Development of the Urogenital System

Describe the embryological development of the organs of the urogenital system

 Development of the urogenital system begins in wk 4 and develops from the intermediate mesenchyme (mesoderm)
 During lateral folding, intermediate mesoderm on each side of the dorsal aorta condenses, and forms bilateral structures called
urogenital ridges.
GR = gonadal
 The urogenital ridges has two parts. The part of the urogenital ridge that gives rise ridge
to the genital system is called the gonadal ridge and while the part of the urogenital N=
ridge that give rise to the urinary system is called the nephrogenic cord. N nephrogenic
cord

 NB = The development of the urinary and genital systems is intimately associated. The
urinary system develops before the genital system

 The intermediate mesoderm gives rise to: nephric structures; portions of the suprarenal glands; gonads; and genital duct system
while extraembryonic mesoderm give rise to primordial germ cells

Kidney and Ureter Development

 Three sets of successive kidneys develop in human embryos. All of these kidneys are continuous with the cloaca eventually. The
3 kidneys are: pronephroi; mesonephroi and the metanephroi.
o The pronephroi are transitory However, they are important because they lay down the duct that eventually gives rise to
the ureter.
o The mesonephroi are functional kidneys and are excretory. The mesonephric duct are important for forming part of the
collecting system.
o The metanephroi are the definitive and permanent kidneys. They begin development ~ 4th week, not functional till ~8th
week. The mesonephroi handles the excretory functions initially before the metanephroi takes over
Pronephroi
 The pronephros arises in the cervical (neck) region.
 They are transitory structures that regress quickly and do not produce urine
 They lay down the duct, which runs from the cervical region all the way down and eventually fuse to the cloaca.
o The pronephroi is analogous to kidneys of lower vertebrates
 They soon degenerate, but most parts of the ducts persist and are used by the next set of kidneys (mesonephroi)
Mesonephroi
 These are large, elongated excretory organs, caudal to the pronephroi.
 The mesonephroi are well developed and function as interim kidneys for approximately 4 weeks, until the permanent kidneys
develop and function
 They consist of glomeruli (10–50 per kidney) and mesonephric tubules
o The mesonephric tubules open into bilateral mesonephric ducts, which were originally the pronephric ducts. The
mesonephric ducts open into the cloaca.
o The mesonephroi degenerate toward the end of the first trimester (around week 12)

Metanephroi
 These are the actual permanent kidneys.

 It begins to develop in the 5th week and become functional approximately 4 weeks later.
o Urine formation continues throughout fetal life. It is excreted into the amniotic cavity and mixes with the amniotic fluid.
Hence, the kidney helps to regulate the amount of amnionic fluid that exist. So, fetuses with no kidney may have
oligohydramnios (little amnionic fluid) and that may be an indication of a defect in the kidney.

 The permanent kidneys develop from two sources:

1. Ureteric bud (metanephric diverticulum) and 2. metanephrogenic blastema (metanephric mass of mesenchyme)
o The ureteric bud is a diverticulum (outgrowth) from the mesonephric duct near its entrance into the cloaca.
o The metanephrogenic blastema is derived from the caudal part of the nephrogenic cord.

 The ureteric bud, which is connected to the mesonephric duct through the ureteric stalk. The ureteric bud grows into the
metanephric blastema and divides to form the renal pelvic, major calyces, minor calyces, and collecting tubules.
o The ureteric stalk becomes the ureter.

 The ureteric bud undergoes repetitive branching that form branches that differentiate into the collecting tubules
o The ureteric bud undergoes 4 divisions until there are 16 ureteric buds
o The first four generations of tubules enlarge and coalesce to form the major calices
o The second four generations coalesce to form the minor calices.
  The cells in the collecting tubules signal adjacent metanephric blastema to form round cell clusters called metanephric
vesicles, which elongate and eventually become nephrons.
o NB = A nephron derived from the metanephrogenic blastema, while collecting tubule derived from the ureteric bud
o The filtration system develops from the metanephric vesicle, which is separate from the collecting system which develops
from the ureteric bud. And at one point, they both meet. This will enable filtration from the vasculatures growing towards
those vesicles and eventually excretion. By birth all the nephrons are formed (200, 000 – 2million nephrons). Nephrons do
not regenerate, once they are damaged, they are gone.

Relocation of kidney
 Initially the primordial permanent kidneys lie close to each other in the pelvis, ventral to the sacrum

 As permanent kidneys develop, it gradually relocate to the abdomen and move farther apart.
o This “ascent” results mainly from the growth of the embryo's body caudal to the kidneys. In effect, the caudal part of the
embryo grows away from the kidney (as they do not move).

Renal anomalies
1. Pelvic kidney. Here the kidney does not move and is in the pelvis.
2. Horse-shoe kidney. Rather than the kidneys growing away from each other, they are joined together to form a horseshoe or u-
shaped kidney. As the body grows away from the kidney and tries to ascend, it ends up been caught by the inferior mesenteric
artery.
3. Blood supply to the kidneys change as the body moves. Initially, the renal arteries were branches of the common
iliac arteries. Later, the kidneys receive their blood supply from the distal end of the aorta.
o When they are located at a higher level, they receive new branches from the aorta. Normally the caudal branches of the
renal vessels undergo involution and disappear.
o However, in some cases this caudal branches don’t go away, as a consequence, the kidneys then have more than one
artery/vein.
4. The renal arteries may constrict the ureters and cause dilation of the renal pelvis
5. Renal agenesis. Complete lack of kidneys. occurs when the ureteric bud fails to develop, thereby eliminating the induction of
metanephric vesicles and nephron formation
6. Bi-fused ureters. Here the ureteric buds do not coalesce.

Development of urinary bladder and urethra

 Remember that the urorectal septum divides the cloaca into anterior urogenital sinus and posterior anorectal canal.
  Also recall that the ureters develop from the ureteric stalk and open into the mesonephric ducts which drains into the cloaca.
 The urogenital sinus is divided into three parts:
1. Vesical part that forms most of the urinary bladder and is continuous with the allantois
2. Pelvic part that becomes the urethra in the neck of the bladder, the prostatic part of the urethra in males, and the entire
urethra in females
3. Phallic part that grows toward the genital tubercle (primordium of the penis or clitoris)

 The entire epithelium lining the bladder is derived from the endoderm of the visceral part of the urogenital sinus, while the
smooth muscle surrounding the bladder is from the splanchnic mesenchyme.

 The bladder is also continuous with the allantois, which constricts and becomes a thick fibrous cord called the urachus.
o The urachus extends from the apex of the bladder to the umbilicus. It becomes the median umbilical ligament in the
adult. Recall, that the medial umbilical ligament covers the umbilical arteries, while the lateral umbilical ligaments cover
the inferior epigastric vessels
 The ureters enter into the dorsal aspect of the bladder in a region known as the trigone.
 Initially the bladder is in the abdomen, as seen in infants and children, it enters the lesser pelvis and becomes a pelvic organ
after puberty.

Bladder Anomalies
1. Urachal fistula. This is a patent opening between the bladder and the umbilical region. Here, urine drips out of the umbilicus.
Other anomalies where the urachus does not clamp down as it is supposed to do includes: umbilical urachal sinus,
vesticourachal diverticulum and urachal cyst.
2. Exstrophy of the bladder. This occurs when the posterior wall of the urinary bladder is exposed
to the exterior. It is caused by a failure of the anterior abdominal wall and anterior wall of
the bladder to develop properly.

Development of Urethra.
 The epithelium of most of the male urethra and the entire
female urethra is derived from endoderm of the urogenital sinus

 In males, the distal part of the urethra in the glans of the penis is
derived from a solid cord of ectodermal cells that grows
inward from the tip of the glans and joins the rest of the
 spongy urethra (endodermal outgrowth)

 Consequently, the epithelium of the terminal part of the urethra is derived from the surface ectoderm. The connective tissue
and smooth muscle of the urethra in both sexes are derived from splanchnic mesenchyme.

Describe the development of the suprarenal glands

Development of the suprarenal glands

 Initially, the formation of the suprarenal gland is closely tied to that of the gonads. Both develop from the intermediate
mesoderm adjacent to the developing kidney.

 The supra renal gland is separated from the gonadal primordia when primordial germ cells enter the gonadal region

 The suprarenal primordia are completely enclosed by a capsule

 Recall that the cortex develops from mesodermal mesenchyme and the medulla from neural crest cells.

 The cortex of the suprarenal glands forms from two episodes of mesoderm proliferation delaminating cells that occur between
the root of the dorsal mesentery and the gonad.
o First episode forms the inner fetal cortex, which grows rapidly in size and secretes DHEA (dehydroepiandrosterone)
 The DHEA hormone converted by the placenta to estradiol, which is essential for maintaining pregnancy
o Second episode forms the definitive thinner cortex seen in adults.
 Much of the fetal cortex rapidly regresses and the remaining definitive cortical cells then organize into the zona
glomerulosa, zona fasciculata, and zona reticularis layers seen in the adult suprarenal gland

 The suprarenal glands are very large in fetus relative to the size of the developing kidney. The kidneys ascend to meet the
suprarenal gland.

Differentiate the development of the male and female reproductive organs.

Development if the gonads.

 Recall that the portion of the urogenital ridge that gives rise to the gonads is called the genital/gonadal ridge.
  The gonadal ridge has a mesoderm core and is covered with epithelium.
 Primordial germ cells travel and settle into the epithelium and produce a bulge on the medial side of the gonadal ridge.
 The primordial germ cells send out signals that cause the gonadal ridge to organize into an undifferentiated gonad.
o The indifferent gonad now consists of an external cortex and an internal medulla.
 The epithelial layer of the gonad then forms fingerlike epithelial cords called gonadal cords (primitive sex cords), which are
epithelial projections that penetrate inwards, into the mesoderm layer of the gonad.

 In embryos (males) with an XX sex chromosome complex, the cortex of the indifferent gonad differentiates into an ovary and
the medulla regresses

 In embryos (females) with an XY sex chromosome complex, the medulla differentiates into a testis and the cortex regresses

Male Gonads
 The development of a testes requires a functional Y chromosome.

 The SRY gene (sex-determining region on the Y chromosome) codes for a testis-determining factor protein has been
localized in the short-arm region of the Y chromosome

 The testis-determining factor (TDF) regulated by the Y chromosome is what determines testicular differentiation
o Under the influence of TDF, tonadal cords differentiate into seminiferous cords (primordia of seminiferous tubules)

 Two gene regulatory networks then prevent ovarian development while enhancing testicular development

 The absence of a Y chromosome results in the formation of an ovary

 The fetal testes, dihydrotestosterone (a metabolite of testosterone), and antimüllerian hormone (AMH) that determines
differentiation of the testes and penis

Female Gonads
 The development of an ovary or female phenotype requires a functional 2 X chromosomes.

 NB = The type of sex chromosome complex established at fertilization of the oocyte determines the type of gonad that
differentiates from the indifferent gonad.
 o The type of gonad then determines the type of sexual differentiation that occurs in the genital ducts and external
genitalia.
 Ovarian development begins about the 12th week and requires germ cell present. Ovary formation also requires DAX-1,
encoded by the X chromosome
 Unlike in the development of testes, the development of the vagina does not depend on hormones; it occurs even if the ovaries
are absent

Development of Testes
 The TDF induces the seminiferous cords to condense and carry the primitive germ cells deeper into the mesoderm of the
indifferent gonad.

 The seminiferous cords develop into the seminiferous tubules, straight tubules, and the rete testis.
o NB = The seminiferous tubules have no lumina until puberty
 The surface epithelial layer of each gonad thins out to become the tunica albuginea (characteristic feature of a developing
testes)

 Some cells in the walls of the seminiferous tubules differentiate into Sertoli cells and other cells between the seminiferous
tubules differentiate into Leydig cells.

 The Sertoli cells secrete a glycoprotein, AMH or anti-Mullerian hormone, while the Leydig cells secrete testosterone and
androstenedione. These hormones induce differentiation of the mesonephric ducts and external genitalia.

o NB = AMH suppresses the development of the paramesonephric ducts, which form the uterus and uterine tubes

o NB = Walls of the seminiferous tubules are composed of two types of cells.

1. Sertoli cells supporting spermiogenesis derived from the surface epithelium of the testis
2. Spermatogonia, primordial sperm cells, derived from primordial germ cells

o The rete testis becomes continuous with 15 to 20 mesonephric tubules that become efferent ductules. These ductules
are connected with the mesonephric duct, which becomes the duct of the epididymis

Female Gonads
  No Y chromosome means the undifferentiated gonads develop into ovaries.
 The gonadal cords extend towards the center of the gonad, (to form rudimentary rete ovarii) but they degenerate soon after.
 The surface epithelium proliferates and forms a second set of projections called cortical cords.

 These cortical cords rearrange to form nests of follicular cells that surround the primordial germ cells - forming ovarian follicles.

 The rest of the reproductive tract acquires female characteristics in the absence of testosterone.

 NB = No oogonia is form postnatally. Although, many oogonia degenerate before birth, the 2 million or so that remain enlarge to
become primary oocyte

 NB = As the ovary separates from the regressing mesonephros, it is suspended by a mesentery—the mesovarium

Genital Ducts
 The genital ducts are initially undifferentiated, and two pairs of genital ducts are present.
1. The mesonephric ducts which play an important part in the development of the male reproductive
system
2. The paramesonephric ducts which have a leading role in the development of the female reproductive system.

 Both ducts start in the thoracic and upper lumbar region and continue down, opening into a part of the cloaca called the
urogenital sinus.

 In males, mullerian inhibiting factor makes the paramesonephric ducts degenerate and sometime form vestigial bodies called the
appendix testis. The paramesonephric ducts do not contribute to anything outside this.

 The mesonephric ducts grow longer under the influence of testosterone and form the reproductive ducts outside the testis.
o Initial secretion of testosterone stimulates mesonephric ducts to transform into a system of organs: epididymis, vas
deferens, and seminal vesicle

o Bulk of the mesonephric duct differentiates into the spermatic duct (vas deferens)

 The efferent ductules connect the (testicular) straight tubules to the epididymis.
  Three accessory glands develop near the junction of the mesonephric ducts and the urethra - the seminal vesicle, prostate,
and bulbourethral gland.

 Portion of the vas deferens (mesonephric duct) between

each seminal vesicle and the urethra is now the
ejaculatory duct

 NB = In males, gonadal cords become seminiferous cords,

the primordia of the seminiferous tubules.

 The parts of the gonadal cords that enter the medulla of the
testis form the rete testis

 In females, the mesonephric ducts degenerate due to the

lack of testosterone and the paramesonephric ducts persist
because the ovaries don’t make mullerian inhibiting factor.
o NB = A few nonfunctional mesonephric ducts persist

 In their upper regions, the two unfused paramesonephric ducts

form uterine tubes (oviducts or Fallopian tubes).

 In the lower regions, the ducts fuse and form the uterovaginal
primordium, which is a tubular structure from which the uterus,
develop. The superior part of the vagina also develops from
here

 NB = The fusion of the paramesonephric ducts also forms a peritoneal fold that becomes the broad ligament, and
forms two peritoneal compartments — the rectouterine pouch and the vesicouterine pouch

Vagina
  Most likely, entire vagina is derived from expansion of the sinusal tubercle, which expands into a solid block of endodermal
tissue called the vaginal plate
 Solid vaginal plate lengthens and subsequently canalizes to form the vaginal lumen

 Inferior end of the developing vagina lengthens and its junction with
the urogenital sinus is translocated caudally until it comes to rest on
the posterior wall of the urogenital sinus and opens separately from the
urethra within the vestibule

 Endodermal membrane temporarily separates the lumen of the vagina

from the UG sinus (vestibule of the vagina)
• This membrane degenerates partially, but its remnant persists as the
vaginal hymen

 NB = The cervix originate from the paramesonephric ducts at its union with the vaginal plate

 Outgrowths from the urethra into the surrounding mesenchyme form the bilateral mucus secreting urethral glands and
paraurethral glands.

 Outgrowths from the urogenital sinus form the greater vestibular glands in the lower third of the labia majora.
o These tubuloalveolar glands also secrete mucus and are homologous to the bulbourethral glands in males

Genital duct anomalies

 When the paramesonephric ducts don fuse properly, this can result to so many anomalies like
o Formation of a double uterus and double vagina, including double cervixes
o Formation of one cervix, double uterus
o Bicornate uterus2 spots for uterus, or 2 uterine cavities.
 A lady who was pregnant and while she was pregnant, became pregnant again at subsequent uterus at a later
time. She has2 fetuses growing simultaneously that were not twins

External Genitalia
 Early on, external genitalia are very similar
 Recall that the urorectal septum separates the urogenital sinus and anorectal canal from one another.
 Recall that the urogenital sinus has 3 parts and one the is the phallic segment.
 Mesoderm anterior and cranial to the phallic segment of the urogenital sinus expands, generating the genital tubercle
o The genital tubercle is the primordium of penis or clitoris
o The genital tubercle eventually forms the phallus

 The cloaca membrane ruptures and most of the floor of the phallic segment
is lost.

 Endodermal extensions form the urogenital plate (or urethral plate) at

the lower surface of the genital tubercle.

 At distal end, remnants of the cloacal membrane adjacent to the genital

tubercle remain as the glans plate

 Labioscrotal swellings and urogenital folds (or cloaca folds)

soon develop on each side of the urogenital plate.

 An expansion of underlying mesoderm flanking the anal membrane forms

the anal folds

 The ventral surface of the urogenital plate opens to form the urethral groove
Distally the urethral groove and urogenital plate terminate at the
solid glans plate

 In males, the differentiation of the external genitalia starts when

testosterone levels (converted into dihydrotestosterone) begin to rise.

 The urethral folds fuse on the midline and converts the urethral groove to form the penile urethra.

 The primordial phallus grows longer, and its tip forms the glans penis, while its body gives rise to the body of the penis,
which encloses the penile urethra.
o The solid glans plate canalizes and joins the developing penile urethra to form the glans urethra and external penile
  The perineal region separating the urogenital sinus from the anus begins to lengthen. That is The distance the urethral groove
and the anus get larger in individuals with a testis but in individuals with an ovary.

 The labioscrotal swellings fuse as well, giving rise to the scrotum.

 In females, the absence of testosterone, the genital tubercle does not lengthen
and the labioscrotal and urethral folds do not fuse across the midline

 The primordial phallus shrinks and turns into the clitoris.

 Phallic portion of the urogenital sinus becomes the vestibule of the vagina

 The urethral folds to remain unfused and form the labia minora.

 The labioscrotal swellings forms the labia majora,

Indifferent (A)
1 = developing glans of penis with the ectodermal cord.
2 = urethral groove
3 = urogenital sinus
4 = labioscrotal swellings
5 = anus

Developing vagina (B)

1. glans of clitoris.
2. external urethral orifice.
3. opening into urogenital sinus
4. urethral fold (primordium of labium minus)
5. labioscrotal swelling (labium majus)
6. anus

Developing penis (C)

1. glans of penis with ectodermal cord. 4. labioscrotal swellings fusing to form the scrotal raphe
2. remains of urethral groove 5. anus
3. urethral folds in the process of closing

External genitalia anomalies

 When the urethral folds don’t close properly, it can lead to an

anomaly called the hypospadias. That incomplete fusion can occur
anywhere along the line of fusion

 Undetermined or ambiguous genitalia. Here the external genitals

don't appear to be clearly either male or female

Suspension of Mesonephric-Gonadal Complex Within Abdomen

 Remember that the testes and ovary are developed in the abdomen.

 Two ligaments the cranial suspensory ligament of the ovaries or testes and the gubernaculum of the ovary or testes help
tether them in their right positions in the anterior abdominal wall. This is all happening retroperitoneally.

 In males, the testes initially develop near the anterior abdominal wall, but they are anchored by the gubernaculum - a fibrous
cord that attaches to the bottom of the scrotum.

 The gubernaculum starts to shorten, pulling the testis down toward the scrotum through the inguinal canal.

 The processus vaginalis herniates through the abdominal body wall and the testes pull the vas deferens and testicular vessels
with them.

 In females, the gubernaculum attaches to the inferior part of the ovary to the future labia majora, and it pulls the ovaries down
the same way it would if they were testis.
o In females, the gubernaculum does not swell or shorten.

 As the ovaries descend, they are swept out into a peritoneal fold called the broad ligament of the uterus. It is a fold of
peritoneum that comes over the uterine tubes as well as the superior surface of the uterus and superior surface of the bladder
 (but it does cover all of it). They are intraperitoneal, that is below the peritoneum. This does not mean they touch; they do
because the broad ligament of the uterus drapes over them.
 In the absence of male hormones, the female gubernaculum remains intact
and grows in step with the rest of the body.
o The superior gubernaculum becomes the round ligament of the
ovary (ovarian ligament) which connects the uterus to the ovary
o The inferior gubernaculum becomes the round ligament of the
o uterus, which connects the fascia of the labia majora to the uterus

Differentiate the derivatives of the mesonephric and paramesonephric ducts

Ducts type Male Female

Mesonephric duct 1. Appendix of epididymis 1. Appendix vesiculosa
2. Epididymis 2. Duct of epoö phoron
3. Ductus vas deferens 3. Gartner’s duct
4. Seminal vesicle
5. Ejaculatory duct

Paramesonephric 1. Appendix of testis 1. Uterine tubes

duct 2. Uterus
3. cervix
4. Superior 1/3 of vagina

Describe common malformations of the urogenital system.

Renal agenesis
 Occurs when the ureteric bud fails to develop, thereby eliminating the induction of metanephric vesicles and nephron formation.
 Unilateral renal agenesis is relatively common. It is asymptomatic and compatible with life because the remaining kidney
hypertrophies.
  Bilateral renal agenesis causes oligohydramnios, which causes compression of the fetus. These infants are usually stillborn or
die shortly after birth.
Renal ectopia
 Occurs when one or both kidneys fail to ascend and therefore remain in the pelvis or lower lumbar area (i.e. pelvic kidney). In
some cases, two pelvic kidneys fuse to form a solid mass, commonly called a pancake kidney.

Renal fusion
 The most common type of renal fusion is the horseshoe kidney, which occurs when the inferior poles of the kidneys fuse across
the midline. Normal ascent of the kidneys is arrested because the fused portion gets trapped behind the inferior mesenteric
artery. Kidney rotation is also arrested, so that the hilum faces ventrally.

Urachal fistula or cyst

 Occurs when a remnant of the allantois persists, thereby forming a fistula or a cyst. It is found along the midline on a path from
the umbilicus to the apex of the urinary bladder.
 A urachal fistula forms a direct connection between the urinary bladder and the outside of the body at the umbilicus, causing
urine drainage from the umbilicus.

Exstrophy of the bladder

 Occurs when the posterior wall of the urinary bladder is exposed to the exterior. It is caused by a failure of the anterior abdominal
wall and anterior wall of the bladder to develop properly. It is associated clinically with urine drainage to the exterior and
epispadias.

Unicornuate uterus anomalies

 Occur when one paramesonephric duct fails to develop or incompletely develops.

Double uterus
 Occurs when there is a complete lack of fusion of the paramesonephric ducts.

Bicornuate uterus anomalies

 Occur when there is partial fusion of the paramesonephric ducts.

Septate uterus anomalies

 Occur when the medial walls of the caudal portion of the paramesonephric ducts partially or completely fail to resorb.
Hypospadias
 Occurs when the urethral folds fail to fuse completely, resulting in the external urethral orifice opening onto the ventral surface of
the penis.

Epispadias
 Occurs when the external urethral orifice opens onto the dorsal surface of the penis.

Hydrocele of the testes

o Occurs when a small patency of the processus vaginalis remains so that the peritoneal fluid can flow into the processus
vaginalis, which results in a fluid-filled cyst near the testes.