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Core
The development of the reproductive and urinary systems overlaps greatly due to their close proximity and common features. They both develop from the urogenital ridge. This is a structure made of mesoderm (the middle one of the three early embryonic cell layers) that develops from intermediate mesoderm along the posterior abdominal wall, next to the developing dorsal body wall. It forms as the trilaminar disc (the three-layered early embryo) undergoes folding around week 4 of development.
The important thing to remember is that, developmentally, both sexes start the same. Hormones then determine which structures of the internal and external genitalia persist.
The development of the gonads (the testes and ovaries) is the first key step in the development of the reproductive system. It dictates how the rest of the internal and external genitalia of the embryo develop. The gonads begin as an indifferent stage meaning that at first, they are the same in male and female embryos. The gonads develop from the urogenital ridge, a pair of longitudinal ridges derived from mesoderm. Germ cells (the cells that become sperm or eggs) then migrate from the yolk sac (a small sac attached to the early embryo) into the urogenital ridges. At the same time, the epithelium of the urogenital ridge penetrates the mesoderm layer to form primitive sex cords. These primitive sex cords and the germ cells together form the indifferent gonad.
Whether the indifferent gonads develop into testes or ovaries depends on the presence of the SRY gene. The SRY (sex-determining region Y) gene is normally found only on the Y chromosome. This means that embryos with the sex chromosomes XY (males) express the SRY gene, whereas embryos with the sex chromosomes XX (females) normally do not.
The SRY gene prompts the primitive sex cords to develop the structure of a testicle, forming the medullary cords of the testicle (the inner cords of tissue in the developing testis). After puberty, these develop into the sperm-producing seminiferous tubules. The seminiferous tubules are lined with Sertoli cells, which produce a hormone called Anti-Mullerian Hormone (this influences internal genitalia development as described below). In between these tubules are Leydig cells, which start to produce testosterone at around 8 weeks of gestation (the age of the pregnancy). This testosterone drives the development of the male internal and external genitalia. Anti-Mullerian hormone (which removes the female ducts) also plays a part in the internal genitalia. In the external genitalia, testosterone acts after it is converted to dihydrotestosterone (DHT).
If no SRY gene is present, the primitive sex cords degenerate, allowing the epithelium of the indifferent gonad to develop into a structure called cortical cords. The cortical cords break up around three months into the pregnancy. Each of the germ cells is then surrounded by an epithelial layer (a layer of lining cells), forming a primordial follicle. A primordial follicle is an oocyte (an immature egg cell) with its surrounding layer of cells.
In summary: with the SRY gene found on the Y chromosome, the primitive sex cords and germ cells form a testis, which will begin to produce testosterone. Without the SRY gene, the primitive sex cords and germ cells form an ovary.
In the first few weeks of development, the cloaca is a hindgut structure (the hindgut is the back part of the early gut tube). It is a common chamber for gut and urinary waste. A series of ducts will open into it as development continues. At this early point it is covered by a membrane, and so is not open.
Two pairs of ducts run towards the cloaca. They are:
- The Mesonephric (Wolffian) Duct - this connects the embryonic kidney (mesonephros) with the cloaca.
- The Paramesonephric (Mullerian) duct - a duct that runs alongside the mesonephric duct and is open at its top end. It runs down to the urogenital sinus (the front part of the divided cloaca, which gives rise to the bladder and urethra).
These ducts have specific roles within the development of the male and female reproductive tracts.
Testosterone, which has been produced by the Leydig cells of the testes, acts on the mesonephric ducts to form the epididymis (where sperm mature and are stored), the vas deferens (the tube that carries sperm) and the seminal vesicles (glands that add fluid to semen).
Anti-Mullerian hormone, produced by the Sertoli cells of the testes, acts on the paramesonephric ducts and causes them to degenerate.
In a nutshell - The mesonephric duct forms the epididymis, vas deferens and seminal vesicles (part of the internal male genitalia).
In the female, there are no Leydig cells to produce testosterone. Without the influence of testosterone, the mesonephric ducts degenerate.
Furthermore, as there are no Sertoli cells to produce anti-Mullerian hormone the paramesonephric ducts do not degenerate. As a result, they continue to develop, forming the uterus, fallopian tubes (the tubes that carry eggs from the ovaries to the uterus), and upper part of the vagina.
The lower part of the vagina is formed by a part of the urogenital sinus, which fuses with the paramesonephric ducts to complete the vagina.
In a nutshell - the paramesonephric duct forms the internal female genitalia.
Diagram - The differences between the development of the internal genitalia of the male and the female as viewed in the coronal plane
SimpleMed original by Dr. Maddie Swannack
Until around 9 weeks of gestation, the external genitalia of male and female embryos are identical. Up until this point, the genitalia have been developing as part of the cloacal membrane.
Earlier in development, mesenchymal stem cells (cells from loose embryonic connective tissue) migrated from the primitive streak (the early groove on the embryo where cells begin to move inwards) to the cloacal membrane, to form two cloacal folds. At the cranial (head) end, the folds fuse to form the genital tubercle (the small bump that becomes the penis or clitoris). At the caudal (tail) end, they divide into the urethral folds (in front) and the anal folds (behind). Genital swellings develop either side of the urethral folds.
Testosterone is produced by the Leydig cells of the testis and is converted to dihydrotestosterone (DHT), which drives the development of the external genitalia of the male.
The genital tubercle grows rapidly, elongating to form the glans penis (the tip of the penis). The urethral folds are pulled with it, forming the shaft of the penis, and the two folds fuse along the shaft by about 13 weeks of gestation to form the urethra.
This step of development is clinically relevant, because failure of this fusion can lead to hypospadias. Hypospadias is a condition in which the opening of the urethra is not at the end of the penis, but somewhere along the underside (ventral surface) of the penis.
The genital swellings move caudally and fuse, becoming the scrotum.
In the female, there are no Leydig cells to produce testosterone. This means that the genital tubercle does not undergo rapid elongation to become the penis, but instead grows slightly to become the clitoris.
Without the elongation of the genital tubercle, the urethral folds do not stretch and fuse, and go on to form the labia minora.
Without the development of the penis, the genital swellings do not need to move caudally, so remain where they are and develop into the labia majora.
The gubernaculum is the fibrous structure that pulls the gonads into their correct position from the lumbar region (the lower back part of the abdomen), where they form. It does this by having one end attached to the gonad, and the other to the genital swellings (precursors to the scrotum or the labia majora). The ‘correct’ position varies between male and female, with the testicles ending up in the scrotum, and the ovaries ending up in the pelvis.
The testes descend in two phases. First, between about 8 and 15 weeks, the gubernaculum swells (a hormone called INSL3, made by the Leydig cells, drives this). This anchors the testes near the future inguinal canal as the fetus grows. Then, between about 25 and 35 weeks, the gubernaculum guides the testes through the inguinal canal (the passage through the lower abdominal wall) and into the scrotum, under the control of testosterone.
As the testes descend, they retain their original blood supply and lymphatic drainage (the vessels that carry tissue fluid, called lymph, away from an organ). Both are lengthened as the testes descend. As a result, the testes have an unusual vascular and lymphatic supply, because it comes from high up on the posterior abdominal wall. The testicular arteries arise from the abdominal aorta and as a result, have a long course down the abdomen and through the inguinal canal. Likewise, the lymphatic drainage of the testes is unusual, as the lymph drains into the para-aortic lymph nodes (the nodes beside the aorta). The scrotum, by contrast, drains into the superficial inguinal nodes in the groin.
The gubernaculum remains after birth as the scrotal ligament.
The ovaries have a very similar path to the testes, and again retain their blood and lymphatic supply from their original position.
However, the ovaries are stopped in their descent by the developing uterus, which prevents the gubernaculum from pulling the ovaries into the inguinal canal.
Instead, the gubernaculum fuses with the uterus and degenerates, forming two ligaments. The ovarian ligament attaches the ovary to the uterus, and the round ligament connects the uterus to the labia majora.
Issues with the Development of Genitalia
As with the development of any organ system, the complexity of the process leaves plenty of chance for error. In the genitalia, these errors often occur due to improper hormone levels.
Increased Testosterone in the Female Embryo
If an XX fetus is exposed to a high level of androgens (male sex hormones such as testosterone) during development, the main effect is virilisation (masculinisation) of the external genitalia, for example an enlarged clitoris. The commonest cause is congenital adrenal hyperplasia (CAH). In CAH, an inherited fault in an enzyme that the adrenal glands need to make cortisol (most often 21-hydroxylase) leads the adrenal glands to make too much androgen. Less often, the androgens come from the mother, for example from an ovarian tumour or a drug.
Because this embryo is XX, it has no Y chromosome and therefore no testicles to produce anti-Mullerian hormone, meaning the paramesonephric ducts will remain and develop as normal.
The internal genitalia (the ovaries, uterus and fallopian tubes) are therefore usually female, even though the external genitalia are virilised.
CAH matters clinically because the classic (severe) form can also cause adrenal insufficiency (the adrenal glands cannot make enough cortisol). This can be life-threatening if it is not treated promptly.
Androgen Insensitivity Syndrome
Androgen insensitivity syndrome is a condition that affects fetuses with the XY genotype. These fetuses have a Y chromosome that carries the SRY gene, so testes will develop normally and release the normal amount of testosterone (an androgen). However, the receptors for testosterone are not functioning properly, meaning the embryo is not ‘sensitive’ to the testosterone. This means that the mesonephric ducts do not develop where they should, because the faulty receptor does not respond to the testosterone in effect developing as if no testosterone has been released i.e. along the lines of female development.
However, because the testes are functioning normally, they produce anti-Mullerian hormone, meaning the paramesonephric ducts degenerate as would be normal in a male.
This results in an embryo that has the XY genotype and no uterus due to the degeneration of the paramesonephric ducts, but due to the lack of response to testosterone, will have the external genitalia of a female. As a result children with this condition are often assigned a female gender at birth due to their phenotype.
Edited by: Dr. Ben Appleby
Reviewed by: Dr. Thomas Burnell and Dr. Marcus Judge
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