A Man’s Brain in an Ambiguous Body: A Case of Mistaken Gender Identity

In genetic XX females, an excess of any of three hormones usually present only in trace amounts can cause ambiguities. Congenital adrenal hyperplasia accounts for most female pseudohermaphroditism cases. All six congenital adrenal hyperplasia types involve enzymatic defects in the cortisol-synthesizing pathway. Cortisol provides negative feedback to ACTH in the hypothalamic-pituitary-adrenal axis. When cortisol is low, ACTH rises, stimulating increased adrenal androgen output. All six types share hypertrophied adrenal glands and excess production of cortisol precursors, all acting androgenically on developing fetuses.

The earlier the androgen exposure, the more masculinized XX fetuses become, with more extensive labioscrotal fusion, more penis-like clitorises, and a higher likelihood of urogenital sinus retention (4) . XX fetuses not exposed until the second trimester sustain only clitoromegaly, although brain organization may be affected. They are more likely to have homosexual fantasies and exhibit masculine characteristics of enhanced aggression and visuospatial ability, even while typically retaining core female gender identity (6) . In sum, internal genitalia are normal female; external genitalia and the brain have androgen-induced virilization (7) .

Whereas too much of any of three hormones—testosterone, dihydrotestosterone, or estrogen—can cause problems for females, the opposite is true for males. Insufficient androgen supplies yield ambiguous or frankly female bodies or brains (4) . Male pseudohermaphrodites have testes, but genitalia may be underdeveloped. Brains may masculinize incompletely, if at all. Causes include inadequate testosterone secretion with testicular dysgenesis, target tissue unresponsiveness to testosterone, or 5-alpha reductase deficiency, an enzyme defect yielding female-appearing fetuses with XY karyotypes.

Although CNS responsiveness to aromatized testosterone is intact and internal genitalia develop normally, the absence of 5-alpha reductase converting testosterone to dihydrotestosterone prevents external virilization (4, 7) . Born with clitoris-like micropenises, these children are often reared as girls until pubertal testosterone surges prompt penile growth. Male gender behaviors and sexual attraction to females may emerge at puberty. Transition from female child to male adolescent goes well in populations familiar with the condition, principally genetic isolates in the Dominican Republic, Turkey, and New Guinea (7) . The protagonist of Middlesex, Jeffrey Eugenides’s best-selling novel, likely had this condition.

Another male pseudohermaphrodite condition illustrates what happens when neither brain nor Müllerian tissue responds to testosterone. In complete androgen insensitivity syndrome, a testosterone-receptor gene defect underlies testosterone unresponsiveness in both brain and peripheral tissue. Externally, these individuals resemble normal females. Internally, their normal testes produce both Müllerian-inhibiting substance and testosterone, but they have neither male nor female structures otherwise. Müllerian-inhibiting substance facilitates resorption of Müllerian derivatives, but the testosterone-receptor defect prevents Wolffian structure formation. A primitive urogenital sinus replacing a vaginal pouch is usually insufficient for sexual penetration (4) .

Unless kindreds know they carry this X-linked condition, complete androgen insensitivity syndrome is not usually diagnosed until abdominal testes herniate or menarche fails to occur. A variant, partial androgen insensitivity syndrome, manifests in incomplete brain and body masculinization (4) .

Ambiguous genitals and masculine gender sensibility notwithstanding, our patient did not fall into the above pseudohermaphrodite categories. Her karyotype revealed another recognizable syndrome: gonadal dysgenesis (4) .

Occurring in complete and incomplete forms, gonadal dysgenesis anomalies range from completely undifferentiated streak gonads through varying degrees of dysgenesis (7) . Incomplete gonadal dysgenesis, also known as partial or mixed gonadal dysgenesis, includes either paired dysgenetic testes or a dysgenetic testis coupled with a streak gonad or a functional testis. Most common with mosaic 45,X/46,XY karyotypes, in which an individual has cells of both genotypes, mixed gonadal dysgenesis phenotypes extend from normal male to Turner female (4, 7) .

Gonadal histology, not chromosomes or external anatomy, distinguishes true hermaphrodites from pseudohermaphrodites. Unlike the latter, the former possess both ovarian and testicular tissue, either intermixed within gonads or as independent testis and ovary. Seminiferous tubules are typically atrophic, but well-developed ovarian follicles may retain reproductive potential (8) .

The rarest form of human intersexuality, true hermaphrodites, result from events as diverse as chromosomal nondisjunction, double fertilization, or Y-chromosome translocation (7) . Neither phenotypes nor karyotypes are predictable. Some appear male, others female, but most are ambiguous (4) . Sixty percent have 46,XX karyotypes; 20% are 46,XY. The remainder show mosaicism, typically of 45,X and 46,XY cell lines.

Mixed gonadal dysgenesis, likewise, expresses itself in a range of different phenotypes. The dysgenetic testes’ capacity for testosterone secretion defines the extent of fetal masculinization (4, 7) . Until 20 years ago, few reports existed of phenotypically normal males with mixed gonadal dysgenesis (9) . Subsequent investigators demonstrated dramatic ascertainment bias, hinging on defects obvious at birth. In a mixed gonadal dysgenesis case series diagnosed by amniocentesis, 75 of 76 newborns had male phenotypes, and 72 of 75 (95%) appeared completely normal (10) . Without amniocentesis, mixed gonadal dysgenesis would have gone undetected in most of these newborns.

Historically, infants with ambiguous genitalia have been at the mercy of medical fashion and societal demands for labeling sex at birth. Before the 1950s, chromosomes could not be factored into decision making. Technical limitations caused most children to be “made” into girls, given the purported surgical challenge of creating realistic—let alone functional—male organ facsimiles (11) .

Failure to impose a definitive gender in infancy was considered unethical and irresponsible, as was letting the growing child assert its own gender identity. Largely through the preeminence of John Money, the doctrine that nurture always trumps nature drove gender assignment in infants with ambiguous genitalia or genital trauma (11) . Clinical decision making within this “optimal gender” paradigm sought to balance 1) genital verisimilitude, 2) fertility potential, and 3) sexual function, emphasizing capacity for adequate penile-vaginal intercourse over neurovascular responsiveness or satisfaction. As long as caregivers enforced feminine accoutrements and expectations, “she” should not doubt “her” femaleness (12) . Ms. C was raised according to Money’s “optimal gender approach.”

Money held that a newborn assumed the parentally assigned gender through postnatal imprinting “by words, attitudes, and comparison of one’s body to that of others” (4) . He defined a “critical period for psychosexual differentiation and the imprinting of a gender role and psychosexual identification as male or female,” placing it between 18 months and 5 years, beyond which “a fixed and irreversible psychosexual identity [has] already [been] established” (13) . Before 18 months was “a period of unlimited freedom of choice,” with development unfolding normally in the assigned sex as long as surgery happened before core gender identity establishment (13) .

Identical male twins, individuals as similar as two humans can be, gave Money the ultimate opportunity to prove his nurture trumps nature theory. When a circumcision accident burned one of the 6-month-old’s penises irretrievably, Money advised castrating him and raising “her” as a girl alongside “her” identical brother. Known as “the Joan/John case,” this experiment had disastrous repercussions, with “Joan” exhibiting depression, oppositionality, male behaviors, and social maladjustment. As early as preschool, “she” would rip off “her” dresses or flatly refuse to wear them. In grade school, “her” anger at being treated like a girl fueled constant insubordinacy and fights with fellow students. Home life was no better, with parents torn over raising their disfigured, combative son relentlessly as a girl. In adolescence, “she” refused follow-up visits with Money, experiences “she” had always considered humiliating and degrading (14) .

At age 14, at the urging of “her” psychiatrist, Keith Sigmundson, “her” parents finally informed “her” of the botched circumcision and sex reassignment but not before “she” had undergone estrogen-induced puberty. Shortly afterward, “she” rejected whatever female vestiges remained and declared “herself” male. Adopting the name David, he embarked upon painful reconstruction of his maleness. Estrogen was discontinued, and testosterone prescribed, a necessity stemming from his orchiectomies in infancy. Years of surgeries, including mastectomies and numerous marginally successful phalloplasties, followed. He eventually married a woman and worked as a tradesman (14) .

Reporting that “Joan” had accepted female gender identity and was living contentedly as a girl, Money cited these results to justify gender reassignment in other genitally ambiguous infants. In the Archives of Pediatric and Adolescent Medicine, Diamond and Sigmundson (15) eventually described what had actually happened with “Joan,” underscoring the failure of the vigorously applied “optimal gender approach” and noting that even “Money no longer holds such extreme views.” The story did not end happily. Two years after his twin killed himself, David did also, dying in 2004 at age 38.

During the last decade, the approach to genitally ambiguous infants has dramatically changed. Reiner and Gearhart (16) further discredited the optimal gender approach as simplistic and reductionistic, given the complexity of neurobiological and psychosexual developmental (15) . With a catastrophic medical condition—cloacal extrophy—they showed that a high proportion of children with androgenized brains assert male core gender identity, regardless of absent male genitalia (16) . Endowed with XY chromosomes and normally functioning abdominal testes, these boys have severe congenital pelvic defects, including gastrointestinal and genitourinary malformations and absent genitals. Under Money’s theory, they were routinely orchiectomized and raised as girls. As with David, the Canadian twin, however, many rebelled against the female role and exhibited male-typical behaviors (16) .

Reiner and Gearhart followed 16 genetic males with cloacal exstrophy, all but two neonatally reassigned as girls. All 16 exhibited stereotypic male behaviors. By the study’s end, eight of the 14 “females” declared themselves male, some as early as age 5. Six of eight were transitioning to life as males. Although self-identified as males, two continued living as females in deference to their parents demanding that they not change. Five considered themselves females. One refused to discuss gender. Given these widely discrepant outcomes, Reiner and Gearhart advocated postponing definitive reassignment surgery until a child is old enough to declare a gender (16) .

Except in the broadest strokes, determinants of gender identity and sexual orientation remain largely unknown. Evidence continues to mount, however, from neuroimaging and neuroanatomical correlations that male and female brains differ. Whereas most humans have genitals agreeing with their self-identifications as male or female, myriad variations do occur. By age 2, most children can clearly name their core gender identity, which usually—regardless of eventual sexual orientation—agrees with chromosomal and phenotypic sex. Moreover, it is a sociocultural truism that most toddlers behave in ways recognizably masculine or feminine.

The “masculinized brain” construct encompasses the postulated effects of in utero testosterone and its estradiol metabolite (17) . Panksepp (5) described implications of mismatched soma and psyche for intersexed children: “If brain and body organization do not match up, the individual will have to discover through painful experience which gender was predominantly imprinted within his or her brain, and to what extent.” Distress intensifies if physicians and family favor visible anatomy over evidence of brain imprinting.

Critical periods for hormonal effects remain largely unknown, although brain differentiation continues throughout fetal life. Sex hormones have “organizational” effects on fetal brains, and “activational” effects are most prominent during pubertal hormonal surges (5) . The hypothalamic sexually dimorphic nucleus exemplifies differential neuroanatomic organization correlating with gender identity and sexual orientation. Males have larger, more cell-dense sexual dimorphic nuclei than females, and homosexual males have sexual dimorphic nuclei intermediate in size between males and females (18) . An activational example involves the anterior hypothalamus, which, measured by positron emission tomography, responds to male sweat pheromone similarly in heterosexual females and homosexual males. The hypothalamic response of heterosexual males and homosexual females to female urine pheromone is parallel (19) .

Correlations between hormonal influences, differences in male and female neuroanatomy and neurofunction, and variations in gender expression and sexual orientation continue to amass. Contemporary formulations acknowledge in utero organizational effects of sex hormones on sex-steroid responsive brain tissue, as well as pubertal activational influences on gender behavior and sexual object choice (3, 5) . In human psychosexual differentiation, however, nothing is absolute. Prenatal androgen exposure facilitates—but does not absolutely determine—male gender identity (4) . Although strongly supporting both organizational and activational influences of prenatal androgens on male gender development, the cloacal extrophy series of Reiner and Gearhart (16) includes self-identified males and females. The extent of atypical behavior does not reliably correlate with degree of virilization, however, thereby illustrating the lack of absolute outcomes for these children (6) .

Degree of brain masculinization appears to affect both sexual orientation and gender identity in individuals with partial androgen insensitivity syndrome, congenital adrenal hyperplasia, 5-alpha-reductase deficiency, and congenitally absent or traumatically lost penises. Failed brain masculinization sheds light on these issues in patients with complete androgen insensitivity syndrome. Given complete testosterone insusceptibility, the situation is straightforward. They show core female gender identity, typical female behaviors, and predominant sexual attraction to males.

For newborns with obviously ambiguous genitalia, a team approach to the workup “to minimize medical, psychological, and social complications” is recommended, with representatives potentially from genetics, endocrinology, urology, gynecology, psychiatry, and social services (20) . Endocrinological screening, karyotype, fertility potential, and external appearance may all factor into initial diagnosis and management. With congenital adrenal hyperplasia the most common cause of ambiguous genitalia, the American Academy of Pediatrics recommends endocrine screening for this disorder in infants with symmetrical external masculinization and nonpalpable gonads (20) .

Without palpable gonads, all four intersex subcategories—female pseudohermaphroditism, male pseudohermaphroditism, gonadal dysgenesis, and true hermaphroditism—are possible, although female pseudohermaphroditism is most common. With two palpable gonads, male pseudohermaphroditism is likely. One palpable gonad rules out female pseudohermaphroditism and pure gonadal dysgenesis and suggests a testis (male pseudohermaphroditism, mixed gonadal dysgenesis) or ovotestis (true hermaphroditism) because ovaries and streak gonads do not descend (7) .

Palpable gonads or a negative congenital adrenal hyperplasia screen mandates further exploration, including pelvic ultrasound seeking a muscular uterine body and a genitogram clarifying whether a vagina, a uterine canal, fallopian tubes, or vasa deferentia are present. Additional laboratory testing may identify testosterone biosynthesis blocks, decreased 5-reductase activity, or androgen insensitivity. Elevated luteinizing hormone and follicle-stimulating hormone levels accompanying nonresponse to human chorionic gonadotropin stimulation suggest the gonadal absence of pure gonadal dysgenesis. Gonadal biopsy reveals mixed gonadal dysgenesis, if present (7) .

Until recently, gonadectomy was immediate, particularly when children with ambiguous genitalia were routinely raised as girls. Although the potential for cancer remains concerning, surgery is no longer automatic. In recommending waiting as long as safely possible before definitive surgeries, ideally until the child can participate in decision making, Diamond and Sigmundson (15) advise “perform[ing] no major surgery for cosmetic reasons alone; only for conditions related to physical or medical health.” They also propose assigning sex “on the nature of the diagnosis rather than only considering the size of functionality of the phallus, respect[ing] the idea that the nervous system involved in adult sexuality has been influenced by genetic and endocrine events” (15) .

Protocol-driven approaches to gender assignment are increasingly eschewed because of limited or inconsistent outcome data about approaches tried for rare disorders (16) . Citing poor predictive power for adult gender identity in newborns with ambiguous genitalia, Houk and Lee (3) advocated doing as little as possible in early childhood, asserting that “the primary problem for transsexual and intersexed children seems to arise from society’s expectations and insistence that gender role and identity align with anatomic sex.”

Houk and Lee advocated individualized approaches as alternatives to optimal gender (3) . Prenatal hormone effects trump chromosomal analysis, which can serve only as a guide. Sexual pleasure is at least as important as genital morphology, and neurovascular supplies to sex organs making sexual responsiveness possible should not be sacrificed to early cosmetic procedures.

Situations nonetheless remain in which early gonadectomy remains the treatment of choice. In mixed gonadal dysgenesis, rudimentary gonads should be excised within the first year because Y-containing gonads most at risk of malignant degeneration are both dysgenetic and intra-abdominal, with more than 30% developing cancers, some as early as prenatally (8) . Histologically normal undescended testes become malignant at a lower rate and later age. Ideally, they should be relocated to the scrotum, with frequent ultrasounds for gonads left within the abdomen. In true hermaphrodites, ovarian tissue is more likely than testicular tissue to be normal. Dysgenetic testicular tissue can be removed, preserving mature female tissue and potential fertility when other reproductive organs are intact. Scrotal testes accompanying a large enough phallus support rearing as a male (8) . Gonads should not be excised before a clear diagnosis and malignant risk are ascertained.

Given the normal testes in complete androgen insensitivity syndrome, they may wait until puberty to permit testosterone conversion to the estradiol-facilitating spontaneous secondary sexual characteristic development. Because the cancer risk for normal abdominal testes rises from the second decade, however, orchiectomy should occur soon after puberty (8) . Children with complete androgen insensitivity syndrome may also require surgery to create a neovagina from the colon, although little is yet known about adult sexual function and satisfaction (21) .

Ultimate gender assignment decisions thus depend upon a constellation of factors: sexual and reproductive capacity, malignant potential, testosterone imprinting, and parental sensibilities. It also depends upon creating room for the growing child to assert gender identity. Early caregiver decisions on the infant’s behalf do not guarantee adult acceptance of assigned gender, as patients such as Ms. C demonstrate. When adults present with gender dysphoria, limitations of current knowledge make the extent of brain masculinization difficult to ascertain. If medical histories are unavailable, tests performed in infancy may need revisiting. Now readily available, karyotyping may offer dramatic explanations, as it did for Ms. C.

Some adult patients with severe dysphoria—transsexuals—have neither history nor objective findings supporting a known biological cause of brain-body disjunction. They require 1) a thorough medical history and physical examination, 2) potential karyotyping, 3) consideration of the degree of brain masculinization, and 4) a thorough psychiatric examination. Absent psychosis or severe character pathology, patients’ subjective assertions are presently the most reliable standards for delineating core gender identity.

Adults presenting today with gender dysphoria may not know the specifics of their medical histories. They may struggle—as our patient did—with an unassembled and incomplete puzzle of surgical scars and medical treatments hinting at something gone terribly awry. Psychiatrists must bring to bear all dimensions of the biopsychosocial model in making sense of the patient’s gender and sexuality.

Our case of mixed gonadal dysgenesis illustrates the value of a careful history and a thorough medical workup, even in midlife, in patients with gender and sexuality concerns. The diagnosis best fitting our patient was mixed gonadal dysgenesis with 45,X/46,XY mosaicism, brain masculinization, and phenotypic elements of Turner’s syndrome, including short stature and diabetes mellitus. Without pathological findings from tissue removed in infancy, it is impossible to know whether Ms. C was born a true hermaphrodite or a pseudohermaphrodite. Regardless, her history of ambiguous genitalia, coupled with aberrant chromosomes, contextualizes her masculine gender sensibility and sexual attraction to females.

Despite Ms. C’s sense of brain and body not matching, she did not want to alter her gender presentation. Knowing she had XY chromosomes, however, helped her to better accept her atypical gender behaviors and sexual attraction to women. The chromosomal findings also changed her diagnosis from gender identity disorder to gender identity disorder not otherwise specified, the classification applied to gender dysphoria in intersex conditions (2) .

Afflicted with a confluence of chromosomes, anatomy, and desires not addressed in scripture, Ms. C’s religious beliefs undermined her comfort with her sexual and gender fluidity until she embraced an intersexual identity. She accepted her iatrogenically modified body, but not without lingering questions.