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Sex assignment in cases of ambiguous genitalia and its outcome

      Every parent approaches the impending arrival of a child with the expectation that this child will be “perfect” and will be either a boy or a girl. If the unexpected dilemma of sexual ambiguity is interjected into this idyllic expectation, parents are thrown into a quagmire of uncertainty and doubt that is emotionally unsettling for them and, potentially, for the child as well. The physician responsible for managing this crisis has the weighty duty of advising distraught parents about the “best” treatment for their child now and for the future.
      Current practice has based these decisions on an amalgam of factors, including genetic sex, phenotypic sex, and the therapy thought most likely to result in sexual function and fertility (if possible). It is the potential for sexual function that engenders, in some circumstances, the greatest degree of uncertainty, as there are few data on which to base a judgement. These uncertainties have produced controversy, in part because of the lack of data, and also because some of the extant data has been challenged.
      • Schober J.M.
      Long-term outcomes and changing attitudes to intersexuality.
      This review of the available data will, we hope, synthesize what is known and aid clinicians in the performance of their duty—primum non nocere (first do no harm).

      Current concepts

      There are at least two schools of thought regarding the sex assignment and treatment of infants with ambiguous genitalia. Money and associates
      • Money J.
      • Hampson J.G.
      • Hampson J.L.
      Hermaphroditism recommendations concerning assignment of sex, change of sex and psychologic management.
      ,
      • Money J.
      Psychology of intersexes.
      have long recommended a proactive approach in which prompt decisions are made, gender-specific role playing is encouraged, and early, aggressive surgical therapy, if indicated, is instituted in an attempt to unambiguously identify the child with the chosen sex of rearing. Proponents of this school postulate that it is not the genetic sex or in utero exposure to androgens that is most responsible for sexual identity, but, rather, the gender-specific social context in which the child is raised, coupled with the defining characteristics of the child’s external genitalia, that are the most important elements in achieving ultimate satisfaction in psychosexual function. Their publications include case reports to support their thesis.
      • Money J.
      • Hampson J.G.
      • Hampson J.L.
      Sexual incongruities and psychopathology the evidence of human hermaphroditism.
      ,
      • Money J.
      • Devore H.
      • Norman B.P.
      Gender identity and gender transposition longitudinal outcome study of 32 male hermaphrodites assigned as girls.
      ,
      • Money J.
      • Norman B.P.
      Gender identity and gender transposition longitudinal outcome study of 24 male hermaphrodites assigned as boys.
      In sharp contrast, Diamond and Sigmundson
      • Diamond M.
      • Sigmundson K.
      Management of intersexuality guidelines for dealing with persons with ambiguous genitalia.
      have argued that irreversible decisions regarding sex assignment should not be made by parents or physicians in the newborn period and should definitely not include major surgery. These authors believe that the ultimate sexual identity will depend not on the appearance of the external genitalia but, rather, on how the central nervous system eventually dictates a sexual identity to the individual.
      • Diamond M.
      • Sigmundson K.
      Management of intersexuality guidelines for dealing with persons with ambiguous genitalia.
      This belief stresses the idea that the nervous system involved in adult sexuality is influenced by genetic and endocrine events that will most likely become manifest with or after puberty. Proponents of this school of thought further argue that refraining from surgical procedures until the patient is able to participate in the decision-making process is critical in terms of protecting the individual’s health rights. They support their thesis with anecdotal testimonials and evidence that at least one of Money’s case reports was incomplete.
      • Diamond M.
      • Sigmundson K.
      Sex reassignment at birth long-term review and clinical implications.
      Regardless of the approach chosen in treating a patient with ambiguous genitalia, all clinicians agree that the ultimate goal in any management strategy is to provide the framework for a child to develop into a well-adjusted, psychosocially stable individual who identifies with and is happy in the chosen sex.

      Classification of patients with ambiguous genitalia

      There are many classifications of patients with genital ambiguity, but for the purpose of this discussion, it seems best to divide patients into those with congenital and those with acquired problems. The former group includes 46 XX girls with virilization in utero (usually secondary to congenital adrenal hyperplasia), 46 XY boys who are undervirilized (hypospadias, cryptorchidism, microphallus, penile agenesis, cloacal exstrophy), and those with chromosomal and/or gonadal problems (mixed gonadal dysgenesis, true hermaphroditism). The latter group includes boys who sustained severe penile injury as a result of trauma (surgical, accidental, or nonaccidental).

      Initial evaluation

      Genital ambiguity is, for parents, one of the most distressing problems encountered at birth, largely because of the uncertainty it produces about the newborn’s most basic identity. The well-meaning physician or nurse often compounds this distress by making premature pronouncements about the infant’s sex. In cases of genital ambiguity, it is best if sex assignment is delayed until enough anatomic, endocrinologic, and karyotypic information is available to make a clinical diagnosis, the patient has been assessed by an experienced pediatric endocrinologist and an experienced pediatric urologist, and extensive discussions have been held with the parents. During this period, it is preferable if the baby is considered gender neutral. Hospital staff, friends, and family should avoid pink or blue signs and clothing. The child should be provided a gender-neutral name or naming should be delayed and the child in the interim referred to simply as “baby.”
      Ideally, genital ambiguity will be treated by a multidisciplinary team that includes pediatric endocrinology, pediatric urology, general pediatrics, and child psychiatry. Early interviews with the family should be carried out by members of the team who will be responsible for long-term follow-up so that a personal relationship with the family can be initiated and maintained. Initial comments should focus on explaining, as Money advised, that nature did not complete the differentiation of the genitalia and that tests are being done to help with sex assignment.
      • Money J.
      • Hampson J.G.
      • Hampson J.L.
      Hermaphroditism recommendations concerning assignment of sex, change of sex and psychologic management.
      ,
      • Hastings D.W.
      Counseling in genital abnormalities.
      Cautious reassurance can be given to the family that with modern medical and surgical therapy, along with ongoing counseling, most of these children can grow up well-adjusted and psychosexually stable.

      Investigation

      The history and physical examination provide the foundation for developing a differential diagnosis. A family history of genital ambiguity, infertility, or unexplained infant death may point to certain diagnoses. Maternal exposure to exogenous hormones or a history of maternal ovarian tumors during pregnancy can be pertinent. A palpable gonad is almost always a testis. The uterus, if present, is often palpable on rectal examination. The phallic stretched length should be noted, as should the location of the urethral orifice. The location of a vaginal orifice, if present, should be sought. The variability of phenotypes within each of the intersex categories cautions against sex assignment until a diagnosis has been established with relative certainty.
      Karyotypes must be obtained on all patients with ambiguous genitalia. Biochemical assays are necessary to diagnose and treat patients with congenital adrenal hyperplasia.
      A genitogram should be obtained in all cases of ambiguous genitalia by injecting contrast material retrograde from the perineal urogenital orifice toward the bladder. Ultrasound can demonstrate a uterus and, often, gonads. Imaging studies alone will not secure a diagnosis; however, these studies are often indispensable in terms of planning sex-assignment surgery.
      Despite the above, some intersex states require open or laparoscopic exploration with gonadal biopsy to establish a definitive diagnosis. It is rare that sex assignment must await definitive pathologic diagnosis, however.

      Goals of sex assignment

      The ultimate goal in any management strategy is to provide a framework that will allow the affected child to develop into a well-adjusted, psychosocially stable individual who identifies with and is happy in the assigned sex. Instrumental in reaching these goals is the recognition by the family that any treatment strategy may fall short of creating an absolutely normal child. Hence, long-term counseling and support for the patient and family are sometimes necessary in the development of a stable sexual identity.
      • Slijper F.M.E.
      • Drop S.L.S.
      • Molenaar J.C.
      • et al.
      Long-term psychological evaluation of intersex children.

      Factors involved in sex assignment

      Age at presentation

      Sexual identity is thought to be largely a conditioning process that is firmly established by 2 years, 6 months of age.
      • Money J.
      Psychology of intersexes.
      For this reason, any attempt to change the sex of rearing beyond this age should be undertaken only when the initial sex assignment has clearly been wrong, and psychiatric assessment unequivocally indicates that sex reassignment is in the best interest of the child; ongoing psychiatric support will be necessary. Studies have shown a higher incidence of gender maladjustment when sex reassignment has taken place in later childhood.
      • Money J.
      • Hampson J.G.
      • Hampson J.L.
      Sexual incongruities and psychopathology the evidence of human hermaphroditism.
      ,
      • Money J.
      • Devore H.
      • Norman B.P.
      Gender identity and gender transposition longitudinal outcome study of 32 male hermaphrodites assigned as girls.

      Brain virilization

      There is increasing evidence that androgen imprinting of the fetal brain may play a role in determining an ultimately male sexual orientation. The effects of androgens on the fetal brain is a current topic of extensive research. Reiner
      • Reiner W.G.
      Sex assignment in the neonate with intersex or inadequate genitalia.
      argues that the organ most critical to psychosexual development and adaptation is not the external genitalia but the brain. Diamond and Sigmundson
      • Diamond M.
      • Sigmundson K.
      Management of intersexuality guidelines for dealing with persons with ambiguous genitalia.
      further postulate that the effect of androgen exposure on the developing brain may be the strongest predictor of ultimate sexual identity. Clinical and research studies lend some support to these concepts. Reports have suggested that girls with congenital adrenal hyperplasia are more tomboyish in their behavior than normal girls and may exhibit an increased trend toward homosexuality.
      • Money J.
      • Schwartz M.
      • Lewis V.
      Adult erotosexual status and fetal hormonal masculinization and demasculinization 46 XX congenital virilizing adrenal hyperplasia and 46 XY androgen-insensitivity syndrome compared.
      Studies in rats reveal a male mating behavior in genetically normal females exposed to androgens perinatally.
      • Ward I.L.
      • Renz F.J.
      Consequences of perinatal hormone manipulation on the adult sexual behavior of female rats.
      McFadden
      • McFadden D.
      Sex differences in the auditory system.
      and McFadden and Pasanen
      • McFadden D.
      • Pasanen E.G.
      Comparison of the auditory systems of heterosexuals and homosexuals click-evoked otoacoustic emissions.
      have shown that otoacoustic emissions produced by the cochleas show a marked sex difference. McFadden’s research suggests that the difference seen between sexes is dependent on the amount of in utero androgen exposure and, for this reason, may have some potential clinical utility in the assessment of the degree of masculinization of the brain.
      • McFadden D.
      A masculinizing effect on the auditory systems of human females having male co-twins.

      Overvirilization

      Most girls with congenital adrenal hyperplasia are assigned a female sex of rearing at birth, regardless of the degree of virilization present. These girls, with good steroidal management, are fully functional as females after reconstruction, require no exogenous estrogens, and are potentially fertile.
      • Hurtig A.L.
      • Radhakrishnan J.
      • Reyes H.M.
      • et al.
      Psychological evaluation of treated females with virilizing congenital adrenal hyperplasia.
      The same can be said for girls virilized by exogenous androgens or maternal ovarian tumors, except that they do not require exogenous steroids. Long-term outcome studies would suggest that, in most instances, surgery is successful in producing anatomy that is appropriate to the female sex and allows for satisfactory sexual function.
      • Hurtig A.L.
      • Radhakrishnan J.
      • Reyes H.M.
      • et al.
      Psychological evaluation of treated females with virilizing congenital adrenal hyperplasia.
      ,
      • Allen L.
      • Hardy B.G.
      • Churchill B.M.
      The surgical management of the enlarged clitoris.
      It is our, admittedly anecdotal, experience that family stress is greatly reduced if this surgery is performed early in infancy. Moreover, it has been shown that early sex assignment leads to a high likelihood of producing a girl secure in her own femininity.
      • Slijper F.M.E.
      • Drop S.L.S.
      • Molenaar J.C.
      • et al.
      Long-term psychological evaluation of intersex children.
      ,
      • Allen L.
      • Hardy B.G.
      • Churchill B.M.
      The surgical management of the enlarged clitoris.
      ,
      • Vates T.S.
      • Fleming P.
      • Leleszi J.P.
      • et al.
      Functional, social, and psychosexual adjustment after vaginal reconstruction.
      In the rare instance in which the patient with congenital adrenal hyperplasia has been erroneously raised as a male because of fully masculinized external genitalia, treatment decisions are less straightforward. Even though exogenous testosterone will be necessary, testicular prostheses will need to be placed, and the patient will be infertile, psychosocial development seems best achieved by continuing in the male role
      • Lee C.K.
      • Hanna M.K.
      • Brock W.A.
      • et al.
      Complete virilization in 46 XX females with congenital adrenal hyperplasia a series of 4 cases.
      ; however, few data are available to support this assumption.

      Undervirilization

      Boys with severe hypospadias, especially if associated cryptorchidism is present, may also raise questions regarding sex assignment. Here, the choice of the sex of rearing is clearly toward the male. Cryptorchidism and hypospadias are both reconstructible, and fertility is theoretically a possibility. Several long-term studies have been done that attest to the efficacy of repair of both hypospadias and cryptorchidism.
      • Mureau M.A.M.
      • Slijper F.M.E.
      • van der Meulen J.C.
      • et al.
      Psychosexual adjustment of men who underwent hypospadias repair a norm-related study.
      ,
      • Berg R.
      • Svensson J.
      • Astrom G.
      Social and sexual adjustment of men operated for hypospadias during childhood a controlled study.
      ,
      • Svensson J.
      • Berg R.
      Micturition studies and sexual function in operated hypospadiacs.
      ,
      • Bracka A.
      Sexuality after hypospadias repair.

      Karyotypic ambiguity

      Children with mixed gonadal dysgenesis (most commonly XY/XO karyotype) or true hermaphroditism are generally assigned a sex of rearing on the basis of the surgical possibilities imposed by their own anatomy. Those who have a testis, or an ovary, have some hope of fertility.
      • Tegenkamp T.R.
      • Brazzell J.W.
      • Tegenkamp I.
      • et al.
      Pregnancy without the benefit of reconstructive surgery in a bisexually active true hermaphrodite.
      ,
      • Mayou B.G.
      • Armon P.
      • Lindenbaum R.H.
      Pregnancy and childbirth in a true hermaphrodite following reconstructive surgery.
      If a testis is present and an adequate phallus with normal erectile function can be constructed, a male sex of rearing would seem appropriate. Similarly, if an ovary, uterus, and vagina are present, a female sex of rearing would seem most appropriate. Unfortunately, there are no long-term data to address the success or failure of these endeavors. In patients in whom fertility is not a potential, the sex of rearing has been influenced largely by the belief that one is more likely to be surgically successful producing a male only if an adequate phallus provides the basis for reconstruction. By default, if an adequate phallus is not present, it will be more likely that a functional vagina can be constructed. Once again, no long-term data are available to address the success or failure of this approach.

      Inadequate phallic length

      Another group of children in whom the sex of rearing is an issue is boys who are born with an absent or inadequate phallus (penile agenesis, microphallus, and cloacal exstrophy). The penile stretched length in infancy is the best predictor of adult penile size.
      • Danish R.K.
      • Lee P.A.
      • Mazur T.
      • et al.
      Micropenis. II. Hypogonadotrophic hypogonadism.
      Boys with a microphallus are undervirilized either because inadequate testosterone was produced in utero or because the tissues could not respond.
      • Aaronson I.A.
      Micropenis medical and surgical implications.
      Some boys have intracranial defects that render them severely developmentally delayed, as well as undervirilized. In these boys, psychosocial development will not be an issue, and the sex of rearing should parallel the genotypic sex. If testosterone is given to the infant with a microphallus, the penis will often respond with growth into the normal range.
      • Guthrie R.D.
      • Smith D.W.
      • Graham C.B.
      Testosterone treatment for micropenis during early childhood.
      Although Husmann and Cain
      • Husmann D.A.
      • Cain M.P.
      Microphallus eventual phallic size is dependent on the timing of androgen administration.
      have questioned this practice on the basis of data from rats, the data of Reilly and Woodhouse
      • Reilly J.M.
      • Woodhouse C.R.J.
      Small penis and the male sexual role.
      would suggest that the penis of boys with a microphallus who are given testosterone in infancy will be adequate after puberty. It has been documented that adult men with a microphallus function adequately sexually
      • Reilly J.M.
      • Woodhouse C.R.J.
      Small penis and the male sexual role.
      but may have psychological problems. The only groups in whom sex reassignment might be considered are those who do not respond to testosterone, those with cloacal exstrophy,
      • Husmann D.A.
      • McLorie G.A.
      • Churchill B.M.
      Phallic reconstruction in cloacal exstrophy.
      and those with penile agenesis. In cloacal exstrophy and penile agenesis, androgen imprinting is a factor to consider; however, in those with a microphallus unresponsive to testosterone, this may not be a factor. Unfortunately, no data are available to guide the clinician.

      Phallic trauma

      Finally, there is a small group of boys who have sustained traumatic injury to the penis early in childhood, usually as a result of a complication of circumcision. In these cases, the penis could not be adequately reconstructed. In several such instances, gender conversion was accomplished, but the limited long-term data available cast significant doubt on the efficacy of this approach.
      • Diamond M.
      • Sigmundson K.
      Sex reassignment at birth long-term review and clinical implications.
      It would seem, therefore, that in these boys with penile trauma and also in boys with cloacal exstrophy and penile agenesis, the surgical construction of a neophallus, as described by Gilbert et al.,
      • Gilbert D.A.
      • Jordan G.H.
      • Devine C.J.
      • et al.
      Phallic construction in pubertal and adolescent boys.
      may portend the best chance of success. Unfortunately, once again, no long-term data are available to support this method of treatment.

      Conclusions

      Parents of children with ambiguous genitalia are faced with the daunting task of deciding for their child an appropriate sex of rearing. This decision can be emotionally draining, and one that, regardless of outcome, is likely to be revisited by these parents for years to come. It is hard to imagine a more socially stressful concern for a family than how to inform friends and relatives that the sex of their newborn child is “to be determined.” It is for these reasons that physicians must counsel parents appropriately and assist them in making an expeditious decision.
      Fortunately, most cases of ambiguous genitalia are relatively straightforward in terms of the sex assignment. The most difficult decisions rest in deciding when it is appropriate to reassign a poorly virilized, genetic male to a female sex of rearing and when it is appropriate to attempt to masculinize such a patient. Such sex-assignment treatment protocols are emotionally charged endeavors, as clinicians acknowledge the scattered case reports of psychosocial maladjustment in individuals treated surgically for ambiguous genitalia. Nevertheless, there is a growing body of reports supporting the adequate adjustment made by most patients treated in early infancy with ambiguous genitalia. These data reveal that successful treatment strategies are predicated on early, effective communication between motivated and educated parents and dedicated, specialized health care personnel. In addition, increased understanding of the factors involved in sexual identity along with refinement of surgical techniques have been instrumental in providing acceptable outcomes in sex-assignment decisions.
      It is apparent in the published reports, however, that there is a lack of long-term outcome studies on patients treated with ambiguous genitalia. Details concerning adult sexual function in patients treated with feminizing or masculinizing surgery are still scant. Pediatric urology has passed from the era in which diseases were described and procedures for their diagnosis and treatment were developed. We now are entering on an era in which the long-term results of these endeavors must be reported so that diagnosis and treatment can be evaluated, refined, and improved. The treatment of sexual ambiguity is definitely an area in which long-term follow-up data are needed.

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