Pediatric Urology Gender Identity in Disorders of Sex Development: Review Article

Jennifer H. Yang Michael DiSandro

, Laurence S. Baskin,

Division of Pediatric Urology, University of California, San Francisco Children's Hospital, San Francisco, California Received 20 February 2009; Accepted 3 July 2009. Available online 14 November 2009. Editorial Comment Urology, Volume 75, Issue 1, January 2010, Pages 159-160, Julian Wan Refers to:

PDF (101 K) |

Editorial Comment Urology, Volume 75, Issue 1, January 2010, Pages 159-160, Julian Wan Refers to:

PDF (101 K) |

Refers to:

Reply Urology, Volume 75, Issue 1, January 2010, Page 160, Jennifer H. Yang, Laurence S. Baskin, Michael DiSandro

PDF (89 K) |

Reply Urology, Volume 75, Issue 1, January 2010, Page 160, Jennifer H. Yang, Laurence S. Baskin, Michael DiSandro Referred to by:

PDF (89 K) |

Editorial Comment Urology, Volume 75, Issue 1, January 2010, Pages 159-160, Julian Wan Referred to by:

PDF (101 K) |

Objectives Many concerns have been raised regarding the treatment and long-term outcome of infants born with complex genital anomalies. Debate among clinicians, psychologists, ethicists, and patient advocate groups regarding the optimal management of these individuals is ongoing. Although determining the most appropriate gender is a difficult task, this review will help clarify some of the issues at hand. Methods A literature review which addresses the challenges of advising families about gender identity in infants and children with disorders of sex development.

Results The evidence for endocrine effects on neurobiological development with regard to sexual behavior is compelling, although the existing outcome studies are largely anecdotal and somewhat contradictory. Conclusions Gender assignment in infants born with a disorder of sex development remains only one of the many difficult decisions faced by both the treatment team and the family. Improved long-term follow-up of these patients will provide much needed feedback on previous and contemporary management. Article Outline Historical Aspects

46,

, ,

One of the most paramount issues arising with the infant with ambiguous genitalia is the most appropriate gender assignment, or from a parents perspective, the sex of rearing. Recommendations will initiate a myriad of psychosocial and psychosexual ramifications for the child and parentsincluding potential intensive medical treatments such as complex surgical interventions and lifelong hormonal manipulations. Historically, recommendations for gender assignment of infants with ambiguous genitalia has been guided by the phenotypic appearance of the genitalia; the practitioner would determine the sex of rearing on the basis of what they believed would facilitate the most functional genitalia and offer the child their best opportunity at normalcy.1 The assumption was that the sex-assignment would later determine the child's future sexual identity. However,

this simplistic approach does not always work. As described below, more recent studies have helped us to better understand what actually determines gender identity, but even now, there is a paucity of outcome data for evidence-based approaches to these rare disorders. The existing studies often present conflicting outcomes, in addition to the tremendous amount of data unveiling the ever-evolving complexities of the neurobiological and psychosexual development regarding gender identity. The development of gender identity is a complex interaction between prenatal and postnatal endocrine factors, genetic influences, and postnatal environmental and psychosocial experiences. In this review, we will address the significant issues of gender identity in infants with disorders of sex development (DSD) through a review of past and current published data. The developmental neurobiological influences in concert with endocrine effects on the developing brain with regard to sexual behaviors will be reviewed. Finally, current recommendations regarding the approach to infants with ambiguous genitalia will be discussed.

Historical Aspects
Since antiquity, individuals neither male nor female have existed outside of societal and cultural norms, at times symbolizing extraordinary powers and deity status. With the passage of time and the advancement of medicine and science, a better understanding of the true sex of such individuals began. During the early colonial period, such individuals became labeled as persons with mistaken sexual identities, because their externalized genitalia or internal reproductive organs differed from the typical mannerisms attributed to a given sex.2 Since the 1950s and 1960s, the common practice of gender assignment was based on the assumption that the gender of rearing was determined by socioenvironmental factors. Infants with sexual ambiguity were assigned the sex most concordant with external genital appearance as opposed to karyotype. Recommendations at that time included early sex assignment with parallel rearing and early medical correction of genitalia including removal of gonads in female sex assignment. In addition, parents and families were counseled to not disclose the intersexual state of the child and often shrouded these conditions in great secrecy. The actual outcome of these decisions were unknown, under-reported or heavily subject to bias.1 In 1975, Money3 reported the successful reassignment of a male toddler to female sex after a traumatic penile loss. The concept of sexual neutrality of the neonate was developed, which accredited postnatal social and environmental influence as the determinants of gender identity. Despite the eventual discovery of the inaccuracy of the reported success of this particular case,4 the concept of nature vs nurture has remained influential in the management of infants and children with ambiguous genitalia. In the last 3 decades, there has been increasing evidence of the role of genetic and prenatal factors in influencing an individual's ultimate gender identity. The potential affect of male hormone levels during fetal development and its influence on the development of the central nervous system remains an important factor. In addition, the recent criticisms for the management of DSD in the past are a result of adults who experienced early interventions and have reported psychological problems, such as gender dysphoria and depression, as well as physical problems because of their sex-

assignment treatments. Many others view their previous management as an abuse of their human rights5 and a considerable number of patients suffer from significant psychological distress as adults.6 This recent heightened interest in intersex has superseded medical discussions, becoming the focus of historical chronicles,7 ethical debates,8 and social and psychological analyses.9 Because DSD are uncommon as a whole, there has been limited data concerning the eventual outcomes regarding gender identity, gender role identification, or sexual orientation. The effect of hormonal imprinting on gender development may be elucidated through existing animal models and also the observations of human case studies in DSD patients.

Hormonal Influence on the Developing Brain

Androgens play an important role in the sexual differentiation of the mammalian brain and behavior. [10] and [11] During certain critical periods in prenatal development, androgens direct developmental processes in neural regions containing the corresponding steroid receptors. As a result, the structure and function of these regions becomes altered, as are the behaviors that they control. In humans, androgens have been thought to influence postpubertal activities, libido, and interests.12 Androgen influence on the central nervous system development and behavior has been best studied in the rodent model. Typically, high concentrations of prenatal androgens results in male-typical behavior; in contrast, female-typical behavior develops in the absence of androgen. [10] and [13] The developing nervous system can be permanently altered causing masculinizing effects in the behavior of the adult animal. Animal studies demonstrate that the addition or removal of hormonal stimulus in early postnatal life can profoundly alter gender-specific behavior in adult animals. In 1959, Phoenix et al14 demonstrated that adult female guinea pigs exposed to androgens during gestation showed less feminine behavior (lordosis) and more masculine behavior. The authors hypothesized that androgen exposure could permanently alter the developing neural network resulting in masculinized behavior in the adult animal. These long-lasting organizational effects of hormones occur during critical periods of neural development. Several other studies have been conducted to elucidate the hormonal effects on reproductive behavior. It has also been shown that androgenized neural networks are permanently altered despite later hormonal treatments with estrogens, in an attempt to induce female behavior. Female rats treated with androgen in the first few days of life do not project femaletypical behavior as adults, despite treatment with estradiol and progesterone as adults.15 Similarly, early castrated male rats respond to injections of female hormones, displaying female-typical behavior (lordosis) but no response to testosterone injections.16 In contrast, estrogens do not seem to be necessary for the neural or organizational development of female sex typical behavior. Female rats treated with antiestrogens at birth exhibited behavior similar to that of control females.17 Despite the absence of androgens resulting in female behavior, estrogen treatment was found to be even more effective than androgen treatment in newborn female rodents in producing masculine behavior. These effects are thought to be secondary to the conversion of testosterone to estrogen via aromatase.18 Recent studies examining the neural pathways of sexually dimorphic

behavior in mice have demonstrated a role for both testosterone and estrogen in the control of gender-specific behavior.19 Reciprocal case studies in humans with DSD lend some insight as to the outcomes of hormonal influences on gender development.

Existing Outcomes Studies Regarding Gender Assignment and Hormonal Imprinting

In humans, androgen exposure is thought to represent an important role in the development of gender-related behavior. Compelling evidence for the role of androgens in the development of sex-typed behavior stems from studies of girls with congenital adrenal hyperplasia (CAH). These patients are exposed to androgen during gestation and are typically born with some degree of genital virilization (Fig. 1A). They are typically assigned female sex of rearing, and many develop tomboyish personalities, choose to play with male-typical toys and engage in more rough play compared with other girls. [20] and [21] In general as a group, women with CAH are sexually attracted to men, and are more likely to have bisexual or homosexual interests compared with normal women.21 Females with CAH have been shown to have higher aggression scores compared with female controls, suggesting that prenatal androgens contribute to human aggression.22

Full-size image (56K) High-quality image (524K) Figure 1. Examples of various patients with DSD. (A) 46,XX DSDFemale infant with CAH, demonstrating markedly virilized external genitalia. (B) 46,XY DSDInfant with mixed gonadal dysgenesis. (C) 46,XY DSDInfant initially identified as female, found to be 46,XY with hypospadias, bilateral undescended testes, work-up suggestive of partial androgen receptor defect. (D) 46,XY DSDInfant with severe hypospadias, bilateral undescended testes, and retained Mullerian structures.

As one of the most common causes of 46,XX DSD, women with CAH have been studied regarding gender identity and sexual orientation as adults. Overall, a majority of 46,XX patients with CAH raised as female develop female gender identity with few cases of gender dysphoria.23 Psychosocial assessments of women with CAH have demonstrated that compared with the controls, CAH women reported more cross-gender role behavior during childhood and fewer had comfort with their sense of femininity during childhood.24 Gender identity in girls with CAH has also been shown not to be related to the degree of virilization nor the age at which reconstructive surgery was done, suggesting that excess androgen exposure early in development may increase the risk of atypical gender behavior not predicted by genital virilization.25 Sex-atypical behavior has

been found to be associated with the degree of inferred prenatal, but not postnatal, androgen excess.20 Meyer-Bahlburg et al26 performed gender assessment in adult women with CAH as a function of disease severity. Women with the nonclassical or late-onset CAH demonstrated few signs of gender shifts, the simple-virilizing women were intermediate and the salt-wasting variants were most severely affected. Two salt-wasting women were gender dysphoric and 1 had changed to male in adulthood. Two rare, autosomal-recessive disorders of sex development, 5-reductase-2 deficiency and 17-hydroxysteriod dehydrogenase deficiency, are unique examples of hormonal influence on the developing brain. Typically, patients are born with female-appearing external genitalia and are raised as girls. Those with 5-reductase-2 deficiency have plasma testosterone levels in the high normal range and those with 17-hydroxysteriod dehydrogenase deficiency typically have deficient testosterone production, although some androgen production may be possible via other 17-hydroxysteriod dehydrogenase isoenzymes. Pubertal virilization occurs secondary to increased production of 5reductase-1 and other 17-hydroxysteriod dehydrogenase isoenzymes, allowing conversion of testosterone to dihydrotestosterone and androstenedione to testosterone, respectively.27 Both these disorders are unique models for evaluating the effect of testosterone, compared with a female upbringing, in determining gender identity. The majority of patients unambiguously raised as girls changed to a male-gender identity at the time of puberty. Exposure of the brain to normal levels of testosterone in utero and postnatally appears to contribute substantially to the formation of male-gender identity, despite the effect of female sex of rearing. [28] and [29] In patients with complete androgen insensitivity syndrome, the typical hormonal influences of androgen are ineffectual secondary to a defect in the androgen receptor. These individuals are born appearing externally as female and raised as females. Psychological outcomes in individuals with complete androgen insensitivity syndrome (CAIS) are similar to women without the condition.30 Women with CAIS are generally satisfied with their female gender and sexual function.31 The development of normal female gender identity in CAIS patients demonstrates the effect of androgen unresponsiveness of the brain in addition to unambiguous female sex of rearing.

Outcomes in Normal 46,XY Males With Severe Genital Anomalies

A disorder of sex development is usually associated with an endocrine disorder, resulting in an overvirilized female or an undervirilized male. Several conditions exist, including cloacal exstrophy, ablation of the penis and penile agenesis, in which genital anomalies are not caused by endocrine dysfunction. Cloacal exstrophy is a multisystem anomaly, which demands a multidisciplinary approach. With the improvement of management, most patients survive through childhood and the focus has been shifted to improving quality of life. About 10 years ago it was a common practice to perform gender reassignment in 46,XY children with cloacal exstrophy secondary to diminutive genitalia, despite evidence that major psychosexual developmental difficulties result in similar patients.32 Male gender assignment was thought to be appropriate for only those with adequate bilateral or unilateral phallic structures.32 Therefore, male infants with inadequate phallic structures would be most appropriately raised as female sex of rearing

managed by early gonadectomy.33 It was also thought that those male patients with severe abnormality or deficiency of genitalia would be confronted with significant psychosexual adjustment. Various institutions have reported the outcome of 46,XY cloacal exstrophy patients reassigned to female sex of rearing at birth. In 2002, a study by Schober et al34 reported that all 14 patients with XY chromosomes with cloacal exstrophy reassigned to female at infancy had feminine typical core gender identity, although at the time of publication all children were too young to assess sexual orientation or other aspects of sexual functioning. Meyer-Bahlburg reviewed published reports of female-raised 46 XY patients with penile agenesis, cloacal exstrophy, or penile ablation. A significant proportion of patients reassigned female converted to male. In contrast, all the male raised patients were living as males with only one report of gender dysphoria. The differences in gender outcome were significant between male-raised and female-raised patients in each age category as well as for the entire sample.35 Reiner published the Johns Hopkins experience with 16 genetic males with cloacal exstrophy in 2004. Of the 16 patients, 14 were assigned female at birth, legally, socially, and surgically by means of orchiectomy and construction of vulvae. Two patients were reared as male secondary to parental refusal for female sex reassignment. Of the 14 female reassigned genetic males, 5 were identified as female, 8 as male (including 6 who had converted to male identity), and 1 patient who refused to discuss sexual identity. The results of this study implicate prenatal androgens as a major biological factor in the development of male sexual identity. In conclusion, Reiner and Gearhart36 suggested that children born genetically and hormonally male may identify themselves as male, regardless of female sex reassignment and rearing. Reiner and Kropp37 also reported a 7-year experience with 18 genetic males with severe phallic inadequacy. All patients demonstrated marked male-typical behaviors and interests. Of the 17 living patients, 10 live as males, 6 as females, and 1 refused to declare sexual identity. These findings suggest that males with severe phallic inadequacy reared as male and those reared as females but later converting to male have the potential for functional psychosocial outcomes. Those reared as female have a realistic likelihood of recognizing male identity and converting to male. Those remaining in female identity may have less successful psychosocial outcomes.37 Unlike other children with a DSD diagnosis, patients with cloacal exstrophy are thought to have normal testicular function. Testes which function normally prenatally, producing normal amounts of masculinizing hormones may initiate sex-specific changes in neural networks, and hence sex-typed behaviors. Not all studies of female assigned 46,XY patients with severe genital ambiguity have resulted in discordant gender outcomes. A recent study by Mukherjee et al,38 which compared psychological functioning in sex-reassigned vs nonassigned patients with cloacal exstrophy found that all patients maintained good psychological functioning. Significant differences were found in the area of depression and XY females demonstrated more male-typical gender behavior. The authors concluded that cloacal exstrophy patients can have remarkably well-adjusted lives provided they receive appropriate support. Most patients with congenital micropenis were satisfied with their gender regardless of

the sex of rearing. In contrast, only 50% of the men and 20% of women were satisfied with their overall sexual function.31 Another area of interest relates to the perception of genitalia and the resultant gender identity in children with complex genital anomalies. Long-term follow-up of case studies have suggested that boys with genital anomalies develop male gender identities in the absence of typical male-appearing genitalia.39

Outcomes of Disorders of Sex Development Patients With Partial Androgen Insensitivity, Androgen Biosynthetic Defects, or Incomplete Gonadal Dysgenesis
The most challenging group of DSD patients are those born with disorders in which the prenatal androgen influences are partial and difficult to quantify, or those whose diagnosis is unknown (Figs. 1B-D). Reiner examined 84 pediatric patients from a pediatric psychosexual clinic comparing the sex of rearing to self-declared gender identity. Of the 73 patients with DSD and a Y chromosome, 60 were raised as female, and more than half (53%) of these patients later declared male identity. Of the total 84 patients, 69 were raised as female, but only 32 lived as female, whereas 29 lived as male. All 15 patients reared as male lived as male including 2 genetic females with CAH. Reiner concluded that in the presence of active prenatal androgen effects, the likelihood of recognition of male identity increases dramatically, independent of sex of rearing.40 In a recent study, Jurgensen et al evaluated the gender-related play preferences, activities, and interests of 33 prepubertal children with 46,XY karyotype and DSD with varying degrees of prenatal androgen exposure compared with same-age children without DSD. The DSD children were grouped into those with complete hypoandrogenization (eg, complete androgen insensitivity syndrome, complete androgen biosynthesis defect) of which all were raised as girls, and those with partial hypoandrogenization, of which 12 were raised as boys and 15 as girls. The authors demonstrated a correlation of behaviors with the degree of presumed prenatal androgen exposure on the basis of the patient's diagnosis. They also found that despite the fact that children with partial androgen effects reared as girls demonstrated increased boyish behavior, they did not demonstrate increased signs of gender identity instability.41 There is very limited long-term follow-up in adult patients with DSD. Outcomes of these individuals with regard to sexual behavior, sexual orientation, and gender identity are anecdotal at best.42 Migeon et al43 reported long-term follow-up in a cohort of 46,XY individuals with severe genital ambiguity raised as male or female. Most participants were exclusively heterosexual with concordant gender identifications. Successful longterm outcomes can result from either male or female sex of rearing in 46,XY individuals, although a significant proportion of patients (23%) were dissatisfied with their sex of rearing. Interestingly, there are a higher number of female to male gender changes (with the exception of CAIS) in all DSD conditions than would be expected on the basis of prevalence of female-to-male transsexualism, which is estimated to be 1:20 000 to 1:30 000 women in the general population.44 Despite these findings, the greater majority of DSD patients develop a gender identity to match their gender of rearing, implicating the

sex of assignment as the best predictor of adult gender identity.45

Current Recommendations
The best possible policy regarding recommendations for the most appropriate gender identity in children with DSD must strike a careful balance between the information we have regarding the potential biological effects, which influence long-term gender identity, and the ability of the individual to eventually decide his or her own outcome. In addition, factors such as potential fertility should also be considered. The degree of genital masculinization does not necessarily correlate with the degree of masculinization of the brain; the gender assignment of a newborn with complex genital anomalies should not be based solely on the appearance of the genitalia at birth. The possible effects of prenatal steroid exposure, the clinical presentation of the child, and our best predictors of future psychosocial and psychosexual outcomes must guide the clinician.46 In addition, assurance of the family's understanding of the child's condition is important, as is their understanding that gender role behavior will evolve as the child grows. Ideally, all these guidelines for sex determination are best established for each patient in a multidisciplinary clinic, which includes pediatric psychiatry, pediatric endocrinology, and pediatric urology. Although assembly of such a specialized clinic may encounter issues with professional commitment in the face of financial constraints, by using fair and equal communication and participation of all members, our institution has experienced great success in maintaining a DSD multidisciplinary clinic, which provides expert opinions and treatment guidelines for many DSD patients and their families. Such a clinic allows all the practitioners and family members to come to a consensus in which all involved are comfortable and consistent. When a specific diagnosis it reached, recommendations for gender identity can be made based on the aforementioned outcomes data. Some general guidelines are mentioned later in the text and summarized in Table 1, but it should be remembered that each DSD patient is unique, and as such, they should be treated with individualized care, preferably with a multidisciplinary approach as stated earlier.

Table 1. Recommendations for gender assignment by DSD diagnosis D i a g n o s i s 4 Sex Projected Gender Assignme Identity nt Level of Evidence

6 , X X D S D C A H 4 6 , X Y D S D 5 R e d u c t a s e 2 d e f i c i e n c Male or female Unknown III [25] , [26] and [48] Female Female III [23] , [45] and [47]

y 1 7 H y d r o x y s t e r i o d d e h y d r o g e n a s e 3 d e f i c i e n c Male or female Unknown III [25] , [26] and [48]

y C o m p l e t e a n d r o g e n i n s e n s i t i v i t y s y n d r o m e D Male or female Unknown III [37] , [38] , [39] and [40] Female Female III [27] , [28] and [46]

i s o r d e r s o f i n c o m p l e t e o r u n k n o w n a n d r o g e n s y n

t h e s i s o r a c t i o n : P a r t i a l a n d r o g e n i n s e n s i t i v

i t y

A n d r o g e n b i o s y n t h e t i c d e f e c t s

I n c o m

p l e t e g o n a d a l d y s g e n e s i s

4 6 , X Y w i t h s e v e r e

Male

Male

III32-34,36

g e n i t a l a n o m a l y

M i c r o p e n i s

A b l a t i o p e n i

C l o a c a l e x s t r o p h y

O v o t e s t i c u l a r D S D

Male or female

Unknown

III47

Level I: Evidence obtained from at least one properly designed randomized controlled trial. Level II-1: Evidence obtained from well-designed controlled trials without

randomization. Level II-2: Evidence obtained from well-designed cohort or case-control analytic studies, preferably from more than one center or research group. Level II-3: Evidence obtained from multiple time series with or without the intervention. Dramatic results in uncontrolled trials might also be regarded as this type of evidence. Level III: Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees. Level of evidence according evidence-based medicine system of stratifying quality of evidence developed by the US Preventive Services Task Force, defined as follows:

A majority of 46,XX patients with CAH raised as female develop female gender identity with few cases of gender dysphoria.23 Thus, 46,XX CAH patients diagnosed within the neonatal period should be raised as female; those with delayed diagnosis may present a more complex dilemma requiring thorough input from an experienced multidisciplinary team. All patients with CAIS assigned female at birth also identify as female, and there is a universal agreement of female sex assignment in these patients.48 5-Reductase-2 deficiency and 17-hydroxysteriod dehydrogenase-3 deficiency are more difficult. In the past, individuals with 5-reductase-2 deficiency and 17-hydroxysteriod dehydrogenase3 deficiency are often raised as females. During adolescence and adulthood, more than 60% of patients with 5-reductase-2 deficiency and 40%-60% of patients with 17hydroxysteriod dehydrogenase-3 deficiency who are assigned as female at birth convert to male sex.27 When these disorders are diagnosed at infancy, the potential for eventual male gender identification and the unknown prospects of fertility must be discussed with the family. These families require significant counseling and medical teaching before sex assignment is determined. The most difficult group of patients for sex assignment are individuals with partial androgen insensitivity, androgen biosynthetic defects, or incomplete gonadal dysgenesis, as almost 25% of these patients report dissatisfaction with being raised as male or female.43 Patients with micropenis should be raised as males, as this would obviate the need for hormonal replacement and feminizing genitoplasty in addition to the potential for fertility.48 In addition, a study of 20 patients with micropenis demonstrated an inarguable establishment of male role by all patients as well as the establishment of successful sexual relationships.48 46,XY patients with cloacal exstrophy have been raised as female in the past, but recent studies suggest a variable outcome with regard to gender identity, with more than 60% of patients assigned as female converting to male gender, as observed in a study.35 In patients with mixed gonadal dysgenesis, prenatal androgen exposure, internal ductal anatomy, gonadal function and location, and phallic appearance must all be considered when deciding on sex assignment. Finally, the guidelines for sex assignment in ovotesticular DSD should include assessment of potential for fertility secondary to the extent of gonadal differentiation and phenotypic genital appearance.49 In addition to decisions regarding the ultimate gender assignment in complex DSD patients, the management of the dysgenetic gonad should also be addressed. The highest risk for malignant transformation is associated with the presence of testis-specific protein Y encoded in patients with pure gonadal dysgenesis or in patients with partial androgen

insensitivity syndrome and intra-abdominal gonads.50 Steps to ensure adequate surveillance and triggers for early intervention are warranted. A prospective, multi-institutional study with a cohesive registry of all DSD patients is the next step in finding answers to many questions raised in this review. A systematic followup inclusive of accessing postoperative outcomes in terms of sexual function as well as use of validated questionnaires to fully document the psychosexual development of these individuals is paramount.

Conclusions
Gender assignment in infants born with a disorder of sex development remains only one of the many difficult decisions faced by both the treatment team and the family. Fundamental to the decision-making process is prompt attention to the clinical needs of the patients and facilitation of a timely diagnosis, preferably using a multidisciplinary team approach. Solid evidence for the hormonal influence on central nervous system development with regard to sexual behavior is evident, but existing outcome studies are largely anecdotal and contradictory. Improved long-term follow-up of these patients will provide much needed feedback on previous and contemporary management. As concepts of gender identity continue to evolve, so will the accepted perspective of treatment of these conditions.

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