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Clinical corelation ofUrogenital Development : 

Clinical corelation ofUrogenital Development


INTRODUCTION The kidneys and the male and female reproductive system develop for the most part from intermediate mesoderm. The reproductive system and the urinary system develop from common sources and therefore there will be overlap The urinary system includes the kidneys, ureter, the bladder and the urethra. In terms of their development, the kidney and the ureter develop from intermediate mesoderm. The bladder and the urethra develop from the urogenital sinus. The bladdder also develops in part from the allantois.


ANATOMICAL POSITION OF THE KIDNEY The kidney is located on the posterior abdominal wall at the high lumbar - low thoracic vertebral level It is situated such that the hilum of the kidney is directed antero-medially and the kidney is lateral to the vertebral bodies The ureters travel inferiorly through the abdomen and cross the iliac arteries to enter the pelvis During their course the ureters are retroperitoneal. As they course through the pelvis they enter the bladder posteriorly.


DEVELOPMENT OF THE KIDNEY The kidneys develop originally as a a pair of structures located in the cervical and thoracic region of the developing embryo They develop from intermediate mesoderm. The intermediate mesoderm is located on either side of the somites and medial to the lateral plate mesoderm. Originally organized as cords the first kidney that is established is the pronephric kidney.

Slide 5: 

Both the urinary and genital components of the urogenital system are derived, to a large extent, from the intermediate mesoderm. Day Gestation: 8 ,Approx. Human Age: 22 days, View: Transverse Cut

Slide 6: 

The pronephros starts as a series of cords of cells that grow dorsally and laterally. The lateral ends open and grow caudally linking together to form a pronephric duct. The pronephric duct continues to grow caudally until it reaches the cloaca where it will enter this structure. The pronephric duct does not function, but plays an important role in the development of the urogenital system in that it will induce the development of the next kidney to form - the mesonephric kidney.

Primitive kidney : 

Primitive kidney The intermediate mesoderm becomes segmented into units termed nephrotomes. The lateral portions of the nephrotomes unite, forming a longitudinal duct on each side of the embryo.

Slide 8: 

The mesonephric kidney arises as another series of tubules that form from intermediate mesoderm. The dorsal aorta will give rise to a tuft of blood vessels that will come in contact with the intermediate mesoderm. This tuft of vessels is called a glomerulus. The tubules that surround the glomerulus elongate and reach the pronephric duct. As this occurs the pronephric duct enlarges and then becomes the mesonephric duct. The growth of the mesonephros at this time causes a bulge of the intermediate mesoderm into the coelomic cavity from the lower cervical to the upper lumbar levels. The bulge is called the urogenital ridge. As development proceeds the cranial segments degenerate as the more caudal segments develop.

Slide 9: 

The lumen of each nephrotome opens into the mesonephric duct as well as into the body cavity. Glomeruli form as small vessels extend from the dorsal aortae. Day Gestation: 9, Approx. Human Age: 27 days ,View: Transverse Cut

Slide 10: 

As the mesonephric duct enters the cloaca, a diverticulum arises. This diverticulum is called the ureter bud. The ureter bud grows cranially and contacts the intermediate mesoderm. As it reaches the mesoderm in the lower lumbar - upper sacral region, a cap of mesoderm cells surrounds it. This cap of cells is the metanephrogenic blastema. The ureter bud divides many times and it will eventually give rise to the pelvis of the kidney, the major and minor calyces of the kidney and the collecting tubules. The metanephrogenic blastema becomes cords of cells which eventually give rise to tubules that will be the nephron. The nephron will have one end that covers a tuft of capillaries(the glomerulus) called Bowman’s capsule. The other end will connect with the collecting tubule.

Slide 11: 

illustrates the mesonephric duct extending toward the cloacal region and the openings of the nephric tubules into the body cavity. Day Gestation: 9, Approx. Human Age: 28 days ,View: Parasagittal Cut

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The kidney will develop over a period of several weeks and will become functional by week 13. However, it is important to remember that the kidney will continue to grow even during the first few months after birth One of the ways the kidney grows is that it originally forms in the pelvic region. As the fetus grows the kidneys assume a more and more cephalic position. Eventually they lies opposite the L1 vertebral body. During this process the blood supply to the kidney arises from sequentially more cranial branches of the aorta.

Slide 13: 

As development progresses, the nephrogenic tissues forms urogenital ridges on the dorsal wall of the body cavity. The boxed area at higher magnification . . . Day Gestation: 10-11, Approx. Human Age: 5-6 weeks ,View: Transverse Cut

Day Gestation: 10 ,Approx. Human Age: 5 weeks View: Transverse Cut : 

Day Gestation: 10 ,Approx. Human Age: 5 weeks View: Transverse Cut illustrates the mesonephric duct, the nephrotome, and the mesoderm covering the urogenital ridge

Slide 15: 

The urogenital ridge consists of the mesonephros and the gonad.

Slide 16: 

The mesonephros consists of excretory tubules that contact a blood vessel medially and enter the mesonephric (Wolffian) duct laterally. At higher magnification Day Gestation: 9 Approx. Human Age: 28 days ,View: Transverse Cut

Day Gestation: 9 Approx. Human Age: 28 days,View : Transverse Cut : 

Day Gestation: 9 Approx. Human Age: 28 days,View : Transverse Cut the relationships of the glomerular vessel, the duct and mesonephric tissue are seen.

Development of baldder : 

Development of baldder The hindgut and the allantois empty into the cloaca early in development. The cloaca ends as the cloacal plate, a region of ectoderm and endoderm without intervening mesoderm. The urorectal septum develops in that region of the cloaca where the allantois and the hindgut meet. This septum grows toward the cloacal plate and divides it into an anal canal and a urogenital sinus. The cloacal plate then gets divided into an anal membrane and a urogenital membrane with a perineal body in between. The mesonephric duct empties into the urogenital sinus

Slide 19: 

The urogenital sinus and the allantois enlarge to form the urinary bladder. The distal ends of the mesonephric ducts become incorporated into the urinary bladder. The urogenital sinus then has three parts: the urinary bladder, the pelvic protion of the urogenital sinus which becomes the proximal urethra in the female and the membranous and prostatic urethra in the male, and the the phalic portion of the urogenital sinus which becomes the penile urethra in the male and the vestibule and part of the urethra and vagina in the female.

Develoment : 

Develoment 1 Primary urogenital sinus2 Mesonephric duct (Wolffian duct)3 Ureter anlage4 drainage urinarypassages5 Pelvic limb of the urogenital sinusa Part of the genital tractb Part of the urinary tract

Anomalies of urinary development : 

Anomalies of urinary development The kidneys can develop multiple renal vessels and these can occur as the kidney ascends and new vessels form yet old vessels do not degenerate. There can also be duplication of the ureter (bifid ureter). This occurs when the ureteric bud branches before it reaches the metanephrogenic tissue. The kidney can also form abnormally into a horseshoe-kidney. In this condition the kidney is found in the region of the abdomen below the inferior mesenteric artery. The reason this condition exists is that the caudal poles of the kidney fuse in the pelvis and then during the cephalic migration of the kidney, the kidney can not migrate past the centrally placed inferior mesenteric artery.

Slide 23: 

Multiple renal arteries Bifid ureters

Horseshoe kidney : 

Horseshoe kidney

Development of reproductive system : 

Development of reproductive system The reproductive system in both the male and female can be divided into the gonads, the internal duct system and the external genitalia. The sex of the embryo is determined by the presence of either an XX or XY genotype. The gonads, ducts and the genitalia develop later. Initially there is a stage of development where the two sexes develop in an identical fashion. This is the indifferent stage. Subsequent to six weeks the two sexes develop differently.

Slide 26: 

During the initial stages, the gonads develop from coelomic epithelium, the mesoderm of the urogenital ridge, and primordial germ cells that enter this region of the embryo. The primordial germ cells migrate into this region through the dorsal mesentary of the hindgut. By six weeks the primordial germ cells reach the urogenital ridge and this tissue bulges into the coelomic cavity and is called the gonadal ridge. Proliferation of both epithelial and mesodermal cells result in the formation of the primitive sex cords. The primaorial germ cells reach these sex cords.

Slide 27: 

The gonads develop as primordial germ cells that form in the wall of the yolk sac close to the allantois migrate along the dorsal mesentery of the hindgut to invade the genital ridges.

Slide 28: 

In the male the presence of the testis-determining factor on the Y-chromosome causes the testis to develop. The primitive sex cords become the testis cords. The testes loose their connection with the surface and a thick connective tissue capsule forms around the cords that is to become the tunica albuginea. Within the testis cords the primordial germ cells become the spermatogonia. Spermatogonia will become the spermatozoa in the adult. The Sertoli cells of the testis arise from the coelomic epithelial cells. The mesenchymal cells become the Leydig cells of the testis. The testis cords empty into mesonephric tubules that will become the efferent ductules.

Slide 29: 

The path of germ cell migration within the dorsal mesentery is shown on this micrograph.

Slide 30: 

In the male the presence of the testis-determining factor on the Y-chromosome causes the testis to develop. The primitive sex cords become the testis cords. The testes loose their connection with the surface and a thick connective tissue capsule forms around the cords that is to become the tunica albuginea. Within the testis cords the primordial germ cells become the spermatogonia. Spermatogonia will become the spermatozoa in the adult. The Sertoli cells of the testis arise from the coelomic epithelial cells. The mesenchymal cells become the Leydig cells of the testis. The testis cords empty into mesonephric tubules that will become the efferent ductules.

Slide 31: 

In the absence of the Y chromosome, the gonad develops more slowly and the primary sex cords degenerate and a new set of sex cords develop called the secondary or cortical cords. These sex cords break up into clusters called primaorddial follicles and these consist of an oogonium surrounded by follicular cells. The oogonia divide during fetal life and those that will mature undergo meiosis and will be arrested at the prophase stage of the first meiotic division.

Slide 32: 

The primordial germ cells become surrounded by cells of the primitive sex cords. At this stage the gonad is "indifferent," as one cannot morphologically distinguish between the male and female.

Slide 33: 

This micrograph shows a cut through the developing gonad with the primitive sex cords surrounding the primordial germ cells. Also apparent is the mesonephric duct. Day Gestation: 11 Approx. Human Age: 6 weeks View:

Development of genital ducts : 

Development of genital ducts During the indifferent stage the mesonephric ducts remain as remenants of the mesonephric kidney. A second set of ducts, the paramesonephric ducts form on the lateral wall of the urogenital ridge, next to the mesonephric ducts. These are the paramesonephric ducts. The paramesonephric ducts maintain an opening with the intraembryonic coelom cranially. The caudal end of the paramesonephric duct crosses the mesonephric duct and then fuses with the paramesonephric duct on the opposite side. When the two ducts combine they are called the uterovaginal canal. The uterovaginal canal will grow toward the urogenital sinus to contact its posterior wall. At the point of contact, the uterovaginal canal protruding into the urogenital sinus is called the Mullerian tubercle.

Slide 35: 

In addition to the mesonephric duct, a paramesonephric duct forms from the the epithelium on the surface of the urogenital ridge. In the male, the mesonephric duct is of greater significance, whereas in the female, the paramesonephric duct is predominant.

Slide 36: 

The intact mesonephric and paramesonephric ducts, the mesonephros and gonad of a 7 week human embryo are shown. Day Gestation: 7 weeks

Development of male genital duct : 

Development of male genital duct The testis develops and produces anti-mullerian hormone (Mullerian Inhibiting Hormone, MIH). This steroid hormone will cause the Leydig cells of the testis to secrete androgens (testosterone and dihydrotestosterone) . The Mullerian Inhibiting Hormone also induces the degeneration of the paramesonephric ducts. The androgens result in the development of the efferent ductules, the epididymis, and the ductus deferens. The seminal vesicles develop as outgrowths from the mesonephric duct. The remaining mesonephric duct becomes the ejaculatory duct and the prostate develops from endoderm from the developing urethra.

Slide 38: 

In the male the primitive sex cords (see image 10) form the testis and the rete testis cords. The latter communicate with tubules of the mesonephric system, thus linking the testis to the mesonephric duct. The mesonephric duct becomes the ductus deferens.

Slide 39: 

In the male, the paramesonephric ducts degenerate, while the mesonephric ducts (ductus deferens) lead from the testis to the prostatic region. The prostate is located between the bladder and gut. Day Gestation: 14, Approx. Human Age: 9, weeks View: Ventral

Development of female genital dutct : 

Development of female genital dutct In the female, the lack of the testis results in the regression of the mesonephric ducts and the growth of the paramesonephric ducts. The cephalic portion becomes the uterine tubes. The fused portion, the uterovaginal canal bedomes the uterus and the upper 1/3 of the vagina. When the uterovaginal canal contacts the urogenital sinus, a pair of sino-vaginal bulbs that are of endodermal origin develop. These sino-vaginal bulbs are originally solid and will form the lower two-thirds of the vagina. The lumen forms later during development. The lumen of the vagina remains separated from the remaining urogenital sinus by a thin membrane, the hymen. The urogenital sinus caudal to the vaginal opening becomes the vestibule.

Slide 41: 

In the female, the primitive sex cords (medullary cords) degenerate. Subsequently, there is no communication between the gonad and the mesonephros.

Development of external genetelia : 

Development of external genetelia During the indifferent stage the mesoderm lateral to the cloacal membrane proliferates and cloacal folds develop. these become urethral (urogenital) folds. The urethral folds in the anterior region where they join rapidly enlarge and become the genital tubercle. Lateral to these folds a second set of swelling appear and they are lcalled the labio-scrotal swellings.

Slide 43: 

The forming external genitalia are not visible in this view of an 8 week human embryo on the left due to the prominent tail. The human tail regresses, as is evident in the 10 week embryo on the right. Day Gestation: 8; 10 wks Approx. View: Caudal

Slide 44: 

In the 8th week of human development, the male and female external genitalia appear the same.

Day Gestation: 9 Approx. ,Human Age: 28 days ,View: Dorsolateral & Ventral : 

Day Gestation: 9 Approx. ,Human Age: 28 days ,View: Dorsolateral & Ventral The external genitalia form around the cloacal plate or membrane.

Slide 46: 

The cloaca is divided into the anorectal and urogenital regions as the urorectal septum contacts the cloacal membrane. The urogenital membrane and anal membrane then begin to break down. Day Gestation: 50 days

Development of the Male External Genitelia : 

Development of the Male External Genitelia In the male the production of androgen causes the genital tubercle to enlarge. It pulls the urethral folls forward so a urethral groove forms. The penile urethra forms from the fusion of the urethral folds. The penis forms from the genital tubercle and the urethral folds. The tip of the penis is ectoderm and this tissue becomes secondarily canalized to form the penile urethra. Thus, part of the penile urethra is from ectoderm and part from endoderm of the urogenital sinus. The labi-scrotal swellings enlarge and fuse to form the scrotum.

In the male the urethral folds fuse, forming the penile urethra. : 

In the male the urethral folds fuse, forming the penile urethra.

Day Gestation: 74 days : 

Day Gestation: 74 days The genital swellings (counterpart to the female labia majora) become the scrotum and the genital tubercle becomes the glans penis.

Decent of testes : 

Decent of testes The caudal remnant of the mesonephric duct remains as the gubernaculum. The gubernaculum passes through the abdominal wall to the region of the labio-scrotal swellings. As the embryo grows the gubernaculum does not and the testis comes to lie in progressively lower positions. At the same time a peritoneal sac called the processes vaginalis follows through the inguinal canal to the scrotum. The testis follows this pathway into the scrotum. Failure of the testis to descend into the scrotum or if the processes vaginalis does not close can result in an inguinal hernia.

Slide 51: 

The testes descend into the scrotal swellings, following the course of the gubernaculum. Day Gestation: 14 Approx. Human Age: 9 weeks View: Ventral

Development of the Female External Genitalia : 

Development of the Female External Genitalia Without androgen, the genital tubercel remains small and becomes the clitoris. The urethral folds do not fuse and they become the labia minora. The labio-scrotal fold remain and become the labia majora.

Slide 53: 

In the female, the urethral folds remain unfused and will form the labia minora, while the genital swellings become the labia majora. Day Gestation: 72 days

Slide 54: 

Comparison of two human females illustrates that the clitoris which is derived from the genital tubercle becomes relatively less prominent as development progresses. Day Gestation: 72 & 76

Abnormalities of the Reproductive System : 

Abnormalities of the Reproductive System There are a multitude of abnormalities that can be seen in the reproductive system. We will highlight only a few to begin to illustrate how the embryology can go awry. In Truner’s syndrome there is gonadal dysgenesis with female internal and external genitalia. The patients are often XO, but those with a Y fragment do not produce testosterone. These individuals are of short stature, have a high arched palate, webbing of the neck and may have other abnormalities as well. There is an absence of oocytes mostly due to the loss of oocytes due to the lack of production of female hormones.

Slide 56: 

In female pseudohermaphro-ditism the patient has 46, XX chromosomes. However, a frequent cause of this syndrome is the decreased production of cortisol by the zona fasciculata of the adrenal gland. This gives rise to excess adrogen production in the zona reticularis of the adrenal. This results in the external genitalia becoming masculinized

Slide 57: 

Male pseudohermaphroditism can occur in patients with a 46, XY chrosome complement. In this syndrome patients have the external appearance of normal females. The tissue of the external genitalia are unresponsive to androgens and develop as female. However, since MIH and testes are present there are no female ducts present. The testes are often found in the inguinal or labial region.

Pax-2 controls multiple steps of urogenital development : 

Pax-2 controls multiple steps of urogenital development Urogenital system development in mammals requires the coordinated differentiation of two distinct tissues, the ductal epithelium and the nephrogenic mesenchyme, both derived from the intermediate mesoderm of the early embryo. The former give rise to the genital tracts, ureters and kidney collecting duct system, whereas mesenchymal components undergo epithelial transformation to form nephrons in both the mesonephric (embryonic) and metanephric (definitive) kidney. Pax-2 is a transcriptional regulator of the paired-box family and is widely expressed during the development of both ductal and mesenchymal components of the urogenital system. We report here that Pax-2 homozygous mutant newborn mice lack kidneys, ureters and genital tracts

Slide 59: 

We attribute these defects to dysgenesis of both ductal and mesenchymal components of the developing urogenital system. The Wolffian and Mullerian ducts, precursors of male and female genital tracts, respectively, develop only partially and degenerate during embryogenesis. The ureters, inducers of the metanephros are absent and therefore kidney development does not take place. Mesenchyme of the nephrogenic cord fails to undergo epithelial transformation and is not able to form tubules in the mesonephros. In addition, we show that the expression of specific markers for each of these components is de-regulated in Pax-2 mutants. These data show that Pax-2 is required for multiple steps during the differentiation of intermediate mesoderm. In addition, Pax-2 mouse mutants provide an animal model for human hereditary kidney diseases.

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