Series Editor: Andrea R. Genazzani Andrea R. Genazzani · Angelica Lindén Hirschberg · Alessandro D. Genazzani · Rossella Nappi · Svetlana Vujovic Editors Amenorrhea Volume 10: Frontiers in Gynecological Endocrinology
Series Editor Andrea R. Genazzani, Endocrinology International Society of Gynecological Endocrinology Pisa, Italy
Society of Gynecological Endocrinology and Springer. The book series includes single monographs devoted to gynecological endocrinology relevant topics as well as the contents stemming from educational activities run by ISGRE, the educational branch of the society. This series is meant to be an important tool for physicians who want to advance their understanding of gynecological endocrinology and master this difficult clinical area. The International Society of Gynecological ad Reproductive Endocrinology (ISGRE) School fosters education and clinical application of modern gynecological endocrinology throughout the world by organizing high-evel, highly focused residential courses twice a year, the Winter l and the Summer Schools. World renowned experts are invited to provide their clinical experience and their scientific update to the scholars, creating a unique environment where science and clinical applications melt to provide the definitive update in this continuously evolving field. Key review papers are published in the Series, thus providing a broad overview over time on the major areas of gynecological endocrinology. **Indexed in Scopus** • Series Editor: Prof. Andrea R. Genazzani argenazzani@gmail.com and isge.aige@gmail.com
Angelica Lindén Hirschberg Alessandro D. Genazzani Rossella Nappi • Svetlana Vujovic Editors Amenorrhea Volume 10: Frontiers in Gynecological Endocrinology
Andrea R. Genazzani International Society of Gynecological Endocrinology Pisa, Italy Alessandro D. Genazzani Department of Obstetrics and Gynecology University of Modena and Reggio Emilia MODENA, Modena, Italy Svetlana Vujovic Faculty of Medicine Clinic of Endocrinology Diabetes and Diseases of Metabolism University of Belgrade University Clinical Center of Serbia Belgrade, Serbia Angelica Lindén Hirschberg Department of Gynecology and Reproductive Medicine Karolinska University Hospital Stockholm, Sweden Rossella Nappi Research Center for Reproductive Medicine, Gynecological Endocrinology and Menopause IRCCS San Matteo Foundation Pavia, Italy ISSN 2197-8735 ISSN 2197-8743 (electronic) ISGE Series ISBN 978-3-031-22377-8 ISBN 978-3-031-22378-5 (eBook) https://doi.org/10.1007/978-3-031-22378-5 © International Society of Gynecological Endocrinology 2023 This work is subject to copyright. All rights are solely and exclusively licensed by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland
1 Müllerian Malformations and Their Treatments������������������������������������ 1 Efthymios Deligeoroglou and Vasileios Karountzos 2 Adolescent Amenorrhea: New Aspects of an Old Problem�������������������� 19 Laura Gaspari, Françoise Paris, Nicolas Kalfa, Samir Hamamah, and Charles Sultan 3 Amenorrhea in Eating Disorders ������������������������������������������������������������ 35 Angelica Lindén Hirschberg 4 The New Forms of Functional Hypothalamic Amenorrhoea���������������� 53 Vincenzina Bruni, Metella Dei, and Simona Ambroggio 5 Exercise and Stress-Related Amenorrhea������������������������������������������������ 67 Alessandro D. Genazzani, Tabatha Petrillo, Nicola Piacquadio, Alessandra Sponzilli, Veronica Tomatis, Fedora Ambrosetti, Melania Arnesano, Elisa Semprini, Christian Battipaglia, and Tommaso Simoncini 6 Sexual Dysfunction in Functional Hypothalamic Amenorrhea ������������ 77 Rossella Nappi, Federica Barbagallo, David Bosoni, Laura Cucinella, Giulia Stincardini, Alessandra Righi, Manuela Piccinino, Roberta Rossini, and Lara Tiranini 7 Endocrine Gland Disorder-Related Amenorrhoea �������������������������������� 85 Diana Jędrzejuk and Andrzej Milewicz 8 Polycystic Ovarian Syndrome������������������������������������������������������������������ 95 Maria A. Christou, Gesthimani Mintziori, Dimitrios G. Goulis, and Basil C. Tarlatzis 9 Amenorrhea Associated with Contraception and the Postpartum Period���������������������������������������������������������������������������������������������������������� 123 Alice Antonelli, Andrea Giannini, Tiziana Fidecicchi, Marisa Ardito, Andrea R. Genazzani, Tommaso Simoncini, and Merki-Feld Gabriele v
Contents 1 0 Amenorrhea in Oncological Patients ������������������������������������������������������ 133 Marta Caretto and Tommaso Simoncini 1 1 Premature Ovarian Insufficiency ������������������������������������������������������������ 157 Svetlana Vujovic, Miomira Ivovic, Milina Tancic Gajic, Ljiljana Marina, and Svetlana Dragojevic-Dikic 1 2 Menopause Is a Natural Condition: Does It Require to Be Corrected? For Whom and for How Long?���������������������������������� 179 Tiziana Fidecicchi, Marisa Ardito, Andrea Giannini, Tommaso Simoncini, and Andrea R. Genazzani
Müllerian Malformations and Their Treatments Efthymios Deligeoroglou and Vasileios Karountzos Abbreviation MM Müllerian malformations 1.1 Introduction Müllerian malformations (MM) are the anomalies resulting from failure of fusion of the paramesonephric ducts in the middle line, during their connection with the urogenital sinus. They occur due to alterations in the formation of the upper vaginal lumen and the uterine lumen, and also because of non-absorption of the septum in the fusion of ducts. Their clinical expression varies from very light disorders to serious obstetrical conditions such as vaginal and uterine agenesis, which is called the Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome [1]. The prevalence of congenital uterine anomalies according to Saravelos et al. [2] was found to be 6.7% in general population, 7.3% in sterile women, and 16.7% in women who had recurrent miscarriages. The septate uterus seems to be the most common anomaly in infertile women and the arcuate uterus the most common among those who have habitual abortion. In another study, Nahum [3] found the above mentioned statistics to be 0.5%, 0.17%, and 3.5%, respectively. What is of great importance is that müllerian E. Deligeoroglou (*) Medical School, National and Kapodistrian University of Athens, Athens, Greece Division of Pediatric-Adolescent Gynecology, MITERA Children’s Hospital, Athens, Greece V. Karountzos Division of Pediatric-Adolescent Gynecology, MITERA Children’s Hospital, Athens, Greece © International Society of Gynecological Endocrinology 2023 A. R. Genazzani et al. (eds.), Amenorrhea, ISGE Series, https://doi.org/10.1007/978-3-031-22378-5_1 1
E. Deligeoroglou and V. Karountzos anomalies present with great diversity giving many diagnostic and treatment options and doubts, while most of the studies include isolated cases or small case series focusing on the obstruction of menstrual flow, obstetric complications, and/or history of sterility [4]. 1.2 Prevalence The prevalence of congenital uterine anomalies in unselected populations is 5.5%, while in infertile patients is 8.0%. This prevalence, especially in infertile women, is not increased and it is approximately the same as that in fertile patients with normal reproductive outcomes [5]. When infertile and fertile women were included in the same study, septate uterus was found in 35%, bicornuate in 26%, arcuate in 18%, unicornuate in 10%, didelphys in 8%, while aplasia in 3% [5]. It is well understood that these frequencies vary regarding the populations that are studied, as well as the criteria that are used to identify these abnormalities. In another well-designed study, including patients with normal reproductive outcomes, septate uterus was found in 90%, bicornuate in 5%, while didelphys in 5% [6]. 1.3 Etiopathology Sexual differentiation is a continuous process that starts with the fertilization of the ovule by the sperm. In women, the normal absence of müllerian inhibitory factor results in degeneration of the mesonephric ducts to paramesonephric ducts. These structures, which are bilateral, suffer from stretching in around the ninth week of pregnancy and remain open and separated in the upper segment, thus originating in the fallopian tubes. In the lower segment, they form after their junction in the upper 2/3 of the vagina [1]. As the fusion has been completed, the septum between the paramesonephric ducts starts to be absorbed and finally the uterovaginal canal. Uterus has a normal shape around the 12th week of pregnancy and is totally completed in the 22nd week [7]. The development of the vagina depends on the fusion between the urogenital sinus with the müllerian structures. Therefore, the upper 4/5 of the vagina is of müllerian origin and the lower 1/5 has its origin in the urogenital sinus. The epithelium of the upper 1/3 of the vagina originates in the uterovaginal primordium and the lower 2/3 in the urogenital sinus, and the hymen is a sign of the endodermal membrane [8]. What is independent of this process is the ovaries, which are developed from cells of a different origin, and as a result they are not associated with müllerian anomalies [1, 9]. Due to the same mesodermal origin of the genital and urinary tracts, any paramesonephric anomaly could be associated with renal anomaly, which should always be investigated in these patients. Congenital malformation of female genital tracts is a result of a failure during embryogenesis, and the most common genes taking part in this procedure are HOXA13 (hand-foot-genital syndrome) [10] and HOXA10, expressed in the embryonic paramesonephric ducts [11]. Genital anomalies induced by environmental agents such as diethylstilbestrol
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