Download Development of the female pelvic organs

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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:

The mechanism of normal sexual determination and differentiation :

Abnormalities that might affect normal differentiation of the female
genital tract.

Clinical complication and presentation of abnormal differentiation of
the female genital tract.

Management of abnormal differentiation.
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
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 epithelium formed
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 first appear
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
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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
induce differentiation 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 cortical zone 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):

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.
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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
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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 1432 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 8-9th week; 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
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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]