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DISORDERS OF SEX DEVELOPMENT: MAKING AMBIGUITY LESS AMBIGUOUS« Back to Volume 23, Issue 3, November 2007 - Table of Contents Christopher P. Houk, MD Peter A. Lee, MD, PhD INTRODUCTIONThe recent consensus conference1,2 on intersex, subsequently referred to as disorder(s) of sex development (DSD), made several important in-roads towards the establishment of an internationally endorsed intersex management guideline; nevertheless, some very fundamental questions remain. Some of the most contentious topics simply were not considered for consensus because of a lack of outcome data on which to anchor objective assessment. Other topics, such as how to make management decisions in the absence of objective data, were not approached. The recent controversy in the medical management of DSD has arisen primarily due to the complaints of adult DSD patients about the lack of full disclosure, absence of participation in treatment decisions, minimal of privacy about their condition, and the consequences of genital surgery. There has also been criticism centered on the use of the “optimal gender” concept for gender assignment, an approach that viewed gender as a largely social construct whose predominant influence was sex of rearing.3 Because postnatal factors were felt to carry great weight for the determination of gender identity, and because DSD management was felt to be complex and confusing, parents were given little information and little input in the decision-making process. In this model, sex assignment was based on potential for fertility, penile-vaginal sexual intercourse, and near-normal appearing genitalia – factors felt to be important for adult quality of life. This paradigm held that when sex assignment was followed by genital surgery, a gender identity consistent with the gender assignment would ensue. This was felt to be true in spite of the knowledge that 46,XX individuals exposed to androgens in utero were more likely to exhibit more male-type gender role behavior,4,5 and, although not well documented, were felt to be more likely to be sexually oriented towards other females.6,7 Over recent decades, it has become obvious that some of the core assumptions about the impact of sex of rearing were incorrect. This has been especially true for 46,XY DSD patients8,9 although issues in virilized 46,XX patients have also emerged.10,11 While inconsistent gender roles and homosexual orientation are not as imposing issues in current society as they were in the past, gender identity opposite to that assigned during infancy suggests a need for better guidelines. While the relative roles played by the various biological and social determinants of gender remain an enigma, there is accumulating evidence that prenatal influences, particularly those related to androgen exposure during fetal life may influence gender identity.9,12,13,14 Furthermore, the position that quality of life could be predicted by the extent to which a DSD individual had normal appearing genitalia or ability to participate in traditional sexual activity is too limited in scope to be helpful to an individual patient. In some cases the attempt to create anatomically ‘correct’ genitals resulted in reduced genital sensitivity and erotic function such that one of the primary goals of surgery – namely satisfying sexual activity – was sacrificed.15,16 Given the degree of alienation reported by parents of DSD children, it was felt that a new treatment paradigm should be developed – one that allows a more informed, evidence-based approach to the DSD patient. REVIEW OF CONSENSUS STATEMENTThe consensus conference (comprised of members of the Lawson Wilkins Pediatric Endocrine Society [LWPES] and the European Society for Paediatric Endocrinology [ESPE]) formed a position when they had reached a collective opinion that there was adequate outcome data to support a position statement and when there was sufficient agreement on the topic. One example of the groups’ opinion was seen in the position that genital surgery should be undertaken for the severely ambiguous infant when parents request it, despite the absence of outcome data to show that this approach is superior to its alternative. Although it was agreed that the impact of prenatal androgen exposure is important to gender outcomes, the group was uncomfortable recommending that treatment be based on an estimate of intrauterine androgen exposure. Another example of this is seen in the groups’ reluctance to recommend that a male sex of rearing be considered in a fully virilized (and hence highly androgen exposed) 46,XX infant with congenital adrenal hyperplasia (CAH). A consensus could not be reached for 2 of the more controversial issues: (1) establishing clear indications for sex of rearing for severe genital ambiguity and (2) establishing complete guidelines on when genital surgery should be deferred. However, it was agreed that surgery should not be done in mildly virilized genetic females (Prader stage 1 or 2). Sex AssignmentGuidelines for gender assignment were addressed only for those DSD patients with substantial outcome data. A review of outcome studies show that: (1) >90% of virilized 46,XX CAH patients identify as females; (2) 100% of 46,XY complete androgen insensitivity syndrome (cAIS) patients identify as female; (3) 100% of 46,XY 5α-reductase deficient patients assigned male at birth identify as male, while more than half of those assigned female who virilized at puberty live as males;17,18 and (4) approximately 50% of 46,XY 17β-hydroxysteroid dehydrogenase (17βHSD) deficient patients assigned female ultimately switch to the male gender. Accordingly, it was recommended that all 46,XX CAH and 46,XY cAIS patients be assigned female. It is important to note that this recommendation was made in spite of a small number of documented cases of initially undiagnosed extremely virilized 46,XX CAH patients assigned male at birth, who maintained the male gender in adulthood and developed a sexual orientation towards females.19 A male sex of rearing was also recommended for 46,XY patients with 5α-reductase deficiency and 17βHSD deficiency (Table 1). The consensus found outcomes for ovotesticular DSD to be so variable that sex assignment recommendations should be based on fertility potential, assuming consistent genitalia.
The consensus did not find the outcome studies sufficiently clear to permit a sound recommendation for sex assignment in 46,XY patients with cloacal extrophy or partial AIS (pAIS). The diagnosis of pAIS is particularly problematic, because the criteria used to establish it are vague and the outcomes seen are so variable, resulting in etiologic heterogeneity within this group of DSD patients. Given these uncertainties in all DSD patients, physical findings alone cannot be used to justify gender assignment. In point, it was felt that the degree of fetal virilization cannot be used as a surrogate of fetal CNS androgen exposure (Figure 1). Accordingly, the use of genital anatomy to guide gender assignment or predict future gender identity should be deemphasized for determining sex of rearing.
It is the authors’ opinion that in these cases the DSD team and the parents must decide whether the genitalia (in some cases, only after androgen stimulation), considered alongside other factors (karyotype, social issues, gonadal function, etc) would permit successful male sex of rearing. The basis of gender assignment and the relative weight of the various interrelated factors are shown in Figure 2. Although other factors should not be underestimated, family support is of capital importance in determining a successful sex assignment (Figure 3). In cases of undervirilized 46,XY patients, initial sex assignment should be approached cautiously given the outcomes seen in this group of DSD patients. In particular, the prospect for 46,XY DSD patients assigned female at birth who then later developed disabling gender dysphoria should be discussed with the family. This is especially true of an idiopathic undervirilized 46,XY patient with evidence of testicular function. In patients with micropenis, it was the consensus that all should be raised male, based on considerations that include the lack of need for surgery, fertility and adult male gender identity.
In terms of gender re-assignment, the consensus strongly felt that all gender re-assignment – that is, assignment after infancy – should only be undertaken after the gender identity is well established and should be patient initiated. Neither homosexuality nor cross-gender behaviors can be used as support that a gender assignment has failed. Decisions about the need for or utility of gender re-assignment should not be influenced by gender role or sexual orientation and should be solely based on the presence of a durable gender identity. Surgical IssuesThe consensus found that the anecdotal reports of DSD individuals dissatisfied with previous genital surgeries was inadequate and insufficiently compelling to recommend that a moratorium be placed on all genital surgeries. The consensus, based upon the recommendations of the surgical subgroup, agreed that the primary goal of genital surgery was to improve functional rather than cosmetic outcome.1 This represents a shift towards a more conservative treatment approach, but is far short of suggesting that all genital surgery be deferred. For the severely virilized 46,XX infant with CAH – the most frequent cause of severe genital ambiguity – early genital surgery is recommended. For 46,XX infants with mild/moderate clitoromegaly, it was advised that genital surgery be deferred until patients can participate in the decision. Given the absence of outcome data showing that it is harmful, it was felt that parental rights and responsibilities as surrogate decision-makers should be respected in cases where informed parents continue to request early genital surgery for their DSD child. This situation further highlights the need for data-driven recommendations. In addition, outcome data were used to stratify gonadal malignancy risk for specific DSD etiologies and evidence-based recommendations were made on the need for and timing of gonadectomy.1
CURRENT STANDARDThe consensus highlighted several standards of care recommendations: (1) gender assignment for all; (2) avoidance of assignment before expert evaluation; (3) open communication; (4) a multidisciplinary team approach; and (5) confidentiality and attention to patient and family concerns.1 It was emphasized that patient and family concerns be carefully considered and that adolescent patients should be offered the strictest confidence. This must take into consideration the fact that parents may not be ready to agree with full disclosure to their children. Hence, while respecting this, adolescent patients should be given opportunities to ask questions and discuss their condition confidentially, without their parents being present. The basis of gender assignment (Figure 2 and Table 2) should include: (1) the most likely adult gender identity; (2) diagnosis; (3) genital appearance; (4) surgical options; (5) potential for fertility; and (6) family/social/cultural circumstance. Data are not available to predict outcome in the majority of DSD patients, therefore the consensus felt that decisions based on psychosocial factors, such as parental wishes, should guide management decisions in cases with uncertain outcomes. This approach recognizes the powerful influence of parental input on outcomes (Figure 3).
Medical decisions in the DSD patient are usually made in what has been referred to as Category III level of evidence (Category III: Opinions of respected authorities, based on clinical experience, descriptive studies and case reports, or reports of expert committees.20 ) Thus, there are major limitations to making recommendations for DSD patients for most issues, particularly those most controversial topics of sex assignment and genital surgery, since the available evidence is considered to be Category III, which is the least compelling. UNRESOLVED ISSUESThe effects of the care given to DSD patients are still not well understood, thus it has been difficult to determine which of the traditional and which of the more contemporary treatment approaches provide the optimal chance for a successful outcome. Despite the advances in our understanding of human sexual development, the sheer number of possible etiologies, the high degree of phenotypic heterogeneity and the overlay of psychological/sexual/social/cultural pressures in DSD patients make it difficult to develop comprehensive guidelines for approaching these issues. This difficulty is compounded by the paucity of outcome data for DSD patients. These factors notwithstanding, it remains important to sort out which questions will be answerable with new information versus those (such as which gender assignment should be proposed in all cases) questions which may never be answerable. DECISION MAKINGThe consensus conference recognized the role of various entities in decision-making for the DSD child including: the parent, the child, and the medical system (Figure 4). However a practical application of these roles and ways to resolve potential conflicts between decision makers were not addressed. The role of other parties, such as advocacy groups, in decision-making was also not addressed. This pertains to those who have an interest in DSD issues based on ethical, human rights, and legal grounds. However, the potential role that support groups can play to facilitate better understanding of DSD patients or improving their quality of life was recognized. Health care professionals were encouraged to offer participation in support groups, although a practical way to broadly implement this was not addressed. NEED FOR OUTCOME DATAThe need for outcome data from a large cohort of randomly selected DSD patients is obvious (Table 3). However, the 1999 North American Task Force on Intersexuality, which was established to address this problem, was unsuccessful for several reasons. These included HIPPA restraints, investigators’ hesitation to pool data, and patients’ reluctance to participate. Hence, the risk of non-representative sampling, the rarity of the disorders, the variability with which patients are managed, and the lack of a well-capitalized central data-collection facility may be factors that will continue to preclude an appropriately designed study. Ideally the collection of such data would involve a centralized collection point and be similar to other NIH/federally/foundation funded projects, such as those seen in other pediatric subspecialties relating to malignancies, hemophilia, or cystic fibrosis. It is tempting to think that support groups could serve as a conduit to help capture the additional data needed to answer some of these questions.
BARRIER TO BETTER STUDIESClear barriers to the study of children with DSD remain. In addition to the relatively poor funding designated to pediatric research, there are inherent issues of recognizing and protecting the rights of children. Furthermore, study of children with DSD presents a unique set of delicate problems given that some of the most important questions revolve around gender identity, genitalia, and sexual function. While the popular literature and the press attempt to be realistic on issues of gender and sexuality, there continues to be a general lack of knowledge and hence a lack of understanding of issues facing the DSD patient. Thus, it would be difficult if not impossible to design, receive approval, and conduct any study tracking the development of human sexuality, particularly the evolution of sexual orientation and sexual function during childhood. It is clear that without answers to these developmental questions, it is much more difficult to anticipate outcomes for most DSD patients with any degree of certainty. It appears, as in most other chronic illness in children, that a good quality of life is largely dependent on a strong family support system (Figure 3). The plan for the care of DSD patients must accommodate cultural and religious sensitivities and incorporate realistic issues regarding DSD patients, such as childhood gender development and sexuality. Currently, this is the context in which research and patient care concerning DSD must operate. A less contentious approach would be to design a case-control study comparing matched DSD patients with good outcomes to those with less than good outcomes to determine what, if any, management, family, or environmental factors are associated with outcome.21,22 UNRESOLVED SURGICAL ISSUESCuriously, the logic used to attack the traditional management paradigms has become one of the greatest hurdles to moving forward; that is, how does one develop a management model in the absence of clear outcome data for the disease/condition in question? The Columbia Court opinion23 stated that children must be viewed as individuals with dignity and rights who are unable to give consent. This opinion states that while it is unclear whether or not genital surgery is necessary and urgent, it is also unclear whether the alternative of delaying surgery would work in society and would force a type of social experimentation. Given our degree of ignorance in DSD, the Columbia court citation declared that in cases where medical issues were unclear the ultimate decision-making rests with the parents – the “pro dubio in familia” rule – seems particularly wise and relevant. Foremost in the discussion of modern genital surgery is the need for outcome data on genital sensitivity and function in adulthood following the use of modern, nerve-sparing genital surgery.24 It is anticipated that function will be greatly improved over previous poor outcomes,25 but the degree of improvement is at this point only theoretical. Unfortunately, confirmation of this improvement will not be possible for years. One problem with postponing genital surgery until the DSD child is capable of exercising a decision is the absence of a clear definition of the age and stage at which children can be expected to rationally make this decision. PSYCHOLOGIST DEFICITThe Lawson Wilkins Pediatric Endocrine Society’s ad hoc Intersex Committee devoted many hours to the completion of the consensus conference to address the continuing need for experienced psychologists who could be part of care teams for DSD patients. However, there has been little progress towards meeting this need in our health care system. Most psychologists receive little training or experience with approaching a gender disordered or DSD patient. The net result has been that most psychologists remain uncomfortable with these patients. There are medical centers which are now supporting obesity centers, using a multidisciplinary approach, in an attempt to demonstrate that a preventative and multi-specialty approach will lead to healthier individuals and ultimately save health care dollars. Perhaps a similar attempt at one or more large medical centers with a functioning DSD team could develop a similar model.
SCIENTIFIC DEFICITThe rapid advance of genetic knowledge has resulted in an expansion in diagnostic categories of the DSD patient. This will likely be helpful if it leads to better understanding of the biologic reproductive function in specific DSD types. Little progress has been gained concerning the age-old dilemma of genetic vs. environmental relative influence (nature vs. nurture). The need for funding agencies to support studies that serve to better understand genetic and endocrine factors of physical and psychological sexual differentiation is clear. Such funding should support the total purview impacting DSD issues; basic molecular and genetic research, differentiation using animal models, surgical techniques, physiological, and psychological, including psychosexual domains. CONCLUSIONIt is important that the caretakers of DSD patients avoid the allure of adopting untested management approaches out of frustration. Regardless of the intent, this sort of approach risks making the same mistake for which the traditional management model stands accused – that is, making medical decisions without a clear understanding of the disorder or most likely outcome in the absence of intervention. An example of this type of thinking would be to advise parents to forego all genital surgeries without providing them a basis on which to frame their own decisions. In this example, one type of prescriptive authority – that is, performing genital surgery on all DSD infants – is exchanged for another – that is, no DSD infant receives genital surgery. Any recommendations must be based either upon clear scientific data or on a synthesis of the effects of the complex interplay between biological, social, and psychological inputs. How parents are expected to make a truly informed decision about sex assignment is unclear. Based on anecdotal experience, it seems that parents often make their decisions in a way that is similar to those championed by the optimal gender approach. A concern about this is that most new parents focus upon the issues at infancy and find it difficult to project their thinking in terms of optimal adult outcome. For example, they often chose surgery out of a desire to create normal appearing genitalia even when it is clear that this intervention might compromise genital sensitivity.
Overall, much work and collaboration is needed to address the multiple issues of DSD management. Most DSD infants are not born in close enough proximity to centers with experienced DSD care teams to allow this team aspect of management to be helpful for the majority of affected children. In summary (Table 4), the management of DSD is inherently confusing (Figure 4). It has become clear that outcomes in DSD patients seem to be best characterized with a multi-factorial disease model that presupposes the simultaneous co-alignment of genetic, physical, and environmental risks for disease expression. We have much to learn from DSD patients and it is our hope that this article will help to encourage a genuine discussion of the issues facing these rarely encountered and poorly understood patients.
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Volume 25 Number 1
June 2009
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