The element of doubt- disorders of sexual differentiation

Dr Caroline Brain, Great Ormond Street Hospital & UCLH, London.

How can Sexual Differentiation go wrong?

In the developing foetus, the genetic or chromosomal sex is determined at the time of
fertilization. Thus a 46XX karyotype would normally give rise to a phenotypic female, and
46XY to a phenotypic male foetus. Differentiation of the gonads into either testes or ovaries
determines the gonadal or hormonal sex and this occurs under the direction of an increasing
number of identified genes and transcription factors which may be specific for either
testicular or ovarian differentiation.
Gonadal hormone secretion determines the differentiation of the common genital tracts into
either male (Wolffian) or female (Mullerian) internal tracts, and also the development of the
external gentitalia which results in the apparent or phenotypic sex.
Subsequent development of the individual will result in the evolution of the psychological or
behavioural sex, which is an important consideration in disorders of sexual development
(DSD).
The process of sex determination and phenotypic development begins as early as the 5th week
of gestation and both internal and external genital differentiation is more or less complete by
the end of the first trimester.
Disorders of sex development arise as a result of a mismatch between the genetic, gonadal
and phenotypic sex and are the result of early disruption in the programming of sex
determination.
Broadly speaking they fall into three categories
1. Undervirilization of a genetic male (46,XY DSD)
2. Virilization of a genetic female (46XX DSD)
3. Sex Chromosome rearrangements/mosaicism e.g. XO/XY etc

1. Undervirilization of Genetic male

Results from inadequate in-utero exposure of the developing male foetus to endogenous
androgens. There are three main diagnostic categories.
Failure of normal testicular development
Gonadal dysgenesis

Impairment of testosterone synthesis/metabolism

Inactivating LH receptor mutation (leydig cell hypoplasia)
Biosynthetic defect (deficiency in specific enzymes within the pathways of
androgen production)
Lipoid hyperplasia (StAR protein deficiency)*
3 beta hydroxysteroid dehydrogenase deficiency*
17 alpha hydroxylase deficiency*
17 beta hydroxysteroid dehydrogenase deficiency

(conversion of Androstenedione to Testosterone)

5 alpha reductase deficiency
(conversion of Testosterone to Dihydrotestosterone)
(Forms of CAH resulting in impaired T synthesis*)
Impairment of responsiveness of end-organ to testosterone
Androgen receptor mutation
Complete androgen insensitivity
Partial androgen insensitivity

2. Virilization of a genetic female

Early exposure of the developing female foetus to androgens will result in development of the
genital tracts towards a male phenotype. Excess androgens usually come from the foetal
adrenal but there are rarer sources of androgen which provide a differential diagnosis.
Excessive foetal adrenal androgen production, usually congenital adrenal hyperplasia
Forms of CAH
21 hydroxylase deficiency
11 Beta hydroxylase deficiency
3 beta hydroxysteroid dehydrogenase deficiency
P450 oxidoreductase deficiency
(combination of 21 hydroxylase and 17 alpha hydroxylase)
Aromatase deficiency
(mother may also show signs of androgen excess)
Foetal gonadal androgen production
Presence of leydig cells (e.g. in Ovotestis)
Maternal/transplacental Androgens
Exogenous (now rare) Danazol, progestagens etc
Endogenous
Adrenal or ovarian tumours: mother may also be virilized
Adrenal Hyperplasia (Hypothetical as rarely causes significant foetal
virilization)

Figure 1. Adrenal steroidogenic pathwaysS

Adrenal Steroidogenesis
ACTH
Cholesterol

StAR
Cyp11a

Pregnenolone
3 -HSD

17OH

Progesterone
21-OH

17OH

DOC
11 -OH

Corticosterone

17, 20 L

DHEA

17-OH-Pregnenolone
3 -HSD

17, 20 L

17-OH-Progesterone
21-OH

3 -HSD

Androstenedione
17 -HSD

11-Deoxycortisol
11 -OH

Cortisol

Testosterone

5-reductase

DHT

Aldosterone

AR

Key to abbreviations
3-HSD =3-hydroxysteroid dehydrogenase
17 OH = Hydroxylase
17, 20 L =17, 20 lyase
21 OH= 21-hydroxylase
11OH = 11-hydroxylase
17-HSD= 17 hydroxysteroid dehydrogenase
DOC= Deoxycortisol
DHEA= Dihydroepiandrosterone
NB. There may be associated Adrenal insufficiency in DSD caused by some forms CAH
and so this must always be excluded early in the investigation protocol.

Management and Investigation

Immediate management
If in doubt never guess the sex of a baby born with genital ambiguity. The initial handling of
the parents and family is crucial to the long term psychological outcome and bonding of the
parents to their new baby.
Subsequent management & investigation
Any infant with a suspected disorder of sexual development should be managed within a
multidisciplinary team, with access to specialised laboratory and radiological facilities.
Key members of such a team ideally should include:
Clinical psychologist, geneticist, endocrinologist, urologist, gynaecologist, clinical nurse
specialist and biochemist, all with appropriate experience in the field.

Early involvement of a clinical psychologist is required to minimize the trauma of having a

baby born with indeterminate sex. This also allows for close follow-up of subsequent
psychosexual development.
Investigations are based on the results of the Karyotype and differential diagnosis and include
assessment of both gonadal and adrenal function as well as assessment of the internal genital
structures usually with Ultrasound and subsequent EUA. 1

New Nomenclature
A recent review meeting of the management of intersex disorders held in Chicago by the
LWPES (Lawson Wilkins Paediatric Endocrine Society) and the ESPE (European Paediatric
Endocrine Society) has resulted in a consensus document with a proposal for the revision of
the nomenclature to what were previously described as conditions of intersex.2
Proposed revised nomenclature
Previous nomenclature
Proposed nomenclature
Disorders of sex development (DSD)
Intersex
Male pseudohermaphrodite
46,XY DSD
Undervirilization of an XY male
Undermasculinisation of an XY male
Female pseudo hermaphrodite
46,XX DSD
Overvirilization of an XX female
Masculinization of an XX female
True hermaphrodite
Ovotesticular DSD
XX male or XX sex reversal
46,XX testicular DSD
XY sex reversal
46,XY complete gonadal dysgenesis

Reference List
1. Ogilvy-Stuart, AL, Brain, CE. Early assessment of ambiguous genitalia.
Arch.Dis.Child. 2004; 89:401-407.
2. Hughes, A, Hook, Ahmed, SF, Lee, PA. Consensus statement on management of
intersex disorders. Arch.Dis.Child. 2006; 91:554-563.