Endocrine Basis of

Intersexual Conditions
By
Prof. A O. Arowojolu (FMCOG; FWACS; FRCOG)
Introduction.
Intersex:
 A state of confusion in the determination of

the sex of an individual.

 Male and female sex organs occurring

together in a single person.
Defining Sex.
Sexual identity (Organic sex)
The biologic sexual differentiation

 Chromosomal sex
 Gonadal sex
 Internal genital sex
 External genital sex
 Hormonal sex
Defining Sex cont.
Gender identity (Psychological sex).

Inner sense of owns maleness / femaleness.

 Sex of rearing
 Gender role
Human sexual differentiation

Chromosomal sex

Gonadal sex

Internal genital sex External genital sex

SEX ASSIGNMENT

Sex of rearing Gender identity

and role
Gonadal development
Genetic basis of sexual
differentiation
 46XX – female
 46XY – male

 Initial development – indifferent

 Y chromosome – presence/absence
determines development of ovary/testis from
indifferent gonad
Summary: Genetic determination
of gonad
 SRY gene – sex determining region of Y
chromosome.

 Located on short arm of Y chromosome (Yp)

 Operate early in development (master gene)

 Controls other genes on autosomes and X

chromosome

 Formation of testis – combined effect of

genes
Y chromosome
Gonadal development
H -Y-gene (TDF)
Short arm of Y chromosome

Present Absent
Bipotential Gonad

2 X chromosomes
Receptors
For H -Y antigen

TESTES OVARY
Other genes involved in gender
differentiation
Conversion of mesoderm to bi-potential
gonad
 WT1 (Wilm’s suppressor gene)
 NR5A1 (nuclear receptor 5 gene group A1)

Differentiation to testis.
 SRY
 SOX genes

Synthesis of steroids (testosterone)

 SF1 gene (chromosome 9)
Other genes involved cont.
Differentiation to ovary
 DAX1 gene (short arm of X chromosome)

Atrophy of paramesonephric (Mullerian)

duct
 Gene coding for AMH (chromosome 9)

Other autosomal loci involved in

testicular/ovarian development
Stages of differentiation of
genital tract
 Differentiation of gonad
 Differentiation of internal genital organs
 Differentiation of external genitalia

Differentiation of internal genital

organs/external genitalia dependent on
endocrine gland functions.

Long course of reproductive development

Summary of Normal Sex
Differentiation
 Genetic sex is determined at fertilization.
 Testes develop in XY fetus, ovaries develop in

XX fetus.
 XY fetus produces MIF and androgens and XX

fetus does not.

 XY fetus develops Wolffian ducts and XX fetus

develops Mullerian ducts.

 XY fetus masculinizes the female genitalia to

make it male and the XX fetus retains female

genitalia.
Summary of hormones contributing
to normal sex development and
differentiation.
 Wolfian evocator: initiates male genital
organs development.
 Mullerian Inhibiting Factor: Degeneration of

Mullerian duct.
 Testoesterone: Initiates and controls internal

male sexual organs development

 Hydroxytestoesterone: controls the

development of male external genitalia.

 Male development
TESTIS

Leydig Sertoli
cells cells
Mullerian inhibiting
Testosterone factor

Wollfian duct 5α-reductase

DHT
Regression of
Mullerian ducts
Urogenital sinus
Male internal
Genital organs Male external genitalia
 Female development
Neutral
Development

OVARY

Urogenital sinus Mullerian ducts

Female external genitalia Female internal genital

. Lower part of vagina Organs
. Most of upper vagina
. Cervix and uterus
Absence of androgen exposure . Fallopian tubes
Internal genital organs development
External genital organs develoment
Urogenital sinus

Male Female
INTERSEX
An individual in whom there is discordance
between chromosomal, gonadal, internal genital,
and phenotypic sex or the sex of rearing.

g INTERSEXUALITY:
Discordance between any two of the organic sex
criteria

g TRANSSEXUALITY:
Discordance between organic sex and
psychological sex components
CLASSIFICATION OF
INTERSEXUALITY

1. Virilization of genetically female fetus

Female pseudohemaphroditism (XX – MALE)
2. Incomplete musculinization of genetically male fetus
Male pseudohermaphroditism (XY-FEMALE)
3. The presence of both ovarian and testicular tissue
in the same individual
True hermaphroditism
4. Chromosomal abnormality
Mixed gonadal dysgenesis ( 45,X0 / 46,XY)
How many children are born
with intersex conditions?
 A conservative estimate is that 1 in 2000 children
born will be affected by an intersex condition.
 98 % of affected babies are due to congenital
adrenal hyperplasia
FEMALE
PSEUDOHERMAPHRODITISM

EXCESS FETAL EXCESS MATERNAL

ANDROGENS ANDROGENS
Congenital adrenal  Maternal androgen
hyperplasia secreting tumours (ovary,
 21 -hydroxylase adrenal)
deficiency  Maternal ingestion of
 11-hydroxylase androgenic drugs
deficiency
 3ß-hydroxysteroid
dehydrogenase
deficiency
21-hydrxylase deficiency
congenital adrenal hyperplasia

Cholesterol
Pituitary
Pregnenolone

Progesterone ACTH

17-OH progesterone

Adrenal cortex

21-hydroxylase

Cortisol Androgens Cortisol Androgens
 Congenital adrenal hyperplasia

• The commonest cause of genital

ambiguity at birth
• 21-hydroxylase deficiency is
most common form
• Autosomal recessive
• Salt wasting form may be lethal
in neonates
• SERUM 17OH-progesterone
(21OHase)
•  SERUM deoxycorticosterone,
11-deoxycortisol (11- OHase)
• Treatment : cortisol replacement
and ? Surgery
Drugs with Androgenic side effects
ingested during pregnancy
- Testosterone
- Synthetic progestins
- Danocrine
- Diazoxide
- Minoxidil
- Phenytoin sodium
- Streptomycin
- Penicillamine
Male pseudohermaphroditism
(XY- FEMALE)

Failure to produce Failure to utilize

testosterone testosterone
 Pure XY gonadal  5-alpha-reductase
dysgenesis (swyer’s deficiency
syndrome)
 Androgen receptor
 Anatomical testicular
failure (testicular deficiency
regression syndrome) * Complete androgen
 Leydig-cell agenesis Insensitivity
 Enzymatic testicular (TFS)
failure * Incomplete androgen
Insensitivity
Pure Gonadal Dysgenesis (Swyer’s
syndrome)

46, XY

No H-Y OR its receptors

STREAK GONADS
- NO MIF (Uterus +)
- NO
SEX STEROIDS

Female external Female Internal

Genitalia Genitalia
 Testicular regression syndrome
(congenital anorchia)
46-XY/SRY

Testis  MIF
(self destruction)

± testosterone
± DHT

Female or ± Male
ambiguous Internal genitalia
External
genitalia
 Leydig-cell agenesis
46-XY/SRY

TESTIS  MIF
( partial / complete absence
Of leydig-cells)

No or  testosterone
No or  DHT

Female or ± Male
ambiguous Internal
external Genitalia
Genitalia
 Testicular enzymatic failure
46-XY/SRY

Testis  MIF Autosomal recessive enzyme deficiency :

(defects in testosterone 20-22
Synthesis) desmolase
3-ß-ol-dehydrogenase
17- β -hydroxylase
17,20-desmolase
 testosterone precursors 17-ß –
hydroxysteroid
DHT oxyreductase

Ambiguous Male Internal

External Genitalia
Genitalia
 46-XY/SRY 5-alpha-reductase
deficiency
Testis  MIF

Testosterone

5-α-reductase

DHT
Female or Ambiguous Male Internal
external Genitalia Genitalia
 46-XY/SRY
Testicular feminization
TESTIS  MIF syndrome
Testosterone
5-α-reductase

DHT

Absent androgen
receptors
Female Male Internal
External Genitalia
Genitalia

Incomplete form  Ambigious genitalia

 Diagnosis of XY Female
Testosterone concentration

Low Normal
Male level

Concentration of
Testosterone precursors DHT

High Low Low Normal

Testicular Absent testes or 5 α-reductase Testicular

enzyme Absent Leydig Deficiency Feminization
Failure -cell Syndrome
Surgical exploration
 MIXED GONADAL DYSGENESIS
 Combined features of Turner’s
syndrome and male
pseudohermaphroditism
 Short stature
 Streak gonad on one side with
a testis on the other
 Unicornuate uterus & fallopian
tube- side of streak gonad
 Karyotype 46XY / 45X0
 Considerable variation in the
sexual phenotype
TRUE HERMAPHRODITISM

• Gonads :
- ovary one side and testis on the other or
- bilateral ovotestis
• Karyotype :
46,XX most common(57%); XY(13%) and
XX/XY(30%)
• Internal genitalia :
Both mullerian and wolffian derivates
• Phenotype is variable
• Gonadal biopsy is required for confirming diagnosis
TRUE HERMAPHRODITISM
CLINICAL PRESENTATION
OF INTERSEXUALITY
 AT BIRTH
Ambiguous genitalia
 DURING CHILDHOOD

Heterosexual features
 AT ADOLESCENCE

Delayed or Heterosexual Puberty

AMBIGUOUS GENITALIA AT BIRTH

The external genital Any one of the following :

organs look unusual,  A small, hypospadiac
making it impossible phallus and unilaterally
to identify the sex of undescended gonad.
the newborn from its  An enlarged phallus
outward appearance. with bilaterally
impalpable gonads.
 An enlarged phallus and

a vagina in the same

infant.
MANAGEMENT OF NEWBORN WITH
AMBIGUOUS GENITALIA
DIAGNOSIS
 History : pregnancy; family
 Detailed examination : abdomen; pelvis; external

genitalia; urethral and anal openings.

Federman ’s rule: a palpable gonad below the
inguinal ligament is testes until proven otherwise
MANAGEMENT OF NEWBORN WITH
AMBIGUOUS GENITALIA

Investigations
• Rule out cong. Adrenal hyperplasia: Serum electrolytes; 17-
OHP level and urinary levels of 17-ketosteroids
• Karyotype ( buccal smear; blood)
• Pelvic US and sometimes MRI or Genitogram
• Skin biopsy; fibroblast culture to measure 5alpha-reductase
activity or dihydrotestosterone binding
• Laparoscopy
• Gonadal biopsy (laparotomy)
INTERSEXUALITY PRESENTING AT
ADOLESCENCE

Primary amenorrhea Ambiguous genitalia

- Complete androgen - Neglected congenital
insensitivity (TFS) adrenal hyperplasia
- Mixed gonadal dysgenesis
- Congenital anorchia
- Partial androgen resistance
( early testicular - Congenital anorchia ( Late )
regression syndrome) - Testicular enzymatic failure
- Complete leydig-cell - Leydig cell agenesis
agenesis ( incomplete)
- Some forms of enzymatic - True hermaphrotidism
testicular failure
Thanks you for
listening.