DOI: 10.1111/tog.

12667 2020;22:257–66
The Obstetrician & Gynaecologist
Review
http://onlinetog.org

Differences of sexual development and their clinical

implications
Rhianna Davies MBBS BSc (Hons) DFMS DPM,*a Lowri Davies BSc (Hons),
b
Djavid Alleemudder MBChB MRCS (Ed)
c d
MRCOG, Jane MacDougall MD FRCOG MEd
a
SpR in Obstetrics and Gynaecology, East Suffolk and North Essex Foundation Trust, Colchester, Essex CO4 5JL, UK
b
Medical Student, St George’s University of London, London SW17 0QT, UK
c
Consultant in Reproductive Medicine, East Suffolk and North Essex Foundation Trust, Ipswich, Suffolk IP4 5PD, UK
d
Consultant in Reproductive Medicine, Cambridge University Hospitals Foundation Trust, Cambridge, Cambridgeshire CB2 2QQ, UK
*Correspondence: Rhianna Davies. Email: rhiannahmdavies@gmail.com

Accepted on 30 September 2019. Published online 9 July 2020.

Key content Learning objectives

 The term ‘differences of sex development’ (DSD) defines a wide
spectrum of conditions in which the development of
chromosomal, gonadal or anatomical sex is atypical.
 Presenting at birth or puberty, or as primary subfertility, the
precise diagnosis is difficult, the clinical management is
controversial and multidisciplinary team care is imperative.
 Following reclassification of the nomenclature and numerous
advances in the field of molecular genetics, our understanding of
the aetiologies underpinning these conditions has expanded.
 While optimal management of DSD remains controversial, it is
clear that individualised, patient-centred and multidisciplinary
care is paramount.
 To understand the basic science of sex determination and gonadal
development under hormonal, environmental and genetic control.
 To understand the natural history, presentation and management
options of DSD.
 To understand the manifold psychosexual and reproductive
ramifications of DSD.
Ethical issues
 Gender assignment, the fate of the gonads and timing of genital
surgery remain controversial.
Keywords: adolescent gynaecology / genetics / infertility /
pathology / reproductive science

Please cite this paper as: Davies R, Davies L, Alleemudder D, MacDougall J. Differences of sexual development and their clinical implications.
The Obstetrician & Gynaecologist 2020;22:257–66. https://doi.org/10.1111/tog.12667

guidance to inform optimum patient-centred care.6 There is

Introduction
Over a decade ago, a radically revised classification was
proposed for a cluster of congenital disorders in which the
development of chromosomal, gonadal or anatomical sex is
atypical.1 A major drive for the new classification was growing
pressure from patient groups regarding the derogatory
connotations of the historical terminology.2 This was
supported by clinicians who, following expansion in
understanding of molecular genetics and increased awareness
of the potential for malignant transformation, were
acknowledging the inaccurate and nonspecific nature of the
previous nomenclature.1,2,3 Controversial terms such as
‘hermaphrodite’, ‘pseudohermaphrodite’ and ‘sex reversal’
were abolished, and the umbrella term ‘intersex disorders’ was
replaced with ‘disorders of sex development’.3,4,5 There is,
however, continuing disquiet with regard to terminology; for
example, the word ‘differences’ is often preferred to ‘disorders’
of sex development and ‘atypical’ preferred to ‘ambiguous’
genitalia.2 Physicians must remain mindful of – and sensitive to
– this issue. This is a highly topical and controversial area, with
a paucity of long-term outcome data or evidence-based
great debate over the timing, technique and ethics of childhood
genital surgery; indeed, it is now banned in some countries.7
Review of normal sex development
Prior to 6 weeks of gestational age, male (with XY karyotype)
and female (with XX karyotype) embryos are
indistinguishable, containing bipotential gonads and both
m€ullerian and wolffian ducts.3 In the presence of a
Y chromosome, the gonads will begin to develop into testes
and the sequential cascade of mediators of the male
developmental programme will be instigated3,5 (Figure 1).
The sex-determining region Y gene (SRY) triggers an intricate
series of gene expression, causing further development and
differentiation of cells within the testes.3,5 Under the influence
of SRY, the testicular Sertoli cells secrete anti-m€ ullerian
hormone (AMH), which stimulates involution of the
m€ullerian ducts.3,8 Production of testosterone by the
testicular Leydig cells promotes maturation of the wolffian
ducts into the male internal genitalia of epididymis, vas
deferens and seminal vesicle.3,5,8 In the female, the lack of AMH

ª 2020 Royal College of Obstetricians and Gynaecologists 257

 Differences of sexual development

XY Bipotential
XX
[SRY] gonad

Gonads Testes Ovaries

No
Testosterone AMH No AMH
testosterone

Maintenance Obliteration Obliteration Maintenance

of wolffian DHT of müllerian of wolffian No DHT of müllerian
ducts ducts ducts ducts

Internal
5AR
genitalia

External
genitalia

Figure 1. Normal sexual development. 5AR = 5a-reductase; AMH = anti-m€

ullerian hormone; DHT = dihydrotestosterone; SRY = sex-determining
region Y gene.

and testosterone results in maintenance of the m€ ullerian ducts
and regression of the wolffian ducts, respectively.3,5 The
m€ullerian ducts mature into the female internal genitalia of
uterus, cervix, fallopian tubes and the upper two-thirds of the
vagina.3,5 In both sexes, the rudimentary external genitalia
comprise the genital tubercle, the urogenital folds and the
genital swelling.3 In the male, under the influence of
dihydrotestosterone (DHT) which is converted peripherally
from testosterone by the enzyme 5a-reductase (5AR), the
tubercle becomes the glans, the folds become the penile shaft
and the swellings become the scrotum.3,5,8 In the female, the
absence of these hormones results in the transformation of the
tubercle to the clitoris, the folds to the labia minora and the
swellings to the labia majora by the 12th gestational week.3,5
Contrary to the previous dogma that female is the default
position, research increasingly shows that the development of
the female also requires active signalling pathways.8
Pathophysiology
Gonadal dysgenesis describes the complete or partial failure of
formation of the gonads caused by genetic error, infection,
infarction or autoimmune events.1,9,10 Ovotesticular
differences of sex development (DSD) describes the presence
of both male- and female-specific gonadal tissue within the
same individual.1,9,10 Testicular DSD describes testicular tissue
in an XX individual.1,9,10 Though truly atypical genitalia affect
only 1 in 4500–5000 live births, the incidence of anomalies of
the genitalia can be as high as 2%.9,11 Grossly, the various
pathologies can be understood by the location of the primary
dysfunction within the stepwise cascade of normal sex
development. Inheritance of one sex chromosome from each
parent dictates whether the embryonic bipotential gonad is
destined to develop into a testis (46, XY) or an ovary (46, XX).
Aberrations in inheritance of these chromosomes include
Turner syndrome (45, X0) and Klinefelter syndrome
(47, XXY).1 It also includes mosaic karyotypes (45, X0/46, XY)
leading to either partial gonadal dysgenesis or ovotesticular
DSD, and chimera karyotypes (46, XX/46, XY) causing
ovotesticular DSD.1,9 Despite normal inheritance of sex
chromosomes, other factors can derail appropriate
transformation of the bipotential gonad into a sex-specific
gonad. For example, translocation of SRY to an X chromosome
of a 46, XX individual activates differentiation of testicular
material within the gonad, resulting in either testicular or
ovotesticular DSD.10 The corollary, defunctioning mutations of

258 ª 2020 Royal College of Obstetricians and Gynaecologists

 Davies et al.

Table 1. Summary and examples of the classification of differences of sex development1

Summary and examples of the classification for DSD1

Sex chromosome DSD 45, X0 Turner syndrome

47, XXY Klinefelter syndrome

45, X/46, XY (mosaic) Mixed gonadal dysgenesis

Ovotesticular DSD

46, XX/46, XY (chimera) Ovotesticular DSD

46, XY disorders Disorders of gonadal development Gonadal dysgenesis (e.g. Swyer syndrome)
Ovotesticular DSD

Disorders in androgen synthesis/action 5AR

CAIS/PAIS
17b-HSD3 deficiency
LH receptor defects

Other Cloacal exstrophy

46, XX disorders Disorders of gonadal development Gonadal dysgenesis

Testicular or ovotesticular DSD

Androgen excess Congenital adrenal hyperplasia

Exogenous androgens

Other Cloacal exstrophy

M€ullerian duct anomalies

17b-HSD3 = 17b-hydroxysteroid dehydrogenase 3; 5AR = 5 a-reductase; CAIS = complete androgen insensitivity syndrome; DSD = differences of sex
development; LH = luteinising hormone; PAIS = partial androgen insensitivity syndrome

SRY in a 46, XY individual causes gonadal dysgenesis
(Swyer syndrome).11 Formation of the internal and external
genitalia depends upon the ability of the gonad, or its
downstream mediators, to function in a gender-specific
pattern.5 Aberrations at this stage of development, subsequent
to appropriately inherited sex chromosomes, result from a
defect in either the synthesis or action of hormones.3,5,12
Classification
DSD has been subdivided into sex chromosome DSD;
46, XY DSD; and 46, XX DSD1 (Table 1). The terminology
can be confusing and, in a bid to stratify conditions by
karotype rather than by phenotype,1 there is considerable
overlap within the classification.
1. Sex chromosome DSD describes an abnormal karyotype –
i.e. Turner syndrome (45, X0), Klinefelter syndrome
(47, XXY), and mosaic (45, X0/46, XY) and chimera
karyotypes (46, XX/46, XY).
2. 46, XY DSD incorporates any condition, irrespective of
physical appearance, in which the karyotype is 46, XY. This
includes XY gonadal dysgenesis – e.g. Swyer syndrome;
46, XY ovotesticular DSD; disorders of androgen synthesis
and action; and miscellaneous entities such as cloacal
exstrophy. The more common 46, XY DSDs are those
resulting in under-virilisation because of defects in
hormonal signalling, including receptor defects, enzyme
deficiencies and end-organ resistance.3,5,12,13
3. 46, XX DSD incorporates any condition, irrespective of
physical appearance, in which the karyotype is 46, XX. This
includes 46, XX gonadal dysgenesis; 46, XX ovotesticular and
testicular DSD; virilisation caused by androgen excess; and
miscellaneous entities such as cloacal exstrophy and
m€ullerian duct anomalies. Virilisation secondary to excess
androgen exposure in congenital adrenal hyperplasia (CAH)
accounts for 60–70% of all atypical genitalia in newborns.5
Virilisation can also occur because of placental aromatase
deficiency or maternal androgen-secreting tumours.11
Sex chromosome DSD
Turner syndrome
Turner syndrome is caused by 45, X0 – the most common
female sex chromosome aneuploidy. It can also be caused by

ª 2020 Royal College of Obstetricians and Gynaecologists 259

 Differences of sexual development
a mosaicism, whereby some cells carry 46, XX and some carry
45, X0.1,14 It commonly presents with short stature, ovarian
hypofunction or premature ovarian failure and, while some
patients may spontaneously enter puberty, few will progress
to menarche and full development of secondary sexual
characteristics without the aid of exogenous hormones.14
46, XY DSD
Complete and partial androgen insensitivity syndrome
Resistance of the androgen receptor or its mediators to the
binding of testosterone and DHT results in androgen
insensitivity syndromes (AISs). In complete AIS (CAIS), the
karyotype is XY and the gonads are testes.3 M€ ullerian
structures appropriately regress under the influence of AMH.
In the presence of minimal testosterone action, the wolffian
ducts are maintained in half of all cases.5 At birth the external
genitalia have female appearances because of a lack of DHT
action.12 Breasts usually develop normally because
testosterone is peripherally converted to estrogen.3 At
puberty, a phenotypic female will present with primary
amenorrhoea, normal breasts and scant pubic and axillary
hair. In childhood they may have bilateral inguinal hernias,
which may contain undescended testes.12 Individuals with
CAIS have usually been assigned a female gender in infancy
and generally continue as such.13 In partial AIS (PAIS), too,
the karyotype is XY and the gonads are testes.5 M€ ullerian
structures regress under the influence of AMH. However,
differing degrees of insensitivity result in varying
development of wolffian structures.3 The appearance of the
external genitalia is variable, but hypospadias is common and
most patients are raised as male.1,4,15.
Luteinising hormone receptor defect
A defect in the luteinising hormone (LH) receptor renders
the testicular Leydig cells of an XY individual insensitive to
stimulation to produce testosterone.16 The presentation is
similar to that of CAIS; however, the defect is deficiency of,
not insensitivity to, testosterone. Hence, deviation of
androgens toward the estrogenic pathway and subsequent
breast development does not occur.16
17b-hydroxysteroid dehydrogenase 3 deficiency
Conversion of the weaker androgen androstenedione to
testosterone is catalysed by the enzyme 17b-hydroxysteroid
dehydrogenase 3 (17b-HSD3).3,5,10 A defect in expression of
17b-HSD3 results in the inability to convert androstenedione
to testosterone in the volumes required for normal
development of male-specific internal structures.10 The
genotype is XY, the gonads are testes and m€ ullerian
structures are appropriately absent because there are intact
Sertoli cells that produce AMH.3 The external genitalia are
atypical or of female phenotype because of insufficient
260
testosterone and, consequently, DHT. Unexpectedly, the
wolffian structures develop to epididymus, vas deferens and
seminal vesicle – a process known to be reliant upon
testosterone.17 This is thought to be associated with
isoenzymes of 17b-HSD3 that are resident in peripheral
tissues outside of the gonad and are unaffected by the genetic
defect in the gene.17 At puberty, increasing levels of LH result
in higher levels of androstenedione, which is converted by
isoenzymes in extragonadal tissues to testosterone. This
causes the development of male secondary sexual
characteristics, such as growth of the external genitalia,
increased muscle mass, body hair and deepening of the
voice.5,12,10,17 Deficiency in 17b-HSD3, often misdiagnosed
as CAIS, is autosomal recessive and rare in most populations.
However, there is increased incidence in Gaza associated with
consanguinity.16,18 Individuals, previously raised as female,
will present at puberty with primary amenorrhoea and
virilisation.12 Some will develop breasts because excess
androstenedione is converted to estrogens.10
5a-reductase deficiency
In the 1970s, reports of the Machihembras (‘first woman,
then man’) led an American endocrinologist to travel to a
village in the Dominican Republic.19 Colloquially called
Guevedoces (‘penis at 12’), 2% of the population were born
with female-appearing genitalia, before developing male
genitalia at puberty.19 They were found to have 5AR
deficiency, preventing the conversion of testosterone to
DHT. With 5AR deficiency, the karyotype is XY, the
gonads are testes, m€ ullerian structures have appropriately
regressed with the presence of AMH and the wolffian ducts
have developed into male internal reproductive tracts under
the influence of testosterone. The external genitalia, however,
have developed in the female-specific pattern in the absence
of DHT. At puberty, alternative isoenzymes that are capable
of converting testosterone to DHT are produced, resulting in
virilisation of the external genitalia.12 Antenatal and postnatal
exposure of the brain to testosterone is thought to contribute
to a male gender identity in many individuals with
5AR deficiency.12
46, XX DSD
Congenital adrenal hyperplasia
CAH describes a spectrum of enzyme deficiencies resulting in
disruption of adrenal steroidogenesis, with varying metabolic
and biochemical consequences depending on the location of
the rate-limiting step (Figure 2). Enzyme deficiencies within
the mineralocorticoid and glucocorticoid pathways result in
absence of glucocorticoid and mineralocorticoid end
products, accumulation of steroid precursors and deviation
toward the androgen pathway of dehydroepiandrosterone
(DHEA), androstenedione and testosterone. In the female,
ª 2020 Royal College of Obstetricians and Gynaecologists
 Davies et al.

Mineralocorticoid Glucocorticoid Sex steroid

pathway pathway pathway

17α-hydroxylase 17α-hydroxylase
Pregnenolone 17-hydroxypregnenolone DHEA
3β-OH dehydrogenase 3β-OH dehydrogenase 3β-OH dehydrogenase
17α-hydroxylase 17α-hydroxylase
Progesterone 17-hydroxyprogesterone Androstenedione Estrone
21-hydroxylase 21-hydroxylase 17β-OH dehydrogenase

11-deoxycorticosterone 11-deoxycorticosol Testosterone Estradiol

11β-hydroxylase 11β-hydroxylase 5α-reductase

Corticosterone Cortisol DHT

18-hydroxylase

18-OH corticosterone
18-OH hydroxylase

Aldosterone

Figure 2. Steroidogenesis with highlighted examples of relevant hormone deficiencies. DHEA = dehydroepiandrosterone;
DHT = dihydrotestosterone.

the classical, more severe subtypes of these enzyme
deficiencies present at birth with virilised external genitalia,
ranging from cliteromegaly to a normal-looking phallus.15
Hyperpigmentation induced by adrenocorticotropic
hormone results from deficiency in glucocorticoid end
products.5 Those with the nonclassical, milder forms are
likely to be born with normal female external genitalia and, at
puberty, present with virilisation and amenorrhoea.10 Their
growth spurt may be earlier, but their ultimate height
potential will be reduced.10 Deficiency of 21-hydroxylase
(21-OH) accounts for over 90% of CAH cases. Of these, 75%
will have the salt-wasting subtype that causes hypotension
because of mineralocorticoid deficiency.10,20 The second
most common cause of CAH is 11b-hydroxylase (11b-OH)
deficiency, which – by contrast with 21-OH deficiency –
results in salt retention and consequential hypertension
caused by accumulation of deoxycorticosterone, a moderately
potent mineralocorticoid.5 Another form of CAH is
3b-hydroxysteroid dehydrogenase (3b-HSD) deficiency.
3b-HSD is active in all three pathways of steroid synthesis,
hence its absence results in degrees of deficiencies in
glucocorticoid, mineralocorticoid and androgen end
products, with or without life-threatening saltwasting,
depending on subtype.5,10,20 The role of 3b-HSD is to
catalyse the conversion of DHEA, a weak androgen, to
androstenedione.20 Deficiency in 3b-HSD causes atypia of
genitalia in both XY and XX individuals.20 In the female,
sufficient DHEA is converted by the liver to cause – often
mild – virilisation of external genitalia.20 It is, however,
insufficient to fully virilise the male, resulting in a range from
hypospadias to completely atypical genitalia.20
Investigation
Thorough investigation includes taking a history,
examination, biochemical analysis, genetic scrutiny,
imaging and possible surgical exploration and biopsy. This
is with the intention of providing a diagnosis at the molecular
genetics level to aid individual management planning, long-
term risk stratification and genetic counselling.6 The number
of examinations should be limited to a minimum and with
explicit and informed consent.6 It is anticipated that whole-
genomeand-exomesequencing will be considered mainstream
within the next 5 years.21
Infant with atypical genitalia and/or bilateral
impalpable gonads
A thorough obstetric history aims to elicit evidence of drug
use that could virilise a female fetus,3,11,22 or maternal
virilisation that may indicate a maternal androgen-secreting
tumour or placental aromatase deficiency.11,23 The
gestational age of the fetus is relevant because, in a
preterm female baby, the clitoris and labia minora are
relatively more prominent, and in the male, the testes
remain undescended until 34 weeks of gestation.11 A family
history includes history of consanguinity, atypical genitalia,
unexplained neonatal death, stillbirth, multiple miscarriage,
abnormal pubertal development, genital surgery, need for

ª 2020 Royal College of Obstetricians and Gynaecologists 261

 Differences of sexual development

steroid replacement and infertility.3,11,22,23 A general
inspection for dysmorphic features, associated anomalies
and stigmata of corticosteroid insufficiency is
important.3,11,23 Examination of the external genitalia
includes assessment for the location of palpable gonads,
position and presence of urethral meatus, degree of fusion
of the labioscrotal folds, presence of a vaginal opening
separate from the labioscrotal folds and size of the genital
tubercle.3,4,11,22,23 An aggregate score is used to give a value
on the External Masculinisation Score, which is currently
being reworked to offer a nonbinary alternative to the
more commonly used Prader Scale.6,24,25
the presence of secondary sexual characteristics, investigation
of primary amenorrhoea is advised at the age of 14. In the
absence of secondary sexual characteristics, investigations
should be commenced at the age of 16, or if 5 years have
passed since the initial onset of breast development.28,29
22,23
1. Assess serum electrolytes
Tests should be performed to establish levels of the following:
- Sodium
- Potassium
2. Assess hormone levels 11,23

3,11,22,23
Tests should be performed to establish levels of the following:
1. Exclude a life-threatening salt-wasting crisis - Estradiol
Tests should be performed to establish the following: - Testosterone
- Serum electrolytes - Androstenedione
- Serum 17OH progesterone - Sex hormone binding globulin (SHBG)
- Plasma glucose - Thyroid function tests
- Urinary steroid profile to confirm a diagnosis of CAH - Prolactin
- Follicle-stimulating hormone (FSH)
2. Ultrasound abdomen/pelvis - LH
Transabdominal ultrasound is considered the first-line
imaging modality to define the internal genitalia, though it 11,23
3. Take an ultrasound of the abdomen/pelvis
may not identify a prepubertal uterus.23,26. Magnetic This is to determine the presence of m€
ullerian structure.
resonance imaging (MRI) is reserved for such cases, or if
there are abnormalities of the renal tract.23 4. Establish karyotype
This is indicated in the presence of normal breast
3. Establish the sex chromosomes development if either a uterus is absent on ultrasound or
If the karyotype is found to be anything other than 46, XX, FSH/LH levels are raised.23
the second cascade of investigations is instigated, which is to
establish the presence and function of testes.23
Adolescent girl presenting with virilisation
4. Establish the presence and function of testes Primary amenorrhoea plus virilisation at puberty is a classic
AMH levels are a marker of Sertoli cell function and, as such, presentation of 17b-HSD3 deficiency and 5AR deficiency.23
can differentiate between those without functioning testicular The psychological impact of examination and medical
tissue and those with androgen biosynthetic defect or photography should be considered.30 Imaging can reduce
insensitivity.3,11,23,27 Human chorionic gonadaotrophin the need for physical vaginal examination, which – if
stimulation, followed by testing levels of the androgens required – should be performed as part of an examination
testosterone, androstenedione and DHT, can be used under anaesthetic.23
similarly.3,11,23,27 This test is invasive and considered second-
line.23 A poor testosterone response may suggest 3b-HSD or 1. Assess hormone levels23
17b-HSD3 deficiencies and is an indication for a short Tests should be performed to establish levels of the following:
SynACTHen test.11,23 Streak gonads can be difficult to visualise - Testosterone
on ultrasound and MRI, so genitoscopy or laparoscopy may be - Androstenedione
indicated.23 Laparoscopy has the benefit of being able to - SHBG
provide a tissue sample, and an attempt to bring the gonads - DHEA
down into the scrotum can be made if required.23 - 17OH progesterone
- FSH
Adolescent girl with primary amenorrhoea - LH
Investigation includes a history of weight loss, exercise, stress,
chronic disease and family history; an assessment of height, 2. Take a urinary steroid profile
weight and blood pressure; and inspection for evidence of This is to diagnose CAH, androgen-secreting adrenal
secondary sexual characteristics and signs of virilisation.23 In tumours and 5AR deficiency.11,23

262 ª 2020 Royal College of Obstetricians and Gynaecologists


3. Take an ultrasound of the abdomen/pelvis
M€ullerian structures will be present in CAH and in cases of
androgen-secreting tumours, but absent in 17b-HSD3
deficiency, 5AR deficiency and CAIS.
4. Establish karyotype
A karyotype is indicated if ultrasound reveals the absence of
m€ullerian structures.23
Management
Psychological support
A baby born with atypical genitalia can be a crisis for the family
and requires sensitive, collaborative and lifelong care.22 An
individualised, patient-centred care plan should be formulated
by an experienced multidisciplinary team, inclusive of
psychological services, alongside a fully informed patient and
their family.2,3,6,22 Transmission of information and
communication should be a continual process, in age-
appropriate language and often in personalised vocabulary.6
Signposting the patient towards peer support networks is
beneficial because these have been shown to improve
psychological wellbeing.6 There is work to be done to better
the psychological management of patients with DSD, especially
in the provision of care during transition from paediatric to
adult services, or lack thereof.6 International registries are being
formed and research collaborations are exploring psychological
outcomes with regard to genital surgery.31
Gender assignment
‘Sex’ is a biological term describing an individual’s karyotype,
gonads or reproductive organs, while ‘gender’ is a social term
that refers to the psychological experience of being male, female
or other.6 Previous wisdom dictated that gender should be
assigned as a matter of urgency to aid familial bonding and
reduce parental distress;32 however, more recently, allowing
time for investigation and multidisciplinary discussion is
encouraged.33 The fundamental aim of gender assignment is
to avoid selecting a gender that is ultimately incongruent with
the patient’s gender identity. How that individual might identify
as they develop into an adult is not wholly predictable; however,
there are certain factors that may aid decisionmaking, such as
fertility potential, fetal brain androgen exposure in utero, the
anatomy of the external genitalia and amenity to functional
surgical repair.2,22 Though rates of gender dysphoria are greater
than background in those with DSD, there is evidence that the
initially assigned gender is the best predictor of gender identity
as an adult.34,35 Alternatively, some families are electing to raise
their child as gender neutral until they are old enough to decide
for themselves.22 Gonadotrophin-releasing hormone can be
given at puberty to temporarily block virilisation by retained
testes to allow the child time to decide their gender.15
ª 2020 Royal College of Obstetricians and Gynaecologists
Davies et al.
Comorbidities
DSD can be associated with increased cardiovascular,
metabolic, autoimmune and neuropsychiatric
morbidities.6,22,26,36,37 Reduced bone mineral density is a
common feature of DSD secondary to estrogen deficiency
and is also found in 70% of women with CAH secondary to
exogenous corticosteroids.2,37,38 Short stature is a feature of
Turner syndrome, and growth hormone is licensed to
promote bone growth and maximise adult height.39
Hormone replacement therapy
Exogenous hormones that are carefully tailored to mimic
physiology can be given to patients with insufficient gonadal
function who may not otherwise spontaneously reach
puberty.2,14,22 Inducing puberty using exogenous estrogens
aims to develop secondary sexual characteristics and growth
of the uterus, promote an adolescent growth spurt, normalise
bone mass and aid psychological maturation.40 There are no
randomised control trials for the optimal approach to
induction of puberty, but guidance led by expert opinion
suggests an ideal starting age of 11–12 years, low starting
doses of estrogen and slow incremental increases, followed by
subsequent introduction of a cyclical progestogen to induce
bleeding and reduce the risk of endometrial hyperplasia.2,40
Suggested estrogen regimens include oral ethinylestradiol,
oral 17b-estradiol and transdermal 17b-estradiol, with no
robust data to suggest either route is superior.40 Estrogen
given at too high a dose early, or increased at too fast a rate,
will impair final height attainment and breast development.40
Hormone replacement therapy should be continued until the
age of natural menopause.40
Fertility
The decision about which gender to raise a child in may be
dictated in part by fertility potential in the chosen gender.2
Fertility is affected by hormone levels, the presence of a uterus
and the ability for sexual functioning, with regard to both
anatomical and psychosexual factors.37 Previous genital surgery
may affect both sexual function and delivery options.37 Some
women with Turner syndrome, especially mosaic Turner
syndrome, may have adequate ovarian function to
spontaneously enter menarche before subsequent premature
ovarian insufficiency.14,41 As such, early oocyte
cryopreservation or embryo freezing may be an option.41 For
those with CAH, spontaneous conception is possible, but the
pregnancy course may be complicated and should be managed
in a specialist centre.37 XY females with a uterus may be able to
carry a pregnancy by egg donation.37 In 2015, the first live birth
following uterine transplant was reported.42 An exciting new
avenue that is currently still at the experimental stage is that of
ovarian tissue freezing – this has the aim of germ cell harvesting
for future autologous retransplantation.43
263
 Differences of sexual development
Gonadectomy
The fate of the testes, often undescended, remains
controversial.2,22 Traditionally, the gonads were removed at
diagnosis.2 Supporters of their early removal cite that the
presence of gonads incongruent with assigned gender is
distressing and, in female-assigned XY individuals, retention
of testes risks virilisation at puberty.12 Malignancy risk is also
a consideration.1,2,44 The prevalence of germ cell tumours is
15% in PAIS, 30–50% in gonadal dysgenesis and 28% in
17b-HSD3 deficiency, compared with 0.8% in CAIS.1,2,44 In
the DSD subtypes with lower malignancy risk, early
gonadectomy has been challenged because delaying it
allows spontaneous onset of puberty and bone maturation
by the aromatisation of testosterone to estrogen without the
need for exogenous hormones.2,37,45 Deferring removal of the
gonads allows the adolescent to make an autonomous
decision regarding surgery.2 Furthermore, there have been
reports of an association between gonadectomy and loss of
libido.2 Increasingly, with the low associated malignancy risk,
women with CAIS are choosing to avoid gonadectomy
entirely.46 They must, however, be counselled that imaging
modalities and tumour markers are not sensitive for
monitoring or screening purposes.46 In DSD groups with
high risk for malignancy, such as 46, XY gonadal dysgenesis,
early gonadectomy continues to be advised.44
Feminising genitoplasty
Genital surgery in DSD includes vaginoplasty and genitoplasty
(cliteroplasty with or without labioplasty). It aims to facilitate
penetrative intercourse and favourable cosmetic appearance, to
separate the vagina and urethra to reduce urinary
complications, and to achieve gender-typical urination.2,45
These procedures are most commonly encountered for virilised
female genitalia in CAH and female-assigned XY DSD.2,45 There
is a lack of agreement on optimal technique and timing of
genitoplasty.2 Historically, surgery was performed in infancy to
align assigned gender with the genital appearance as it was
thought to enhance psychological wellbeing.47,48 However,
there has been considerable opposition in recent years, and it has
been argued that the data are scant and the evidence base is
poor.1,6,45,49,50 The long interval between childhood procedure
and follow-up for adult outcome means the surgical technique
studied is often no longer contemporaneously used.6 There is
some evidence of improved surgical outcomes when performed
in infancy.15,51 Recent intrauterine exposure to estrogens may
make vaginal tissue more amenable to reconstruction, though
exogenous estrogen levels are higher after puberty.45,51 When
performed as a single procedure, resected tissue can be utilised;
for example, phallic skin removed at cliteroplasty can be used in
the reconstruction of the vagina.2 However, vaginal stenosis is a
common complication and the need for postoperative long-
term vaginal dilatation is almost universal.52 There is no
264
functional need for a vagina in childhood, so delaying a
potential vaginoplasty until adolescence allows the patient to
participate in vaginal dilatation either as a standalone
intervention or postoperatively.45 Some argue early
genitoplasty may commit a patient to an undesired gender
assignment, therefore deferring surgery until the individual is
old enough to make an autonomous decision about their own
gender identity may be desirable.6,15 A study found 39% of
patients who had undergone genitoplasty showed regrowth of
the clitoris in adolescence, further supporting the argument for
delayed surgery.52 Cliteroplasty is particularly contentious
because the sole function of the clitoris is sexual pleasure and the
main risk of cliteroplasty is impaired innervation.45 Evidence
suggests DSD patients who have undergone genitoplasty report
decreased sexual activity, reduced libido and increased pain
with intercourse.53,54 Studies also show poor patient and
physician satisfaction with postoperative cosmetic results.53 As
such, there has been a move towards avoidance of infant genital
surgery unless medically indicated and avoidance of
cliteroplasty in cases of mild virilisation.1,49,50 Activists have
lobbied for a ban on genital surgery without the patient’s
informed consent; this has become legislation in some
countries, such as Germany.7 The Chicago Consensus1 and
Endocrine Society49 recommend consideration of feminising
genitoplasty in cases of CAH with moderate and severe
virilisation. The current guidance is that if a child is
undergoing genitoplasty for virilised genitalia, then
vaginoplasty with separation of the common urogenital sinus
should be performed at the same time.33,49 For those with a
hypoplastic vagina, first-line treatment is nonsurgical vaginal
dilatation.55 This should not be attempted prior to adolescence
because it requires the patient’s commitment and motivation.2
Success rates, as measured by vaginal calibre and ability to have
intercourse, are quoted as being as high as 80%.56 For those who
find vaginal dilatation unsuccessful, unacceptable or
intolerable, surgical vaginoplasty is considered the second-
line treatment.2
Conclusion
DSD encompasses a complex cluster of conditions with
lifelong ramifications for the patient, their family and their
partners. Scientific expansion in the areas of molecular
genetics and assisted reproductive techniques has improved
the diagnosis, management and fertility potential for many of
these individuals. Decisions about which gender to raise a
child as, genital surgery and the fate of the gonads (often
incongruent with assigned gender) remain controversial.
Positive changes have been made with regard to
nomenclature, but there is scope for further clarity and
sensitivity. The lack of evidence-based guidance, twinned
with pressures from patient user and support groups, is
driving change and raising research collaborations. While our
ª 2020 Royal College of Obstetricians and Gynaecologists
 Davies et al.

knowledge of the exact mechanisms underpinning several of 20 Sahakitrungruang T. Clinical and molecular review of atypical congenital
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