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Embriología

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3
Embryology for the Urologist
Allan Johnston1, Maike F. Eylert2, Tarik Amer1, and Omar M. Aboumarzouk1, 3
1
Glasgow Urological Research Unit, Department of Urology, Queen Elizabeth University Hospital, Glasgow, UK
Department of Urology, University Hospital of Wales, Cardiff, UK
3
University of Glasgow, School of Medicine, Dentistry & Nursing, Glasgow, UK
2
Abstract
The urogenital tract is largely derived from the mesoderm. Initial kidney structures appear in the fourth week of embryogenesis,
but definitive kidney development occurs from the 5th-10th week. The bladder and urethra start to form at the same time as
the definitive kidney. Sexual development is indifferent until the sixth week of gestation, with the sex-determining region Y
(SRY) gene being the primary driver for male foetal development. This is largely through further action of anti-müllerian hormone (AMH) and testosterone. The mesonephric ducts become the male genital duct system, and the paramesonephric ducts
become the female genital duct system. Testicular descent is initially dependent on AMH and insulin-like hormone 3, and later
testosterone. Dihydrotestosterone drives male external genital development. The overall sequence of urogenital development
is well established and can explain the majority of congenital malformations that may present to the urologist. Additional
details will only be of interest to the subspecialist and the researcher
Keywords anti-müllerian hormone (AMH); development; dihydrotestosterone; embryology; genital tubercle; gonadal ridges;
gubernaculum; insulin-like hormone 3; labioscrotal folds; mesonephric duct; mesonephros; metanephros; paramesonephric
duct; pronephros; SRY gene; testicular descent; testosterone; trigone; ureteric bud; urethral plate; urogenital sinus;
Key Points
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Three kidney systems: pronephros, mesonephros, and
metanephros.
The ureteric bud arises from the mesonephric duct and
forms the entire upper tract drainage system.
The mesonephric ducts become the male genital duct
system.
The paramesonephric ducts become the female genital
duct system.
The urogenital sinus gives rise to the bladder and the
urethra with the exception of the fossa navicularis and
male urethral meatus.
Blandy’s Urology, Third Edition. Edited by Omar M. Aboumarzouk.
© 2019 John Wiley & Sons Ltd. Published 2019 by John Wiley & Sons Ltd.
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The sex‐determining region Y (SRY) gene, anti‐müllerian
hormone (AMH), insulin‐like hormone 3, testosterone,
and dihydrotestosterone are essential in the normal
development of the male foetus.
Testicular descent happens in two phases; initially
dependent on AMH and insulin‐like hormone 3 and
then dependent on testosterone.
Dihydrotestosterone drives male external genital
development.
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3 Embryology for the Urologist
3.1 ­Historical Consideration
Embryology stems from the Greek words of ‘embry’,
meaning the ‘unborn’, and –‘ology’, which is the subject of
study or a branch of knowledge. [1, 2]
The Greeks were the first to describe their thoughts on
the origins of man in the womb. More notably, Aristotle
postulated that the foetus was formed in the uterus from
a coagulum of blood (menstrual blood), and the foetus
itself was fully developed in miniaturised form in the
sperm. This chain of thought was carried on for centuries through Europe, even as late as the seventeenth century, when Marcello Malphigi (1672) described poultry
eggs as containing a miniature chick and extrapolated
that humans were fully formed in the sperm.
In 1694, 21 years after the invention of the microscope
by Antonie van Leeuwenhoek, did Nicolaas Harsoeker
postulate that humans were formed from the joining of
the spermatozoon and ovum, further described by
Lazzaro Spallanzani in 1775.
Interestingly, a revelation to the Prophet Mohamed
(peace be upon him) in the seventh century detailed
descriptions for embryological development, including
the formation of the embryo from both the male and
female ‘drops’ (i.e. sperm and ovum). Multiple Quranic
verses were revealed detailing the formation of the
embryo to the fully developed foetus. However, it was
not until the nineteenth and twentieth centuries when
these revelations were confirmed as fact and held as a
true representation of embryo‐foetal development.
From the experimental works of Karl Ernst von Baer,
Charles Darwin, and Ernest Haeckel, to the chemical and
mechanical discoveries of embryology by Otto Warburg,
paving the way for Ross Harrison, Frank R. Lillie, and
Glomeruli
Cortex
Medulla
Ducts of
bellini
Papilla
Calix
Figure 3.1 The basic unit of the kidney is the pyramid, with a
flower bunched arrangement in a vase.
Hans Spemann to describe the more detailed mechanisms of embryonic development throughout the early
twentieth century. It was late in the twentieth century,
with the advent of more sophisticated instruments such
as the electron microscope and spectrophotometer, that
embryology in its modern form took place. More notably
the work of Keith Moore described the embryological
and foetal development to the finest detail, giving rise to
the established current knowledge of embryology.
3.2 ­Introduction
A description of each urological organ will be
described individually; hence, overlap and repetition
will inevitably exist to allow a detailed understanding
of the development of each organ. Three basic cell
layers comprise the embryonic disc which becomes
the embryo: the ectoderm (originates from the amniotic surface), the mesoderm (originates form inpouring cells from the ectoderm), and the endoderm (yolk
sac). The majority of the urogenital tract is derived
from the mesoderm. Organ development in general
occurs between the 3rd and 10th week of gestation
(Table 3.1).
3.3 ­Embryology of the Kidneys
and Ureters
The basic unit of the kidney is the renal pyramid, which
is arranged like a bunch of flowers in a vase (Figure 3.1).
The flowers are the glomeruli; the stalks are the collecting tubules; and the vase is the calix. The design of the
normal pyramid is important in preventing reflux of
urine up into the renal parenchyma.
There are three paired kidney systems during foetal
development (Figure 3.2), with only the third system
being of functional importance. First, the pronephros
forms and rapidly regresses in the cervical region of
the intermediate mesoderm during the fourth week.
The pronephros in humans is both rudimentary and
segmented.
Later in the fourth week, the unsegmented mesonephros forms from the intermediate mesoderm in the
upper thoracic to upper lumbar segments. These appear
as a pair of sausage‐shaped swellings on the posterior
abdominal wall on either side of the mesentery – the
genitourinary ridges. A faint groove demarcates each
ridge into a medial gonadal and lateral nephrogenic part
(Figures 3.3 and 3.4). These swellings lengthen and
acquire primitive nephron‐like structures, which is a collection of capillaries that form a glomerulus at the medial
extremity, and Bowman’s capsule, which forms around
3.3 Embryology of the Kidneys and Ureters
Table 3.1 Table of developmental timings.
Structure
Development starts
Disappears
Comments, ultimate structures
Pronephros
4th week
4th week
No functional relevance
Mesonephros
4th week
8th week
No permanent function
Mesonephric duct (male)
4th week
—
Central zone of the prostate, ejaculatory ducts, vas
deferens, seminal vesicles, epididymis, and efferent
ductules
Mesonephric duct (female)
4th week
8th week
Remnants: epoophoron, paroophoron, Gartner cyst
Metanephros
5th week
—
Permanent kidney including glomeruli, convoluted
tubules, loop of Henle. Urine production from
10th week.
Ureteric bud
5th week
—
Collecting ducts, minor calyces, major calyces, renal
pelvis, ureter
Urogenital sinus
5th week
—
Bladder, posterior urethra (male) or entire urethra (female),
anterior urethra (male) up to the edge of the glans penis
Gonadal ridges
Germ cells migrate
in 6th week
—
Testes or ovaries
Paramesonephric duct (male)
6th week
8th week
Remnants: appendix testes, utricle
Paramesonephric duct (female)
6th week
—
Fallopian tubes, uterus, and the upper two‐thirds of the
vagina
Genital tubercle enlargement (male) 6th week
—
Penis. Urethral plate closes to form tubular urethra
12th week
Urethral endoderm and surrounding 13th week
mesoderm (male)
—
Prostate
Ingrowth of ectoderm from the tip
of the glans penis (male)
15th week
—
Fossa navicularis and urethral meatus
Testicular descent (abdominal)
8–15th week
—
AMH and insulin‐like hormone 3 dependent
Testicular descent (inguinal)
24–28th week
—
Testosterone dependent
Testicular descent (scrotal)
28–33rd week
—
Testosterone dependent
AMH, anti‐müllerian hormone.
the glomerulus, forming the renal corpuscle. These
simple excretory units may function briefly before
regressing in the eighth week. The mesonephros functions for a short time during early foetal life by producing
urine from the sixth through to the eighth weeks of
development.
On the lateral aspect and adjacent to the mesonephros,
the mesonephric ducts advance distally to drain into
the cloaca (this is the primitive hindgut which goes on
to form the bladder and rectum) at the caudal end of
the embryo. Whilst the caudal aspects of the tubules
are differentiating, the cranial tubules and the glomeruli degenerate, with the majority of the mesonephros
absent by the end of the second month of gestation. The
mesonephric system disappears completely in the
female around the eighth week. In the male, the
­mesonephric ducts (also known as the wolffian ducts)
persist, giving rise to the efferent ductules of the testes,
the epididymis, vasa, seminal vesicles, and appendix
epididymis.
Pronephros
Mesonephros
Metanephros
Figure 3.2 Locations of pronephros (fourth week), mesonephros
(fourth to eighth weeks), and metanephros (from fifth week) in
the embryo.
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3 Embryology for the Urologist
Gonadal ridge
Mesonephros
Urogenital ridge
Gut
Figure 3.3 The mesonephros runs along the length of the foetus on the lateral side of the genitourinary ridge.
Heart
Lung
Mesonephros
Gonadal ridge
Figure 3.4 The mesonephros can be identified in the four‐week‐
old human embryo.
Third, the metanephros (the permanent kidneys)
develops from the fifth week from metanephric mesoderm in the most caudal region of the nephrogenic ridge,
the lateral aspect of the genitourinary ridge. As the tail
end of the foetus curls up, the hindgut is curled with it
and so are the nephrogenic ridges with their wolffian
ducts, which twist upwards and inwards. Branches from
the most caudal part of the wolffian (mesonephric) ducts
enter the metanephros. These branches, or outgrowths,
are called the ‘ureteric buds’ (Figure 3.5). In contrast to
the first two systems, excretory units only form by a process called ‘reciprocal induction’ between the ureteric
bud and metanephric tissue caps.
The collecting ducts develop from the ureteric bud
(fifth week, Figure 3.6). The ureteric bud subdivides and
induces formation of the glomeruli in the mesenchyme
of the metanephros. The branches of the bud then grow
peripherally into the cortex, dilating and splitting repeatedly until about 15 generations of ducts have formed
(Figure 3.7). The first four or five generations of the
dividing ureteric branches become dilated and incorporated in the eventual renal pelvis (Figure 3.8). The next
four or five generations form the major calices and
­collecting tubules (Figure 3.8) [3]. The successive generations elongate and converge on the minor calyx (seventh
week), thereby forming the renal pyramid in the flower–
vase configuration described previously. Subsequent
generations elongate and converge to form renal
­pyramids, and ultimately, they form around one million
collecting ducts per kidney (until the fifth month).
3.3 Embryology of the Kidneys and Ureters
(a)
(b)
Genital ridge
Mesonephros
Mesonephros
Wolffian duct
Cloaca
Wolffian duct
Metanephros
Metanephros
Ureteric bud
Figure 3.5 (a) The caudal part of the mesonephros becomes the metanephros. It receives its own branch from the mesonephric (wolffian)
duct, the ureteric bud. (b) As the foetus curls up, the wolffian duct and the ureteric bud are bent around.
Figure 3.6 The ureteric bud develops as an
outgrowth of the mesonephric duct close to
the urogenital sinus (fifth week).
Mesonephros
Allantois
Foetal
hindgut
Mesonephric duct
Urogenital
sinus
Metanephric tissue cap
Ureteric bud
The metanephric tissue caps covering each collecting
tubule form renal vesicles which develop into nephrons.
Capillaries grow into the opposite end of the nephron
giving rise to glomeruli (Figure 3.9). From about the 10th
week, urine is produced by the metanephros; however,
nephrons continue to form until birth. After birth, no
further nephrons will form (approximately 700 000 per
kidney), but existing ones will continue to grow. This
growth is responsible for the change from lobulated kidneys at birth to kidneys with a smooth outline.
The metanephros ascends during weeks 6–10 as a
result of the elongation of the sacral and lumbar regions
of the embryo as well as loss of the initial curvature of the
embryo. The arterial supply originates from the aorta,
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3 Embryology for the Urologist
Generations 6–15
Fifth generation
First
generation
Second
generation
Forth generation
Third
generation
Figure 3.7 The ureteric bud splits repeatedly until about 15
generations of ducts have formed. The first generation becomes
the renal pelvis, the second the major calyces, the third to fifth
minor calyces, and the remainder become renal pyramids and
collecting ducts.
Collecting
tubules
Metanephros
and serial arteries are formed and regress during renal
ascent. Some vessels may remain as accessory renal
arteries.
During the fourth to sixth weeks of gestation, while
the caudal end of the foetus curls up and bends the
hindgut into a U configuration, the mesoderm grows
down into the gap between the future rectum and bladder, thus forming the urorectal septum (Figure 3.10).
This septum separates the cloaca into a primary urogenital sinus (ventrally) and rectum (dorsally). The
wolffian ducts lie in this wedge‐shaped septum, and
grow down with it. They also become bent into a loop
and take the ureteric buds with them (Figure 3.10) [4].
Part of this septum is incorporated into the bladder to
form the trigone, and because of the incorporated loop
of the wolffian duct, the ureteric duct comes to open
into the bladder cephalad to the duct. In males, the
wolffian duct becomes the vas deferens and seminal
vesicles, whilst in the females these ducts regress in the
absence of testosterone [4]. At this stage, the tail end of
the foetus is roughly 1‐cm long and the space between
the tail and the umbilical cord is filled by the cloacal
membrane. On either side of this membrane are the
two small genital tubercles (Figure 3.11). This membrane is formed by tightly packed ectoderm and endoderm cells with no intervening mesoderm. As this
Collecting tubule
Metanephric tissue cap
Calices
Pelvis
Capillary
Renal vesicle
Nephron
Figure 3.8 As the ureteric bud approaches the metanephros, it
branches repeatedly. The branches induce the formation of
glomeruli. The first four or five generations of branches become
incorporated into the renal pelvis.
Glomerulus
Figure 3.9 The metanephric tissue caps covering each collecting
tubule form renal vesicles which develop into nephrons.
Capillaries grow into the opposite end of the nephron, giving rise
to glomeruli.
3.3 Embryology of the Kidneys and Ureters
Figure 3.10 The urorectal septum grows
down between the future bladder and
rectum.
Mesonephros
Wolffian duct
Bladder
Ureter
Cloacal membrane
Urorectal septum
Rectum
Figure 3.11 The cloacal membrane
disappears and the phallic tubercles meet in
the midline.
Umbilical cord
Genital tubercle
Cloacal
membrane
Urorectal
septum
Tail
Bladder
Phallus
Tail
Rectum
Urorectal
septum
Rectum
Tail
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3 Embryology for the Urologist
membrane dissolves, the two genital tubercles fuse to
form the united phallic tubercle (Figure 3.11).
While all this is taking place, the mesonephros is withering away, but as it regresses, the wolffian duct generates a second duct, parallel and lateral to it, the müllerian
duct (Figure 3.12). As the urogenital ridge twists round,
so the müllerian ducts approach each other, meet in the
midline in front of the wolffian ducts, and burrow down
in the urorectal septum (Figure 3.12). The urorectal septum is partially absorbed into the trigone, and the müllerian ducts open into the urethra medial to, and in front
of, the wolffian ducts.
The subsequent fate of the wolffian and müllerian
ducts is determined by the X and Y chromosomes. Until
the fourth week, the urogenital ridge is neuter. At four
weeks it is invaded by gonadal cells, which migrate by
amoeboid movements from the yolk sac across the coelom and burrow into the gonadal ridge (Figure 3.13). By
the sixth week, it is estimated that there are about 60 000
gonadal cells in each gonadal ridge. The male ones are
active at once; the female gonadocytes stay dormant for
another two weeks.
3.3.1 Relevant Congenital Malformations
Partial or complete ureteric duplication results from
early splitting of the ureteric bud. In a complete duplex
system, the Weigert‐Meyer rule states that the ureter
(a)
Gonadal ridge
Wolffian duct
Mesonephros
Müllerian duct
Ureter
Metanephros
(b)
Ovary
Müllerian
ducts
Metanephros
Figure 3.12 (a) A second (müllerian) duct forms on the lateral side of the mesonephros. (b) The müllerian duct roll towards each other, meet
in the midline in front of the wolffian ducts, and burrow down into the urorectal septum to form the uterus and fallopian tubes in the female.
3.4 Embryology of the Bladder
draining the lower moiety tends to reflux as a result of a
shorter submucosal tunnel positioned laterally and superior; the upper pole tends to obstruct, be ectopic, or form
ureteroceles and is positioned medially and inferiorly
(Figure 3.14). An ectopic ureter may drain into the bladder,
bladder neck, or prostatic urethra in males, or into the
vagina, uterus, or ovary in females (Figure 3.15). The
pathophysiology of duplex kidney is explained by the
insertion of the ureter into the bladder, whilst the lower
pole tends to reflux due to a shorter submucosal tunnel,
and the upper pole tends to obstruct, be ectopic, or form
ureteroceles.
Genital ridge
Failure of renal ascent gives rise to a pelvic kidney
(Figure 3.16). Midline fusion of both kidneys during their
ascent gives rise to a horseshoe kidney, with further
ascent limited by the root of the inferior mesenteric
artery. The midpoint joining both kidneys is known as
the isthmus (Figure 3.17). Crossed fused renal ectopia
results from both kidneys ascending on the same side of
the body and fusing in the process (Figure 3.18).
Renal agenesis results from failed reciprocal induction,
intrinsic defects within the mesenchyme, or involution
of a multicystic dysplastic kidney. Multicystic dysplastic
kidney may be the result of faulty ureteric bud development. Renal dysplasia results from defects in reciprocal
induction or from obstruction during the foetal period.
3.4 ­Embryology of the Bladder
Germ cells
Coelom
Yolk sac
Figure 3.13 Migration of the germ cells from the yolk sac to the
genital ridge.
The foetal hindgut is curled, following the outline of the
tail end of the embryo, in the shape of a hook (Figure 3.19).
The caudal most part of the hindgut remains in communication with the allantois and will form the bladder. As
stated, the urorectal septum descends at four to six weeks
to separate the cloaca into the urogenital sinus anteriorly
and the anal canal posteriorly. The cloacal membrane
dissolves to open both canals (Figures 3.20 and 3.21).
As the allantois shrinks it becomes a solid cord – the
urachus – linking the apex of the bladder to the umbilicus.
In clinical terms, the urachus becomes the median umbilical ligament upon closing. If it remains patent, the patient
will have a congenital umbilical fistula. The urogenital
Figure 3.14 Complete duplex system on the
left. The Wiegert‐Meyer rule states that the
ureter from the upper moiety will enter
inferomedial to the lower moiety ureter.
Upper moiety
Lower moiety
Normal kidney
Normal ureter of
lower moiety
Normal ureter
Normal ureteric
orifices
Bladder neck
Prostate
Ectopic ureter of
lower moiety
(showing two possible
terminations)
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3 Embryology for the Urologist
Figure 3.15 The ureter from the upper ­
half‐kidney may open into the vagina below
the sphincter and cause incontinence.
Ureter from
upper half-kidney
draining into
ectopic orifice
External sphincter
Ectopic ureter
Superior mesenteric
artery
Pelvic kidney
Horseshoe
kidney
Figure 3.17 If the lower end of the metanephros fuse together,
they remain ‘rotated’, and their course up the abdomen is held by
the superior or, rarely, the inferior mesenteric arteries.
Figure 3.16 If the kidney remains in the pelvis, it stays ‘rotated’.
sinus itself will give rise to the bladder, the posterior urethra (male) or entire urethra (female), and the anterior
urethra (male) up to the edge of the glans penis. These are
all endodermal (originates from yolk sac) in origin.
The male anterior urethra is not initially tubular, but
rather a flattened urethral plate, which is pulled forwards
with the growing phallus (Figure 3.22). It then folds in
sideways and closes along the midline at around 12 weeks
(Figure 3.23 and 3.24). The terminal part of the male
3.4 Embryology of the Bladder
­ rethra (fossa navicularis and external urethral meatus)
u
is formed by ingrowth of ectoderm (derived from amniotic sac) from the tip of the glans penis (15 weeks).
The lower ends of the mesonephric ducts (due to become
the vasa efferentia) and the lower ends of the ureters
become incorporated into the posterior wall of the bladder,
and thus form the trigone (Figures 3.25 and 3.26). Descent
of the testes then causes the vas deferens on either side to
swing anteriorly over the ureter (‘water under the bridge’).
3.4.1 Relevant Congenital Malformations
Failure of fusion of the urethral folds results in hypospadias.
Epispadias results if the genital tubercle (see discussion
in this chapter) forms in the urorectal septum with part
Urogenital septum
Cloaca
Figure 3.19 The foetal hindgut bends round and the urogenital
septum descends to separate the bladder from the rectum; the
patent urachus keeps the future cladder in continuity with the
allantois.
Figure 3.18 Crossed renal ectopia.
Allantois
Urogenital sinus
Cloacal membrane
(dissolving)
Urorectal septum
Anal canal
Figure 3.20 The urorectal septum descends at four to six weeks to separate the cloaca into the urogenital sinus anteriorly and the anal
canal posteriorly. The cloacal membrane dissolves to open both canals.
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3 Embryology for the Urologist
Figure 3.21 As the urogenital septum
reaches the perineum, the cloacal
membrane dissolves to reveal two
openings, the urethra and the rectum.
Wolffian mesonephric duct
Urogenital sinus
Metanephros
Bladder
Allantois
Urachus
Ureter
Genital tubercle
Cloacal membrane
Ureteric bud
Rectum
Urorectal septum
Urethral plate
Phallus
Phallus
Urethral plate
Urogenital sinus
Hindgut
Figure 3.23 The male anterior urethra folds in sideways and
closes along the midline at around 12 weeks. The genital and
labioscrotal folds move caudally and fuse to form the scrotum
with the midline scrotal septum.
Figure 3.22 The male anterior urethra is not initially tubular, but
rather a flattened urethral plate, which is pulled forwards with the
growing phallus.
of the membrane cranial to the genital tubercle.
Exstrophy of the bladder (which always includes epispadias) is caused by failure of the abdominal wall to form.
3.5 ­Embryology of the Indifferent
Genital System
The gonads begin their development from the urogenital
ridge, located behind the coelom. They divide longitudinally, in the third week, to form the gonadal or genital
Inrolling folds
forming urethra
Figure 3.24 The skin rolls in on either side to form the urethra.
3.6 Embryology of the Male Genital System
Figure 3.25 The lower ends of the
mesonephric ducts (due to become the vasa
efferentia) and the lower ends of the ureters
become incorporated into the posterior wall
of the bladder, and thus form the trigone.
Descent of the testes then causes the vas
deferens on either side to swing anteriorly
over the ureter.
Ureter
Bladder
Allantois
Vas deferens
Kidney
Trigone
Testis
Phallus
Wolffian
duct
Bladder
Rectum
Figure 3.26 The urogenital septum brings down the wolffian
ducts, which will become the ureters.
ridge on the medial side and the embryonic mesonephros on the lateral side, which later becomes the urinary tract. Paramesonephric ducts (müllerian ducts)
develop from these genital ridges.
Between weeks five and six of embryonic development, the germ cells arising from the yolk sac integrate
into the gonadal ridge after travelling by amoeboid
movement through the umbilical cord and the coelom
(Figures 3.27–3.28). Upon the arrival of germ cells, primitive sex cords form in the still indifferent gonad. Failure
of gonadal development occurs if the germ cells do not
reach the gonadal ridges because they trigger the development of the gonad into ovary or testis [5].
In the human embryo, the gonads remain undifferentiated until about week seven of development. Depending
on the XY genetic constitution they then differentiate
into the testes or the ovaries [6].
Labioscrotal fold
Figure 3.27 Cloacal folds form in the third week and will become
genital folds. The genital tubercle forms at the same time.
Indifferent labioscrotal folds form lateral to the genital folds.
3.6 ­Embryology of the Male
Genital System
Once in the gonadal ridge, the presence of the s­ex‐
determining region Y (SRY) gene located on the short
arm of the Y chromosome leads to testicular development
and male phenotyping. Down streaming from SRY
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3 Embryology for the Urologist
differentiate to become the seminiferous tubules. The
tubuli recti are formed from the narrowing of the deeper
portion of the semiferous tubules, and it converges into
the tubuli recti. The tubules’ connections with the germinal epithelium are discontinued with the formation of
a dense network of fibrous connective tissue known as
the ‘tunica albuginea’ [5].
Male genital development depends on the SRY gene,
anti‐müllerian hormone (AMH; also called müllerian
inhibitory substance [MIS]), insulin‐like hormone 3,
­testosterone, and dihydrotestosterone (DHT).
The gene does two things consecutively:
Yolk sac
Coelom
Urogenital ridge
Figure 3.28 The germ cells pass from the yolk sac across the
coelom to the gonadal ridge.
­ roduces steroidogenesis factor (SF1) and SOX9 that
p
­stimulate testicular cellular differentiation. This induces
the first step of the organogenesis of the testes, the formation of gonadocytes, and proliferation of Leydig cells
and sustentacular cells of Sertoli (Figures 3.29 and 3.30)
[7]. This development not only relies on the presence of
the SRY gene, but also the lack of the DAX1 gene (which
can down regulate the SRY gene action) and WNT4 gene,
which is responsible for female gonadal development.
These cells then proliferate with the aid of SRY gene
proteins and form the primary sex cords. These further
proliferate and extend into the medulla of the gonad to
form the testis or medullary cords. Once here, the cords
branch with their deep ends anastomosing to form the
tubules of the rete testis. The gonadal cords further
develop to give rise to the testicular cords which
1) It makes the gonadocytes differentiate into Sertoli
cells which secrete another simple polypeptide, the
müllerian duct‐inhibiting factor. This has a dramatic
effect: the entire müllerian duct system disappears
within a single day, leaving behind only the tiny vestige of the utriculus masculinis in the verumontanum (Figure 3.31). MIS also inhibits the formation
of the uterus and fallopian tubes (the müllerian
structures) [7–9].
2) Approximately one week later (approximately week
eight), the SRY gene enables the differentiation of the
germ cells located between the testicular cords into
Leydig cells derived from the mesenchyme of the
gonadal ridge. These contain 17‐ketosteroid reductase which is involved in the synthesis of testosterone,
which is activated by the enzyme 5‐alpha reductase to
5‐alpha DHT. This active substance reacts with a
cytosol receptor in the phallic tubercles and wolffian
ducts to secrete growth factor. This results in the two
changes necessary to convert the neuter foetus into
the male. The cytosol receptor factor is a product of
one of the genes in the X chromosome.
In the presence of testis determining factor (SRY
­protein), medullary cords of the testis, and the rete testis
Figure 3.29 Sertoli cells secrete müllerian duct
inhibiting factor. About a week later, Leydig cells
secrete testosterone, which is activated to
dihydrotestosterone, and causes descent of the
testicles and formation of the penis and urethra.
Gonadocytes
Sertoli cells
Leydig cells
17 – ketoreductase
Testosterone
Müllerian duct
inhibitory factor
3.6 Embryology of the Male Genital System
SRY gene:
Foetal pituitary
LH
Leydig cells
Testicular
development
FSH
Foetal testicles
Sertoli cells
Regression of
the müllerian
ducts
Anti-müllerian
hormone
Testosterone
Dihydrotestoste
Differentiation
of genital
tubercle and
urogenital sinus:
External
Genitalia
Prostate
Differentiation
of the wolffian
ducts:
Testicular
descent
Seminal Vesicles
Vas Deferens
Epididymis
Figure 3.30 Male hormone dependence.
Wolffian
duct
Utriculus
masculinus
(Müllerian)
Müllerian
duct
Ureteric
bud
Wolffian duct
Testis
Figure 3.31 The müllerian duct‐inhibiting factor from Sertoli cells cause the müllerian ducts to disappear except for the pit in the
verumontanum.
form (Figure 3.32). Formation of the tunica albuginea
follows. Sertoli cells (from epithelium) and Leydig cells
(from mesenchyme) form dependent on the SRY protein.
SRY protein stimulates AMH production by Sertoli cells
(seventh week), which in turn causes Leydig cells to produce testosterone and insulin‐like hormone 3 (ninth
week). The testis cord continues to remain solid until the
onset of puberty, when it acquires a lumen to form the
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3 Embryology for the Urologist
persist (i.e. appendix testes, utricle). Testosterone influences
development of the mesonephric ducts and male external
genitalia. Mesonephric ducts differentiate into the
central zone of the prostate, ejaculatory ducts, vas deferens, seminal vesicles, epididymis, and efferent ductules
(Figures 3.33 and 3.34)
Mesonephros
Vitelline duct
Gonadal ridge
Germ cells
Hindgut
seminiferous tubules, which connects with the rete testis
and enters the ductuli efferentes, which are remnants of
the mesonephric system. The ductus deferens is formed
when rete testis is joined to the wolffian duct with the aid
of the ductuli efferentes [5].
AMH causes involution of the paramesonephric ducts.
Only small remnants from the paramesonephric ducts
(b)
Testicular descent happens in two phases, guided by the
action on the gubernaculum (Figure 3.35).
1) Passive phase: Dependent on AMH/MIS and insulin‐
like hormone 3 guiding abdominal descent to the
inguinal ring (8–15th week)
2) Active phase: Dependent on testosterone through the
inguinal canal (24–28th week), and to the base of the
scrotum (28th‐33rd week).
Figure 3.32 Upon arrival of germ cells, primitive sex cords form in
the then‐indifferent gonad. In the presence of testis determining
factor (SRY protein), medullary cords of the testis and the rete
testis form.
(a)
3.6.1 The Descent of the Testis
(c)
During their descent, the testes acquire a layer of
­peritoneum, which becomes the tunica vaginalis.
During development the testis begins its journey in the
lumbar area of the retroperitoneum. It transfers from
here to the scrotum near the end of the third month of
pregnancy. This is mediated by testosterone and the
gubernaculum (Figure 3.36), a lump of jelly, which forms
an expanding track, which leads to and inserts into the
genital swelling, the future scrotum [10]. Ectopic testes
are formed when the gubernaculum leads them in the
wrong direction, such as towards the penis or the thigh,
and incomplete descent occurs if the gubernaculum fails
to form a path to the scrotum (Figure 3.37) [11–13].
(d)
Phallic
tubercles
Figure 3.33 (a–d) Testosterone from the Leydig cells cause the phallus to grow and the urethra to roll in from either side.
3.6 Embryology of the Male Genital System
Figure 3.34 In males, the wolffian duct
becomes the vas deferens, epididymis, and
seminal vesicles.
Vas deferens
Seminal vesicle
Appendix
epididymis
[Müllerian]
[Müllerian]
appendix
testis
Utriculus
masculinus
Peritoneum
Testicle
Gubernaculum
Tunica vaginalis
Figure 3.35 Testicular descent happens in two phases: (1) dependent on AMH and insulin‐like hormone 3 during abdominal descent to
the inguinal ring (8–15th week) and (2) dependent on testosterone through the inguinal canal (24–28th week),and to the base of the
scrotum (28–33rd week). Both phases are guided by the gubernaculum. During their descent, the testes acquire a layer of peritoneum,
which becomes the tunica vaginalis.
Figure 3.36 Normal migration of the testicle.
Peritoneum
Processus
vaginalis
Gubernaculum
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3 Embryology for the Urologist
Ecotopic (‘off course’)
Incompletely descended
(‘on course’)
Abdominal
Abdominal
Entrant
inguinal
Penile
High
retractile
Perineal
Low
retractile
Crural
Figure 3.37 The maldescended testis may be off its normal course of descent (ectopic) or on the normal course (incomplete) descent.
Encysted hydrocele of the cord
Congenital hydrocele
Hernia magna
Intra-abdominal hydrocele
Figure 3.38 Varieties of hydrocele and hernia.
3.6.2
Relevant Congenital Malformations
As the testis descends, it is accompanied by the processus
vaginalis. The lumen of the processus vaginalis is normally obliterated within a few weeks of birth; ­however, if
it persists, it gives rise to defects such as a congenital hernia, hydrocele, an encysted hydrocele of the cord, or an
abdominoscrotal hydrocele (Figures 3.38 and 3.39) [14].
Maldescent of a testis results in an undescended testis.
Malposition of the gubernaculum or an abnormally long
3.7 Embryology of the Prostate
(a)
(b)
(c)
(d)
(e)
(f)
Figure 3.39 Various types of hernia and hydrocele. (a) Common hydrocele, (b) encysted hydrocele, (c) ‘double’ hydrocele, (d) hernia and
hydrocele, (e) ‘hernia magna’, and (f ) abdominoscrotal hydrocele.
gubernaculum result in an ectopic testis. Failure of,
incomplete, or inappropriate development of the genital
system leads to disorders of sexual differentiation.
In males, the müllerian duct lingers as two tiny
vestiges, the utriculus masculinis in the verumontanum and the appendix testis, neighbouring the
appendix epididymis which is a vestige of the wolffian duct (Figures 3.31 and 3.34) [5]. If there is a congenital deficiency of MIS, phenotypical males are
born with fallopian tubes and a uterus, usually found
by chance at laparoscopic orchidopexy or hernia
repair, and occasionally, associated with testicular
tumours [7].
3.7 ­Embryology of the Prostate
As described previously, the male foetus develops in the
presence of a Y chromosome, which encodes the SRY
protein, thus enabling testicular differentiation and the
production of androgens such as testosterone. In addition to the actions of SRY protein and androgens, a third
factor is required for male development, AMH, also
known as MIS [15]. This causes the müllerian (paramesonephric) duct to degenerate, forming the prostatic
utricle (or utriculus masculinis). Blandy originally
described this as, ‘a volcanic crater on the summit of the
verumontanum’.
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3 Embryology for the Urologist
Testis
Figure 3.40 The prostate begins to form in the
mesenchyme of the urogenital septum in the
vicinity of the opening of the wolffian ducts.
Wolffian duct
Bladder
Metanephros
Ureter
Urorectal septum
Rectum
Tail
The prostate forms in the mesenchyme of the urogenital septum. The cloacal membrane, a thin film which
covers the convexity of the hindgut, regresses to leave
gaps in front of and behind the urogenital septum, and in
so doing, forming the urethra and anus. Running down
in this septum are the müllerian and wolffian ducts and
the ureteric buds (Figure 3.40).
At approximately week eight, the Leydig cells of the
foetal testis secrete testosterone [16, 17], and as a
consequence, the human prostate begins its development at about the 10th week of gestation. The initial
outgrowths of the epithelial ‘prostatic’ buds from the
urethra into the urogenital sinus (UGS) occur in
response to the binding of 5α‐dihydrotestosterone to
androgen receptors localised in the surrounding
­mesenchymal tissue [18–21]. There are five pairs of
buds. The top pairs are derived from mesoderm (i.e.
wolffian structures) and form the transitional, periurethral, and central zones of the prostate, whereas,
the bottom pairs are derived from endoderm and
form the peripheral zone.
These prostatic buds begin as solid cords of epithelial cells that elongate and undergo extensive branching morphogenesis during the latter stages of foetal
growth to develop primitive lumens [22]. During weeks
13–15, serum testosterone elevates and remains high
until week 25, which in turn induces epithelial differentiation. At this point, the three important epithelial
populations, other than the stem cells, are distinct:
luminal, basal, and neuroendocrine cells [22]. The
stromal component compromises of fibroblasts,
smooth muscles, and myofibroblasts. At week 25, the
testosterone level diminishes, and the gland remains in
a quiescent state until puberty. The central zone is primarily sensitive to testosterone, whereas the peripheral and transitional/periurethral are sensitive to DHT.
Summary: DHT prompts development of the prostate
from urethral endoderm and surrounding mesoderm
(13–16th weeks), giving rise to the transitional zone and
peripheral zone. The central zone is formed from the
mesonephric duct.
3.8 ­Embryology of the Penis and Urethra
Two crucial events occur in the male embryo, between
the fifth and seventh week:
●●
●●
the disappearance of the müllerian ducts
the transformation of the phallic tubercles
Both events are orchestrated by the two sex chromosomes. On the Y chromosome, the SRY gene controls germ
cell differentiation into Sertoli cells (whose müllerian
inhibiting factor causes the müllerian ducts to ­disappear).
By the eighth week of gestation, the mesenchymal cells of
the genital ridge differentiate into Leydig cells which
secrete testosterone, which enters the wolffian ducts and
the phallic and genital tubercles. These tissues contain 5‐
alpha reductase, an enzyme which activates testosterone to
a more potent form, DHT. DHT binds to a cytosol receptor
protein and sets off the changes in growth, which allow the
wolffian ducts to develop into the vasa efferentia, seminal
vesicles, and epididymis. The phallic and genital tubercles
become the penis, scrotum, and urethra (Figure 3.41). A
gene on the X chromosome codes the cytosol receptor
3.8 Embryology of the Penis and Urethra
Figure 3.41 The Y chromosome produces the HY
gene, which turns germ cells either into Sertoli
cells, which secrete the müllerian duct‐inhibiting
factor, or Leydig cells. The Leydig cells secrete
testosterone, which is hydrogenated to
dihydrotestosterone, and binds to receptors in the
wolffian ducts and phallic tubercles.
Y chromosome
HY gene
Germ cells
Sertoli cell
Leydig cells
Testosterone
Müllerian ductinhibiting factor
Müllerian
Dihydrotestosterone
Wolffian
Urogenital sinus
Penis and urethra
Umbilical
cord
Phallic
tubercle
Urogenital
sinus
Genital
tubercles
Urogenital
septum
Rectum
Figure 3.42 When the cloacal membrane dissolves, the bladder
opens behind the genital tubercle.
protein. Each step on this ladder of events is carried out by
a certain enzyme coded by a single gene. In the absence of
this organised testicular development, the differentiated
gonads will develop into ovaries by the 13th and 14th
weeks of gestation [23]. Each step may go wrong and result
in one of the variations of intersex.
By week seven, the cloacal membrane dissolves, and
the primitive bladder opens on the ventral aspect of the
Dihydrotestosterone
Figure 3.43 Under the influence of dihydrotestosterone, the
genital tubercle elongates, and a groove folds in on either side to
form the urethra, up to the groove behind the solid glans penis.
genital tubercle (Figure 3.42). This elongates to form the
penis under which a groove is folded in from either side
to form the urethra (Figure 3.43). Rods of mesenchyme
in each fold differentiate into the corpora cavernosa and
corpus spongiosum. At the tip of the penis, a groove
demarcates the glans through which a solid cord extends
and then becomes canalised as, the terminal urethra
(Figure 3.44). Skin grows forwards from the coronal sulcus to enclose the glans in the prepuce and then becomes
adherent.
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3 Embryology for the Urologist
Figure 3.44 A cord extends through the solid
glans and then becomes canalised to form the
terminal urethra. Skin grows forwards from the
coronal sulcus to enclose and adhere to the
glans.
Figure 3.45 The scrotum is formed by the ­
in‐rolling of the two genital tubercles over the
urethra.
The scrotum is formed by the meeting together in the
midline of the two genital tubercles over the urethra
(Figure 3.45).
All these processes must be complete within a critical
window of time. If the genital folds and penis are not
completed by the 12th week they never will be. However
much androgen is given later on, all it can do is slightly
enlarge the penis [24, 25].
Summary: Under the influence of DHT (formed
from testosterone by the action of 5‐α‐reductase), the
penis, scrotum, and prostate form. DHT causes elongation of the genital tubercle after six weeks to form
the phallus with the urethral plate. The genital and
labioscrotal folds on either side move caudally and fuse
along the midline, which carries the urethra to the tip
of the formed penis and forms the scrotum with the
midline scrotal septum. DHT sets off the train of
events leading to the growth and fusion of the phallus,
in‐rolling of the urethral tube, formation of the scrotal
sac, and the downward migration of the testes [7, 8].
The wolffian ducts are dependent on t­estosterone to
develop and form the epididymis, vas deferens, and
seminal vesicles.
3.9 ­Neuter State
Without a Y chromosome or its SRY genes, the foetus
stays neuter. The neuter state seems at first glance to be
female: There is no phallus; the müllerian ducts persist;
and the wolffian ducts fail to turn into the vas deferens.
3.10 ­Embryology of the Female
Genital System
The paramesonephric ducts form the basis of the female
genital system. In the absence of the SRY gene, default
development is down the female pathway. The mesonephric
ducts regress and only leave a few remnants, including
Gartner’s cysts, paroophoron, and epoophoron. The paramesonephric ducts develop into fallopian tubes, uterus,
and the upper two‐thirds of the vagina (Figure 3.46).
With regards to external genitalia, the genital tubercle
develops into the clitoris, the urogenital sinus forms the
introitus and vestibule of the vagina (distal one‐third),
the genital folds become the labia minora, and the labioscrotal folds become the labia majora (Figure 3.47).
3.11 Embryology of the Adrenal Gland
Fallopian tube
Genital tubercle/clitoris
Genital folds/labia minora
Uterus
Ovary
Labioscrotal folds/labia majora
Vagina
Sinovaginal bulb
Figure 3.47 Female external genital development: the genital
tubercle develops into the clitoris, the genital folds become the
labia minora, and the labioscrotal folds become the labia majora.
Figure 3.46 Derivatives of the paramesonephric duct in
females: fallopian tubes, uterus, and the upper two‐thirds of
the vagina.
Neural tube
Migration of neuroblasts
(Week 7)
Adrenal cortex
Adrenal medulla
Fetal cortex arising from
genitourinary ridge (Week 5)
Genitourinary ridge
Figure 3.48 Migration of neuroectodermal cells from neural crest.
3.11 ­Embryology of the Adrenal Gland
There are two distinct components of the adrenal
gland: cortex and medulla. The cortex is derived from
the mesoderm. At about the fifth to sixth weeks of
life, the foetal cortex develops arising from the genitourinary ridge, subsequently surrounded by a second
wave of mesothelial cells, which will eventually form
the definitive cortex near the developing gonads and
kidneys; tiny rests of adrenal cortical tissue are common in the renal cortex, retroperitoneum, and testis
as well as the broad ligament near the ovary (Figures 3.48
and 3.49). After birth, the foetal cortex regresses
except for its outermost layer, which differentiates
into the reticular zone. The adrenal cortex shares
many of the enzymes of gonads – notably those for
the synthesis of steroids – so that some inborn errors
of metabolism affect them both.
71
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3 Embryology for the Urologist
Figure 3.49 The cortex arises in the mesoderm
of the ‘intermediate cell mass’, which later
forms the genitourinary ridge.
Neuroectodermal cells migrate into it from the
neural crest to form the medulla.
Ectoderm
Neural crest
Intermediate cell mass
Gut
Coelom
Ingrowth of neuroectoderm
Genitourinary ridge
Cortex
Medulla
In the seventh week of foetal life, neuroblasts from the
sympathetic system of the neural crest (ectodermal
cells) invade the medial aspect of the developing adrenal
­cortex to form the medulla. After a week, they differentiate into sympathicoblasts and pheochromocytes
­containing the intracellular catecholamines, adrenaline,
and noradrenaline.
Cells derived from the neural crest migrate on each
side of the aorta to form the sympathetic chains. It is
from these paraganglia cells that extra‐adrenal neuro‐
ectodermal tumours (paragangliomas) arise.
Expert Opinion
The overall sequence of urogenital development is well
established and can explain the majority of congenital
malformations that may present to the urologist.
Additional details will only be of interest to the subspecialist and the researcher.
In foetal life, the adrenals are larger than the kidneys
and are still about one‐third of their size at birth.
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