Development of the Female Pelvic Organs

1

Development of the female pelvic organs

Introduction:

From the moment of conception, the chromosomal sex is determined as male or female according to the sperm that succeed in the fertilization of the ovum,either X or Y carrying sperm.Subsequent sexual determination and differentiation are sequential processes that involve successive determination of gonadal sex, followed by the differentiation of the genital apparatus (internal and external), by the gonadal sex, into the phenotypic sex. At puberty normal gonadal function is essential for completion of the normal sexual and behavioral maturation of the individual

Thus sex determination may be defined as the process concerned with control of the development of the primary or gonadal sex, while sex differentiation encompasses the events subsequent to gonadal organogenesis. These processes are regulated by a myriad of different genes located on sex chromosomes and autosomes that act through a variety of mechanisms, including organizing factors, gonadal steroid and peptide hormones, and tissue receptors.

Early embryos of both sexes possess indifferent, common primordia that have an inherent tendency to feminize unless there is active interference by masculinizing factors. Thus the default for both the external and internal genitalia is for female differentiation. Masculinization occurs in the presence of an intact and functioning Y chromosomes and male gonads i.e. testes. The testes produce two important substances Mullerian inhibiting hormone (MIH) and testosterone. The MIH inhibits the growth of the female primitive duct system (known as Mullerian duct), while testosterone is responsible for differentiation of the male primitive duct system (known as Wollfian duct). Testosterone is also responsible for the differentiation of the external genitalia into the male phenotype. Furthermore in utero exposure of the central nervous system to the fetal androgens seems to play an important role in programming the central nervous system into the masculinize behavior that characterize male individuals..

Abnormal sexual differentiation may occur as a result of defaults in any of the determinants of sex i.e. chromosomal sex, gonadal sex, internal genital sex, external genital sex and the behavioral elements. The results may be identified immediately at birth as ambiguous genitalia. Alternatively it may not be diagnosed except late at puberty as in cases of intersex e.g. the XY female.

This chapter describes:

1. The mechanism of normal sexual determination and differentiation :

1. Abnormalities that might affect normal differentiation of the female genital tract.
2. Clinical complication and presentation of abnormal differentiation of the female genital tract.

1. Management of abnormal differentiation.

• Embryology of The Genital Tract (Mechanism of sexual determination and differentiation):

Sexual determination may be defined as the process concerned with control of the development of the primary or gonadal sex, while sexual differentiation encompasses the events subsequent to gonadal organogenesis. These processes are regulated by a myriad of different genes located on sex chromosomes and autosomes that act through a variety of mechanisms, including organizing factors, gonadal steroid and peptide hormones, and tissue receptors.

Each of the three major elements of the genital tract i.e. the gonads, internal and external genital tracts goes through two phases: a Bipotential phase (undifferentiated phase) followed by phase of differentiation into either a male or female organs.

The Development of the Gonads (Gonadal Sex):

The phase of indifferent gonads: (Fig 1) although the sex of the embryo is determined genetically at the time of fertilization, morphologically the gonads remains indifferent until the seventh week of development. During this phase the gonads, known as the "genital ridge", can be identified as an elevation or bulge on the medial side of the mesonephros on each side of mesentery underneath the coelomic epitheliumformed by proliferation of the covering endothelium and condensation of the underlying mesenchyme (stroma). The germ cells (known as the primordial germ cells) do not appear in the genital ridge until the sixth week of development. They firstappear among the endodermal cells in the wall of the yolk sac. It then migrates, by amoeboid movement, along the root of the dorsal mesentery of the hindgut, to invade the genital ridge around the sex week. The germ cells seem to have an inductive influence on development of the gonad into ovary or testes because if the germ cells fail to reach the genital ridges the gonads do not develop. Together with the arrival of the germ cells the covering epithelium proliferates and sends cluster of cells into the underlying mesoderm known as the cells of the sex cords (Figure 1 A, B page 339 from Sadler). The three elements of the gonads which are still "indifferent" are now completed; the germ cells, the cells of the sex cords (the potential granulosa or Sertoli cells), and the mesenchymal stroma (potential theca/Leydig cells).

The phase of Gonadal Determination: Begins at about the 6th-7th week of gestation the gonads starts to differentiate into testis or ovaries depending on the presence or absence of the Y chromosome in the germ cells. 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. The SRY is a single copy gene expressed in the genital ridge only during the appropriate time of embryonic development when testicular cord forms. The mechanism by which SRY promotes differentiation of the testis is not well understood. But it seems that SRY directly control male development through sequences-specific regulation of target genes (Speroof Ref 13). Deletion of this SRY gene results in XY female. Similarly translocation of this gene to an X chromosome results in an XX male. However for normal testicular development at least four additional genes including autosomal genes are also required [3 ref from uptodate].

- The Wilms' tumor-related gene (WT-1) is located on chromosome 11 and is deleted in patients with Wilms' tumour nephroblastoma hence the name.

- Steroidogenic factor 1 (SF-1), and Dosage-sensitive sex reversal-adrenal hypoplasia congenita critical region of the X chromosome gene 1 (DAX-1): both are the located on the X chromosome, are nuclear receptors for which specific ligands have not been identified (orphan receptors). SF1 acting through another transcription factor "SPX9" to inducedifferentiation of Sertoli and Leydig cells.

- SRY-related HMG-box 9 (SOX9).

Testis Differentiation:The first sign of testicular differentiation of the gonads is further proliferation of primitive sex cords and their penetration deep into the gonadal medulla to form the testis or medullary sex cords (at puberty it canalizes and become the seminephrous tubules). Towards the hilum of the tests the cords break up into a network of tiny cell strands which later gives rise to the tubules of the rete testes. At the same time the cortical region (the surface) of the testis, regress to make a dense fibrous connective tissue “the tunic albuginea”. The rete testis joins the Mesonephric tubule, which later form the epididymis.

Ovarian Differentiation: In the absence of Y chromosome and SRY protein, the gonads differentiate into ovaries. This occurs two weeks later (about the 8th week). The first sign of ovarian differentiation is reflected in the rapid multiplication of germ cells by mitotic division. Unlike testicular differentiation the corticalzone that contain the germ cells develop to a much greater extent than in the testis, while the medulla regress. By the fourth month each germ cell, now become known as 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. They remain in this resting phase until puberty and beginning of ovulation. Around the 20th week of gestation the ovary contains about 7 million germ cells (see chapter on ovulation). Degeneration and atresia begins around 20 weeks and by birth approximately 20 million germ cells remain.

Differentiation of the Genital Ducts (The Internal Genital Organs):

1. The Indifferent stage:

Examination of the embryo at this stage (6 weeks), whether in male or female, reveals two genital ducts (Figure 14-23 page 342 from Sadler):

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. Cranially it opens into the coelomic cavity with a funnel-like structure. 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.

Stage of Ductal differentiation:

Shortly following gonadal determination (8 weeks of intrauterine life) begins the process of ductal differentiation.

Differentiation of male internal organs

The testis produces two important substances; the Mullerian Inhibiting Hormone (MIH) and testosterone. The Mullerian inhibiting hormone (MIH) is a glycoprotein produced by the Sertoli cells (activated by SRY) soon after testicular differentiation. It is responsible for regression of the ipsilateral paramesonephric ducts (an example of local paracrine effect) before the emergence of testosterone and stimulation of the Wolffian duct (Ref 28 Speroff). The gene for MIH has been mapped to the short arm of chromosome 19, and the MIH receptor gene is on chromosome 12. MIH has other extra mullerian function namely: inhibitory effect on oocytes maturation and important role in descent of the testes.

Testosterone is secreted by the Leydig cells at around the 8th week. It reaches peak level by the 16-18 week. Testosterone is responsible for development of the mesonephric duct into the male internal genitalia (vas deference, epididymis, and seminal vesicles). Like, AMH, testosterone act on the ipsilateral Wolffian duct(local paracrine effect).

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. However it seems that complete regression of the Wolffian system require estrogen hormone (ref 34 from sperof).

Development of the fallopian tubes, uterus (Figure 14-42 page 342 Sadler): The solid core of the Mullerian ducts canalizes to form the Fallopian Tubes in its upper part. In its caudal part as the two tubes meet and canalize, anterior to the mesonephric duct, they form the corpus of the uterus and the cervix. It latter takes a horizontal position and acquire covering peritoneal folds (broad ligaments). The remnants of the Wolffian ducts form tubules like structures known as the epoöphorons, paroophoron and Gartner’s dust.

Development of the vagina (Figure 14-29 page 347) Sadler): At the point where the Mullerian tubercle reaches the urogenital sinus a solid cord of epithelial cells derived form the urogenital sinus grows upwards (sinovaginal bulbs), increasing the distance between the tubercle and the urogenital sinus. By approximately the fifth month the central core of this cord breaks down to form the vaginal canal. Thus the vagina has a dual origin; the upper 1/3 is derived from the Mullerian tubes while its lower 2/3 is derived from the urogenital sinus. The hymen marks the site from which the upward growth of cells from the urogenital sinus began. Thus its epithelium is derived from the urogenital sinus.

Development of the External Genitalia:

The Phase of undifferentiated external genitalia:

During the phase of undifferentiated external genitalia, both the urogenital sinus and the hind gut open into a common opening known as the Cloaca. On either side of the cloaca develops a pair of slightly elevated folds of Mesenchymal cells known as the cloacal folds. Anteriorly the cloacal folds unite to form the genital tubercle (Figure 14-32 page 249 Sadler). In the mean time another pari of elevation, genital swellings appear on each side of the urogenital membrane. Later around the 6 week a septum of mesodermal cells appears to divide the cloaca into an anterior part (the urogenital membrane) and a posterior part.Unlike the internal genitalia where there are two duct systems one for male and one for female, 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.

Differentiation to male phenotype:

The testis begins secretion of testosterone by the 8-9thweek; masculinization of the genitalia is observed about a week later (the 10th week) and is completed by the 14th week (Speerof page 345). 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 (Figure of Actions of testosterone). DHT has other function in male namely: temporal hair regression, facial and body hair growth and development of acne in addition to the action on the external genitalia and prostate.

Differentiation to female phenotype:

In the absence of DHT the bipotential external genitalia differentiate into female. The genital tubercle elongates slightly to form the clitoris. The inner genital folds (urethral folds) develop into the labia minora. The labia major develop from the genital swellings. Finally the urogenital membrane disappears, so that the vestibule communicates with the exterior through the vulva.

The steps of Müllerian development include elongation, fusion, canalization, and septal resorption. Müllerian ducts can be identified in embryos of both sexes at 6 weeks' gestation. By the ninth week the ducts elongate and reach the urogenital sinus. The uterovaginal canal is formed and inserts into the urogenital sinus at Müller's tubercle. The two ducts fuse proceeding caudad to cephalad up to the level of the uterine fundus. Internal canalization and septum resorption occurs by approximately 20 weeks' gestation. The hymen is formed and becomes perforate by birth.[2]