Best Practice & Research Clinical Endocrinology & Metabolism RSS feed: Current Issue. Best Practice & Research Clinical Endocrinology & Metabolism is a topical serial publication integrating the results from the latest original research into practical, evidence-based review articles that seek to address the key clinical issues of diagnosis, treatment and patient management. Each issue follows a problem-orientated approach which focuses on the key questions to be addressed, clearly defining what is known and highlighting topics for future research. Management is described in practical terms so that it can be applied to the individual patient. The series is aimed at the physician either in practice or in training. In practical paperback format, each 200 page issue of Best Practice & Research Clinical Endocrinology & Metabolism provides a comprehensive review of clinical practice and thinking within one specific area of endocrinology and metabolism. Each issue, written by an international team of contributors and guest edited by a renowned expert, form part of a continuous update of current clinical practice. • Attractive format and two-colour text layout • Six issues published annually • Highlighting the latest 'best practice' and 'clinical evidence' • Topic-based, problem-orientated approach • Recommendations on diagnosis, treatment and patient management The objective of the series is to provide the physician with the most up-to-date source of information in the field. Click here to view a full table of contents on ScienceDirect. Topics covered in 2008: Volume 22 Issue 1 Fetal and Neonatal Endocrinology P. Mullis & W. Kiess Volume 22 Issue 2 Endocrinology and the Prostate F. Labrie Volume 22 Issue 3 The Small for Gestational Age Child L.B. Johnson & M.O. Savage Volume 22 Issue 4 Endocrine and Metabolic Determinants of Cancer Risk J.M.P. Holly Volume 22 Issue 5 Osteoporosis R. Rizzoli Volume 22 Issue 6 Thyroid Nodules and Cancer F. Pacini The Publisher Andrew Miller Publishing Editor Health Sciences, Elsevier Ltd The Boulevard, Langford Lane Kidlington Oxford, OX5 1GB UK Tel: +44 1865 843823 Fax: +44 1865 843997 Email: andrew.miller@elsevier.com http://www.bprcem.com/?rss=yesElsevier Inc.en © 2010 Elsevier Ltd. All rights reserved. Best Practice & Research Clinical Endocrinology & Metabolism1521-690X242April 2010 © 2010 Elsevier Ltd. All rights reserved. healthpermissions@elsevier.comhttp://www.bprcem.com/article/PIIS1521690X1000031X/abstract?rss=yesIt is a privilege to act as Guest Editor for this Volume on Disorders of Sex Development (DSD). The subject is vast and many areas within the field have changed beyond recognition in recent years. It is this fluidity which makes DSD such an exciting medical and scientific subject in which to work currently. Indeed, it has been proposed that a quiet revolution has taken place, ranging from nomenclature and classification systems, to changes in surgical practice, empowerment of families in sex assignment decisions and the appreciation of the essential role of psychological support in a multi-disciplinary team.PrefaceIeuan A. Hughes10.1016/j.beem.2010.03.004Best Practice & Research Clinical Endocrinology & Metabolism 24, 2 (2010)2010-04-01Best Practice & Research Clinical Endocrinology & Metabolism2010-04-01242S1521-690X(10)X0003-3viiviihttp://www.bprcem.com/article/PIIS1521690X10000321/abstract?rss=yesThe approach to the management of disorders of sex development (DSD) has undergone major changes in recent years. The catalyst has been a revised nomenclature, new classification of the causes of DSD and a willingness for health professionals to work in a multi-disciplinary format. In a remarkably short length of time, these revolutionary changes are becoming accepted practice across a range of medical and scientific disciplines.The quiet revolutionIeuan A. Hughes10.1016/j.beem.2010.03.005Best Practice & Research Clinical Endocrinology & Metabolism 24, 2 (2010)2010-04-01Best Practice & Research Clinical Endocrinology & Metabolism2010-04-01242S1521-690X(10)X0003-3159162http://www.bprcem.com/article/PIIS1521690X09001481/abstract?rss=yesThe process of sexual differentiation is central for reproduction of almost all metazoan, and therefore, for maintenance of practically all multicellular organisms. In sex development, we can distinguish two different processes, sex determination, that is the developmental decision that directs the undifferentiated embryo into a sexually dimorphic individual. In mammals, sex determination equals gonadal development. The second process known as sex differentiation takes place once the sex determination decision has been made through factors produced by the gonads that determine the development of the phenotypic sex. Most of the knowledge on the factors involved in sexual development came from animal models and from studies of cases in whom the genetic or the gonadal sex does not match the phenotypical sex, that is, patients affected by disorders of sex development (DSDs).Generally speaking, factors influencing sex determination are transcriptional regulators, whereas factors important for sex differentiation are secreted hormones and their receptors.This review focusses on these factors and whenever possible, references regarding the ‘prismatic’ clinical cases are given.Control of sex developmentAnna Biason-Lauber10.1016/j.beem.2009.12.002Best Practice & Research Clinical Endocrinology & Metabolism 24, 2 (2010)2010-04-01Best Practice & Research Clinical Endocrinology & Metabolism2010-04-01242S1521-690X(10)X0003-3163186http://www.bprcem.com/article/PIIS1521690X09001456/abstract?rss=yesIn 2006, a task force of 50 specialists sponsored by the European Society for Paediatric Endocrinology (ESPE) and the Lawson Wilkins Pediatric Endocrine Society (LWPES) devised a Consensus Statement outlining the recommendations for the management of disorders of sex development (DSDs; then referred to as ‘intersex’ disorders) as well as proposing a new nomenclature and DSD classification system. In the 2 years subsequent to its publication, the Statement has been widely cited and endorsed in the literature as a model for patient care. In addition, much of the scientific literature incorporates the newly proposed nomenclature and classification system as part of its own discourse. However, without a systematic analysis of the uptake of recommendations of the Statement, it is not possible to make valid conclusions regarding the uptake of the recommendations within clinical practice. Here we discuss the Consensus Statement and its impact with respect to the newly proposed nomenclature and psychosocial management according to a new study following 60 DSD centres throughout Europe. Finally, we discuss future directions for research in the management of DSD, beginning at the moment of disclosure.Impact of the consensus statement and the new DSD classification systemV. Pasterski, P. Prentice, I.A. Hughes10.1016/j.beem.2009.11.004Best Practice & Research Clinical Endocrinology & Metabolism 24, 2 (2010)2010-04-01Best Practice & Research Clinical Endocrinology & Metabolism2010-04-01242S1521-690X(10)X0003-3187195http://www.bprcem.com/article/PIIS1521690X0900147X/abstract?rss=yesInfants rarely present with truly ambiguous genitalia and such children should be evaluated by experts who work within a multidisciplinary team that is dedicated for evaluation and management of children and adults with suspected and confirmed disorders of sex development. The paediatric endocrinologist who is a vital and often the central member of this clinical team not only needs to lead the clinical evaluation of the infant systematically but also needs to be sensitive to the needs of the infant, the parents and the rest of the team. A thorough knowledge of the underlying pathophysiology and the strengths and weaknesses of the investigative tools that are available for reaching a diagnosis is crucial.Investigation and initial management of ambiguous genitaliaS. Faisal Ahmed, Martina Rodie10.1016/j.beem.2009.12.001Best Practice & Research Clinical Endocrinology & Metabolism 24, 2 (2010)2010-04-01Best Practice & Research Clinical Endocrinology & Metabolism2010-04-01242S1521-690X(10)X0003-3197218http://www.bprcem.com/article/PIIS1521690X09001420/abstract?rss=yesThe 46,XX disorders of sex development (DSDs) cause virilisation or masculinisation of the female foetus. The final common pathway of all 46,XX DSDs is excess dihydrotestosterone (DHT) or potent foreign androgen in the genital tissue during the critical period of sexual differentiation. Whereas the foetal testis is source of androgen in the male, it is the foetal adrenal that produces the DHT precursors in the female. By understanding the principles of human steroid biosynthesis, the pathogenesis of each disorder may be logically deduced, and treatment strategies are rationally constructed. In practice, however, therapies for many of these diseases are fraught with complications and caveats, and current approaches leave much room for improvement. This review discusses these diseases, their pathogenesis and approaches to therapy. We emphasise areas where improved treatments are sorely needed.46,XX DSD: the masculinised femaleRichard J. Auchus, Alice Y. Chang10.1016/j.beem.2009.11.001Best Practice & Research Clinical Endocrinology & Metabolism 24, 2 (2010)2010-04-01Best Practice & Research Clinical Endocrinology & Metabolism2010-04-01242S1521-690X(10)X0003-3219242http://www.bprcem.com/article/PIIS1521690X09001444/abstract?rss=yesDisorders of androgen production can occur in all steps of testosterone biosynthesis and secretion carried out by the foetal Leydig cells as well as in the conversion of testosterone into dihydrotestosterone (DHT).The differentiation of Leydig cells from mesenchymal cells is the first walk for testosterone production. In 46,XY disorders of sex development (DSDs) due to Leydig cell hypoplasia, there is a failure in intrauterine and postnatal virilisation due to the paucity of interstitial Leydig cells to secrete testosterone. Enzymatic defects which impair the normal synthesis of testosterone from cholesterol and the conversion of testosterone to its active metabolite DHT are other causes of DSD due to impaired androgen production. Mutations in the genes that codify the enzymes acting in the steps from cholesterol to DHT have been identified in affected patients.Patients with 46,XY DSD secondary to defects in androgen production show a variable phenotype, strongly depending of the specific mutated gene. Often, these conditions are detected at birth due to the ambiguity of external genitalia but, in several patients, the extremely undervirilised genitalia postpone the diagnosis until late childhood or even adulthood. These patients should receive long-term care provided by multidisciplinary teams with experience in this clinical management.46,XY DSD due to impaired androgen productionBerenice B. Mendonca, Elaine M.F. Costa, Alicia Belgorosky, Marco Aurelio Rivarola, Sorahia Domenice10.1016/j.beem.2009.11.003Best Practice & Research Clinical Endocrinology & Metabolism 24, 2 (2010)2010-04-01Best Practice & Research Clinical Endocrinology & Metabolism2010-04-01242S1521-690X(10)X0003-3243262http://www.bprcem.com/article/PIIS1521690X09001432/abstract?rss=yesInsensitivity to the action of androgens is a common cause of undermasculinisation in 46,XY individuals. These disorders are a result of the failure of major androgens to act via the intracellular androgen receptor and, thus, the genomic effects of androgen signalling are disrupted. The phenotype of affected individuals can vary considerably, depending on the dysfunction of the receptor. In childhood, the diagnosis is often complicated due to the lack of sensitive biochemical determinants, whilst during adolescence and in adults, the diagnosis can be readily made because of the striking clinical feminisation and a conclusive laboratory analysis. A variety of mutations in the androgen receptor have been analysed, providing insight into the complex pathways of intracellular processing and signal transduction via the androgen receptor. Endocrine therapy in androgen-insensitivity syndrome is controversial, because till date the special hormonal profiles in androgen insensitivity have not been acknowledged in replacement strategies.46,XY disorders of sex development – the undermasculinised male with disorders of androgen actionRalf Werner, Helga Grötsch, Olaf Hiort10.1016/j.beem.2009.11.002Best Practice & Research Clinical Endocrinology & Metabolism 24, 2 (2010)2010-04-01Best Practice & Research Clinical Endocrinology & Metabolism2010-04-01242S1521-690X(10)X0003-3263277http://www.bprcem.com/article/PIIS1521690X09001407/abstract?rss=yesThe prevalence of male reproductive disorders, such as testicular cancer and impaired semen quality, is increasing in many, albeit not all, countries. These disorders are aetiologically linked with congenital cryptorchidism and hypospadias by common factors leading to perinatal disruption of normal testis differentation, the testicular dysgenesis syndrome (TDS). There is recent evidence that also the prevalence of genital malformations is increasing and the rapid pace of increase suggests that lifestyle factors and exposure to environmental chemicals with endocrine disrupting properties may play a role. Recent prospective studies have established links between perinatal exposure to persistent halogenated compounds and cryptorchidism, as well as between phthalates and anti-androgenic effects in newborns. Maternal alcohol consumption, mild gestational diabetes and nicotine substitutes were also identified as potential risk factors for cryptorchidism. It may be the cocktail effect of many simultaneous exposures that result in adverse effects, especially during foetal life and infancy.Genital anomalies in boys and the environmentKatharina M. Main, Niels E. Skakkebæk, Helena E. Virtanen, Jorma Toppari10.1016/j.beem.2009.10.003Best Practice & Research Clinical Endocrinology & Metabolism 24, 2 (2010)2010-04-01Best Practice & Research Clinical Endocrinology & Metabolism2010-04-01242S1521-690X(10)X0003-3279289http://www.bprcem.com/article/PIIS1521690X09001390/abstract?rss=yesDisorders of sex development (DSD), previously referred to as intersex, has been recognised as one of the main risk factors for development of type II germ cell tumours (GCTs), that is, seminomas/dysgerminomas and non-seminomas (e.g., embryonal carcinoma, yolk sac tumour, choriocarcinoma and teratoma). Within the testis, this type of cancer is the most frequent malignancy in adolescent and young adult Caucasian males. Although these males are not known to have dysgenetic gonads, the similarities in the resulting tumours suggest a common aetiological mechanism(s), –genetically, environmentally or a combination of both. Within the group of DSD patients, being in fact congenital conditions, the risk of malignant transformation of germ cells is highly heterogeneous, depending on a number of parameters, some of which have only recently been identified. Understanding of these recent insights will stimulate further research, with the final aim to develop an informative clinical decision tree for DSD patients, which includes optimal (early) diagnosis without overtreatment, such as prophylactic gonadectomy in the case of a low tumour risk.Gonadal tumours and DSDLeendert H.J. Looijenga, Remko Hersmus, Bertie H.C.G.M. de Leeuw, Hans Stoop, Martine Cools, J. Wolter Oosterhuis, Stenvert L.S. Drop, Katja P. Wolffenbuttel10.1016/j.beem.2009.10.002Best Practice & Research Clinical Endocrinology & Metabolism 24, 2 (2010)2010-04-01Best Practice & Research Clinical Endocrinology & Metabolism2010-04-01242S1521-690X(10)X0003-3291310http://www.bprcem.com/article/PIIS1521690X09001419/abstract?rss=yesSummary: Disorders of sexual development (DSD) include three main groups of patients: (1) The virilised 46,XX DSD essentially represented by congenital adrenal hyperplasia (CAH) ; (2) The undervirilised 46,XY DSD essentially represented by hypospadias; and (3) the chromosomic jigsaws essentially represented by mixed gonadal dysgenesis. It is in this last group that gender assignment remains a difficult decision involving various indicators, which can be split into four categories: (1) the inside sex (i.e., genes, hormones and target tissues); (2) the outside sex (i.e., anatomy of genitalia including size of the genital tubercle, mullerian cavity and potential adult height of the patient); (3) the functional sex (i.e., potential sexuality and fertility); and (4) and the social sex (i.e., the cultural medium in which the child is brought up). The challenge is to outline the future individual identity of the child in the postnatal period using these indicators. Current evolutions of surgical techniques of ‘feminisation’ and ‘masculinisation’ are described as well as their outcomes.Surgical options in disorders of sex development (dsd) with ambiguous genitaliaIsabelle Vidal, Daniela Brindusa Gorduza, Elodie Haraux, Claire-Lise Gay, Pierre Chatelain, Marc Nicolino, Pierre-Yves Mure, Pierre Mouriquand10.1016/j.beem.2009.10.004Best Practice & Research Clinical Endocrinology & Metabolism 24, 2 (2010)2010-04-01Best Practice & Research Clinical Endocrinology & Metabolism2010-04-01242S1521-690X(10)X0003-3311324http://www.bprcem.com/article/PIIS1521690X09001468/abstract?rss=yesPsychosocial aspects of the treatment of disorders of sex development (DSDs) concern gender assignment, information management and communication, timing of medical interventions, consequences of surgery, and sexuality. Although outcome is often satisfactory, a variety of medical and psychosocial factors may jeopardise the psychological development of children with DSDs. This sometimes results in the desire to change gender later in life. The clinical management of gender dysphoria in individuals with DSD may profit from methods and insights that have been developed for gender dysphoric individuals without DSD. In DSD care, clinical decisions are often made with long-lasting effects on quality of life and should be based on empirical evidence. Yet, such evidence (e.g., regarding gender assignment, information management and timing of surgery) is largely non-existent. DSD-specific protocols and educational materials need to be developed to standardise and evaluate interventions in order to facilitate decision making of professionals and individuals with DSD and enhance psychosocial care in this area.Psychosocial and psychosexual aspects of disorders of sex developmentP.T. Cohen-Kettenis10.1016/j.beem.2009.11.005Best Practice & Research Clinical Endocrinology & Metabolism 24, 2 (2010)2010-04-01Best Practice & Research Clinical Endocrinology & Metabolism2010-04-01242S1521-690X(10)X0003-3325334http://www.bprcem.com/article/PIIS1521690X10000254/abstract?rss=yesDisorder of sex development (DSD) presents a unique challenge, both diagnostically and in terms of acute and longer-term management. These are relatively rare conditions usually requiring a multidisciplinary approach from the outset and the involvement of a tertiary centre for assessment and management recommendations. This article describes the structure of the multidisciplinary team (MDT) at our centre, with contributions from key members of the team regarding their individual roles. The focus is on the newborn referred for assessment of ambiguous genitalia, rather than on individuals who present in the adolescent period or at other times, although the same MDT involvement is likely to be required. The approach to the initial assessment and management is discussed and the subsequent diagnosis and follow-up presented, with emphasis on the importance of careful transition and long-term support.Holistic management of DSDCaroline E. Brain, Sarah M. Creighton, Imran Mushtaq, Polly A. Carmichael, Angela Barnicoat, John W. Honour, Victor Larcher, John C. Achermann10.1016/j.beem.2010.01.006Best Practice & Research Clinical Endocrinology & Metabolism 24, 2 (2010)2010-04-01Best Practice & Research Clinical Endocrinology & Metabolism2010-04-01242S1521-690X(10)X0003-3335354http://www.bprcem.com/article/PIIS1521690X10000515/abstract?rss=yesKeyword index10.1016/S1521-690X(10)00051-5Best Practice & Research Clinical Endocrinology & Metabolism 24, 2 (2010)2010-04-01Best Practice & Research Clinical Endocrinology & Metabolism2010-04-01242S1521-690X(10)X0003-3I1I1