Disorders of Sexual Differentiation: A Amirhakimi, MD Pediatric Endocrinologist Shiraz University of Medical Sciences

Disorders of Sexual
Differentiation
A Amirhakimi, MD
Pediatric Endocrinologist
Shiraz University of Medical Sciences
Development of Reproductive
Systems
Begins at 4 to 5 weeks’ gestation
May be considered complete with the

development of secondary sexual
characteristics and fertility (i.e., production of
viable gametes) after puberty
Sex Determination and Sex
Differentiation
Sex determination: the bipotential gonad
develops into a testis or an ovary.
Sex differentiation: the developing gonad

functions appropriately to produce peptide
hormones and steroids.
Determination
Differentiation
Sex Development
Three major components:
1. Chromosomal sex: the karyotype (46,XX, 46,XY, or variants).
2. Gonadal sex: the presence of a testis or ovary after the process of
sex determination.
3. Phenotypic (anatomic) sex: the appearance of the external
genitalia and internal structures after the process of sex
differentiation.
Psychosexual development (“brain sex”): an unpredictable

outcome of several biologic factors, as well as
environmental and social influences.
Chromosomal Sex
Determined at the time of fertilization
A single Y chromosome:
◦ usually is sufficient to drive testis development, even
in the presence of multiple copies of chromosome X.
◦ Contains 2% of the DNA genome
X chromosome:
◦ Contains 5% of the DNA genome
Gonadal Sex
The bipotential gonad

remains indifferent
until 42 d (6wks)
The internal & external

genitalia are formed
between 9 &13 wks of
gestation.
Phenotypic or Anatomic Sex
Male Sexual Differentiation
(a more active developmental process)
Regression of Müllerian structures (uterus, fallopian
tubes, and the upper one third of the vagina)
Stabilization of Wolffian structures (seminal vesicles,
vasa deferentia, and epididymides)
Androgenization of the external genitalia (penis and
scrotum)
Descent of the testes from their origin in the
urogenital ridge to their final position in the scrotum
SertoliCells → AMH (7th wk) → Regression of
mullerian structures (9-12th wk)
Fetal Leydig Cells and Steroidogenesis

◦ Androgen production (8-9th wk, LH & hCG
independent)
◦ LH/hCG receptor (10-12th wk):
 first 2 trimesters: hCG
 after 20th wk: LH
◦ Massive leydig cell expansion (14-18th wk) → marked
testosterone secretion (16th wk)
Local
production of testosterone → stabilization of Wolffian structures
DHT → androgenization of the external genitalia and urogenital sinus
◦ urogenital sinus → prostate and prostatic urethra
◦ genital tubercle → glans penis
◦ urogenital (urethral) folds → shaft of the penis
◦ urogenital (labioscrotal) swellings → scrotum
Testis Descent (from 8th wk to mid 3rd trimester)

1. Transabdominal stage (8-15th wk)
2. Transinguinal (inguinoscrotal) stage (25-35th wk)
Subsequent Testicular Development (2nd & 3rd trimester)

Female Sexual Differentiation
Ovary is steroidogenically quiescent until the
time of puberty (estrogen synthesis → breast
and uterine development and follicular
development → regular menstrual cycles)
Specific complement of genes are implicated in
ovarian development and integrity, some of
which may actively antagonize testis
differentiation.
Female Sexual Differentiation
Mullerian structures persist
Uterine development
Lack of local testosterone → Wolffian
degeneration
External Genitalia:
 urogenital sinus → urethra and lower portion of the vagina
 genital tubercle → clitoris
 urogenital (urethral) folds → labia minora
 urogenital (labioscrotal) swellings → labia majora
Normal Sexual Development
XY
Testes
AMH Testosterone
Mullerian Testicular Wolffian DHT

Regression Descent Stabilization
Development of Male External Genitalia
Psychosexual Development
Gender identity: a person's self-representation

or identification as male or female (established
at 18-36 m/o)
Gender role (sex-typical behaviors): expression
of psychological characteristics that are sexually
dimorphic within the general population (toy
preferences, physical aggression, …)
Sexual orientation: choice of sexual partner
(e.g., heterosexual, bisexual, homosexual)
Case 1
◦ A 15y/o girl with short stature and primary
amenorrhea.
◦ Hx of recurrent ear infections, has quit school
◦ Physical exam: ht:142cm, webbed neck, low hair
line, abnormal nails
◦ Lab data: FBS: 140mg/dl, increased FSH & LH,
low estradiol
1. The most likely diagnosis?

2. Further work ups?
Case 2
◦ A 15y/o girl with primary amenorrhea.
◦ Hx of inguinal hernia repair in infancy,
episodes of weakness and paralysis.
◦ Physical exam: BP:160/100, Ht: 170cm, breast
stage: I.
◦ Lab: K:2.5, Testosterone: low, FSH & LH:
high, bone age: 11y/o
Most likely diagnosis and the most

important work up?
DSDs (Disorders of Sexual Differentiation)
Defined as “congenital conditions in which

development of chromosomal, gonadal, or
anatomic sex is atypical”
The most common cause of ambiguous
genitalia of the newborn, CAH, is classified as
46,XX DSD
The next most common cause, PAIS, is
classified as 46,XY DSD
Revised Nomenclature
DSDs = Intersex
46,XY DSD =
◦ Male pseudohermaphrodite
◦ Undervirilization of an XY male
◦ Undermasculinization of an XY male
46,XX DSD =
◦ Female pseudohermaphrodite
◦ Overvirilization of an XX female
◦ Masculinization of an XX female
Truehermaphrodite = Ovotesticular DSD

XX male or XX sex reversal = 46,XX testicular DSD
XY sex reversal = 46,XY complete gonadal dysgenesis
Ambigous Genitalia
Ambigous genitalia at birth: 1/4000
Sex assignment is based on the birth
phenotype, simultaneously accompanied by
gender assignment and sex of rearing as male
or female.
Reaching a final decision may be delayed by
the nature and complexity of the
investigations and assessments required.
Virilization of the 46XX Female (46XX
DSD)
Presence of excessive androgens during 8-13

wks of gestation
Magnitude of changes: mild clitoral
enlargement → male phallus with a penile
urethra and fused scrotum with raphe
Isolated
clitoromegaly occurs from later
androgen exposure.
Causes of Virilization in the Female
Additional Features Condition

Salt loss in some Hydroxylase Deficiency-21
Salt loss 3β-Hydroxysteroid
Dehydrogenase Deficiency
Salt retention/ HTN 11β-Hydroxylase Deficiency
Between 9 & 12 wks of gestation Androgenic Drug Exposure
Karyotype: 46XY/ 45X Mixed Gonadal Dysgenesis
Testicular and ovarian tissue True Hermaphrodite
present
Rare, Positive history Maternal Virilizing Adrenal or
Ovarian Tumor
Inadequate Masculinization of the
46XY Male (46XY DSD)
Small penis + variable degrees of
hypospadias & associated chordee or ventral
binding of the phallus + unilateral or bilateral
cryptorchidism
Microphallus without ambigous genitalia as
a result of congenital gonadotropin
deficiency is often combined with GH &
ACTH deficiencies (neonatal hypoglycemia).
Causes of Inadequate Masculinization
of the Male
Condition Additional Features
StAR Deficiency Salt loss
3β-Hydroxysteroid Salt loss
Dehydrogenase Deficiency
17-Hydroxylase Deficiency Salt retention/ hypokalemia/HTN
17-Hydroxysteroid Adrenal function: normal
Oxidoreductase Deficiency
Dysgenetic Testes Possible abnormal karyotype
Leydig Cell Hypoplasia Rare
CAIS or Testicular Feminization Female external genitalia, absence of
mullerian structures
PAIS As above with ambigous external
genitalia
5α-Reductase Deficiency Autosomal recessive, virilization at
puberty
Approach to the Infant with Genital
Ambiguity
Rapid identification of any life-threatening
condition (CAH).
Prenatal androgen exposure causes a tendency
toward a male gender identity & male gender
role.
Feasibility of genital reconstruction &
potential fertility are more important.
Extensive open discussion with parents.
Individualized treatment by a team of experts.
Diagnosis
Inguinal gonads:
◦ Testes
◦ Ovaries
◦ Ovotestes
Absent female internal genitalia: presence of AMH
secreted by fetal testes
Karyotype
Most virilized females → CAH( 21-hydroxylase def) →
17-hydroxyprogestrone & androstendione
Diagnosis is more difficult in undervirilized males.
Abnormalities of sex chromosomes may be associated
with dysgenetic gonads or persistent mullerian structures.
Treatment
Hormone replacement
◦ Steroids in CAH
◦ Testosterone
Surgical reconstruction(by 2 y/o / ?later)
Psychological support (whole family)
Removal of discordant gonad or internal organs
Risk of gonadoblastoma or dysgerminoma in
dysgenetic gonads with Y-genetic material.
Possibility of later change of gender

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Disorders of Sexual

May be considered complete with the

Sex differentiation: the developing gonad

Psychosexual development (“brain sex”): an unpredictable

The bipotential gonad

The internal & external

Fetal Leydig Cells and Steroidogenesis

Testis Descent (from 8th wk to mid 3rd trimester)

Subsequent Testicular Development (2nd & 3rd trimester)

Mullerian Testicular Wolffian DHT

Gender identity: a person's self-representation

1. The most likely diagnosis?

Most likely diagnosis and the most

Defined as “congenital conditions in which

Truehermaphrodite = Ovotesticular DSD

Presence of excessive androgens during 8-13

Additional Features Condition

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