Embryology Notes - Em

M1SDemb: Embryology Embryological development can be divided into 3 main stages: 1. Early Development (1st to 3rd week): Fertilisation, Implantation, Gastrulation 2. Embryonic Period (4th to 8th week): Differentiation, Organogenesis 3. Fetal Period (9th week to 9th month): Growth and Specialisation of the fetus

1. Early development Week 1 Once the ovum has been fertilized by the spermatozoon, a zygote (single cell) is formed. This undergoes a rapid succession of mitotic divisions (cleavage) without an increase in size, forming blastomeres, and eventually a morulla (12-32 blastomeres). - A hollow cavity (blastocoele) forms at around day 3, marking the blastocyst stage. - The centrally placed cells are called inner cell mass (embryonic pole, or embryonic stem cells) and ultimately form tissues of the embryo (embryoblast). - The outer cells, called the outer cell mass, form the trophoblast, which plays an important role in the formation of the placenta and the embryonic membranes. At around days 5-6, implantation of the blastocyst on the endometrial lining of the uterus occurs. Ectopic Pregnancy An ectopic pregnancy is a complication of pregnancy in which the fertilized ovum is implanted in any other tissue other than the uterine wall. Most ectopic pregnancies occur in the Fallopian tubes (tubal pregnancy), but implantation can also occur in the cervix (placenta praevia), ovaries, internal os, or abdominal cavity. The fetus produces enzymes that allow it to implant in varied types of tissues, and thus an embryo implanted elsewhere than the uterus can cause great tissue damage in its efforts to reach a sufficient supply of blood. Week 2 Trophoblast cells surrounding the embryonic cells proliferate and invade deeper into the uterine lining. Differentiation of the cell masses occur: - Embryoblast (ICM) differentiates to form the epiblast and hypoblast. - Trophoblast cells (OCM) differentiates to form the cytotrophoblast and syncytiotrophoblast. Movement of the hypoblast laterally and downwards forms the primitive yolk sac; and the amniotic cavity, between the epiblast and amnioblast occurs.

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Week 3 Gastrulation occurs, in which distinct layers are formed from within embryo, which will later grow into different organs. The epiblast (embryonic cells) flattens into a bilaminar embryonic disc, composed of 2 germ layers: the upper ectoderm and the lower endoderm. As growth proceeds, the embryonic disc becomes pear-shaped, and a narrow streak appears on its dorsal surface formed of ectoderm, called the primitive streak. The further proliferation of the cells of the primitive streak forms a layer of cells that will extend between the ectoderm and the endoderm to form the mesoderm. Further thickiening of the ectoderm gives rise to the neural plate on the dorsal surface of the embryo. The plate sinkw beneath the surface of the embryo to form the neural tube, which ultimately gives rise to the CNS. A notochord, derived from mesoderm, forms in the centre of the embryonic disc and on the ventral surface of the neural tube. This notochord will eventually develop to form the vertebral column. The primitive yolk sac becomes modified to become the secondary yolk sac, while a chorionic cavity develops between the 2 layers of mesoderm. Eventually, the placenta develops. Embryonic Period The initially flat embryonic disc develops into a “C-shaped” cylindrical structure. Cephalocaudal flexion (in the longitudinal direction) and lateral folding (in the transversal folding) occur simultaneously, forming the abdominal wall, permitting a delimitation of the embryo. This also leads to enclosure of mesoderm and endoderm by the ectoderm, which later forms the epidermis. Neurulation, development of the CNS, also occurs. Derivatives of the Germ layers Ectoderm Epidermis: Hair, Nails, Sebaceous Glands CNS: Brain and Spinal Cord PNS Sensory epithelium of sense organs Inner ear Eye (lens) Pituitary gland (hypophysis) Teeth (enamel) Epithelium of some organs

Mesoderm Connective Tissue, Cartilage, Bones and Joints Walls of Heart Muscles: Smooth, Striated and Cardiac Urogenital System: Kidneys, Gonads and their Ducts, Suprarenal Cortex Mesothelium (Serous membranes): Pleura, Pericardium, Peritoneum Blood and Lymph cells

Endoderm Epithelium of Digestive tube: Foregut, Midgut, Hindgut Parenchyma of Digestive tube: Tonsil, Thyroid, Parathyroids, Thymus, Liver, Pancreas

Epithelium of Respiratory Tract: Lungs Middle Ear (Tympanic Cavity and Eustachian tube) Part of Bladder and Urethra

Fetal Period 2

The foetal period (9th week to 9th month) is about continued differentiation of organs and tissues, most importantly this period is about growth both in size and weight. Organogenesis - Early development: Any organ develops from a primordium (bud) derived from one or more germ layers found in the germ disc during early development. - Embryonic period: After folding is completed, the primordial of many organs become easily recognizable as a simple shape. Primordium undergoes changes in shape, size and site to become anatomically recognizable. - Fetal period: Differentiation of cells in the developing organ into specific cell types help with maturation whereby the organ becomes capable of normal function.

Development of the Lungs and Pleura Germ layer: - Lungs: Endoderm – Ventral wall of primitive foregut - Pleura: Mesoderm surrounding diverticulum Primordium: Laryngotracheal diverticulum Embryonic Period 1. The diverticulum is partially partitioned off by the formation of the tracheoesophagal septum from the tracheoesophagal ridges/grooves on either side. This divides the foregut into the laryngotracheal tube (ventral) and the esophagus (dorsal). 2. The partitioned portion of the laryngotracheal diverticulum separates off by splitting along the septum from the esophagus. The caudal end enlarges to form the lung bud, which is surrounded by splanchnic mesoderm. 3. Several generations of branching progressively increases the surface area for gas exchange. This branching takes place mostly dichotomously except after the formation of the primary when the R. divides into 3 and L. into 2. By the end of the embryonic period, the lungs have the correct appearance but are still immature. Fetal Period - Cells lining terminal sacs become progressively flattened (increase efficiency of gas exchange) - Rich vasculature develops around the terminal sacs (increase perfusion of alveoli) - Type 2 cells in terminal sacs secrete increasing amounts of surfactant (reduces surface tension in the fluid in the sacs to facilitate easy expansion of lungs at birth. Hence premature birth predisposes to respiratory distress syndrome) - Endodermal cells differentiate into respiratory epithelium and glands - Mesodermal cells give rise to cartilaginous plates, smooth muscles and connective tissue. o Splanchnic mesoderm forms visceral pleura o Somatic mesoderm forms parietal pleura Esophageal atresia and Tracheoesophagal Fistula Atresia is a condition where the laryngotracheal septum formed by fusion of the laryngotracheal ridges are deviated posteriorly, resulting in a reduced lumen diameter; while a fistula results when the margins of the laryngotracheal ridges fail to fuse adequately, resulting in an abnormal opening left between the laryngotracheal tube and the esophagus. Newborn infants with these malfunctions cough and choke during eating due to aspiration of food and saliva into lungs due to blocked esophagus, and may result in pneumonia. 3

Development of the Diaphragm Germ Layer: Mesoderm formed in neck by fusion of myotomes of 3rd, 4th and 5th cervical segments. Hence, the diaphragm’s nerve supply is derived from the phrenic nerve (C3, C4, C5). Primordium: Septum Transversum – An incomplete mesodermal partition on ventral aspect of embryo caudal to developing heart. The incompleteness is due to 2 pleuroperitoneal canals dorsal to it (one on each side) which allows communication between the pleural and peritoneal cavities. The diaphragm is formed from: 1. Septum Transversum: Forms the muscle and central tendon 2. 2 Pleuroperitoneal membranes: Forms peripheral areas of diaphragmatic pleura and peritoneum covering its upper and lower surfaces 3. Dorsal meso-esophagus: Forms crura Development 1. Pleuroperitoneal folds develop from the dorsolateral body wall growing ventromedially to fuse with the septum transversum and the dorsal meso-oesophagus, thereby forming the pleuroperitoneal membranes. This effectively closes the pleuroperitoneal canals. 2. The developing lungs growing caudally (especially at the periphery) helps add the peripheral portions of the diaphragm from the body wall, as well as create the dome shape. Hence, the periphery of the diaphragm shares nerve supply with the thoracic nerves. 3. Progressive caudal migration of the diaphragm results in the phrenic nerve taking a course more in line with the body axis. Diaphragmatic Hernia Congenital hernia can occur as the result of incomplete fusion of the 3 components. Abdominal contents can then be pushed up through the hiatus into the thoracic cavity. The herniae occur at the following sites: - Pleuroperitoneal canal (caused by incomplete fusion of pleuroperitoneal folds with septum transversum) - Opening between xiphoid and costal origins of the diaphragm - Esophageal hiatus

Development of the Cardiovascular System Germ Layer: Mesoderm Primordium: Endocardial Heart Tubes Formation of the Heart Tube Clusters of cells arise in the mesenchyme (mesoderm) at the cephalic end of the embryonic disc, cephalic to the site of the developing mouth and CNS. They form a plexus of endothelial blood vessels that fuse to form the R. and L. endocardial tubes, which soon fuse to form a single median endocardial tube. As the head fold of the embryo develops, the endocardial tube and pericardial cavity rotate on a transverse axis through almost 180: to come ventral to the esophagus and caudal to the developing mouth.

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The heart tube starts to bulge into the pericardial cavity. Meanwhile, the endocardial tube becomes surrounded by a thick layer of mesenchyme, which will differentiate into myocardium (cardiac muscle) and visceral layer of the serious pericardium. The primitive heart has been established, and the cephalic end is the arterial end and the caudal end is the venous end. The arterial end is continuous beyond the pericardium with a large vessel, the aortic sac. Further development of the heart tube The heart tube then undergoes differential expansion so that several dilatations, separated by grooves result. From the arterial to venous end, these dilatations are the bulbus cordis, ventricle, atrium, and the R. and L. horns of the sinus venosus. The bulbus cordis and ventricle elongate and bend, finally forming a compound S-shape, such that the atrium lies posterior to the ventricle. The passage between the atrium and ventricle narrows to form the atrioventricular canal. A gradual migration of the heart tube occurs so that the heart passes from the neck to the thoracic region. Development of the Atria 1. Atrioventricular canal becomes divided into R. and L. halves by appearance of ventral and dorsal atrioventricular cushions, which fuse to form the septum intermedium 2. A septum primum develops from the roof of the primitive atrium and grows down to fuse with the septum intermedium. The opening between the lower edge of the septum primum and the septum intermedium is the foramen primum. 3. Before total obliteration of the foramen primum has taken place, degenerative changes occur in the central portion of the septum primum, such that a foramen secundum appears, so that the atrial chambers can communicate again. 4. A thicker septum secundum grows down from the atrial roof on the R. side of the septum primum. The lower edge of the septum secundum overlaps the foramen secundum in the septum primum but does not reach the atrial floor and does not fuse with the septum intermedium. The space between the free margin of the septum secundum and septum primum is the foramen ovale. 5. Before birth, the foramen ovale allows oxygenated blood that has entered the R. atrium from the IVC to pass into the L. atrium. At birth, however, owing to the raised BP in the R. atrium, the septum primum is pressed against the septum secundum and fuses with it, and the foramen ovale is closed, separating the atria. The lower edge of the septum secundum seen in the R. atrium becomes the annulus ovalis, and the depression below this is the fossa ovalis. The R. and L. auricles later develop as small diverticula from the R. and L. atria. 5

Development of the Ventricles 1. A muscular ventricular septum projects upward from the floor of the primitive ventricle. The space bounded by the upper edge of the septum and the septum intermedium is the interventricular foramen. 2. Bulbar ridges (spiral endocardial thickenings) appear in the distal part of the bulbus cordis grow and fuse to form a spiral aorticopulmonary septum. The proliferation of bulbar edges and septum intermedium results in the closure of the interventricular foramen. 3. The aorticopulmonary septum grows down and fuses with the upper edge of the muscular ventricular septum to form the membranous part of the septum. This effectively shuts off interventricular communication; while ensuring R. ventricular communication with the pulmonary trunk and L. ventricular communication with the aorta. The truncus arteriosus (distal part of bulbus cordis) is divided by the spiral aorticopulmonary septum to form the roots and proximal portions of the aorta and pulmonary trunk. The proximal portion of the bulbus cordis becomes incorporated into the R. ventricle as the conus arteriosus/infundibulum; and into the L. ventricle as the aortic vestibule. Two coronary arteries arise just distal to the aortic valves. Atrial Septal Defects In 25% of hearts, the foramen ovale persists. Oxygenated blood from the L. atrium passes over the R. atrium, decreasing the efficiency of circulation. Ventricular Septal Defects This occurs when the fusion between the membranous and muscular parts of the ventricular septum is incomplete. Blood under high pressure passes through the defect from L. to R., causing enlargement of the R. ventricle. Tetralogy of Fallot This occurs when the bulbar ridges fail to fuse correctly to form the aorticopulmonary septum, resulting in unequal division of the bulbus cordis, and consequent narrowing of the pulmonary trunk resulting in interference with R. ventricular outflow. The anatomic abnormalities include large ventricular septal defect; stenosis of pulmonary trunk; exit of aorta immediately above the ventricular septal defect; and severe hypertrophy of the R. ventricle. Embryonic Dilatation Sinus venosus Primitive atrium Primitive ventricle Bulbus cordis Truncus arteriosus

Adult Structure Smooth part of right atrium (sinus venarum), coronary sinus, oblique vein of left atrium Trabeculated parts of right and left atria Trabeculated parts of right and left ventricles Smooth part of right ventricle (conus arteriosus), smooth part of left ventricle (aortic vestibule) Aorta, pulmonary trunk

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Development of the GIT The components of the GIT develop from the primitive gut which is an endodermal tube surrounded by mesoderm resulting from folding of the trilaminar germ disc. - Endoderm: Gives rise to lining epithelium and parenchyma of glands in the form of tubular outgrowths (e.g. liver, pancreas) - (Splanchnic) Mesoderm: Differentiates into muscular wall (typical 4 layers), blood vessels and connective tissue in gut wall. The 3 main subdivisions, from cranial to caudal, are foregut, midgut (opposite yolk sac) and hindgut. Most of the primitive have a dorsal mesentery (mesogastrium, mesentery, mesocolon). From the dorsal aorta in the midline, 3 main branches of arteries (celiac, sup. mesenteric, inf. mesenteric) run down the mesentery to supply the foregut, midgut and hindgut respectively. A ventral mesentery mostly disappears soon after formation, except in relation to the stomach and liver.

Development of the Stomach Germ layer: - Stomach Walls: Endoderm of primitive foregut - Greater momentum: Mesoderm – Dorsal and Ventral Mesentery Primordium: Fusiform swelling (dilatation in caudal part of foregut, dorsal to septum transversum) 1. With growth of the foregut, the primitive stomach grows caudally into the abdominal cavity and acquires a ventral mesogastrium. Insufficient movement may result in a hernia. 2. Besides showing increased growth over the dorsal aspect, the stomach undergoes rotation through a longitudinal axis resulting in a change of position of the closely related vagus nerves. Rotation through a ventrodorsal axis moves the caudal end (pylorus) of the stomach to the right. The L. vagus nerve now lies on the anterior surface of the stomach. Excessive development of muscle in the pylorus results in hypertrophic pyloric stenosis where food is unable to leave the stomach, leading to projectile vomiting. 3. The dorsal mesogastrium grows and projects ‘sac-like’ towards the left-side and helps form the lesser sac of the peritoneal cavity and the greater omentum in its caudal part. 4. Portions of the dorsal mesogastriun (cranial part) depending on their connections are referred to as the gastrosplenic and splenorenal ligaments.

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Development of Liver Germ Layer: Endoderm of distal end of ventral foregut Primordium: Liver Diverticulum (Hepatic bud) 1. The liver diverticulum appears on the ventral side of the foregut just caudal to the septum transversum. It forms the gall bladder component (cystic) caudally and the liver (hepatic) component cranially. 2. The hepatic part grows into the septum transversum and divides in a dichotomous fashion repeatedly. The terminal (distal) parts of this branching system differentiate into the hepatocytes, which secrete bile into the more proximal parts which will form the bile ducts. 3. As the liver becomes too large for the septum transversum, it grows out caudally into the abdominal cavity and separates the ventral mesogastrium into the falciform ligament and the lesser omentum. Biliary Atresia Failure of the bile ducts to canalize during development causes atresia (lack of a lumen). Jaundice soon appears after birth; clay-coloured stools and very dark coloured urine is produced.

Development of the midgut The duodenum (except 1st part), jejunum, ileum, ascending colon and proximal ⅔ of the transverse colon are developed from the midgut. Destined to develop into the longest segment of the gut, the midgut undergoes rapid elongation during the embryonic period. 1. Loop formation 2. Coiling (cranial segment) 3. Physiological Herniation with associated 90: counterclockwise rotation. This occurs in the umbilical cord which contains a space that is a continuation of the primitive peritoneal cavity. 4. Return to the abdominal cavity along with a further 180: counterclockwise rotation. This results in the sup. mesenteric artery occupying a position between the duodenum and the transverse colon. 5. Fixation: Parts of the original mesentery (all midgut viscera except transverse colon) become attached to the posterior abdominal wall, rendering these associated segments retroperitoneal. 6. Vitellointestinal duct is obliterated.

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Potential Complications 1. Failure to return will result in hernia in the umbilical region 2. Incomplete rotation (e.g. during return will result in coon being on the left side). Abnormal adhesions form, which run across the anterior surface of the duodenum and cause obstruction in the second part. 3. Reverse rotation (i.e. clockwise) results in duodenum lying anterior to the transverse colon. Also causes duodenal obstruction, leading to vomiting. 4. Inadequate fixation gives abnormal motility to the gut which could predispose to complications like volvulus (a loop getting twisted around itself and getting strangulated) Meckel’s Diverticulum This represents a persistent portion of the vitellointestinal duct. It may possess a small area of gastric mucosa, and bleeding may occur from a “gastric” ulcer in its mucous membrane. Moreover, the pain from this ulcer may be confused with pain from appendicitis. Should a fibrous band connect the diverticulum to the umbilicus, a loop of small bowel may become wrapped around it, causing intestinal obstruction.

Development of the Pancreas Germ layer: Endoderm of the caudal end of the dorsal and ventral foregut Primordia: Dorsal and Ventral Diverticula - The ventral diverticulum which appears immediately caudal to the liver diverticulum. - The dorsal diverticulum is located slightly cranial to the ventral diverticulum. 1. Both diverticula grow and branch repeatedly to give rise to glandular portions more distally and ducts more proximally to the gut. The endocrine portions arise from the most peripheral branches by budding off. 2. The ventral pancreas, with its duct and the common bile duct associated with it, migrates around the right side of the duodenal loop to a position on the concave aspect of the duodenum just caudal to the dorsal pancreas. Hence, the duct of the ventral pancreas opens into the duodenum just below that of the dorsal pancreas. 3. The common bile duct is brought to the R. side of the duodenum by this migration. When the duodenum turns to the right to become retroperitoneal, the common bile duct lies posterior to the proximal part of the duodenum. This also explains why the ventral pancreas lies posterior to the sup. mesenteric artery. 4. The ducts of the 2 glands become connected and the final main pancreatic duct is derived from the proximal ventral and distal dorsal pancreatic ducts and the connecting portion. The proximal dorsal pancreatic duct remains as the accessory pancreatic duct. The duodenum develops from the caudal end of the foregut as well as the cranial-most part of the midgut; hence its blood supply is from both the celiac trunk (splenic artery and hepatic artery --- sup. pancreaticoduodenal branch) and the sup. mesenteric artery (inf. pancreaticoduodenal branch) 9

Development of the Kidney Germ layer: Intermediate mesoderm along posterior wall of abdominal cavity Primordium: Metanephric diverticulum and metanephric mass The kidney develops from 3 different, slightly overlapping systems (from cranial to caudal): - Pronephros: Rudimentary and non-functional. Consist of 7-10 solid cell groups in the cervical region and forms nephrotomes (vestigial excretory units) at the beginning of the 4th week. Earlier groups of cells regress before more caudal groups are formed. By the end of the 4th week, the pronephros disappears. -

Mesonephros: Functions for a short time in early foetal life. The mesonephros and mesonephric ducts are derived from the upper thoracic to upper lumbar (L3) segments. In the middle of the 2nd month, the mesonephros forms a large ovoid organ on each side of the midline (with the developing gonad lying on the medial side). o Mesonephric ducts: The first excretory tubules of mesonephros appear early in the 4th week. The tubules acquire a glomerular capillary tuft at the medial end and enter the longitudinal mesonephric (Wolffian) duct at the lateral end. Cranial tubules start degenerating while caudal tubules are still differentiating, but most of them disappear by the end of the 2nd month.

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Metanephros: Forms the permanent kidney. It appears in the 5th week and becomes functional at the end of the 1st trimester. However, it is not responsible for excretion of waste products, which is achieved by the placenta. Urine passed into the amniotic cavity mixes with the amniotic fluid and is swallowed by the fetus to enter the intestinal tract and absorbed by the bloodstream. The process then repeats. o Nephrons (the excretory system) develop from the metanephric mesoderm in a similar way as the mesonephric system. The mesodermal intermediate cell mass of the lower lumbar and sacral regions develops into the metanephric tissue cap. Upon contact with the elongating ureteric bud, it is induced to condense around the ureteric bud, forming small renal vesicles, and becoming comma-shaped bodies, followed by S-shaped bodies, and finally metanephric tubules.  The proximal end forms the Bowman’s capsule, which is deeply indented by glomerulus  The distal end is in open connection with collecting tubules.  As the nephron lengthens, the PCT, DCT, and LoH develops. There is no increase in number of nephrons post-natally. The kidneys were lobulated at birth, but the lobulation disappears with growth of nephrons.

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The collecting system develops from the ureteric bud, an outgrowth of the mesonephric duct. The bud penetrates metanephric tissue, dilating to form the renal pelvis and the branches repeatedly, into the major and minor calyces and finally the collecting tubules.

Ascent of kidneys The kidneys were initially located in the pelvic region and supplied by the pelvic branch of the aorta. However, due to diminution of body curvature and growth of body in the lumbar and sacral regions, the kidneys shift to a more cranial position in the abdomen and becomes supplied by the arteries originating from the abdominal aorta. The lower vessels then degenerate. Renal Agenesis This condition refers to the failure of development of one or both kidneys. - Unilateral renal agenesis: Usually not of any major concern as long as the other kidney is healthy. However, people with this condition have considerably higher chances of hypertension. - Bilateral renal agenesis: The absence of kidneys causes a deficiency of amniotic fluid (oligohydramnios) in pregnant women. Normally, the amniotic fluid acts as a cushion for the developing fetus. Insufficient amniotic fluid may result in compression of the fetus, resulting in further malformations. Most infants that are born alive do not live beyond 4 hrs. Ectopic/Pelvic Kidney The kidney is arrested in some part of its normal ascent and usually found at the pelvic brim. Such a kidney may present with no signs or symptoms and may function normally. However, should it be inflamed, it may, because of its unusual position, give rise to a mistaken diagnosis. Horseshoe Kidney This condition is the result of the fusion of the caudal ends of both kidneys as they develop. Both kidneys commence to ascend from the pelvis, but the interconnecting bridge becomes trapped behind the inf. mesenteric artery so that the kidneys come to rest in the low lumbar region. Both ureters are kinked as they pass inferiorly over the bridge of renal tissue, producing urinary stasis, which may result in infection and stone formation. Surgical division of the bridge corrects the condition. Duplications of urinary tract / Double Pelvis / Bifid ureter Double pelvis of the ureter is usually unilateral. The upper pelvis is small and drains the upper group of calyces; the larger lower pelvis drains the middle and lower groups of calyces. This cause is a premature division of the ureteric bud near its termination. In bifid ureter, the ureters may join in the lower 3rd of their course, may open through a common orifice into the bladder, or may open independently into the bladder. In the latter case, one ureter crosses its fellow and may produce urinary obstruction.

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Ectopic ureter Instead of opening into the bladder, the ureter may open into the urethra, vagina or uterus. The result is constant dribbling of urine (urinary incontinence). Supernumerary Renal Arteries These arteries represent persistent fetal renal arteries, which grow in sequence from the aorta to supply the kidney as it ascends from the pelvis. They may cross the pelviureteral junction and obstruct the outflow of urine, producing dilatation of the calyces and the pelvis, known as hydronephrosis.

Development of the Bladder and Urethra A urorectal septum divides the cloaca into the anorectal canal and urogenital sinus between the 4th and 7th weeks. The cloaca membrane is divided into the urogenital membrane and the anal membrane. The urogenital sinus has 3 portions: - Vesical part: This is the largest part of the urogenital sinus and forms the urinary bladder. It is initially continuous with the allantois, which will eventually be obliterated to form a thick fibrous cord called the urachus, which eventually forms the median umbilical ligament, connecting the apex of the bladder with the umbilicus. - Pelvic part: This is a narrow canal which forms the prostatic and membranous parts of the urethra in males. - Phalic / Definitive part: This part is flattened from side to side, and is separated from the exterior by the urogenital membrane.

The caudal end of the mesonephric duct is absorbed into the developing bladder and forms the trigone and part of the urethra (in males, the prostatic urethra). In the male, the cranial end of the mesonephric duct is joined to the developing testis by the efferent ductules of the testes, and so it becomes the duct of the epididymis, the vas deferens and the ejaculatory duct. In the female, the mesonephric duct largely disappears. Only small remnants persist as the ducts of the epoophoron and paroophoron.

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The mucosa of the bladder is formed by incorporation of the mesonephric ducts and ureters in the trigone region, and is hence of mesodermal origin. However, the mesodermal lining is replaced by endodermal epithelium with time, and eventually, the entire bladder is lined by epithelium of endodermal origin. The urethra is of endodermal origin from the urogenital sinus. In males, the distal (penile) part is derived from the urethral plate. The surrounding connective tissue and smooth muscle tissues are derived from splanchnic mesoderm.

Development of the Reproductive Systems Genetic sex is determined at fertilization. It is the Y chromosome which is key to sexual dimorphism. In males, the SRY (sex-determining region on Y) gene located on Yp11 encodes a testis-determining transcription factor that initiates male sex determination. Females have an XX sex chromosome complement, without a Y chromosome or testis-determining factor. Indifferent Gonads (Common to both males and females) Like the kidneys, the indifferent gonads develop from the intermediate mesoderm along the posterior wall of the abdominal cavity. The gonads appear initially as longitudinal gonadal ridge, medial to the urogenital ridge. Primordial germ cells appear among endoderm cells in the wall of the yolk sac close to the allantois. They migrate along the dorsal mesentery of the hind gut to arrive at the primitive gonads at the beginning of the 5th week, invading the gonadal ridges in the 6th week. If germ cells are absent, gonads do not develop. The epithelium proliferates and penetrates the condensed mesenchyme (mesoderm) to form the primitive sex cords, which are connected to the surface epithelium. ---------------------------------------------------------------Testis Under the Y chromosome influence (SRY gene), the primitive sex cords proliferate and penetrate deep into the medulla to form the testis/medullary cords. The testis cords develop and become horseshoe shaped in the 4th month. They comprise primitive germ cells and sustentacular/Sertoli cells derived from the gonadal surface epithelium. Meanwhile the cords near the testis hilum break up to form the rete testis, a network of tiny cell strands. At puberty, the solid testis cords acquire a lumen to form seminiferous tubules which connect to the rete testis. The mesenchyme of the gonadal ridge develop shortly after the onset of testis cord differentiation to form the interstitial Leydig cells which lie between the testis cords. These cells produce testosterone from the 8th week onwards to influence differentiation of genital ducts and external genitalia.

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Ovary The primitive sex cords dissociate into irregular cell clusters containing groups of primitive germ cells and occupy the medullary part of the ovary. The medullary cords later disappear, and are replaced by vascular stroma to form the ovarian medulla. The surface epithelium continues to proliferate to give rise to secondary cortical cords at the 7th week. They penetrate the underlying mesenchyme and split into isolated cell clusters, each surrounding 1 or more primitive germ cells. The germ cells develop into oogonia; while the surrounding epithelial cells form follicular cells. ------------------------------------------------------Descent of the testis The gubernacula, which are folds of mesenchymal tissue/peritoneum attached to the caudal end of the testis, aid in the descent of the testis. It extends to the inguinal region between the internal and external oblique muscles, and forms an extra-abdominal portion extending towards the scrotal swellings. As the testis descends behind the peritoneum, it drags along the fascia/muscles in its course: Origin Processus vaginalis Transversalis fascia Int. oblique Ext. oblique Transversus abdominis

Structure Parietal and visceral layers of tunica vaginalis Internal spermatic fascia Cremasteric fascia and muscle External spermatic fascia (does not cover path of migration)

The processus vaginalis is an evagination of peritoneum into the ventral abdominal wall. It follows the course of the gubernaculums into the scrotal swellings and forms the inguinal canal together with the muscular and fascial layers of abdominal wall. Its connection with the peritoneal cavity is obliterated at or shortly after birth. The descent of the testis is controlled by the outgrowth or regression of the extra-abdominal portion of the gubernaculums, increase in intra-abdominal pressure due to organ growth and hormonal influences, e.g. androgens and Mullerian-inhibiting substances. 14

Congenital Inguinal Hernia This occurs when the processus vaginalis is unobliterated, and intestinal loops descend into the scrotum via the inguinal canal from the deep inguinal ring through the superficial ring. The remains of the processus vaginalis form the hernial sac. Hydrocele of testis and/or spermatic cord The processus vaginalis may become very much narrowed but not completely obliterated; hence its lumen remains in communication with the abdominal cavity. Peritoneal fluid accumulates in it around the testis in the tunica vaginalis, forming a hydrocele. The hydrocele can be tapped to remove the excess fluid by inserting a fine trocar and cannula through the scrotal skin. Cryptorchidism This refers to imperfect descent of the testis, which could be due to abnormal androgen production. This results in inability to produce mature spermatozoa as the temperature within the body retards spermatogenesis. The descent may be incomplete, and the testis fails to reach the floor of the scrotum and may be found within the abdomen, within the inguinal canal at the superficial inguinal ring, or high up in the scrotum. Maldescent, in which the testis travels down an abnormal path, and may be found in the superficial fascia of the ant. abd. wall above the inguinal ligament, in front of the pubis, in the perineum or in the thigh. -------------------------------------------------------------------------------------------------------------------------------------Descent of the ovaries The gubernacula (genital ligament), attached to the caudal ends of the ovaries, aid in their descent, which is much less than that in males. The ovaries are located just below the rim of the true pelvis. - The cranial part of the gubernaculum, together with the ovarian artery and vein, forms the suspensory ligament of the ovary, which suspends the ovary from the pelvic wall - The caudal part of the gubernaculum forms the ligament of ovary proper and the round ligament of the uterus, which supports the ovary and uterus in the pelvis. ------------------------------------------------------------------------------------------------------------------------------------Genital Ducts 2 pairs of indifferent genital ducts, the mesonephric/Wolffian and paramesonephric/Mullerian ducts, are initially present in both males and females. Their development is influenced by hormones.

Mesonephric / Wolffian ducts Paramesonephric / Mullerian ducts

Male Testosterone, major androgen produced by Leydig cells, causes virilisation of these ducts Mullerian-inhibiting substance (MIS) / Anti-mullerian hormone (AMH) produced by Sertoli cells causes regression of these ducts

Female Absence of testosterone causes regression of these ducts Oestrogens (maternal, placental, foetal) and absence of MIS causes ducts to develop into uterine tubes, uterus, and upper part of the vagina

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Male Genital Ducts - Efferent ductules: Arise from mesonephric excretory tubules. Connect to rete testis. - Mesonephric duct: Main genital duct o Elongate and become highly convoluted near efferent ductules to form epididymis o Obtain thick muscular coat to form vas deferens from tail of epididymis to seminal vesicles o Forms the ejaculatory ducts beyond the seminal vesicles ----------------------------------------------------------------------------------------------------------------------------------Female Genital Ducts Paramesonephric duct: Formed from a longitudinal invagination of epithelium on the anterolateral surface of the urogenital ridge, this duct forms the main female genital ductal system. - Cranial vertical part: Opens into the abdominal cavity with funnel-like structure with fimbriae. - Horizontal part: Runs lateral to the mesonephric duct then crosses ventrally in the caudomedial direction. Establishes the broad ligament of the uterus, dividing the pelvic cavity into uterovesical pouches and Pouch of Douglas - Caudal vertical part: Comes into close contact with opposite paramesonephric duct in the midline. The caudal tip projects into the posterior wall of the urogenital sinus. Both parts are initially separated by a septum, but later fuse to form the uterus and cervix. The surrounding mesenchyme forms myometrium; while the peritoneal covering forms the perimetrium. Vagina The vagina is of dual origin: - Sinovaginal bulbs: These are evaginations from the pelvic part of the urogenital sinus which proliferate to form a solid vaginal plate. By the 5th month, it will be completely canalized to from the lower part of the vagina. The lumen is separated from the urogenital sinus by the hymen. - Vaginal fornices: These wing-like expansions of the upper part of the vagina form around the end of the uterus. These are of paramesonephric origin.

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Agenesis of the Uterus This is a rare condition where the uterus is absent as the result of a failure of the paramesonephric ducts to develop. Infantile Uterus This is a condition in which the uterus is much smaller than normal and resembles that present before puberty. Amenorrhea is present, but the vagina and ovaries may be normal. Failure of Fusion of the paramesonephric ducts Failure of the paramesonephric ducts to fuse may cause a variety of uterine defects: - Uterus may be duplicated with 2 bodies and 2 cervices - There may be a complete septum through the uterus, making 2 uterine cavities and 2 cervices - There may be 2 separate uterine bodies with one cervix - One paramesonephric duct may fail to develop, leaving one uterine tube and half of the body of the uterus. ---------------------------------------------Indifferent External Genitalia The indifferent external genitalia comprises of: - Cloacal folds: Slightly elevated regions around the cloacal membrane formed by migration of mesenchymal cells from the primitive streak (ectoderm) during the 3rd week of development. o Cranial to cloacal membrane: Folds unite to form genital tubercle (phallus) o Caudal to cloacal membrane: Divided into the urethral folds and anal folds when the cloacal membrane is subdivided into urogenital and anal membranes at the 6th week - Genital swellings (Labioscrotal folds): Pair of elevation on either side of urethral folds.

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Development Genital swellings

Genital tubercle Urogenital groove

-

Urethral folds

-

-

Male Influenced by androgens Initially located in inguinal region Move caudally and fuse, each making up half the scrotum Halves separated by scrotal septum Rapidly elongates, pulling urethral folds forward to form urethral groove Extends along the caudal aspect of the elongated genital tubercle Lined by endodermal cells to form a urethral plate Fuse over urethral plate to form penile urethra at end of 3rd month. The canal does not extend to the tip of the phallus Ectodermal cells from the tip of the glans penetrate inward to form epithelial cord at the 4th month Canalizes to form the external urethral meatus.

Female Stimulated by oestrogens Enlarge to form the labia majora

Elongates slightly to form the clitoris Remains open to form vestibule

Do not fuse; Forms the labia minora

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