoid receptor mutation in hypertension exacerbated by pregnancy. Science. 2000; 289: 119– 123. 10Causevic M, Mohaupt M. 11beta-hydroxysteroid dehydrogenase type 2 in pregnancy and preeclampsia. Mol Aspects Med. 2007; 28: 220– 226. 11Armanini D, Bordin L, Donà G, et al. Polycystic ovary syndrome: implications of measurement of plasma aldosterone, renin activity and progesterone. Steroids. 2012; 77: 655– 658. 12Riester A, Reincke M. Mineralcorticoid receptor antagonists and management of primary aldosteronism in pregnancy. Eur J Endocrinol. 2015; 172: R23– R30. 13Armanini D, Zennaro CM, Martella L, et al. Mineralocorticoid effector mechanism in preeclampsia. J Clin Endocrinol Metab. 1992; 74: 946– 949. 14Garelli S, Masiero S, Plebani M, et al. High prevalence of chronic thyroiditis in patients with polycystic ovary syndrome. Eur J Obstet Gynecol Reprod Biol. 2013; 169: 248– 251. Citing Literature Volume17, Issue10October 2015Pages 783-785 ReferencesRelatedInformation