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Developmental Endocrine Influences on
Gender Identity:
Implications for Management of Disorders of Sex Development
WILLIAM BYNE, M.D., PH.D.
Abstract
When a baby is born, the first medical pronouncement is usually, “It’s a boy,” or “It’s a girl.” In most cases, this pronouncement is
based simply upon the appearance of the child’s external genitalia. Due to variations in the process of sexual differentiation, some-
times the gender that should be assigned is not apparent from inspection of the external genitalia, either because they are “ambigu-
ous” or because their appearance is not congruent with the internal anatomy. Decisions must be made not only about the most
appropriate gender to assign the infant but also about the medical and rearing practices that will facilitate optimal psychological
development and quality of life for the affected individual. This article will review the approach to managing gender disorders that
has evolved since the 1950s. Three issues are identified as central to current shifts that are occurring in the management of these
disorders: (a) increased understanding of the biological substrates of gender identity; (b) questions regarding the indications for irre-
versible cosmetic genital surgeries as a means of reinforcing gender assignments in infancy, and (c) ethical issues pertaining to
informed consent and who is entitled to give it, particularly with regard to surgical gender reassignments in infancy. In keeping with
the neuropsychiatry theme of this issue, the focus of this article is on prenatal sexual differentiation of the brain as it pertains to the
question of psychosexual neutrality at birth.
Key Words: Intersex, sexual differentiation, sex assignment, gender assignment.
Introduction
P
ARTICULAR TERMS
may be defined differently by
various authors, so it may be helpful to begin by
defining those terms as they will be used here. Sex
will be used to refer to the biological variables that
can be described as either male or female (e.g.,
genes, chromosomes, gonads, internal and external
genital structures), while gender will refer to so-
cial categories (e.g., man or woman, boy or girl) or
factors related to living in the social role of a man
or a woman. Gender identity refers to one’s sense
of belonging to the male or female gender category
(1), while gender role refers to behaviors (manner-
isms, style of dress, activities etc.) that convey to
others one’s membership in one of those categories
(1). Sexual orientation refers to one’s pattern of
erotic responsiveness and will be described here as
androphilic (attracted to men), gynephilic (at-
tracted to women), or bisexual (attracted to both).
The course of normative development culmi-
nates in full concordance among all of the biolog-
ical variables of sex (i.e., either all male or all fe-
male). In intersex disorders, however, one or more
of those variables is discordant with the others or
its differentiation is intermediate between male
and female norms. Intersex became the preferred
term to encompass a variety of syndromes previ-
ously classified on the basis of gonadal histology
as true hermaphroditism in which both testicular
and ovarian tissue are present in a single individ-
ual, and pseudohermaphroditism in which only
one type of gonadal tissue is present. Due to dis-
agreements as to whether or not particular disor-
ders should be considered intersexed (2), the term
disorder of sex development is gaining currency to
refer to any congenital condition in which devel-
opment of chromosomal, gonadal or anatomical
sex is atypical (3). It has been estimated that a
child is born with external genitalia so noticeably
atypical that a specialist in sexual differentiation is
consulted about once in every 1,500–2,000 births.
This article deals primarily with that population,
whether or not all meet a particular authority’s de-
finition of intersex. For discussion of the defini-
tions and frequency of intersex, the reader is re-
ferred elsewhere (2, 4, 5).
950 ©THE MOUNT SINAI JOURNAL OF MEDICINE Vol. 73 No. 7 November 2006
Associate Professor, Department of Psychiatry, Mount Sinai
School of Medicine, New York, NY.
Address all correspondence to William Byne, M.D., Ph.D.,
Research Bldg, Room 2F39, Bronx VAMedical Center, 130 W. Kings-
bridge Road, Bronx, NY 10468; email: william.byne@mssm.edu
Vol. 73 No. 7 DISORDERS OF SEXUAL DEVELOPMENT—BYNE 951
Beginning in the 1950s, John Money and col-
leagues (6) observed that because intersexes are
neither completely male nor completely female
they “are likely to grow up with contradictions ex-
isting between the sex of assignment and rearing,
on the one hand, and various physical sexual vari-
ables, singly or in combination.” They collected
data on the psychosexual development of children
born with various intersex conditions in order to
determine whether their gender role and identity
were more likely to be concordant with the sex of
assignment and rearing, or with one or another of
the physical variables of sex. Of 105 intersexes
studied, only 5 had a gender role or identity that
was “ambiguous and deviant from the sex of as-
signment and rearing.” Thus, they concluded,
along with Ellis (7), that the sex of assignment and
rearing is a much better predictor of gender role
and identity than the biological variables of sex.
This evidence for the early malleability of gen-
der identity instigated a shift away from prior at-
tempts to assign gender to intersexed individuals
on the basis of gonadal histology or chromosomal
analysis. Instead an “optimal gender policy for
psychosocial and medical management” of inter-
sex conditions was developed (8, 9), aimed at op-
timizing their prognosis with respect to six vari-
ables: reproductive potential, sexual function, min-
imization of medical procedures, gender-appropri-
ate appearance, stable gender identity and psycho-
logical well-being. Although it was appreciated at
that time that intrauterine hormones might exert
sexually differentiating effects on the fetal brain, it
was widely accepted that the effects of nurture out-
weigh those of nature with respect to psychosexual
development. Prompt surgical normalization of ex-
ternal genital anomalies was, therefore, viewed as
necessary to establish the dominance of nurture
over nature. More specifically, external morphol-
ogy congruent with the assigned gender was
viewed as essential both to convince the affected
child that he/she was truly a member of the as-
signed gender and to convince the parents who
were responsible for unambiguously rearing the
child as a member of the assigned gender (8).
Compared to phalloplasty, vaginoplasty provides
better cosmetic and functional results, and a small
penis was believed to be a tremendous psychoso-
cial burden for a boy (8, 10). Thus, due to the be-
lief in the early malleability of gender, a majority
of intersexed infants with an absent or small phal-
lus were assigned as female regardless of the sta-
tus the other biological variables of sex. Even male
infants who were not intersexed but who had a
stretched phallus length of less than 2 cm were
sometimes reassigned as female (10).
Over the past half century, a variety of lines of
converging evidence—including follow-up studies
of intersexed individuals and non-intersexed indi-
viduals whose gender was surgically reassigned in
infancy—suggests that the organizing effects of
prenatal endocrine factors on the subsequent emer-
gence of gender identity is much stronger than pre-
viously thought (11–13). Consequently, the man-
agement of intersex disorders, particularly the ini-
tial gender assignment, is increasingly taking into
account exposure to these factors. Moreover, the
practice of performing cosmetic genital surgeries
on infants to reinforce gender assignments is cur-
rently being challenged on a variety of medical and
ethical grounds including the fact that these surg-
eries generally cannot be reversed if the affected
individual subsequently rejects the assigned gen-
der (14– 17). This article will begin by reviewing
the neurobiology of gender identity with an em-
phasis on the role of prenatal endocrine factors,
and will conclude by considering this information
in the broader context of shifts that are taking
place in the management of intersex and other dis-
orders of sex development.
Neurobiology and Gender Identity
Overview of Sexual Differentiation
Hormonal contributions to sexual differentia-
tion of the brain have been extensively reviewed
recently elsewhere (18, 19). Animal studies have
contributed substantially to the formulation of a
prenatal hormonal hypothesis for both sexual ori-
entation and gender identity. The prenatal hor-
monal hypothesis draws largely on the observation
that the balance between male and female copula-
tory and other reproductive behaviors in animals is
strongly influenced by the magnitude and timing
of early androgen exposure. In addition, anatomi-
cal sex differences in regions of the rodent brain
implicated in the regulation of these behaviors
have been found to have a similar developmental
hormonal dependence. The best studied of these
neuroanatomical sex differences, the sexually di-
morphic nucleus of the preoptic area (SDN-POA)
in rats appears to have a homologue in the primate
(20) and human (12, 21, 22) hypothalamus. The
human nucleus, known as the third interstitial nu-
cleus of the anterior hypothalamus (INHA3), is
larger in males than in females (12, 21, 22). It has
been reported to vary with sexual orientation such
that it is larger in gynephilic compared to an-
drophilic individuals (12). In addition, the size of a
portion of the bed nucleus of the stria terminalis
has been reported to be sexually dimorphic in rats
952 THE MOUNT SINAI JOURNAL OF MEDICINE November 2006
and humans, and to vary in humans as a function
of gender identity but not sexual orientation (13,
23). Specifically, the nucleus was reported to be
larger in individuals with a male as opposed to a
female gender identity, regardless of their genetic,
gonadal or hormonal status and regardless of the
direction of their sexual orientation (13, 23). These
human studies must be viewed tentatively pending
corroboration, and, to date, there have been no em-
pirical investigations into the prenatal hormonal
dependence of the putative hypothalamic dimor-
phisms in humans.
The mammalian embryo is initially sexually
bipotential (19). In the course of normal male dif-
ferentiation a testis-determining gene, SRY, which
is normally on the Y chromosome directs the de-
velopment of testes. Subsequently, testicular secre-
tions orchestrate the differentiation of the male
genitalia and brain. Müllerian inhibitory sub-
stance, a nonsteroidal testicular secretion, induces
regression of female internal genital structures,
while the 5α-reduced metabolite of testosterone,
5α-dihydrotestosterone (DHT), is required for the
development of male internal genital structures
and for the differentiation of male external geni-
talia. Activation of androgen receptors by testos-
terone itself or by DHT appears to contribute to the
masculinization of brain structure and function in
some species (24). In laboratory rodents the con-
version of testosterone to estrogen by aromatase
enzymes within the brain plays a greater role, al-
though the activation of both androgen and estro-
gen receptors may be required for full masculin-
ization (24, 25). Not only do males and females
have different hormonal requirements, but animal
studies suggest that the various aspects of somatic
and brain sexual differentiation occur during dif-
fering periods of development in a sequence of
temporally overlapping steps (24, 26). Thus, vari-
ous parameters hypothesized to reflect sexual dif-
ferentiation of the brain (e.g., gender identity and
sexual orientation) could vary independently from
one another and from genital morphology. In the
absence of the cascade set in motion by the testis-
determining gene, female development ensues, at
least to a first approximation.
Human testes begin to secrete androgens by
the seventh or eighth week of gestation (27), a
process that is initially regulated by human chori-
onic gonadotropin secreted by the placenta (28).
By the fifteenth week of gestation, the regulation
of androgen secretion is taken over by go-
nadotropin from the fetal pituitary, which is in turn
regulated by the fetal hypothalamus. Gonadotropin
secretion decreases toward the end of gestation.
Thus, fetal androgen in males is elevated between
weeks 8– 24 of gestation, with peak levels occur-
ring between weeks 14– 16 (29). In males, the level
of testosterone increases from birth to a peak at
1–3 months and then decreases to prepubertal lev-
els by 4– 6 months (30). The ovary is relatively qui-
escent prenatally but secretes substantial levels of
estradiol during the first 6– 12 months after birth. A
sharp reduction of gonadal activity then occurs in
both sexes until 10 or 12 years of age, when sex-
characteristic adult hormonal profiles emerge (19).
Thus, hormonal influences could conceivably influ-
ence psychosexual differentiation prenatally (8– 24
weeks of gestation), during the first 6– 12 months
postnatally, and again at puberty.
Human Studies Relevant to Biology and
Gender Identity
Clinical data spanning more than half a cen-
tury, relevant to the question of early hormonal in-
fluences on gender identity, have been reviewed
extensively by Zucker (8). The following is a sum-
mary and update of that review, with an emphasis
on cases that were followed at least into late ado-
lescence and in which an assessment of gender
identity and role were documented. The syndromes
are grouped into those in which the developing
brain was exposed to either a full or a partial com-
plement of masculinizing influences. This division
is based on the hypothesis that the likelihood of
problems with the acceptance of a female gender
assignment is related to the degree of early brain
masculinization. Various syndromes will be de-
scribed first, with their implications regarding gen-
der differentiation discussed at the end of this sec-
tion. For discussion of disorders of sex develop-
ment not reviewed below, the reader is referred
elsewhere (3, 31– 33).
Syndromes with a Normal Complement of
Masculinizing Hormonal Influences Prenatally
Ablatio penis does not refer to a disorder of sex
development but instead refers to the accidental or
traumatic loss of the penis in infancy in otherwise
normal males. Four cases reassigned to the female
gender prior to 2 years of age have been reported
(8). Of these, at least 2 had switched to a male gen-
der identity by or during puberty, while 2 had re-
tained a female identity at last follow-up (ages 17
and mid-20s). Detailed information is available for
only two of these cases. The first detailed case was
first described by Money and Ehrhardt (1) and has
been widely publicized as the case of John/Joan.
This case will be discussed in some detail because
of the inordinate impact it has had on the field.
Vol. 73 No. 7 DISORDERS OF SEXUAL DEVELOPMENT—BYNE 953
One of a pair of normal monozygotic 46XY twins
suffered accidental penile ablation at the age of
seven months. A decision for gender reassignment
was made at 17 months, with orchiectomy and pre-
liminary vaginoplasty occurring at 21 months (1,
8, 31). Follow-up at seven years suggested that the
patient had accepted the female gender identity
and that the twin brother was a normal male (1).
Two years later, the patient was described as hav-
ing tomboyish traits but that “Her activity is so
normally that of an active little girl....” (34). It was
concluded that “...gender identity is sufficiently in-
completely differentiated at birth as to permit suc-
cessful assignment of a genetic male as a girl….”
(34). Over the next two decades that conclusion
was cited in innumerable medical review articles
and textbooks, and formed the crux of theories
concerning the malleability of gender and surgical
gender reassignment in intersexes (35). Follow-up
when the patient was in his early 30s, however, re-
vealed that he had rejected the female identity, re-
sisted feminizing estrogen therapy, and had begun
to live as a male by the age of 14. At that time he
received a mastectomy and began testosterone re-
placement therapy and surgical procedures for
phallus reconstruction (11, 35). He married a
woman at age 25 and adopted her children. His sui-
cide in 2004 has been attributed by some to the
contribution of gender reassignment and its after-
math to his anguished history (36).
In the second detailed case, the patient’s penis
was destroyed during an electrocautery circumci-
sion at 2 months (37) and surgical reassignment
was begun at 7 months. At 26, she was reported to
be confident of her female gender. Although she
was sexually active with a man, she reported pri-
marily gynephilic fantasies and described her sex-
ual orientation as bisexual.
Cloacal exstrophy, a disorder of embryogene-
sis involving the genitourinary and intestinal
tracts, affects both genetic males and females. Its
incidence is believed to be less than one in 400,000
births. In genetic males, the external genitalia are
often grossly anomalous or absent; however, tes-
ticular function is generally believed to be normal
(38, 39). Genetic males with this disorder are often
reassigned as female, castrated to prevent emer-
gence of masculine secondary sexual characteris-
tics, and treated with estrogen at puberty to stimu-
late the development of female secondary sexual
characteristics. No detailed post-pubertal follow-
up studies have been published on reassigned indi-
viduals. In one case report, an affected male reared
as female from birth lived as a woman for 52 years.
Then, upon the death of her parents, she underwent
reconstruction as a man. In a series of 10 affected
46XY individuals between the ages of 4 and 14
who were castrated and unequivocally raised as
girls from birth, all were close to the male range in
attitudes, activities and behaviors (38). Three had
declared themselves to be male (at ages 8, 9, and
12 years, respectively). In a detailed clinical study
of affected adolescents who were reared as males,
all were described as exhibiting psychosexual dys-
function and anxiety leading to social and sexual
developmental impairment (40). Nevertheless, all
retained a male gender identity.
Penile agenesis is a condition in which the
penis fails to differentiate, although the scrotum is
normal and contains normally functioning testes
(41). No hormonal abnormality of prenatal onset
has been reported in patients with this rare disorder
of mixed etiology. Although more than 20 cases
have been reported (8), post-pubertal follow-up
with assessment of gender identity is available for
only a few. Of 4 assigned males, all had retained a
male identity at last follow-up, at ages 13, 15, 22
and 45, respectively. Of more than a dozen as-
signed and reared as females, post-pubertal assess-
ment is available for only two. Of those, one was
reported to be content with her female assignment
at age 13. The other identified as female at age 15
but was living as a man at age 27.
Syndromes with an Incomplete Complement of
Masculinizing Influences
Congenital adrenal hyperplasia, which occurs
approximately once in 13,000 births (4), involves
an enzymatic abnormality in cortisol synthesis that
results in an overproduction of androgens begin-
ning during the fetal period (42). In genetic males,
no genital abnormality ensues; however, in genetic
females varying degrees of external genital mas-
culinization occur ranging from mild clitoral en-
largement to complete fusion of the labioscrotal
folds with a phallic urethra (43). There is at times
uncertainty regarding gender assignment at birth.
Cortisol replacement therapy can minimize further
virilization after birth and allow normal ovarian
function and fertility to emerge with puberty. In
one large cohort 9% of genetic females were as-
signed and reared as males without reported com-
plications (42). As early detection increases due to
state-mandated neonatal screening, the proportion
assigned as male is likely to decrease in keeping
with the optimal gender policy, which places em-
phasis on female reproductive potential.
Affected individuals who were reared as fe-
males have been studied extensively with regard to
cognitive profiles (44), childhood gender confor-
mity (45), gender identity (46), and sexual orienta-
954 THE MOUNT SINAI JOURNAL OF MEDICINE November 2006
tion (47). The vast majority of affected individuals
retain their female gender identity into adulthood
although with a statistically increased incidence of
gender nonconformity (45, 46), gender dysphoria
(48) or ambivalence about gender (49) in childhood
and gynephilia in adulthood (46, 47). Four cases,
however, have been described in which a male iden-
tity emerged gradually between late adolescence
and adulthood despite having been assigned as fe-
male within a few weeks of birth (50). Gender dys-
phoric subjects appear to be less willing to partici-
pate in follow-up studies compared to subjects
without gender dysphoria (8). The proportion of af-
fected individuals who change from female to male
gender identity is difficult to know with any degree
of certainty; however, various authors have esti-
mated that proportion to be as low as 2% and no
higher than 10% (3, 8). Both estimates are much
higher than the rate (approximately 1 per 34,000) of
transsexuality among normal females (8).
Complete androgen insensitivity is believed to
have a minimal incidence of one per 99,000 births
but may be as high as one per 13,000 (4). In this
condition 46XY individuals develop normally
functioning testes but lack functional androgen re-
ceptors (24). They develop normal female external
genitalia because their tissues are unable to re-
spond to androgens. They are capable of respond-
ing to Müllerian inhibitory substance, however, so
their internal female genital structures regress. Un-
treated, they develop breasts and female-typical fat
distribution at puberty in response to estrogens de-
rived from testosterone synthesized by their testes.
Historically, these individuals were assumed to be
normal females at birth and did not come to med-
ical attention until testes descended into the labia,
or until they failed to menstruate or conceive chil-
dren. The published literature does not contain any
reports of affected individuals changing to a male
gender identity (9). Thus, in the absence of func-
tional androgen receptors, female gender identity
appears to be the rule in individuals with an XY
karyotype and normally functioning testes. While
it has been suggested that in the absence of func-
tioning androgen receptors, these individuals
would have female-typical brain differentiation
(19), in laboratory rodents androgens appear to or-
chestrate differentiation of the male brain primar-
ily by interaction with estrogen receptors after
conversion to estrogen by aromatase enzymes in
the brain (24). It has, therefore, been suggested
that humans, in contrast to rodents, require func-
tional androgen receptors for male brain develop-
ment (24).
Partial androgen insensitivity refers to disor-
ders in which there is a partial resistance to andro-
gens, which results in external genitalia that are
only partially masculinized. No reliable statistics
are available for the frequency of this disorder,
which is generally believed to occur with a lower
incidence, perhaps one tenth that of complete an-
drogen insensitivity (4). The degree of external
genital masculinization varies with the degree of
androgen resistance, leading to considerable phe-
notypic variation and overlap in appearance with
other syndromes. Affected individuals have been
assigned and reared as either males or females de-
pending in part on the degree of external genital
virilization. In one series of 6 individuals assigned
as female (8), 5 retained the female gender identity
into adulthood. Following a long history of mascu-
line gender role interests and gynephilia, the sixth
requested gender reassignment at age 30. Another
report describes 10 affected individuals of whom
eight were reared as boys, one as a “hermaphro-
ditic girl” and one as a girl (51). At follow-up be-
tween 13– 39 years it was concluded that gender
identity differentiated in accordance with the gen-
der of rearing. Athird report describes 8 patients, 7
of whom were assigned as female at birth (48) and
followed up between the ages of 6– 23. Details on
gender identity were not given; however, the au-
thors concluded that the female assignment had
been wrong on the basis of the patients’ “boyish
behavior.... In particular, the wild, rough play ...
[which was] difficult for their parents to regulate.”
5α-reductase deficiency affects 46XY individ-
uals. During fetal development the gonads differ-
entiate into normal testes and secrete appropriate
amounts of testosterone; however, due to the defi-
ciency of 5?-reductase, affected individuals are un-
able to convert testosterone to dihydrotestosterone
in amounts sufficient for the external genitalia to
masculinize normally. Consequently the newborn
may have a phallus that more closely resembles a
clitoris than a penis, and unfused labioscrotal folds
resembling labia majora. In the absence of sophis-
ticated diagnostic testing, affected individuals
have often been assumed to be females at birth and
have been reared accordingly (52, 53). At puberty,
however, testosterone and not dihydrotestosterone
is the essential androgen for growth of the male ex-
ternal genitalia and the emergence of male sec-
ondary sex characteristics (54). Thus, a masculin-
izing puberty ensues: the phallus markedly en-
larges, the testes descend into the labioscrotal
folds, the beard grows, the voice deepens and a
masculine habitus develops (52, 53).
The prevalence of this disorder in the general
population is unknown (4). It has been studied ex-
tensively in the village of Las Salinas, Dominican
Republic, where its prevalence is unusually high
Vol. 73 No. 7 DISORDERS OF SEXUAL DEVELOPMENT—BYNE 955
due to consanguineous marriages (52, 53). Of 18
individuals who reportedly had been assigned and
reared as females from birth, 17 changed to a male
gender identity and 16 to a male gender role at pu-
berty. The authors suggested that male gender
identity and gynephilia “appear to be testosterone
and not dihydrotestosterone related...and that sex
of rearing as females...appears to have a lesser role
than the presence of two masculinizing events—
testosterone exposure in utero and again at puberty
with the development of a male phenotype.” Be-
cause the studied individuals came from inter-re-
lated families living in the same village, questions
have been raised about the possibility of ambigui-
ties in the gender socialization of many of the af-
fected individuals (53, 55). Similar accounts of
gender change from female to male have been
made in cohorts from Mexico, Papua New Guinea
and Brazil (8, 54, 56).
17β-hydroxysteroid dehydrogenase deficiency
usually results from a missense mutation (54) and
occurs with unknown frequency. The mutation re-
sults in a deficiency of the enzyme that catalyzes
the terminal step in testosterone synthesis. Af-
fected 46XY infants are born with female external
genitalia despite the presence of testes and male
internal structures (54). The deficit in testosterone
produces a corresponding deficit in its androgenic
and estrogenic metabolites believed to play a role
in masculinization of the brain. The deficiency
usually becomes less severe with time and many
affected individuals eventually have male-typical
testosterone levels. They are usually assigned as
female at birth and come to medical attention be-
cause of virilization at puberty or a failure to men-
struate. Between 40% and 50% of affected indi-
viduals, even one who made essentially no hy-
droxysteroid dehydrogenase (17β-HSD) (54), have
been reported to switch from a female to male
identity postpubertally.
Micropenis is a condition in which penile
length is at or below the 10th percentile for age-
graded norms (8). Androgens are necessary at two
points in fetal development for a normal penis to
form: early in fetal life to sculpt the bipotential
genital precursor into a penis and scrotum and sub-
sequently in fetal life to enlarge the penis. Mi-
cropenis is believed to occur in XY individuals if
androgen levels are insufficient for the penile
growth after the initial masculinization of the ex-
ternal genitalia has already occurred. Of 16 re-
ported cases who were assigned and reared female,
follow-up is available only for 8 (ages 10– 25), all
of whom were described as having appeared to
have developed a female identity, although a de-
tailed history was obtained from only one adult
subject (8). In contrast, adulthood follow-up is
available for 22 affected individuals who were as-
signed and reared as males (8). Of these, all were
judged to have retained a male gender identity.
One, however, expressed feelings of inferiority re-
lated to his small penis and reported childhood fan-
tasies of gender reassignment. After gynephilic ex-
perimentation, he exhibited an androphilic orienta-
tion in adulthood. In one group study of 9 individ-
uals in which all retained a male identity, child-
hood gender nonconformity was noted in 4, an an-
drophilic orientation in three and gynephilic orien-
tation in six. In a second group study of 12, all re-
tained a male identity and a gynephilic orientation
was assumed for at least nine, seven of whom were
married or cohabitating with a woman.
Summary and Implications of Clinical
Observations
The above review underscores the paucity of
intersexed and gender reassigned cases for which
detailed follow-up is available into adulthood.
Moreover, it is clear that an individual may un-
dergo a transition in gender identity while restrict-
ing the social contexts in which gender role behav-
ior reflects that transition, and that such transitions
may occur as late as middle age. The likelihood of
rejecting female assignment appears to be in-
creased in androgen-responsive individuals born
with testicular tissue the longer that tissue is left in
place, even prior to puberty. This could reflect the
duration of reinforcement of a male identity prior
to reassignment or ambivalence resulting in delays
in the reassignment. Alternatively, it could reflect
increased masculinization of the brain during the
early postnatal surge of testosterone secretion (30).
The data on individuals with 5?-reductase and
17β-HSD deficiencies suggest that the probability
of switching to a male gender identity and role
after female reassignment is increased further in
androgen-sensitive individuals whose testes are
left in place until puberty. The data do not justify
the conclusion that prenatal androgen exposure
produces a brain that is hardwired for male gender
identity at birth. Instead, an effect of prenatal an-
drogens may be reinforced by the elevated andro-
gen secretion that occurs in the neonatal period and
again at puberty.
Implications Regarding Hormonal Pathways
Involved in Gender Differentiation
Although individuals with complete androgen
insensitivity possess normal testes and all the hor-
mones and metabolic machinery necessary to mas-
956 THE MOUNT SINAI JOURNAL OF MEDICINE November 2006
culinize the rodent brain (i.e., testosterone, aro-
matase enzyme, estrogen receptors), all reported
cases have been reared unambiguously as females,
have retained that identity into adulthood, and
have been described as having stereotypically fem-
inine interests and behaviors as children (8). Thus,
if prenatal hormones exert an organizing influence
on the human brain with respect to gender, mas-
culinization of the brain in this regard must be me-
diated primarily via androgen receptors. The evo-
lution of masculine behavior and male identity
among individuals with 5α-reductase deficiency
suggests that those androgen receptors may be ac-
tivated by testosterone in the absence of 5α- re-
duction. Moreover, the outcomes among individu-
als with 17β-HSD, and presumably very little
testosterone production in utero, suggest that very
little testosterone is required to bias gender iden-
tity in the male direction. Compared to gender
identity, sexual orientation appears to be even
more sensitive to androgenic influences, as evi-
denced by the proportion of androgenized females
who develop a bisexual or gynephilic orientation
while retaining a female gender identity. On the
other hand, that the androgenic requirements for
male gender identity and gynephilia appear to be
so low detracts from the hypothesis that either an-
drophilia or transgenderism in otherwise norma-
tively developed XY men results from an early an-
drogen deficiency. The variability of gender out-
comes even among related intersexed individuals
known to share identical genetic mutations, sug-
gests the importance of psychological, social and
cultural factors as co-mediators of gender develop-
ment. The current dominance of the hormonal the-
ory of sexual differentiation may give the impres-
sion that gonadal secretions are fully responsible
for all aspects of brain sexual differentiation. Re-
cent work, primarily in animals, however, suggests
that XX and XY brain cells behave differently, in
part, because of the cell-autonomous actions of X
and Y genes (18). The possibility that such actions
could contribute to gender identity is only now be-
ginning to be considered. As discussed elsewhere
(57), cognitive and experiential factors must also
be considered.
Implications for Gender Assignment
While this review strongly suggests that bio-
logical factors contribute to gender identity, the
exact nature and magnitude of their impact are un-
certain. During infancy it is not possible to predict
a given individual’s ultimate gender identity with
certainty. A small minority of individuals (i.e.,
transgendered individuals) who appear norma-
tively developed at birth develop a gender identity
incongruent with the known biological variables of
sex. Nevertheless, development of a male identity
is strongly correlated with exposure to androgenic
influences in early development. Thus, it would
seem imprudent to assign infants with a small or
absent phallus to the female gender if they were
exposed to a full complement of masculinizing in-
fluences prenatally (e.g., individuals with penile
agenesis, micropenis, cloacal exstrophy). As re-
viewed above, male assignment of these individu-
als is not without complications; however, it mini-
mizes surgery (e.g., castration to prevent masculin-
ization at puberty) and in many cases preserves
fertility (3). Similarly, preservation of fertility as
males is possible for individuals with 5α-reductase
deficiency and may also be possible with 17β-
HSD deficiency (3). Current estimates suggest that
a majority of these individuals who are reared as
females, eventually live as males. Barring cultural
indications to the contrary, male assignment
should be the rule.
There are no known cases of 46XY individuals
with complete androgen insensitivity assuming a
male gender identity. These individuals, who will
be infertile regardless of assignment, should al-
ways be assigned female. In order to preserve fer-
tility, female assignment is also currently recom-
mended by most authorities in all 46XX cases of
congenital adrenal hyperplasia (3). This recom-
mendation holds even for those cases involving ex-
treme masculinization of the external genitalia (3)
and who, according to the above review, could
likely live successfully as infertile men and are at
high risk of rejecting the female assignment.
Guidelines for the initial gender assignment are
less straightforward in other syndromes, especially
those involving exposure to intermediate levels of
masculinizing influences prenatally (e.g., partial
androgen insensitivity, abnormalities of gonadal
differentiation or function), and for whom there is
no potential for fertility. In such cases, decisions
must be made on an individual basis using all that
is known about the child’s particular disorder, how
the child’s disorder is likely to influence his or her
gender identity, and how the family’s cognitive ca-
pacity and beliefs will impact their nurturing of the
child. The aim is to optimize the prognosis with re-
spect to the endpoints identified by the optimal
gender policy as described above.
Ethical Issues in Management of Disorders of
Sex Development
Adistinction must be made between gender as-
signment (a social labelling process) and the cos-
Vol. 73 No. 7 DISORDERS OF SEXUAL DEVELOPMENT—BYNE 957
metic genital surgeries that may be done in an ef-
fort to reinforce that assignment. While it is gener-
ally agreed that parents have a legal right to deter-
mine the nature of their child’s medical care, some
recipients of childhood surgeries have raised the
complex question of whether their parents had an
ethical right to consent to irreversible genital/go-
nadal procedures done for non-medically threaten-
ing conditions. They hold that because genitals are
concealed from the public by clothing, gender as-
signment and social reinforcement of that assign-
ment can be accomplished without surgery (58,
59). While atypical genitals rarely cause illness or
pain, surgery and its associated scarring may cause
pain, diminution of sexual pleasure, and anorgas-
mia as well as other complications (17). Genito-
plasty frequently involves multiple procedures
throughout childhood and even the best surgical
efforts sometimes fail to produce acceptable func-
tional or cosmetic results (60, 61). Furthermore,
surgery is difficult or impossible to reverse and, as
children or adults, individuals with disorders of
sex development may reject the gender that was
assigned in infancy. Some have, therefore, sug-
gested that elective genital surgeries should not be
considered until the affected individual is old
enough to possess the intellectual capacity to make
an informed decision (62). In appropriate cases,
puberty and the development of secondary sex
characteristics may be delayed medically so that a
patient’s decision-making is not rushed. Many be-
lieve, however, that early surgery to address geni-
tal anomalies relieves parental distress and,
thereby, improves bonding between parent and
child as well as the parents’ ability to nurture the
child (3, 50). Systematic evidence supporting this
belief is critically lacking, however. To date no
studies have addressed whether this important
issue is better addressed by surgery as opposed to
psycho-education and counseling of the parents.
Beyond the issue of who is ethically entitled to
consent to procedures employed in intersex man-
agement is the issue of what constitutes informed
consent. While physicians may understandably
fear that particular details of their child’s sexual
anomalies may exacerbate parental anxiety, par-
ents cannot make informed decisions if informa-
tion is withheld from them. Informed consent re-
quires full disclosure of relevant information, such
as physical findings, karyotype and diagnosis, as
well as the known potential risks and benefits of
withholding or performing each intervention that
may be considered. For example, early castration
requires subsequent postpubertal hormone replace-
ment therapy, which poses its own risks. These
may include elevated rates of cardiovascular dis-
ease, cancers (63, 64), or osteoporosis secondary
to poor compliance with hormone replacement.
Some have suggested further that in order to give
informed consent, parents should also be made
aware of the lack of scientific agreement on theo-
ries of gender development as well as the paucity
of outcome studies following particular procedures
commonly employed in intersex management (14).
In some cases full disclosure of the intersex status
to the parents and/or affected individual has been
withheld for fear that it would introduce ambigui-
ties into the reinforcement of the assigned gender
and lead to an unstable gender identity (65). Not
only is age-appropriate disclosure of one’s biolog-
ical status a prerequisite for informed consent, it
precludes the possibility that a patient will dis-
cover his or her intersex status in an uncontrolled
setting in which a catastrophic psychological reac-
tion is possible.
Conclusions
Detailed long-term follow-up and assessment
of quality of life have been reported for exceed-
ingly few individuals with disorders of sex devel-
opment. More research is clearly needed to eluci-
date, on a syndrome-by-syndrome basis, what clin-
ical practices are likely to yield the best quality of
life in affected individuals. Three issues are central
to current shifts that are occurring in the manage-
ment of these disorders: (a) increased understand-
ing of the biological substrates of gender identity;
(b) the indications for cosmetic genital surgeries in
the management of these disorders; and (c) ethical
issues pertaining to informed consent and who is
entitled to give it. In addition, a re-examination of
many aspects of intersex management has been
precipitated by input from advocacy groups com-
prising adults with disorders of sex development
and the parents of intersexed children (66, 67, 68).
One such group, which also includes health care
providers, The Consortium on the Management of
Disorders of Sex Development, has recently pub-
lished clinical guidelines for health care profes-
sionals (59) and a handbook for parents (58).
Among other sets of published guidelines, these
uniquely reflect the input of those with the highest
stake in intersex management decisions—the re-
cipients of interventions based on those decisions.
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