laparoscopic adrenalectomy, more often on the right (17%) than the one-tenth of the gland, which is dark red or greyish, depending on its
left (9%). Common variants included an absent main suprarenal vein; content of blood (see Fig. 71.4; Fig. 71.5). The medulla is completely
two or more suprarenal veins draining one side; and veins draining to enclosed by cortex, except at the hilum. The gland has a thick collagen-
the inferior phrenic vein or, on the left, to the inferior vena cava. ous capsule from which trabeculae extend deep into the cortex. The
capsule contains a rich arterial plexus (see above) that supplies branches
Lymphatic drainage
to the gland.
Lymphatic channels within the capsule of the suprarenal gland com-
municate with subserous lymphatics that drain medially to para-aortic
Suprarenal cortex
and paracaval nodes (Merklin 1966). A few capsular lymphatics com-
municate with lymph vessels that pass through the diaphragm.
The suprarenal cortex is composed of a zona glomerulosa, a zona fasci-
culata and a zona reticularis (see Fig. 71.5). The outer, subcapsular, zona
INNERVATION glomerulosa consists of a narrow region of small polyhedral cells
arranged in rounded clusters. The cells have deeply staining nuclei and
The suprarenal gland, relative to its size, has a greater autonomic supply a basophilic cytoplasm containing a few lipid droplets. Ultrastructur-
than any other organ. The nerves are distributed throughout the gland: ally, their cytoplasm displays an abundant smooth endoplasmic reticu-
around blood vessels (regulating blood flow), in the medulla (stimulat- lum that is typical of steroid-synthesizing cells. The broader, intermediate,
ing the release of catecholamines from chromaffin cells), and in the zona fasciculata consists of large polyhedral basophilic cells arranged
cortex (where they may influence steroid hormone production; Tóth in straight columns, two cells wide, separated by parallel fenestrated
et al (1997)). A suprarenal plexus lies between the medial aspect of venous sinusoids. The cells contain many lipid droplets and large


each gland and the coeliac and aorticorenal ganglia. It contains pre- amounts of smooth endoplasmic reticulum. The innermost part of the
dominantly preganglionic sympathetic fibres that originate in the lower cortex, the zona reticularis, consists of branching interconnected
thoracic spinal segments, reach the plexus via branches of the greater columns of rounded cells with cytoplasm containing smooth endoplas-
splanchnic nerves, and synapse on clusters of large medullary chromaf- mic reticulum, numerous lysosomes and aggregates of brown lipofuscin
fin cells (which can be regarded as homologous with postganglionic pigment that accumulate with age.


SuPRAREnAl (AdREnAl) glAnd
1198
8
nOITCES
Cortical cells produce several hormones, and the cells of the zonae tumour. For other tumours and disorders of the suprarenal gland
fasciculata and reticularis are also rich in ascorbic acid. Cells in the zona requiring surgery, minimally invasive techniques are now generally pre-
glomerulosa produce mineralocorticoids, e.g. aldosterone, which regu- ferred. The original laparoscopic approaches were described in 1992
lates electrolyte and water balance; cells in the zona fasciculata produce (transabdominal; Gagner et al 1992) and 1995 (posterior retroperito-
hormones maintaining carbohydrate balance (glucocorticoids), e.g. cor- neal; Mercan et al 1995). The posterior approach is considered superior
tisol (hydrocortisone); and cells in the zona reticularis produce sex on account of its safety, rapidity, avoidance of the peritoneal cavity, and
hormones (progesterone, oestrogens and androgens). The suprarenal the ability to operate on both sides without repositioning the patient
cortex is essential to life and its complete removal is lethal without (Morris and Perrier 2012). This has been confirmed in several large
replacement therapy. It exerts considerable control over lymphocytes cohort studies (Walz et al 2006, Dickson et al 2011).
and lymphoid tissue; an increased secretion of corticosteroids can result Nevertheless, conventional laparoscopy has certain disadvantages,
in a marked reduction in lymphocyte numbers. such as a two-dimensional view, unstable camera platform, and rigid
The deeper part of the zona fasciculata widens in pregnancy. Cortical instrumentation. Robotic surgery is a new and emerging technique now
atrophy in elderly males is greatest in the same region. performed in many centres and offers the advantages of a three-
dimensional stable platform, seven degrees of freedom, and enhanced
Suprarenal medulla vision (Taskin and Berber 2013). During the last decade, experience
with robotic adrenalectomy has highlighted several facets, including a
steep learning curve, no significant reduction in the need to convert to
The suprarenal medulla is composed of groups and columns of chro-


an open procedure, operative complications or blood loss compared to
maffin cells (phaeochromocytes), separated by wide venous sinusoids
conventional laparoscopy, and longer operative times (although this
and supported by a network of reticular fibres. Chromaffin cells, so
decreases with experience). Robotic surgery is also more expensive.
called from their colour reaction to dichromate fixatives, form part of
However, with appropriate patient selection, robotic adrenalectomy can
the neuroendocrine system and are functionally equivalent to postgan-
be advantageous. For example, patients with familial suprarenal disor-
glionic sympathetic neurones. They synthesize, store (as granules) and
ders, who are more likely to have bilateral pathology, require cortical
release the catecholamines noradrenaline (norepinephrine) and adren-
sparing, or have glands that may be difficult to access posteriorly, are
aline (epinephrine) into the venous sinusoids. Release is under pregan-
particularly good candidates for robotic surgery.
glionic sympathetic control, mediated by the sympathetic neurones that
In the posterior retroperitoneal approach, the patient is placed in
occur either singly or in small groups in the medulla.
the prone jack-knife position to open up the interval between the costal
The majority of chromaffin cells synthesize adrenaline and store it
margin and iliac crest posteriorly. A small incision is made 2 cm inferior
in small granules with a dense core. Less numerous noradrenaline-
and parallel to the twelfth rib, and the perinephric fascia is entered
secreting cells have larger granules with a dense eccentric core. Some
using blunt dissection or with the aid of laparoscopic visualization. A
cells synthesize both hormones. Chromogranin proteins package cate-
dissecting balloon is then inserted and inflated under laparoscopic
cholamines within the granules, which also contain enkephalins,
control, after which a 12 mm trocar is inserted into the cavity and CO
opiate-like proteins that may have endogenous analgesic effects in some 2
is insufflated up to a pressure of 20–25 mmHg. The 0° laparoscope is
circumstances. All of the cells are large, with large nuclei and basophilic,


replaced by a 45° telescope, and two additional 5- or 10 mm ports are
faintly granular cytoplasm. They form single rows along the venous
inserted medial and lateral to the initial port. Dissection is initiated at
sinusoids. Sympathetic axon terminals synapse with the chromaffin
the superior aspect of the suprarenal gland and proceeds laterally and
cells on the surfaces that face away from the sinusoids.
then inferiorly. The medial surface of the gland is dissected last and the
The sinusoids are lined by fenestrated endothelium and drain to the
adrenal vessels isolated and divided either with clips or a harmonic
central medullary vein and hilar suprarenal vein. Under normal circum-
scalpel (Lal and Clark 2010).
stances, little adrenaline or noradrenaline is released; secretion is
Similar steps are taken in the robotic approach. The robot is docked
increased in response to fear, anger or stress. Unlike the cortex, the
after insertion of the 5- and 10 mm secondary ports; the robotic grasper
suprarenal medulla is not essential to life.
is placed in the lateral port and the harmonic scalpel in the medial
before proceeding with the dissection.
In obese (or Cushingoid) patients, identification of a relatively
SUPRARENAL GLAND EXCISION normal-sized suprarenal gland can be extremely difficult and time-
consuming. The suprarenal vein emerges from the lower medial border
Removal of one or both of the suprarenal glands may be performed of the gland and is often a very substantial structure. In contrast, the
using ‘open surgery’, which remains the standard of care for patients supplying arteries tend to be small and named arteries are often difficult
with adrenocortical carcinoma who require en bloc resection of the to identify during surgery.
KEY REFERENCES
Cesmebasi A, Du Plessis M, Iannatuono M et al 2014 A review of the Manso JC, DiDio LJ 2000 Anatomical variations of the human suprarenal
anatomy and clinical significance of adrenal veins. Clin Anat 27: arteries. Ann Anat 182:483–8.
1253–63. A study of vascular corrosion casts, demonstrating anatomical variations of


Reviews the surgical anatomy of the suprarenal veins, including their the arterial supply to the suprarenal gland.
development.


Suprarenal (adrenal) gland
1198.e1
17
RETPAHC
REFERENCES
Altin MA, Gündo H, Aksoy F 1992 Adrenal rests in the inguinal region in Merklin RJ 1966 Suprarenal gland lymphatic drainage. Am J Anat 119:
children. Pediatr Surg Int 7:446–8. 359–74.
Cesmebasi A, Du Plessis M, Iannatuono M et al 2014 A review of the Morris L, Perrier N 2012 Advances in robotic adrenalectomy. Curr Opin in
anatomy and clinical significance of adrenal veins. Clin Anat 27: Onc 24:1–6.
1253–63. Mravec B 2005 A new focus on interoceptive properties of adrenal medulla.
Reviews the surgical anatomy of the suprarenal veins, including their Auton Neurosci 120:10–7.
development.
Parnaby CN, Galbraith N, O’Dwyer PJ 2008 Experience in identifying the
Dickson PV, Jimenez C, Chisholm GB et al 2011 Posterior retroperitoneo- venous drainage of the adrenal gland during laparoscopic adrenalec-
scopic adrenalectomy: a contemporary American experience. J Am Coll tomy. Clin Anat 21:660–5.
Surg 212:659–65. Sholten A, Cisco R, Vriens M et al 2013 Variant adrenal venous anatomy in
Dutta S 2010 Suprarenal gland – arterial supply: an embryological basis and 546 laparoscopic adrenalectomies. JAMA Surg 148:378–83.
applied importance. Rom J Morphol Embryol 51:137–40. Taskin HE, Berber E 2013 Robotic adrenalectomy. Cancer J 19:162–6.
Gagner M, Lacroix A, Bolte E 1992 Laparascopic adrenalectomy in Cushing’s Tóth IE, Vizi ES, Hinson JP et al 1997 Innervation of the adrenal cortex, its
syndrome and pheochromocytomas. New Engl J Med 327:1033. physiological relevance, with primary focus on the noradrenergic trans-


Lal G, Clark OH 2010 Thyroid, parathyroid, and adrenal. In: Brunicardi FC, mission. Microsc Res Tech 36:534–45.
Andersen DK, Billiar TR et al (eds) Schwartz’s Principles of Surgery, 9th Vincent JM, Morrison ID, Armstrong P et al 1994 The size of normal adrenal
ed. New York: McGraw-Hill; Ch. 38. glands on computed tomography. Clin Radiol 49:453–5.
Loukas M, Louis RG Jr, Hullett J et al 2005 An anatomical classification Walz M, Alesina P, Wegner F et al 2006 Posterior retroperitoneoscopic
of the variations of the inferior phrenic vein. Surg Radiol Anat 27: adrenalectomy – results of 560 procedures in 520 patients. Surgery
566–74. 140:843–8.
Manso JC, DiDio LJ 2000 Anatomical variations of the human suprarenal Wang X, Jin ZY, Xue HD et al 2013 Evaluation of normal adrenal gland
arteries. Ann Anat 182:483–8. volume by 64-slice CT. Chin Med Sci J 27:220–4.
A study of vascular corrosion casts, demonstrating anatomical variations of
Williams LR, Leggett RW 1989 Reference values for resting blood flow to
the arterial supply to the suprarenal gland.
organs of man. Clin Phys Physiol Meas 10:187–217.
Mercan S, Seven R, Ozarmagan S et al 1995 Endoscopic retroperitoneal
adrenalectomy. Surgery 118:1071–5.


SUBSECTION: Urogenital system
CHAPTER
72
Development of the urogenital system
A pronephros is present in human embryos only as clusters of cells in
URINARY SYSTEM
the most cranial portions of the nephrogenic cord (see Figs 72.1–72.2).
More caudally, similar groups of cells appear and become vesicular. The
The urinary and reproductive systems develop from intermediate mes dorsal ends of the most caudal of the vesicles join the primary excretory
enchyme and are intimately associated with one another, especially in duct. Their central ends are connected with the coelomic epithelium by
the earlier stages of their development. The urinary system develops cellular strands, which probably represent rudimentary peritoneal
ahead of the reproductive or genital systems. funnels. Glomeruli do not develop in association with these cranially
Intermediate mesenchyme is disposed longitudinally in the trunk, situated nephric tubules, which ultimately disappear. It is doubtful
subjacent to the somites (in the folded embryo), at the junction between whether external glomeruli develop in human embryos.
the splanchnopleuric mesenchyme (adjacent to the gut medially) and
the somatopleuric mesenchyme (subjacent to the ectoderm laterally) Primary excretory duct
(Fig. 72.1). In lower vertebrates, intermediate mesenchyme typically In stage 11 embryos of approximately 14 somites, the primary excretory
develops serial, segmental, epithelial diverticula termed nephrotomes. duct can be seen as a solid rod of cells in the dorsal part of the neph
Each nephrotome encloses a cavity, the nephrocele, which communi rogenic cord. Its cranial end is about the level of the ninth somite and
cates with the coelom through a peritoneal funnel, the nephrostome its caudal tip merges with the undifferentiated mesenchyme of the cord.
(Fig. 72.2). The dorsal wall of a nephrotome evaginates as a nephric It differentiates before any nephric tubules and, when the latter appear,
tubule. The dorsal tips of the cranial nephric tubules bend caudally and it is at first unconnected with them. In older embryos, the duct has


fuse to form a longitudinal primary excretory duct, which grows cau lengthened and its caudal end becomes detached from the nephrogenic
dally and curves ventrally to open into the cloaca. The more caudally cord to lie immediately beneath the ectoderm. From this level, it grows
placed, and therefore chronologically later, tubules open secondarily caudally, independent of the nephrogenic mesenchyme, and then
into this duct or into tubular outgrowths from it. Glomeruli, specific curves ventrally to reach the wall of the cloaca. It becomes canalized
arrangements of capillaries and overlying coelomic epithelium, arise progressively from its caudal end to form a true duct, which opens into
from the ventral wall of the nephrocele (internal glomeruli) or the roof the cloaca in embryos at stage 12. Clearly, up to this stage, the name
of the coelom adjacent to the peritoneal funnels (coelomic or external ‘duct’ is scarcely appropriate.
glomeruli), or in both situations (see Fig. 72.2).
Mesonephros
It has been customary to regard the renal excretory system as three
organs – the pronephros, mesonephros and metanephros – succeeding From stage 12, mesonephric tubules, which develop from the interme
each other in time and space, such that the last to develop is retained diate mesenchyme between somite levels 8–20, begin to connect to the
as the permanent kidney (see Figs 72.1–72.2). However, it is difficult primary excretory duct, which is now renamed the mesonephric duct.
to provide reliable criteria by which to distinguish these stages or to More caudally, a continuous ridge of nephrogenic mesenchyme extends
define their precise limits in embryos. to the level of somite 24. The mesonephric tubules (nephrons) are not
metameric; there may be two or more mesonephric tubules opposite
Pronephros
each somite.
The intermediate mesenchyme becomes visible in stage 10 embryos and Within the mesonephros, each tubule first appears as a condensation


can be distinguished as a nephrogenic cord when 10 somites are present. of mesenchyme cells, which epithelialize and form a vesicle. One end
A B C Fig. 72.1 A, The major epithelial
populations within a stage 11
Neural tube embryo, viewed from a
ventrolateral position. B, The
position of pronephros and
mesonephros on the posterior
Foregut thoracic and abdominal walls.
C, The position of mesonephros
Pericardial and metanephros.
cavity
Peritoneal
Pronephros
funnels
Pericardio-
peritoneal
canals
Intraembryonic
coelom
Mesonephros Mesonephros
Peritoneal
cavity
Mesonephric Metanephros
duct
Allantois Cloaca Ureteric bud
Mesenchyme around Mesenchyme around
connecting stalk connecting stalk
1199


DeveloPment of the urogenital system
1200
8
noitCes
Neural tube Fusion forms primary Primary excretory
Somite cavity Nephric tubules excretory duct duct grows caudally
Ectoderm evaginate and to reach cloaca
turn caudally
Lateral splanchnic arteries
Coelom
Endoderm Single fused aorta
Notochord Nephrostome
Internal and
Right aorta Nephrocele external glomeruli
Nephrogenic cord of
intermediate mesoderm
Aorta Postcardinal vein
Pronephros
Rudimentary in mammals Primary excretory
duct now termed
Mesonephric
mesonephric
duct
(Wolffian) duct
Gut
Genital ridge
Mesonephros
Mesonephric tubule
Mesonephric
tubule
Metanephros Metanephric cap
Collecting ducts
Lobulated
fetal kidney
Renal corpuscle
Medullary loop
Allantois Ureteric bud
branching
dichotomously
Early bladder
Urachus
Ureter
Urogenital sinus
Bladder
Vas deferens
Genital Seminal vesicle
tubercle
Trigone of bladder
Fig. 72.2 Principal features of the primitive vertebrate nephric system for comparison with the development of the human nephric system. A
considerable period of embryonic and fetal life has necessarily been compressed into a single diagram. (Modified with permission from Williams PL,
Wendell-Smith CP, Treadgold S 1969 Basic Human Embryology, 2nd edn. London, Pitman Medical & Scientific.)


urinary system
1201
27
retPahC
of the nephric ridge, and, at the caudal end of the ridge, it projects into
the cavity of the coelom in the substance of a mesonephric fold (see
Fig. 72.3). As the mesonephric ducts from each side approach the uro
genital sinus, the two mesonephric folds fuse, between the bladder
ventrally and the rectum dorsally, forming a transverse partition across
the cavity of the pelvis, which is somewhat inappropriately called the
genital cord (see Fig. 72.3). In the male, the peritoneal fossa between
Tubal fold the bladder and the genital cord becomes obliterated, but it persists in
(mesonephric fold) the female as the uterovesical pouch. In the male, the mesonephric duct
Aorta
itself becomes the canal of the epididymis, vas deferens and ejaculatory
duct.
Mesonephros
urogenital sinus
Arterial supply The primitive hindgut ends in a cloacal region. This is connected ven
Gonad to glomerulus trally with a blindending diverticulum, the allantois, which is inti
mately related to the development of the caudal portion of the urinary
Mesonephric
system. The enteric and allantoic portions of the hindgut are separated
nephron
by the proliferation of the urorectal septum, a partition of mesenchyme
and endoderm in the angle of the junction of hindgut and allantois
Mesonephric duct
(Fig. 72.4; see Fig. 72.7). Molecular markers of the urorectal septum
Hindgut Paramesonephric mesenchyme, also termed the intercloacal mesenchyme, include Six1
(Müllerian) duct and Six2 (Wang et al 2011, Wang et al 2013). The endodermal epithe
lium beneath the mesenchyme of the urorectal septum approaches but
Genital cord does not fuse with the cloacal membrane; it effectively divides the
membrane into anal (dorsal) and urogenital (ventral) membranes, and
the cloacal region into dorsal and ventral portions. The dorsal portion


Urogenital sinus of the cloacal region is the putative rectum. The ventral portion can be
further divided into: a cranial vesicourethral canal, continuous above
with the allantoic duct; a middle, narrow channel, the pelvic portion;
and a caudal, deep, phallic section, which is closed externally by the
urogenital membrane. The second and third parts together constitute
the urogenital sinus. The ventral pericloacal mesenchyme contributes
to the genital tubercle (Wang et al 2013) (see Fig. 72.20).
Fig. 72.3 The relative positions of the mesonephros and early gonad in
Metanephros
the abdomen in the ambisexual stage of development. The mesonephric
and paramesonephric ducts run within the tubal fold to the urogenital The pronephros and mesonephros are linear structures. They both
sinus. contain stacks of tubules distributed along the craniocaudal axis of the
embryo, an arrangement that results in the production of hypotonic
urine. In marked contrast, the tubules in the metanephric kidney are
arranged concentrically, and the loops of Henle are directed towards
of the vesicle grows towards and opens into the mesonephric duct, the renal pelvis. This arrangement allows different concentration gradi
while the other dilates and invaginates. The outer stratum forms the ents to develop within the kidney and results in the production of
glomerular capsule, while the inner cells differentiate into mesonephric hypertonic urine. Metanephric nephrons do not join with the existing
podocytes, which clothe the invaginating capillaries to form a glomer mesonephric duct but with an evagination of that duct, which branches
ulus. The capillaries are supplied with blood through lateral branches dichotomously to produce a characteristic pattern of collecting ducts.
of the aorta. It has been estimated that 70–80 mesonephric tubules and The metanephric kidney develops from three sources. An evagina
a corresponding number of glomeruli develop. However, these tubules tion of the mesonephric duct, the ureteric bud, and a local condensa


are not all present at the same time; it is rare to find more than 30–40 tion of mesenchyme, the metanephric blastema, form the nephric
in an individual embryo because the cranial tubules and glomeruli structure (Fig. 72.5). Angiogenic mesenchyme migrates into the
develop and atrophy before the development of those situated more metanephric blastema slightly later to produce the glomeruli and vasa
caudally. recta. It is possible that an intact nerve supply is also required for
By the end of the sixth week, each mesonephros is an elongated, metanephric kidney induction. The actions of a range of intra and
spindleshaped organ that projects into the coelomic cavity, one on each extracellular factors involved in metanephric development have been
side of the dorsal mesentery, from the level of the septum transversum presented (Kanwar et al 2004).
to the third lumbar segment. This whole projection is called the mesone An epithelial–mesenchymal interaction between the duct system and
phric ridge, mesonephros or Wolffian body (see Fig. 72.1B–C; Fig. 72.3). the surrounding mesenchyme occurs in both mesonephric and meta
It develops subregions, and a gonad develops on its medial surface. nephric systems. In the mesonephric kidney, development proceeds in
There are striking similarities in structure between the mesonephros a craniocaudal progression, and cranial nephrons degenerate before
and the permanent kidney or metanephros, but the mesonephric neph caudal ones are produced. In the metanephric kidney, a proportion of
rons lack a segment that corresponds to the descending limb of the the mesenchyme remains as stem cells that continue to divide and
loop of Henle. The mesonephros is believed to produce urine by which enter the nephrogenic pathway later, when the individual col
stage 17. A detailed comparison of the development and function of lecting ducts lengthen. The temporal development of the metanephric
the mesonephros and metanephros in staged human embryos is not kidney is patterned radially, such that the outer cortex is the last part


available. to be formed. The following interactions occur in the development of
In stage 18 embryos (13–17 mm), the mesonephric ridge extends the metanephric kidney (see Fig. 72.5). The ureteric bud undergoes a
cranially to about the level of rib 9. In both sexes, the cranial end of series of bifurcations within the surrounding metanephric mesenchyme,
the mesonephros atrophies; in embryos 20–mm in length (stage 19), a and forms smaller ureteric ducts. At the same time, the metanephric
mesonephros is found only in the first three lumbar segments, although mesenchyme condenses around the dividing ducts to form Sshaped
it may still possess as many as 26 tubules. The most cranial one or clusters, which transform into epithelia and fuse with the ureteric ducts
two tubules persist as rostral aberrant ductules (see Fig. 72.13); the at their distal ends. Blood vessels invade the proximal ends of the
succeeding five or six tubules develop into either the efferent ductules Sshaped clusters to form vascularized glomeruli.
of the testis and lobules of the head of the epididymis (male), or the The ureteric bud bifurcates when it comes into contact with the
tubules of the epoophoron (female); the caudal tubules form the caudal metanephric blastema in response to extracellular matrix molecules
aberrant ductules and the paradidymis (male), or the paroophoron synthesized by the mesenchyme. Both chondroitin sulphate proteogly
(female). can synthesis and chondroitin sulphate glycosaminoglycan processing
are necessary for the dichotomous branching of the ureteric bud. In
mesonephric duct metanephric culture, incubation of fetal kidneys in βDxyloside, an
Once mesonephric nephrons connect to the primary excretory duct, it inhibitor of chondroitin sulphate synthesis, dramatically inhibits uret
is renamed the mesonephric duct. This runs caudally in the lateral part eric bud branching.


DeveloPment of the urogenital system
1202
8
noitCes
A
B
Peritoneal
cavity Peritoneal cavity
Allantois
Midgut
Mesonephric ducts
entering back of
urogenital sinus
Mesenchymal proliferation
of urorectal septum grows
Hindgut
towards and fuses with
cloacal membrane
Cloacal membrane forming:
U r ogenital membrane
Cloaca Anal membrane
Connecting stalk
C
Rectum
Anal membrane
Urogenital membrane
Urinary bladder
Peritoneal
Peritoneal cavity cavity
Urachus
Urinary bladder
Amnion Pubic
symphysis
Urethra
Fig. 72.4 The division of the hindgut into urinary and enteric
Perineal body
parts: left ventrolateral view of the intraembryonic coelom and
Anal membrane corresponding midsagittal sections. A, The early cloaca.
Urachus B, Proliferation of the urorectal septum. C, Complete separation of
Rectum the urethra and anal canal, and position of the perineal body.
Subsequent divisions of the ureteric bud and associated mesen the angiogenic mesenchyme produce fibronectin and other components
chyme define the gross structure of the kidney and the major and minor of the glomerular basement membrane. The isoforms of typeIV colla
calyces, the distal branches of the ureteric ducts that will form the col gen within this layer follow a specific programme of maturation as the
lecting ducts of the kidney. The proximal position of the ureteric bud filtration of macromolecules from the plasma becomes restricted.
elongates to form the developing ureter (see Fig. 72.6). As the collecting Although the timing of human development is not the same as other
ducts elongate, the metanephric mesenchyme condenses around them. mammalian species, similar growth and transcription factors are
An adhesion molecule, syndecan, can be detected between the mesen thought to underpin kidney development (Chai et al 2013, Batchelder
chymal cells in the condensate. The cells switch off expression of neural et al 2010, Davidson 2009, Faa et al 2012). A number of genes involved


cell adhesion molecule (NCAM), fibronectin and collagen I, and start in the development of the renal medulla and vasa recta in the mouse
to synthesize liver cell adhesion molecule (LCAM; also called E cad have been identified (Song and Yosypiv 2012). The genetic, epigenetic
herin) and the basal lamina constituents, laminin and collagen IV. The and in utero environmental factors in the pathogenesis of nonsyndromic
mesenchymal clusters are thus converted to small groups of epithelial forms of human congenital anomalies of the kidney and urinary tract
cells, which undergo complex morphogenetic changes. Each epithelial (CAKUT) have been considered (Yosypiv 2012).
group elongates, and forms first a commashaped, then an Sshaped, Plateletderived growth factor (PDGF) βchain and the PDGF recep
body, which continues to elongate and subsequently fuses with a branch tor βsubunit (PDGFR β) have been detected in developing human
of the ureteric duct at its distal end, while expanding as a dilated sac at glomeruli between 54 and 109 days’ gestation. PDGF βchain is local
its proximal end (see Fig. 72.5). The latter involutes, and cells differenti ized in the differentiating epithelium of the glomerular vesicle during
ate locally such that the outer cells become the parietal glomerular cells, its comma and Sshaped stages, while PDGFR β is expressed in the
while the inner ones become visceral epithelial podocytes. The podo undifferentiated metanephric blastema, vascular structures and intersti
cytes develop in close proximity to invading capillaries derived from tial cells. Both PDGF βchain and PDGFR β are expressed by mesangial
angiogenic mesenchyme outside the nephrogenic mesenchyme. This cells, which may promote further mesangial cell proliferation.
third source of mesenchyme produces the endothelial and mesangial Metanephric mesenchyme will develop successfully in vitro, which
cells within the glomerulus. The (metanephricderived) podocytes and makes experimental perturbation of kidney development comparatively


urinary system
1203
27
retPahC
A
Metanephric
mesenchyme
Mesonephric
duct
Expansion of the
first six divisions
produces the
Ureteric bud branches renal pelvis,
Ureteric bud dichotomously into the major and
metanephric mesenchyme minor calyces
B C
Metanephric mesenchyme Branching collecting
proliferates and separates ducts and proliferating
with the branching of the duct metanephric mesenchyme
Metanephric
mesenchyme
locally converts
to epithelia
at the sides Collecting duct
of the duct from ureteric bud
Comma- and S-shaped
metanephric vesicles
Metanephric epithelium
forms comma-shaped
vesicles
Branches from
the collecting
duct elongate Fully formed
metanephric
nephrons joined
to collecting ducts
Fully formed
metanephric
nephrons join to
Metanephric vesicles the collecting duct
become S-shaped
and elongate
Elongated loop
of Henle
Fig. 72.5 An overview of metanephric kidney development. A, The ureteric bud arises from the mesonephric duct. The metanephric mesenchyme
proliferates and separates with each subdivision of the ureteric bud. B, The metanephric mesenchyme converts to epithelia, forming comma- and
S-shaped vesicles, which become metanephric nephrons. C, All stages of metanephric development are present concurrently. The most recently formed
nephrons are on the outer aspect of the kidney.
easy to evaluate. Early experimental studies demonstrated that other greater values for renal volume than female fetuses from the third tri
mesenchymal populations, and spinal cord, were able to induce ureteric mester onwards. Kidney weight is lower in infants with a birth weight
bud division and metanephric development. Nerves enter the develop less than −2 SDs for gestational age, reflecting a decreased number of
ing kidney very early, travelling along the developing ureter. If develop nephrons. This relative smaller kidney size continues into early child


ing kidney rudiments are incubated with antisense oligonucleotides, hood and may be a factor in adult kidney pathology (Geelhoed et al
which neutralize nerve growth factor receptor (NGFR) mRNA, neph 2009).
rogenesis is completely blocked, suggesting that metanephric mesen
chyme induction is a response to innervation. The powerful inductive endocrine development of the kidney
effect of the spinal cord on metanephric mesenchyme may be a further The kidney functions not only as an excretory organ, but also as an
expression of this phenomenon. All stages of nephron differentiation endocrine organ, secreting hormones that are concerned with renal
are present concurrently in the developing metanephric kidney (see Fig. haemodynamics. Before birth, homeostasis is controlled by the pla
72.5). Antigens for the brush border of the renal tubule appear when centa. The fetal kidney produces amniotic fluid. The kidneys of pre
the Sshaped body has formed. They appear first in the inner cortical mature babies of less than 36 weeks are immature. They contain
area. The metanephric kidney is lobulated throughout fetal life, but incompletely differentiated cortical nephrons, which compromise their
this condition usually disappears during the first year after birth (see ability to maintain homeostasis. Problems of immaturity are further
Fig. 72.8). Varying degrees of lobulation occasionally persist through compounded by the effects of hypoxia and asphyxia, which modify
out life. renal hormones.
The growth of left and right kidneys is well matched during develop Renal hormones include the renin–angiotensin system, renal pros
ment. Fetal kidney volume increases most during the second trimester taglandins, the kallikrein–kinin system and renal dopamine. Renin is
in both sexes. For reasons that are not understood, male fetuses show found in the smooth muscle cells of arterioles, interlobular arteries and


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A B C
Allantois
Mesonephric duct
Urogenital sinus Ureteric bud
Early ureter
The mesonephric ducts and ureters The ureters open directly and separately into the urogenital
enlarge as they enter the urogenital sinus above the mesonephric ducts. The openings of the
sinus. They become absorbed into mesonephric ducts descend; their walls are incorporated
the posterior wall of the sinus into the urogenital sinus, forming the trigone of the bladder
D E
Urachus
Urinary bladder
Ureter
Ureteric opening
Region of trigone
Region of trigone
Uterovaginal duct
from fused Mesonephric duct
paramesonephric
duct
Urethra
In the female the fused paramesonephric In the male the mesonephric ducts
ducts form the uterovaginal duct. form the vasa deferentia and ejaculatory ducts,
The mesonephric ducts degenerate which enter the urethra through the prostate gland
Fig. 72.6 The development of the urinary part of the urogenital sinus and formation of the trigone of the bladder. A–C, E, Posterior views. D, Male and
female, median sagittal sections. (Based on Tuchmann-Duplessis H, Haegel P 1972 Illustrated Human Embryology, Vol 2 Organogenesis. London:
Chapman and Hall. With kind permission of Springer Science+Business Media.)
branches of the renal artery, and has also been described in the distal ureter
convoluted tubule cells. Kallikrein has been demonstrated in rat fetal The wall of the early ureter is initially highly permeable. Its lumen later
kidney, and prostaglandins have been demonstrated in the renal becomes obliterated and is subsequently recanalized. Both of these
medulla and renal tubule. Renal dopamine is produced (mainly) by the processes begin in intermediate portions of the ureter and proceed
enzymatic conversion of Ldopa to dopamine in the early segments of cranially and caudally. Recanalization is not associated with metane


the proximal convoluted tubule, and is also sourced locally from phric function, but perhaps reflects the rapid elongation of the ureter
dopaminergic nerves. Other renal hormones include an antihyperten as the embryo grows. Two fusiform enlargements appear at the lumbar
sive lipid, which is produced in the interstitial cells of the renal medulla, and pelvic levels of the ureter at 5 and 9 months, respectively (the pelvic
and, possibly, histamine and serotonin. Growth factors produced by enlargement is inconstant). As a result, the ureter shows a constriction
human embryonic kidney cells include erythropoietin and interleukin at its proximal end (pelviureteric region) and another as it crosses the
β (which stimulate megakaryocyte maturation) and transforming pelvic brim. A third narrowing is always present at its distal end and is
growth factorβ. related to the growth of the bladder wall.
At first, the distal end of the ureter is connected to the dorsomedial
ascent of the kidney aspect of the mesonephric duct but, as a result of differential growth,
The metanephric kidney is initially sacral. As the ureteric outgrowth this connection comes to lie lateral to the duct.
lengthens, it becomes positioned more and more cranially. The
metanephric pelvis lies on a level with the second lumbar vertebra urinary bladder
when the embryo reaches a length of about 13 mm. During this period The urinary bladder develops from the cranial vesicourethral canal,
the ascending kidney receives its blood supply sequentially from arter which is continuous above with the allantoic duct (see Fig. 72.4; Figs
ies in its immediate neighbourhood, i.e. the middle sacral and 72.6, 72.7). The mesonephric ducts open into the urogenital sinus early
common iliac arteries. The definitive renal artery is not recognizable in development. The ureters develop as branches of the mesonephric
until the beginning of the third month. It arises from the most caudal ducts, which attain their own access to the developing bladder, and their
of the three suprarenal arteries, all of which represent persistent meso orifices open separately into the bladder on the lateral side of the


nephric or lateral splanchnic arteries. Additional renal arteries are opening of the mesonephric ducts. Later, the two orifices become sepa
relatively common, and may enter at the hilum or at the upper or rated still further and, although the ureter retains its point of entry into
lower pole of the gland – they also represent persistent mesonephric the bladder, the mesonephric duct opens into that part of the urogenital
arteries. sinus that subsequently becomes the prostatic urethra (see Fig. 72.6E).


urinary system
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A Urorectal septum B Allantoic duct
Mesonephric
duct
Umbilical artery
Metanephric
Hindgut
Allantoic duct (ureteric)
Bladder diverticulum
Notochord
Enteric hindgut
Spinal cord
Cloaca, showing
Cloacal membrane ridge produced by
urorectal septum
Endodermal cloaca
Postanal gut
Postanal gut
C Allantoic duct Mesonephric ducts D
Metanephric diverticulum (ureteric bud)
Umbilical vessels
Enteric hindgut Mesonephric duct
Urorectal septum
Ureter
Peritoneum Pelvis of ureter
Allantoic duct
Bladder
Genital tubercle
Endodermal cloaca
Cloacal membrane
Umbilical
cord
Postanal gut Notochord Tail Future rectum Notochord
Endodermal cloaca Spinal cord Spinal cord
E Fused paramesonephric ducts Colon F
Mesonephric duct Ureter
Centrum of vertebra
Allantoic duct
Pubic symphysis
Urinary bladder Bladder Mesonephric
ducts
Lower limb Ureter
Fused
paramesonephric
ducts
Glans clitoridis
Phallic portion of
urogenital sinus
Spinal cord
Proctodeum
Pelvic portion of Notochord
urogenital sinus Sinus tubercle
Rectum
Fig. 72.7 A, The caudal end of a human embryo, 4 weeks, showing the left lateral aspects of the spinal cord, notochord and endodermal cloaca. B, The
endodermal cloaca of a human embryo, near the end of the fifth week. Part of the left wall of the cloaca, including the left mesonephric duct, has been
removed, together with the adjoining portions of the walls of the developing bladder and rectum. A piece of the ectoderm around the cloacal membrane
has been left in situ. A wire is shown passing along the right mesonephric duct into the cloaca. C, The caudal end of a human embryo, 5 weeks, showing


the endodermal cloaca. D, The caudal end of a human embryo, 6 weeks. The cloaca is becoming divided by the urorectal septum. E, The caudal end of
a female human fetus, 81–9 weeks, from the left-hand side, showing structures in and near the median plane. The cloaca is now completely divided into
2
urogenital and intestinal segments. F, Part of the vesico-urethral portion of the endodermal cloaca of a female human fetus, 81–9 weeks. The sinus
2
tubercle is the elevation on the posterior wall of the urogenital sinus, caused by the fusion with the paramesonephric ducts.


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The remainder of the vesicourethral canal forms the body of the
Right inferior phrenic Inferior vena cava
bladder and urethra, and its apex is prolonged to the umbilicus as a vein and artery
narrow canal, the urachus.
For many years, it was believed that the absorption of the mesone
phric ducts into the urogenital sinus contributed a mesodermal epithe Left suprarenal
lium into the endodermal bladder, limited to the trigone and the dorsal Right suprarenal gland
gland
wall of the proximal half of the prostatic urethra to the opening of the
Coeliac trunk
prostatic utricle and ejaculatory ducts, or its female homologue, the
Superior mesenteric
whole female urethral dorsal wall. Antibody labelling and studies on Right kidney artery
transgenic mice have now demonstrated that the region of the com
bined ducts close to the urogenital sinus, referred to as the common Right renal vein Left renal vein
and artery
nephric duct, undergoes local apoptosis as a part of the normal develop Left kidney
ment of the trigone region of the bladder and the establishment of
Inferior mesenteric
separate entry points for the ureters and mesonephric ducts (Mendel artery
Right ureter
sohn 2009). Retinoic acid is required for ureter insertion into the uro
Abdominal aorta
genital sinus (Batourina et al 2005). There is no mesodermal epithelial
Left ureter
contribution to the bladder at the trigone. This is further supported by
Right gonadal artery
the observations that tissue combination of fetal urogenital sinus mes
and vein
enchyme with epithelial mesoderm or endoderm produces different
outcomes. Tissue recombinant with endoderm gives rise to prostatic
epithelium, whereas the same mesenchyme combined with epithelial Rectum
mesoderm forms seminal vesicle epithelium. Trigone epithelium dif
ferentiates into prostatic epithelium, confirming an endoderm lineage Bladder deflected
Right umbilical artery downwards
(Tanaka et al 2010).


The previous mechanism for trigone development also suggested
Fig. 72.8 The posterior abdominal wall of a full-term neonate. Note the
that the muscle in that region derived from the ureter and contributed
lobulated kidneys and relatively wide calibre of the ureters.
to the valvelike entry point that prevents urinary reflux. Studies have
now shown that the ureter passes through a tunnel in the bladder wall
in parallel with blood vessels. Such a tunnel forms even in the absence
of ureters (Viana et al 2007). Study of smooth muscle progenitors present at birth (Fig. 72.8; see Fig. 14.6C). Addition of new cortical
shows that the bulk of the trigone derives from bladder muscle (detru nephrons continues in the first few months of postnatal life, after which
sor), with a limited contribution from ureteral longitudinal smooth general growth of the glomeruli and tubules results in the disappear
muscle fibres at the lateral edges. Eponymous muscle such as Mercier’s ance of lobulation. The renal blood flow is lower in the neonate; adult
bar and Bell’s muscle, which were thought to arise from the ureter, are values are attained by the end of the first year. The glomerular filtration
derived from bladder muscle (Viana et al 2007). rate at birth is approximately 30% of the adult value, which is attained
Bladder filling and emptying cycles are required for normal bladder by 3–5 months of age.
remodelling during fetal development; in this process, detrusor smooth The neonatal urinary bladder is eggshaped and the larger end is
muscle cells undergo cyclical apoptosis and proliferation. Mechanical directed downwards and backwards (Figs 72.9–72.10; see Figs 14.6B–
stretching promotes proliferation. Bladders in which the fluid is 14.7). Although described as an abdominal organ, nearly onehalf of
diverted do not show this cycle, and do not enlarge or undergo normal the neonatal bladder lies below a line drawn from the promontory of
remodelling; the detrusor stops growing, producing a lowvolume, low the sacrum to the upper edge of the pubic symphysis, i.e. within the


compliance bladder, although the serosal connective tissues continue cavity of the true pelvis. From the bladder neck, the bladder extends
to expand (Wei et al 2012). As yet, there is little information on the anteriorly and slightly upwards in close contact with the pubis, until it
development of bladder interstitial cells of Cajal, which are present reaches the anterior abdominal wall. The apex of the contracted bladder
within detrusor, bladder microvessels and the mucosal lamina propria lies at a point midway between the pubis and the umbilicus. When the
(Johnston et al 2010). bladder is filled with urine, the apex may extend up to the level of the
umbilicus. It is therefore possible to obtain urine by inserting a needle,
Ultrasound antenatal imaging of the
connected to a syringe, into the bladder through the abdominal wall
urinary system about 2 cm above the pubic symphysis, and then aspirating the con
The fetal bladder may be identified by ultrasound examination at 9–11 tents into the sterile syringe. The success rate of the procedure is variable
weeks’ gestation in transverse and sagittal section. Filling and emptying and depends on the bladder being full; a much higher success rate has
over a 30–45 minute cycle can be demonstrated. The absence of a been reported by using an ultrasound scanner to locate the bladder and
bladder image at 13 weeks or later is considered abnormal. At 20 weeks, confirm that it contains urine prior to insertion of the needle.
the kidneys are best visualized in a section of the abdomen caudal to There is no true fundus in the fetal bladder as there is in the adult.
that used for abdominal circumference estimation. The diameter of the Although the anterior surface is not covered with peritoneum, perito
renal pelvis is reported in the anterior posterior view; 7 mm or less is neum extends posteriorly as low as the level of the urethral orifice.
considered normal at midgestation (To and Periera 2015). Because the apex of the bladder is relatively high, pressure on the lower
The routine use of ultrasound as an aid to in utero diagnosis of abdominal wall will express urine from an infant bladder. Moreover,
abnormalities has revealed a prevalence of 1–2 abnormal fetuses per because the bladder remains connected to the umbilicus by the obliter


1000 ultrasound procedures, of which 20–30% are anomalies of the ated remains of the urachus (see Fig. 14.7), stimulation of the umbilicus
genitourinary tract, detectable as early as 12–15 weeks’ gestation. The can initiate micturition in babies. The elongated shape of the bladder
decision to be made after such a finding is by no means clear. Urinary in neonates means that the ureters are correspondingly reduced in
obstruction is considered an abnormality, yet transient modest obstruc length and they lack a pelvic portion. The bladder does not gain its
tion is considered normal during canalization of the urinary tract, and adult, pelvic, position until about the sixth year. A distinct interureteric
has been reported in 10–20% of fetuses in the third trimester. A delay fold is present in the contracted neonatal bladder.
in canalization, or in the rupture of the cloacal membrane, can produce
Anomalies of the urinary system
a dilation. Similarly, the closure of the urachus at 32 weeks may be
associated with highresistance outflow for the system, which again Congenital anomalies of the kidney and urinary tract are relatively
produces transient obstruction. Distension of the fetal bladder, which common (3–6% of live births) (Yosypiv 2012). Renal agenesis is the
may indicate lower urinary tract obstruction, affects 2.2/10,000 births, absence of one or both kidneys. In unilateral renal agenesis, the remain
more commonly in males (Hodges et al 2009, Dias et al 2014). Over ing kidney exhibits compensatory hypertrophy and produces a nearly
half of such cases are caused by the development of posterior urethral normal functional mass of renal tissue. Atresia of the ureter during
valves (a congenitally obstructing posterior urethral membrane); there development causes a nonfunctional multicystic dysplastic kidney,
may also be a dilated posterior urethra and thickened bladder wall. thought to be secondary to urinary obstruction being present while the
tubules are still forming. Problems with kidney ascent can result in a
Neonatal urinary system
pelvic kidney. Alternatively, the kidneys may fuse together at their


At fullterm parturition, the two kidneys weigh approximately 23 g. caudal poles, producing a horseshoe kidney, which cannot ascend out
They function early in development and produce the amniotic fluid that of the pelvic cavity because the inferior mesenteric artery prevents
surrounds the fetus. The lobulated appearance of fetal kidneys is still further migration. A duplex kidney arises when two ureteric buds meet


urinary system
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Fimbriated end of uterine tube Suspensory ligament of ovary
Inferior epigastric artery
and vein
Mass of meconium Median umbilical ligament
Round ligament of uterus
Sacrum
Urinary bladder
Fundus of uterus
Left ovary
Vesico-uterine pouch
Body of uterus
Vaginal fornices
Pubic symphysis
Suspensory ligament of clitoris
Recto-uterine pouch
Body and glans of clitoris
Coccyx
Sphincter urethrae
Levator ani Urethra
External anal sphincter Longitudinal vaginal
columns
Deep transverse
perineal muscle
Anus Anal columns External anal
of anal canal sphincter
Fig. 72.9 A midsagittal section through the pelvis of a full-term female neonate. Note the abdominal position of the urinary bladder and uterus. (After
Crelin ES 1969 Anatomy of the Newborn. Philadelphia: Lea and Febiger.)
Ossification centre of
Superior rectal artery Left hypogastric nerve
first vertebral segment
of sacrum Left ureter Rectovesical pouch
Ileum
Sacral canal Median umbilical ligament
Dorsal sacral
Apex of urinary bladder
foramina
Body of bladder
Fundus of bladder
Pelvic sacral
foramina Ampulla of vas deferens
Ejaculatory duct
Retropubic space
Prostate gland
Prostatic part of urethra
Suspensory ligament of penis
Rectovesical septum
Corpus cavernosum
Coccyx
Glans
Levator ani
External anal sphincter
Internal anal sphincter
Corpus spongiosum and
spongiose part of urethra
Bulbospongiosus
Anal column of anal canal
External spermatic fascia
Anal valve enclosing left testis
Dartos tunic of scrotum
Membranous part Bulb
Remains of gubernaculum testis and tail
of urethra
of epididymis within external spermatic fascia
Fig. 72.10 A midsagittal section through the pelvis of a full-term male neonate. Note the abdominal position of the urinary bladder. (After Crelin ES 1969


Anatomy of the Newborn. Philadelphia: Lea and Febiger.)


DeveloPment of the urogenital system
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Umbilical cord
Genital
tubercle
Urogenital
membrane
Urogenital
swellings
Urogenital
Anal membrane
membrane
Genital
tubercle
Anal membrane
Normal Exstrophy of the bladder and epispadias
Fig. 72.11 Bladder exstrophy. Misalignment of the genital tubercle and urogenital swellings with the urogenital membrane during early development
results in subsequent malposition of the bladder, urethra and associated sphincters. The disappearance of the urogenital membrane exposes the
posterior wall of the bladder, and the urethral opening is on the superior side of the penis or clitoris. (Redrawn from Tuchmann-Duplessis H, Haegel P
1972 Illustrated Human Embryology, Vol 2 Organogenesis. London: Chapman and Hall. With kind permission of Springer Science+Business Media.)
the metanephros; it is characterized by two pelvicalyceal systems and is germ cells are delineated very early in development, they are seques
associated with ureterocele, ectopic insertion of the ureter, and vesico tered in the extraembryonic tissues until the gonadal ridge is ready to
ureteric reflux. receive them. It was thought that development to one or other sexual
It was thought that renal cysts arose from clumps of vesicular cells, phenotype occurred after migration of the primordial germ cells to the
which persisted when the tips of branches from the ureteric diverticu indifferent gonads. However, it is now recognized that the development
lum failed to fuse with metanephrogenic cap tissue. It is now believed of male or female gonads, genital ducts and external genitalia is far
that they are wide dilations of a part of otherwise continuous nephrons. more complicated, and is the result of a complex interplay between
In most cases, autosomal dominant polycystic kidney disease results genetic expression, timing of development and the influence of sex
from mutations of PKD1 or PKD2 genes, which are expressed in human hormones. As development proceeds, a significant proportion of early
embryos from 5–6 weeks of development within the mesonephros embryonic urinary tissue is incorporated into the reproductive tracts,


and later the metanephros (Chauvet et al 2002). In this condition, especially in the male. The earliest stage of reproductive development,
the cystic dilation may affect any part of the nephron, from Bowman’s prior to the arrival of the primordial germ cells into the gonad, is termed
capsule to collecting tubules. Less common is infantile cystic renal the indifferent or ambisexual stage.
disease, inherited as a recessive trait, in which the proximal and distal
Early gonadal development (ambisexual or
tubules are dilated to some degree but the collecting ducts are grossly
affected. indifferent stage)
There is evidence that infants born small for gestational date retain Essentially, four different cell lineages contribute to the gonads. Cells
smaller kidneys throughout childhood. A causal relationship between are derived from: proliferating coelomic epithelium on the medial side
low birth weight and later chronic kidney disease is speculated, as well of the mesonephros; underlying mesonephric mesenchyme; invading
as susceptibility to hypertension in adult life (White et al 2009). angiogenic mesenchyme already present in the mesonephros; and
Anomalies of the ventral body wall caudal to the umbilicus, espe primordial germ cells that arise from the epiblast very early in develop
cially with inappropriate siting of the genital tubercle, can result in ment and later migrate from the allantoic wall.
exstrophy of the bladder (Fig. 72.11) (Suzuki et al 2009, Williams The formation of the gonads is first indicated by the appearance of
2013). In this condition, the urorectal septum (internal) is associated an area of thickened coelomic epithelium on the medial side of the
with the genital tubercle (external), which means that the urogenital mesonephric ridge in the fifth week, stage 16 (Figs 72.12–72.13; see
and anal membranes are widely separated. When the urogenital mem Fig. 72.16). Elsewhere on the surface of the ridge, the coelomic epithe
brane involutes, the posterior surface of the bladder is exposed to the lium is one or two cells thick, but over this gonadal area it becomes


anterior abdominal wall. The lower part of the abdominal wall is, multilayered. Thickening rapidly extends in a longitudinal direction
therefore, occupied by an irregularly oval area, covered with mucous until it covers nearly the whole of the medial surface of the ridge. The
membrane, on which the two ureters open. The periphery of this extro thickened epithelium continues to proliferate, displacing the renal cor
verted area, which is covered by urothelium, becomes continuous with puscles of the mesonephros in a dorsolateral direction, and forms a
the skin. projection into the coelomic cavity: the gonadal ridge. Surface depres
The volume of amniotic fluid is used as an indicator of renal func sions form along the limits of the ridge, which is, thus, connected to
tion but, because other sources produce amniotic fluid in early gesta the mesonephros by a broad mesentery, the mesogenitale. In this way,
tion, amniotic volume does not reflect fetal urinary output until the the mesonephric ridge becomes subdivided into a lateral part – the
second trimester (see p. 179). Too little amniotic fluid is termed oligo tubal fold, containing the mesonephric and paramesonephric ducts,
hydramnios; too much, polyhydramnios. Although variation in the and a medial part – the gonadal fold. The tubal fold also contains the
amount of amniotic fluid may suggest anomalies of either the gut or nephric tubules and glomeruli at its base (see Fig. 72.3).
the kidneys, it is not always possible to correlate even severe oligohy Up to the seventh week, the ambisexual gonad possesses no sexually
dramnios with renal dysfunction. There is an important relationship differentiating feature. From stage 16, the proliferating coelomic epithe
between the volume of amniotic fluid, lung development and maturity, lium forms a number of cellular epithelial cords (sometimes called
and oligohydramnios has been shown to be associated with pulmonary primary sex cords), separated by mesenchyme. The cords remain at
hypoplasia (Ch. 52). the periphery of the primordium and form a cortex. Proliferation and


labyrinthine cellular condensation of the mesonephric mesenchyme,
including angiogenic mesenchyme, produce a central medulla.
REPRODUCTIVE SYSTEM
Reproductive ducts
Development of the reproductive organs from the intermediate mesen The paramesonephric, Müllerian, ducts develop in embryos of both
chyme starts from stage 14, about 10 days later than the urinary system. sexes, but become dominant in the development of the female repro
Bilateral paramesonephric (Müllerian) ducts develop alongside the ductive system. They are not detectable until the embryo reaches a
mesonephric ducts, and the midportion of each mesonephros under length of 10–12 mm (early sixth week). Each begins as a linear invagi
goes thickening to form the gonadal ridge. Although the primordial nation of the coelomic epithelium, the paramesonephric groove, on the


reproductive system
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A B
Amniotic cavity
Amnion
Neural tube Somite
Notochord
Mesonephros
Mesonephric duct
Gonad
X Y
Gonad Paramesonephric
(Müllerian) duct
Mesonephros
Midgut
Midgut
Mesonephric duct Intraembryonic
Metanephros coelom
Allantois Yolk sac
Fig. 72.12 A, The position of the gonads on the posterior abdominal wall, anteromedial to the mesonephros. B, A transverse section of figure A, through
the line X–Y.
A
Mesonephros
Mesonephric nephrons Proliferating coelom epithelium
Paramesonephric (Müllerian) duct
Mesonephric duct
B Appendix epididymis C
Gubernaculum
Tunica albuginea
Appendix testis
Efferent
ductules Testis Urogenital sinus Ovary
Epididymis
Uterine tube
Epoophoron
Vas deferens
Gubernaculum ovarii Uterus
Seminal vesicle
Gartner’s duct
Gubernaculum
testis Utricle of prostate
Cervix
Fig. 72.13 A, The indifferent or ambisexual stage of development. B, Male. The mesonephric ducts are retained (left) and the paramesonephric ducts
involute (right). C, Female. The paramesonephric (Müllerian) ducts are retained (right) and the mesonephric ducts involute (left).
lateral aspect of the mesonephric ridge near its cranial end. The blind caudal end of the mesonephros in the eighth week. It turns medially
caudal end continues to grow caudally into the substance of the ridge and crosses ventral to the mesonephric duct to enter the genital cord,
as a solid rod of cells, which becomes canalized as it lengthens. Through where it bends caudally in close apposition with its fellow from the


out the extent of the mesonephros, it is lateral to the mesonephric duct, opposite side (see Fig. 72.13). The two ducts reach the dorsal wall of
which acts as a guide for it. The paramesonephric duct reaches the the urogenital sinus during the third month, and their blind ends


DeveloPment of the urogenital system
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produce an elevation called the Müllerian or sinus tubercle (see Figs defined as the cranial end of the mesonephros degenerates. The caudal
72.7F, 72.19). vertical parts of the two ducts fuse with each other to form the utero
At the end of the indifferent stage, each paramesonephric duct con vaginal primordium (Fig. 72.14). This gives rise to the lower part of the
sists of vertical cranial and caudal parts and an intermediate horizontal uterus, and, as it enlarges, it takes in the horizontal parts to form the
region. The mesonephric ducts course caudally, medial to the parameso fundus and most of the body of the adult uterus. A constriction between
nephric ducts, and both duct systems open into the urogenital sinus. the body of the uterus and the cervix can be found at 9 weeks. The
The genital ducts possess an external serosa on some surfaces, derived stroma of the endometrium and the uterine musculature develop from
from coelomic epithelium; a smooth muscle muscularis, derived from the surrounding mesenchyme of the genital cord.
underlying mesenchyme; and an internal mucosa, derived either from Failure of fusion of the two paramesonephric ducts can lead to a
the mesonephric duct or from the invaginated tube of coelomic epithe range of anomalies summarized in Figure 72.15. These fusions can also
lium that forms the paramesonephic duct. The layers are invaded by contribute to anomalies of vaginal development.
angiogenic mesenchyme and by nerves. At birth, the uterus is 2.5–5 cm long (average 3.5 cm), 2 cm wide
between the uterine tubes, and a little over 1 cm thick (see Figs 72.9,
uterus and uterine tubes 14.6C–14.7). The body of the uterus is smaller than the uterine cervix,
In the female, the mesonephric duct is vestigial. Cranially, it becomes which forms twothirds or more of the length. The isthmus between the


the longitudinal duct of the epoophoron, while, caudally, it is referred body and the cervix is absent. The fetal female reproductive tract is
to as Gartner’s duct (Table 72.1). The cranial part of the paramesone affected by maternal hormones and undergoes some enlargement in
phric ducts forms the uterine tubes, and the original coelomic invagina the fetus. The endocervical glands are active before birth and the cervical
tion remains as the pelvic opening of the tube. The fimbriae become canal is usually filled with mucus. The uterus is relatively large at birth
and, subsequently, involutes to about onethird of its length and more
than half of its weight; it does not regain its neonatal size and weight
Table 72.1 Homologies of the parts of the urogenital system in male and female until puberty. The uterine tubes are relatively short and wide.
The position of the uterus in the pelvic cavity depends, to a great
Gonad Testis Ovary
extent, on the state of the bladder anteriorly and the rectum posteriorly.
Gubernacular cord Gubernaculum testis Ovarian and round ligaments If the bladder contains only a small amount of urine, the uterus may
Mesonephros Appendix epididymis (?) Appendices vesiculosae (?) be anteverted but it is often in a direct line with the vagina (see Figs
(Wolffian body) Efferent ductules Epoophoron 72.9, 72.19).
Lobules of epididymis
Paradidymis Paroophoron vagina
Aberrant ductules
At approximately 60 mm crown–rump (CR) length, an epithelial pro
Mesonephric duct Duct of epididymis Duct of epoophoron (Gartner’s duct)
(Wolffian duct) Vas deferens liferation, the sinuvaginal bulb, arises from the dorsal wall of the uro
Ejaculatory duct genital sinus in the region of the sinus tubercle (see Figs 72.7F, 72.14B).
Part of bladder and prostatic Part of bladder and urethra Its origin marks the site of the future hymen. The proliferation gradually
urethra
extends cranially as a solid, anteroposteriorly flattened plate inside the


Paramesonephric Appendix testis Uterine tube tubular condensation of the uterovaginal primordium, which will,
(Müllerian) duct Uterus
eventually, become the fibromuscular vaginal wall. The caudal tip of
Prostatic utricle Vagina (?)
the paramesonephric duct epithelium recedes until, at about 140 mm
Allantoic duct Urachus Urachus
(CR), its junction with the epithelial proliferation lies in the cervical
Cloaca:
canal.
Dorsal part Rectum and upper part of anal Rectum and upper part of anal
canal canal Starting from its caudal end and gradually extending cranially
Ventral part Most of bladder Most of bladder and urethra through its whole extent, the solid plate formed by the sinus prolifera
Part of prostatic urethra tion enlarges into a cylindrical structure. After this, the central cells
Urogenital sinus Prostatic urethra distal to desquamate to establish the vaginal lumen. As the upper end of the
utricle vaginal plate enlarges, it grows up to embrace the cervix, and then is
Bulbourethral glands Greater vestibular glands
excavated to produce the vaginal fornices. The boundary of origin of
Rest of urethra to glans Vestibule
the vaginal mucosa, between the epithelial contribution of the para
Genital folds Ventral penis Labia minora
mesonephric ducts and the sinuvaginal bulb, has been defined in the
Genital tubercle Penis Clitoris
mouse (Kurita 2010, Kurita 2011). Anomalies of paramesonephric duct
Urethra in glans
fusion can produce related vaginal anomalies (see Fig. 72.15). The
A B
Urachus Uterine tube
Broad ligament
Mesonephric kidney Uterovaginal canal
and gonad descend
Bladder
Ureter
Sinuvaginal tubercle
Allantois
Recto-uterine
Metanephric pouch (of Douglas) Rectum
Urogenital sinus kidney ascends
Gubernaculum
Fig. 72.14 Relative movements of the gonads and associated tubes. A, Gonads and mesonephros move caudally, and the metanephros ascends. B, A


posterior view of the mesonephric ducts (ureters) and the fused paramesonephric ducts (uterovaginal canal) in the female. For earlier development, see
Figure 72.3. (Based on Tuchmann-Duplessis H, Haegel P 1972 Illustrated Human Embryology, Vol 2 Organogenesis. London: Chapman and Hall. With
kind permission of Springer Science+Business Media.)


reproductive system
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Partial or total failure of fusion of the terminal portion of the paramesonephric (Müllerian) ducts and also that, once the epithelial cells no longer secrete a basal lamina,
the remaining ductal epithelial cells transform into mesenchyme that
remains in the vicinity of the involuting duct (Allard et al 2000). Ves
tigial remnants of the paramesonephric ducts are most likely to persist
cranially and/or caudally, at the limits of the local exocrine effects of
AMH. A vestige of the cranial end of the duct persists as the appendix
testis (see Figs 72.13, 72.19; see Table 72.1). The fused caudal ends of
the two ducts are connected to the wall of the urogenital sinus by a
solid utricular cord of cells, which soon merges with a proliferation of
sinus epithelium, the sinuutricular cord. The latter is similar to, but
less extensive than, the sinus proliferation in the female. The proliferat
ing epithelium is claimed to be an intermingling of the endoderm of
Uterus didelphyd Bicervical uterus Unicervical uterus
with double vagina bicornis bicornis the urogenital sinus with the lining epithelia of the mesonephric and
paramesonephric ducts, which have extended on to the surface of the
Failure of resorption of the uterovaginal septum after fusion of the paramesonephric (Müllerian) ducts sinus tubercle. As the sinuutricular cord grows, so the utricular cord
recedes from the tubercle. In the second half of fetal life, the composite
cord acquires a lumen and becomes dilated to form the prostatic utricle,
the lining of which consists of hyperplastic stratified squamous epithe
lium. The sinus tubercle becomes the colliculus seminalis.
The main reproductive ducts in the male are derived from the meso
nephric ducts; the latter persist under the action of androgens that are
probably secreted down the ducts themselves, and are subsumed into
the male reproductive system as the metanephric kidney develops. The


mesonephric duct gives rise to the canal of the epididymis, vas deferens
and ejaculatory duct. The seminal vesicle and the ampulla of the vas
deferens appear as a common swelling at the end of the mesonephric
Completely Bilocular Bilocular
duct during the end of the third and into the fourth months. Their
bilocular uterus unicervical uterus bicervical uterus
appearance coincides with degeneration of the paramesonephric ducts,
although no causal relation between the two events has been estab
Partial or total atresia of the terminal portion of one or both paramesonephric (Müllerian) ducts
lished. Separation into two rudiments occurs at about 125 mm crown–
heel length. The seminal vesicle elongates, its duct is delineated and
hollow diverticula bud from its wall. Around the sixth month (300 mm
crown–heel length), the growth rate of both vesicle and ampulla is
greatly increased. Figure 72.10 shows the position of the ampulla of the
vas deferens in the neonate, possibly in response to increased secretion
of prolactin by the fetal or maternal hypophysis, or to the effects of
placental hormones. The tubules of the prostate show a similar increase
in growth rate at this time.
Primordial germ cells
Unilateral atresia Partial bilateral atresia: Partial bilateral atresia:
The primordial germ cells are formed very early from the epiblast (see
uterus bicornis unicollis atresia of cervix atresia of vagina
Fig. 10.3). They are larger (12–20 µm in diameter) than most somatic
Fig. 72.15 Uterovaginal anomalies. (Based on Tuchmann-Duplessis H, cells, and are characterized by vesicular nuclei with welldefined nuclear
Haegel P 1972 Illustrated Human Embryology, Vol 2 Organogenesis. membranes, and by a tendency to retain yolk inclusions long after these
London: Chapman and Hall. With kind permission of Springer
have disappeared from somatic cells. It is not yet clear whether the
Science+Business Media.)
primordial germ cells are derived from particular blastomeres during
cleavage, if they constitute a clonal line from a single blastomere, or if


they are the product of a progressive concentration of the nucleus of
the fertilized ovum by unequal partition at successive mitoses. Primor
urogenital sinus undergoes relative shortening craniocaudally to form dial germ cells spend the early stages of development within the extra
the vestibule, which opens on the surface through the cleft between the embryonic tissues near the end of the primitive streak and in the
genital folds. The lower end of the vaginal plate grows caudally so that, connecting stalk (see Fig. 10.4). In this situation, they are away from
in 109 mm embryos, the vaginal rudiment approaches the vestibule. In the inductive influences to which the majority of the somatic cells are
fetuses of 162 mm, the vaginal lumen is complete, except at the cephalic subjected during early development.
end, where the fornices are still solid; they are hollow by 170 mm. At Primordial germ cells can be identified in human embryos in stage
approximately halfway through gestation (180 mm), the genital canal 11, when the number of cells is probably not more than 20–30. When
is continuous with the exterior. During the later months of fetal life, the tail fold has formed, they appear within the endoderm and the
the vaginal epithelium is greatly hypertrophied, apparently under the splanchnopleuric mesenchyme and epithelium of the hindgut, as well
influence of maternal hormones, but, after birth, it assumes the inactive as in the adjoining region of the wall of the yolk sac. They migrate
form of childhood. dorsocranially in the mesentery, by amoeboid movements and by
In the neonate, the vagina is 2.5–3.5 cm long and 1.5 cm wide at growth displacement, and pass around the dorsal angles of the coelom
the fornices, and the uterine cervix extends into the vagina for about (medial coelomic bays) to reach the genital ridges from stage 15 (see
1 cm. The posterior vaginal wall is longer than the anterior wall, giving Fig. 72.16). It is believed that the genital ridges exert longrange effects


the vagina a distinct curve (see Figs 72.9, 72.19, 14.7). The cavity is on the migrating primordial germ cells, in terms of controlling their
filled with longitudinal columns covered with a thick layer of cornified, direction of migration and supporting the primordial germcell popula
stratified, squamous epithelium. These cells slough off after birth, when tion. Primordial germ cells contact each other via long processes and
the effect exerted by maternal hormones is removed. retain cytoplasmic bridges when they divide. They are usually in close
The orifice of the vagina is surrounded by a thick, elliptical ring of proximity to somatic cells, which may modify the local environment,
connective tissue: the hymen. During childhood, the hymen becomes forming junctional complexes with them. The surface of primordial
a membranous fold along the posterior margin of the vaginal lumen. germ cells displays binding sites for extracellular matrix macromole
Should the fold form a complete diaphragm across the vaginal lumen, cules. A range of molecular markers associated with the migration and
it is termed an imperforate hymenal membrane. proliferation of primordial germ cells has been described (SotoSuazo
and Zorn 2005, Runyan et al 2006, De Felici 2013).
reproductive ducts in the male Primordial germ cells proliferate both during and after migration to
In the male, most of the paramesonephric ducts atrophy (see Fig. 72.13) the mesonephric ridges. Cells that do not complete this migration
under the influence of antiMüllerian hormone (AMH; also called mainly degenerate, but if they survive, they can give rise to germ cell
Müllerian inhibiting substance, or MIS), which is released into the tumours, usually in the midline (Runyan et al 2006). After segregation,
mesonephric duct by the Sertoli cells of the testis. It is thought that the when they are often termed primary gonocytes, they divide to form
epithelial cells of the paramesonephric duct initially undergo apoptosis secondary gonocytes.


DeveloPment of the urogenital system
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Indifferent stage
Aorta
Primordial germ cells
Lateral coelomic bay
Medial coelomic bay
Mesonephric (Wolffian) duct
Invaginating paramesonephric
Median dorsal mesentery
(Müllerian) duct
Mesonephric tubule
Gut tube
Genital ridge
Paramesonephric (Müllerian) duct
Primordial germ cells associate with sex cords
Mesonephric glomerulus
Sex cord
Female Male
Mesonephric duct
and tubules begin
to degenerate Some mesonephric
Primordial germ cells tubules fuse with
enclosed with cord cells medullary ends
Rete ovarii
of sex cords
Retrogression
Uterine tube
Mesovarium
Vestigial duct
and tubule of epoophoron Seminiferous tubules
Mesorchium
Rete ovarii Efferent ductules
Tunica albuginea
Broad ligament Ductus deferens
Interstitial cells
Uterine tube Rete testis
Degenerating Interlobular septum
Stromal cells paramesonephric
duct
Primordial ovarian follicles
Fig. 72.16 The development of the gonads and associated ducts, as seen in transverse section, to show the fate of the primordial germ cells,
mesonephric duct and tubules, and paramesonephric duct in males and females. (Modified with permission from Williams PL, Wendell-Smith CP,
Treadgold S 1969 Basic Human Embryology, 2nd edn, London, Pitman Medical & Scientific.)


reproductive system
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Development of the gonads medulla. The majority remain in the cortex, where they may be joined
by a second proliferation from the coelomic epithelium overlying the
The factors that lead to formation of either testis or ovary are described
gonad. In histological sections of ovaries from the third and subsequent
below and in Figure 72.16. The morphological events that occur in each
months, the epithelial cords appear as clusters of cells, which may
type of gonadal development are presented first.
contain primitive germ cells, separated by fine septa of undifferentiated
mesenchyme. An ovarian rete condenses in the medullary mesenchyme
testis
and some of its cords may join mesonephric glomeruli. The medulla
Most studies support the hypothesis that the seminiferous tubules are
subsequently regresses, and connective tissue and blood vessels from
formed from cords of epithelial cells derived from the proliferating
this region invade the cortex to form the ovarian stroma. During this
coelomic epithelium (see Figs 72.13, 72.16). The cords lengthen, partly
invasion, the clusters of epithelial cortical cells break into individual
by addition from the coelomic epithelium, and encroach on the
groups of supporting cells (now identified as granulosa cells), which
medulla, where they unite with a network of cells derived from the
surround the primordial germ cells (now identified as primary oocytes)
mesonephric mesenchyme destined to become the rete testis. Primor
that have entered the prophase of the first meiotic division. Primary
dial germ cells are incorporated into the cords, which later become
oocytes are derived from a mitotic division of the primordial germ cells
enlarged and canalized to form the seminiferous tubules. The cells
(naked oogonia). Their epithelial capsules consist of flattened pregranu
derived from the surface of the early gonad form the supporting Sertoli
losa cells derived from proliferations of coelomic epithelium. The ovary
cells. The latter proliferate throughout fetal and early postnatal life (less
now has its full complement of primary oocytes. The majority undergo


than 6 months) and perhaps again at puberty initiation (Sharpe et al
atresia, a hormonally controlled apoptotic process, but the remainder
2003); when they stop dividing, they mature and cannot be reactivated.
resume development after puberty, when they complete the first meiotic
Each Sertoli cell can only support a fixed number of germ cells during
division shortly before ovulation. The granulosa cells at this time
their development into spermatozoa, i.e. the number of Sertoli cells
enlarge and multiply to form the stratum granulosum; as they do so,
produced at this time determines the maximal limit of sperm output
they become surrounded by thecal cells, which differentiate from the
(Sharpe et al 2003). Because the germ cells make up the bulk of the
stroma.
adult testis, the number of Sertoli cells is a major determinant of the
There are temporospatial changes within the developing ovary. Neu
size to which the testes will grow (factors that impair the process of
rotropins and their receptors have been shown to be expressed within
spermatogenesis, resulting in the loss of germ cells, will also affect
the fetal ovary between 13 and 21 weeks. NT4 is localized initially in
testicular size). Variation in Sertoli cell number is probably the most
epithelioid cells mingled with oogonia, then within oogonial mRNA,
important factor in accounting for the enormous variation in sperm
and finally in granulosa cells of the primordial follicles, with lesser
counts between individual men, whether fertile or infertile. Indeed, the
expression in the enclosed oocytes (Anderson et al 2002).
available data for adult men indicate that Sertoli cell numbers vary
Expression of p450c17, a steroidogenic enzyme involved in the pro
across a fiftyfold range (Sharpe et al 2003). Although some of this
duction of androgens, has been shown in the human fetal ovary during
variation may result from attrition of Sertoli cell numbers because of
the second and third trimesters (Cole et al 2006). Its temporospatial
ageing, the major differences in Sertoli cell numbers will have been
expression showed a movement from the cortex to the medulla, with
determined by events in fetal and/or childhood life.


its presence in primary interstitial cells in the cortex from 14 weeks to
The interstitial cells of the testis are derived from mesenchyme and,
23 weeks, but not in hilus interstitial cells; between 27 and 33 weeks,
possibly, also from coelomic epithelial cells that do not become incor
few cells stained for p450c17, but there was an increase after 33 weeks
porated into the tubules. Among other cell lines, they form the embry
in theca interstitial cells associated with preantral follicles. Positive
onic and fetal cells of Leydig, which secrete testosterone and insulinlike
staining hilus interstitial cells were rarely seen before 33 weeks. The
factor 3 (Insl3). A later migration of mesenchyme beneath the coelomic
temporospatial expression was similar in anencephalic fetuses of the
epithelium forms the tunica albuginea of the testis.
same age, indicating that anterior pituitary function is not regulating
The cords of the rete testis become connected to the glomerular
this maturation. The authors suggest a possible role for insulin in regu
capsules in the persisting part of the mesonephros. Ultimately, they
lating fetal ovary androgen production. It is noted that overexpression
become connected to the mesonephric duct by the 5–12 most cranial
of interstitial androgen production is a component in the pathophysiol
persisting mesonephric tubules. These become exceedingly convoluted
ogy of polycystic ovary syndrome (Cole et al 2006).
and form the lobules of the head of the epididymis. The mesonephric
duct, which was the primitive ‘ureter’ of the mesonephros, becomes the sex determination in the embryo
canal of the epididymis and the vas deferens of the testis. The seminifer
It was believed that the gonads were indifferent or ambisexual until the
ous tubules do not acquire lumina until the seventh month; the tubules
arrival of the primordial germ cells in the gonadal ridge, at which point
of the testicular rete become canalized somewhat earlier.
the sex of the embryo was ‘turned on’ by the presence of the male or
Disorders of development of the testis and reproductive tract in the


female germ cells. It is now clear that the germ cells may be essentially
male fetus seem to be increasing in incidence. Testicular maldescent
irrelevant to testis determination; embryos in which the genital ridges
(cryptorchidism) and hypospadias appear to have doubled or trebled
are devoid of germ cells may still undergo otherwise normal testis
in incidence in the last 30–50 years, while testicular cancer has increased
development. It is not clear if the germ cells are necessary for ovarian
by an even greater margin and is now the most common cancer of
determination. They are required for the proper organization and dif
young men. Although testicular cancer is primarily a disease of young
ferentiation of the ovary, and their absence results in the development
men (95% of cases affect 15 to 45yearold males), it is now established
of ‘streak gonads’, where only lines of follicular cells can be seen, as in
that this age incidence reflects activation of premalignant carcinoma-in-
Turner’s syndrome.
situ (CIS) cells, which are present at birth and which almost certainly
The processes of sex determination and differentiation involve inter
arise during fetal life. It is now accepted that CIS cells are primordial
acting pathways of gene activity, which lead to the total patterning of
germ cells/gonocytes that have failed to complete differentiation into
the embryo as either male or female.
spermatogenic germ cells (RajpertDe Meyts 2006). Anomalies of devel
In the current, generally accepted, model of sex determination in
opment of the testis and reproductive tract (e.g. gonadal dysgenesis,
humans, the female pathway is considered to be the ‘setup’ programme;
cryptorchidism, small testes) are important risk factors for the develop
in other words, this is the course of events that will occur, unless there
ment of testicular germ cell cancer. However, the most dramatic change
is modification via differentiation of Sertoli cells, which leads to testis
that appears to have occurred in the relatively recent past is a fall in
formation. The trigger for the latter is the presence of a Y chromosome,
sperm counts of around 40–50% (1% per year over the last 50 years).
which diverts development into the testicular pathway. The resulting


Although this dramatic decrease is obviously manifest only in adult
cellular changes convert the indifferent gonad into a testis, which then
hood, as is the case with testicular cancer there is growing evidence that
produces three key hormones (AMH, Insl3 and testosterone), which
it may reflect impaired testicular development during fetal or childhood
collectively induce masculinization of the fetus and, thus, acquisition
life (Dean and Sharpe 2013).
of male secondary sexual characteristics.
The possession of a Y chromosome is usually associated with a male
ovary developmental pathway. Deletion mapping of the Y chromosome in a
The ovary develops from the middle part of the gonadal ridge only. The class of XX males arising from abnormal X : Y interchange at meiosis
cranial part of the gonadal ridge becomes the suspensory ligament of showed that the maledetermining region of the chromosome was a
the ovary (infundibulopelvic fold of peritoneum), and its caudal region conserved sequence located near its tip, termed the testisdetermining
is incorporated into the ovarian ligament. factor (TDF). This sequence contains a gene that is established to be the
The ovary closely resembles the testis early in development, except ‘master switch’ that programmes the direction of sexual development,
that its characteristically female features are slower to differentiate (see the socalled SRY gene (sexdetermining region on the Y chromosome).
Figs 72.13, 72.16). Few, if any, of the epithelial cords invade the It is believed to be genetically and functionally equivalent to the TDF.


DeveloPment of the urogenital system
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The SRY gene acts initially within the epithelial cords of cells derived involves two phases – transabdominal and inguinoscrotal – which are
from the coelomic epithelium of the ambisexual gonad. These cells can regulated by distinct morphological and endocrine factors (Barteczko
potentially differentiate into either Sertoli or granulosa cells (the sup and Jacob 2000).
porting cells for the germ cells in the testis and ovary, respectively).
Studies indicate that SRY initiates testis formation from the indifferent Transabdominal phase
gonad by directing the development of supportingcell precursors as Each testis initially lies on the dorsal abdominal wall. As it enlarges, its
Sertoli rather than granulosa cells (Albrecht and Eicher 2001). Gene cranial end degenerates and the remaining organ therefore occupies a
expression is seen first in cells designated as preSertoli, located cen more caudal position. It is attached to the mesonephric fold by the
trally in the developing gonad, and then later in the cranial and caudal mesorchium (the mesogenitale of the undifferentiated gonad), a peri
poles. Once the developmental pathway of Sertoli cells is directed, this toneal fold that contains the testicular vessels and nerves, and a quantity
influences the differentiation of the other cell types in the testicular of undifferentiated mesenchyme. It also acquires a secondary attach
pathway, so that Leydig cells appear later, and the connective tissue ment to the ventral abdominal wall, which has a considerable influence
becomes organized into a male pattern. The germ cells are also affected on its subsequent movements. At the point where the mesonephric fold
by this environment. When they arrive, they become enclosed within bends medially to form the genital cord (see Fig. 72.3), it becomes
the Sertoli cells and do not enter meiosis; they continue to proliferate connected to the lower part of the ventral abdominal wall by an inguinal
(which is characteristic of spermatogenesis), instead of ceasing prolif fold of peritoneum covering a mesenchymal cord, termed the guber


eration and entering meiosis and meiotic arrest, as occurs in the ovary. naculum or genitoinguinal ligament (see Figs 72.3, 72.13; Fig. 72.17).
Thus, the development of male characteristics follows the expression of The distal end of this cord seems to align to the inguinal part of the
SRY, and female characteristics develop in its absence. milk line which extends from the axilla to the femoral region (see Fig.
Studies of XY individuals with sex reversal (i.e. XY females) and cor 53.28). It has been suggested that this line corresponds to the original
responding gene knockout studies in mice have established that SRY lateral edge of the embryo, which expresses the apical ectodermal ridges
initiates testis development by inducing the expression of another gene, and mesenchymal progress zones of the upper and lower limbs (Hutson
SOX9 (SRYlike HMGbox protein 9), and expression of the latter in the 2013, Hutson et al 2014).
absence of SRY is sufficient for male determination. It is now known Up to about 10 weeks, the gubernaculum in male and female
that there is a multistep cascade of gene expression changes that essen embryos is the same, but then production of Insl3 from the Leydig cells
tially works to reinforce SOX9 expression and, thus, to consolidate stimulates enlargement (known as the ‘swelling reaction’) of the guber
development down the male pathway; these genes include WT1 naculum in males. This serves to anchor the fetal testis near the future
(Wilm’s tumour gene), GATA4 (GATAbinding protein 4), FGF9 (fibrob inguinal canal as the abdominal cavity enlarges between 10 and
last growth factor 9) and DAX-1 (orphan nuclear receptor DAX1) 15 weeks. By comparison, the gubernaculum in females remains thin
(BiasonLauber 2010, Munger et al 2013). This cascade also actively and subsequently develops into the round ligament (see below). The
represses expression of genes that promote development along the cranial attachment of the urogenital ridge, known as the cranial suspen


female pathway; these include RSPO1 (Rspondin 1), WNT4 (Wingless sory ligament, regresses in males under the action of androgens.
type MMTV integration site family member 4) and FOXL2 (Forkhead After the midgut loop returns to the abdomen, the anterior abdomi
box L2). In turn, activation of the female cascade of gene expression nal wall inferior to the umbilical cord lengthens. As each umbilical
actively suppresses expression of SOX9 and/or other genes in the ‘male artery runs ventrally from the dorsal to the ventral wall, it pulls up a
cascade’. Therefore, development of either a testis or an ovary results falciform peritoneal fold, which forms the medial boundary of a peri
from a reinforcing programme of gene expression changes, and inacti toneal fossa, the saccus vaginalis of lateral inguinal fossa, into which
vating mutations in any one of these genes, or their aberrant expression each testis projects.
in the wrong sex fetus, has the potential to interfere, partially or com
pletely, with normal gonad formation and, thus, with downstream Inguinoscrotal phase
sexual development (BiasonLauber 2010, Munger et al 2013). However, The caudal end of the gubernaculum is initially associated with a spe
fewer than 50% of disorders of sex development (DSD) in humans can cific portion of the milk line of the abdominal wall around which the
be explained by alterations in the expression of known genes, such as future inguinal canal is formed by differentiating abdominal wall
those listed; this means that more genes and new pathways remain to muscles. An interaction with the mammary line ectoderm and underly
be discovered, and these may involve completely new mechanisms. ing mesenchyme may trigger gubenacular meristematic growth similar
Very recently, the first example of sex reversal (in mice) due to an epi to that seen in the progress zone of the limb bud. Between 25 and 35
genetic change was reported, which resulted from the inactivating weeks, the male gubernaculum begins to bulge out from the abdominal


mutation of a gene (JMJD1A) involved in histone demethylation of muscles and elongate across the pubis and into the scrotum (see Fig.
genes, thus allowing their expression (Kuroki et al 2013). Absence of 72.17). An outpocketing of peritoneum, the processus vaginalis, extends
this demethylase prevented normal demethylation of the Sry gene and, into the gubernaculum, hollowing it out so that the proximal part is
thus, failure of its expression in an otherwise normal XY mouse with a divided into a crescentic parietal layer within which the cremaster
normal Sry gene. muscle develops, and a central column attached to the epididymis.
Subsequent development of the male phenotype requires fetal secre Elongation of the soft, gelatinous end of the gubernaculum, which, in
tion of testosterone, AMH and Insl3. Of these, testosterone is the most the early stage, is formed mainly of hyaluronic acid, is controlled by
important, as it has bodywide effects, both on the developing repro androgens. The exact mechanism mediating elongation in humans is
ductive system/genitalia and on numerous other organs/tissues, includ uncertain. In rodent models, there is good evidence that androgens
ing the brain. Also important is the development of the appropriate cause sexual dimorphism of the sensory branches of the genitofemoral
cytoplasmic testosteronebinding receptor protein (the androgen recep nerve, which supplies the gubernaculum, the developing cremaster
tor). Sertoli cells synthesize AMH, which causes the regression of the muscle within it, and part of the scrotum. The genital branch of the
Müllerian ducts, and Leydig cells produce testosterone, which promotes nerve releases calcitonin generelated peptide (CGRP), which stimulates
the development of the mesonephric ducts, sets into process the devel growth of the gubernacular tip along a chemotactic gradient to the
opment of male external genitalia, and sensitizes other tissues to testos scrotum.
terone. Absence of a functional androgen receptor, as occurs in the The testis remains in apposition with the deep inguinal ring, held


complete androgen insensitivity syndrome (CAIS), results in XY indi by the gubernaculum during the fourth to sixth months (Barteczko and
viduals who have testes and degenerated Müllerian ducts, but cannot Jacob 2000). From 35 weeks the extracellular matrix of the gubernacu
respond to the circulating testosterone produced by their testes; they lum is resorbed and it forms a fibrous attachment to the inside of the
therefore develop female secondary sexual characteristics. scrotum. Testis descent during the inguinoscrotal phase occurs relatively
rapidly about the seventh month, the left testis usually descending
Descent of the gonads ahead of the right. It is thought that intraabdominal pressure acting
The gonads develop on the posterior abdominal wall bilaterally along through the patent processus vaginalis contributes to this migration
the central portion of the mesonephros. This region receives a rich (Hutson 2012). In fullterm male neonates, over 95% have descended
blood supply, which is directed to the gonads as the mesonephros testes, although, in premature babies, descent may not be complete.
involutes. Both gonads descend, the testis to lie outside the abdominal After descent, the distal processus vaginalis persists as a ‘tiny satellite
cavity, and the ovary to the pelvis; however, they both retain their early peritoneal cavity’ around the testis as the tunica vaginalis, which
blood supply from the dorsal aorta. becomes firmly attached to the surrounding scrotum within a few
weeks. The proximal part of the processus vaginalis then obliterates,
Descent of the testis and there is evidence that this also is controlled by androgens indirectly
The mechanism of testicular descent is not completely understood and, via CGRP released from the genitofemoral nerve. Both exogenous CGRP
to some extent, remains controversial. Recent evidence suggests that it and hepatocyte growth factor can cause obliteration in vitro of the


reproductive system
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27
retPahC
A B
Metanephric
kidney
Ureter
Testis External
oblique muscle
Epididymis
Transversalis
Epididymis Testis fascia
Abdominal gubernaculum Internal
Vas deferens oblique muscle
External oblique aponeurosis
Abdominal Interstitial gubernaculum
gubernaculum
Subcutaneous gubernaculum
Interstitial
Superficial
gubernaculum
inguinal ring
Subcutaneous C Deep
inguinal ring Epididymis
gubernaculum
Gubernaculum Transversalis fascia =
internal spermatic fascia Vas deferens
Processus
vaginalis Internal oblique muscle = Seminiferous
Transversalis cremaster muscle tubules
fascia
External oblique muscle = Tunica
Internal external spermatic fascia albuginea
oblique muscle
Processus
vaginalis
Fig. 72.17 The descent of the testis. The testis is retroperitoneal throughout development. It becomes obliquely orientated during abdominal descent.
A, The gubernaculum attached to the lower part of the testis has an abdominal part covered with developing peritoneum, an interstitial part and a distal
end embedded in the anterior abdominal wall at the site of the future inguinal canal. B, The gubernaculum swells, becoming similar in width to the testis.
The distal-most portion of the gubernaculum bulges into abdominal wall muscles and grows 3–5 cm over the superior pubic ramus and into the scrotum.
A crescentic column of peritoneum, the processus vaginalis, develops in the expanding gubernaculum. C, The testis gains a crescentic covering of
visceral and parietal peritoneum (which forms the tunica vaginalis) and muscle and connective tissue layers as it passes through the deep and superficial
inguinal rings. The coverings remain around the ductus deferens, whereas the proximal processus vaginalis normally becomes obliterated by 3 weeks
after birth. (Based on Tuchmann-Duplessis H, Haegel P 1972 Illustrated Human Embryology, Vol 2 Organogenesis. London: Chapman and Hall. With
kind permission of Springer Science+Business Media.)