ORIGINAL ARTICLE
Year : 2006  |  Volume : 22  |  Issue : 1  |  Page : 42-45

Female-assigned genetic males with severe hypospadias: Psychosocial changes and
psychosexual treatment

RB Nerli, SM Kamat, IR Ravish
Department of Urology, KLES Kidney Foundation and J N Medical College, Belgaum,
Karnataka, India

Correspondence Address:
I R Ravish
Deptartment of Urology, KLES Hospital, Nehrunagar, Belgaum 590 - 010
India

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0970-1591.24653

Abstract

Introduction: Disorders such as severe hypospadias presenting as ambiguous
genitalia have serious and potentially life-long consequences for affected
individuals and, depending on the underlying cause, are likely to entail surgery
in childhood and in later life, psychosocial and psychosexual support and
possible fertility treatment including assisted conception.
Materials and Methods: Genetic males with severe hypospadias who were wrongly
brought-up as females formed the study group. They were reassigned as males and
underwent surgery for correction of hypospadias.
Results: Three children with severe hypospadias were reassigned to male gender.
Psychosocial changes were made psychosexual counseling was done. All three have
adjusted to their new environment and gender.
Conclusions: Management of children with wrongly assigned sex is complex. It is
preferable to reassign these children who are genetic males but wrongly assigned
as females at birth. Repair of hypospadias, psychosocial changes and
psychosexual counseling will help these children to reorient themselves.

Keywords: Genetic male, hypospadias, psychosexual dysfunction

How to cite this article:
Nerli RB, Kamat SM, Ravish IR. Female-assigned genetic males with severe
hypospadias: Psychosocial changes and psychosexual treatment. Indian J Urol
2006;22:42-5

How to cite this URL:
Nerli RB, Kamat SM, Ravish IR. Female-assigned genetic males with severe
hypospadias: Psychosocial changes and psychosexual treatment. Indian J Urol
[serial online] 2006 [cited 2009 Nov 18];22:42-5. Available from:
http://www.indianjurol.com/text.asp?2006/22/1/42/24653


Intersexuality represents a rare but important group of disorders, which usually
present at birth with ambiguity of the external genitalia. It is imperative that
these conditions are recognized early and steps taken to identify the underlying
cause as, in some cases, a delay may result in sudden collapse and death from an
underlying metabolic disorder. The investigation of these cases is best managed
by a team comprising a pediatric urologist, a pediatric endocrinologist, a
geneticist, a radiologist, a pathologist and a clinical psychologist or
pediatric psychiatrist, all of whom should have a special interest in
intersexuality.

General guidelines regarding approach to the neonate with ambiguous genitalia
have been laid down.[1],[2] When the phenotypic appearance of the genitalia is
ambiguous, appropriate biochemical, radiographic and chromosomal studies should
be completed. The degree of external virilization be carefully noted and
recorded. Careful photographs be recorded. The parents need to be informed of
the ambiguity and clinical investigations carried out. The parents need to be
advised that a sex assignment decision will be based on the appropriate data.
The child psychiatrist needs to assess the psychological effects of such
ambiguity on the parents and initiate appropriate interventions. These may be
supportive, educational, cognitive, or a combination of these.

The decision making process about sex assignment in the newborn with ambiguous
genitalia is in a state of transition.[3] Diagnoses and etiologies of disorders
of sexual differentiation can be carefully delineated using appropriate
biochemical, radiographic and chromosal studies. Yet few descriptive outcome
data are available and it is not at all clear that a definitive diagnosis will
dictate the choice of sex of rearing.[4],[5] It is clear that errors of sexual
differentiation create an unusual and unique matrix for the development of
psychosexual and psychosocial vulnerabilities and disorders in such children.
Psychosocial and psychosexual ramifications of sex assignment decisions are by
nature complex and profound.[5],[6],[7] Longitudinal follow-up studies of
homogenous target populations are only now underway.[6],[7] It is sufficient to
note that sex assignment decisions will have lifelong effects on the child.

Hypospadias is one of the most common congenital urogenital problems. It also
continues to be one of most challenging and gratifying problems. The newborn
with severe perineal hypospadias and an abnormally small penis may present as a
case of ambiguous genitalia. Such newborns should undergo early determination of
sex as well as the capability for penile growth in the future. We report our
experience with three children who were genetic males but wrongly assigned as
females at birth, due to severe hypospadias and micropenis, which caused
ambiguity in genital appearance.

Materials and methods
Genetic males with severe hypospadias and small penis and wrongly assigned as
females formed the study group. A detailed history including antenatal history
was noted. A detailed physical examination was done. Careful measurement of the
penis (stretched dorsal length and diameter), location of urethral meatus,
presence of testes in the scrotum, development of scrotum, pubic hair, facial
hair and the built was noted. Investigations including routine blood and urine
examinations were carried out. Buccal smear for Barr bodies, abdominal
ultrasonography for internal organs, hormone assays and genitourethrography were
done in all. When gonads were not palpable then abdominal laparoscopy was done
to note the intra abdominal gonads. Once the diagnosis of a genetic male was
made, the parents were informed and counseled. Decision to bring up the children
as males was made by the parents after a detailed discussion with psychiatrists,
urologists, paediatricians and family physicians.

The children with their parents were informed regarding the need for genital
reconstruction, reorientation of the child to male sex, need for multiple
sessions of surgery, failure of surgery and eventual outcome. Social changes
were advised, such as, changing over to a boy's school, hair cut and a male
name. Relocating the child to newer environment, change of residence, change of
school was advised to reduce peer pressure.

Correction of external genitalia was planned in stages. Children received four
intramuscular injections of testosterone depot (100 mg/m 2 every 2 weeks).
Repair of hypospadias was done either in one or multiple stages. Orchiopexy for
undescended testes was done simultaneously.The child and the family were
provided with appropriate psychosocial support. Questions about gender and
sexuality are extremely anxiety provoking and emotionally upsetting, hence the
family was kept well informed and were involved in the entire decision making
process. The psychosocial support was begun with a counselor who explained the
etiology and genetics. A child psychiatrist or child psychologist was involved
in giving emotional support to the family and facilitating communication between
the family and the medical team.

Results
During the period January 2000 to July 2004, three children presented to us with
history of virilization and/or abnormal genitalia. All three children were
brought up as girls and all three came from lower middle class families

Case 1
A 6-year-old girl child was brought to the Urology OPD with history of large
clitoris. The child was the last of six children, with three elder brothers and
two elder sisters. All the other siblings were normal. The child was shy and
appeared timid. Examination revealed that the child had perineal hypospadias
with bifid scrotum and small penis with severe chordee. Testes were palpable
bilaterally, but of small volume. The right testes was retractile. Abdominal
ultrasonography revealed no abnormality. Genitourethrography revealed a normal
proximal urethra. The case was discussed with the parents and elder brother. The
child underwent psychiatric evaluation. Paediatricians, Psychiatrist,
endocrinologist and social workers were involved in making a decision of sex
reassignment. The parents strongly felt that the child needs to be brought up as
a male. The child was put on hormonal treatment. The child's name was changed;
the child was admitted in a school at his maternal uncle's place. The child
underwent multiple sessions with the clinical and child psychologist. Over a
period of 6 months the child started accepting his gender. Hypospadias surgery
was done in two stages. The child has been on follow up since then. The child is
still shy and does feel awkward in a boy's dress. The child has male friends
though not aggressive in playing with them.

Case 2
A 11-year-old girl presented with genital virilization. On examination, the
child had severe perineal hypospadias with small penis. The child had bifid
scrotum with the right testes not palpable. The child was male on investigation.
The child and his parents were inclined towards reassignment of gender sex to
male. The child underwent counseling and hypospadias repair. Right-sided
laparoscopic orchiopexy was done in the same sitting.

Case 3
A 13-year-old child presented to urology OPD with history of fascial hair and
genital virilization. The child preferred dressing as a male and liked to play
with male children. On examination, the child had severe perineal hypospadias
with a small penis and bilateral small testes. This child and her parents
readily agreed to reassignment to male gender. The child underwent counseling
and hypospadias repair.

All the three children are on follow up of more than 15 months. They have been
attending school as male children and have become well adjusted to their newer
identity. The older two children have been experiencing erections and all three
are having good urinary flow. The two older children have been playing with
other boys and are comfortable in their new identity. The smallest of the three
has overcome his shyness over a period of 12-15 months.

Discussion
Gender assignment or re-assignment poses some of the most emotive and
contentious ethical dilemmas encountered in any area of medical practice. To the
layperson this is straightforward, as overwhelming majority of the human race
can be easily identified as male or female by virtue of their genital anatomy,
secondary sexual characteristics and behavior. Arriving at a satisfactory
scientific definition is more difficult as gender reflects the outcome of
complex interactions occurring from the time of conception and extending
throughout pre and postnatal life. Behavior and gender identity is perhaps the
most complex and certainly the least well understood. It raises controversial
issues about the relative importance of 'nature vs . nurture' and more
specifically the concept of the male or female brain. The determinants of
gender-related behavior patterns can be arbitrarily subdivided into
neuroendocrine factors (principally the effects of testosterone on the brain)
and sociocultural factors, which include rearing, interaction with siblings and
peers and the culture to which the individual is exposed.

Management of children with wrongly assigned gender is complex. Not much
material is available in literature regarding management of children with
wrongly assigned gender. Questions arise as to whether these children need to be
reassigned for gender sex. The criteria for reassigning gender in such children
are strongly dependent on local culture. This effect has been particularly
studied in multicultural nation of Malaya. Amongst muslim malays, women can have
a prominent role in public life, inherit money and property and, in some areas,
determine the line of family descent. Amongst Indian and Chinese families, women
are a considerable financial burden and society revolves around the male members
of the community.[8] Similarly, in India, society is said to be happier to
accept an inadequate male rather than an inadequate female.[9] It is
self-evident that a small infant or child who is female assigned genetic male
with hypospadias cannot contribute to decisions relating to gender assignment,
nor provide informed consent for any genital surgery. Until very recently
therefore it was accepted that responsibility for these difficult decisions lay
with the parents, in the light of advice and information received from doctors
caring for their child. However, this approach has been strongly challenged by
some patient groups and ethicists who assert that responsibility for this
decision belongs, as a right, to the affected individual. In their view gender
assignment/reassignment and surgery should be deferred until such an age when
the individual can make informed decisions.[10] In our three patients, the
decision to reassign to male gender and do reconstructive surgery was made by
the parents after discussions with the treating urologists, psychiatrists and
pediatricians. Two of these children who were more than 10-year old also
participated in making this decision. One other child who was only 6-year old
could not understand the relevance of the discussion and was a passive to his
parents' decision.

Some authors feel that the first step in managing these children is to make a
casual diagnosis as soon and as accurately as possible, to determine the
different elements that must be considered in deciding to rear the patient as a
male or a female.[11] This requires a strategy of clinical and biological
investigations, including molecular biological techniques and specific imaging.
Schematically, it is mandatory to make an anatomical description of the external
genitalia as completely as possible. The second step is to investigate the
quality of testicular synthesis (from leydig to  Sertoli cells More Details) and
equally important to evaluate the action of testosterone on its target organs,
the external genitalia in particular. At each step the parents must be informed
on the different therapeutic options. Test of sensitivity to androgens is very
useful not only for diagnostic purposes but also to provide arguments for making
the decision about the sex of rearing. Failure to respond indicates a complete
resistance to the action of androgens, while a positive response is a clear
increased length or diameter of the penis.[11]

Sixteen genetic males with cloacal exstrophy who underwent neonatal assignment
to female sex socially, legally and surgically were assessed. Detailed
questionnaires extensively evaluated the development of sexual role and identity
as defined by the subject's persistent declarations of their sex.[12] Eight of
the 14 subjects assigned to female sex declared themselves male during the couse
of this study, whereas the two raised as males remained male. Five subjects were
living as females; three were living with unclear sexual identity, although two
of the three had declared themselves male. Eight were living as males, six of
whom had reassigned themselves to male sex. All 16 subjects had moderate to
marked interests and attitudes that were considered typical of males. The
authors concluded that routine neonatal assignment of genetic males to female
sex because of severe phallic inadequacy can result in unpredictable sexual
identification. Clinical interventions in such children should be reexamined in
the light of these findings. The parents of each of the eight subjects living as
male - including the two raised as male - felt that their child was happy living
as a boy.[12]

The divergent sexual outcomes of such subjects highlight issues of clinical
concern.

First, how would subjects who remained females would react if they discover
their birth status in the future. All genetic males with hypospadias have normal
gonads hence require only genital reconstruction. Prenatal androgens appear to
be a major biologic factor in the development of male sexual identity. The
specific actions of androgen on the developing brain as well as the specific
mechanisms of the development of male sex itself remain largely unknown and the
epigenetic processes as well as socially mediated influences remain
indeterminate.[13],[14] In view of these findings, it is preferable to reassign
these children who are genetic males with hypospadias but wrongly assigned to
female sex. Genital reconstruction in the form of hypospadias repair,
psychosocial changes and psychosexual counseling will help in managing these
children. In children with most severe hypospadias there is a considerable
overlap with intersex abnormalities such as micropenis. Even with hypospadias as
severe as this intercourse still occurs. In a series of 19 patients born with
ambiguous genitalia, subsequently determined to be caused by perineal
hypospadias, it was reported that 12 had had intercourse, but only four had a
regular partner.[15] Men with a very small penis can have satisfying sexual
intercourse with female partners. It seems therefore that an abnormal or
rudimentary phallus can form the basis for sexual activity in a male role.
Nothing is known of the satisfaction of their partners, but it would be
unreasonable to base decisions on the opinions of a putative partner some years
in the future.

Reconstructive surgery has been the standard of care for patients with
hypospadias. Hypospadias surgery remains a difficult challenge, as several
factors contributing to success remain unknown. In the medical sense the goals
of management of hypospadias could be defined as restoring normality by
reconstructing normal external genital anatomy and by ensuring the development
of normal secondary sex characteristics in such a way as to permit normal sexual
function (arousal, sensation, penetrative intercourse and orgasm) and the
potential for fertility. However, despite developments in recent decades and
ongoing research it is clear that for the foreseeable future, these ambitious
goals are likely to remain unachievable for many patients.

Conclusion
Assignment of genetic males to female sex because of severe hypospadias and
phallic inadequacy can result in unpredictable sexual identification. Androgens
have long been thought to influence prenatal brain development as well as
postpubertal activity, interests and libido. The ability of androgen to act on
target tissues in utero could affect subsequent sexual identity. Children who
are genetic males with severe hypospadias but wrongly assigned females at birth
should be reassigned as males. Psychosocial changes in environment, school, home
and relations must be made. Psychosexual counseling and orientation will help
the children to cope with their new identity.

References
1. Bradley SJ, Oliver GD, Chernik AB, Zucker KJ. Experiment of nurture: ablation
penis at 2 months, sex reassignment at 7 months and a psychological follow-up in
young adulthood. Pediatrics 1998;102:132-3.
2. Glassberg KI. The intersex infant: early gender assignment and surgical
reconstruction. J Pediatr Adolesc Gynecol 1998;11:151-4.    [PUBMED]
3. Wilson BE, Reiner WG. Management of intersex; A shifting paradigm. J Clin
Ethics 1998;9:360-9.    [PUBMED]
4. Reiner WG. Sex assignment in the neonate with intersex or inadequate
genitalia. Arch Pediatr Adolesc Med 1997;151:1044-5.    [PUBMED]
5. Reiner WG. Assignment of sex in neonates with ambiguous genitalia. Curr Opin
Pediatr 1999;11:363-5.    [PUBMED]  [FULLTEXT]
6. Reiner WG. Psychosexual dysfunction in males with genital anomalies: Pre- and
early adolescence, Tanner stages I-III. 2000.
7. Reiner WG, Meyer-Bahlburg HF, Gearhart JP. Female assigned genetic males:
Androgens and male gender identity. 2000.
8. Kuhnle U, Krahl W. The impact of culture on sex assignment and gender
development in intersex patients. Perspectives Biol Med 2002;45;85-103.
9. Gupta DK, Menon PS. Ambiguous genitalia-an Indian perspective. Indian J
Pediatr 1997;64:189-94.
10. Thomas DF. Gender assignment: Background and current controversies. Br J
Urol 2003;93:47-50.
11. Nicolino M, Bendelac N, Jay N, Forest MG, David M. Clinical and biological
assessments of the undervirilized male. Br J Urol 2003;93:20-5.
12. Reiner WG, Gearhart JP. Discordant sexual identity in some genetic males
with cloacal exstrophy assigned to female sex at birth. NEJM 2004;350:333-41.   
[PUBMED]  [FULLTEXT]
13. Wilson JD. The role of androgens in male gender role behavior. Endocr Rev
1999;20:726-37.    [PUBMED]  [FULLTEXT]
14. Berenbaum SA, Bailey JM. Effects on gender identity of prenatal androgens
and genital appearance: evidence from girls with congenital adrenal hyperplasia.
J Clin Endocrinol Metab 2003;88:1102-6.    [PUBMED]  [FULLTEXT]
15. Miller MA, Grant DB. Severe hypospadias with genital ambiguity: adult
outcome after staged hypospadias repair. Br J Urol 1997;80:485-8.    [PUBMED]

doi:10.1016/j.urology.2009.07.1286
Copyright © 2009 Elsevier Inc. All rights reserved.
Pediatric Urology

Gender Identity in Disorders of Sex Development: Review Article

Jennifer H. Yang, a, , Laurence S. Baskina and Michael DiSandroa
aDivision of Pediatric Urology, University of California, San Francisco
Children's Hospital, San Francisco, California

Received 20 February 2009;  accepted 3 July 2009.  Available online 14 November
2009.

Objectives
Many concerns have been raised regarding the treatment and long-term outcome of
infants born with complex genital anomalies. Debate among clinicians,
psychologists, ethicists, and patient advocate groups regarding the optimal
management of these individuals is ongoing. Although determining the most
appropriate gender is a difficult task, this review will help clarify some of
the issues at hand.

Methods
A literature review which addresses the challenges of advising families about
gender identity in infants and children with disorders of sex development.

Results
The evidence for endocrine effects on neurobiological development with regard to
sexual behavior is compelling, although the existing outcome studies are largely
anecdotal and somewhat contradictory.

Conclusions
Gender assignment in infants born with a disorder of sex development remains
only one of the many difficult decisions faced by both the treatment team and
the family. Improved long-term follow-up of these patients will provide much
needed feedback on previous and contemporary management.

Article Outline
Historical Aspects
Hormonal Influence on the Developing Brain
Existing Outcomes Studies Regarding Gender Assignment and Hormonal Imprinting
Outcomes in Normal 46,XY Males With Severe Genital Anomalies
Outcomes of Disorders of Sex Development Patients With Partial Androgen
Insensitivity, Androgen Biosynthetic Defects, or Incomplete Gonadal Dysgenesis
Current Recommendations
Conclusions
References

One of the most paramount issues arising with the infant with ambiguous
genitalia is the most appropriate gender assignment, or from a parents
perspective, the sex of rearing. Recommendations will initiate a myriad of
psychosocial and psychosexual ramifications for the child and parents—including
potential intensive medical treatments such as complex surgical interventions
and lifelong hormonal manipulations. Historically, recommendations for gender
assignment of infants with ambiguous genitalia has been guided by the phenotypic
appearance of the genitalia; the practitioner would determine the sex of rearing
on the basis of what they believed would facilitate the most functional
genitalia and offer the child their best opportunity at normalcy.1 The
assumption was that the "sex-assignment" would later determine the child's
future sexual identity. However, this simplistic approach does not always work.
As described below, more recent studies have helped us to better understand what
actually determines gender identity, but even now, there is a paucity of outcome
data for evidence-based approaches to these rare disorders. The existing studies
often present conflicting outcomes, in addition to the tremendous amount of data
unveiling the ever-evolving complexities of the neurobiological and psychosexual
development regarding gender identity.

The development of gender identity is a complex interaction between prenatal and
postnatal endocrine factors, genetic influences, and postnatal environmental and
psychosocial experiences. In this review, we will address the significant issues
of gender identity in infants with disorders of sex development (DSD) through a
review of past and current published data. The developmental neurobiological
influences in concert with endocrine effects on the developing brain with regard
to sexual behaviors will be reviewed. Finally, current recommendations regarding
the approach to infants with ambiguous genitalia will be discussed.

Historical Aspects
Since antiquity, individuals neither male nor female have existed outside of
societal and cultural norms, at times symbolizing extraordinary powers and deity
status. With the passage of time and the advancement of medicine and science, a
better understanding of the "true sex" of such individuals began. During the
early colonial period, such individuals became labeled as persons with mistaken
sexual identities, because their externalized genitalia or internal reproductive
organs differed from the typical mannerisms attributed to a given sex.2 Since
the 1950s and 1960s, the common practice of gender assignment was based on the
assumption that the gender of rearing was determined by socioenvironmental
factors. Infants with sexual ambiguity were assigned the sex most concordant
with external genital appearance as opposed to karyotype. Recommendations at
that time included early sex assignment with parallel rearing and early medical
correction of genitalia including removal of gonads in female sex assignment. In
addition, parents and families were counseled to not disclose the intersexual
state of the child and often shrouded these conditions in great secrecy. The
actual outcome of these decisions were unknown, under-reported or heavily
subject to bias.1 In 1975, Money3 reported the successful reassignment of a male
toddler to female sex after a traumatic penile loss. The concept of sexual
neutrality of the neonate was developed, which accredited postnatal social and
environmental influence as the determinants of gender identity. Despite the
eventual discovery of the inaccuracy of the reported success of this particular
case,4 the concept of nature vs nurture has remained influential in the
management of infants and children with ambiguous genitalia.

In the last 3 decades, there has been increasing evidence of the role of genetic
and prenatal factors in influencing an individual's ultimate gender identity.
The potential affect of male hormone levels during fetal development and its
influence on the development of the central nervous system remains an important
factor. In addition, the recent criticisms for the management of DSD in the past
are a result of adults who experienced early interventions and have reported
psychological problems, such as gender dysphoria and depression, as well as
physical problems because of their sex-assignment treatments. Many others view
their previous management as an abuse of their human rights5 and a considerable
number of patients suffer from significant psychological distress as adults.6
This recent heightened interest in intersex has superseded medical discussions,
becoming the focus of historical chronicles,7 ethical debates,8 and social and
psychological analyses.9 Because DSD are uncommon as a whole, there has been
limited data concerning the eventual outcomes regarding gender identity, gender
role identification, or sexual orientation. The effect of hormonal imprinting on
gender development may be elucidated through existing animal models and also the
observations of human case studies in DSD patients.

Hormonal Influence on the Developing Brain
Androgens play an important role in the sexual differentiation of the mammalian
brain and behavior.[10] and [11] During certain critical periods in prenatal
development, androgens direct developmental processes in neural regions
containing the corresponding steroid receptors. As a result, the structure and
function of these regions becomes altered, as are the behaviors that they
control. In humans, androgens have been thought to influence postpubertal
activities, libido, and interests.12 Androgen influence on the central nervous
system development and behavior has been best studied in the rodent model.
Typically, high concentrations of prenatal androgens results in male-typical
behavior; in contrast, female-typical behavior develops in the absence of
androgen.[10] and [13] The developing nervous system can be permanently altered
causing masculinizing effects in the behavior of the adult animal.

Animal studies demonstrate that the addition or removal of hormonal stimulus in
early postnatal life can profoundly alter gender-specific behavior in adult
animals. In 1959, Phoenix et al14 demonstrated that adult female guinea pigs
exposed to androgens during gestation showed less feminine behavior (lordosis)
and more masculine behavior. The authors hypothesized that androgen exposure
could permanently alter the developing neural network resulting in masculinized
behavior in the adult animal. These long-lasting organizational effects of
hormones occur during critical periods of neural development. Several other
studies have been conducted to elucidate the hormonal effects on reproductive
behavior.

It has also been shown that androgenized neural networks are permanently altered
despite later hormonal treatments with estrogens, in an attempt to induce female
behavior. Female rats treated with androgen in the first few days of life do not
project female-typical behavior as adults, despite treatment with estradiol and
progesterone as adults.15 Similarly, early castrated male rats respond to
injections of female hormones, displaying female-typical behavior (lordosis) but
no response to testosterone injections.16 In contrast, estrogens do not seem to
be necessary for the neural or organizational development of female sex typical
behavior. Female rats treated with antiestrogens at birth exhibited behavior
similar to that of control females.17 Despite the absence of androgens resulting
in female behavior, estrogen treatment was found to be even more effective than
androgen treatment in newborn female rodents in producing masculine behavior.
These effects are thought to be secondary to the conversion of testosterone to
estrogen via aromatase.18 Recent studies examining the neural pathways of
sexually dimorphic behavior in mice have demonstrated a role for both
testosterone and estrogen in the control of gender-specific behavior.19
Reciprocal case studies in humans with DSD lend some insight as to the outcomes
of hormonal influences on gender development.

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


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

View Within Article


As one of the most common causes of 46,XX DSD, women with CAH have been studied
regarding gender identity and sexual orientation as adults. Overall, a majority
of 46,XX patients with CAH raised as female develop female gender identity with
few cases of gender dysphoria.23 Psychosocial assessments of women with CAH have
demonstrated that compared with the controls, CAH women reported more
cross-gender role behavior during childhood and fewer had comfort with their
sense of femininity during childhood.24 Gender identity in girls with CAH has
also been shown not to be related to the degree of virilization nor the age at
which reconstructive surgery was done, suggesting that excess androgen exposure
early in development may increase the risk of atypical gender behavior not
predicted by genital virilization.25 Sex-atypical behavior has been found to be
associated with the degree of inferred prenatal, but not postnatal, androgen
excess.20 Meyer-Bahlburg et al26 performed gender assessment in adult women with
CAH as a function of disease severity. Women with the nonclassical or late-onset
CAH demonstrated few signs of gender shifts, the simple-virilizing women were
intermediate and the salt-wasting variants were most severely affected. Two
salt-wasting women were gender dysphoric and 1 had changed to male in adulthood.

Two rare, autosomal-recessive disorders of sex development, 5á-reductase-2
deficiency and 17â-hydroxysteriod dehydrogenase deficiency, are unique examples
of hormonal influence on the developing brain. Typically, patients are born with
female-appearing external genitalia and are raised as girls. Those with
5á-reductase-2 deficiency have plasma testosterone levels in the high normal
range and those with 17â-hydroxysteriod dehydrogenase deficiency typically have
deficient testosterone production, although some androgen production may be
possible via other 17â-hydroxysteriod dehydrogenase isoenzymes. Pubertal
virilization occurs secondary to increased production of 5á-reductase-1 and
other 17â-hydroxysteriod dehydrogenase isoenzymes, allowing conversion of
testosterone to dihydrotestosterone and androstenedione to testosterone,
respectively.27 Both these disorders are unique models for evaluating the effect
of testosterone, compared with a female upbringing, in determining gender
identity. The majority of patients unambiguously raised as girls changed to a
male-gender identity at the time of puberty. Exposure of the brain to normal
levels of testosterone in utero and postnatally appears to contribute
substantially to the formation of male-gender identity, despite the effect of
female sex of rearing.[28] and [29]

In patients with complete androgen insensitivity syndrome, the typical hormonal
influences of androgen are ineffectual secondary to a defect in the androgen
receptor. These individuals are born appearing externally as female and raised
as females. Psychological outcomes in individuals with complete androgen
insensitivity syndrome (CAIS) are similar to women without the condition.30
Women with CAIS are generally satisfied with their female gender and sexual
function.31 The development of normal female gender identity in CAIS patients
demonstrates the effect of androgen unresponsiveness of the brain in addition to
unambiguous female sex of rearing.

Outcomes in Normal 46,XY Males With Severe Genital Anomalies
A disorder of sex development is usually associated with an endocrine disorder,
resulting in an overvirilized female or an undervirilized male. Several
conditions exist, including cloacal exstrophy, ablation of the penis and penile
agenesis, in which genital anomalies are not caused by endocrine dysfunction.
Cloacal exstrophy is a multisystem anomaly, which demands a multidisciplinary
approach. With the improvement of management, most patients survive through
childhood and the focus has been shifted to improving quality of life. About 10
years ago it was a common practice to perform gender reassignment in 46,XY
children with cloacal exstrophy secondary to "diminutive genitalia," despite
evidence that major psychosexual developmental difficulties result in similar
patients.32 Male gender assignment was thought to be appropriate for only those
with "adequate bilateral or unilateral phallic structures."32 Therefore, male
infants with inadequate phallic structures would be most appropriately raised as
female sex of rearing managed by early gonadectomy.33 It was also thought that
those male patients with severe abnormality or deficiency of genitalia would be
confronted with significant psychosexual adjustment.

Various institutions have reported the outcome of 46,XY cloacal exstrophy
patients reassigned to female sex of rearing at birth. In 2002, a study by
Schober et al34 reported that all 14 patients with XY chromosomes with cloacal
exstrophy reassigned to female at infancy had feminine typical core gender
identity, although at the time of publication all children were too young to
assess sexual orientation or other aspects of sexual functioning. Meyer-Bahlburg
reviewed published reports of female-raised 46 XY patients with penile agenesis,
cloacal exstrophy, or penile ablation. A significant proportion of patients
reassigned female converted to male. In contrast, all the male raised patients
were living as males with only one report of gender dysphoria. The differences
in gender outcome were significant between male-raised and female-raised
patients in each age category as well as for the entire sample.35 Reiner
published the Johns Hopkins experience with 16 genetic males with cloacal
exstrophy in 2004. Of the 16 patients, 14 were assigned female at birth,
"legally, socially, and surgically by means of orchiectomy and construction of
vulvae." Two patients were reared as male secondary to parental refusal for
female sex reassignment. Of the 14 female reassigned genetic males, 5 were
identified as female, 8 as male (including 6 who had converted to male
identity), and 1 patient who refused to discuss sexual identity. The results of
this study implicate prenatal androgens as a major biological factor in the
development of male sexual identity. In conclusion, Reiner and Gearhart36
suggested that children born genetically and hormonally male may identify
themselves as male, regardless of female sex reassignment and rearing. Reiner
and Kropp37 also reported a 7-year experience with 18 genetic males with severe
phallic inadequacy. All patients demonstrated marked male-typical behaviors and
interests. Of the 17 living patients, 10 live as males, 6 as females, and 1
refused to declare sexual identity. These findings suggest that males with
severe phallic inadequacy reared as male and those reared as females but later
converting to male have the potential for functional psychosocial outcomes.
Those reared as female have a realistic likelihood of recognizing male identity
and converting to male. Those remaining in female identity may have less
successful psychosocial outcomes.37 Unlike other children with a DSD diagnosis,
patients with cloacal exstrophy are thought to have normal testicular function.
Testes which function normally prenatally, producing normal amounts of
masculinizing hormones may initiate sex-specific changes in neural networks, and
hence sex-typed behaviors.

Not all studies of female assigned 46,XY patients with severe genital ambiguity
have resulted in discordant gender outcomes. A recent study by Mukherjee et
al,38 which compared psychological functioning in sex-reassigned vs nonassigned
patients with cloacal exstrophy found that all patients maintained good
psychological functioning. Significant differences were found in the area of
depression and XY females demonstrated more male-typical gender behavior. The
authors concluded that cloacal exstrophy patients can have remarkably
well-adjusted lives provided they receive appropriate support.

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

Outcomes of Disorders of Sex Development Patients With Partial Androgen
Insensitivity, Androgen Biosynthetic Defects, or Incomplete Gonadal Dysgenesis
The most challenging group of DSD patients are those born with disorders in
which the prenatal androgen influences are partial and difficult to quantify, or
those whose diagnosis is unknown (Figs. 1B-D). Reiner examined 84 pediatric
patients from a pediatric psychosexual clinic comparing the sex of rearing to
self-declared gender identity. Of the 73 patients with DSD and a Y chromosome,
60 were raised as female, and more than half (53%) of these patients later
declared male identity. Of the total 84 patients, 69 were raised as female, but
only 32 lived as female, whereas 29 lived as male. All 15 patients reared as
male lived as male including 2 genetic females with CAH. Reiner concluded that
in the presence of active prenatal androgen effects, the likelihood of
recognition of male identity increases dramatically, independent of sex of
rearing.40

In a recent study, Jurgensen et al evaluated the gender-related play
preferences, activities, and interests of 33 prepubertal children with 46,XY
karyotype and DSD with varying degrees of prenatal androgen exposure compared
with same-age children without DSD. The DSD children were grouped into those
with complete hypoandrogenization (eg, complete androgen insensitivity syndrome,
complete androgen biosynthesis defect) of which all were raised as girls, and
those with partial hypoandrogenization, of which 12 were raised as boys and 15
as girls. The authors demonstrated a correlation of behaviors with the degree of
presumed prenatal androgen exposure on the basis of the patient's diagnosis.
They also found that despite the fact that children with partial androgen
effects reared as girls demonstrated increased boyish behavior, they did not
demonstrate increased signs of gender identity instability.41

There is very limited long-term follow-up in adult patients with DSD. Outcomes
of these individuals with regard to sexual behavior, sexual orientation, and
gender identity are anecdotal at best.42 Migeon et al43 reported long-term
follow-up in a cohort of 46,XY individuals with severe genital ambiguity raised
as male or female. Most participants were exclusively heterosexual with
concordant gender identifications. Successful long-term outcomes can result from
either male or female sex of rearing in 46,XY individuals, although a
significant proportion of patients (23%) were dissatisfied with their sex of
rearing.

Interestingly, there are a higher number of female to male gender changes (with
the exception of CAIS) in all DSD conditions than would be expected on the basis
of prevalence of female-to-male transsexualism, which is estimated to be 1:20
000 to 1:30 000 women in the general population.44 Despite these findings, the
greater majority of DSD patients develop a gender identity to match their gender
of rearing, implicating the sex of assignment as the best predictor of adult
gender identity.45

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

When a specific diagnosis it reached, recommendations for gender identity can be
made based on the aforementioned outcomes data. Some general guidelines are
mentioned later in the text and summarized in Table 1, but it should be
remembered that each DSD patient is unique, and as such, they should be treated
with individualized care, preferably with a multidisciplinary approach as stated
earlier.


Table 1.
Recommendations for gender assignment by DSD diagnosis

Diagnosis Sex Assignment Projected Gender Identity Level of Evidence
46,XX DSD
  CAH Female Female III[23], [45] and [47]
46,XY DSD
  5á-Reductase-2 deficiency Male or female Unknown III[25], [26] and [48]
  17â-Hydroxysteriod dehydrogenase-3 deficiency Male or female Unknown III[25],
[26] and [48]
  Complete androgen insensitivity syndrome Female Female III[27], [28] and [46]
Disorders of incomplete or unknown androgen synthesis or action:

  Partial androgen insensitivity

  Androgen biosynthetic defects

  Incomplete gonadal dysgenesis
  Male or female Unknown III[37], [38], [39] and [40]
46,XY with severe genital anomaly

  Micropenis

  Ablatio penis

  Cloacal exstrophy
  Male Male III32-34,36
Ovotesticular DSD Male or female Unknown III47

Full-size table
• Level I: Evidence obtained from at least one properly designed randomized
controlled trial.

• Level II-1: Evidence obtained from well-designed controlled trials without
randomization.

• Level II-2: Evidence obtained from well-designed cohort or case-control
analytic studies, preferably from more than one center or research group.

• Level II-3: Evidence obtained from multiple time series with or without the
intervention. Dramatic results in uncontrolled trials might also be regarded as
this type of evidence.

• Level III: Opinions of respected authorities, based on clinical experience,
descriptive studies, or reports of expert committees.

  Level of evidence according evidence-based medicine system of stratifying
quality of evidence developed by the US Preventive Services Task Force, defined
as follows:

View Within Article



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

In addition to decisions regarding the ultimate gender assignment in complex DSD
patients, the management of the dysgenetic gonad should also be addressed. The
highest risk for malignant transformation is associated with the presence of
testis-specific protein Y encoded in patients with pure gonadal dysgenesis or in
patients with partial androgen insensitivity syndrome and intra-abdominal
gonads.50 Steps to ensure adequate surveillance and triggers for early
intervention are warranted.

A prospective, multi-institutional study with a cohesive registry of all DSD
patients is the next step in finding answers to many questions raised in this
review. A systematic follow-up inclusive of accessing postoperative outcomes in
terms of sexual function as well as use of validated questionnaires to fully
document the psychosexual development of these individuals is paramount.

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

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Reprint requests: Jennifer H. Yang, M.D., Department of Urology, University of
California, San Francisco, 400 Parnassus Ave, Box 0738, San Francisco, CA 94143


Urology Article in Press, Corrected Proof

doi:10.1016/j.bpobgyn.2009.09.009
Copyright © 2009 Elsevier Ltd All rights reserved.

The XY Female

Lina Michala, MRCOGa, , Consultant Gynaecologist and Sarah M Creighton, MD,
FRCOGb, , , Consultant Gynaecologist
aAlexandras Hospital, 6 Lampsakou street, Athens, Greece
bUCL Elizabeth Garrett Anderson Institute for Women's Health, 250 Euston Road
London NW1 2PG, UK


Available online 6 November 2009.

Sexual differentiation depends upon a series of complex events that leads to the
differentiation of gonads into testicular tissue and the production and action
of androgens on genital tissue. Variations in any of the pathways affecting the
above events can lead into conditions where the phenotype and genotype are
discordant, conditions nowadays called disorders of sex development (DSDs).

These conditions may have some aspects in common such as infertility and the
need for feminising surgery or gonadectomy. However, each entity has its
particularities, and it is necessary that every effort is made to reach the
correct diagnosis. As genetic information becomes more readily available, these
conditions can be diagnosed with more ease and appropriate counselling can be
provided to other members of the family regarding the treatment options and
risk.

Due to the rarity of DSDs, it is important that their management is undertaken
in tertiary referral centres with accumulated experience on diagnosis and
management and where a multidisciplinary team can provide the necessary medical
and surgical support. Disclosure of the diagnosis should be done in a sensitive
way by experienced staff, and psychological counselling should be readily
available to patients and their family.

Keywords: 46XY DSD; swyer syndrome; frasier syndrome; denys–Drash syndrome;
CAIS; PAIS; 5a reductase deficiency; 17b ketosteroid hydroxylase deficiency;
feminising surgery; disclosure

Article Outline
Sexual differentiation
Classification/Nomenclature
Clinical presentation
Disorders of testicular development
Complete gonadal dysgenesis – Swyer syndrome
Gonadal dysgenesis associated with Wilms tumour suppressor gene mutations
(Denys–Drash syndrome and Frasier syndrome)
Mixed or Partial Gonadal Dysgenesis
Vanishing testes syndrome or testicular regression syndrome (TRS)
Disorders in androgen synthesis or action
Congenital lipoid adrenal hyperplasia
5a- reductase deficiency
17b ketosteroid hydroxylase deficiency
Complete androgen insensitivity syndrome (CAIS)
Partial androgen insensitivity syndrome (PAIS)
Leydig cell dysfunction
Congenital or acquired anomalies of the external genitalia
Disclosure of diagnosis
References

Sexual differentiation
Genetic sex is determined at conception, when the ovum is fertilised by an X or
Y chromosome containing spermatozoon. The presence of the Y chromosome will
direct testicular development, through a switch gene present on its short arm,
called the SRY gene.1 This, along with other testes determining factors (TDFs),
will guide the differentiation of the undifferentiated gonad into testicular
tissue.2

Further genital differentiation is promoted by hormones that are produced by
testicular tissue and that will lead to virilisation. Sertoli cells produce
anti-Mullerian hormone (AMH), which triggers the regression of Mullerian
structures whilst Leydig cells secrete testosterone, which promotes the
development of Woolfian structures into the vas deferens, seminal vesicles and
epididymis.3 Testosterone is further converted into dihydrotestosterone (DHT) in
the periphery, and this potent androgen leads to the virilisation of the
external genitalia.4

Ovarian tissue develops in the absence of TDFs and in the face of the
anti-testicular action of the genes DAX1, Rspo1 and WNT4. Ovaries do not produce
hormones during foetal life and the development of female genitalia is
independent of hormone production. The foetus is recognisable as male or female
at 12 weeks and this can be identified ultrasonographically from the second
trimester of pregnancy onwards.5

Classification/Nomenclature
A new terminology was proposed following a consensus conference that looked at
several aspects of care of disorders of sex development (DSDs). Conclusions from
the conference were summarised in a statement that was simultaneously published
in Europe6 and the United States7 and proposed, among other things, that
previous terms such as intersex, hermaphrodite and sex reversal should be
abandoned. Instead, the term disorders of sex development (DSDs) replaces
previous terms8; conditions are now divided, according to their chromosomal
component, into 46XX DSD, 46XY DSD and chromosomal DSD. The latter category
encompasses conditions such as Klinefelter and Turner syndrome. Each category is
then further subdivided aetiologically, into subcategories. For 46XY DSDs,
conditions are subdivided as follows:

1. Conditions where testicular development is abnormal, such as in gonadal
dysgenesis and gonadal regression,

2. Conditions where androgen biosynthesis or action is defective, such as in
enzymatic defects in the androgen biosynthesis cascade (Table 1), defects in the
androgen receptor or Leydig cell dysfunction, and

Table 1.
Enzymes involved in androgen biosynthesis.



Full-size table

View Within Article



3. Congenital anomalies of the genitalia, such as hypospadias, microphalia or
cloacal exstrophy.

The purpose of the current article is to describe conditions where there is an
XY DSD and the sex of rearing is female.

Clinical presentation
In cases where there is no potential for virilisation, such as in complete
androgen insensitivity syndrome (CAIS) or Swyer syndrome, the atypical
chromosomes are usually identified in adolescence during investigations for
primary amenorrhoea and/or delayed puberty. In conditions such as partial
androgen insensitivity or androgen biosynthesis enzymatic defects, presentation
is either at birth because of ambiguous genitalia or, if no ambiguity is
detected at birth, presentation can be with virilisation at puberty. In certain
cases where the undescended testes are within the inguinal canal, they can cause
pressure and lead to the formation of inguinal hernias in childhood, which will
hint to the diagnosis.

Asymptomatic children can be investigated if an older sibling is diagnosed with
a DSD and, finally, prenatal diagnosis allows for the knowledge of karyotype
prior to birth, which may be discordant with the phenotype as identified on
antenatal ultrasound or at birth (Table 2).


Table 2.
Clinical presentation of an XY female.

Presentation of an XY DSD Possible cause
Primary amenorrhoea with normal breast development and absent of scanty pubic
and axillary hair CAIS
Primary amenorrhoea with delayed puberty Swyer syndrome, complete gonadal
dysgensis
Ambiguous genitalia at birth Mixed gonadal dysgenesis,
5a reductase deficiency
17b hydroxysteroid dehydrogenase deficiency
PAIS
Leydig cell hypoplasia
Virilisation at puberty Mixed gonadal dysgenesis,
5a reductase deficiency
17b hydroxysteroid dehydrogenase deficiency
PAIS
Leydig cell hypoplasia
Inguinal herniae CAIS,
5a reductase deficiency
17b hydroxysteroid dehydrogenase deficiency
PAIS
Discordant phenotype to karyotype following prenatal diagnostic testing All
conditions
Testing following the diagnosis of an affected sibling All conditions

Full-size table

View Within Article



Disorders of testicular development
Complete gonadal dysgenesis – Swyer syndrome

Swyer syndrome was first described by Swyer in 19559 and was identified as yet a
new form of `hermaphroditism', where, unlike the more common forms, a uterus and
vagina were present. The condition is now thought to be caused by a mutation of
the SRY gene1 as seen in 10% of cases or a defect in a different TDF, such as
the SF-1 gene.10

The gonads remain dysgenetic and thus produce no hormones in utero, postnatally
or in puberty. As a consequence, there is no virilisation and the genitalia are
unambiguously female at birth. The lack of secretion of AMH results in the
normal development of the uterus, fallopian tubes and vagina. The affected
person typically presents in adolescence because of primary amenorrhoea,
associated with delayed puberty. The stature is tall and the uterus – although
present – may not be identified at initial assessment as it has not been
stimulated by oestrogen production.11 The mutation leading to the disorder is
usually sporadic, although certain familial cases have been described12 and,
therefore, sisters of affected individuals should be screened for the condition.
Making the diagnosis as early as possible is crucial, as the gonads have an
increased risk of becoming malignant. This can be as high as 40% and occur in
childhood or early adolescence, even before the condition is suspected.13

Management consists of induction of puberty with oestrogen administration, and
after withdrawal bleeding has occurred, administration of a combined hormonal
preparation containing oestrogen and progesterone.

The uterus has the potential to develop and grow and pregnancy is possible
through egg donation.[14], [15] and [16] Gonadectomy should be performed as soon
as the diagnosis is made, and this can be performed laparoscopically.17
Salpingectomy is usually performed at the same time, as it is important to
remove the gonads with a wide margin to remove the risk of malignancy.18 This
may, in fact, improve fertility rates, as the operated adnexum can develop
adhesions and this can lead to the formation of hydrosalpinges, which can reduce
the success of assisted reproduction.

Gonadal dysgenesis associated with Wilms tumour suppressor gene mutations
(Denys–Drash syndrome and Frasier syndrome)

The Wilms tumour suppressor gene (WT1) plays an important role in renal and
genital development and its mutations lead to renal disease, ranging from
early-onset nephropathy and nephroblastoma to gonadal dysgenesis in XY
individuals.19 Patients with Denys–Drash syndrome typically present with early
onset nephrotic syndrome and hypertension, secondary to glomerular diffuse
mesangial sclerosis resistant to treatment. Patients with a 46XY karyotype have
ambiguous genitalia and abnormally developed testes, whereas in a 46XX
karyotype, ovaries develop normally and allow for normal pubertal development.
The conditions quickly progresses to end-stage renal failure, at which time it
is usually recommended that the kidneys are removed, because there is an
increased risk of developing Wilms tumour, a form of nephroblastoma.20

Frasier syndrome is caused by mutations in intron 9 of the WT1 gene.21 Unlike
the Denys–Drash syndrome, there does not seem to be an increased risk of Wilms
tumour and the progression of renal failure is slower and occurs later in life.
Patients usually present in mid- to late childhood with focal segmental
glomerular sclerosis (FSGS), leading to nephrotic syndrome. XY individuals have
an unambiguously female phenotype with normal mullerian structures. The gonads
are, however, streak and the condition is usually identified because of primary
amenorrhoea and delayed puberty.

As with the Swyer syndrome, bilateral gonadectomy should be performed as soon as
the diagnosis has been made, because of the risk of gonadal malignancy.22

Mixed or Partial Gonadal Dysgenesis

This is a form of DSD where the gonads are dysgenetic but testicular
determination has occurred to a certain extent. Such cases present with
ambiguous genitalia and a mixture of Woolfian and mullerian intra-abdominal
structures. This condition can be associated with a 45X0/46XY mosaicism present
only in the gonad, which may not be detectable through peripheral karyotyping.
The gonads can be streak, although testicular tissue can be identified, often on
the side where mullerian regression and woolfian tube development has occurred.
Cases of mixed gonadal dysgenesis typically present at birth because of
ambiguous genitalia. It is essential that the gonads are removed, as there is a
potential for malignancy in all dysgenetic gonads.

Vanishing testes syndrome or testicular regression syndrome (TRS)

In this condition, gonadal tissue is not identified, either because of
non-formation, or because of in utero regression or destruction. It is thought
to be a rare condition with a wide spectrum of phenotypes, depending on the
timing of testicular regression, ranging from clear female phenotype, ambiguous
genitalia or male genitalia with absent testes.23 In most cases, the cause for
testicular regression is thought to be secondary to torsion during testicular
descent, leading to ischaemic necrosis of the gonadal tissue.24

Disorders in androgen synthesis or action
Congenital lipoid adrenal hyperplasia

This is due to a defect in the conversion of cholesterol to pregnenolone, the
first step in steroid production both in the adrenal glands and the gonads. The
condition is caused by a mutation in the steroidogenic acute regulatory protein
(StAR protein), which is responsible for the transfer of cholesterol within the
mitochondria.

In early congenital lipoid adrenal hyperplasia, there is some degree of
steroidogenesis, as a proportion of cholesterol is transported independently to
the StAR protein. However, as increased adrenocorticotrophic hormone (ACTH) is
produced to stimulate steroidogenesis, more cholesterol accumulates within the
cell in lipid droplets, which, in turn, damage the cellular structure and
function, further diminishing steroid production.

In XY individuals, the process of lipoid degeneration also occurs within the
testes, as their stimulation begins in utero. This leads to destruction of the
testicular structure and because no androgens are produced, the newborn is
phenotypically female.

In XX individuals, the ovaries remain unaffected until puberty, because of the
lack of stimulation. Although pubertal development occurs and withdrawal
bleeding is possible, cycles are usually anovulatory.25

5a- reductase deficiency
This condition is found in patients born with female or mildly ambiguous
genitalia, who then go on to become severely virilised at puberty, which can
lead, in some cases, to a change in gender. Larger numbers of individuals with
5a reductase deficiency were identified in the Dominical Republic, where the
condition was known as `guevedoce' meaning penis at 12 in the local dialect.
Investigation in these patients led to the identification of the defect in the
enzyme 5a reductase,26 which is necessary for the reduction of testosterone to
the more potent androgen dihydrotestosterone. The defect is transmitted in an
autosomal recessive somatic fashion and therefore is more common in
consanguineous families.

The anatomical features vary, although typically the phallus is small and the
urethral opening is on the perineum. The vagina can be absent or with its
opening not obviously visible, or it can be present, but short and blind ending.
The testes are thought to always be extra-abdominal, lying in the inguinal
canal, labia majora or scrotum.27 Spermatogenesis is impaired, possibly
secondary to the hormonal defect or to the incomplete descent of the testes.
Diagnosis is based on the clinical findings and is confirmed biochemically with
an increased testosterone-to-dihydrotestosterone ratio.

In patients where the sex of rearing is female, the gonads are removed early, to
prevent virilisation, which can be profound in puberty. Depending on the degree
of virilisation, feminising surgery may be considered to reduce the size of the
clitoris and lengthen the vagina.

Timing of genital surgery is an issue of great debate. Until recently, the
accepted practice was to perform feminising genitoplasty in infancy, as this was
thought to reinforce gender identity. However, it is now becoming clearer that
clitoral surgery affects its sensitivity.28 Furthermore, surgery performed in
childhood is likely to require revisions in adolescence.29 With this in mind,
the tendency is nowadays for avoiding surgery in cases of mild clitoromegaly.
Parents should be informed of the risks of surgery with regard to sensitivity of
genital structures and future sexual function.

If a vaginoplasty is required, this should be performed in late adolescence to
early adulthood. The preferred procedure for women with no vaginal dimple is the
laparoscopic Davydov procedure,30 where the space between bladder and rectum is
dissected and lined with peritoneum.31

17b ketosteroid hydroxylase deficiency
The enzyme 17b ketosteroid hydroxylase is necessary for the conversion of
androstenedione to testosterone. The condition is caused by a mutation in an
autosomal recessive gene and the condition, as in 5a-reductase deficiency, is
more common in consanguineous families.

It is thought to be a rare condition, although it is more commonly seen in
populations with significant geographical isolation32 or increased
consanguinity.33

The phenotype varies, although virilisation is less prominent when compared to
5a-reductase deficiency and thus, the majority of patients are reared as females
and identified at puberty because of virilisation.[*33] and [34] The diagnosis
can be made earlier if an older affected sibling is diagnosed or if the gonads
are palpable within the inguinal region. Early diagnosis allows for earlier
gonadectomy to prevent non-reversible virilisation at puberty (e.g.,
clitoromegaly, male body habitus and deepening of the voice).

Diagnosis is supported biochemically by a reduced
testosterone-to-androestenedione ratio, especially after stimulation with human
chorionic gonadotropin (hCG) and is confirmed with mutational analysis of the
enzyme.35

Complete androgen insensitivity syndrome (CAIS)
This is the most common of conditions leading to the presentation of an XY
female with an estimated incidence of 1 in 40000–60000 births.36 The condition
most commonly becomes identified in adolescence because of primary amenorrhoea,
in association with normal breast development and scanty pubic and axillary hair
growth. The external genitalia are unambiguously female. However, the vagina is
blind ending of variable length and the uterus is absent. This is because testes
produce AMH in normal amounts in utero, and this leads to the regression of
mullerian structures, including the upper third of the vagina.

The syndrome was first described by Morris in 1953 (37) and was initially called
`testicular feminisation syndrome', a name that has subsequently been rejected
as both derogatory and incorrect in its description. Testes in women with
complete androgen insensitivity syndrome (CAIS) show many similarities with
those seen in cryptorchidism, suggesting that anomalies in CAIS testes depend on
abnormal testicular position rather than androgen resistance. This is further
supported by the fact that germ cells numbers are normal in testes removed at
less than 1 year.38 Testes are normally developed and can lie anywhere within
their line of descent. They can often be located within the inguinal canal and
this can lead to the formation of an inguinal hernia. In a retrospective review
of 120 cases of CAIS, more than half had presented in childhood with a
unilateral or bilateral inguinal hernias. In approximately one-third of cases,
the gonads were palpable within the inguinal canal.39 This has led to the
conclusion that female infants with bilateral inguinal hernias should be
screened for CAIS or another XY DSD.

The cause for CAIS is a defect in the androgen receptor (AR), a nuclear receptor
that mediates the action of all androgens.40 In CAIS, as the name implies, there
is complete absence of receptor activity, whereas, in partial androgen
insensitivity syndrome (PAIS), activity can be variable, leading to a wide
spectrum of phenotypes. The gene encoding for the AR is located in the long arm
of the X chromosome and the condition is therefore X linked.

There is a small risk of seminoma; however, this appears to be low, in the range
of 3–5%, similar to cryptorchidism, and does not warrant removal of testes prior
to puberty, as few cases of malignancy have been described in adolescence.

Leaving testes in situ until after puberty allows for breast development to
happen naturally without the need for puberty induction with exogenous
administration of oestrogen. It also permits for the patient herself to make an
informed decision about the timing of surgical procedure.

After gonadectomy has been performed, women with CAIS need to remain on
long-term oestrogen replacement, mainly to protect bone mineral density.
Nevertheless, it has been shown that women with CAIS fare less well in terms of
risks of osteopenia and osteoporosis, when compared with other XY females,
possibly because of the role of androgens in cortical bone mineralisation.41 It
is, therefore, crucial, that women with CAIS remain under regular review with
bone mineral density scans, to adjust the dosage of oestrogen or add other
medication to prevent or treat osteoporosis.

Women with CAIS have a female gender identity and in the vast majority have a
female heterosexual orientation.42 The perceived impression is that they have a
potential for normal sexual satisfaction; however when this was objectively
assessed with standardised questionnaires, sexual function was shown to be
deficient, mainly due to psychological maladaptation to having a DSD and vaginal
penetration difficulties due to vaginal hyoplasia.43

Vaginal hypoplasia can be effectively managed with vaginal dilation, provided
this is accompanied by adequate psychological support in a multidisciplinary
team setting.44 Vaginal dilation, also known as the Frank method,45 consists of
inserting vaginal moulds of gradually increasing sizes and applying pressure to
the existing vaginal dimple. Completion of treatment is usually achieved in 3–5
months and is effective in approximately 80% of cases.44

Where vaginal dilation has not been effective, vaginal elongation can be
achieved with the laparoscopic Vecchietti method.46

Partial androgen insensitivity syndrome (PAIS)
If the androgen receptor retains some activity, incomplete virilisation occurs.
This leads to a wide spectrum of phenotypes, ranging from subtle virilisation,
such as mild clitoromegaly to subtle undermasculinisation, such as hypospadias
or microphallus. Thus, children with PAIS can be assigned either male or female,
depending on the degree of virilisation.47 This variation depends on the type of
mutation leading to androgen insensitivity, but can also be seen in patients
with the same mutation, sometimes even within the same family. This can be
caused by somatic mosaicism, where virilisation is mediated through the normally
functioning wild-type androgen receptor,48 or it can be caused by differences in
5a DHT availability within the genital fibroblasts.49

Where the sex of rearing has been decided as female, it is important to remove
the gonads early, to prevent further virilisation. Surgery may also be required
to reduce the size of the clitoris and create a vagina. The same principles
apply similar to those mentioned in patients with 5a reductase deficiency.

Leydig cell dysfunction
This is due to a defect in the luteinising hormone (LH) receptor (LHR). The
gonad initially develops normally into testicular tissue; however, because hCG
needs the LHR to stimulate Leydig cells, no testosterone is produced and Leydig
cells remain atrophic. Testes produce AMH normally and this leads to the
regression of mullerian structures.50 LHR inactivity leads to a variety of
phenotypes, ranging from a female adolescent that presents because of primary
amenorrhoea to a child with genital ambiguity. Diagnosis is confirmed on
histology of the gonad, which shows absence of Leydig cells.51

Congenital or acquired anomalies of the external genitalia
There are certain conditions, where male infants may be reassigned to a female
sex of rearing and undergo gonadectomy and feminising genital surgery. These
include cases where the penis is either congenitally absent, such as in
congenital microphalia, or has been traumatically ablated or in cloacal
exstrophy, where the penis is small and bifid. The tendency for many years was
to determine the sex of rearing based upon the size of the phallus, with the
presumption that phalloplasty would be technically more difficult than
vaginoplasty. However, improved surgical techniques and suggestions from
long-term outcome studies that these patients are often poorly adjusted have
challenged this practice.

Disclosure of diagnosis
Traditionally, concealment of diagnostic and treatment information from patients
was the standard practice. Doctors worried that disclosure of an XY chromosome
to a female patient would cause unbearable shock, possible psychiatric illness
and would interfere with gender identity and orientation.[37] and [52] It is
likely that this policy has contributed to a sense of secrecy and stigma as well
as preventing open and appropriate medical care. Secrecy surrounding the
diagnosis meant that families lived in fear of the child finding out of her
diagnosis. Without full information and discussion, patients are unable to give
true informed consent to investigations, treatments, genetic testing and
research. In addition, they are unable to seek support and information from
other affected individuals, leaving them feeling alone and isolated.
Dissatisfaction and dissent with this policy led to questioning of this
practice, mainly through the advent of support groups, who empowered patients to
voice their concerns.

It is now established practice to disclose the genotype53 in all cases of XY
DSDs, and this is usually done gradually in childhood and adolescence, depending
on the level of understanding and knowledge.

Disclosure of the karyotype helps explain and answer many concerns that patients
have about their condition and allow for better co-operation with the medical
profession and compliance with medical treatment. Explaining to patients and
their family about their condition means that they can make informed decisions
about their management, such as, for example, timing of gonadectomy and type of
genital surgery. It also allows for other members of the family to be screened
to detect whether they are carriers of the same condition. Such information is
difficult for doctors to disclose and for patients to understand and expert
psychological support through the process is essential.

In brief, XY females are rare conditions where a patient with a 46XY DSD is
assigned a female sex of rearing. The cause of the DSD can occur at any point of
the sexual differentiation process, such as testicular formation (gonadal
dysgenesis) and production and action of androgens (5a reductase deficiency, 17b
hydroxysteroid dehydrogenase deficiency, CAIS and PAIS).

Expert psychological support is necessary, especially around the time of
disclosure and thereafter. Management depends on precise diagnosis; however,
there are certain common features in treatment modalities, such as the surgical
removal of the gonads, the timing of which depends on the risk of malignancy and
the risk of virilisation. Feminising genitoplasty may be required in cases where
genitalia are ambiguous; however, current practice advocates delaying this
surgery until adolescence, so as to enable for informed consent on behalf of the
patients, improve compliance with postoperative treatment and reduce the risk of
repetitive corrective surgery in later life.


• A new nomenclature has been introduced, using the term DSD, short for Disorder
of Sex Development

• 46XY DSDs will present either at birth with ambiguous genitalia or in
adolescence with virilisation or primary amenorrhoea. In certain cases, a child
can be investigated when an older sibling is diagnosed with a DSD, or when there
is discordance with the anticipated karyotype result obtained during prenatal
diagnostic testing.

• Causes of 46XY DSDs included gonadal dysgensis, androgen biosynthetic defects
and androgen resistance. In certain cases, a child is reared as female in the
absence of an endocrinological abnormality. This is the case of cloacal
exstrophy, where the phallus is often deemed too small to be reconstructed.

• History and clinical examination will guide through diagnosis in many cases

• Gonadectomy will be required in most cases of XY females, because of the risk
of virilisation and malignancy

• Feminising surgery, if required should be undertaken with caution, given the
few long-term outcome data that are available. Vaginoplasty should be performed
in adolescence to prevent the risk of stenosis.

• Information regarding the condition and the karyotype should be provided to
the patient and her family.

• All DSDs should be managed in tertiary referral centres and by a
multidisciplinary team.

• Long-term outcome data on feminising surgery

• Genetic background of sexual differentiation

• Adjustment of DSDs in adulthood


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Best Practice & Research Clinical Obstetrics & Gynaecology
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