Sexual

Sexual Differentiation
Differentiation

Prof.Dr.
Prof.Dr. Rveyde
Rveyde BUNDAK
BUNDAK

Sex
Sex determination
determination and
and
differentiation
differentiation
is
is aa sequential
sequential process
process that
that
involves
involves at
at least
least four
four
characteristics
characteristics that
that are
are
delineated
delineated in
in various
various stages
stages

Fertilisation

Genetic sex

Genetic sex

Gonadal sex

Gonadal sex

Phenotypic sex

Hormones + Social environment

Psychologic sex

Gender identitiy

 Genetic
Genetic sex
sex is
is determined
determined at
at
fertilization
fertilization
Gonadal
Gonadal sex
sex is
is determined
determined by
by genetic
genetic
sex
sex
Sexual
Sexual differentiation
differentiation of
of the
the gonads
gonads
leads
leads to
to the
the development
development of
of internal
internal
genital
genital tracts
tracts and
and the
the external
external
genitalia
genitalia and
and hence
hence the
the Phenotypic
Phenotypic
sex
sex

 The
The development
development of
of seconder
seconder sex
sex
characteristics
characteristics provides
provides additional
additional
visible
visible phenotypic
phenotypic manifestations
manifestations at
at
puberty.
puberty.
Psychological
Psychological sexual
sexual identity
identity is
is
acquired
acquired postnatally
postnatally by
by sociological
sociological
imprinting
imprinting on
on the
the developing
developing
personality.
personality.
This
This postnatal
postnatal process,together
process,together with
with
prenatal
prenatal hormonal
hormonal influences
influences
,dedected
,dedected the
the gender
gender identity
identity or
or
psychological
psychological sex
sex..

Genetic
Genetic sex
sex

The human genome consists of two copies

of each of 23 chromosomes (a total of 46).
One set of 23 comes from the mother and
one set comes from the father. Of these
23 pairs of chromosomes, 22 are
autosomes, and one is a sex chromosome.
There are two kinds of sex
chromosomes"X" and "Y". In humans and in
almost all other mammals, females carry
two X chromosomes, designated XX, and
males carry one X and one Y, designated
XY.

A human egg contains only one set of

chromosomes (23) and is said to be haploid.
Sperm also have only one set of 23
chromosomes and are therefore haploid.
When an egg and sperm fuse at fertilization,
the two sets of chromosomes come together
to form a unique "diploid" individual with 46
chromosomes.

Human Karyotype

The sex chromosome in a human egg is

always an X chromosome, since a female
only has X sex chromosomes. In sperm,
about half the sperm have an X chromosome
and half have a Y chromosome. If an egg
fuses with a sperm with a Y chromosome,
the resulting individual is usually male. If an
egg fuses with a sperm with an X
chromosome, the resulting individual is
usually female. An egg's sex chromosome is
always an X, so it is the sperm's sex
chromosome that determines an individual's
sex

Gonadal
Gonadal sex
sex
and
and
Phenotypic
Phenotypic sex
sex

 Sex is not really determined by

chromosomes
Genes are the underlying basis for sex
determination
Some on sex chromosomes, others on
autosomes

Intrauterine sexual differentiation

Differentiation of gonads,
Differentiation of internal genital ducts,
Differentiation of external genitalia
I. Differentiation of gonads:
-Until approximately 42 days of gestation
embryonic gonads of males and females are
indistinguishable, there is a primitive gonadal structure
-Subsequent differentiation of gonads into testes or
ovary depends on the presence of testes determining
gene or Sex determining Region of Y on
Y chromosome

*Dr. Peter Koopman was

able to prove that the SRY
gene is the TDF from
studies on XX male

*SRY is Y specific, and

there is no analogue on the
X chromosome

Intrauterine sexual differentiation

Genes important for gonadal diff.
SRY gene:
-On short arm of Y chromosome, in close proximity with
pseudoautosomal region.
-SRY codes for a DNA binding protein and facilitates transcription
of downstream genes.
-Deletion of SRY in a 46 XY person results in female development
with dysgenetic gonads
-Transfection of SRY into 46 XX mice embryo
results in male development with testes (but sterile)
-During meiosis in male , pseuodoautosomal regions of the X and Y
chromosomes are exchanged.
-During this exchange, SRY can be transferred to the X chromosome
(XX males)

Genital ridge

Somatic cells

Germ cells

WT1
SF1
Lim1
Emx2
Fgf9

Bipotential gonad
DAX1

SRY

Wnt4

SOX9
DMRT2
ATRX

Ovary
Mullerian ducts (+)
Wolffian ducts (-)

Testes

External genitalia

Testes

Sertoli cells
AMH
AMHR
3HSD2
CYP17/POR
HSD173

Leydig cells

LHR
StAR

5aR

Testosterone
AR

Mllerian ducts (-)

Internal Genitalia

DHT
AR

Wolffian ducts (+)

External Genitalia

-By 42 days of gestation germ cells appear

-If SRY is present, 43-50 days ---> differentiation
into TESTES
Leydig cells : 60 days
Male external genitalia : 65-77 days
-If SRY is not present, within 77-84 days
primitive gonad differentiates into-------> OVARY

Other genes important for gonadal diff.

DSS gene: is on short arm of Chromosome X
-Dosage sensitive sex reversal gene
-Dublication of DSS gene in a 46 XY embryo results
in 46 XY females

WT-1 gene (Denny-Drash , WAGR syndrome)

SOX-9 gene (Camptomelic dwarfism)

Intrauterine sexual differentiation

II. Differentiation of internal genital ducts

-Up to 7 weeks: no internal duct differentiation
primordial structure contains both
Mullerian and Wolfian ducts

-After 7 weeks: development of internal genital ducts depends on

the presence or absence of a functional fetal testes and completed
by 12 weeks. -Fetal testes secrete two different substances:
1. Mullerian inhibiting factor (MIF, AMH): -by Sertoli cells:
causes regression of Mullerian ducts(ipsilaterally)
2. Testosterone:-by Leydig cels:
a) causes further development of Wolfian ducts
b)by being converted to dihydrotestosteron(DHT)
promotes masculinization of external genitalia

-In the female fetus,there is no testes

--> no MIF--> Mullerian duct develops further
--> no testosteron---> regression of Wolfian ducts
Mullerian ducts: Uterus, Fallopian tubes, cervix
1/3 upper part of the vagina
Wolfian ducts: Vas deference, epididymis, seminal
vesicles, ejaculatory duct

Gonadal differentiation

Intrauterine sexual differentiation

II. Differentiation of external genitalia:
-Critical period (8-12 weeks)
-Up to 8 weeks, no external genital differentiation is present
-There is a primitive external genital structure which
contains:
Male
Female
*Genital tubercle:
Glans penis
Clitoris
*Urethral folds:
Shaft of the penis L. minora
*Urethral groove:
Penile uretra
Lower 2/3 vagina.
*Labioscrotal swelling Scrotum
L. majora
-If testes, DHT, and androgen receptor present: differentiation into
male external genitalia completed by 16 weeks.

 DHT: binds to androgen receptor on genital structures

and causes:
-fallic enlargement
-zipping-up genital groove into penile urethra
-zipping-up labioscrotal swelling into scrotum
-prostate growth

XY

SEX DIFFERENTIATION
SRY

Bipotential Gonad
6 week(W)

Genes SOX3
SOX4

Dii ynnde

Testes
(8W)
MIS
Atrophy of
Mullerian
Srtuctures

XX

Testosterone
Internal
genitalia

(9W)

Dihidrotestsoteron
External genitalia