Normal and abnormal sexual development
Definition and elements of sex
Normal Sexual Differentiation:
Genetic factors:
Gonadal Factors:
Hormonal Factors:
Central nervous system differentiation.
Abnormal Sexual differentiation:
Sex: Is the gender assigned to an individual based on appropriate and
compatible morphologic features, function and behaviour.
Determinants of normal sexual differentiation: include the following
elements: Genetic sex, Gonadal sex, internal genital sex, external genital sex
and behavioural sex.
Intersexuality: Is said to occur whenever there is a conflict between one or
more of the elements of sexual differentiation.
Normal Sexual differentiation:
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Genetic Sex:
Is assigned the moment fertilisation takes place. Based on a normal genetic
make up the gonadal sex will be determined as ovaries or testis.
For example normal differentiation of the gonads to testis depends on the
presence of functioning testicular determining factor gene
Also loss of one of the X chromosome or deletion of important part of it will
result in the gonads being fibrous streaks.

Gonadal sex:
The gonads appears at 5 weeks as protuberance overlying the mesonephric
ducts.
migration of the germ cells into the genital ridge to induce gonadal
differentiation. Development of the gonads goes into two stages:
Stage of Indifferent gonads (up to 6 weeks): The gonads are bipotential i.e. can
differentiate into ovaries or testis. It is formed of : Cortical area, medullary
area, germ cells, epithelial cells ( granulosa cells or Sertoli cells) and
mesenchyme (Theca or lyeding cells).
Failure of migration of the germ cells results in gonadal agenesis.
Differentiation into testis occur between 6-8 weeks in case of XY germ cells. If
the genetic make up is XX ovarian differentiation begins from around 8
weeks.

Development of the Internal genital system (Duct system
differentiation)
At one stage the embryo will harbour both elements for male and female duct
system i.e. the Wollfian (mesonephric) duct and the Mullerian
(paramesonephric) duct.
Differentiation begin at around 8-10 weeks into male depending on:
AniMullerian hormone (AMH), synthesised by Sertoli cells soon after
testicular differentiation. It results into regression of the ipsilateral Mullerian
duct which takes place by about 8 weeks before the production of testosterone
begins and subsequent development of the Wollfian duct.
The gene for AMH is located on the short arm of chromosome 19. While the
receptor for AMH is located on chromosome 12. Genetic defects in production
of AMH or its receptors results in persistence of the Mullerian duct system
(later to be the uterus and tubes) in otherwise normal male.
AMH is also important for descent of the testis in the scrotal region.
Testosterone Is secreted by the Leyding cells from about 8th week. It results in
Wollfian duct differentiation into epidedymes, vas difference and seminal
vesicles. It has a paracrine effect (the ipsilateral duct). Therefore the Wollfian
duct can not be stimulated in females exposed to adrenal or exogenous
androgen. The testosterone hormone reaches peak by 15-18 weeks. Secretion
of testosterone depends on normal Leyding cell function, HCG and latter fetal
pituitary LH.
In the absence Y chromosome, the duct system differentiation into the default
female. The Wollfian duct regress and the Mullerian duct differentiate into
tubes, uterus and upper vagina.
However oestrogen hormone seems to play a role in the regression of the
Wollfian system.

External Genital differentiation:
Stage of indifferent genitalia: At 6 weeks the external genitalia is bipotential
state i.e. can differentiate into male or female. Its main elements include:
The genital tubercle: in male give the penis and in female the clitoris.
The labioscrotal swelling to become the scrotum or the labia minora.
The urogenital sinus to make the penile urethra or the labia minora.
With the sinus to give the urethra and vaginal in female.
The target tissue of the external genitalia must convert testosterone into
dihyrotestesterone using the 5 alpha reductase enzyme. Deficiency in this
enzyme with leads to variable degrees of ambiguous genitalia. Other effects of
DHT are temporal hair line recession, growth of facial and body hair,
development of acne, development of external genitalia and prostate.
Abnormal Sexual differentiation
Disorders of Fetal endocrinology (hormonal factors)
Masculinized females (Female pseudohermaphroditism)
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Congenital Adrenal hyperplasia:
Elevated androgen in the maternal circulation:
Aromatase (P450arom) deficiency
Incompletely Masculinized males (male psuedohermaphroditism)
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Androgen insensitivity syndromes
5 Alpha reductase deficiency
Testosterone biosynthesis defects
Gonadotropin resistant testes
Anti-mullerian hormone deficiently.
Disorders of Gonadal Development:

Male pseudohermaphroditism
Primary gonadal defect
True hermaphroditism
Gonadal dysgenesis:

Turner syndrome

Mosaicism

Normal karyotype (Noonan syndrome)
Congenital Adrenal Hyperplasia (Adrenogenital Syndrome):
In female the syndrome is characterised by masculinization of external
genitalia. It is diagnosed by the demonstration of excessive androgen
production by the adrenal cortex, caused by either tumour or hyperplasia. It
may appear in utero or develop postnatally.
The features and severity depends on the time of onset, quantity available and
duration of exposure. Signs of virilisation of the external genitalia are varying
degrees of: fusion of the labioscrotal folds, clitoral hypertrophy, and
anatomical changes of the urethra and vagina (deformity of the urogenital
sinus).
The internal genitalia differentiated is not affected because it is completely
formed by the 10th week whereas adrenal cortex does not reach a level of
significant function until 10-12 weeks.
Because the female external genitalia is not completed until 20 weeks of fetal
age early androgen excess (10-12 weeks) may fully musculinize, whereas late
(18-20 weeks) androgen may create limited ambiguity of the basically female
appearance of the external genitalia.
Postnatally if untreated the female infant will develop progressive signs of
virilization (pubic hair at age 2-4 years, followed by axillary hair, body hair
and beard) bone age is advanced by age.
In addition to sexual changes patients can present with metabolic disorders
such as salt-wasting, hypertension, rarely hypoglycaemia.
The condition is an inherited monogenic autosomal recessive trait.
Masculinization due to elevated androgen in the maternal circulation:
Abnormal (P450arom) Deficiency: Placental aromatase deficiency result in
accumulation of fetal androgen precursors normally utilised in placental
synthesis. The result is virilisation of the mother during the second half of
pregnancy, low oestrogen levels in the mother and masculinization of a female
fetus.
Incompletely musculinized Males:
Those are male by genetic sex ( XY) and possess testicles but the external
genitalia are not normally male (pseudohermaphrodits):
1234-
Androgen Insensitivity Syndrome.( X linked recessive trait)
Abnormal androgen synthesis.
Gonadotropin resistant testes.
Absent or defective anti-mullerian hormone.
Androgen Insensitivity Syndromes:
1Complete. (Testicular femenisation syndrome)
2Incomplete Androgen Insensitivity.
Abnormal Androgen Synthesis:
This may result in defective male development if it occurs at a critical time of
sexual differentiation.
Gonadotrophin resistant Testes:
Due to agenesis or abnormal differentiation of the Leyding cells thus reduced
response to LH/HCG.
Absent or defective anti-mullerian hormone:
Individuals in this syndrome are normal males with uterus and tubes.
Disorder of Gonadal Development:
Bilateral dysgensis of the testes: normal female external and internal genitalia
but the gonads are streaked fibrous tissue. The karyotype is XY.
True hermaphroditism:
Individual who possess both ovarian and testicular tissue. Either on the same
side (ovotestis) or one on each side. About 60% are genetic females’ (XX) few
are XY the rest are mosaic.
Gonadal Dysgenesis (Turner syndrome):
The typical complete case is due to absence of the X chromosome in all cell
lines result in bilateral streaked gonads. This occurs in 60 % of cases.
The rest has either structural abnormality in one of the X-chromosomes or
mosaicism with an abnormal X.
Mixed Gonadal Dysgenesis:
The most common example is the mosaic individuals with 45X/46XY. The can
exhibit a wide variety of phenotypes range from new-borns with ambiguous
genitalia to normal fertile males or normal phenotype female with bilateral
streaked gonads.