Whether or not the etiology of the genital ambiguity can be determined, a sex of rearing must be elected (1). Ideally, we believe that the sex of rearing for newborns who present with ambiguous genitalia should be decided within the first 3-4 weeks of life. Sex assignment or reassignment later in childhood is difficult for both the child and the child’s family (50, 51). We also believe that the final choice of sex assignment should be made by parents after receiving recommendations and education from the medical team. The role of this team (pediatric endocrinologist, pediatric surgeon, geneticist, psychologist and others) is to inform parents about the process of sex determination and differentiation, and the specific abnormality (when known) that affects their child (1). As knowledge concerning the long-term outcome of people affected by DSD is obtained, this too must be shared with parents (1-3, 21, 25, 28, 29, 32, 52-62). The following recommendations for assigning a sex of rearing apply to infants who present as newborns with ambiguous genitalia (1).
As noted earlier, masculinization of newborns with a 46,XX chromosomal complement is usually a result of CAH and rarely results from exposure to androgenic substances transferred from the mother to the fetus. The most common etiology of ambiguous genitalia in genetic females is CAH due to 21-hydroxylase deficiency (40). Masculinization due to 21-hydroxylase deficiency does not impair the development of the ovaries or the Müllerian ducts. Historically, female sex of rearing has been recommended for this group as most develop a female gender identity/role (53-55) and female assignment allows for future fertility potential. However, actual fertility rates in women affected by 21-hydroxylase deficiency are low (63) and tomboyism is more common in girls with 21-hydroxylase deficiency compared to their unaffected siblings (53-55). Very little is known about the medical and psychosexual outcome of 46,XX newborns affected by 21-hydroxylase deficiency and raised male. For this reason, female sex of rearing is recommended for even the most severely masculinized 46,XX newborns affected by 21-hydroxylase deficiency (64).
Generally, people believe that the so-called “sex chromosomes” indicate a person’s “true sex” and laws exist, to the detriment of some individuals affected by DSDs, to support this idea (49). Scientifically speaking, it is clear that the majority of genes on the X chromosome do not influence sex development and differentiation, although the AR gene is necessary for normal phenotypic masculinization. Concerning the Y chromosome, only the SRY gene contributes to testicular formation. In fact, most of the genes required for normal sex development and differentiation are found on the autosomes (1). As such, a 46,XY chromosomal complement does not necessarily dictate female sex of rearing in newborns affected by 46,XY DSDs.
Newborns presenting with a 46,XY chromosome complement and normal-appearing, female external genitalia due to complete androgen insensitivity syndrome (CAIS), complete gonadal dysgenesis (Swyer syndrome) or other complete abnormality of testosterone biosynthesis function successfully when assigned a female sex of rearing. Female assignment in such cases is widely accepted by patients throughout their lives despite challenges that they experience regarding sexual dysfunction and infertility (1, 21, 37, 56).
A second category of 46,XY DSD in which a particular sex of rearing is optimal is in cases of micropenis without hypospadias. While individuals with congenital micropenis can accept either a male or female sex of rearing, female assignment is complicated by feminizing surgery of the genitalia. In contrast, individuals reared male require no genital surgery and may attain an adult penile length within or close to the normal range following testosterone treatment. Thus, we recommend male sex of rearing for newborns with congenital micropenis (1, 28, 29, 57, 58).
Another category of 46,XY DSD in which male rearing is preferable is in newborns affected by 5α-reductase-2 or 17β-hydroxysteroid dehydrogenase deficiency (1, 31, 59, 60). At puberty affected individuals secrete normal male levels of testosterone and thus masculinize. In both conditions gender role frequently changes toward male in patients reared female (59). Additionally, future fertility potential exists for newborns raised male (1, 32).
The most difficult 46,XY DSD patients, in terms of recommending a sex of rearing, are those newborns with ambiguous external genitalia including a small phallus and perineo-scrotal hypospadias (25, 61, 62). In those cases genital surgeries are often required regardless of sex of rearing; therefore, consideration of factors beyond genital appearance must be evaluated when considering male or female rearing. Evidence-based information pertaining to satisfaction with sex of rearing, number and type of surgical procedures anticipated for male versus female assignment, future sexual function and the possibility for future fertility needs to be collected (1). Regarding satisfaction with sex of rearing, either male or female assignment is possible (25, 61, 62). In terms of the number of genital surgeries, female sex of rearing typically requires fewer procedures (25). People with 46,XY DSD report some problems with long-term sexual function whether they are raised male or female (23, 25, 31, 34). When judged by physicians, patients with ambiguous genitalia reared female show a superior cosmetic result of their genital reconstruction than their male counterparts. Despite these seeming advantages, 46,XY DSD patients raised female reported a similar degree of dissatisfaction with both the appearance and function of their genitalia compared to those raised male (25). Additional long-term outcome studies are needed to develop better medical and surgical treatment for newborns with ambiguous genitalia.
In all cases it must be understood that DSDs result in congenital malformations of the sex organs, and in many instances in malformations of other body systems as well, At this time, much can be done to ameliorate the adverse effects associated with DSDs. However, hormonal and surgical management do not result in perfection and cannot be considered cures. Hence, long-range medical, surgical and psychological support are required.