DSD/intersex: historical context and current perspectives.

Intersex/Disorders/Differences of sex development conditions have been recognized for millennia. An organized approach was adopted in the 1960-70s using the philosophy that gender identity was fluid and malleable. Consequences of this approach were the lack of disclosure, stigmatization, and excessive surgery to "normalize" the genitalia. Often this led to quality of life issues for those patients. There have been many modifications in approach since then to avoid the problems noted. There is consensus on many of these changes (e.g. disclosure) but continued controversy on others (e.g. the benefits of early surgery). This review summarizes the historical context and the current areas of consensus and controversy.

The Long Path to Our Current Understanding Regarding Care of Children with Differences/Disorders of Sexual Development.

Testes were associated with maleness from antiquity, and ancient societies had fanciful myths about the origins of the sexes and about fetal sexual development. 17th century anatomists developed the concept that mammals developed from eggs and discovered sperm in semen; in 1878, Hertwig observed sperm entering eggs (of sea urchins), establishing the cellular basis of sex development. Individuals with atypical genitalia were known clinically in the 17th century, with much debate about their origins, but by the late 19th century it was generally accepted that gonads determined sex, and that sex determined gender role. Testosterone was isolated in 1935, and Alfred Jost showed that both circulating testosterone and diffusible anti-Mullerian hormone were needed for male development. Patients with apparent androgen insensitivity were reported in 1937 and shown to be unresponsive to exogenous androgen by Lawson Wilkins in 1957; androgen receptor mutations were reported in 1989. Steroidogenic errors were associated with differences in sex development (DSDs) starting in the 1940s, and finding mutations in the responsible enzymes explained many forms of hyper- and hypo-androgenism in both sexes. Sex chromosomes were identified in the early 20th century; Y was associated with maleness, and the responsible SRY gene was identified in 1991. Early efforts to manage patients with DSDs were confounded by philosophical perspectives on the relative roles of prenatal biology versus postnatal environment. Approaches to natal sex assignment evolved in the later 20th century and now emphasize a team approach based on data, not guessing, parental involvement, cultural considerations, and the acknowledgement of uncertainty.

Fully Masculinized 46,XX Individuals with Congenital Adrenal Hyperplasia: Perspective Regarding Sex of Rearing and Surgery.

Current guidelines for gender assignment for all 46,XX congenital adrenal hyperplasia (CAH) continue to be female. This decision is most challenging for individuals with a 46,XX karyotype born with (CAH) having severely masculinized genitalia (Prader 4 or 5). They may be at significant risk for quality of life (QoL) and psychological health. More outcome information currently exists for such individuals assigned male than female. Most available data for those raised females do not indicate the extent of masculinization at birth, so there are minimal outcome data to compare with those raised males. Gender dissatisfaction among those raised females may be related to the degree of prenatal androgen excess in the brain evidenced by external genital masculinization. Also, additional brain maturation after birth, especially during puberty, is impacted by postnatal androgen excess resulting from inadequate androgen suppression. The purpose of this perspective is to suggest that both female and male assignment be considered. Most who have been raised male at birth have positive adult outcomes. This consideration should occur after discussions with full disclosure to the parents. The lack of more outcome data highlights the need for further information. This perspective also suggests that surgery should be deferred whether assigned female or male at least until gender identity is apparent to preserve the potential for male sexual function and prevent irrevocable loss of sensitive erotic tissue. While the gender fluidity is recognized, it is important to consider potential subsequent need for gender reassignment and extent of masculinization, particularly at the time of gender determination.

Individualized care for patients with intersex (disorders/differences of sex development): part I.

The care of individuals with disorders/differences of sex development aims to enable affected individuals and their families to have the best quality of life, particularly those born with severe genital ambiguity. Two of the biggest concerns for parents and health professionals are: (1) making a gender assignment and (2) the decisions of whether or not surgery is indicated, and if so, when is best for the patient and parents. These decisions, which can be overwhelming to families, are almost always made in the face of uncertainties. Such decisions must involve the parents, include multidisciplinary contributions, have an underlying principle of full disclosure, and respect familial, philosophical, and cultural values. Assignment as male or female is made with the realization that gender identity cannot be predicted with certainty. Because of the variability among those with the same diagnosis and complexity of phenotype-genotype correlation, the use of algorithms is inappropriate. The goal of this article is to emphasize the need for individualized care to make the best possible decisions for each patient's unique situation.

Use of Gonadotropin-Releasing Hormone Analogs in Children: Update by an International Consortium.

This update, written by authors designated by multiple pediatric endocrinology societies (see List of Participating Societies) from around the globe, concisely addresses topics related to changes in GnRHa usage in children and adolescents over the last decade. Topics related to the use of GnRHa in precocious puberty include diagnostic criteria, globally available formulations, considerations of benefit of treatment, monitoring of therapy, adverse events, and long-term outcome data. Additional sections review use in transgender individuals and other pediatric endocrine related conditions. Although there have been many significant changes in GnRHa usage, there is a definite paucity of evidence-based publications to support them. Therefore, this paper is explicitly not intended to evaluate what is recommended in terms of the best use of GnRHa, based on evidence and expert opinion, but rather to describe how these drugs are used, irrespective of any qualitative evaluation. Thus, this paper should be considered a narrative review on GnRHa utilization in precocious puberty and other clinical situations. These changes are reviewed not only to point out deficiencies in the literature but also to stimulate future studies and publications in this area.

Growth Hormone Deficiency Causing Micropenis: Lessons Learned From a Well-Adjusted Adult.

This report of a 46,XY patient born with a micropenis consistent with etiology from isolated congenital growth hormone deficiency is used to (1) raise the question regarding what degree testicular testosterone exposure to the central nervous system during fetal life and early infancy has on the development of male gender identity, regardless of gender of rearing; (2) suggest the obligatory nature of timely full disclosure of medical history; (3) emphasize that virtually all 46,XY infants with functional testes and a micropenis should be initially boys except some with partial androgen insensitivity syndrome; and (4) highlight the sustaining value of a positive long-term relationship with a trusted physician (R.M.B.). When this infant presented, it was commonly considered inappropriate to gender assign an infant male whose penis was so small that an adult size was expected to be inadequate, even if the karyotype was 46,XY, and testes were functional. Concomitantly, female gender assignment was considered the appropriate decision, believing that parental rearing in the assigned gender was considered the major factor determining established adult gender identity. Full disclosure of medical information was considered inappropriate. Progress in appreciating the complexities of gender identity development, which is not yet completely understood, and sexuality, coping ability, and outcome data has resulted in a change of practice in initial gender assignment. A 46,XY individual with functional testes and verified androgen responsiveness should be assigned and reared as male, regardless of penis size. Without androgen responsiveness, the multiple factors must be carefully considered and disclosed.

Pragmatic approach to intersex, including genital ambiguity, in the newborn.

The evaluation and management of a newborn with ambiguous genitalia must be undertaken as quickly as possible and with great sensitivity for the child's family. Where possible, a comprehensive team approach with a pediatric urologist, endocrinologist, geneticist, neonatologist, and child psychiatrist/psychologist should work closely with the family to establish the diagnosis and determine gender. Although the preferred gender assignment is not always clear, a thorough examination of endocrine function, karyotype, and potential for fertility should guide the determination. While some disorders of sex development (DSD) sex assignments are relatively straightforward, those with more advanced genital ambiguity and unclear gonadal function represent a major challenge. A child's phenotypic sex results from the differentiation of internal ducts and external genitalia under the influence of hormones and transcription factors. Any discordance among these processes results in ambiguous genitalia or DSD. Currently, the main categories of DSD are 46,XX DSD, 46,XY DSD, sex chromosome DSD, ovotesticular DSD, and 46,XX testicular DSD. Priority is given to rule out more immediate life-threatening disorders like salt wasting CAH. Many centers in the United States lack the comprehensive "team members" and not all conditions necessitate this team approach. This article aims to provide guidance for initial workup and identify the specific conditions for which expert guidance is needed.

Changing and Unchanging Perspectives regarding Intersex in the Last Half Century: Topics Presented in the Lawson Wilkins Lecture* at the 2015 Pediatric Endocrine Society Meeting.

The understanding, care and treatment of patients born with intersex or disorders of sex development conditions has evolved considerably over the last five decades. Regarding those who require evaluation before gender assignment is made, each "generation" of approach has been based upon and reflects the contemporary biological, social and psychological understanding. The most recent generation needs to consider the dramatically changed societal viewpoints regarding the acceptance and expansion beyond a binary perception of sexuality. This together with advances in genetic etiologies, surgical refinements and psychological support should result in better care and quality of life (QoL) outcomes for patients with these conditions. This paper reviews the successive generations of approach and discusses the multiple challenges facing the multidisciplinary teams caring for these patients today.

Global Disorders of Sex Development Update since 2006: Perceptions, Approach and Care.

The goal of this update regarding the diagnosis and care of persons with disorders of sex development (DSDs) is to address changes in the clinical approach since the 2005 Consensus Conference, since knowledge and viewpoints change. An effort was made to include representatives from a broad perspective including support and advocacy groups. The goal of patient care is focused upon the best possible quality of life (QoL). The field of DSD is continuously developing. An update on the clinical evaluation of infants and older individuals with ambiguous genitalia including perceptions regarding male or female assignment is discussed. Topics include biochemical and genetic assessment, the risk of germ cell tumor development, approaches to psychosocial and psychosexual well-being and an update on support groups. Open and on-going communication with patients and parents must involve full disclosure, with the recognition that, while DSD conditions are life-long, enhancement of the best possible outcome improves QoL. The evolution of diagnosis and care continues, while it is still impossible to predict gender development in an individual case with certainty. Such decisions and decisions regarding surgery during infancy that alters external genital anatomy or removes germ cells continue to carry risk.

Varicocele: a dilemma in adolescent males.

Varicoceles are the most common cause of infertility in men. Despite the high prevalence of varicoceles, only a small percentage of men with varicoceles have subfertility or infertility. In adolescents, the prevalence of varicoceles increases dramatically during puberty to reach adult prevalence rates. The development of varicoceles during puberty can impair testicular growth and function. Data on hormonal and semen parameters in adolescents with varicoceles are limited, making it harder to determine which varicoceles are associated with infertility and which may benefit from surgery. The main indications for varicocelectomy in adolescents with varicoceles include a volume differential between unaffected and affected testes or abnormality in semen analysis.

Key discussions from the Working Party on Disorders of Sex Development (DSD) evaluation, Foundation Merieux, Annecy, France, March 14-17, 2012.

Four topics from the DSD Working Party, a meeting to provide information regarding future studies, reported here are the complexities of hypospadias, surgical treatment of virilized genitalia of 46,XX DSD individuals, advances in phalloplasty and psychological, social and sexual outcomes.

Evaluation and management of children and adolescents with gender identification and transgender disorders.

PURPOSE OF REVIEW: Gender identity development is poorly understood but impacted by central nervous system (CNS) factors, genes, gonadal hormones and receptors, genitalia, and social/environmental factors. Gender identity disorder (GID) is the diagnostic term to describe persons discontent with the sex they were assigned at birth and/or the gender roles associated with that sex. It is crucial that the diagnosis be verified as persistent, since gender confusion among those young persists among only a portion. RECENT FINDINGS: Recent publications do not yet provide an overall perspective but involve observations regarding outcome information, unusual variables, incidence of cross-gender behavior, and CNS differences related to GID and bi-gender descriptions. Approaches to therapy for GID and task force guidelines are noted. SUMMARY: Although the concept of gender identity is a relatively new paradigm and remains an area of active and exciting investigation, findings reported here provide items of information for understanding and treatment of GIDs and illustrate the need for further research.

Cryptorchidism.

PURPOSE OF REVIEW: Cryptorchidism remains a major cause of male infertility and can be associated with germ cell tumors. Recent reports regarding cause, diagnosis, treatment and outcome of this disorder continue to inform our understanding of this common and important problem. The frequency of the problem makes cryptorchidism an area where diagnostic knowledge is particularly important for healthcare professionals. RECENT FINDINGS: The literature reviewed in this article approach cryptorchidism from multiple aspects. Reports regarding cause include studies of molecular genetics, endocrine chemical disruptors, the association with galactosemia, the association with low birth weight, and for acquired cryptorchidism, the relationship to infant feeding. In regard to treatment, the benefit of surgical repair at 9 months of age and compliance with recommendations is demonstrated. Further reports continue to document the cryptorchidism's negative impact on fertility, the higher risk of future gonadal malignancy and the lack of function of the unrepaired unilateral cryptorchid testis in adulthood. Management considerations such as the benefit of testicular biopsy at orchiopexy are also reviewed. It was concluded from an analysis of data from the Danish national registry that this can be a valid research tool for future evaluation of the outcome after cryptorchidism. SUMMARY: Early recognition and surgery, before 1 year of age, remain the most important interventions to reduce the negative impact of both unilateral and bilateral cryptorchidism. Further research is needed to better understand causes of cryptorchidism and the mechanisms by which it exerts its negative effects and to clarify outcome factors to direct the best clinical management of cryptorchidism.

Early diagnosis and treatment referral of children born small for gestational age without catch-up growth are critical for optimal growth outcomes.

Approximately 10% of children born small for their gestational age (SGA) fail to show catch-up growth and may remain short-statured as adults. Despite treatment guidelines for children born SGA that recommend referral for growth hormone (GH) therapy evaluation and initiation by ages 2 to 4 years, the average age of GH treatment initiation is typically much later, at ages 7 to 9 years. Delayed referral for GH treatment is problematic as studies show younger age at GH treatment initiation in children born SGA is an independent predictor for responses such as optimal growth acceleration, normalization of prepubertal height, and most importantly, adult height (AH). This review discusses the importance and associated challenges of early diagnosis of children born SGA who fail to show catch-up growth, contrasts the recommended age of referral for these patients and the average age of GH treatment initiation, and discusses studies showing the significant positive effects of early referral and treatment with GH on AHs in short-statured children born SGA. To optimize the eventual height in short-statured SGA children who fail to manifest catch-up growth, a lowering of the average age of referral for GH therapy evaluation is needed to better align with consensus recommendations for SGA management. The importance of increasing parental and physician awareness that most children born SGA will do well developmentally and will optimally benefit from early initiation of GH treatment when short-statured is addressed, as is the need to shift the age of referral to better align with consensus recommendations.

Long-term outcome and adjustment among patients with DSD born with testicular differentiation and masculinized external genital genitalia.

This report of long-term outcome and quality of life among 6 patients with DSD born with varying amounts of both testicular differentiation and masculinization of external genitalia, with 46,XY karyotypes among 4, attempts to assess numerous aspects. Assessment of 5 patients who were assigned female at birth and a sixth whose maleness was never questioned. Findings from the neonatal period are reported, focusing upon initial diagnosis, gender assignment, parental involvement, surgical and medical care, gender behaviors, psychological counseling and support, mental health and school experiences through adolescent years. Family, social, work, and physical, sexual and mental health status during adult life forms a basis for quality of life. Outcome vary from poor to good; influenced by parents' ability and commitment to support, the patients' personality and ability to accept their condition, quality of medical and surgical care, and family and friend support. Each of these factors could be improved by newer surgical techniques and more skilled psychological support. A basic underlying principal is the fact that in such complex cases, all factors cannot become ideal, especially those related to fertility potential and sexual responsiveness, while with support of family and loved ones, quality of life can be satisfying and productive.

Cognitive and psychosocial development concerns in children born small for gestational age.

Outcome information for infants born small for gestational age (SGA), whether term or premature, suggests poorer cognitive function compared with appropriate size for gestational age (AGA) infants. Poorer outcome is associated with smaller size for gestational age and with lack of catch-up growth after birth. Such data have been reported from early childhood to young adulthood. Diminished head circumference at birth and growth thereafter has also been associated with poor outcome. Based on available reports, the impact of SGA birth upon psychosocial development remains unclear. While it has not been shown that growth hormone (GH) therapy impacts either cognitive or psychosocial outcome, increased head circumference standard deviation scores have been shown to occur with GH therapy. These data need to be interpreted with caution since study populations do not define etiology of SGA and definitions of SGA vary. Further, generalized group data are not applicable to individuals.

Update on disorders of sex development.

PURPOSE OF REVIEW: To review the recent information regarding disorders of sex development (DSD) which contribute to, as well as highlight, the need for greater understanding of genetic mutations and the dire need for specific outcome information. RECENT FINDINGS: New information is primarily related to the identification of genetic mutations and other gene variations that impact reproductive system development. These new data add to the increasingly complex list of genes and the multigenetic effects involved in DSD. Several reviews outline the approach to diagnosis and management of the patient with DSD and the importance of a multidisciplinary team. These reviews continue to demonstrate the lack of specific guidelines for complex DSD patients for whom sex assignment is problematic. SUMMARY: Although genetic research continues to define new and multigenetic factors involved in the development of DSD, this review of the medical literature also underscores the fact that scientific understanding remains inadequate in many areas of DSD to provide solid guidelines for approaching the more controversial questions in the DSD patient. Accordingly, the need for larger, outcome studies using subjects with verified diagnoses are needed. Optimally, these studies would account for potentially confounding differences in genetic, social, and psychological factors to help answer the pressing question facing every clinician dealing with DSD patients - what is the relationship between medical decision-making (such as sex assignment and genital surgery) and future quality of life and adaptation.

Optimizing potential for fertility: fertility considerations for the pediatrician.

Whether for the prepubertal or pubertal child, the goal of fertility preservation is to obtain cells or tissues to be used to produce future children. For the prepubertal child, preservation efforts involve germ cells, earlier forms of sperm, and immature follicles, rather than mature spermatozoa or follicles. Options for prepubertal children include for boys freezing testicular tissue and extracting testicular sperm or for girls obtaining ovarian cortical or follicular tissue for storage. These procedures involve extraction and storage of immature gametes for subsequent in vitro maturation, although attempts for sperm currently involve only animal studies. For adolescent subjects who have sufficient gonadal development and reserve, sperm, oocytes, and ovarian cortex can be retrieved as among adults.