title: Influence of steroid hormones on ventricular repolarization.
abstract: QT interval prolongation, corrected for heart rate (QTc), either spontaneous or drug-induced, is associated with an increased risk of torsades de pointes and sudden death. Women have longer QTc than men and are at higher risk of torsades de pointes, particularly during post-partum and the follicular phase. Men with peripheral hypogonadism have longer QTc than healthy controls. The role of the main sex steroid hormones has been extensively studied with inconsistent findings. Overall, estradiol is considered to promote QTc lengthening while progesterone and testosterone shorten QTc. New findings suggest more complex regulation of QTc by sex steroid hormones involving gonadotropins (i.e. follicle-stimulating hormone), the relative concentrations of sex steroid hormones (which depends on gender, i.e., progesterone/estradiol ratio in women). Aldosterone, another structurally related steroid hormone, can also prolong ventricular repolarization in both sex. Better understanding of pathophysiological hormonal processes which may lead to increased susceptibility of women (and possibly hypogonadic men) to drug-induced arrhythmia may foster preventive treatments (e.g. progesterone in women). Exogenous hormonal intake might offer new therapeutic opportunities or, alternatively, increase the risk of torsades de pointes. Some exogenous sex steroids may also have paradoxical effects on ventricular repolarization. Lastly, variations of QTc in women linked to the menstrual cycle and sex hormone fluctuations are generally ignored in regulatory thorough QT studies. Investigators and regulatory agencies promoting inclusion of women in thorough QT studies should be aware of this source of variability especially when studying drugs over several days of administration.
authors.affiliation: INSERM, CIC-1421 and UMR ICAN 1166, France; AP-HP, Pitié-Salpêtrière Hospital, Department of Pharmacology and CIC-1421, France; Sorbonne Universités, UPMC Univ Paris 06, Faculty of Medicine, France; Institute of Cardiometabolism and Nutrition (ICAN), F-75013 Paris, France.
authors.forename: Joe-Elie
authors.initials: JE
authors.lastname: Salem
authors.affiliation: Normandie Université, France; EA 4650, Signalisation, Electrophysiologie et Imagerie des Lésions d'Ischémie-reperfusion Myocardique, France; Pharmacology Department, CHU Caen, F-14032 Caen, France.
authors.forename: Joachim
authors.initials: J
authors.lastname: Alexandre
authors.affiliation: AP-HP, Pitié-Salpêtrière Hospital, IE3M, Department of Endocrinology and Reproductive Medicine, and Centre de Référence des Maladies Endocriniennes Rares de la croissance et Centre des Pathologies gynécologiques Rares, and CIC-1421, F-75013 Paris, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Bachelot
authors.affiliation: INSERM, CIC-1421 and UMR ICAN 1166, France; AP-HP, Pitié-Salpêtrière Hospital, Department of Pharmacology and CIC-1421, France; Sorbonne Universités, UPMC Univ Paris 06, Faculty of Medicine, France; Institute of Cardiometabolism and Nutrition (ICAN), F-75013 Paris, France. Electronic address: christian.funck-brentano@aphp.fr.
authors.forename: Christian
authors.initials: C
authors.lastname: Funck-Brentano
mesh_terms: D000450:Aldosterone / Q000378:metabolism; D000818:Animals; D016757:Death, Sudden, Cardiac / Q000209:etiology; D004958:Estradiol / Q000378:metabolism; D005260:Female; D012739:Gonadal Steroid Hormones / Q000008:administration & dosage / Q000378:metabolism*; D006352:Heart Ventricles / Q000378:metabolism; D006801:Humans; D008133:Long QT Syndrome / Q000209:etiology / Q000503:physiopathology*; D008297:Male; D011374:Progesterone / Q000378:metabolism; D012107:Research Design; D012737:Sex Factors; D013739:Testosterone / Q000378:metabolism; D016171:Torsades de Pointes / Q000209:etiology / Q000503:physiopathology*
chemical_list: D012739:Gonadal Steroid Hormones; D013739:Testosterone; D000450:Aldosterone; D011374:Progesterone; D004958:Estradiol
keywords: Aldosterone; Gonadal steroid hormones; Gonadotropins; Long QT syndrome; Mineralocorticoid receptor antagonists; QTc