[EMBRYO]LEC_206_EMBRYONIC DEVELOPMENT OF THE UROGENITAL SYSTEM.pdf

(006) EMBRYOLOGIC DEVELOPMENT OF UROGENITAL SYSTEM DR. M.E GUERRERO| 01/18/21...

(006) EMBRYOLOGIC DEVELOPMENT OF UROGENITAL SYSTEM DR. M.E GUERRERO| 01/18/21 OUTLINE A. PRONEPHROS I. UROGENITAL SYSTEM At the beginning of the fourth week AOG. II. URINARY SYSTEM Represented by 7 to 10 solid cell groups in the cervical A. Pronephros region. B. Mesonephros These groups form vestigial excretory units, nephrotomes, C. Metanephros: the definitive kidney that regress before more caudal ones are formed. III. COLLECTING SYSTEM By the end of the fourth week, all indications of the IV. EXCRETORY SYSTEM pronephric system have disappeared. V. MOLECULAR REGULATION OF KIDNEY DEVELOPMENT VI. POSITION OF THE KIDNEY VII. FUNCTION OF THE KIDNEY VIII. BLADDER AND URETHRA IX. GENITAL SYSTEM A. Gonads B. Testis C. Ovary X. GENITAL DUCTS A. Genital ducts in male B. Genital ducts in female C. Molecular regulation of genital duct Figure 1. Transverse sections through embryos at various stages development of development showing formation of nephric tubules. A. 21 days. XI. VAGINA B. 25 days. Note formation of external an internal glomeruli and XII. EXTERNAL GENITALIA the open connection between the intraembryonic cavity and the A. External genitalia in male nephric tubule. B. External genitalia in female XIII. DESCENT OF TESTES XIV. DESCENT OF OVARIES I. UROGENITAL SYSTEM Urogenital system can be divided into two entirely different components: - urinary system - genital system They are intimately interwoven embryologically and anatomically Both develop from a common mesodermal ridge (intermediate mesoderm) along the posterior wall of the Figure 2. A. Relationship of the intermediate mesoderm of the abdominal cavity. pronephric, mesonephric, and metanephric systems. In cervical Initially, the excretory ducts of both systems enter a and upper thoracic regions, intermediate mesoderm is segmented; common cavity, the cloaca. in lower thoracic, lumbar, and sacral regions, it forms a solid, unsegmented mass of tissue, the nephrogenic cord. Note the longitudinal collecting duct, formed initially by the pronephros but II. URINARY SYSTEM later by the mesonephros [mesonephric duct], B. Excretory tubules of the pronephric and mesonephric systems in a 5-week Kidney Systems embryo. Three slightly overlapping kidney systems are formed in a cranial-to-caudal sequence during intrauterine life in B. MESONEPHROS humans: Mesonephros and mesonephric ducts - Pronephros – rudimentary and nonfunctional. - derived from intermediate mesoderm from upper - Mesonephros – may function for a short time during thoracic to upper lumbar (L3) segments the early fetal period. - Metanephros – forms the permanent kidney. Page 1 of 17 CMED 1D  (006) EMBRYOLOGIC DEVELOPMENT OF UROGENITAL SYSTEM DR. M.E GUERRERO| 01/18/21 Early in the fourth week of development, during regression of the pronephric system, the first excretory tubules of the mesonephros appear They lengthen rapidly, form an S-shaped loop, acquire a tuft of capillaries that will form a glomerulus at their medial extremity Around the glomerulus, the tubules form Bowman capsule, and together these structures constitute a renal corpuscle. Laterally, the tubule enters the longitudinal collecting duct known as the mesonephric or Wolffian duct. Figure 4. Relation of the hindgut and cloaca at the end of the fifth In the middle of the second month, mesonephros forms week. The ureteric bud penetrates the metanephric mesoderm a large ovoid organ on each side of the midline. [blastema]. Because the developing gonad is on its medial side, ridge formed by both organs is known as the urogenital ridge. III. COLLECTING SYSTEM While caudal tubules are still differentiating, cranial tubules and glomeruli show degenerative changes, and by the end Ureteric Bud of the second month, majority have disappeared. Where collecting ducts of the permanent kidney develop In male, a few of the caudal tubules and the mesonephric from the ureteric bud. ducts persist and participate in the formation of the genital An outgrowth of the mesonephric duct close to its entrance system, but they disappear in female. to the cloaca. Bud penetrates the metanephric tissue, which is molded over its distal end as a cap. Renal Pelvis The bud dilates, forming the primitive renal pelvis, splits into cranial and caudal portions forming major calyces. Each calyx forms two new buds while penetrating the metanephric tissue. These buds continue to subdivide until 12 or more generations of tubules have formed. Meanwhile at the periphery, more tubules form until the end of the fifth month. Tubules of the 2nd order enlarge and absorb those of the 3rd and 4th generations, forming the minor calyces of the renal pelvis. Figure 3. A. Transverse section through the urogenital ridge in the During further development, collecting tubules of the fifth lower thoracic region of a 5 week embryo showing formation of an and successive generations elongate considerably and excretory tubule of the mesonephric system. Note the appearance converge on the minor calyx, forming the renal pyramid. of Bowman capsule and the gonadal ridge. The mesonephros and Ureteric bud gives rise to the ureter, the renal pelvis, the gonad are attached to the posterior abdominal wall by a broad major and minor calyces, and approximately 1 to 3 million urogenital mesentery. B. Relation of the gonad and the collecting tubules. mesonephros. Note the size of the mesonephros. The mesonephric duct [Wolffian duct] runs along the lateral side of the mesonephros. C. METANEPHROS: THE DEFINITIVE KIDNEY Third urinary organ Also known as the “permanent kidney”. Appears in the fifth week Its excretory units develop from metanephric mesoderm in the same manner as in the mesonephric system. Figure 5. Development of the renal pelvis, calyces, and collecting The development of the duct system differs from that of the tubules of the metanephros. A. 6 weeks. B. At the end of the sixth other kidney systems. week. C. 7 weeks. D. Newborn. Note the pyramid form of the collecting tubules entering the minor calyx. Page 2 of 17 CMED 1D  (006) EMBRYOLOGIC DEVELOPMENT OF UROGENITAL SYSTEM DR. M.E GUERRERO| 01/18/21 IV. EXCRETORY SYSTEM Figure 6. A – F. Development of a metanephric excretory unit. Arrows, the place where the excretory unit (blue) establishes an open communication with the collecting system (yellow), allowing each newly formed collecting tube is covered at its distal flow of urine from the glomerulus into the collecting ducts. end by metanephric tissue cap under the inductive influence of the tubule, cells of the tissue form small vesicles, renal vesicles, which in turn V. MOLECULAR REGULATION OF KIDNEY give rise to small S-shaped tubules DEVELOPMENT capillaries grow into the pocket at one end of the S and differentiate into glomeruli as with most organs, differentiation of the kidney involves these tubules together with their glomeruli, form nephrons epithelial mesenchymal interactions or excretory units example, epithelium of the ureteric bud from the proximal end of each nephron forms Bowman capsule, mesonephros interacts with mesenchyme of the which is deeply indented by a glomerulus metanephric blastema distal end forms an open connection with one of the WT1 collecting tubules, establishing a passageway from expressed by mesenchyme Bowman capsule to the collecting unit a transcription factor that makes this tissue competent to continuous lengthening of the excretory tubule results in respond to induction by the ureteric bud formation of proximal convoluted tubule, loop of Henle, also regulates production of glial-derived neurotrophic and distal convoluted tubule growth factor (GDNF) and hepatocyte growth factor kidney develops from two sources: (HGF, or scatter factor) by the mesenchyme, and these o metanephric mesoderm, which provides proteins stimulated branching and growth of the ureteric excretory units buds o ureteric bud, which gives rise to the collecting tyrosine kinase receptors RET, for GDNF, and MET, for system HGF, are synthesized by the epithelium of the ureteric buds, nephrons are formed until birth at which time there are establishing signaling pathways between the two tissues approximately 1 million in each kidney in turn, the buds induce the mesenchyme via fibroblast urine production begins in the 12th week, following growth factors 2 (FGF2) and bone morphogenic protein 7 differentiation of the glomerular capillaries, which start to (BMP7) form by the 10th week both of these growth factors block apoptosis and stimulate at birth, the kidneys have a lobulated appearance, but the proliferation in the metanephric mesenchyme while lobulation disappears during infancy as a result of further maintaining production of WT1 growth of the nephrons, although there is no increase in conversion of the mesenchyme to an epithelium for their number nephron formation is also mediated by the ureteric buds through expression of WNT9B and WNT6 which upregulate PAX2 and WNT4 in the metanephric mesenchyme PAX2 promotes condensation of the mesenchyme preparatory to tubule formation, whereas WNT4 causes the condensed mesenchyme to epithelialize and form tubules because of these interactions, modifications in the extracellular matrix also occur fibronectin, collagen I, and collagen III are replaced with laminin and type IV collagen, characteristic of an epithelial basal lamina in addition, the cell adhesion molecules syndecan and E- cadherin, which are essential for condensation of the mesenchyme into an epithelium, are synthesized Page 3 of 17 CMED 1D  (006) EMBRYOLOGIC DEVELOPMENT OF UROGENITAL SYSTEM DR. M.E GUERRERO| 01/18/21 GDNF produced by metanephric mesoderm produces branching and growth of the ureteric bud, thus, mutations in genes that regulate GDNF expression of signaling may result in renal agenesis, e.g. the gene SALLI, responsible for Townes Brock syndrome; PAXZ that causes renal coloboma syndrome; and EYAI that results in branchiootorenal syndrome. Bilateral renal agenesis occurs in I/I0,000 births due to renal failure. baby presents with Potter sequence Potter sequence characterized by anuria, oligohydramnios [decreased Figure 7. Genes involved in differentiation of the kidney. A. WT1, volume of amniotic fluid], and hypoplastic lungs secondary expressed by the mesenchyme, enables this tissue to respond to to the oligohydramnios. induction by the ureteric bud. Glial-derived neurotrophic factor In 85% of cases, other severe defects, including absence (GDNF) and hepatocyte growth factor (HGF), also produced by the or abnormalities of the vagina and uterus, vas deferens, mesenchyme, interact through their receptors, RET and MET, and seminal vesicles. respectively, in the ureteric bud epithelium, to stimulate growth of Common associated defects in other systems include the bud and maintain the interactions. The growth factors fibroblast cardiac anomalies, tracheal and duodenal atresias, cleft lip growth factor 2 (FGF2) and bone morphogenic protein 7 (BMP7) and palate, and brain abnormalities. stimulate proliferation of the mesenchyme and maintain WT1 because of the oligohydramnios, the uterine cavity is expression. B. WNT9B and WNT6 secreted by branches of the compressed resulting in a characteristic appearance of the ureteric bud epithelium cause upregulation of PAX2 and WNT4 in fetus, including a flattened face [Potterfacies] and club feet the surrounding mesenchyme. In turn, these genes cause the Congenital polycystic kidney disease mesenchyme to epithelialize (PAX2) and to then form tubules numerous cysts form. (WNT4). Changes in the extracellular matrix also occur, such that inherited as an autosomal recessive or autosomal dominant laminin and type IV collagen form a basement membrane (orange) disorder for the epithelial cells. Autosomal recessive polycystic kidney disease [ARPKD], I/5,000births RENALS TUMORS AND DEFECT A progressive disorder in which cysts form from collecting Wilms tumor ducts. Cancer of the kidneys the kidneys become very large affects children by 5 years old but may also occur in the renal failure occurs in infancy or childhood. fetus Autosomal dominant polycystic kidney disease due to mutations or microdeletion in WT1, PAX6 (anidria) cysts form from all segments of the nephron and usually do gene on chromosome 11p13, not cause renal failure until adulthood. associated with other abnormalities and syndromes, e.g. The autosomal dominant disease is more common [1/500 WAGR syndrome characterized by Wilms tumor, aniridia, to I/I,OOO births] but less progressive than the autosomal gonadoblastomas, and mental retardation recessive disease. Denys-Drash syndrome Both types of disease are linked to mutations in genes. Renal failure, ambiguous genitalia, and Wilms tumor These abnormalities belong to group of diseases called the Renal dysplasias and agenesis ciliopathies severe malformation, represent; primary diseases requiring ▪ due to mutations in cilia-related proteins. These dialysis and transplantation in first years of life disorders include Bardet-Biedl syndrome, Multicystic dysplastic kidney characterized by renal cysts, obesity, intellectual numerous ducts are surrounded by undifferentiated cells. disability, and limb defects, and Meckel-Gruber Nephrons fail to develop, reteric bud fails to branch, thus syndrome, characterized by renal cysts, the collecting ducts never form. hydrocephalus, microphthalmia, cleft palate, In some cases, these defects cause involution of the absence of the olfactory tract, and polydactyly. kidneys and renal agenesis Because cilia are present on most cell types and Renal agenesis in most tissues, many organ systems can be arise if the interaction between metanephric mesoderm affected by abnormalities and ureteric bud fails to occur Page 4 of 17 CMED 1D  (006) EMBRYOLOGIC DEVELOPMENT OF UROGENITAL SYSTEM DR. M.E GUERRERO| 01/18/21 metanephros receives its arterial supply from a pelvic branch of the aorta (lower vessels usually degenerate only few remains) Figure 8. Surface view of fetal kidney with multiple cyst characteristics of polycystic kidney disease. Note: Duplication of the ureter results from early splitting of the ureteric bud [Fig.16.9]. Splitting may be partial or Figure 8. A-C Ascent of the kidneys. Note the change in position complete, and metanephric tissue may be divided into two between the mesonephric and metanephric system. Mesonephric parts, each with its own renal pelvis and ureter. More system degenerates almost entirely only a few remnants persist in frequently, however, the two parts have a number of lobes cloae contact with the gonad. The gonads descend from their in common as a result of intermingling of collecting tubules. original level to a much lower position. In rare cases, one ureter opens into the bladder, and the other is ectopic, entering the vagina, urethra, or vestibule VII. FUNCTION OF THE KIDNEY [Fig. 16.9C]. This abnormality results from development of two ureteric buds. One of the buds usually has a normal position, whereas the abnormal bud moves down together Definitive kidney become functional near the 12th week with the mesonephric duct. Thus, it has a low, abnormal AOG entrance in the bladder, urethra, vagina, or epididymal Urine is passed into the amniotic cavity and mixes with the region. amniotic fluid, swallowed by the fetus and recycles through the kidneys During fetal life, the kidneys are not responsible for excretion of waste products because the placenta serves this function. VIII. BLADDER AND URETHRA 4th-7th weeks of development, the cloaca divides into the urogenital sinus anteriorly and the anal canal posteriorly Ururectal septum A layer of mesoderm between the primitive anal canal and the urogenital sinus. Perineal body Tip of the urogenital septum, site of insertion of several perineal muscles. Three portions of the urogenital sinus Figure 7. A, B. A complete and a partial double ureter (U) C. 1. Urinary bladder Possible sites of ectopic ureteral openings in the vagina, urethra Upper part and largest, continuous with allantois but if and vestibule. D, E. Photomicrographs of complete and partial the lumen of allantois is obliterated URACHUS duplications of the ureters. Arrows, duplicated hilum; B, bladder, (Median Umbilical Ligament in adult) remains in K, kidneys; ML, median umbilical ligament. connect the apex of the bladder and umbilicus 2. Pelvic part of the urogenital sinus VI. POSITION OF THE KIDNEY In Male will give rise to prostatic and membranous part of urethra. Initially a pelvic organ but later shift to a more cranial 3. Phallic part position in the abdomen, this ascent s due to diminution Flattened from side to side which will be pulled ventrally of body curvature and by growth of the body in the lumbar as it grows. and sacral regions Development of the phallic part of the urogenital sinus differs greatly between the two sexes During differentiation of the cloaca Page 5 of 17 CMED 1D  (006) EMBRYOLOGIC DEVELOPMENT OF UROGENITAL SYSTEM DR. M.E GUERRERO| 01/18/21 Caudal portions of the mesonephric ducts are CLINICAL CORRELATES absorbed into the wall of the urinary bladder. URACHAL FISTULA - cause urine to drain from the Ureters, initially outgrowths from the mesonephric umbilicus ducts, enter the bladder separately. - Due to the lumen of the intraembryonic portion of As a result of ascent of the kidneys, the orifices of the the allantois persists. ureters move farther cranially; those of the URACHAL CYST - oniy a local area of the allantois mesonephric ducts move close together to enter the persists, secretory activity of its lining results in a cystic prostatic urethra and in the male become the dilation ejaculatory ducts URACHAL SINUS - When the lumen in the upper part MESONEPHRIC DUCTS, URETERS AND THE MUCOSA persists OF THE BLADDER FORMED BY INCORPORATION OF - usually continuous with the urinary bladder THE DUCTS (THE TRIGONE OF THE BLADDER) ARE EXSTROPHY OF THE BLADDER - ventral body wall ALL MESODERMAL IN ORIGIN defect in which the bladder mucosa is exposed. TRIGOME MESODERMAL LINING WILL BE REPLACED Epispadias is a constant feature and the open urinary BY ENDODODERMAL EPITHELIUM. tract extends along the dorsal aspect of the penis through At the end of the third month, epithelium of the prostatic the bladder to the umbilicus. urethra proliferate, forms outgrowths that penetrate the - Due failure of lateral body wall to close in midline surrounding mesenchyme. pelvic region. Fates - Very rare 2/10,000 o Male - these buds form the prostate gland Exstrophy of the cloaca - severe ventral body wall defect in which o Female - the cranial part of the urethra gives rise to the progression and closure of the lateral body wall folds are disrupted urethral and paraurethral glands. to a greater degree than is observed in bladder exstrophy. - normal development of the urorectal septum is altered - malformations and imperforate anus occur - genital swellings are widely spaced resulting in defects in the external genitalia Figure 9. Divisions of the cloaca into the urogenital sinus and the anorectal canal. The mesonephric duct is gradually absorbed into the wall of the urogenital sinus and the ureters enter separately. Figure 11. A. Urachal Fistula. B. Urachal Cyst C. Urachal Sinus A. At the end of the 5th week B. 7th week and C. 8th week. (Open or Close) PELVIC KIDNEY - kidneys pass through the arterial fork formed by the umbilical arteries, but occasionally, one of them fails to do so. Remaining in the pelvis close to the com- mon iliac artery HORSESHOE KIDNEY - kidneys are pushed so close together during their passage through the arterial fork, that the lower poles fuse usually at the level of the lower lumbar vertebrae because its ascent is prevented by the root of the inferior mesenteric artery Figure 10. A. Development of the urogenital sinus into the urinary The ureters arise from the anterior surface of the kidney bladder and definitive urogenital sinus. B. In the male, the and pass ventral to the isthmus in a caudal direction. definitive urogenital sinus develops into the penile urethra. Horseshoe kidney is found in 1/600 people Prostate gland is formed by buds from the urethra, and seminal vesicles are formed by budding from the ductus deferens. Page 6 of 17 CMED 1D  (006) EMBRYOLOGIC DEVELOPMENT OF UROGENITAL SYSTEM DR. M.E GUERRERO| 01/18/21 ACCESSORY RENAL ARTERIES - common; they Originate in the epiblast, migrate through the primitive derive from the persistence of embryonic vessels that streak and by the third week, reside among endoderm cells formed during ascent of the kidneys. These arteries in the wall of the yolk sac close to the allantois usually arise from the aorta and enter the superior or inferior poles of the kidneys At 4th week, migrate by ameboid movement along the dorsal mesentery of the hindgut arriving at the primitive gonads at the beginning of the fifth week and invading the genital ridges. Figure 12. A. Exstrophy of the bladder B. Cloacal exstrophy in new born. Figure 14. A. 3—week embryo showing the primordial germ cells in the wall of the yolk sac close to the attachment of the allantois. B. Migrational path of the primordial germ cells along the wall of the hindgut and the dorsal mesentery into the genital ridge. B. TESTIS Male - the primordial germ cells carry an XY sex chromosome Figure 13. A. Unilateral Pelvic Kidney showing the position of the complex. adrenal gland on the affected side. B, C. Drawing and Tunica albuginea - a dense layer of fibrous connective tissue photomicrograph, respectively, of horseshoe kidneys showing the that separates the testis cords from the surface epithelium. position of the inferior mesenteric artery. Interstitial cells of Leydig - derived from the original mesenchyme of the gonadal ridge, lie between the testis IX. GENITAL SYSTEM cords. Eighth Week - Leydig cells begin production of testosterone Sex Differentiation is a complex process that involves many and the testis is able to influence sexual differentiation of the genes, including some that are autosomal. genital ducts and external genitalia. The key to sexual dimorphism is the Y chromosome which Fourth month - testis cords become horseshoe-shaped, and contain the SRY (sex-determining region on Y) gene their extremities are continuous with those of the rete testis. protein - is the testis-determining factor; under its influence, male development occurs; in its absence, female development is established. A. GONADS Sex of the embryo is determined genetically at the time of fertilization Appear initially as a pair of longitudinal ridges – genital or gonadal ridges Germ cell appear at the ridges at the start of 6 weeks of development Figure 15. A. Transverse section through the testis in the eighth Primordial germ cells appear at the genital ridges at the start week, showing the tunica albuginea, testis cords, rete testis, and of 6 weeks of development. primordial germ cells. The glomerulus and Bowman capsule of the Formed by proliferation of the epithelium and a condensation mesonephric excretory tubule are degenerating. B. Testis and of underlying mesenchyme. genital duct in the fourth month. The horseshoe—shaped testis cords are continuous with the rete testis cords. Note the ductuli Primordial germ cells efferentes [excretory mesonephric tubules], which enter the mesonephric duct. Page 7 of 17 CMED 1D  (006) EMBRYOLOGIC DEVELOPMENT OF UROGENITAL SYSTEM DR. M.E GUERRERO| 01/18/21 C. OVARY Female - embryos with an XX sex chromosome complement and no Y chromosome, primitive sex cords dissociate into irregular cell clusters. Seventh week - Gives rise to a second generation of cords, cortical cords, which penetrate the underlying mesenchyme but remain close to the surface. Follicular cells - layer of epithelial cells that surround each oogonium. Primordial follicle – constitute by oogonia and follicular cells. Figure 17. Genital ducts in the sixth week in the male [A] and female [B]. The mesonephric and paramesonephric ducts are present in both. Note the excretory tubules of the mesonephros and their relation to the developing gonad in both sexes. Figure 16. A. Transverse section of the ovary at the seventh week, showing degeneration of the primitive [medullary] sex cords and formation of the cortical cords. B. Ovary and genital ducts in the fifth month. Note degeneration of the medullary cords. The excretory mesonephric tubules [efferent ductules] do not communicate with the rete. The cortical zone of the ovary contains groups of oogonia surrounded by follicular cells. Figure 18. A. Genital ducts in the female at the end of the second X. GENITAL DUCTS month. Note the paramesonephric [miillerian] tubercle and formation of the uterine canal. B. Genital ducts after descent of the Initially both male and female embryos have two pairs of ovary. The only parts remaining from the mesonephric system are genital ducts: the epoophoron, paroophoron, and Gartner cyst. Note the MESONEPHRIC (WOLFFIAN)DUCTS-open into the suspensory ligament of the ovary, ligament of the ovary proper, urogenital sinus on either side of the sinus tubercle and round ligament of the uterus. PARAMESONEPHRIC (MFILLERIAN) DUCTS-arises as a longitudinal invagination of the epithelium on the anterolateral surface of the urogenital ridge. Cranially: duct opens into the abdominal cavity with a funnel- like structure Caudally: runs lateral to the mesonephric duct, then crosses it ventrally to grow caudomedially. In the midline, it comes in close contact with the paramesonephric duct from the opposite side. Sinus tubercle-caudal tip of the combined ducts projects into the posterior wall of the urogenital sinus, where it causes a small swelling Figure 19. Influence of the sex glands on further sex differentiation. Page 8 of 17 CMED 1D  (006) EMBRYOLOGIC DEVELOPMENT OF UROGENITAL SYSTEM DR. M.E GUERRERO| 01/18/21 A. GENITAL DUCTS IN MALE (1) a cranial vertical portion that opens into the abdominal Testosterone – stimulate to develop and are derived cavity, from parts of the mesonephric kidney system (2) a horizontal part that crosses the mesonephric duct, and Efferent ductules of the testis-form from some of the (3) a caudal vertical part that fuses with its partner from the original excretory tubules (epigenital tubules) establish opposite side contact with cords of the rete testis. With descent of the ovary, the first two parts develop into Excretory tubules along the caudal pole of the testis, the the uterine tube and the caudal parts fuse to form the paragenital tubules, do not join the cords of the rete testis. uterine canal. Their vestiges are collectively known as the When the second part of the paramesonephric ducts moves paradidymis. mediocaudally, the urogenital ridges gradually come to lie except for the most cranial portion, appendix epididymis, in a transverse plane. After the ducts fuse in the midline, a the mesonephric ducts persist and form the main genital broad transverse pelvic fold is established ducts This fold, which extends from the lateral sides of the fused (Ductus) Epididymis-immediately below the entrance of paramesonephric ducts toward the wall of the pelvis, is the the efferent ductules, the mesonephric ducts elongate broad ligament of the uterus. The uterine tube lies in its and become highly convoluted. upper border, and the ovary lies on its posterior surface. Ductus Deferens-form from the tail of the epididymis to The uterus and broad ligaments divide the pelvic cavity into the outbudding of the seminal vesicle, the mesonephric the uterorectal pouch and the uterovesical pouch. ducts obtain a thick muscular coat. The fused paramesonephric ducts give rise to the corpus Ejaculatory Duct-region of the ducts beyond the seminal and cervix of the uterus and the upper portion of the vagina. vesicles. uterus is surrounded by a layer of mesenchyme that forms ANTI-MIILLERIAN HORMONE (AMH; ALSO CALLED both its muscular coat, the myometrium, and its peritoneal MIILLERIAN INHIBITING SUBSTANCE [MIS])- covering, the perimetrium. produced by Sertoli cells, paramesonephric ducts in the absence of testosterone, mesonephric ducts in the female male degenerate except for a small portion at their cranial degenerate ends, the appendix testis Figure 21. Transverse sections through the urogenital ridge at progressively lower levels. AB. The paramesonephric ducts approach each other in the midline and fuse. C. As a result of fusion, a transverse fold, the broad ligament of the uterus, forms in the pelvis. The gonads come to lie at the posterior aspect of the Figure 20. A. Genital ducts in the male in the fourth month. Cranial transverse fold. and caudal [paragenital tubule] segments of the mesonephric system regress. B. Genital ducts after descent of the testis. Note the horse-shoe-shaped testis cords, rete testis, and efferent C. MOLECULAR REGULATION OF GENITAL ductules entering the ductus deferens. The paradidymis is formed DUCT DEVELOPMENT by remnants of the paragenital mesonephric tubules. The SRY- transcription factor and the master gene for testes paramesonephric duct has degenerated except for the appendix development. It appears to act in conjunction with the testis. The prostatic utricle is an outpocketing from the urethra. autosomal gene SOX9, a transcriptional regulator, that can also induce testes differentiation for a potential pathway for B. Genital Ducts in Female these genes). presence of estrogen and the absence of testosterone and SOX9-bind to the promoter region of the gene for AMH AMH (MIS), paramesonephric ducts develop into the main (M18) and probably regulates this gene’s expression. genital ducts of the female. SRY and/or SOX9 induce the testes to secrete FGF9 that three parts can be recognized in each duct: acts as a chemotactic factor that causes tubules from the mesonephric duct to penetrate the gonadal ridge. Page 9 of 17 CMED 1D  (006) EMBRYOLOGIC DEVELOPMENT OF UROGENITAL SYSTEM DR. M.E GUERRERO| 01/18/21 Without penetration by these tubules, differentiation of the XI. VAGINA testes does not continue. SRY either directly or indirectly (through SOX9) upregulates production of STEROIDOGENESIS FACTOR 1 (SF1) that stimulates differentiation of Sertoli and Leydig cells. SF 1 working with SOX9 elevates the concentration of AMH leading to regression of the paramesonephric (miillerian) ducts. SF 1 upregulates the genes for enzymes that synthesize testosterone. Testosterone enters cells of target tissues where it may remain intact or be converted to dihydrotestosterone by a 5-0: reductase enzyme. Testosterone and dihydrotestosterone bind to a specific high-affinity Figure 23. Formation of the Uterus and Vagina intracellular receptor, and this hormone receptor complex is transported to the nucleus where it binds to DNA to regulate transcription of tissue-specific genes and their protein products. Testosterone receptor complexes-mediate differentiation of the mesonephric ducts to form the vas deferens, seminal vesicles, efferent ductules, and epididymis. Dihydrotestosterone receptor complexes-modulate differentiation of the male external genitalia. WNT4 - ovary-determining gene-upregulates DAXI, a Figure 24. Sagittal sections showing formation of the uterus and member of the nuclear hormone receptor family, that vagina at various stages of development A. 9 weeks. B. End of inhibits the function of SOX9. ; regulates expression of third month. C. Newborn. other genes responsible for ovarian differentiation TAFIH 05 gene, whose protein product is a subunit for the Shortly after the solid tip of the paramesonephric ducts TATA-binding protein for RNA polymerase in ovarian contacts the urogenital sinus, (Labelled A and D) two solid follicular cells evaginations grow out from the pelvic part of the sinus. Estrogens-involved in sexual differentiation, and under (Labelled B and E) their influence, the paramesonephric (miillerian) ducts are Sinovaginal bulbs stimulated to form the uterine tubes, uterus, cervix, and - These are the evaginations that will proliferate and upper vagina; act on the external genitalia at the indifferent form a solid vaginal plate. stage to form the labia majora, labia minora, clitoris, and Proliferation continues at the cranial end of the plate, lower vagina. increasing the distance between the uterus and the urogenital sinus. By the fifth month, the vaginal outgrowth is entirely canalized. The wing-like expansions of the vagina around the end of the uterus, the vaginal fornices, are of paramesonephric origin. (Labelled F) Thus, the vagina has a dual origin: - Upper portion - derived from the uterine canal - Lower portion- derived from the urogenital sinus. Figure 22. Schematic showing genes responsible for The lumen of the vagina remains separated from that of the differentiation of the testes and ovaries. In both males and urogenital sinus by a thin tissue plate called the hymen females, SOX9 and WNT4 are expressed in the gonadal ridges. In (Labelled C and F) which consists of the epithelial lining of males, the expression of SRY upregulates SOX9, which in turn the sinus and a thin layer of vaginal cells. It usually develops activates expression of SF] and other genes responsible for testes a small opening during perinatal life. differentiation while inhibiting expression of WNT4. In females, the uninhibited expression of WNT4 upregulates DAXlthat in turn inhibits SOX9 expression. Then, under the continued influence of WNT4, other downstream target genes [perhaps TAF/l705] induce ovarian differentiation. Page 10 of 17 CMED 1D  (006) EMBRYOLOGIC DEVELOPMENT OF UROGENITAL SYSTEM DR. M.E GUERRERO| 01/18/21 side. Because its lumen usually does not communicate with the vagina, complications are common. - Cervical Atresia If the atresia involves both sides - Double Vagina develops if the sinovaginal bulbs fail to fuse - Atrasia of the Vagina develops if the sinovaginal bulbs do not develop at all. Figure 25. Genital Ducts after the descent of the ovary A small vaginal pouch originating from the paramesonephric ducts usually surrounds the The female may retain some remnants of the cranial and opening of the cervix. caudal excretory tubules in the mesovarium where they form the epoophoron and paroophoron, respectively. XII. EXTERNAL GENITALIA (Figure 25) The mesonephric duct disappears except for a small cranial portion found in the epoophoron and occasionally a small caudal portion that may be found in the wall of the uterus or vagina. Later in life, it may form Gartner cyst. (Figure 25) UTERUS AND VAGINAL DEFECTS Figure 27. Indifferent stages of the external genitalia Cloacal folds (Labelled A) - A pair of slightly elevated structures that are formed in the 3rd week of development, wherein the mesenchyme cells originating in the region of the primitive streak migrate around the cloacal membrane Figure 26. Main abnormalities of the uterus and vagina caused Cranial to the cloacal membrane, the folds unite to form the by persistence of the uterine septum or obliteration of the lumen genital tubercle. of the uterine canal. Caudally, the folds are subdivided into urethral folds anteriorly and anal folds posteriorly (Labelled B) Duplications of the uterus result from lack of fusion of the In the meantime, another pair of elevations, the genital paramesonephric ducts in a local area or throughout their swellings, becomes visible on each side of the urethral normal line of fusion. folds. These swellings later form the scrotal swellings in - Uterus didelphys the male (Labelled A) and the labia majora in the female. At Extreme Form the end of the sixth week, however, it is impossible to Uterus is entirely double distinguish between the two sexes. - Uterus arcuatus Least severe form A. EXTERNAL GENITALIA IN MALE Only slightly indented in the middle - Uterus bicornis Relatively common The uterus has two horns entering a common vagina This condition is normal in mammals below the primates. - Uterus bicornis with one rudimentary horn In patients with complete or partial atresia of one of the paramesonephric ducts, the rudimentary part lies as an appendage to the well-developed Figure 28. Development of the male external genitalia Page 11 of 17 CMED 1D  (006) EMBRYOLOGIC DEVELOPMENT OF UROGENITAL SYSTEM DR. M.E GUERRERO| 01/18/21 Development of the external genitalia in the male is under the penis, usually near the glans, along the shaft, or near the influence of androgens secreted by the fetal testes and the base of the penis. is characterized by rapid elongation of the genital tubercle - In rare cases, the urethral meatus extends along the called the phallus (Labelled A) scrotal raphe. When fusion of the urethral folds fails During this elongation, the phallus pulls the urethral folds entirely, a wide sagittal slit is found along the entire length forward so that they form the lateral walls of the urethral of the penis and the scrotum. The two scrotal swellings groove. then closely resemble the labia majora. This groove extends along the ventral aspect of the Epispadias (Labelled D) elongated phallus but does not reach the most distal part, - a rare abnormality [1/30,000 births] in which the urethral the glans. meatus is found on the dorsum of the penis. Urethral plate (Labelled B) - most often associated with exstrophy of bladder and - Formed by the epithelial lining of the groove, abnormal closure of the ventral body wall. which originates in the endoderm. Micropenis penile urethra (Labelled B) - Occurs when there is insufficient androgen stimulation for - Formed by the two urethral folds closing over growth of the external genitalia. the urethral plate at the end of the third month - Usually caused by primary hypogonadism or This canal does not extend to the tip of the phallus. This hypothalamic or pituitary dysfunction. most distal portion of the urethra is formed during the fourth - The penis is 2.5 standard deviations below the mean in month. length as measured along the dorsal surface from the External urethral meatus (Labelled C) pubis to the tip with the penis stretched to resistance - Formed when the ectodermal cells from the tip Bifold Penis or Double Penis of the glans penetrate inward and form a short - May occur if the genital tubercle splits. epithelial cord - this cord later obtains a lumen. - This canal does not extend to the tip of the B. EXTERNAL GENITALIA IN FEMALE phallus. This most distal portion of the urethra is formed during the fourth month Scrotal swellings - Genital swellings that arise in the inguinal region. With further development, they move caudally, and each swelling then makes up half of the scrotum. The two are separated by the scrotal septum (Labelled D) - DEFECTS IN THE MALE GENITALIA Figure 30. Development of the External Genitalia in Females in 5 months (A) and in newborn (B) Estrogen - stimulate development of the external genitalia of the female. Clitoris (Labelled A) - Formed by the slight elongation of the genital tubercle. Labia minora - Urethral folds do not fuse, as in the male, but develop into the Labia minora. Labia majora. Figure 29. Defects of the Male Genitalia - Formed by the enlargement of the genital swellings. Hypospadias (Labelled A, B and C) Vestibule (Labelled B) - Occurs in 3 to 5/1,000 births, and this rate represents a - The urogenital groove is open and forms the doubling over the past 15 to 20 years. vestibule - Fusion of the urethral folds is incomplete, and abnormal openings of the urethra occur along the ventral aspect of Page 12 of 17 CMED 1D  (006) EMBRYOLOGIC DEVELOPMENT OF UROGENITAL SYSTEM DR. M.E GUERRERO| 01/18/21 Although the genital tubercle does not elongate extensively in abdominal portion of the gubernaculum produces intra- the female, it is larger than in the male during the early stages abdominal migration, that an increase in intra-abdominal of development pressure due to organ growth produces passage through Using tubercle length as a criterion (as monitored by the inguinal canal, and that regression of the extra- ultrasound) has resulted in mistakes in identification of the abdominal portion of the gubernaculum completes sexes during the third and fourth months of gestation. movement of the testis into the scrotum. Normally, the testes reach the inguinal region by XIII. DESCENT OF TESTES approximately 12 weeks’ gestation, migrate through the inguinal canal by 28 weeks, and reach the scrotum by 33 weeks The process is influenced by hormones, including androgens and M18. During descent, blood supply to the testis from the aorta is retained, and testicular vessels extend from their original lumbar position to the testis in the scrotum. Independently from descent of the testis, the peritoneum of the abdominal cavity forms an evagination on each side of the midline into the ventral abdominal wall. This evagination, the processus vaginalis, follows the course of the gubernaculum testis into the scrotal swellings (Labelled B) Hence, the processus vaginalis, accompanied by the muscular and fascial layers of the body wall, evaginates into Figure 31. Descent of the testes during the second month (A), the scrotal swelling, forming the inguinal canal (Figure 32) middle of the third month (B), seventh month (C) and shortly after birth (D). The testes develop retroperitoneally in the abdominal region and must move caudally and pass through the abdominal wall to reach the scrotum. Passage through the abdominal wall is via the inguinal canal, which is about 4 cm long and lies just superiorly to the medial half of the inguinal ligament. - Entry to the canal is by the deep (internal) inguinal ring, - Exit is by the superficial (external) ring near the pubic tubercle. Toward the end of the second month, the urogenital mesentery attaches the testis and mesonephros to the posterior abdominal wall. With degeneration of the mesonephros, the attachment serves as a mesentery for Figure 32. Drawing showing the coverings of the testes that are the gonad. Caudally, it becomes ligamentous and is known derived from constituents of the abdominal wall. as the caudal genital ligament. Also extending from the caudal pole of the testis is a The testis descends through the inguinal ring and over the mesenchymal condensation rich in extracellular matrices, rim of the pubic bone and is present in the scrotum at birth. called the gubernaculum. The testis is then covered by a reflected fold of the Prior to descent of the testis, this band of mesenchyme processus vaginalis (Labelled D). terminates in the inguinal region between the differentiating - The peritoneal layer covering the testis is the Visceral internal and external abdominal oblique muscles. layer of the tunica vaginalis; Later, as the testis begins to descend toward the internal - the remainder of the peritoneal sac forms the parietal inguinal ring, an extra-abdominal portion of the layer of the tunica vaginalis gubernaculum forms and grows from the inguinal region The narrow canal connecting the lumen of the vaginal toward the scrotal swellings process with the peritoneal cavity is obliterated at birth or When the testis passes through the inguinal canal, this shortly thereafter. extra-abdominal portion contacts the scrotal floor. In addition to being covered by peritoneal layers derived Factors controlling descent of the testis are not entirely from the processus vaginalis, the testis becomes clear. It appears, however, that outgrowth of the extra- Page 13 of 17 CMED 1D  (006) EMBRYOLOGIC DEVELOPMENT OF UROGENITAL SYSTEM DR. M.E GUERRERO| 01/18/21 ensheathed in layers derived from the anterior abdominal - In 97% of male newborns, testes are present in the wall through which it passes. scrotum before birth. In most of the remainder, - the transversalis fascia forms the internal spermatic descent will be completed during the first 3 months fascia postnatally - the internal abdominal oblique muscle gives rise to - The undescended testes fail to produce mature the cremasteric fascia and muscle spermatozoa, and the condition is associated with a - the external abdominal oblique muscle forms the 3% to 5% incidence of renal anomalies. external spermatic fascia The transversus abdominis muscle does not contribute a DISORDERS OF SEX DEVELOPMENT layer because it arches over this region and does not cover Because sexual development of males and females begins the path of migration. in an identical fashion, it is not surprising that abnormalities in differentiation and sex determination occur. XIV. DESCENT OF OVARIES Ambiguous genitalia Descent of the gonads is considerably less in the female than in the male, and the ovaries finally settle just below the rim of the true pelvis. Cranial genital ligament - forms the suspensory ligament of the ovary Caudal genital ligament - forms the ligament of the ovary proper and the round ligament of the uterus. HERNIAS AND CRYPTORCHIDISM Figure 33. Male [46, XY] infant with ambiguous genitalia. - may appear as a large clitoris or a small penis. - a child may be born with a typically female appearance, but with a large clitoris [clitoral hypertrophy] or typically male with a small penis that is open on its ventral surface [hypospadias] - In some cases, these abnormalities result in individuals with characteristics of both sexes Ovotesticular disorders of sex development [formerly called true hermaphrodism] - both ovarian and testicular tissues are present. - Thus, gonadal tissue may be any combination of ovary, testis, or ovotestis, which is present in 2/3 of cases. Figure 33. Inguinal Hernia (A) and Hydrocele (B) 46,XX Disorders of Sex Development - Genitalia are always ambiguous, but there is a tendency Congenital indirect inguinal hernia toward masculinization. In 70% of cases, the karyotype is - The connection between the abdominal cavity and 46,XX the processus vaginalis through the inguinal canal - females that have been exposed to excessive amounts and into the scrotal sac normally closes in the first of androgenic compounds that masculinize the external year after birth. If this passageway remains open, genitalia causing them to be ambiguous intestinal loops may descend into the scrotum, 1. Congenital adrenal hyperplasia [CAH] causing a congenital indirect inguinal hernia. - most common cause of ambiguous (Labelled A) genitalia, accounting for approximately - Sometimes, obliteration of this passageway is 60% of all DSDs. Individuals are genetically irregular, leaving small cysts along its course. Later, female [46,XX] but excessive these cysts may secrete fluid, forming a hydrocele androstenedione -H produced by the of the testis and/or spermatic cord. adrenal glands results in masculinization of Cryptorchidism the external genitalia. - one or both testes fail to descend in