EMBRYO-LC13-Embryonic Development of the Urogenital System.pdf

OUTLINE I. UROGENITAL SYSTEM II. URINARY SYSTEM A. Pronephros B. Mesonephros C. Metanephros: The Definitive Kidney III. COLLECTING SYSTEM IV. EXCRETORY SYSTEM V. MOLECULAR REGULATION...

OUTLINE I. UROGENITAL SYSTEM II. URINARY SYSTEM A. Pronephros B. Mesonephros C. Metanephros: The Definitive Kidney III. COLLECTING SYSTEM IV. EXCRETORY SYSTEM V. MOLECULAR REGULATION OF KIDNEY DEVELOPMENT VI. POSITION OF THE KIDNEY VII. FUNCTION OF THE KIDNEY VIII. BLADDER AND URETHRA IX. GENITAL SYSTEM Figure 1. Transverse sections through embryos at various stages of development A. Gonads showing formation of nephric tubules. A. 21 days. B. 25 days. Note formation of B. Testes external and internal glomeruli and the open connection between the C. Ovary intraembryonic cavity and the nephric tubule. X. GENITAL DUCTS A. Genital ducts in male B. Genital ducts in female C. Molecular regulation of genital duct development XI. VAGINA XII. EXTERNAL GENITALIA A. External genitalia in male 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 Figure 2. A. Relationship of the intermediate mesoderm of the pronephric, They are intimately interwoven embryologically and anatomically mesonephric, and metanephric systems. In cervical and upper thoracic regions, ○ any abnormality in one of the system affects the functions intermediate mesoderm is segmented; in lower thoracic, lumbar, and sacral of the other regions, it forms a solid, unsegmented mass of tissue, the nephrogenic cord. Both develop from a common mesodermal ridge (intermediate Note the longitudinal collecting duct, formed initially by the pronephros but later mesoderm) along the posterior wall of the abdominal cavity. by the mesonephros (Mesonephric duct). B. Excretory tubules of the pronephric Initially, the excretory ducts of both systems enter a common cavity, and mesonephric systems in a 5-week embryo. the cloaca. MESONEPHROS II. URINARY SYSTEM Mesonephros and mesonephric ducts - derived from intermediate mesoderm from upper thoracic to upper lumbar (L3) segments KIDNEY SYSTEMS Early in the fourth week of development, during regression of the Three slightly overlapping kidney systems are formed in a pronephric system, the first excretory tubules of the mesonephros cranial-to-caudal sequence during intrauterine life in humans: appear - Pronephros: rudimentary and nonfunctional. They lengthen rapidly, form an S-shaped loop, acquire a tuft of - First step of the development of the kidney capillaries that will form a glomerulus at their medial extremity system Around the glomerulus, the tubules form Bowman’s capsule, and - Mesonephros: may function for a short time during the together, these structures constitute a renal corpuscle. early fetal period. Laterally, the tubule enters the longitudinal collecting duct known as - Metanephros: forms the permanent kidney. the mesonephric or wolffian duct. In the middle of the second month, mesonephros forms a large ovoid PRONEPHROS organ on each side of the midline. At the beginning of the fourth week age of gestation (AOG). Because the developing gonad is on its medial side, the ridge formed Represented by 7 to 10 solid cell groups in the cervical region. by both organs is known as the urogenital ridge. These groups form vestigial excretory units, nephrotomes, that While caudal tubules are still differentiating, cranial tubules and regress before more caudal ones are formed. glomeruli show degenerative changes, and by the end of the second By the end of the fourth week, all indications of the pronephric month, the majority have disappeared. system have disappeared In males, a few of the caudal tubules and the mesonephric ducts persist and participate in the formation of the genital system, but they disappear in females. Page 1 of 14 [EMBRYOLOGY] 1.13 EMBRYONIC DEVELOPMENT OF THE UROGENITAL SYSTEM – Dr. M. E. Guerrero, MD During further development, collecting tubules of the fifth and successive generations elongate considerably and converge on the minor calyx, forming the renal pyramid. Ureteric bud gives rise to the ureter, the renal pelvis, the major and minor calyces, and approximately 1 to 3 million collecting tubules. Figure 3. A. Transverse section through the urogenital ridge in the lower thoracic Figure 4. Relation of the hindgut and cloaca at the end of the fifth week.The region of a 5-week embryo showing the formation of an excretory tubule of the ureteric bud penetrates the metanephric mesoderm (blastema). mesonephric system. Note the appearance of Bowman’s capsule and the gonadal ridge. The mesonephros and gonad are attached to the posterior abdominal wall by a broad urogenital mesentery. B. Relation of the gonad and the mesonephros. Note the size of the mesonephros. The mesonephric duct (wolffian duct) runs along the lateral side of the mesonephros. METANEPHROS the definitive kidney Third urinary organ Also known as the “permanent kidney”. Appears in the fifth week ○ In a span of one week, three kidney systems were established 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 tubules of the The development of the duct system differs from that of the other metanephros. A. 6 weeks.. At the end of the sixth week. C. 7 weeks. D. kidney systems. Newborn. Note the pyramid form of the collecting tubules entering the minor calyx. III. COLLECTING SYSTEM IV. EXCRETORY SYSTEM URETERIC BUD Where collecting ducts of the permanent kidney develop from the Each newly formed collecting tube is covered at its distal end by ureteric bud. metanephric tissue cap. An outgrowth of the mesonephric duct close to its entrance to the It is under the inductive influence of the tubule, cells of the tissue cloaca. that form small vesicles, renal vesicles, which in turn give rise to Bud penetrates the metanephric tissue, which is molded over its small S-shaped tubules. distal end as a cap. Capillaries grow into the pocket at one end of the S and differentiate ○ the ureteric bud starts as a very simple collecting tubule into glomeruli. that will lengthen to form the renal vesicles; the bowman These tubules together with their glomeruli, forming nephrons or capsule forms excretory units. The proximal end of each nephron forms Bowman capsule, which is RENAL PELVIS deeply indented by a glomerulus. The bud dilates, forming the primitive renal pelvis, splits into cranial The distal end forms an open connection with one of the collecting and caudal portions forming major calyces. tubules, establishing a passageway from Bowman capsule to the Each calyx forms two new buds while penetrating the metanephric collecting unit. tissue. The continuous lengthening of the excretory tubule results in These buds continue to subdivide until 12 or more generations of formation of: tubules have formed. ○ Loop of Henle Meanwhile at the periphery, more tubules form until the end of the ○ Proximal convoluted tubule fifth month. ○ Distal convoluted tubule Tubules of the 2nd order enlarge and absorb those of the 3rd and 4th Kidney develops from two sources: generations, forming the minor calyces of the renal pelvis. ○ Metanephric mesoderm: provides excretory units ○ Ureteric bud: gives rise to the collecting system Page 2 of 14 [EMBRYOLOGY] 1.13 EMBRYONIC DEVELOPMENT OF THE UROGENITAL SYSTEM – Dr. M. E. Guerrero, MD Nephrons are formed until birth at which time there are Fibronectin, Collagen I, and Collagen II are also replaced with approximately 1 million in each kidney. laminin and type IV collagen, a characteristic of an epithelial basal The urine production begins in the 12th week, following the lamina. differentiation of the glomerular capillaries, which start to form by In addition, the cell adhesion molecules syndecan and E-cadherin, the 10th week. which are essential for condensation of the mesenchyme into an At birth, the kidneys have a lobulated appearance. epithelium, are synthesized. Then, during infancy, the lobulation disappears as a result of further growth of nephrons, without increase in their number. Figure 7. Genes involved in differentiation of the kidney. A. WT1, expressed by the mesenchyme, enables this tissue to respond to induction by the ureteric bud. Glial-derived neurotrophic factor (GDNF) and hepatocyte growth factor (HGF), also produced by the mesenchyme, interact through their receptors, RET and MET, respectively, in the ureteric bud epithelium, to stimulate growth of the bud and maintain the interactions. The growth factors fibroblast growth factor 2 (FGF2) and bone morphogenic protein 7 (BMP7) stimulate proliferation of the mesenchyme and maintain WT1 expression. B. WNT9B and WNT6 secreted by branches of the ureteric bud epithelium cause upregulation of PAX2 and WNT4 in the surrounding mesenchyme. In turn, these genes cause the mesenchyme to Figure 6. A – F. Development of a metanephric excretory unit. Arrows, the place epithelialize (PAX2) and to then form tubules (WNT4). Changes in the where the excretory unit (blue) establishes an open communication with the extracellular matrix also occur, such that laminin and type IV collagen form a collecting system (yellow), allowing flow of urine from the glomerulus into the basement membrane (orange) for the epithelial cells. collecting ducts. RENAL TUMORS AND DEFECTS Wilms’ tumor: Usually affects children 5 years of age but may also V. MOLECULAR REGULATION OF KIDNEY DEVELOPMENT occur in the fetus. ○ It is due to mutations in the WT1 gene on 11p13, and it As with most organs, differentiation of the kidney involves epithelial may be associated with other abnormalities and mesenchymal interactions. syndromes such as: ○ For example: epithelium of the ureteric bud from the WAGR syndrome: characterized by aniridia, mesonephros interacts with the mesenchyme of the hemihypertrophy, and Wilms’ tumor. metanephric blastema. Denys-Drash syndrome consists of renal WT1 failure, pseudohermaphroditism, and Wilms’ Expressed by mesenchyme tumor. A transcription factor that makes this tissue competent to respond to Renal dysplasia and Agenesis: severe malformations that represent induction by the ureteric bud. the primary diseases requiring dialysis and transplantation in the first It also regulates production of glial-derived neurotrophic growth years of life. factor (GDNF) and hepatocyte growth factor (HGF or scatter factor) ○ Multicystic dysplastic kidney: example in which numerous by the mesenchyme, and these proteins stimulate branching and ducts are surrounded by undifferentiated cells. Nephrons growth of the ureteric buds. fail to develop and the ureteric bud fails to branch, so that Tyrosine kinase receptors (RET) for GDNF, and MET for HGF, are the collecting ducts never form. In some cases these synthesized by the epithelium of the ureteric buds, establishing defects cause involution of the kidneys and renal signaling pathways between two tissues. agenesis. In turn, the buds induce the mesenchyme via fibroblast growth ○ Renal agenesis: may also occur if the ureteric bud fails to factors 2 (FGF2) and bone morphogenic protein 7 (BMP7). contact and/or induce the metanephric mesoderm. Both of these growth factors block apoptosis and stimulate Bilateral renal agenesis: Results in renal failure proliferation in the metanephric mesenchyme while maintaining which occurs in 1/10,000 births. production of WT1. Potter sequence, characterized by anuria, The conversion of the mesenchyme to an epithelium for nephron oligohydramnios (decreased volume of formation is also mediated by the ureteric buds through expression amniotic fluid), and hypoplastic lungs of WNT9B and WNT6, which upregulate PAX2 and WNT4 in the secondary to the oligohydramnios. metanephric mesenchyme. 85% of cases that accompany this PAX2 promotes condensation of the mesenchyme preparatory to condition show absence or tubule formation, whereas WNT4 causes the condensed abnormalities of the vagina and mesenchyme to epithelialize and form tubules due to the uterus, vas deferens, and seminal interactions and modifications in the extracellular matrix. vesicles. Page 3 of 14 [EMBRYOLOGY] 1.13 EMBRYONIC DEVELOPMENT OF THE UROGENITAL SYSTEM – Dr. M. E. Guerrero, MD Common associated defects in Perineal Body other systems include cardiac Tip of the urogenital septum anomalies, tracheal and duodenal Site of insertion of several perineal muscles atresias, cleft lip and palate, and brain abnormalities. A. THREE PORTIONS OF THE UROGENITAL SINUS Congenital polycystic kidney: a numerous cysts form which may be 1. Urinary Bladder inherited as an autosomal recessive or autosomal dominant disorder Upper part and largest or may be caused by other factors. Continuous with allantois but if the lumen of allantois is obliterated, ○ Autosomal recessive polycystic kidney disease: kidneys urachus (median umbilical ligament in the adult) remains and become very large, and renal failure occurs in infancy or connects the apex of the bladder with the umbilicus. childhood that occurs in 1/5,000 births, is a progressive disorder in which cysts form from collecting ducts. 2. Pelvic Part of the Urogenital Sinus ○ Autosomal dominant polycystic kidney disease: cysts form Will give rise to the prostatic and membranous part of the urethra in from all segments of the nephron and usually do not males. cause renal failure until adulthood which is more common (1/500 to 1/1,000 births) but less progressive than the 3. Phallic Part autosomal recessive disease. Flattened from side to side which will be pulled ventrally Development of the phallic part of the urogenital sinus differs greatly between the two sexes. VI. POSITION OF THE KIDNEY During differentiation of the cloaca: Initially a pelvic organ but later shift to a more cranial position in the The caudal portions of the mesonephric ducts are absorbed into the abdomen, this ascent is due to diminution of body curvature and by wall of the urinary bladder. growth of the body in the lumbar and sacral regions Consequently, the ureters, initially outgrowths from the mesonephric In the pelvis the metanephros receives its arterial supply from a ducts, enter the bladder separately pelvic branch of the aorta. During its ascent to the abdominal level, it As a result of ascent of the kidneys, the orifices of the ureters move is vascularized by arteries that originate from the aorta at farther cranially; those of the mesonephric ducts move close continuously higher levels. The lower vessels usually degenerate, but together to enter the prostatic urethra and in the male become the some may remain. ejaculatory ducts TRIGONE OF THE BLADDER Mesonephric ducts, ureters, and the mucosa of the bladder formed by incorporation of the ducts Mesodermal in origin The mesodermal lining of the trigone is replaced by endodermal epithelium, so that finally, the inside of the bladder is completely lined with endodermal epithelium. The epithelium of the urethra in both sexes originates in the endoderm; the surrounding connective and smooth muscle tissue is derived from visceral mesoderm. Figure 8. A to C. Ascent of the kidneys. Note the change in position between the mesonephric and metanephric systems. The mesonephric system degenerates END OF 3RD MONTH almost entirely, and only a few remnants persist in close contact with the gonad. Epithelium of the prostatic urethra begins to proliferate and forms a In both male and female embryos, the gonads descend from their original level number of outgrowths that penetrate the surrounding mesenchyme. to a much lower position. In the male, these buds form the prostate gland In the female, the cranial part of the urethra gives rise to the VII. FUNCTION OF THE KIDNEY urethral and paraurethral glands. The definitive kidney formed from the metanephros becomes functional near the 12th week AOG Urine is passed into the amniotic cavity and mixes with the amniotic cavity and mixes with the amniotic fluid, the fluid is swallowed by the fetus and recycles through the kidneys. During fetal life, the kidneys are not possible for excretion of waste products 4th-7th weeks of development, the cloaca divides into the urogenital sinus anteriorly and the anal canal posteriorly. VIII. BLADDER AND URETHRA 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. A. At During the fourth to seventh weeks of development, the cloaca divides the end of the 5th week B. 7th week and C. 8th week. into: 1. Urogenital sinus - anteriorly 2. Anal canal - posteriorly Urorectal Septum A layer of mesoderm between the primitive anal canal and the urogenital sinus Page 4 of 14 [EMBRYOLOGY] 1.13 EMBRYONIC DEVELOPMENT OF THE UROGENITAL SYSTEM – Dr. M. E. Guerrero, MD Figure 12. A. Exstrophy of the bladder. B. Cloacal exstrophy in a newborn. Figure 10. A. Development of the urogenital sinus into the urinary bladder and definitive urogenital sinus. B. In the male, the definitive urogenital sinus develops into the penile urethra. Prostate gland is IX. GENITAL SYSTEM formed by buds from the urethra, and seminal vesicles are formed by budding from the ductus deferens. Sex Differentiation is a complex process that involves many genes, including some that are autosomal. B. CLINICAL CORRELATES The key to sexual dimorphism is the Y chromosome which contains Bladder defects: the SRY (sex-determining region on Y) gene protein is the testis Urachal fistula determining factor; under its influence, male development occurs; in - When the lumen of the intraembryonic portion of the its absence, female development is established. allantois persists, urachal fistula may cause urine to drain from the umbilicus. GONADS Urachal cyst Sex of the embryo is determined genetically at the time of - If only a local area of the allantois persists, secretory fertilization activity of its lining results in a cystic dilation. Appear initially as a pair of longitudinal ridges – genital or gonadal Urachal sinus ridges - When the lumen in the upper part persists, it forms a Germ cell appear at the ridges at the start of 6 weeks of sinus which is usually continuous with the urinary bladder. development Exstrophy of the bladder Primordial germ cells appear at the genital ridges at the start of 6 - is a ventral body wall defect in which the bladder mucosa weeks of development. is exposed, and the open urinary tract extends along the Formed by proliferation of the epithelium and a condensation of dorsal aspect of the penis through the bladder to the underlying mesenchyme. umbilicus. Primordial germ cells - Probably due to failure of the lateral body wall folds to ○ Originate in the epiblast, migrate through the primitive close in the midline in the pelvic region. streak and by the third week, reside among endoderm - This anomaly is rare, occurring in 2/10, 000 live births. cells in the wall of the yolk sac close to the allantois Exstrophy of the cloaca ○ At 4th week, migrate by ameboid movement along the - more severe ventral body wall defect in which progression dorsal mesentery of the hindgut arriving at the primitive and closure of the lateral body wall folds are disrupted to gonads at the beginning of the fifth week and invading a greater degree than is observed in bladder exstrophy. the genital ridges. - In addition to the closure defect, normal development of the urorectal septum is altered, such that anal canal malformations and imperforate anus occur. - Furthermore, because the body does not fuse, the genital swellings are widely spaced resulting in defects in the external genitalia. - Occurrence of this defect is rare (1/ 30, 000). Figure 13. A. 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. TESTES Male, the primordial germ cells, carry an XY sex chromosome Figure 11. A. Urachal fistula B. Urachal cyst. C. Urachal sinus. The sinus may or complex. may not be in open communication with the urinary bladder. Tunica albuginea is a dense layer of fibrous connective tissue that separates the testis cords from the surface epithelium. Page 5 of 14 [EMBRYOLOGY] 1.13 EMBRYONIC DEVELOPMENT OF THE UROGENITAL SYSTEM – Dr. M. E. Guerrero, MD Interstitial cells of Leydig derived from the original mesenchyme of Cranially: duct opens into the abdominal cavity with a funnel like the gonadal ridge, lie between the testis cords. structure Eighth Week Leydig cells begin production of testosterone and the Caudally: runs lateral to the mesonephric duct, then crosses it testis is able to influence sexual differentiation of the genital ducts ventrally to grow caudomedially. and external genitalia. In the midline, it comes in close contact with the paramesonephric Fourth month testis cords become horseshoe shaped, and their duct from the opposite side. extremities are continuous with those of the rete testis. Sinus tubercle: the caudal tip of the combined ducts projects into the posterior wall of the urogenital sinus, where it causes a small swelling. Figure 14. A. Transverse section through the testis in the eighth week, showing the tunica albuginea, testis cords, rete testis, and primordial germ cells.The glomerulus and Bowman’s capsule of the mesonephric excretory tubule are degenerating. B. Testis and genital duct in the fourth month.The horseshoe-shaped testis cords are continuous with the rete testis cords. Note the ductuli efferentes (excretory mesonephric tubules), which enter the mesonephric duct. OVARY Figure 16. Genital ducts in the sixth week in the male (A) and fe­male (B). The Female embryos with an XX sex chromosome complement and no Y mesonephric and paramesonephric ducts are present in both. Note the excretory chromosome, primitive sex cords dissociate into irregular cell tubules of the mesonephros and their relation to the developing gonad in both clusters. sexes. 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 15. A. Transverse section of the ovary at the seventh week, showing Figure 17. A. Genital ducts in the female at the end of the second month. Note degeneration of the primitive (medullary) sex cords and formation of the cortical the paramesonephric [Müllerian] tubercle and formation of the uterine canal. B. cords. B. Ovary and genital ducts in the fifth month. Note degeneration of the Genital ducts after descent of the ovary. The only parts remaining from the medullary cords.The excretory mesonephric tubules (efferent ductules) do not mesonephric system are the epoophoron, paroophoron, and Gartner cyst. Note communicate with the rete.The cortical zone of the ovary contains groups of the suspensory ligament of the ovary, ligament of the ovary proper, and round oogonia surrounded by follicular cells. ligament of the uterus. X. GENITAL DUCTS Initially both male and female embryos have two pairs of genital ducts: 1. MESONEPHRIC (WOLFFIAN) DUCTS: open into the urogenital sinus on either side of the sinus tubercle 2. PARAMESONEPHRIC (MULLERIAN) DUCTS: arises as a longitudinal invagination of the epithelium on the anterolateral surface of the urogenital ridge. Page 6 of 14 [EMBRYOLOGY] 1.13 EMBRYONIC DEVELOPMENT OF THE UROGENITAL SYSTEM – Dr. M. E. Guerrero, MD formed by remnants of the paragenital mesonephric tubules. The paramesonephric duct has degenerated except for the appendix testis. The prostatic utricle is an outpocketing from the urethra. GENITAL DUCTS IN FEMALE presence of estrogen and the absence of testosterone and AMH (MIS), paramesonephric ducts develop into the main genital ducts of the female. three parts can be recognized in each duct: 1. a cranial vertical portion that opens into the abdominal cavity; 2. a horizontal part that crosses the mesonephric duct; and 3. a caudal vertical part that fuses with its partner from the opposite side With descent of the ovary, the first two parts develop into the uterine tube and the caudal parts fuse to form the uterine canal. When the second part of the paramesonephric ducts moves mediocaudally, the urogenital ridges gradually come to lie in a transverse plane. After the ducts fuse in the midline, a broad transverse pelvic fold is established This fold, which extends from the lateral sides of the fused paramesonephric ducts toward the wall of the pelvis, is the broad ligament of the uterus. The uterine tube lies in its upper border, and the ovary lies on its posterior surface. Figure 18. Influence of the sex glands on further sex differentiation. The uterus and broad ligaments divide the pelvic cavity into the uterorectal pouch and the uterovesical pouch. GENITAL DUCTS IN MALE The fused paramesonephric ducts give rise to the corpus and cervix Testosterone stimulate to develop and are derived from parts of the of the uterus and the upper portion of the vagina. mesonephric kidney system Uterus is surrounded by a layer of mesenchyme that forms both its Efferent ductules of the testis form from some of the original muscular coat, the myometrium, and its peritoneal covering, the excretory tubules (epigenital tubules) establish contact with cords of perimetrium. the rete testis. absence of testosterone, mesonephric ducts in the female Excretory tubules along the caudal pole of the testis, the paragenital degenerate tubules, do not join the cords of the rete testis. Their vesti es are collectively known as the paradidymis. Except for the most cranial portion, appendix epididymis, the mesonephric ducts persist and form the main genital ducts (Ductus) Epididymis immediately below the entrance of the efferent ductules, the mesonephric ducts elongate and become highly convoluted. Ductus Deferens form from the tail of the epididymis to the outbudding of the seminal vesicle, the mesonephric ducts obtain a thick muscular coat. Ejaculatory Duct region of the ducts beyond the seminal vesicles. ANTI MULLERIAN HORMONE (AMH; ALSO CALLED MULLERIAN INHIBITING SUBSTANCE [MIS]) produced by Sertoli cells, paramesonephric ducts in the male degenerate except for a small portion at their cranialends, the appendix testis. Figure 20. 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 transverse fold. MOLECULAR REGULATION OF GENITAL DUCT DEVELOPMENT SRY transcription factor and the master gene for testes development. It appears to act in conjunction with the autosomal gene SOX9, a transcriptional regulator, that can also induce testes differentiation for a potential pathway for these genes). SOX9 bind to the promoter region of the gene for AMH (M18) and probably regulates this gene’s SRY and/or SOX9 induce the testes to secrete FGF9 that acts as a chemotactic factor that causes tubules from the mesonephric duct to penetrate the gonadal ridge. Without penetration by these tubules, differentiation of the testes Figure 19. A. Genital ducts in the male in the fourth month. Cranial and caudal does not continue. [paragenital tubule] segments of the mesonephric system regress. B. Genital SRY either directly or indirectly (through SOX9) upregulates ducts after descent of the testis. Note the horse- shoe-shaped testis cords, rete production of STEROIDOGENESIS FACTOR 1 (SF1) that stimulates testis, and efferent ductules entering the ductus deferens. The paradidymis is differentiation of Sertoli and Leydig cells. SF 1 working with SOX9 Page 7 of 14 [EMBRYOLOGY] 1.13 EMBRYONIC DEVELOPMENT OF THE UROGENITAL SYSTEM – Dr. M. E. Guerrero, MD elevates the concentration of AMH leading to regression of the The lumen of the vagina remains separated from that of the paramesonephric (millerian) ducts. urogenital sinus by a thin tissue plate called the hymen (see Figure SF 1 upregulates the genes for enzymes that synthesize testosterone. 22 and 23, C) which consists of the epithelial lining of the sinus and a Testosterone enters cells of target tissues where it may remain intact thin layer of vaginal cells. It usually develops a small opening during or be converted to dihydrotestosterone by a 5-0: reductase enzyme. perinatal life. Testosterone and dihydrotestosterone bind to a specific high affinity 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 member of the nuclear hormone receptor family, that inhibits the function of SOX9. ; regulates expression of other genes responsible for ovarian differentiation TAFIH 05 gene , whose protein product is a subunit for the TATA binding protein for RNA polymerase in ovarian follicular cells Estrogens involved in sexual differentiation, and under their Figure 22. Formation of the Uterus and Vagina influence, the paramesonephric (mi illerian) ducts are stimulated to form the uterine tubes, uterus, cervix, and upper vagina; act on the external genitalia at the indifferent stage to form the labia ma jora, labia minora, clitoris, and lower vagina Figure 23. Sagittal sections showing formation of the uterus and vagina at various stages of development A. 9 weeks. B. End of third month C. Newborn The female may retain some remnants of the cranial and caudal excretory tubules in the mesovarium where they form the epoophoron and paroophoron, respectively (see Figure 24, B) The mesonephric duct disappears except for a small cranial portion found in the epoophoron and occasionally a small caudal portion Figure 21. Schematic showing genes responsible for differentiation of the testes that may be found in the wall of the uterus or vagina. Later in life, it and ovaries. In both males and females, S0X9 and WNT4 are expressed in the may form Gartner cyst (see Figure 24, B) gonadal ridges. In males, the expression of SRY upregulates S0X9, which in turn activates expression of SFl and other genes responsible for testes differ­entiation, while inhibiting expression of WNT4. In females, the uninhibited expression of WNT4 upregulates DAXl that in turn inhibits S0X9 expression. Then, under the continued influence of WNT4, other downstream target genes (perhaps TAFinOB] induce ovarían differentiation. XI. VAGINA Shortly after the solid tip of the paramesonephric ducts contacts the urogenital sinus, (see Figures 22 and 23, A) two solid evaginations grow out from the pelvic part of the sinus (see Figures 22 and 23, B) These evaginations, the sinovaginal bulbs, will proliferate and form a solid vaginal plate. Proliferation continues at the cranial end of the plate, 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 (see Figure 23, C) Thus, the vagina has a dual origin: Figure 24. Genital ducts after the descent of the ovary - Upper portion derived from the uterine canal - Lower portion derived from the urogenital sinus. Page 8 of 14 [EMBRYOLOGY] 1.13 EMBRYONIC DEVELOPMENT OF THE UROGENITAL SYSTEM – Dr. M. E. Guerrero, MD UTERUS AND VAGINAL DEFECTS ○ these swellings later form the scrotal swellings in the male and the labia majora in the female Hence, scrotum and labia majora are homologous - have the same origin (genital swelling of the urethral fold) At the end of the 6th week, however, it is impossible to distinguish between the two sexes. Figure 25. Main abnormalities of the uterus and vagina caused by persistence of the uterine septum or obliteration of the lumen of the uterine canal Duplications of the uterus result from lack of fusion of the paramesonephric ducts in a local area or throughout their normal line of fusion. - Uterus didelphys Extreme Form Figure 26. Indifferent stages of the external genitalia A. Approximately 4 weeks Uterus is entirely double B. Approximately 6 weeks. C. In utero photograph of a 56-day embryo showing - Uterus arcuatus continued growth of the genital tubercle and elongation of the urethral folds Least severe form that have not yet initiated fusion.The genital swellings remain indistinct. Only slightly indented in the middle - Uterus bicornis EXTERNAL GENITALIA IN MALE Relatively common Development of the external genitalia in the male is under the The uterus has two horns entering a common vagina influence of androgens secreted by the fetal testes and is This condition is normal in mammals below the primates. characterized by rapid elongation of the genital tubercle, which is - Uterus bicornis with one rudimentary horn now called the phallus (and later on, the penis). In patients with complete or partial atresia of one of the During elongation, the phallus pulls the urethral folds forward so that paramesonephric ducts, the rudimentary part lies as an they form the lateral wall of the urethral groove. appendage to the well developed side. Because its lumen ○ failure to do so will result to abnormalities of the urethral usually does not communicate with the vagina, opening (e.g. Hypospadias) complications are common. This groove (urethral groove) extends along the caudal aspect of the - Cervical Atresia elongated phallus but does not reach the most distal part, the glans. If the atresia involves both sides The epithelial lining of the groove, which originates in the endoderm, - Double Vagina forms the urethral plate. develops if the sinovaginal bulbs fail to fuse At the end of the 3rd month, the two urethral folds close over the - Atresia of the Vagina urethral plate, forming the penile urethra. develops if the sinovaginal bulbs do not develop at all. ○ This canal does not extend to the tip of the phallus. A small vaginal pouch originating from the ○ This most distal portion of the urethra is formed during paramesonephric ducts usually surrounds the opening of the 4th month, when ectodermal cells from the tip of the the cervix. glans penetrate inward and form a short epithelial cord. ○ This cord later obtains a lumen, thus forming the external urethral meatus. XII. EXTERNAL GENITALIA The genital swellings, known in the male as the scrotal swellings, arise in the inguinal region. with further development, they move - The external genitalia of the male and female initially cannot be caudally and each swelling then makes up half of the scrotum. differentiated (WHY? - recall: they came from the same origin) ○ The two are separated by the scrotal septum. Indifferent Stage In the third week of development, mesenchyme cells originating in the region of the primitive streak migrate around the cloacal membrane to form a pair of slightly elevated cloacal folds ○ Cranial to the cloacal membrane, the folds unite to form the genital tubercle. ○ Caudally, the folds are subdivided into urethral folds anteriorly and anal folds posteriorly. In the meantime, another pair of elevations, the genital swellings, become visible on each side of the urethral folds. Page 9 of 14 [EMBRYOLOGY] 1.13 EMBRYONIC DEVELOPMENT OF THE UROGENITAL SYSTEM – Dr. M. E. Guerrero, MD Figure 29. A. Hypospadias showing the various locations of abnormal urethral orifices. B. Patient with glandular hypospadias. The urethra is open on the ventral surface of the glans penis. C. Patient with hypospadias involving the Figure 27. A. Development of external genitalia in the male at 10 weeks. Note glans and shaft of the penis the deep urethral groove flanked by the urethral folds. B. Transverse sections through the phallus during formation of the penile urethra.The urogenital 2. EPISPADIAS groove is bridged by the urethral folds. C. Development of the glandular portion - a rare abnormality (1/30,000 births) in which the urethral of the penile urethra. D. Newborn. meatus is found on the dorsum of the penis. - Although it may occur as an isolated defect, it is most often associated with exstrophy of the bladder and abnormal closure of the ventral body wall. Figure 28. A. In utero photograph of the genitalia of a male fetus at 12 weeks. Note that the urethral folds are fusing and that the scrotal swellings are enlarging to merge in the midline. B. Genitalia of a female fetus at 11 weeks. Note that the urethral folds, which will become the labia minora, have not fused and that the enital swellings that are forming the labia majora are widely separated. Figure 30. Epispadias combined with exstrophy of the bladder. Bladder mucosa DEFECTS IN THE MALE GENITALIA is exposed. 1. HYPOSPADIAS - fusion of the urethral folds is incomplete, and abnormal 3. MICROPENIS openings of the urethra occur along the inferior aspect of - occurs when there is insufficient androgen stimulation for growth of the penis, usually near the glans, along the shaft, or near the external genitalia. It is usually caused by primary hypogonadism the base of the penis. or hypothalamic or pituitary dysfunction. - In rare cases, the urethral meatus extends along the ○ The penis is 2.5 standard deviation below the mean in scrotal raphe. length as measured along the dorsal surface from the - When fusion of the urethral folds fails entirely, a wide pubis to the tip with the penis stretched to resistance. sagittal slit is found along the entire length of the penis ○ Bifid or double penis may occur if the genital tubercle and the scrotum. splits. - The two scrotal swellings then closely resemble the labia majora. EXTERNAL GENITALIA IN FEMALE - The incidence of hypospadias is 3 to 5 / 1,000 births, and Estrogens stimulate development of the external genitalia of the this rate represents a doubling over the past 15 to 20 female years. The genital tubercle elongates only slightly and forms the clitoris. - Reasons for the increase are not known, but one ○ Male: genital tubercle elongates to form the phallus - hypothesis suggests it could be a result of a rise in therefore the penis and the clitoris are homologous environmental estrogens (endocrine disruptors). embryonically - they have the same origin Urethral folds do not fuse, as in the male, but develop into the labia minora. ○ Male: they fuse - homologous to penile urethra Genital swellings enlarge and form the labia majora. ○ Male: enlarge and form scrotum The urogenital groove is open and forms the vestibule. Page 10 of 14 [EMBRYOLOGY] 1.13 EMBRYONIC DEVELOPMENT OF THE UROGENITAL SYSTEM – Dr. M. E. Guerrero, MD Although the genital tubercle does not elongate extensively in the Normally, the testes reach the inguinal region by approximately 12 female, it is larger than in the male during the early stages of weeks gestation, migrate through the inguinal canal by 28 weeks, development. and reach the scrotum by 33 weeks (Figure 32) ○ Using tubercle length as a criterion (as monitored by The process is influenced by hormones, including androgens and ultrasound) has resulted in mistakes in identification of M18. During descent, blood supply to the testis from the aorta is the sexes during the 3rd and 4th months of gestation. retained, and testicular vessels extend from their original lumbar (mislabelling) position to the testis in the scrotum. so early identification (gender) based on Independently from descent of the testis, the peritoneum of the genital tubercle is not very reliable method of abdominal cavity forms an evagination on each side of the midline identifying the gender of the baby because in into the ventral abdominal wall. This evagination, the processus the early development, it is more prominent vaginalis, follows the course of the gubernaculum testis into the among female but a lot larger in males later scrotal swellings (Fig. 32B) on Figure 31. Development of the external genitalia in the female at 5 months A and B. in newborn. Figure 32. Descent of the testis. A. During the second month. B. In the middle of XIII. DESCENT OF TESTES the third month. Peritoneum lining the body cavity evaginates into the scrotal swelling, where it forms the vaginal process [túnica vaginalis], C. In the seventh month. D. Shortly after birth. In order to reach the abdominal wall, the testes must migrate caudally through the abdominal wall after developing Hence, the processus vaginalis, accompanied by the muscular and retroperitoneally in the abdominal region. fascial layers of the body wall, evaginates into the scrotal swelling, The inguinal canal, which is roughly 4 cm long and located just forming the inguinal canal (Fig. 33). superior to the medial part of the inguinal ligament, allows passage The testis descends through the inguinal ring and over the rim of the through the abdominal wall. The superficial (external) ring close to pubic bone and is pres- ent in the scrotum at birth. The testis is then the pubic tubercle serves as the exit from the canal and the deep covered by a reflected fold of the processus vaginalis (Fig. 32D). (internal) inguinal ring serves as the entrance. ○ The peritoneal layer cover- ing the testis is the visceral Toward the end of the second month, the urogenital mesentery layer of the tunica vaginalis attaches the testis and mesonephros to the posterior abdominal ○ The remainder of the peritoneal sac forms the parietal wall. With degeneration of the mesonephros, the attachment serves layer of the tunica vaginalis as a mesentery for the gonad. Caudally, it becomes ligamentous and The narrow canal connecting the lumen of the vaginal process with is known as the caudal genital ligament. the peritoneal cavity is obliterated at birth or shortly thereafter. Also extending from the caudal pole of the testis is a mesenchymal In addition to being covered by peritoneal layers derived from the condensation rich in extracellular matrices, the gubernaculum processus vaginalis, the testis becomes ensheathed in layers derived (FIgure 32B) from the anterior abdominal wall through which it passes. Prior to descent of the testis, this band of mesenchyme terminates in Thus, the inguinal region between the diíferentiating internal and external ○ Transversalis fascia forms the internal spermatic fascia abdominal oblique muscles. ○ Internal abdominal oblique muscle gives rise to the Later, as the testis begins to descend toward the internal inguinal cremasteric fascia and muscle ring, an extra-abdominal portion of the gubernaculum forms and ○ External abdominal oblique muscle forms the external grows from the inguinal region toward the scrotal swellings. When spermatic fascia the testis passes through the inguinal canal, this extra-abdominal ○ The transversus abdominis muscle does not contribute a portion contacts the scrotal floor (the gubernaculum forms in layer because it arches over this region and does not females also, but in normal cases, it remains rudimentary). cover the path of migration. (Fig. 33) Factors controlling descent of the testis are not entirely clear. ○ It appears, however, that outgrowth of the extra-abdominal portion of the gubernaculum produces intra-abdominal migration, that an increase in intra-abdominal pressure due to organ growth produces passage through the inguinal canal, and that regres- sion of the extra-abdominal portion of the gubernaculum completes movement of the testis into the scrotum. Page 11 of 14 [EMBRYOLOGY] 1.13 EMBRYONIC DEVELOPMENT OF THE UROGENITAL SYSTEM – Dr. M. E. Guerrero, MD - In 97% of male newborns, testes are present in the scrotum before birth. In most of the remainder, descent will be completed during the first 3 months postnatally - The undescended testes fail to produce mature spermatozoa, and the condition is associated with a 3% to 5% incidence of renal anomalies. DISORDERS OF SEX DEVELOPMENT Because sexual development of males and females begins in an identical fashion, it is not surprising that abnormalities in differentiation and sex determination occur Figure 33: Drawing showing the coverings of the testes that are derived from the constituents of the abdominal wall. These coverings are formed as the testes migrate through the wall in route from their retroperitoneal location in the abdominal cavity in the scrotum. XIV. DESCENT OF OVARIES 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. Figure 35. Male (46,XY) infant with ambiguous genitalia. Note partial fusion of the scrotal swellings and a small penis with hypospadias. There are two ligaments - the suspensory ligament of the ovary and the round ligament of the uterus, which will hold the ovary in place. Ambiguous genitalia - may appear as a large clitoris or a small penis. Cranial genital ligament - a child may be born with a typically female appearance, but with a - forms the suspensory ligament of the ovary large clitoris [clitoral hypertrophy] or typically male with a small Caudal genital ligament penis that is open on its ventral surface [hypospadias] - forms the ligament of the ovary proper and the round ligament of - In some cases, these abnormalities result in individuals with the uterus. characteristics of both sexes Ovotesticular disorders of sex development [formerly called true HERNIA AND CRYPTORCHIDISM hermaphroditism] - 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. 46,XX Disorders of Sex Development - Genitalia are always ambiguous, but there is a tendency toward masculinization. In 70% of cases, the karyotype is 46,XX - females that have been exposed to excessive amounts of androgenic compounds that masculinize the external genitalia causing them to be ambiguous 1. Congenital adrenal hyperplasia [CAH] - most common cause of ambiguous genitalia, accounting for approximately 60% of all DSDs. Individuals are genetically female [46,XX] but excessive androstenedione -H produced by the adrenal glands results in masculinization of the external genitalia. - There is a spectrum of defects, involving phallic enlargement, degree of urethral fold fusion, and size and Figure 34. Inguinal Hernia (A) and Hydrocele (B) opening of the vagina - In 90% of patients, there is a 21- hydroxylase enzyme Congenital indirect inguinal hernia deficiency, inherited as an autosomal recessive trait that - The connection between the abdominal cavity and the processus results in a mineralocorticoid deficiency and an increase vaginalis through the inguinal canal and into the scrotal sac normally in androgenic compounds closes in the first year after birth. If this passageway remains open, - A rarer form of CAH is caused by a deficiency of intestinal loops may descend into the scrotum, causing a congenital 11-B—hydroxylase that causes similar biochemical effects indirect inguinal hernia (Labeled A). and, therefore, similar effects on the external genitalia. - Sometimes, obliteration of this passageway is irregular, leaving small Yet, another form of CAH is caused by a deficiency of cysts along its course. Later, these cysts may secrete fluid, forming a 17-A-hydroxylase that results in a decrease in prenatal hydrocele of the testis and/or spermatic cord. and pubertal sex steroids. Cryptorchidism - one or both testes fail to descend in