13. Development of the female genital organs. Malformations

Learning objectives

• What are the indifferent gonads?
• Up until which week of development are the gonads of the different sexes indistinguishable?
• Which gene is the major determinant of sex, and on which chromosome is it located?
• Describe how the presence or absence of the Y chromosome determines the sex
• At which point of development is the sex determined?
• Describe the journey of the primordial germ cells from their origin to their target
• What are the gonadal ridges?
• What are the primitive sex cords?
• Describe the process of differentiation of the gonadal ridges into ovaries
• How are the ovaries essential for the formation of other female genital organs?
• What is the Müllerian (paramesonephric) duct, and what does it give rise to?
• What is anti-Müllerian hormone?
• Describe the development of the fallopian tubes and uterus
• Describe the development of the vagina
• Describe the development of the indifferent external genital organs
• Describe the development of the external female genital organs
• What causes duplicated uterus?
• What are disorders of sex development (DSDs)?
• What is congenital adrenal hyperplasia?
• What is androgen insensitivity syndrome?
• What is Klinefelter syndrome?
• What is Swyer syndrome?
• What is Turner syndrome?

Development of the indifferent gonads

Up until week 7 of development the gonadal development is the same regardless of biological sex. The gonads which are formed are known as indifferent gonads up until this point.

Determination of sex

The major determinant of sex lies on the Y chromosome. On the short arm of this chromosome is a gene called SRY, which stands for “Sex-determining Region on Y”. This gene codes for a transcription factor called TDF (testis-determining factor), which influences many genes. These genes will induce the indifferent gonads to differentiate into testes.

In the absence of this gene (in XX embryos, which are destined to become female), the sexual organs will “default” into becoming female.

This means that the sex of the embryo is determined at the time of fertilization, when it’s decided whether it should be XX or XY. Despite this, there are no morphological differences in the embryo until week 7 of development.

Primordial germ cells

The primordial germ cells, which will give rise to sperm cells in the male and oocytes in the female, originate in the epiblast. They first migrate to the wall of the yolk sac close to the allantois, after which they will migrate into the gonadal ridges.

Gonadal ridges

At around week five of development the so-called gonadal ridges appear. They arise from proliferation of coelomic epithelium and mesenchyme and lie close to the mesonephros.

The gonadal ridges initially don’t contain any primordial germ cells. After the ridges have been formed the primordial germ cells migrate from the yolk sac along the dorsal mesentery and into the gonadal ridges. This migration begins in week 4, and they reach the ridges in week 6.

The primordial germ cells are essential for the further development of the gonads. Without them, the gonads will not develop.

The gonadal ridge, along with the mesonephros, are attached to the posterior body wall by the urogenital mesentery. When the mesonephros degenerates, the mesentery only attaches to the gonadal ridge. This mesentery forms the cranial and caudal genital ligaments, attaching to the superior and inferior poles of the gonadal ridges, respectively. The caudal genital ligament is also known as the gubernaculum.

Primitive sex cords

While the primordial germ cells are migrating to and invading the gonadal ridges, the epithelial covering of the gonadal ridges proliferates and penetrates the underlying mesenchyme. Here they form the so-called primitive sex cords, which are irregularly shaped cords. These cords have open connection to the surface of the ridges.

Development of ovary

Formation of follicular cells

In the female, the primitive sex cords, now known as medullary cords, degenerate. However, a second “generation” of sex cords are formed. They are also formed by epithelium penetrating the mesenchyme but lie closer to the surface. These are the cortical cords.

The cortical cords eventually split into isolated clusters of cells, after which they’ll begin to surround each oogonium. At this point the epithelial cells of the cortical cords have become the follicular cells of the follicle. Together with the oogonium the follicular cells form the primordial follicle.

Oestrogen production

When the primordial follicles have been established the ovaries will begin to produce oestrogens. These female sex hormones are essential for formation of the rest of the female genital organs.

Descent of the ovary

The ovaries don’t descend as far as the testes, settling just below the rim of the true pelvis. The cranial genital ligament forms the suspensory ligament of the ovary, while the gubernaculum (caudal genital ligament) forms the ligament of the ovary proper and the round ligament of the uterus.

Development of the female genital ducts

The indifferent genital ducts

The two indifferent genital ducts are the mesonephric (Wolffian) and paramesonephric (Müllerian) ducts. The Wolffian ducts degenerate in the female, due to the absence of testosterone.

The Müllerian ducts, also known as the paramesonephric ducts, give rise to the fallopian tubes, uterus, and upper third of the vagina. Like the name paramesonephric implies, the Müllerian ducts runs beside the Wolffian ducts, on the lateral side.

Anti-Müllerian hormone and oestrogens

In the male, Sertoli cells of the testes produce a hormone called Anti-Müllerian hormone (AMH), also called Müllerian inhibiting substance (MIS). Like the name implies, this hormone stimulates the degeneration of the Müllerian ducts. In the female, AMH is obviously absent, allowing the Müllerian ducts to avoid degeneration.

Oestrogens produced by the ovaries are also necessary for proper development of the Müllerian duct.

Development of the uterus

At the cranial end, the Müllerian duct opens into the abdominal cavity. At the caudal end, the two Müllerian ducts come in close contact with each other and fuse, entering (but not yet opening into) the urogenital sinus at the so-called sinus tubercle. The Müllerian ducts cross over the Wolffian duct right before they meet.

The fused caudal parts of the Müllerian ducts form the corpus of the uterus, the cervix, and the upper portion of the vagina.

Development of the fallopian tubes

When the ovary descends to its final position, the cranial end of the Müllerian tube follows it. The cranial parts of the Müllerian ducts form the fallopian tubes, with the cranial ends forming fimbriae which remain in close contact with the ovary.

Development of vagina

As already mentioned, the upper third of the vagina originates from the Müllerian ducts. This includes the vaginal fornices, which are of Müllerian origin.

The lower two thirds originate in the vaginal plate. The vaginal plate is a solid plate of tissue originating from the sinovaginal bulbs, which are outgrowths of the sinus tubercle of the urogenital sinus. A lumen appears in the vaginal plate. This lumen continually enlarges, hollowing out the plate and eventually transforming it into a “tube”. The tube eventually opens at the cranial end, establishing communication with the upper third of the vagina.

The caudal end of the vagina remains separated from the urogenital sinus by a thin plate of tissue called the hymen.

Development of external female genital organs

The indifferent external genital organs

The external genital organs of the two sexes are indistinguishable until the eighth week.

In week 3, mesenchymal cells form a pair of folds around the cloaca, the so-called cloacal folds. At the cranial end they fuse and form the genital tubercle. Later, as the urorectal septum separates the cloaca into the urogenital sinus anteriorly and the anal canal posteriorly, the cloacal folds separate into urethral folds anteriorly and anal folds posteriorly.

Laterally to the urethral folds, the so-called genital swellings develop. These swellings will give rise to the scrotum in the male and the labia majora in the female.

The presence of oestrogens induces the indifferent external genital organs to become female, while the presence of DHT (dihydrotestosterone, a more potent form of testosterone) induces them to become male.

Development of the clitoris

The genital tubercle forms the clitoris.

Development of the labiae

The urethral folds form the labia minora, while the genital swellings form the labia majora.

Development of the vestibule

The vaginal vestibule originates from the urogenital sinus.

Malformations

Duplication of uterus

If the two Müllerian ducts don’t fuse completely, the uterus can be duplicated. This may rarely be accompanied by a double vagina.

Disorders of sex development

I’m not sure whether disorders of sex development belong to this topic in neuro, but I’ve included it anyway.

Disorders of sex development (DSDs) are a large group of congenital conditions that cause abnormalities in sex differentiation. This often causes a sexual phenotype which doesn’t correspond with the genotype. These disorders are also associated with other organ malformations.

Some of these disorders can cause ambiguous genitalia, external genitalia which have neither complete male nor female morphology.

Congenital adrenal hyperplasia

Congenital adrenal hyperplasia is one of the most common causes of ambiguous genitalia. These individuals are 46XX but have a congenital enzyme defect in the adrenal glands which increases the production of an androgen called androstenedione. This causes the external genitalia to take on a more male morphology.

Androgen insensitivity syndrome

Androgen insensitivity syndrome occurs in 46XY individuals. These people have a congenital defect which makes them insensitive to androgens, often due to a deficiency of androgen receptors. This prevents androgens from inducing differentiation of male genitalia, giving them female external genitalia and phenotype. Because they still have anti-Müllerian hormone, they form no Müllerian ducts and therefore no internal female genitalia.

Klinefelter syndrome

Klinefelter syndrome is the most common disorder of sex chromosomes and occurs when an individual is 47XXY. These individuals have male phenotype but abnormal testicular development, giving them clinical features of testosterone deficiency like gynecomastia and infertility.

Swyer syndrome

Swyer syndrome occurs in 46XY individuals with a mutation in the SRY gene on the Y chromosome. These individuals have female phenotype but abnormal ovarian development, which becomes apparent when they never initiate puberty. These abnormal ovaries are called streak gonads and must be surgically removed as they have a high risk of becoming cancerous.

Turner syndrome

Turner syndrome occurs in 45X0 individuals. These individuals have female phenotype as well as a characteristic short stature, webbed neck, and shield-like chest. Like in Swyer syndrome the ovaries are replaced by streak gonads.

Summary

• What are the indifferent gonads?
  • Up until week 7 the gonads are the same regardless of biological sex, making them “indifferent” gonads
• Up until which week of development are the gonads of the different sexes indistinguishable?
  • Week 7
• Which gene is the major determinant of sex, and on which chromosome is it located?
  • The SRY gene, located on the short arm of the Y chromosome
• Describe how the presence or absence of the Y chromosome determines the sex
  • When the Y chromosome is present the SRY gene influences the indifferent gonads to become testes
  • When the Y chromosome is absent the indifferent gonads will “default” to become ovaries
• At which point of development is the sex determined?
  • At the fertilization, depending on the chromosome content of the sperm cell
• Describe the journey of the primordial germ cells from their origin to their target
  • They originate in the epiblast and migrate to the wall of the yolk sac close to the allantois during gastrulation. From there they migrate into the gonadal ridges
• What are the gonadal ridges?
  • The precursors of the gonads, which arise from proliferation of coelomic epithelium and mesenchyme
• What are the primitive sex cords?
  • They’re cords inside the gonadal ridges, formed by proliferation of the epithelial covering
• Describe the process of differentiation of the gonadal ridges into ovaries
  • The medullary cords degenerate, but new cortical cords form and give rise to the follicular cells of the ovarian follicles
• How are the ovaries essential for the formation of other female genital organs?
  • The ovaries produce oestrogens, which are essential for the formation of the other genital organs
• What is the Müllerian (paramesonephric) duct, and what does it give rise to?
  • It’s a duct that runs laterally to the Wolffian duct
  • It gives rise to the fallopian tubes, uterus, and upper third of the vagina
• What is anti-Müllerian hormone?
  • A hormone produced by Sertoli cells in the testes which stimulates the degeneration of the Müllerian duct
• Describe the development of the fallopian tubes and uterus
  • The cranial end of the Müllerian ducts form fimbriae and remain in close contact with the ovary
  • The caudal part of the Müllerian ducts fuse and form the uterus and upper third of the vagina
• Describe the development of the vagina
  • The upper third derives from the fusion of the Müllerian ducts
  • The lower two-thirds derive from the vaginal plate, a solid plate of tissue which originates from the sinovaginal bulbs
  • The vaginal plate continually hollows out, forming the lumen of the lower two-thirds of the vagina
  • The cranial end of the vaginal plate opens, establishing communication with the upper third of the vagina
• Describe the development of the indifferent external genital organs
  • Cloacal folds form around the cloaca
  • At the cranial end, these folds fuse and form the genital tubercle
  • As the urorectal septum separates the cloaca the anterior part of the cloacal folds become the urethral folds
  • Laterally to the urethral folds, the genital swellings form
• Describe the development of the external female genital organs
  • The genital tubercle forms the clitoris
  • The urethral folds form the labia minora
  • The genital swellings form the labia majora
• What causes duplicated uterus?
  • Failure of the two Müllerian ducts to fuse
• What are disorders of sex development (DSDs)?
  • Congenital conditions which cause abnormal sex differentiation, sometimes ambiguous genitalia
• What is congenital adrenal hyperplasia?
  • A DSD characterised by an enzyme defect which causes increased androgen production, giving 46XX individuals ambiguous genitals
• What is androgen insensitivity syndrome?
  • A DSD characterised by organs which are insensitive to androgens, often due to androgen receptor deficiency
  • These 46XY individuals have female phenotype
• What is Klinefelter syndrome?
  • A DSD characterised by 47XXY genotype
  • These individuals have male phenotype but abnormal testicular development and hypogonadism
• What is Swyer syndrome?
  • A DSD characterised by a mutation in the SRY gene
  • These individuals have female phenotype, but dysfunctional ovaries called streak gonads
• What is Turner syndrome?
  • A DSD characterised by 45X0 genotype
  • These individuals have female phenotype, streak gonads, and characteristic morphological features