SPECIAL ARTICLE
Summary of Consensus Statement on Intersex
Disorders and Their Management
Christopher P. Houk, MD, PhDa, Ieuan A. Hughes, FMedSci, FRCPCHb,c, S. Faisal Ahmed, FRCPCHd, Peter A. Lee, MD, PhDe,c; Writing Committee
for the International Intersex Consensus Conference Participants
aDepartment of Pediatrics, Backus Children’s Hospital, Mercer University School of Medicine, Savannah, Georgia;bDepartment of Paediatrics, University of Cambridge,
Addenbrooke’s Hospital, Cambridge, United Kingdom;dDepartment of Child Health, Royal Hospital for Sick Children, Glasgow, Scotland, United Kingdom;eDepartment
of Pediatrics, Penn State College of Medicine, Milton S. Hershey Medical Center, Hershey, Pennsylvania
The authors have indicated they have no financial relationships relevant to this article to disclose.
A
DVANCES in understanding of genetic control of sexual determination and differentiation, improvements in diagnostic testing and surgical genital re-pair, 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 pa-tients, and identify and prioritize questions that need additional investigation. This is a summary statement.NOMENCLATURE AND DEFINITIONS
Advances in molecular genetic causes of abnormal sexual development and heightened awareness of the ethical and patient-advocacy issues mandate
reex-amination of existing nomenclature for patients with intersex.1Terminology 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,3and to meet the need for psychologi-cally sensitive yet descriptive medical terminology. Nomenclature should be flex-ible enough to incorporate new information, robust enough to maintain a consis-tent 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 month’s issue of Pediatrics Electronic
Edition).
Three traditionally conceptualized domains of psychosexual development are gender identity (one’s self-representation [ie, male or female]), gender role (sex-ually dimorphic behaviors within the general population, such as toy preferences, aggression, and spatial ability), and sexual orientation (direction[s] of erotic in-terest). Gender dissatisfaction denotes unhappiness with assigned sex and may
www.pediatrics.org/cgi/doi/10.1542/ peds.2006-0737
doi:10.1542/peds.2006-0737
cCo-chairs
Key Words
intersex, sexual differentiation, ambiguous genitalia, genital surgery
Abbreviations
DSD— disorder(s) of sex development AE—androgen exposure
CAH— congenital adrenal hyperplasia 5␣-RD2—5␣-reductase deficiency CAIS— complete androgen insensitivity syndrome
Accepted for publication Mar 22, 2006 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: [email protected]
result in gender self-reassignment. Psychosexual devel-opmental factors relate to parental psychopathology, parent-child attachment, or parenting practices (eg, not discouraging cross-sex behavior). Dissatisfaction occurs more frequently in individuals with DSD than the gen-eral population, is not predictable by karyotype, andro-gen exposure (AE), degree of andro-genital virilization, or as-signed sex,5and has not been well studied with regard to social, personal, or biological factors.
BACKGROUND INFORMATION
Psychosexual development is influenced by multiple fac-tors including sex-chromosome genes, brain structure, social circumstance, family dynamics, and prenatal AE.6
AE is apparently dose related7 (eg, childhood play
be-haviors in girls with congenital adrenal hyperplasia [CAH]) and associated with development of male gender identity (patients with 46,XY cloacal exstrophy who were gonadectomized neonatally). Androgen effect on genital development apparently occurs independently of effect on neural and behavioral development; genital appearance does not predict gender-role change. Out-come cannot be predicted by degree of prenatal AE for any DSD, with variability relating to both prenatal and
postnatal AE differences (eg, 5␣-reductase deficiency
[5␣-RD2]).
Emerging evidence suggests direct effects of
sex-chro-mosome genes on brain and behavior,8but behavioral
roles for Y-chromosome genes have not been identified.9 A Y-chromosome and male-typical prenatal AE does not unequivocally entrain adult male gender identity.10
Sex differences in brain structures have been
identi-fied across species.11Human postmortem and
neuroim-aging studies have found that male brains are 8% to 10% larger than female brains. Sexual dimorphism in specific neural subcomponents persists after adjustment for brain size. The limbic system and hypothalamus are important because of roles in reproduction; specific nu-clei show sexual dimorphism on postmortem studies (bed nucleus of the stria terminalis, suprachiasmatic nu-cleus, and the interstitial nucleus of the anterior hypo-thalamus 3), although it is unknown when these differ-ences emerge. Relationships between structural brain differences and psychosexual development are unclear. DSD may carry stigma. Environmental and cultural factors influence gender role (gender-change frequency differences in 5␣-RD2 deficiency in different counties). Religious, philosophical, fatalism, or guilt viewpoints in-fluence parents’ actions. In some societies, female infer-tility precludes marriage, employment prospects, and economic independence. Poverty impairs access to health care.12
Standard-of-care concepts for best clinical
manage-ment of DSD13 include a gender assignment for all;
avoiding gender assignment before expert evaluation in newborns; open communication; multidisciplinary-team
evaluation and management; family/patient particition in decision-making; respect and attenparticition to pa-tient/family concerns; and strict confidentiality.
Key points to address during the crucial initial paren-tal contact include: children with DSD have the potential to become well-adjusted persons; DSD is not shameful, but privacy is respected; and although the best course of action may not be obvious, caregivers with parents ar-rive at the best possible decisions.
A core team ideally includes pediatric endocrinolo-gists, surgeons, urologists or gynecoloendocrinolo-gists, psycholo-gists/psychiatrists, geneticists, neonatologists, social
workers, nurses, and medical ethicists14with
communi-cation with the primary care physician.15Consensus re-garding diagnosis, gender assignment, and treatment op-tions must be reached before making recommendaop-tions, with one team member primarily interacting with the family.16 The surgeon’s role involves outlining surgical sequences and consequences of aligning genitalia for assigned gender, establishing functional genital anat-omy, and, if indicated, timely gonadectomy. Support groups can play a positive role.17
EVALUATION
Criteria suggesting DSD include overt genital ambiguity; apparent female genitalia (enlarged clitoris, posterior labial fusion, inguinal/labial mass); apparent male geni-talia (nonpalpable testes, micropenis, isolated perineal hypospadias, or mild hypospadias with undescended tes-tis); a family history of DSD (eg, complete androgen insensitivity syndrome [CAIS]); and genital and karyo-type discordance.
DSD in older individuals may include unrecognized genital ambiguity, inguinal hernia in a female, delayed/ incomplete puberty, virilization in a female, primary amenorrhea, male breast development, and gross hema-turia in a male.
Clinical evaluation includes family and prenatal his-tory and physical examination with an accurate and objective assessment of genitalia and any dysmorphic features. To minimize psychological distress, the patient/ family should be informed exactly what will be done and why. Medical photography requires sensitivity and con-sent.18
A specific molecular diagnosis is identified in only ⬃20% of gonadal differentiation defects.19Most virilized 46,XX infants have CAH; only 50% of undervirilized 46,XY patients receive a definitive diagnosis.20,21 Given the spectrum of findings and diagnoses, no specific single evaluation protocol can be used. Plasma hormone con-centrations must be interpreted using normal ranges for gestational and chronological age for the assay used.
gonadotropins, anti-Mullerian hormone, and electro-lytes. Usually, results that are sufficient for diagnosis should be available within 48 hours. Although cases must be individualized, practical decision-making algo-rithms are available22 to guide additional investigation. Although mutations in established genes may be readily identified by clinical laboratories, current molecular di-agnosis is limited by cost, accessibility, quality control, and inadequate functional interpretation.23
MANAGEMENT
Newborn Gender Assignment
Outcome data indicate that ⬎90% of patients with
46,XX CAH and all patients with 46,XY CAIS who are assigned female sex in infancy identify as females. Two
thirds of patients with 5␣-RD2 who were initially
as-signed female sex who virilize at puberty, and all who were assigned male, live as males. Gender-role changes
are reported for approximately half of the 17
-hy-droxysteroid dehydrogenase-3-deficient patients who are raised as girls. The recommendations are to raise infants with 46,XY CAIS and 46,XX CAH as females,
whereas for infants diagnosed with 5␣-RD2 or 17
-hydroxysteroid dehydrogenase-3 deficiency, a male
as-signment should be considered.24
Sexual functioning, psychosocial adjustment, mental health, quality of life, and social participation are under-studied. Attention has been toward dissatisfaction with assigned sex or gender self-reassignment. Dissatisfaction is found in⬃25% of 46,XY patients with partial viriliza-tion regardless of assigned gender.25 Data support male rearing in most XY infants with significant phallic tissue and all with micropenis.26Assignment for patients with ovotesticular DSD must consider fertility potential as-suming consistent genitalia. In the child with mixed gonadal dysgenesis, AE, phallic size, gonadal function, and location are considered. Outcome data for 46,XY child with cloacal exstrophy are conflicting precluding clear assignment recommendations. Hence, decisions should be made with the families’ full input and consent after they know the potential risks and benefits and potential impact of options. Available evidence-based data concerning fertility potential and surgical proce-dures must be provided.
Assignment should be made as quickly as thorough diagnostic evaluation permits. Influencing factors in-clude diagnosis, genital appearance, therapeutic options, fertility potential, cultural practices and pressures, and parental views. Individual DSD outcome data regarding gender identity, quality of life, avoidance of unnecessary surgery, hormone replacement, and fertility preserva-tion must be considered. Fertility-potential consider-ations include expected fertility in virilized females with a well-developed uterus and ovaries, unlikely fertility in undermasculinized males without assisted-reproduction
techniques, and fertility in some patients with ovotestic-ular DSD. Appearance-altering surgery is not urgent. Somatosexual and psychosexual differentiation infor-mation and treatment options are needed. Balanced, technologically sound, Web-based information may be helpful.27Ample time should be provided for discussion, repeating information, and reassessment of understand-ing. To assist parents in coping, information to be shared with siblings and others should be discussed.
Surgery
Rationale for early reconstruction28 includes beneficial effects of estrogen on infant tissues, avoiding complica-tions from anatomic anomalies, satisfactory outcomes,29 minimizing family concern and distress,30and mitigating the risks of stigmatization and gender-identity confusion of atypical genital appearance. Adverse outcomes have led to recommendations to delay unnecessary genital surgery to an age of patient informed consent, although relative risks and benefits are unknown. Age-specific preparatory procedures including coping-skill training and behavior-therapy techniques are psychologically beneficial.31The goals of genital surgery are to maximize anatomy to enhance sexual function and romantic part-nering.
Feminizing genital surgery involves external genitalia reconstruction and vaginal exteriorization, with early separation of the vagina and urethra.32Clitoral reduction is considered with severe virilization and performed in conjunction with common urogenital sinus repair. Vag-inal dilatation should not be performed during
child-hood. Refinement is generally necessary at puberty.33
Procedures should emphasize functional cosmetic ap-pearance and be designed to preserve erectile function and enervation. Vaginoplasty should be performed in the teenage years; each of the techniques (self-dilata-tion, skin or bowel substitution) has specific advantages and disadvantages,34and all carry potential for scarring that would require modification before sexual func-tion.35
Masculinizing genital surgery involves more surgical procedures and urologic difficulties than feminizing genitoplasty. Standard surgical repair involving hypo-spadias includes chordee correction, urethral
reconstruc-tion, and judicious testosterone supplementation.36 If
needed, adult-sized testicular prostheses should be in-serted after sufficient pubertal scrotal development. The enormity of the undertaking and complexity of phallo-plasty must be considered during the initial counseling period.37 Care should be taken to avoid unrealistic ex-pectations about penile reconstruction.
gonads. The lowest risk (⬍5%) is found in ovotestis38 and genetically confirmed CAIS. Intraabdominal gonads of high-risk patients (gonadal dysgenesis plus GBY and partial androgen insensitivity syndrome) should be re-moved at diagnosis. Gonadectomy of streak gonads should be performed in childhood in mixed gonadal dysgenesis and in females with gonadal dysgenesis and Y-chromosome material. Patients with DSD, raised as males with scrotal gonads, should have a gonadal biopsy at puberty.39
Gender Reassignment
Gender reassignment, which should always be initiated by the patient, should be approached very cautiously. Because childhood gender dissatisfaction may remit, the key challenge is to identify multiple determinants of gender identity, additional biological factors, social fac-tors (especially parent characteristics, family function-ing, peer relationships), and personal characteristics. Discordant gender-role behavior, which is more com-mon in children with DSD, should not be considered an indication for gender reassignment, because sex-typical behavior, sexual orientation, and gender identity should be considered separately. Homosexual orientation (rela-tive to sex of rearing) or strong cross-sex interest in an individual with DSD is not an indication of incorrect sex assignment. In patients with DSD who have significant gender dysphoria, a comprehensive psychological eval-uation40and extensive parental discussion is required. A patient with persistent desire for gender change should be referred to a skilled specialist.
If needed, timing of the pubertal induction should be individualized. Hormone effects, reproduction, sexual-ity, and the patient’s expectations should be discussed. Sex-steroid replacement induces pubertal changes, growth, and bone mineralization and provides for
psy-chosocial and psychosexual maturation.41Androgens for
males include testosterone esters (oral [testosterone un-decanoate] and transdermal preparations). Females with hypogonadism require estrogen supplementation fol-lowed by progestin breakthrough bleeding (unneeded if the uterus is absent).
Data on fertility are limited for most DSD. Females with an adequately formed uterus and males with evi-dence of functional seminiferous tubules may have fer-tility potential with assisted-reproduction techniques.
Psychosocial management with a practitioner who has expertise in sexuality is integral for patients with DSD to promote positive adaptation. Specialized psycho-social assessment can guide team decisions about gender assignment/reassignment, timing of surgery, and sex-hormone replacement. Coping should be evaluated in the context of overall vulnerability (developmental his-tory, temperamental characteristics, cognitive level, family and social environment).42Psychological issues to be addressed include sexuality, fertility, culture, and
so-cial circumstances. The most frequent sexual problems in patients with DSD are avoidance of intimacy, sexual aversion, and lack of arousability, often misinterpreted as low libido.43The process of relationship-building in-cludes informing a partner about one’s condition, ad-dressing fears of rejection, and focusing on relationships rather than solely on sexual function and activity.
Disclosure of salient and sensitive aspects of the pa-tient’s condition (karyotype, gonadal status, fertility) are integral parts of patient care and a flexible individual-based approach. Disclosure should be planned with par-ents for ongoing dialogue.44Generally, disclosure is as-sociated with enhanced psychosocial adaptation,45but it may not always be helpful.
INTERNATIONAL INTERSEX CONSENSUS CONFERENCE PARTICIPANTS
Olaf Hiort (Lu¨beck, Germany), Eric Vilain (Los Angeles, CA), Melissa Hines (London, UK), Sheri Berenbaum (University Park, PA), Copeland, Ken (Oklahoma City, OK), Patricia Donohoue (Iowa City, IA), Laurence Baskin (San Francisco, CA), Pierre Mouriquand (Lyon, France), Heino Meyer-Bahlburg (New York, NY), Polly Carmichael (London, UK), Stenvert Drop (Rotterdam, Netherlands), Garry Warne (Melbourne, Australia) John Achermann (London, UK), Erica Eugster (Indianapolis, IN), Vincent Harley (Victoria, Australia), Yves Morel (Lyon, France), Robert Rapaport (New York, NY), Jean Wilson (Dallas, TX), Peggy Cohen-Kettenis (Amsterdam, Netherlands), Jay Giedd (Bethesda, MD), Anna Norden-stro¨m (Stockholm, Sweden), William Reiner (Oklahoma City, OK), Emilie Rissman (Charlottesville, VA), Sylvano Bertelloni (Pisa, Italy), Felix Conte (San Francisco, CA), Claude Migeon (Baltimore, MD), Chris Driver (Aber-deen, UK), Kenji Fujieda (Asahikawa, Japan), John Brock (Nashville, TN), Melvin Grumbach (San Fran-cisco, CA), Phillip Ransley (London, UK), Richard Rink (Indianapolis, IN, Christopher Woodhouse (London, UK), Hertha Richter-Appelt (Hamburg, Germany), David Sandberg (Buffalo, NY), Norman Spack (Boston, MA), Barbara Thomas (Rottenburg am Neckar, Ger-many), Kenneth Zucker (Toronto, Ontario, Canada), Leendert Looijenga (Rotterdam, Netherlands), Berna-dice Mendoca (Sao Paulo, Brazil), Paul Saenger (New York, NY), Justine Schober (Erie, PA), Ute Thyen (Lu¨-beck, Germany), Amy Wisniewski (Des Moines, IA), and Cheryl Chase (Rohnert Park, CA).
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DOI: 10.1542/peds.2006-0737
2006;118;753
Pediatrics
Committee for the International Intersex Consensus Conference Participants
Christopher P. Houk, Ieuan A. Hughes, S. Faisal Ahmed, Peter A. Lee and Writing
Summary of Consensus Statement on Intersex Disorders and Their Management
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DOI: 10.1542/peds.2006-0737
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Christopher P. Houk, Ieuan A. Hughes, S. Faisal Ahmed, Peter A. Lee and Writing
Summary of Consensus Statement on Intersex Disorders and Their Management
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