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Genital Treatment Practices Under Scrutiny in Disorders of Sex Development

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THE PAST THE PRESENT, THE FUTURE GENITAL TREATMENT PRACTICES IN DISORDERS OF SEX DEVELOPMENT UNDER SCRUTINY 3 “ The truth is rarely pure and never simple “ Oscar Wilde Promotor Prof. dr. Martine Cools Vakgroep Pediatrie en Genetica Copromotor Prof. dr. Piet Hoebeke Vakgroep: Urogynaecologie Overige leden promotiecommissie: dr. Griet De Cuypere dr. Arianne Dessens Decaan Prof. dr. Guy Vanderstraeten Rector Prof. dr. Anne De Paepe This doctoral thesis was made possible by a research fellowship grant from the Flanders Research Foundation (FWO). The research described was done at the Departments of Pediatric Endocrinology and Urology, University Hospital Ghent, Belgium, Ghent University 4 (Research groups Pediatrics and Genetics, and Urogynecology) and the Department of Pediatric Endocrinology, Sophia Children’s Hospital - Erasmus Medical Center Rotterdam, The Netherlands. Financial support for the distribution costs of this thesis was provided by Pelvitec. Document Design: Sterck.co Illustrations: Eva De Block & Sterck.co Printed by: University Press © Nina Callens ISBN: 978-90-9028-080-6 No part of this thesis may be reproduced, stored in a retrieval system or transmitted in any form or by any means without permission of the author, or, when appropriate, of the publishers of the publications. 5 Faculteit Geneeskunde & Gezondheidswetenschappen NINA CALLENS THE PAST, THE PRESENT, THE FUTURE: GENITAL TREATMENT PRACTICES IN DISORDERS OF SEX DEVELOPMENT UNDER SCRUTINY Proefschrift voorgelegd ter verkrijging van de graad van Doctor in de Medische Wetenschappen 2014 6 7 Acknowledgments It has taken a small army of people to get me through finishing this doctoral thesis and I have them all to thank. Warm thanks are due to all the remarkable women and men who participated in this project. They have been extraordinarily generous with their time, experience and honesty and this project was entirely dependent upon their willingness to share their stories. It was my good fortune to have been affiliated with a unique group of researchers, at Ghent University Hospital and Erasmus Medical Center Rotterdam, whose interest and knowledge regarding hormones, genitals, brain and behavior span the territory from molecules to (wo) man. I owe the greatest debt of gratitude to my advisor, Prof. dr. Martine Cools. Martine, you welcomed my first naive thoughts about this complicated issue and strengthened my critical capacities and development of my own voice in the writing, with unimaginable patience. Thank you for providing me with direction and redirection, and for letting me explore other psychological projects beyond this one. I admire your ability to combine highest standards of academic work with a true interest in the people you work with. You helped me to see –with your never ending and highly appreciated enthusiasm- that this work is relevant not only to the clinical setting, but also to further the reach of academic work in the broader world. I hope that this dissertation is only the first step towards a long and pleasant collaboration beyond ‘academic puberty’. I also want to thank my co-advisers, Prof. dr. Piet Hoebeke and dr. Griet De Cuypere, who were more than generous with their time, support and expertise than I could have hoped for. Piet, your feedback and many of your comments found their way into the articles. Griet, thank you for restoring my faith in my own convictions along the way. This project would also not have been possible without the support of numerous collaborators. 8 Prof. dr. Guy T’Sjoen, Prof. dr. Stan Monstrey, Prof. dr. Steven Weyers, Bie Stockman, Birgit van Hoorde, dr. Eline Van Hoecke, dr. Kristien Roelens, dr. Mireille Merckx, An Desloovere, dr. Erik Van Laecke and all the other members of the DSD team at Ghent University Hospital, your input and support were greatly appreciated. It was a pleasure for having worked with people who not only enjoy a common passion for the topic, but also their time with each other. I want to say a special thanks to Eline Van Hoecke and the child psychology team, for giving me the opportunity to find connection with the Child Psychology Department and to Bie Stockman for her unwavering support in the vaginal dilation program ('What you do yourself, you do usually better'). I am also grateful to Guy Bronselaer and Prof. dr. Petra De Sutter, for the fruitful collaboration in the genital sensitivity project. Petra, conducting research with you was not only an intellectually stimulating, but also truly pleasant work experience. An, Marleen, Mieke and Dimitri, thank you for making me look forward to coming to work during the times that we ‘shared’ an office. I am also particularly grateful to my co-advisor dr. Arianne Dessens, and Prof. em. dr. Stenvert Drop from the Erasmus Medical Center in Rotterdam for my participation in the Dutch DSD project. Arianne & Sten, your knowledgeable, detailed and thoughtful readings of the manuscripts and your critical insights, as well as encouragement during the course of this project were highly appreciated. I owe special thanks to Yvonne van der Zwan. Yvonne, I have benefitted enormously from our friendship and research time together. Numerous colleagues from the Dutch Study Group on DSD from Erasmus Medical Center Rotterdam, Vrije Universiteit Medical Center Amsterdam, Radboud University Medical Center Nijmegen and University Medical Center Utrecht have helped with the challenging data collection and analysis, and provided wonderful provocative ideas and insight along the way, with special thanks to dr. Katja Wolffenbuttel, Prof. dr. Leendert Looijenga, dr. Marjan van den Berg, and Prof. em. dr. Peggy Cohen-Kettenis. Annastasia Ediati, thank you for the inspiring multicultural discussions. In addition, I would like to thank dr. Melissa Hines at Cambridge University, whose keen insight and intellectual rigor inspired me during my unforgettable training experience prior to this doctoral quest. 9 Moreover, I want to thank the members of the exam commission, far and near, for reading this thesis. Prof. em. dr. Peggy Cohen-Kettenis, at Vrije Universiteit Medical Center Amsterdam, dr. Vickie Pasterski at Cambridge University, dr. Erica van den Akker at Erasmus Medical Center Rotterdam, Prof. dr. Jean De Schepper at Free University of Brussels & Ghent University, and Prof. dr. Johan Vande Walle, Prof. dr. Hans Verstraelen & dr. Kristien Roelens at Ghent University. Warm thanks also go to dr. Ira Haraldsen and Swavek Wojniusz from the Rikshospitalet in Oslo, Norway. Although our work on heart rate variability and neurocognitive functioning of girls with precocious puberty is not included in this dissertation here, your enthusiasm and encouragement were always highly appreciated and I truly enjoyed working with you. Thank you for providing me with a warm and caring home whenever I was in Oslo. In the end, it is to my family and friends that I owe the greatest thanks and acknowledgment. My parents, Johan Callens & Marie-Claire De Block, and sister, Kee Callens, for encouraging me to explore the world and for always offering a safe haven to return to. Aunts, uncles, cousins and grandparents for their hospitality and excellent food (for thought). Stijn Van Herck and Eva De Block for the brilliant, creative coming - together of this booklet. Michael Boiger, Joana Lima & Charlotte Le Divelec, for enduring my physical and mental absences, but more specifically for wholeheartedly teaching me the art of living. Kiran Vanbinst & Anja Waegeman for being constant unconditional supporters. Ines Ghijselings, Stijn Van Herck, Bernard Derveaux, Annelore Willaert & Daan Nevens for always encouraging me to go that extra mile. Vincent Van der Velde, Vincent Ginis, Naomi Vanlessen, Bram Dewolfs, Sven Retore, Tom Lootens, Marieke Dewitte, Pauline Steverlynck, Sarah Slembrouck, Ellen Marcelis, Lynn Vercammen & Inge Peeters: friendship is no small matter to a person staring down deadlines. Thank you for reminding me that life needs to include love & play. Nina Callens Bruxelles, October 2013 10 List of Abbreviations AIS: androgen insensitivity syndrome AMH: anti-Müllerian hormone CAIS: complete androgen insensitivity syndrome CAH: congenital adrenal hyperplasia DHT: dihydrotestosterone DSD: disorders of sex development GA: gestational age GD: gonadal dysgenesis LH: luteneizing hormone MIS: Müllerian inhibiting substance MRKH: Mayer-Rokitansky-Küster- Hauser syndrome PAIS: partial androgen insensitivity syndrome QOL: quality of life SPL: stretched penile length 11 List of Definitions 17ß hydroxysteroid dehydrogenase deficiency (17ß HSD): genetic disorder of steroid formation, caused by a deficiency of the testicular enzyme 17ß hydroxysteroid dehydrogenase that produces testosterone from androstenedione. Plasma testosterone and dihydrotestosterone (DHT) are decreased and androstenedione is increased. It is characterized in XY individuals by ambiguous or feminine-appearing external genitalia at birth, with masculinization at puberty. 5α reductase deficiency (5α RD): genetic disorder of steroid formation, caused by a deficiency of the testicular enzyme 5α reductase that produces dihydrotestosterone (DHT) from testosterone. Plasma DHT is decreased, testosterone is increased. It is characterized in XY individuals by ambiguous or feminine-appearing external genitalia at birth, with masculinization at puberty. Androgen insensitivity syndrome (AIS): X-linked genetic disorder that results in the inability of receptors to respond to androgens. The receptor deficiency can be partial
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