Download Development of Male and Female Reproductive System

Development of Male and
Female Reproductive
System
Dr. Qasim El Dwairi. MD PhD
Learning Goals
• To learn the development and congenital
abnormalities of testes and the ovaries
• To learn the sex determination
• To learn the development and congenital
abnormalities of genital ducts
• To learn the development and congenital
abnormalities of external genitalia
SEX DIFFERENTIATION
• Y Chromosomes contains Testis
Determining Gene Called SRY (Sex
Determining Region On Y) gene on
its short arm.
• If SRY Present
Male
Develops
• If SRY Absent
Female
Develops
5th week
Development of genital
system
• Genetic sex is established at
fertilization by the kind of sperm that
fertilizes the ovum
• The gonads begin to attain sexual
characteristics from 7th week.
• Early genital systems in two sexes
are similar; this initial period is
called İndifferent State Of Sexual
Development
Genital System
• Gonads (primitive
sex glands)
• Genital ducts
• External genitalia
İndifferent stage
Sex Determination
• Chromosomal and Genetic
Sex İs Established At
Fertilization
• The type of gonads that develop
is determined by the sex
chromosome complex of the
embryo (XX or XY)
• Before 7th week gonads of 2
sexes are identical (indifferent
gonads)
• Male phenotype requires Y
chromosome (SRY-sex
determining region on Y gene)
for a testis determining factorTDF.
• Female phenotype requires two
X chromosomes with a number
of genes
• The Y chromosome has a testis
determining effect on the
MEDULLA of indifferent cords .
TDF (regulated by Y chrom)
differentiate the gonadal cords
into primordia of seminiferous
tubules
• Absence of a Y chromosome
(XX sex chrom) results in the
formation of the ovary
• Types Of Present Gonads
Determines The Type Of
Sexual Differentiation Of
The Genital Ducts And
External Genitalia.
• Testosterone produced by
the fetal testes determines
maleness.
• Primary female sexual
differentiation Does Not
Depend On Hormones
(Maternal Estrogen));
occurs even if the ovaries are
absent (depending possibly on
an autosomal gene)
ORIGIN OF GONADS
• Gonads are derived from Three Sources:
• 1. Mesothelium (mesodermal)
epithelium lining the posterior
abdominal wall)
• 2. The underlying Mesenchyme –
Embryonic connective tissue
(Mesodermal)
• 3. The Primordial Germ Cells.
(Endodermal)
• Initially the gonads appear as genital or
Gonadal Ridge formed by mesothelium &
mesenchyme.
Molecular regulation of male genital duct
development (X)
•
•
•
SRY is a transcription factor and the master
gene for testes development; possibly acting in
conjunction with the autosomal gene SOX9 a
transcription regulator also inducing testes
differentiation
SOX9 binds the promoter region of the gene
for antimullerian hormone/mullerian inhibiting
substance (AMH, MIH) regulating this genes
expression
At the begining SRY and/or SOX9 induce the
testes to secrete FGF-9 acting as a chemotactic
factor that causes tubules from the
mesonephric duct to penetrate the
gonadal ridge.
• Without penetration by these tubules
differentiation of the testes does not
continue.
•
•
Next SRY directly or indirectly through SOX9
upregulates production of stetoidogenesis
factor-1 (SF-1) that stimulates differention of
Sertoli and Leydig cells. SF1 with SOX9
increase AMH leading to regression of the
paramesonephric (mullerian)ducts.
SF1 upregulates the genes for enzymes that
synthesize testosterone
SRY
SOX9
SF1
Other genes
Testes
Molecular regulation of female
genital duct development
• WNT4 is the ovary determining
gene; upregulating DAX1 which is a
member of the nuclear hormone
receptor family
• DAX1 inhibits the function of SOX9
• WNT regulates expression of other
genes (TAFII105....TATA binding
protein for RNA polimerase in
ovarian follicular cells) responsible
for ovarian differentiation
• Estrogens are involves in
sexual differentiation;
under their influence
paramesonephric
(mullerian) ducts are
stimulated to form ext
genitalia
WNT4
DAX1
Other genes
TAFII 105
Ovaries
Continue
• Primordial Germ Cells (PGC) first
appear During 4th Week In The
Wall Of Yolk Sac (Endodermal).
• Migrate by amoeboid movement.
• Arrive at Primitive Gonad At 5th
Week.
• Invade The Genital Ridge In 6th
Week.
• During 6th Week Primordial Germ
Cells enter the underlying
mesenchyme and are İncorporated
İn The Gonadal Cords.
Indifferent gonads: Testes/Ovary
• During the 5th week a thickened area of
mesothelium develops on the medial side
of the mesonephros: A Pair Of
Gonadal(genital) Ridges
• Finger-like epithelial cords (Gonadal
Cords) grow into the underlying
mesenchyme
• The indifferent gonad now consists of An
External Cortex And An İnternal
Medulla.
• If The Embryo İs XX: CORTEX Will
Differentiate İnto An Ovary, Medulla
Regress
• If The Embryo İs XY MEDULLA
Differentiates İnto A Testis, Cortex
Regress except for vestigial remnants
TESTIS
• If the embryo is genetically male,
PGC will carry XY chromosome &
thus SRY gene on the Y chromosome
will be present.
• Under the influence of SRY gene,
following events will take place:
– Primitive Sex Cords continue to
Proliferate & Penetrate Deep in the
MEDULLA & form Testis Or Medullary
Cords.
Continue
• Testes
Differentiating
Factor
(TDF) induces the gonadal cords
(Seminiferous Cords) Towards the
hilum, To Break To Form Rete Testis.
• A Dense Fibrous Tissue layer called
Tunical Albuginea Appears & separate
the testis cord from surface epithelium
• In the 4th month, Testis Cord Become
Horse Shoe Shaped & Consists of
– Primitive Germ Cells (Spermatogonia)
– Sustantacular Cells of Sertoli
from Surface Epithelium).
(derived
Development of testes
• Interstitial cells of
Leydig derived from the
Original Mesenchyme
Of The Gonadal Ridge
begin development
shortly after onset of
differention of these
cords
• Leydig cells lie between
the testis cords and
begin Testosterone
Production by 8th
Week of gestation
• Thus the testis is able
to influence sexual
differentiation of the
genital ducts and
external genitalia.
Development of testes
• Testis cords Remain Solid
Untill Puberty; when they
ARE CANALYZED forming
Seminiferous Tubules
• Thus they join rete testis
tubules, which in turn enter
the Ductuli Efferentes which
are the remaining parts of the
excretory tubules of the
mesonephric system
• They link the rete testis and
the mesonephric or Wolffian
Duct which becomes
Ductus Defferens (Vas
Deferens)
GENITAL DUCTS (indifferent
stage)
• Initially Two Ducts are present in
both male & female.
• Mesonephric
(Wolffian)
Duct
((Male)).
• Paramesonephric
(Mullerian)
Duct ((Female)).
Development of gonad
Endoderm cells
of yolk sac
１.Development of
undifferentiated gonad
4th week
Proliferation,
differentiation
Primordial germ cells
6th week
Gonadial ridge
6th week
Superficial epithelium
→cell cords
Migration in one week
Primary sex
cord
GENITAL DUCTS IN MALE
• The mesonephros (developing kidney system)
regresses & show 2 types of excretory tubules.
– In the cranial part – Epigenital Tubules
– In the caudal part – Paragential Tubules
• Epigenital Tubules Establish Connection
with Rete Testis & Form Efferent
Ductules.
• (X) Paragenital Tubules do Not Join The Rete
Testis & Regress. Their ramnant are called
paradidymis.
• (X) The most cranial portion of Mesonephric Duct
Regresses & its ramnant is called appendix
epididymis.
Continue
• Remaining part of Mesonephric
Duct Persists & Form The Main
Genital Ducts.
• Immediately below the entrance of
the efferent ductules into rete testis,
the mesonephric duct elongate &
become
highly
Convoluted
Forming The Ductus Epididymis.
Continue
• From the tail of epididymis to the
outbudding of seminal vesicle, the
mesonephric duct Obtain A Thick
Muscular Coat & Form The
Ductus Deferens.
• Seminal Vesicle are formed by the
Outbudding Of The Mesonephric
Ducts.
Continue
• The region of the Mesonephric
Duct Beyond The Seminal Vesicle
Become The Ejaculatory Ducts.
• Paramesonephric Ducts In The
Male Degenerates except for a
small portion at their upper end
called Appendix Testis.
EXTERNAL GENITALIA
INDIFFERENT STAGE:
 In the 3rd wk, mesenchyme move around
Cloacal Membrane & Form A Pair Of Cloacal
Folds
 Cloacal Folds Unite cranial to cloacal membrane
& Form Genital Tubercle
 Caudally the cloacal folds are subdivided into
urethral folds & anal folds posteriorly
 Another pair of elevations become visible on each
side of urethral folds called Genital Swellings
 These swellings later form the scrotal
sweelings in males & labia majora in
females
 It is impossible to distinguish between two sexes
Till 6th Wk.
EXTERNAL GENITALIA IN
MALES
 It is under the Influence Of Androgens
secreted by the fetal testis
 Genital Tubercle Elongates Rapidly &
Form Phallus
 Phallus pulls the urethral folds which form
the lateral wall of the urethral groove
 Epithelial lining of the urethral groove
is endodermal in origin. It thickens &
forms urethral plate.
CONTD.
 In The 3rd Month urethral folds close
over urethral plate & form the Penile
Urethra
 Ectodermal Cells from the Tip Of The
Glans Penetrate Inward & form a short
epithelial cord which obtains a lumen &
Forms External Urethral Meatus
 Genital swellings also known as scrotal
swellings develop into two halves of
scrotum separated by a Scrotal Septum
Descent of the testes
•
Testicular descent is associated
with
– Enlargement of testes and atrophy
of mesonephroi (mesonephric
kidneys)
– Atrophy of mesonephric ducts
induxed by the MIS
– Enlargement of processus
vaginalis guiding the testis
through inguinal canal into
scrotum
• By 26 weeks have descended
•
•
•
retroperitoneally from the
posterior abdominal wall to the
deep inguinal rings
Androgens, gubernaculum (a
mesenchymal condensation) may
guide the descent
Descent may take 2-3 days and
the inguinal canal contracts after
they enter the scrotum
As the testis and the ductus
deferens descend they are
enshetaed by the facial
extensions of the abdominal wall
Congenital anomalies of descent of the
testes
• Cryptorchidism Or Undescended Testis:
occurs in 30 % of premature, 3-4% of full-term
males. It may be uni or bilateral. Failure of
descent in the first year causes atrophy of testes.
It may be in the abdominal cavity or anywhere
along the descent path, usually in the inguinal
canal. It may be caused by teh defficiency of
androgen production in testes.
• Ectopic Testes: After traversing the inguinal
canal, the testis may deviate from its usual path
of descent and lodge in various abnormal
locations.
DEFECTS IN MALE GENITALIA
1. HYPOSPADIAS
Definition: Abnormal Openings Of The
Urethra Along The Inferior Surface
Of The Penis due to Incomplete
Fusion Of The Urethral Folds.
Sites: usually Near The Glans, along the
shaft, near the Base Of The Penis,
rarely along the scrotal raphe
Incidence: 3-5/1000 births
Cause: Could be rise in environmental
estrogens
2. EPISPADIAS
Definition: Abnormal openings of the urethra along
the Dorsal Surface Of The Penis.
Incidence: Rare1/30,000 births
Cause: Genital tubercle , instead of developing at
the cranial margin of the cloacal membrane,
forms in the region of the urorectal septum.
Hence a portion of cloacal membrane is found
cranial to the genital tubercle & when this
ruptures, it result in Epispadias
Association: It is associated with exstrophy of the
urinary bladder
3. MICROPENIS
Definition:The penis is 2.5 standard
deviations below the mean in length as
measured along the dorsal surface from
the pubis to the tip with the penis
stretched to resistance
Cause: Insufficient Androgen
Stimulation for the growth of external
gentalia as in Primary Hypogonadism,
Hypothalamic Or Pituitary
Dysfunction.
Hypospadias
Female UGS Origins
• Urogenital Sinus:
– Urinary Bladder
– Urethra
– Paraurethral Gland
– Hymen
• Mesonephric Duct:
– Ovary
• Paramesonephric Duct:
– Uterus
– Fallopian Tube
Urogenital ridge:-
A. Relation of the genital ridge and the mesonephros showing location of the
mesonephric duct.
B. Transverse section through the mesonephros and genital ridge at the level indicated
in A.
Development of ovaries
• Gonadal development occurs slowly in female
• In XX embryo Primitive Sex Cords Dissociate İnto
İrregular Cell Clusters Containing Groups Of Primitive
Germ cells in the Medullary Part Of Ovary
• Later they disappear and are replaced by a vascular stroma
that forms the Ovarian Medulla
２. Differentiation of female reproductive tract
End of upper segment：Fimbria
Paramesonephric
duct：
Upper and middle segment：oviduct
Lower segment： Uterus
End：
Sinus tubercle： Vaginal plate
Mesonephric
ducts and
tubules
Vaginal fornix
Vagina
Degeneration
Development of ovaries
• Surface Epithelium of
the female gonad (unlike that
of the male) continues to
Proliferate Giving Rise To A
Second Generation Of
Cords (cortical cords) in the
7th week.
• Cortical Cords penetrate the
underlying mesenchyme but
remain close to the surface
• In the 4th Month Cortical
Cords Split İnto
İsolated Cell Clusters
with each surrounding one or
more Primitive Germ Cells
• Germ Cells Develop
İnto Oogonia, surrounding
epithelial cells,
descendants of the surface
epithelium form follicular
cells.
Descent of the ovaries
• Descent is considerably
less in female
• The ovaries settle below
the rim of the true pelvis
• Cranial genital ligament
forms the suspansory
ligament of ovary
• Caudal genital ligament
forms the ligament of the
ovary proper and the
round ligament of the
uterus
Development of genital ducts: Indifferent stage
• At the begining both male and female embryos have
genital ducts:
2 pairs of
– 1. Mesonephric (wolffian) ducts
– 2. Paramesonephric (mülerian) ducts arising as a longitudinal
invagination of the epithelium on the antro-lateral surface of
the urogenital ridge
• Two ducts are separated by a septum but later fuse to form The
Uterine Canal
• The caudal tip of the combined ducts projects into the posterior wall of
the urogenital sinus causing a swelling (Paramesonephric/Müllerian
Tubercle)
• The Mesonephric Ducts Open into the Urogenital Sinus an either
side of the müllerian tubercle
Genital duct development in
female
• Paramesonephric ducts
develop into the MAİN
GENİTAL DUCTS
• Initially 3 parts can be
recognized in each duct:
 Cranial vertical portion that
opens into the abdominal
cavity....develop into Fimbria
Uterine Tube
 Horizontal part that crosses the
mesonephric duct...develop into
Uterine Tube
 Caudal vertical part that fuses
with its partner from the
opposite side...fuse to form
Uterine Canal
２. Differentiation of female reproductive tract
End of upper segment：Fimbria
Paramesonephric
duct：
Upper and middle segment：oviduct
Lower segment： Uterus
End：
Sinus tubercle： Vaginal plate
Mesonephric
ducts and
tubules
Vaginal fornix
Vagina
Degeneration
Genital duct development in female ((Ligaments))
• Second part of the paramesonephric ducts move medio-caudally;
urogenital ridges gradually come to lie in a transvers plane
• The ducts fuse in the midline; a broad transverse pelvic fold
(broad ligament of uterus) is established. The uterine tube lies in
its upper border and the ovary lies on its posterior surface
• Uterus and broad ligs divide the pelvic cavity into uterorectal
pouch and the uterovesical pouch
• Fused paramesonephric ducts differentiate into corpus and cervix
of the uterus. They are surrounded by a layer of mesenchyme that
forms the myometrium and the perimetrium
Development of vagina
• After the Solid Tip Of The
Mesonephric Ducts
reaches the urogenital sinus;
two solid evaginations
(Sinovaginal Bulbs) grow
out from the pelvic part of the
sinus.
• Sinovaginal bulbs proliferate
and form a Solid Vaginal
Plate.
• Proliferation continues at the
cranial end of the plate;
increasing the distance between
the uterus and the urogenital
sinus.
• By the 5th month vaginal
outgrowth is entirely
Canalized. Vaginal fornices
(wing-like expansions of the
vagina around the end of
uterus) are of paramesonephric
origin
Development of vagina
• Thus the vagina has two
origines:
– Upper Portion
Derived From The
Uterine Canal
– Lower Portion
Derived From The
Urogenital Sinus
• Lumen of the vagina
remains separated from
that of the urogenital sinus
by a thin tissue plate; the
Hymen
• Hymen consists of
epithelial lining of the sinus
and a thin layer of vaginal
cells. It usualy develops an
opening during perinatal
life
Development of external genitalia in
female
• Stimulated by estrogens, genital tubercle elongates only
slightly forming the clitoris
• Urethral Folds Do Not Fuse; develop into labia minora
• Genital swellings enlarge and form the labia majora
• Urogenital groove is open and forms the vestibule
• Although the genital tubercle does not elongate extensively
in female, its larger than in male during the early stages;
resulting in mistakes in identification of the sex by USG
examination.
Congenital anomalies of uterus and
vagina
• Double uterus (uterus didelphys): results from failure of
fusion of the inferior parts of the paramesonephric ducts. It
may be associated with double or single vagina.
• Bicornuate uterus: One paramesonephric duct is retarded in
its growth and does not fuse with other one.
• Bicornuate uterus with rudimentary horn: the rudimentary
horn may not communicate with uterine cavity
• Unicornuate uterus: One paramesonephric duct fails to
develop; resulting in a uterus with one uterine tube.
• Absence of vagina and uterus: Reslts from the failure of
sinovaginal bulbs to develop.
• Vaginal atresia: Failure of the canalization of the vaginal
plate.
• Imperforate hymen: Failure of perforation of the inferior
end of the vaginal plate
Congenital anomalies of hymen
Uterine
anomalies
A. Normal uterus
and vagina
B. Double uterus
C. Double uterus
with single
vagina
D. Bicornuate
uterus
E. Bicornuate
uterus with a
rudimentary left
horn
F. Septate uterus
G. Unicornuate
uterus
Abnormal sex chromosome
complexes
• XXX, XXY
• Number Of X Chromosome Appears To Be
Unimportant İn Sex Determination
• If a normal Y chromosome is present the embryo
develops as a male. If Y chromosome or its testis
determining region is absent female development
occurs
Turner syndrome (45X)
Congenital malformations:Determination of
fetal sex
• Ambiguous genitalia: if there is normal sexual
differentiation, internal and external genitalia are consistent
with the chromosome complement
• True hermaphroditism: having ovarian and testicular tissue
either in the same or opposite gonads (70 % are 46 XX, 20
% 46 XX/46 XY mosaicism, 10 % 46XY)
• Female pseudohermaphroditism: 46 XX, having ovaries,
resulting from the exposure from excessive androgens of
female fetus. Virilization of ext genitalia occurs. Common
cause is congenital adrenal hyperplasia, rare cause may be
maternal masculinizing tumor.
• Male pseudohermaphroditism: 46XY having testis, with no
sex chromatin. Int and ext genitalia are varible caused by
inadequate production of testosterone and MIF by testes.
Congenital malformations:Determination of
fetal sex
• Androgen insensitivity syndrome (testicular feminization):
Normal appearing females with the presence of testes and
46XY chromosomes. They are medically and legally female.
There is resistambce to the action of testosterone at the
cellular receptor
• Mixed gonadal dysgenesis: very rare, having chromatin
negative nuclei (sex chromatin negative), a testis on one
side, an undifferentiated gonad on the other side. The
internal genitalia are female, but may have male
derivatives. The external genitalia may vary from female to
male.
Androgen insensitivity syndrome
(testicular feminization):46XY
２. Development of testis
Primary sex cord (H-Y antigen)
7th week
Separated from surface
Mesenchymal
cell
Cells of sex cord Primordial germ cells
Interstitial cell
+ Sustantacular cell
+
Spermatogonium
Testis
３. Development of ovary
Superficial epithelium
Primary sex
(No H-Y antigen)
Mesenchymal cells
Secondary sex cord (cortical cord)
cord
After 10th
16th week
week
Primordial
Degeneration
follicle
Cells of sex cord
Stroma
+
Follicular cells
Primordial germ cells
+
Oogonium
Ovary
Cortex
Medulla
Cortical
Cord
Testis
Ovary
Rete testis
Tubule rectus
Follicle
Seminiferous
tubule
Testis
Rete testis
Ovary
Tubule rectus
Follicle
Seminiferous
tubule
Spermatogonium
Primary oocyte
Sustantacular
cell
Follicular cell
Seminiferous tubule
Follicle
Development of reproductive tracts
1. Undifferentiated stage:
Mesonephric
tubule
Gonad
Mesonephri
c duct
Sinus
tubercle
A. Male
Paramesonephri
c tubule
Urogenital
sinus
B. Female
２. Differentiation of female reproductive tract
End of upper segment：Fimbria
Paramesonephric
duct：
Upper and middle segment：oviduct
Lower segment： Uterus
End：
Sinus tubercle： Vaginal plate
Mesonephric
ducts and
tubules
Vaginal fornix
Vagina
Degeneration
3. Differentiation of male reproductive tract
Metanephric Head ── Epididymal duct
Tail ── Spermaduct
duct
Mespnephric
tubules
Most of →degeneration
Some of → Efferent ducts
Paramesonephric
duct
Degeneration
Ovary
Testis
Urogenital
sinus
Urogenital
sinus
Oviduct
Spermaduct
Uterus
Vaginal
plate
Efferent duct
Epididymal duct
Abnormality of reproductive system
1. Cryptorchidism
2. Congenital inguinal hernia
3. Double uterus
4. Vaginal atresia
5. Hypospadias
6. Hermaphroditism