Ieuan A. Hughes

Consensus statement on management of intersex disorders

The birth of an intersex child prompts a long-term management strategy that involves a myriad of professionals working with the family. There has been progress in diagnosis, surgical techniques, understanding psychosocial issues and in recognizing and accepting the place of patient advocacy. The Lawson Wilkins Paediatric Endocrine Society (LWPES) and the European Society for Paediatric Endocrinology (ESPE) considered it timely to review the management of intersex disorders from a broad perspective, to review data on longer term outcome and to formulate proposals for future studies. The methodology comprised establishing a number of working groups whose membership was drawn from 50 international experts in the field. The groups prepared prior written responses to a defined set of questions resulting from an evidence based review of the literature. At a subsequent gathering of participants, a framework for a consensus document was agreed. This paper constitutes its final form.

Psychological outcomes and gender-related development in complete androgen insensitivity syndrome.

We evaluated psychological outcomes and gender development in 22 women with complete androgen insensitivity syndrome (CAIS). Participants were recruited through a medical database (n = 10) or through a patient support group (n = 12). Controls included 14 males and 33 females, of whom 22 were matched to women with CAIS for age, race, and sex-of-rearing. Outcome measures included quality of life (self-esteem and psychological general well-being), gender-related psychological characteristics (gender identity, sexual orientation, and gender role behavior in childhood and adulthood), marital status, personality traits that show sex differences, and hand preferences. Women recruited through the database versus the support group did not differ systematically, and there were no statistically significant differences between the 22 women with CAIS and the matched controls for any psychological outcome. These findings argue against the need for two X chromosomes or ovaries to determine feminine-typical psychological development in humans and reinforce the important role of the androgen receptor in influencing masculine-typical psychological development. They also suggest that psychological outcomes in women with CAIS are similar to those in other women. However, additional attention to more detailed aspects of psychological well-being in CAIS is needed.

Androgen insensitivity syndrome

Androgen insensitivity syndrome in its complete form is a disorder of hormone resistance characterised by a female phenotype in an individual with an XY karyotype and testes producing age-appropriate normal concentrations of androgens. Pathogenesis is the result of mutations in the X-linked androgen receptor gene, which encodes for the ligand-activated androgen receptor--a transcription factor and member of the nuclear receptor superfamily. This Seminar describes the clinical manifestations of androgen insensitivity syndrome from infancy to adulthood, reviews the mechanism of androgen action, and shows examples of how mutations of the androgen receptor gene cause the syndrome. Management of androgen insensitivity syndrome should be undertaken by a multidisciplinary team and include gonadectomy to avoid gonad tumours in later life, appropriate sex-hormone replacement at puberty and beyond, and an emphasis on openness in disclosure.

Summary of Consensus Statement on Intersex Disorders and Their Management

Advances in understanding of genetic control of sexual determination and differentiation, improvements in diagnostic testing and surgical genital repair, and the persistent controversies inherent to clinical management were all compelling factors that led to the organization of an international consensus conference. The goals were to acknowledge and discuss the more controversial issues in intersex management, provide management guidelines for intersex patients, and identify and prioritize questions that need additional investigation. This is a summary statement. Advances in molecular genetic causes of abnormal sexual development and heightened awareness of the ethical and patient-advocacy issues mandate reexamination of existing nomenclature for patients with intersex.1 Terminology such as “pseudohermaphroditism” is controversial, potentially pejorative to patients,2 and inherently confusing. Therefore, the term “disorders of sex development” (DSD) is proposed to indicate congenital conditions with atypical development of chromosomal, gonadal, or anatomic sex. Additional rationale for new classification is the need for modern categorization to integrate the modern molecular genetic aspects, to maximize precision when applying definitions and diagnostic labels,3 and to meet the need for psychologically sensitive yet descriptive medical terminology. Nomenclature should be flexible enough to incorporate new information, robust enough to maintain a consistent framework, use descriptive terms, reflect genetic etiology, accommodate phenotypic variation spectrum, and be useful for clinicians, scientists, patients, and families. Hence, we propose a new classification (see “Consensus Statement on Management of Intersex Disorders”4 in this months issue of Pediatrics Electronic Edition ). Three traditionally conceptualized domains of psychosexual development are gender identity (ones self-representation [ie, male or female]), gender role (sexually dimorphic behaviors within the general population, such as toy preferences, aggression, and spatial ability), and sexual orientation (direction[s] of erotic interest). Gender dissatisfaction denotes unhappiness with assigned sex and may result in gender self-reassignment. Psychosexual developmental factors relate to parental psychopathology, parent-child … Address correspondence to Peter A. Lee, MD, PhD, Department of Pediatrics, MC-H085, Penn State College of Medicine, Milton S. Hershey Medical Center, Box 850, 500 University Dr, Hershey, PA 17033-0850. E-mail: plee{at}psu.edu

The descriptive epidemiology of congenital and acquired cryptorchidism in a UK infant cohort

Introduction: Recent studies in other European countries suggest that the prevalence of congenital cryptorchidism continues to increase. This study aimed to explore the prevalence and natural history of congenital cryptorchidism in a UK centre. Methods: Between October 2001 and July 2008, 784 male infants were born in the prospective Cambridge Baby Growth Study. 742 infants were examined by trained research nurses at birth; testicular position was assessed using standard techniques. Follow-up assessments were completed at ages 3, 12, 18 and 24 months in 615, 462, 393 and 326 infants, respectively. Results: The prevalence of cryptorchidism at birth was 5.9% (95% CI 4.4% to 7.9%). Congenital cryptorchidism was associated with earlier gestational age (p<0.001), lower birth weight (p<0.001), birth length (p<0.001) and shorter penile length at birth (p<0.0001) compared with other infants, but normal size after age 3 months. The prevalence of cryptorchidism declined to 2.4% at 3 months, but unexpectedly rose again to 6.7% at 12 months as a result of new cases. The cumulative incidence of “acquired cryptorchidism” by age 24 months was 7.0% and these cases had shorter penile length during infancy than other infants (p = 0.003). Conclusions: The prevalence of congenital cryptorchidism was higher than earlier estimates in UK populations. Furthermore, this study for the first time describes acquired cryptorchidism or “ascending testis” as a common entity in male infants, which is possibly associated with reduced early postnatal androgen activity.

Longer term outcome in females with congenital adrenal hyperplasia (CAH): the Cardiff experience

OBJECTIVE The outlook for fertility and attaining full adult height is poor in women with congenital adrenal hyperplasia. Such outcomes have followed treatment regimes with variable ages at onset, compliance rates and monitoring. We review final height, vaginal anatomy, ovulation rates and fertility in a group of adult females with the disease.

Congenital hypothyroidism, spiky hair, and cleft palate.

Two brothers are described with athyroidal hypothyroidism, spiky hair, choanal atresia, cleft palate, and bifid epiglottis. Polyhydramnios was present in the third trimester of each pregnancy. These abnormalities appear to represent a new syndrome.

The role of a clinical score in the assessment of ambiguous genitalia

Objective To improve the initial assessment of ambiguous genitalia in infants.

Factors controlling testis descent.

Descent of the testis from an intra-abdominal site in foetal life to an extracorporeal location after birth is a mandatory developmental process to ensure that the mature testis promotes normal spermatogenesis. The two phases of transabdominal and inguinoscrotal descent occur approximately during the first and last thirds of gestation respectively. Key anatomical events to release the testis from its urogenital ridge location and to guide the free gonad into the scrotum are the degeneration of the cranio-suspensory ligament and a thickening of the gubernaculum. Androgens play a role in both these processes, particularly with respect to enabling the testis to traverse the inguinal canal in the final phase of descent. Experiments in animals suggest that androgens mediate this effect via the release of calcitonin gene-related peptide by the genitofemoral nerve, but direct evidence for such a mechanism is lacking in humans. The transabdominal phase of descent is under the control of insulin-like 3 (INSL3), a product of the Leydig cells. Definitive evidence of its role in rodent testis descent is illustrated by the phenotype of bilateral cryptorchidism in Insl3-/- null mice. Circulating levels of INSL3 are higher in boys at puberty, are undetectable in girls and are lower in boys with undescended testes. A minority also have a mutation either in the INSL3 gene or affecting its receptor gene, relaxin/insulin-like family peptide receptor 2 (LGRF8). Other factors that may play a role in testis descent include the anti-Mullerian hormone and members of the HOX gene family. Evidence that the prevalence of undescended testis may be increasing provides a phenotypic readout for the effects of postulated chemicals in the environment interfering in some way with the action of factors that control testis descent. Epidemiological studies point to profound geographical variations in prevalence in countries such as Denmark and Finland. Associations have been found with levels of chemicals labelled as endocrine disruptors being higher in breast milk samples from mothers with cryptorchid boys when compared with controls. The adverse effects of these compounds (e.g. bisphenol A) can be replicated in the offspring of dams exposed during pregnancy. A sensitive marker of an anti-androgen effect of a compound is a reduction in the anogenital distance, an anthropometric measurement that is significantly greater in males compared with females. The observation of an association between the anogenital distance in infant boys and the level of pesticides in the urine of their mothers in late gestation indicates that this has the potential to be a useful surrogate marker of the effects of environmental chemicals on testis descent in human population studies. The rightful place for the testis at birth is in the scrotum in order to provide the temperature differential essential for normal spermatogenesis. Appropriate screening programmes and early surgical intervention are the prerequisites to ensure optimal fertility in adulthood and a considerably lessened risk of testis cancer.

Anogenital Distance from Birth to 2 Years: a Population Study

Background Anogenital distance (AGD) is sexually dimorphic in rodents and humans, being 2- to 2.5-fold greater in males. It is a reliable marker of androgen and antiandrogen effects in rodent reproductive toxicologic studies. Data on AGD in humans are sparse, with no longitudinal data collected during infancy. Objective This study was designed to determine AGD from birth to 2 years in males and females and relate this to other anthropometric measures. Materials and Methods Infants were recruited from the Cambridge Baby Growth Study. AGD was measured from the center of the anus to the base of the scrotum in males and to the posterior fourchette in females. Measurements were performed at birth and at 3, 12, 18, and 24 months of age. Results Data included 2,168 longitudinal AGD measurements from 463 male and 426 female full-term infants (median = 2 measurements per infant). Mean AGD (± SD) at birth was 19.8 ± 6.1 mm in males and 9.1 ± 2.8 mm in females (p < 0.0001). AGD increased up to 12 months in both sexes and in a sex-dimorphic pattern. AGD was positively correlated with penile length at birth (r = 0.18, p = 0.003) and the increase in AGD from birth to 3 months was correlated with penile growth (r= 0.20, p = 0.001). Conclusion We report novel, longitudinal data for AGD during infancy in a large U.K. birth cohort. AGD was sex dimorphic at all ages studied. The availability of normative data provides a means of utilizing this biological marker of androgen action in population studies of the effects of environmental chemicals on genital development.