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Introduction:

An understanding of the development and anatomy of the female genital tract is important in the practice of gynecology. Both the urinary and genital systems develop from a common mesodermal ridge running along the posterior abdominal wall. It is important to remember that congenital anomalies of the genital tract may also be associated with congenital anomalies of the urinary tract.


Following fertilization the normal embryo contains 23 sets of chromosomes ,including 22 autosomes and one sex chromosomes from each parent. 46XY embryo will develop as a male 46XX embryo will develop as a female It’s the presence or the absence of the Y chromosome which determines whether the undifferentiated gonad becomes a testis or an ovary.

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.


Although genetic sex is determined at fertilization, the early genital system is indistinguishable between the two sexes in the embryonic stage. This is known as the “indifferent stage” of genital development, during which both male and female fetuses have gonads with prominent cortical and medullary regions, dual sets of genital ducts, and external genitalia that appear similar.

Clinically, sex is not apparent until about the twelfth week of embryonic life and depends on the elaboration of testis determining factor and, subsequently, androgens by the male gonad. Female development has been called the “basic developmental path of the human embryo,” requiring not estrogen but the absence of testosterone.

Normal Sexual Determination And Differentiation

Genetic Sex
Gonadal Sex
Phenotypic sex
Undifferentiated Phase
Differentiation Phase

Gonads:The phase of indifferent gonads (Genital Ridge): 

The gonads do not acquire male or female morphological features until the 7th week of development.The primitive gonad appears in embryos at around 5 weeks’ gestation. At this time coelomic epithelium develops on the medial aspect of the urogenital ridge and following proliferation leads to the establishment of the gonadal ridge (a pair of longitudinal ridges lie ventro-medial to the mesonephric kidney. These are epithelium covered condensations of mesenchyme).

Neural tube Dorsal aorta Dorsal mesentery Mesonephros Gonadal ridges Gut

Gonadal Ridges


Epithelial cords then grow into the mesenchyme (primary sex cords) and the gonad now possesses an outer cortex and an inner medulla. In embryos with an XX complement, the cortex differentiates to become the ovary and the medulla regresses. The primordial germ cells develop by the 4th week in the endodermal cells of the yolk sac and during the 5th week they migrate along the dorsal mesentery of the hindgut to the gonadal ridges, eventually becoming incorporated into the mesenchyme and the primary sex cords by the end of the 6th gestational week. If they fail to reach the ridges, the gonads do not develop.

Migratory Path Of Primordial Germ Cells From The Yolk Sac Along The Hindgut Mesentery, To The Urogenital Ridge At Approximately 5 Weeks

It is impossible to differentiate between the male and the female gonad. Hence the gonad is known as the indifferent gonad.
the germ cells
mesenchymal stroma (potential theca/Leydig cells).
sex cords (granulosa or Sertoli cells)

The phase of Gonadal Differentiation

The differentiation of the gonads into testis depends on the presence of sex determining region or gene (SRY) located on the short arm of the Y chromosome. Deletion of this SRY gene results in XY female.
Testis Differentiation sex determining region or gene (SRY)


Ovarian Differentiation Occur in the absence of Y chromosome and SRY protein it occurs two weeks later (about the 8th week).

Ovary

If no Y chromosome is present, the gonad, by default, forms an ovary; the cortex develops, the medulla regresses, and oogonia begin to develop within follicles. The surface epithelium 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.

44 + XY 44 + XX Y Influence Absence of Y

Indifferent Sex Testis Ovary Medullary cords develop Medullary cords degenerate No cortical cords Cortical cords develop Thick tunica albuginea No tunica albuginea
Y Chromosome Influence


The oogonia are derived from the primitive germ cells by a series of about 30 mitoses, for fewer than the number required for spermatogenesis. Beginning at about the end of the third month, the oogonia enter meiosis I, but this this process is arrested at a stage called dictyotene, in which the cell remains until ovulation occurs many years later. The number of oocytes is greatest during pregnancy and thereafter declines. It is found that the total population of germ cells rose from 600,000 at 2 months to a peak of 7 million at 5 months. At birth the number falls to 2 million, of which half are atretic.

(4th month) (Oogonia) Germ cell surrounded by a single layer of epithelial cells

Oogonia
Primary Oocytes 1st meiotic division and arrest in prophase
(20th week) The ovary contains about 7 million germ cells Degeneration and atresia begins
At birth approximately 2 Million germ cells remain.

Genital Ducts: Indifferent Stage

Both male and female embryos start with two pairs of genital ducts: the mesonephric ducts and paramesonephric ducts. The Mesonephric (Wolffian) duct: run on either side of the primitive gut as a longitudinal ridge, covered by the coelomic epithelium. The Mullerian duct (Paramesonephric ducts): Runs lateral to the Mesonephric duct. At its caudal part the Mullerian ducts pass medially across the front of the Wolffian ducts. The Mullerian ducts, from each side, meet and fuse as a single solid rod of cells. They further extend caudally until they make contact with the urogenital sinus; produce a prominent elevation in its posterior wall, known as the Mullerian tubercle (sinusal tubercle).


Indifferent Stage

Genital Ducts (6th Week)

Male
Female

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 .

Stage of Ductal differentiation (8 weeks):

Differentiation of male internal organs - The Mullerian Inhibiting Hormone (MIH) (Sertoli cells ): responsible for regression of the ipsilateral paramesonephric ducts - Testosterone (Leydig cells): responsible for development of the mesonephric duct into the male internal genitalia

Differentiation of Female Internal Organs In the absence of testes (MIF and testosterone) the mesonephric system regress and the Mullerian duct develop to give the fallopian tube, uterus, and upper vagina.

The paramesonephric (mullerian) duct:

The coelomic epithelium lateral to the Wolffian duct is invaginated to form the Mullerian duct which grows caudally, at first it is solid, but later it becomes canalized It deviates more and more medially till it meets its fellow of the opposite side . The septum between the 2 Mullerian ducts disappear . The proximal parts of the Mullerian ducts form the fallopian tubes , while the distal parts meet together to form the body and cervix of the uterus and the upper 4/5 th of the vagina . The stroma and muscles develop from the surrounding mesoderm .

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

Remnants of the mesonephric (wolffian) ducts that may persist in the anterolateral vagina or adjacent to the uterus within the broad ligament or mesosalpinx.

Vagina

The Mullerian ducts reach down to the urogenital sinus and at the meeting point , form the Mullerian tubercle which meet a pair of endodermal sinovaginal bulbs which arise from the urogenital 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 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.

9 Weeks 12 Weeks Newborn

Vagina

Development of the External Genitalia:

There is a common indifferent stage consisting of two genital folds, two genital swellings and a midline anterior genital tubercle.
The Phase of undifferentiated external genitalia

Differentiation to male phenotype:

The testis begins secretion of testosterone by the 8-9th week. masculinization of the genitalia is observed about a week later (the 10th week) and is completed by the 14th week. However the target cells of the external genitalia must be able to convert testosterone to its active product Dihydrotestosterone (DHT) under the influence of the intracellular enzyme 5 alpha reductase

Differentiation to female phenotype:

In the absence of DHT the bipotential external genitalia differentiate into female


Clitoris develops from the genital tubercle (by slight elongation) Labia minora develop from the genital folds (by remaining separate) Labia majora develop from the genital swellings (by enlarging greatly) Vestibule develops from the lower most part of the urogenital sinus.

External Genitalia In Female

5 Week Embryo Newborn

Summary of Normal Sex Differentiation

The SRY gene directs the gonad to become a testis. The absence of the SRY gene allows the gonad to become an ovary. The presence or absence of androgen determines external genital development. The presence of gonadal testosterone production leads to Wolffian duct differentiation into vas deferens, epidydmus and seminal vesicle. The presence of gonadal AMH production leads to Mullerian duct regression. The absence of gonadal AMH production allows Mullerian duct differentiation into upper vagina, cervix,uterine gland and epithelium and fallopian tubes. The absence of gonadal testosterone production allows Wolffian duct regression.

Gonadal development

SRY-gene (TDF) Short arm of Y chromosome
Bipotential Gonad
2 X chromosomes
Receptors For H -Y antigen
OVARY
TESTES
Present
Absent

Leydig cells

Sertoli cells
Testosterone
Mullerian inhibiting factor
Wollfian duct
5a-reductase
Urogenital sinus
Regrsession of Muuleian ducts
Male external genitalia
Male internal Genital organs
DHT
TESTIS
Male development


Urogenital sinus
Female external genitalia . Lower part of vagina
OVARY
Mullerian ducts
Female internal genital Organs . Most of upper vagina . Cervix and uterus . Fallopian tubes
Neutral Development
Absence of androgen exposure
Female development