Embryology of the Male & Female Reproductive System By Vijay Kapal

Genital System
Sex differentiation, a complex process, involves not only the the sex chomosomal genes but also the autosomal ones. Sexual dimorphism is due to Y chromosome. Y chromosome contains the SRY (sex-determining region on Y) gene on its short arm. The protein product of this gene is a transcription factor that initiates a cascade of downstream genes that determine the fate of primordia of the sexual organs. The SRY protein is the testis-determining factor; its presence influences the male development, while its absence establishes the female development.

Gonads
The sex of the embryo is determined genetically at the time of fertilization. The gonads do not acquire male or female morphological features until the 7th week of development. A pair of longitudinal ridges lie ventro-medial to the mesonephric kidney. These are epithelium covered condensations of mesenchyme & are called genital or gonadal ridges. Germ cells start appearing in these ridges after 5th week. Primordial germ cells appear in the endoderm of the yolk sac. They migrate by ameboid movements, via dorsal mesentery, reach the genital ridges during 5th week & invading the genital ridges in the 6th week. If they fail to reach the ridges, the gonads do not develop. The primitive sex cords arise from the epithelium, penetrate the underlying mesenchyme & still keep contact with the surface epithelium in both sexes. It is impossible to differentiate between the male and the female gonad. Hence the gonad is known as the indifferent gonad.

Gonadal Ridges

Neural tube Dorsal aorta Dorsal mesentery Mesonephros Gonadal ridges Gut

Early Gonads
Neural tube

Notochord
Dorsal aorta Mesonephros

Gonads
Dorsal mesentery Cross Section

Primordial Germ Cells

Dorsal mesentery

Primordial germ cells

Gonad

Mesonephros Abdominal cavity

Primordial Germ Cells

Gut Umbilical cord Mesonephros

Gonad Allantois

Mesonephric duct Cloaca

Ureteric bud

Primordial germ cells Metanephric primordia

Differentiation (Testis & Ovary)

Testis
Genetically males primordial germ cells, the SRY gene on Y sex chromosome encodes the testis-determining factor and thus the primitive sex cords continue to proliferate and penetrate deep into the medulla to form the medullary cords of the testis. Towards the hilum of the testis, these cords break up into a network of strands that later give rise to tubules of the rete testis. During further development a layer of dense connective tissue, the tunica albuginea, seperates the surface epithelium from the testis cords. In 4th month, these testis cords become horse-shoe shaped and their ends continue into the rete testis. The testis cords cells are derived from the surface epithelium and they will differentiate into Sertoli cells. Germ cells are embedded into these cords & are surrounded by the Sertoli cells. Mesnchyme lying between the cords of the gonads will give rise to the testosterone producing cells of the testis called Interstitial cells or Leydig cells. The Leydig cells start producing testosteroe by 8th week to influence the differentiation of the genital ducts and the external genitalia. Testis cords become hollow around puberty and are called seminiferous tubules.

Ovary
In female embryos, there is no Y sex chromosome, the primitive cords (primary sex cords) break into clusters of cells surrounding a group of primitive germ cells. These cell clusters start degenerating & disappearing from from the medulla. Ovarian medulla is all connective tissue. The surface epithelium in females give rise to a second generation of cords, the cortical cords (secondary sex cords). These cords will split into cell clusters, each holding a primitive germ cell. Germ cell develop into oocyte and surrounding cord cells become a single layer of flat cells, the follicular cells & whole structure as the primordial follicle.

Y Chromosome Influence
44 + XY Y Influence 44 + XX Absence of Y

Indifferent Sex

Testis

Ovary

Medullary cords develop

No cortical cords Thick tunica albuginea

Medullary cords degenerate

Cortical cords develop No tunica albuginea

Genital Ducts
Indifferent Stage: Molecular Regulation of Duct Genital Development: Genital Ducts in the Male: Genital Ducts in the Female:

Indifferent Stage
Both male and female embryos start with two pairs of genital ducts: the mesonephric ducts and paramesonephric ducts. Paramesonephric duct originates as longitudinal invagination of the coelomic epithelium lateral to the mesonephric duct. Cranially it stays open into the abdominal cavity as a funnel shaped structure. Caudally it runs lateral to the mesonephric duct, then crosses it ventrally to take a medial position & come in close contact with the paramesonephric duct from the opposite side. The caudal tips of these ducts project into the wall of the urogenital sinus, where it causes a small swelling, the paramesonephric or mullerian tubercle. Mesonephric ducts are opening into the urogenital sinus on either side of the mullerian tubercle.

Indifferent Stage

Genital Ducts (6th Week)

Male

Female

Genital Ducts in Female A(After 8th week), B(After descent of Ovary)

Formation of Urogenital Sinus

5 Week Old Embryo

Neural tube Metanephrogenic tissue

Ureteric bud
Hind gut Cloaca Cloacal membrane Urogenital sinus

Genital tubercle
Allantois Mesonephric duct

9 Week Old Embryo

Spinal cord

Vertebral bodies
Rectum

Urogenital sinus Mesonephric duct

Genital tubercle
Ureter Bladder

Paramesonephric duct

Molecular Regulation of Genital Duct Development

Male sex determination is controlled by the SRY gene, the testis determining factor on the Y chromosome. SRY gene product act as a transcription factor that induces expression of downstream genes leading to production of Mullerian inhibiting substance (MIS), and testosterone . MIS, produced by Sertoli cells, causes regression of the paramesonephric ducts. Testosterone produced by the Leydig cells influences the differentiation of the mesonephric ducts into male genital ducts and modulates the differentiation of the male external genitalia. The female produces no MIS and its absence causes paramesonephric ducts to stay & develop into the uterine tubes and uterus. Since testosterone is absent, the mesonephric duct system regresses. In the absence of androgens, the indifferent external genitalia are stimulated by estrogens and differentiate into labia majora, labia minora, clitoris, and part of the vagina.

Genital Ducts in the Male

As the mesonephros regresses, a few excretory tubules establish contact with cords of the rete testes and finally form the efferent ductules. Right below the entry of the efferent ductules, the mesonephric duct elongate & coil extencively to form epididymis. From the tail of the epididymis to the site of the out-budding of the seminal vesicle, the mesonephric duct becomes a very muscular tube called the vas deferens. The region of the mesonephric duct between the seminal vesicles and the its opening into the urethra is called the ejaculatory duct. The paramesonephric ducts in the male degenerate.

Genital Ducts in the Female

The mesonephric ducts degenerate in the female. The paramesonephric ducts develop into the main genital ducts of the female. Its cranial part that opens into the abdominal cavity forms the uterine tube and the long middle part form the uterine tube and the caudal part fuse with its counter part to give rise to the uterine canal. This fused region will develop into the body of the uterus and the cervix. Mesenchyme around this canal will form muscular layer (myometrium) and the peritoneal covering the epimetrium. After the ducts fuse in the midline, a broad transverse pelvic fold is established that extends from the lateral sides of the fused paramesonephric ducts towards the wall of the pelvis. This is the broad ligament of the uterus.

Vagina
At the junction of the paramesonephric ducts and the urogenital sinus, two solid epithelial evaginations develop from the wall of the sinus. These evaginations, the sinovaginal bulbs, proliferate and form a solid vaginal plate. By the 5th month, the vaginal plate is entirely canalized to form vagina. The vaginal fornices are derived from the paramesonephros. Thus the vagina has a dual origin, upper part from the paramesonephros and the lower part from the urogenital sinus. The lumen of the vagina remains seperated from the urogenital sinus by a thin tissue plate, the hymen, which consists of the epithelial lining of the sinus and a thin layer of the vaginal cells. It usually develops a small opening during perinatal life.

Vagina

9 Weeks

12 Weeks

Newborn

External Genitalia
Indifferent Stage External Genitalia in the Male External Genitalia in the Female

Indifferent Stage
In the 3rd week, the mesenchymal cells migrate around the cloacal membrane to form a pair of slightly elevated folds called the cloacal folds. Cranial to the cloacal membrane, these folds unite to form the genital tubercle. Caudally the folds are subdivided into urethral folds anteriorly and anal folds posteriorly. In the mean time, an elevation appears to the outside of each urethral fold. These are called the genital swellings. The genital swellings will be called scrotal swellings and form scrotum in male. The genital swelling will give rise to the labia majora.

External Genitalia
Genital tubercle
Urethral groove Urogenital orifice

Urogenital fold
Labioscrotal fold Anus

7th Week Old Embryo

9th Week Old Embryo

External Genitalia in the Male

Fetal testes produce testosterone that influences the rapid growth of the genital tubercle, now called the phallus. During this elongation, the phallus pulls the urethral folds forward so that they form the lateral walls of the urethral groove. The urethral groove extends along the caudal aspect of the elongated phallus but does not reach the most distal part, the glans. The epithelial lining og the groove, which is endodermal, forms the urethral plate. At the end of 3rd month, the two urethral folds fuse and close over the urethral plate, forming the penile urethra. During the 4rth month, the ectodermal cells at the tip of the glans move inward and form a solid rod of cells which later contains a lumen. This is external urethral meatus. The genital swellings, called scrotal swelling in male, move caudally and grow into two halves of the scrotum seperated by the scrotal septum.

External Genitalia of 12 Week Old Fetus

Glans penis

Glans clitoris
Urethral groove Urethral orifice Vestibule of vagina Labia minora

Labia majora
Scrotal raphe Scrotum Female Male

Anus

External Genitalia in the Female

Estrogens play a role in development of the external genitalia in the females. The genital tubercle elongates only slightly and forms the clitoris. Urethral folds do not fuse as in male but develop into the labia minora. Genital swellings enlarge and form the labia majora. The urogenital groove is open and form the vestibule. During the early stages of development (3- 4 month old fetus), genital tubercle is larger in the female.

External Genitalia In Female

5 Week Embryo

Newborn

Hormonal Influence on Sex Differentiation

Testis
Mullerian inhibiting Substance (Sertoli cells) Testosterone (Leydig cells)

Paramesonephric ducts suppressed

Mesonephric ducts stimulated & form epididymis & vas deferens

Ovary
Estrogens

Paramesonephric ducts stimulated &

Form uterine tube, uterus, upper portion of vagina

External genitalia stimulated &

form labia, clitoris & lower portion of vagina

Descent of the Testes

At the end of 2nd month, testis and the mesonephros are attached to the posterior body wall by the urogenital mesentry. Then mesonephros degenerates and the mesentry is holding the testis only. Its caudal part becomes caudal genital ligament. Also extending from the caudal pole of the testis is a mesenchymal condensation rich in extracellular matrix, the gubernaculum. Prior to decent of the testis, gubernaculum extends up to the inguinal region between the differentiating internal & external oblique muscles. Later as the testis begins to descend towards the inguinal ring, an extra-abdominal portion of the gubernaculum forms and grows from the inguinal region towards the scrotal swellings. When the testis passes through the ingunal canal, this extra abdominal portion contracts the scrotal floor. An invaginations of the body cavity extend into each scrotum and is called process vaginalis. It is accompanied by muscle and fascial layers of the body wall and eventually forms the inguinal canal. Testicular descent is influenced by hormones androgens & MIS.

Descent of Testis

Descent of Testes (Early Stage)

Gonad Mesonephros

Mesonephric duct

Gubernaculum

Descent of the Ovaries

Descent of the gonads in female is much less. Ovaries move and settle just below the rim of the true pelvis. Cranial genital ligament forms the suspensory ligament of the ovary, where as the caudal genital ligament forms the ligament of the ovary proper and the round ligament of the uterus. The later extends into the labia majora.

Adult Derivatives
Male
Testis Seminiferous tubules Rete testis Gubernaculum testis

Embryonic Structure Indifferent Gonad Cortex Medulla Gubernaculum

Female
Ovary Ovarian follicles Rete ovarii Ovarian ligament & Uterine round ligamn.

Efferent ductules Mesonephric tubules Epididymus Mesonephric duct Vas deferens Ureter, pelvis, calyces, CTs Ejaculatory duct Seminal vesicle

Ureter, pelvis, calyces, & collecting tubules

Adult Derivatives
Male Embryonic Structure Female Paramesonephric Duct
Urogenital Sinus Uterine tube Uterus Urinary bladder Urethra Vagina Urethral & paraurethral glands Greater vestibular glands Hymen Clitoris Glans clitoris Corpora cavernosa clitor. Bulb of vestibule Labia minora Labia majora

Urinary bladder Urethra Prostatic gland Bulbourethral glands

Penis Glans penis Corpora cavernosa penis Corpus spongiosum penis Ventral aspect of penis Scrotum

Sinus Tubercle Phallus

Urogenital Folds Labioscrotal swellings