Normal and Abnormal Embryology of the Female Genital Tract

1. Normal and Abnormal Embryology of the Female Genital Tract Professor Hassan Nasrat Chairman Department f Obstetrics and Gynecology (Fourth Year Medical Students)

2. Definitions: Sexual Determination And sexual Differentiation • Normal Sexual Differentiation: • Differentiation Of The Gonads • Development Of The Internal Genital System. • Differentiation Of The External Genital System. • Abnormal Differentiation: • Anomalies Of The External Genital Organs: • Anomalies Of The Internal Genital Tract "Müllerian Anomalies“

3. Embryology of The Genital Tract (Sexual determination and Differentiation) Sexual determination: is related to the Genetic Make Up At Fertilization Sexual differentiation: encompasses the events subsequent to gonadal Sex

4. Normal Sexual Determination And Differentiation Genetic Sex: Undifferentiated Phase Gonadal Sex: Internal Genital Sex: Differentiation Phase External Genital Sex:

5. Genetic Sex The Gonads Differentiate into testis or ovaries depends on the presence or absence of the Y chromosome in the germ cells.

6. Normal Sexual Determination And Differentiation Genetic Sex: Gonadal Sex: Undifferentiated Phase Internal Genital Sex: Differentiation Phase External Genital Sex:

7. (Gonadal Sex)The Development of the Gonads The phase of indifferent gonads (Genital Ridge): By the 6th week the germ cells (primordial germ cells) migrate to the genital ridge The germ cells influence development of the gonad into ovary or testes The covering epithelium proliferates and sends cluster of cells into the underlying mesoderm known as the cells of the sex cords. sex cords (granulosa or Sertoli cells) the germ cells mesenchymal stroma (potential theca/Leydig cells).

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

9. 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. Similarly translocation of this gene to an X chromosome results in an XX male. Ovarian Differentiation Occur in the absence of Y chromosome and SRY protein it occurs two weeks later (about the 8th week). • Testis Differentiation

10. Ovarian Differentiation The cortical zone that contain the germ cells develop to a much greater extent, while the medulla regress. (4th month) Each germ cell (Oogonia), is surrounded by a single layer of epithelial cells The oogonia are transformed into Primary Oocytes as they enter the 1st meiotic division and arrest in prophase until puberty and beginning of ovulation. (20th week) The ovary contains about 7 million germ cells. Degeneration and atresia begins around 20 weeks and by birth approximately 20,000 germ cells remain.

11. Primary Oocytes 1st meiotic division and arrest in prophase Oogonia At birth approximately 2 Million germ cells remain. (4th month) (Oogonia) Germ cell surrounded by a single layer of epithelial cells (20th week) The ovary contains about 7 million germ cells Degeneration and atresia begins

12. Normal Sexual Determination And Differentiation Genetic Sex: Undifferentiated Phase Gonadal Sex: Internal Genital Sex: Differentiation Phase External Genital Sex:

13. Normal embryologic processes in development of the internal female genitalis (fallopian tubes, uterus, cervix, and the upper two thirds of the vagina): • The differentiation of two paired mullerian ducts. • Lateral fusion of the lower segment of the mullerian ducts in the midline to form the uterus, cervix and upper two third of the vagina. • Resorption of the central septum between the two mullerian ducts.

14. Differentiation of the Genital Ducts (The Internal Genital Organs) The Indifferent stage: 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. It develops, as a longitudinal invagination of coelomic epithelium that runs caudally as a solid cord cells. 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.

15. 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.

16. PD: Paramesonephric duct MD: Mesonephric Duct US: Urogenital Sinus MT: Mullerian Tubrcle UVP: Uterovaginal primordium VP: Vaginal plate

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

19. Development of the External Genitalia: The external genitalia are derived from common anlagen: the genital tubercle, the genital swellings, and the genital folds that are capable of development into male or female genitalia under the influence of androgenic hormones produced by the Leydig cells of the testes. The Phase of undifferentiated external genitalia

20. 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

22. Differentiation to female phenotype: In the absence of DHT the bipotential external genitalia differentiate into female

23. Indifferent Stage (Approximately 7 weeks)

24. Development of the external female genitalia Approximately 10 weeks Approximately 12 weeks

27. Definitions: Sexual Determination And sexual Differentiation • Normal Sexual Differentiation: • Differentiation Of The Gonads • Development Of The Internal Genital System. • Differentiation Of The External Genital System. • Abnormal Differentiation: • Anomalies due to Genetic Factors (Intersex) • Anomalies Of The External Genital Organs (Ambiguous Genitalia): • Anomalies Of The Internal Genital Tract "Müllerian Anomalies“

28. Abnormalities due to Genetic Factors (Intersex ) Diagram of a G-banded Y chromosome. Y-linked genes are shown. SHOX/PHOG, short stature/pseudoautosomal homeobox-containing osteogenic gene on the X; MIC2, a cell-surface antigen recognized by the monoclonal antibody 12E7; SRY, sexdetermining region Y; RPS4Y, ribosome protein S4Y; ZFY, zinc finger Y; TSPYA, TSPYB, testes-specific protein Y; PRKY, a member of the cyclic adenosine monophosphate-dependent serine threonine protein kinase gene family, homologous to PRKX. DAZ, deleted in azoospermia; AZF, azoospermific factor.

29. Anomalies of the external genital organsAmbiguous Genitalia Ambiguous Genitalia (Defect of the clitoris and labia):

30. genital deformities seen in female infants who are masculinized Sagittal views of A,Minimal masculinization with slight enlargement of the clitoris. B,Labial fusion and more marked enlargement of the clitoris. C,Complete labial fusion, enlargement of the clitoris, and formation of a partial penial urethra.

31. Anomalies of the internal genitaltract "Müllerian anomalies" • Obstructive Mullerian Anomalies • Longitudinal Fusion Anomalies • Agenesis/Hypoplasia And Other • Miscellaneous Anomalies

32. Obstructive Müllerian anomalies transverse vaginal septa: cervical agenesis Imperforate hymen (embryo logically not of mullerian origin) Patients with this type of anomaly will usually presents with amenorrhea or Cyclic pain due to accumulated menstrual flow.

34. Potential sites of transverse vaginal septa. A. High septum. B. Midvaginal septum. C. Low septum.(From Simpson JL, Verp MS, Plouffe L Jr: Female genital system.

35. Vaginal atresia

36. a,Isolated congenital cervical atresia with normal vaginal development.

37. b, Congenital cervical atresia with complete vaginal agenesis

38. Imperforate Hymen: The hymen represents the junction of the sinovaginal bulbs with the urogenital sinus; hence it is formed form the endoderm of the urogenital sinus epithelium. Clinically: May be discovered at birth ( "mucocolpos or hydrocolpos" More commonly at puberty: hematocolpos.

40. Diagram of hematometra and hematocolpos with imperforate distal transverse vaginal septum

41. Defects of Mullerian Duct fusion: Unlike obstructive anomalies that usually presents with primary amenorrhea, fusion anomalies are often associated with gynecological as well as obstetrics complications e.g. infertility, recurrent pregnancy loss and poor obstetrics outcome in pregnancy Some case where there is partial obstruction e.g. a unilateral rudimentary horn, may present early in the years following puberty usually with primary cyclic dysmenorrhea.

42. Anomalies of lateral fusion of the mullerian ducts: This may be partial or complete failure of fusion. Anomalies due to unilateral defects of Mullerian duct development: Diethylstilbestrol Associated anomalies:

43. Uterine fusion anomalies A. Normal uterus Unicornuate uterus Arcuate uterus Didelphic uterus with a septate vagina Septate uterus Bicornuate uterus

45. Bulging mass in a complete obstructive longitudinal vaginal septum

47. Rudimentary horn attached to the unicornuate uterus with a band of tissue. Dashed lines represent the dissection planes.

48. Normal sexual development in embryogenesis consists of three related sequential processes]: Establishment of chromosomal sex at fertilization, with XY as male and XX as female. For the first two months of gestation the two sexes develop in an identical fashion.Determination of gonadal sex when the indifferent gonad develops into an ovary or a testis, beginning at week 8. . Development of sexual phenotypes as the result of gonadal differentiation when the indifferent anlagen of the internal and external genitalia develop into their characteristic male or female structures

50. In females, the müllerian ducts give rise to the fallopian tubes, uterus, and upper vagina, and the wolffian ducts persist in vestigial form.    In males, the wolffian ducts give rise to the epididymides, vasa deferentia, seminal vesicles, and ejaculatory ducts, and the müllerian ducts regress.