Langman's Medical Embryology 13th Edition PDF

unctionally, the urogenital system can during the early fetal period; the third forms the be divided into two entirely diíferent permanent kidney. components: the urinary system and...

unctionally, the urogenital system can during the early fetal period; the third forms the be divided into two entirely diíferent permanent kidney. components: the urinary system and Pronephros the genital system. Embryologically and ana- At the beginning of the fourth week, the pro­ tomically, however, they are intimately interwo- nephros is represented by 7 to 10 solid cell groups ven. Both develop from a common mesodermal in the cervical región (Figs. 16.1 and 16.2). These ridge (intermedíate mesoderm) along the pos­ groups form vestigial excretory units, nephro- terior wall of the abdominal cavity, and initially, tomes, that regress before more caudal ones are the excretory ducts of both systems enter a formed. By the end of the fourth week, all indica- common cavity, the cloaca. tions of the pronephric system have disappeared. URINARY SYSTEM________________ Mesonephros The mesonephros and mesonephric ducts are Kídney Systems derived from intermedíate mesoderm from Three slightly overlapping kidney systems are upper thoracic to upper lumbar (L3) segments formed in a cranial-to-caudal sequence during (Fig. 16.2). Early in the fourth week of devel- intrauterine life in humans: the pronephros, opment, during regression of the pronephric mesonephros, and metanephros. The first of system, the first excretory tubules of the meso­ these systems is rudimentary and nonfunc- nephros appear. They lengthen rapidly, form an tional; the second may function for a short time S-shaped loop, and acquire a tuft of capillaries Paraxial mesoderm Somite Intermediate mesoderm Internal ll^^glom erulus Nephric tubule Somatic External meso­ glomerulus derm U ll Endoderm Spianchnic mesoderm B FIGURE 16.1 T ra n s v e rs a s e c tio n s th ro u g h e m b ry o s a t v a rio u s s ta g e s o f d e v e lo p m e n t s h o w in g fo rm a tio n o f n e p h ric tu b u le s. A. 21 d ays. B. 25 d ays. N o te fo rm a tio n o f e x te rn a l a n d in te rn a l g lo m e ru li a n d th e o p e n c o n - n e c tio n b e tw e e n th e in tra e m b ry o n ic c a v ity a n d th e n e p h ric tu b u le.  Chapter16 Urogenital System Segmented intermediate mesoderm (pronephric system) Vestigial pronephric system Vitelline duct Unsegmented intermediate mesoderm Meso- (mesonephric system) nepliric excretory units Mesonephric Mesonephric duct duct »5U.R. Unsegmented mesoderm Ureteric bud (metanephric system) B FIGURE 16.2 A. R e la tio n s h ip o f th e in te rm e d ia te m e s o d e rm o f th e p ro n e p h ric , m e s o n e p h ric , a n d m e ta n e p h ­ ric s y s te m s. In c e rv ic a l a n d u p p e r th o ra c ic re g io n s , in te rm e d ia te m e s o d e rm is s e g m e n te d ; in lo w e r th o ra c ic , lu m b a r, a n d s a c ra l re g io n s , it fo rm s a s o lld , u n s e g m e n te d m a s s o f tis s u e , th e n e p h ro g e n ic c o rd. N o te th e lo n g itu d in a l c o lle c tin g d u c t, fo rm e d in itia lly b y th e p ro n e p h ro s b u t la te r b y th e m e s o n e p h ro s [m e s o n e p h ric d u c t], B. E x c re to ry tu b u le s o f th e p ro n e p h ric a n d m e s o n e p h ric s y s te m s in a 5 -w e e k e m b ry o. that will form a glomerulus at their medial in the mesonephric system. The development extremity (Fig. 16.3A). Around the glomeru­ of the duct system differs from that of the other lus, the tubules form Bowman’s capsule, and kidney systems. together these structures constitute a renal cor- Collecting System puscle. Laterally, the tubule enters the longitu­ dinal collecting duct known as the mesonephric Collecting ducts of the permanent kidney de­ or Wolffian duct (Figs. 16.2 and 16.3). velop from the ureteric bud, an outgrowth of In the middle of the second month, the meso­ the mesonephric duct cióse to its entrance to the nephros forms a large ovoid organ on each side cloaca (Fig. 16.4). The bud penetrales the meta­ of the midline (Fig. 16.3). Because the develop- nephric tissue, which is molded over its distal ing gonad is on its medial side, the ridge formed end as a cap (Fig. 16.4). Subsequently, the bud by both organs is known as the urogenital ri(^e dilates, forming the primitive renal pelvis, and (Fig. 16.3). While caudal tubules are still differenti- splits into cranial and caudal portions, the fu- ating, cranial tubules and glomeruli show degener- ture major calyces (Fig. 16.5A,B). ative changes, and by the end of the second month, Each calyx forms two new buds while pen- the majority have disappeared. In the male, a few etrating the metanephric tissue. These buds con­ of the caudal tubules and the mesonephric duct tinué to subdivide until 12 or more generations persist and particípate in formation of the genital of tubules have formed (Fig. 16.5). Meanwhile, at system, but they disappear in the female. the periphery, more tubules form until the end of the fifth month. The tubules of the second order M etanephros: The D efinitive Kidney enlarge and absorb those of the third and fourth The third urinary organ, the metanephros or generations, forming the minor calyces of the permanent kidney, appears in the fifth week. renal pelvis. During ñirther development, coUect- Its excretory units develop from metanephric ing tubules of the fifth and successive generations mesoderm (Fig. 16.4) in the same manner as elongate considerably and converge on the minor  Part II Systems-Based Embryology Excretoty tubule of mesonephros Urogenital mesentety Mesonephric duct Paramesonephric duct Mesentery Glomerulus Gonad Bowman’s capsule Mesonephros Vitelline duct Mesonephric duct Allantois Paramesonephric duct Gonad Cloaca FIGURE 16.3 A. T ra n s v e rs a s e c tio n th ro u g h th e u ro g e n ita l rid g e in th e lo w e r th o ra c ic re g ió n o f a 5 -w e e k e m b ry o s h o w in g fo rm a tio n o f an e x c r e to ry tu b u le o f th e m e s o n e p h ric s y s te m. N o te th e a p p e a ra n c e o f B o w m a n ’s c a p s u le a n d th e g o n a d a l rid g e. T h e m e s o n e p h ro s a n d g o n a d a re a tta c h e d to th e p o s te rio r a b d o m in a l w a ll b y a b ro a d u ro g e n ita l m e s e n te ry. B. R e la tio n o f th e g o n a d a n d th e m e s o n e p h ro s. N o te th e s iz e o f th e m e s o n e p h ro s. T he m e s o n e p h ric d u c t [W o lffia n d u c t) ru n s a lo n g th e la te ra l s id e o f th e m e s o n e p h ro s. FIGURE 16.4 R e la tio n o f th e h in d g u t and Mesonephric Mesonephric Hindgut c lo a c a a t th e e n d o f th e fifth w e e k. T he u re - duct te ric b u d p e n e tr a le s th e m e ta n e p h ric m e s o - Allantois d e rm [b la s te m a ]. Urorectal septum Cloaca Ureteric bud Metanephric blastema  Chapter16 Urogenital System Collecting tubules Outgrowing collecting tubules Major calyx Metanephric blastema Pelvis Minor calyx Ureter Renal A B pelvis FIGURE 16.5 D e v e lo p m e n t o f t lie re n a l pe lvis, ca ly ce s , a n d c o lle c tin g tu b u le s o f th e m e ta n e p h ro s. A. 6 w eeks. B. A tt h e e n d o f th e s ix th w e e k. C. 7 w e eks. D. N e w b o rn. N o te th e p y ra m id fo rm o fth e c o lle c tin g tu b u le s e n te r- in g th e m in o r c a ly x. calyx, forming the renal pyramid (Fig. 16.5D). nephrons, although there is no increase in their The ureteric bud gives rise to the ureter, the number. renal pelvis, the major and minor calyces, and Molecular Regulation of approximately 1 to 3 million collecting tubules. Kidney Development Excretory System As with most organs, differentiation of the kid- Each newly formed collecting tubule is covered ney involves epithelial mesenchymal interac- at its distal end by a metanephric tissue cap tions. In this example, epithelium of the ureteric (Fig. I 6.6A). Under the inductive influence of the bud from the mesonephros interacts with mesen- tubule, cells of the tissue cap form small vesicles, chyme of the metanephric blastema (Fig. 16.7). the renal vesicles, which in turn give rise to small The mesenchyme expresses W T l, a transcrip- S-shaped tubules (Fig. 16.65,C). Capillaries grow tion factor that makes this tissue competent to into the pocket at one end of the S and differentiate respond to induction by the ureteric bud. W Tl into glomeruli. These tubules, together with their also regulates production of GLIAL-DERIVED glomeruli, form nephrons, or excretory units. The NEUROTROPHIC FACTOR (GDNF) and proximal end of each nephron forms Bowman’s HEPATOCYTE GROWTH FACTOR (HGF, capsule, which is deeply indented by a glomerulus or SCATTER FACTOR) by the mesenchyme, (Fig. 16.6C,D). The distal end forms an open con- and these proteins strmulate branching and nection with one of the collecting tubules, estab- growth of the ureteric buds (Fig. 16.7A). The tyro- lishing a passageway from Bowman’s capsule to sine kinase receptors RET, for GDNF, and MET, the collecting unit. Continuous lengthening of the for HGF, are synthesized by the epithelium of the excretory tubule results in formation of the proxi­ ureteric buds, establishing signaling pathways mal convoluted tubule, loop of Henle, and distal between the two tissues. In turn, the buds induce convoluted tubule (Fig. 16.6E,F). Henee, the kid- the mesenchyme via FIBROBLAST GROWTH ney develops from two sources: ( 1) metanephric FACTOR 2 (FGF2) and BONE MORPHO- mesoderm, which provides excretory units, and GENETIC PROTEIN 7 (BMP7) (Fig. 16.7A). (2 ) the ureteric bud, which gives rise to the col­ Both of these growth factors block apoptosis and lecting system. strmulate proliferation in the metanephric mes­ Nephrons are formed until birth, at which enchyme while maintaining production of W Tl. time there are approximately 1 million in each Conversión of the mesenchyme to an epithelium kidney. Uriñe production begins early in ges- for nephron formation is also mediated by the tation, soon after differentiation of the glo- ureteric buds through expression of WNT9B and merular capillaries, which start to form by the WNT6, which upregulate PAX2 and WNT4 in lOth week. At birth, the kidneys have a lobulated the metanephric mesenchyme. PAX2 promotes appearance, but the lobulation disappears dur- condensation of the mesenchyme preparatory ing infancy as a result of further growth of the to tubule formation, whereas WNT4 causes the  Part II Systems-Based Embryology Metanephric tissue caps Bowman’s capsule Distal convoluted Distal convoluted tubule ^ tubule Glomerulus l Glomerulus Henle loop Proxlmal convoluted Bowman’s Bowman’s tubule capsule capsule Henle loop Ascending and descending D llmb of Henle loop FIGURE 16.6 A-F. D e v e lo p m e n t o f a m e ta n e p h ric e x c re to ry u n it. Arrows, th e p la c e w h e re th e e x c re to ry u n it [blue] e s ta b lis h e s an o p e n c o m m u n ic a tio n w ith th e c o lle c tin g s y s te m [yellow], a llo w in g flo w o f u riñ e fro m th e g lo m e ru lu s in to th e c o lle c tin g d u c ts. Metanephric tissue caps B tubule FIGURE 16.7 G enes in v o lv e d in d iffe re n tia tio n o f th e kid n e y. A. WTI, e x p re s s e d b y th e m e s e n c h y m e , e n a b le s th is tis s u e to re s p o n d to in d u c tio n b y th e u re te ric bud. G lia l-d e riv e d n e u ro tro p h ic fa c to r [GDNF) a n d h e p a to - c y te g ro w th fa c to r [HGF], a is o p ro d u c e d b y th e m e s e n c h y m e , in te ra c t th ro u g h th e ir re c e p to rs , RET a n d MET, re s p e c tiv e ly , in th e u re te ric b u d e p ith e liu m , to s tim u la te g ro w th o f th e b u d a n d m a in ta in th e in te ra c tio n s. T he g ro w th fa c to rs fib ro b la s t g ro w th fa c to r 2 (FGF2] a n d b o n e m o rp h o g e n e tic p ro te in 7 [BMP7] s tim u la te p ro life ra tio n o f th e m e s e n c h y m e a n d m a in ta in WTI e x p re s s io n. B. W N T 9B a n d W N T 6 s e c re te d b y b ra n c h e s o f th e u re te ric b u d e p ith e liu m c a u s e u p re g u la tio n o f PAX2 a n d WNT4 in th e s u rro u n d in g m e s e n c h y m e. In tu rn , th e s e g e n e s c a u s e th e m e s e n c h y m e to e p ith e lia liz e [PAX2] a n d to th e n fo rm tu b u le s [WNT4]. C h a n g e s in th e e x tra c e llu la r m a trix a is o o c c u r, s u c h t h a t la m in in a n d ty p e IV c o lla g e n fo rm a b a s e m e n t m e m b ra n e [oronge] f o r t h e e p ith e lia l ce lls.  Chapter16 Urogenital System condensed mesenchyme to epithelialize and form collagen, characteristic of an epithelial basal tubules (Fig. 16.7B). Because of these interac- lamina (Fig. 16.7B). In addition, the cell adhesión tions, modifications in the extracellular matrix molecules syndecan and E-cadherin, which are also occur. Thus, fibronectin, collagen I, and col- essential for condensation of the mesenchyme lagen III are replaced with laminin and type IV into an epithelium, are synthesized. Clinical Correlates L Renal Tumors and Defects o r a b n o r m a litie s o f t h e v a g in a a n d u te ru s , v a s Wilms tum or is a c á n c e r o f th e k id n e y s t h a t d e fe re n s , a n d s e m in a l v e s ic le s , a c c o m p a n y th is u s u a lly a ff e c t s c h ild r e n b y 5 y e a rs o f a g e b u t c o n d itio n. C o m m o n a s s o c ia te d d e fe c ts in o th e r m a y a ls o o c c u r in t h e fe tu s. W ilm s t u m o r is s y s te m s in c lu d e c a rd ia c a n o m a lie s , tr a c h e a l a n d d u e t o m u t a t io n s in th e WT1 g e n e o n 11p13, d u o d e n a l a tre s ia s , c le ft lip a n d p a la te , a n d b ra in a n d i t m a y b e a s s o c ia te d w it h o t h e r a b n o r - a b n o rm a litie s. B e c a u s e o f th e o lig o h y d ra m n io s , m a litie s a n d s y n d r o m e s. F o r e x a m p le , WAGR th e u te rin e c a v ity is c o m p re s s e d re s u ltin g in a syndrome is c h a ra c te r iz e d b y W ilm s tu m o r , c h a ra c te ris tic a p p e a ra n c e o f th e fe tu s , in c lu d ­ a n ir id ia , g o n a d o b la s to m a s ( tu m o r s o f th e in g a fla tte n e d fa c e ( P o tte r fa c ie s ) a n d c lu b fe e t. g o n a d s ), a n d m e n ta l r e t a r d a t io n ( in te lle c tu a l In congenítal polycystic kidney disease d is a b ility ). T h e c o n s te lla tio n o f d e fe c ts is d u e (Fig. 1 6.8 ], n u m e ro u s c y s ts fo rm. It m a y b e in - t o a m ic r o d e le tio n in c h r o m o s o m e 11 t h a t in - h e r ite d a s a n a u to s o m a l re c e s s iv e o r a u to s o m a l c lu d e s b o th th e PAX6 ( a n irid ia ] a n d WTI g e n e s d o m in a n t d is o r d e r o r m a y b e c a u s e d b y o th e r t h a t a re o n iy 7 0 0 k b a p a r t. S im ila rly , Denys- fa c to rs. Autosomal recessive polycystic kid­ Drash syndrome c o n s is ts o f re n a l fa ilu r e , ney disease (ARPKD), w h ic h o c c u rs in 1 /5 ,0 0 0 a m b ig u o u s g e n ita lia , a n d W ilm s tu m o r. b irth s , is a P ro g re s s iv e d is o r d e r in w h ic h c y s ts Renal dysplasias a n d agenesis a re a s p e c - fo r m fr o m c o lle c tin g d u c ts. T h e k id n e y s b e c o m e t r u m o f s e v e re m a lfo r m a tio n s t h a t r e p re s e n t th e v e r y la rg e , a n d re n a l fa ilu re o c c u rs in in fa n c y o r p rim a r y d is e a s e s r e q u irin g d ia ly s is a n d tr a n s - c h ild h o o d. In autosomal dominant polycystic p la n ta tio n in th e f ir s t y e a rs o f life. Multicystic kidney disease (ADPKD), c y s ts fo r m fr o m all dysplastic kidney is o n e e x a m p le o f th is g ro u p s e g m e n ts o f th e n e p h ro n a n d u s u a lly d o n o t o f a b n o r m a litie s in w h ic h n u m e r o u s d u c ts a re c a u s e re n a l fa ilu r e u n til a d u lth o o d. T h e a u to s o ­ s u r ro u n d e d b y u n d iffe r e n tia t e d c e lls. N e p h ro n s m a l d o m in a n t d is e a s e is m o re c o m m o n (1 /5 0 0 fa il t o d e v e lo p , a n d th e u r e te r ic b u d fa ils to to 1 /1 ,0 0 0 births] b u t le s s Progressive th a n th e b ra n c h , s o t h a t th e c o lle c tin g d u c ts n e v e r fo rm. a u to s o m a l recessive disease. B o th ty p e s o f In s o m e c a s e s , th e s e d e fe c ts c a u s e in v o lu tio n d is e a s e a re lin k e d t o m u ta tio n s in g e n e s t h a t o f th e k id n e y s a n d renal agenesis. R e n a l a g e n ­ e n c o d e p ro te in s lo c a liz e d in c ilia a n d t h a t a re e s is m a y a ls o a ris e if th e in te r a c tio n b e tw e e n im p o r ta n t f o r c ilia ry fu n c tio n. T h e s e a b n o r ­ th e m e ta n e p h r ic m e s o d e rm a n d th e u re te r ic m a litie s b e lo n g to a g ro w in g g r o u p o f d is e a s e s b u d fa ils t o o c c u r. N o rm a lly , d u rin g th e in te r a c ­ c a lle d th e ciliopathies t h a t a re d u e t o m u ta tio n s tio n , GDNF p ro d u c e d b y th e m e ta n e p h r ic m e ­ s o d e rm p ro d u c e s b ra n c h in g a n d g r o w th o f th e u r e te r ic b u d. T h u s , m u ta tio n s in g e n e s t h a t re g ­ ú la te GDNF e x p re s s io n o f s ig n a lin g m a y re s u lt in re n a l a g e n e s is. E x a m p le s in c lu d e th e g e n e SALL1, re s p o n s ib le f o r T o w n e s -B ro c k s y n d ro m e ; PAX2 t h a t c a u s e s re n a l c o lo b o m a s y n d ro m e ; a n d EYA1 t h a t re s u lts in b r a n c h io o to r e n a l s y n ­ d ro m e. B ila te ra l re n a l a g e n e s is , w h ic h o c c u rs in 1 /1 0 ,0 0 0 b irth s , re s u lts in re n a l fa ilu re. T h e b a b y p re s e n ts w ith Potter sequence, c h a ra c ­ te r iz e d b y a n u ria , o lig o h y d ra m n io s (d e c re a s e d v o lu m e o f a m n io tic flu id ), a n d h y p o p la s tic lu n g s FIGURE 16.8 S urface v ie w o f a fe ta l k idney w ith m ú l­ s e c o n d a ry t o th e o lig o h y d ra m n io s. In 8 5 % o f tip le cy sts c h a ra c te ris tic o f p o ly c ys tic k idney disease. c a s e s , o th e r s e v e re d e fe c ts , in c lu d in g a b s e n c e (continued)  Part II Systems-Based Embryology in c ilia - r e la te d p ro te in s. T h e s e d is o rd e rs in c lu d e tis s u e m a y b e d iv id e d in to tw o p a rts , e a c h w ith Bardet-BiedI syndrome, c h a ra c te riz e d b y re n a l its o w n re n a l p e lv is a n d u re te r. M o re fre q u e n tly , c y s ts , o b e s ity , in te lle c tu a l d is a b ility , a n d lim b h o w e v e r, th e tw o p a rts h a v e a n u m b e r o f lo b e s d e fe c ts , a n d Meckel-Gruber syndrome, c h a ra c ­ in c o m m o n a s a re s u lt o f in te rm in g lin g o f c o lle c t- te r iz e d b y re n a l c y s ts , h y d ro c e p h a lu s , m ic ro p h - in g tu b u le s. In ra re c a s e s , o n e u r e te r o p e n s in to th a lm ia , c le f t p a la te , a b s e n c e o f th e o lfa c to r y th e b la d d e r, a n d th e o th e r is e c to p ic , e n te rin g tr a c t, a n d p o ly d a c ty ly. B e c a u s e c ilia a re p re s e n t th e v a g in a , u re th r a , o r v e s tib u le (Fig. 16.9C). T h is o n m o s t c e ll ty p e s a n d in m o s t tis s u e s , m a n y a b n o r m a lity re s u lts fr o m d e v e lo p m e n t o f tw o o rg a n s y s te m s c a n b e a ffe c te d b y a b n o r m a li- u r e te r ic bucis. O n e o f th e b u d s u s u a lly h a s a n o r ­ tie s in c ilia r y s tr u c tu r e a n d fu n c tio n. m a l p o s itio n , w h e re a s th e a b n o rm a l b u d m o v e s D u p líc a tio n o f th e u r e te r re s u lts fr o m e a rly d o w n to g e th e r w ith th e m e s o n e p h ric d u c t. T h u s , s p iittin g o f th e u re te r ic b u d (F ig. 16.9). S p iittin g it h a s a lo w , a b n o rm a l e n tra n c e in th e b la d d e r, m a y b e p a rtia l o r c o m p le te , a n d m e ta n e p h ric u re th r a , v a g in a , o r e p id id y m a l re g ió n. Normal ureter FIGURE 16.9 A,B- A c o m p le te a n d a p a rtia l d o u b le u re te r. C. P o ss ib le s ite s o f e c to p ic u re te ra l o p e n in g s in th e v a g in a , u re th ra , a n d v e s tib u le. D,E. P h o to m ic ro g ra p h s o f c o m p le te a n d p a rtia l d u p lic a tio n s o f th e u re te rs [U]. Arrows, d u p lic a te d h ilu m ; 6 , b la d d e r; K. k id n e y s ; ML, m e d ia n u m b ilic a l lig a m e n t.  Chapter16 Urogenital System Gonad and remnants of Metanephros Mesonephros mesonephros Gonad Allantois Cloaca - Rectum Metanephric Ureter Urogenital sinus tissue FIGURE 16.10 A-C. A s c e n t o f th e k id n e y s. N o te th e c h a n g e in p o s itlo n b e tw e e n th e m e s o n e p h ric a n d m e ta ­ n e p h ric s y s te m s. T he m e s o n e p h ric s y s te m d e g e n e ra te s a lm o s t e n tire ly , a n d o n iy a fe w re m n a n ts p e rs is t in ció s e c o n ta c t w ith th e g o n a d. In b o th m a le a n d fe m a le e m b ry o s , th e g o n a d s d e s c e n d fro m th e ir o rig in a l level to a m u c h lo w e r p o s itlo n. Position of the Kídney fetal life, the kidneys are not responsible for ex- The kidney, initially in the pelvic región, later cretion of waste producís because the placenta shifts to a more cranial position in the abdo­ serves this function. men. This ascent of the kidney is caused by diminution of body curvature and by growth Bladder and Urethra o f the body in the lumbar and sacral regions During the fourth to seventh weeks of devel- (Fig. 16.10). In the pelvis, the metanephros opment, the cloaca divides into the urogenital receives its arterial supply from a pelvic branch sinus anteriorly and the anal canal posteri- o f the aorta. During its ascent to the abdominal orly (Fig. 16.12) (see Chapter 15, p. 247). The level, it is vascularized by arteries that origínate urorectal septum is a layer of mesoderm be­ from the aorta at continuously higher levels. tween the primitive anal canal and the urogeni­ The lower vessels usually degenerate, but some tal sinus. The tip of the septum will form the may remain. perineal body, a site of insertion of several perineal muscles (Fig. 16.12C). Three portions Function of the Kidney of the urogenital sinus can be distinguished; the The definitive kidney formed from the metaneph­ upper and largest part is the urinary bladder ros becomes functional near the 12th week. Uriñe (Fig. 16.13A). Initially, the bladder is continu- is passed into the amniotic cavity and mixes with ous with the allantois, but when the lumen the amniotic fluid. The fluid is swallowed by the of the allantois is obliterated, a thick flbrous fetus and recycles through the kidneys. During cord, the urachus (Fig. 16.135), remains and Clinicat Correlates Abnormal Location of the Kidneys p re v e n te d b y th e r o o t o f t h e in fe r io r m e s e n te ric D u rin g t h e ir a s c e n t, th e k id n e y s p a s s th r o u g h a r te r y (F ig. 16.11S]. T h e u r e te r s a ris e fr o m th e t h e a r te r ia l fo r k fo r m e d b y t h e u m b ilic a l a r te r ­ a n te r io r s u rfa c e o f th e k id n e y a n d p a s s v e n tr a l ie s , b u t o c c a s io n a lly , o n e o f th e m fa ils t o d o t o t h e is th m u s in a c a u d a l d ir e c tio n. H o rs e s h o e so. R e m a in in g in th e p e lv is c ió s e t o th e c o m - k id n e y is fo u n d in 1 /6 0 0 p e o p le. m o n ilia c a r te r y , i t is k n o w n a s a pelvic kidney Accessory renal arteries a re c o m m o n ; th e y (F ig. 16.11-4). S o m e tim e s , th e k id n e y s a re p u s h e d d e riv e fr o m th e p e rs is te n c e o f e m b ry o n ic v e s ­ s o c ió s e t o g e t h e r d u r in g t h e ir p a s s a g e t h r o u g h s e ls t h a t fo rm e d d u rin g a s c e n t o f th e k id n e y s. t h e a r te r ia l fo rk , t h a t t h e lo w e r p o le s fu s e , T h e s e a rte rie s u s u a lly a ris e fr o m th e a o rta a n d f o r m in g a horseshoe kidney [F ig. 16.116,C]. T h e e n te r th e s u p e rio r o r in fe rio r p o le s o f th e k id n e y s. h o rs e s h o e k id n e y is u s u a lly a t th e le v e l o f th e lo w e r lu m b a r v e r te b r a e b e c a u s e its a s c e n t is [continued]  Part II Systems-Based Embryology A d ren al gland Renal artery v e n a cava Inferior m esenteric P elvic kidney artery C om m on iliac artery U reters B FIGURE 16.11 A. U n ila te ra l p e lv ic k id n e y s h o w - in g th e p o s itio n o f th e a d re n a l g la n d on th e a f- fe c te d side. B,C. D ra w in g a n d p h o to m ic ro g ra p h , re s p e c tiv e ly , o f h o rs e s h o e k id n e y s s h o w in g th e p o s itio n o f th e in fe rio r m e s e n te ric a rte ry. connects the apex of the bladder with the um- During differentiation of the cloaca, the bihcus (Fig. 16.13B). In the adult, it forms the caudal portions of the mesonephric ducts are median umbilical ligament. The next part is absorbed into the wall of the urinary bladder a rather narrow canal, the pelvic part of the (Fig. 16.14). Consequently, the ureters, initially urogenital sinus, which in the male gives rise outgrowths from the mesonephric ducts, enter to the prostatic and membranous parts of the the bladder separately (Fig. 16.14B). As a result urethra. The last part is the phallic part of the of ascent of the kidneys, the orifices of the ureters urogenital sinus. It is flattened from side to side, move farther cranially; those of the mesonephric and as the genital tubercle grows, this part of ducts move cióse together to enter the prostatic the sinus will be pulled ventrally (Fig. 16.I3A). urethra and in the male become the ejacula- (Development of the phallic part of the urogeni­ tory ducts (Fig. 16.14C,D). Because both the tal sinus differs greatly between the two sexes.) mesonephric ducts and ureters origínate in the  Chapter16 Urogenital System Mesonephric Mesonephric Bladder duct Allantois duct Primitive urogenital sinus , ^ ^ Perineal"' Cloacal Hindgut Anorectal body tnembrane sepium ^anal A B C FIGURE 16.12 D iv is io n s o f th e c lo a c a in to th e u ro g e n ita l s in u s a n d a n o re c ta l c a n a l. T he m e s o n e p h ric d u c t is g ra d u a lly a b s o rb e d in to th e w a ll o f th e u ro g e n ita l sin u s , a n d th e u re te rs e n te r s e p a ra te ly. A. A t th e e n d o f th e fifth w e e k. B. 7 w e e k s. C. 8 w e eks. Urinary bladder Urachus Allantois Pelvic part of Prostate urogenital gland sinus Definitive Penile urethra urogenital sinus Prostatic and Anorectal canal membranous urethra A B FIGURE 16.13 A. D e v e lo p m e n t o f th e u ro g e n ita l s in u s in to th e u rin a ry b la d d e r a n d d e fin itiv e u ro g e n ita l sin u s. B. In th e m a le , th e d e fin itiv e u ro g e n ita l s in u s d e v e lo p s in to th e p e n ile u re th ra. T he p ro s ta te g la n d is fo rm e d b y b u d s fro m th e u re th ra , a n d s e m in a l v e s ic le s a re fo rm e d b y b u d d in g fro m th e d u c tu s d e fe re n s. Posterior wall of the FIGURE 16.14 D orsa l v ie w s o f th e b la d d e r s h o w in g th e re la tio n o f th e u re te rs a n d m e s o n e p h ric d u c ts d u rin g d e v e lo p m e n t. In itia lly , th e u re te rs a re fo rm e d b y a n o u tg ro w th o f th e m e s o n e p h ric d u c t (A), b u t w ith tim e , th e y a s s u m e a s e p a ra te e n tra n c e in to th e u rin a ry b la d d e r (B-D). N o te th e trig o n e o f th e b la d d e r fo rm e d by in c o rp o ra tio n o f th e m e s o n e p h ric d u c ts (C,D).  Part II Systems-Based Embryology mesoderm, the mucosa of the bladder formed connective and smooth musde tissue is de- by incorporation of the ducts (the trigone of the rived from visceral mesoderm. At the end of bladder) is also mesodermal. With time, the me- the third month, epithelium of the prostatic sodermal hning of the trigone is replaced by en- urethra begins to proliferate and forms a num- dodermal epithehum, so that finally, the inside ber of outgrowths that penetrate the surround­ of the bladder is completely lined with endoder- ing mesenchyme. In the male, these buds form mal epithelium. the prostate gland (Fig. 16.13B). In the female, The epithelium of the urethra in both sexes the cranial part of the urethra gives rise to the originates in the endoderm; the surrounding urethral and paraurethral glands. Cfinical Correlates Bladder Defects fa ilu r e o f th e la te r a l b o d y w a ll f o ld s t o c ió s e W h e n t h e lu m e n o f th e in tr a e m b r y o n ic p o r - in th e m id lin e in th e p e lv ic r e g ió n (s e e C h a p te r t io n o f t h e a lla n to ís p e r s is ts , a urachal fístula 7, p. 9 9 ]. T h is a n o m a ly is ra re , o c c u r r in g in m a y c a u s e u r iñ e t o d r a in fr o m th e u m b ilic u s 2 /1 0 ,0 0 0 liv e b ir th s. (F ig. 16.15A ]. If o n iy a lo c a l a re a o f th e a l- Exstrophy of th e cloaca [F ig. 1 6.1 6 6 ] is a la n to is p e rs is ts , s e c r e to r y a c t iv it y o f it s lin - m o re s e v e re v e n tr a l b o d y w a ll d e fe c t in w h ic h in g r e s u lts in a c y s t ic d ila tio n , a urachal cyst p ro g r e s s io n a n d c lo s u r e o f th e la te r a l b o d y (F ig. 1 6.1 5 8 ]. W h e n th e lu m e n in t h e u p p e r p a r t w a ll fo ld s a re d is r u p te d t o a g r e a te r d e g re e p e r s is ts , i t f o r m s a urachal sinus. T h is s in u s t h a n is o b s e rv e d in b la d d e r e x s tr o p h y (s e e is u s u a lly c o n tin u o u s w it h th e u r in a r y b la d d e r C h a p te r 7, p. 9 9 ]. In a d d itio n t o t h e c lo s u re (F ig.1 6.1 5 C ]. d e fe c t, n o rm a l d e v e lo p m e n t o f th e u r o r e c ta l Exstrophy of the bladder (F ig. 1 6.1 6 4 ] is s e p tu m is a lte r e d , s u c h t h a t a n a l c a n a l m a l- a v e n tr a l b o d y w a ll d e f e c t in w h ic h th e b la d ­ f o r m a tio n s a n d im p e r fo r a te a n u s o c c u r (s e e d e r m u c o s a is e x p o s e d. E p is p a d ia s is a c o n - C h a p te r 15, p. 2 4 7 ]. F u r th e r m o r e , b e c a u s e th e s t a n t f e a t u r e (F ig. 1 6.3 4 ], a n d th e o p e n u r in a r y b o d y fo ld s d o n o t fu s e , th e g e n ita l s w e ilin g s t r a c t e x te n d s a lo n g t h e d o r s a l a s p e c t o f th e a re w id e ly s p a c e d r e s u ltin g in d e fe c ts in th e p e n is t h r o u g h th e b la d d e r t o th e u m b ilic u s. e x te r n a l g e n ita lia (F ig. 16.16B ]. O c c u rre n c e o f E x s tr o p h y o f t h e b la d d e r is p r o b a b ly d u e to t h e d e fe c t is ra re (1 /3 0 ,0 0 0 ]. FIGURE 16.15 A. U ra ch a l fis tu la. B. U ra ch a l c y st. C. U ra ch a l sin u s. T he s in u s m a y o r m a y n o t be in o p e n c o m m u n ic a tlo n w ith th e u rin a ry b la d d e r.  Chapter16 Urogenital System FIGURE 16.16 A. E x s tro p h y o f th e b la d d e r. B. C loacal e x s tro p h y In a n e w b o rn. GENITAL SYSTEM not acquire male or female morphological char- acteristics until the seventh week of development. Sex diíferentiation is a complexprocess that involves Gonads appear initially as a pair of longi­ many genes, including some that are autosomal. tudinal ridges, the genital or gonadal ridges The key to sexual dimorphism is the Y chromo- (Fig. 16.17). They are formed by proliferation some, which contains the testis-determining gene of the epithelium and a condensation of un- called the SRY (sex-determíning región on Y) derlying mesenchyme. Germ cells do not ap­ gene on its short arm (Ypl 1). The protein product pear in the genital ridges until the sixth week of of this gene is a transcription factor initiating a cas- development. cade of downstream genes that determine the fate Primordial germ cells origínate in the epi- of mdimentary sexual organs. The SRY protein is blast, migrate through the primitive streak, and the testís-determining factor; under its influence, by the third week reside among endoderm cells male development occurs; in its absence, female in the wall of the yolk sac cióse to the allantois development is established. (Fig. 16.18A). During the fourth week, they mi- grate by ameboid movement along the dorsal Gonads mesentery of the hindgut (Fig. 16.18A,B), arriv- Although the sex of the embryo is determined ge- ing at the primitive gonads at the beginning of neticaUy at the time of fertilization, the gonads do the fifth week and invading the genital ridges in Mesonephros Mesonephric duct Excretory tube Glomerulus \ Mesonephric A orta duct Intestinal loop Dorsal mesentery Genital Mesonephric ridge ridge Gonad B FIGURE 16.17 A. R e la tio n o f th e g e n ita l rid g e a n d th e m e s o n e p h ro s s h o w in g lo c a tio n o f th e m e s o n e p h ric d u c t. B. T ra n s v e rs e s e c tio n th ro u g h th e m e s o n e p h ro s a n d g e n ita l rid g e a t th e level in d ic a te d in (A).  Part II Systems-Based Embryology Foregut Hindgut Allantois Genital ridge Hindgut Primordial germ Genital cells ridge Cloaca Mesonephros Yolk sac FIGURE 16.18 A. A 3 -w e e k e m b ry o s h o w in g th e p rim o rd ia l g e rm c e lls in th e w a ll o f th e y o lk sac c ió s e to th e a tta c h m e n t o f th e a lla n to is. B. M ig ra tio n a l p a th o f th e p rim o rd ia l g e rm c e lls a lo n g th e w a ll o f th e h in d g u t a n d th e d o rs a l m e s e n te ry in to th e g e n ita l ridge. the sixth week. If they fail to reach the ridges, the or medullary cords (Figs. 16.20A and 16.21). gonads do not develop. Henee, the primordial Toward the hilum of the gland, the cords break up germ cells have an inductive influence on devel- into a network of tiny ceU strands that later give opment of the gonad into ovary or testis. rise to tubules of the rete testis (Fig. 16.20A,5). Shortly before and during arrival of primor­ During fiirther development, a dense layer of ñ- dial germ ceUs, the epithelium of the genital ridge brous connective tissue, the túnica albuginea, proliferates, and epithelial cells penetrate the separates the testis cords from the surface epithe­ underlying mesenchyme. Here they form a num- lium (Fig. 16.20). ber of irregularly shaped cords, the primitive In the fourth month, the testis cords become sex cords (Fig. 16.19). In both male and female horseshoe-shaped, and their extremities are con- embryos, these cords are connected to surface tinuous with those of the rete testis (Fig. 16.20B). epithelium, and it is impossible to difFerentiate Testis cords are now composed of primitive between the male and female gonad. Henee, the germ cells and sustentacular cells of Sertoli de- gonad is known as the indifferent gonad. rived from the surface epithelium of the gland. Interstitial cells of Leydig, derived from the Testis original mesenchyme of the gonadal ridge, lie be­ If the embryo is genetically male, the primordial tween the testis cords. They begin development germ ceUs carry an XY sex chromosome complex. shortly after onset of differentiation of these Under influence of the Si? Y”gene on the Y chromo­ cords. By the eighth week of gestation, Leydig some, which encodes the testis-determining factor, cells begin production of testosterone and the the primitive sex cords continué to proliferate and testis is able to influence sexual differentiation of penetrate deep into the meduUa to form the testis the genital ducts and external genitalia. FIGURE 16.19 T ra n s v e rs e s e c tio n th ro u g h Mesonephric th e lu m b a r re g ió n o f a 6 -w e e k e m b ry o s h o w ­ Aorta duct in g th e in d iffe re n t g o n a d w ith th e p rim itiv e s e x c o rd s. S o m e o f th e p rim o rd ia l g e rm c e lls a re s u rro u n d e d b y c e lls o f th e p rim itiv e s e x co rd s. Primordial germ cells Proliferating Paramesonephric Primitive duct body epithelium sex cords  Chapter16 Urogenital System Túnica D egenerating a lbuginea m e so ne ph ric tubule Rete testis cords H orseshoe- shaped Testis te stis cords cords - Túnica albuginea P a ram esonephric Excretory P a ram esonephric duct m eso n e p h ric tubules duct M e son e ph ric (ductuli efferentes) duct M esonephric duct A B (ductus defere ns) FIGURE 16.20 A. T ra n s v e rs e s e c tio n th ro u g h th e te s tis in th e e ig h th w e e k , s h o w in g th e tú n ic a a lb u g in e a , te s tis c o rd s , re te te s tis , a n d p rim o rd ia l g e rm ce lls. T he g lo m e ru lu s a n d B o w m a n ’s c a p s u le o f th e m e s o n e p h ­ ric e x c re to ry tu b u le a re d e g e n e ra tin g. B. T e s tis a n d g e n ita l d u c t in th e fo u rth m o n th. T he h o rs e s h o e -s h a p e d te s tis c o rd s a re c o n tin u o u s w ith th e re te te s tis c o rd s. N o te th e d u c tu li e ffe re n te s [e x c re to ry m e s o n e p h ric tu b u le s ], w h ic h e n te r th e m e s o n e p h ric d u c t. Testis cords remain solid until puberty, when and are replaced by a vascular stroma that forms they acquire a lumen, thus forming the seminif- the ovarían meduUa (Fig. 16.22). erous tubules. Once the seminiferous tubules The surface epithelium of the female gonad, are canalized, they join the rete testis tubules, unlike that of the male, continúes to proliferate. which in turn enter the ductuli efferentes. These In the seventh week, it gives rise to a second gen- eíferent ductules are the remaining parts of the eration of cords, cortical cords, which penetrate excretory tubules of the mesonephric system. the underlying mesenchyme but remain cióse They link the rete testis and the mesonephric to the surface (Fig. 16.22A). In the third month, or Wolffian duct, which becomes the ductus these cords split into isolated cell clusters. Cells deferens (Fig. 16.20B). in these clusters continué to proliferate and begin to surround each oogonium with a layer of epi- O vary thelial cells called follicular cells. Together, the In female embryos with an XX sex chromosome oogonia and follicular cells constitute a primor­ complement and no Y chromosome, primitive dial follicle (Fig. 16.22B; see Chapter 2, p. 26). sex cords dissociate into irregular cell clusters It may thus be stated that the genetic sex of an (Figs. 16.21 and 16.22A). These clusters, contain- embryo is determined at the time of fertilization, ing groups of primitive germ cells, occupy the depending on whether the spermatocyte carries medullary part of the ovary. Later, they disappear an X or a Y chromosome. In embryos with an 44 + XY 44 + XX Y influence Absence oí Y Indifferent gonad Testis O v a ry Medullary cords develop Medullary cords degenerate No cortical cords Cortical cords develop Thick túnica albugínea No túnica albugínea FIGURE 16.21 In flu e n c e o f p rim o rd ia l g e rm c e lls on in d iffe re n t g o n a d.  Part II Systems-Based Embryology Surface Degenerating Urogenital epithelium mesonephric tubule mesentety Degenerating medullary cords Primary oocyte Cortical Follicular cords cells Ductuli efferentes Paramesonephric |\/iesonephric Surface epithelium Paramesonephric duct duct Mesonephric duct A FIGURE 16.22 A. T ra n s v e rs e s e c tio n o f th e o v a ry a t th e s e v e n th w e e k , s h o w in g d e g e n e ra tio n o f th e p rim i- tiv e [m e d u lla ry ] s e x c o rd s a n d fo rm a tio n o f th e c o rtic a l c o rd s. B. O v a ry a n d g e n ita l d u c ts in th e fifth m o n th. N o te d e g e n e ra tio n o f th e m e d u lla ry c o rd s. T he e x c re to ry m e s o n e p h ric tu b u le s (e ffe re n t d u c tu le s ] d o n o t c o m m u n ic a te w ith th e re te. The c o rtic a l z o n e o f th e o v a ry c o n ta in s g ro u p s o f o o g o n ia s u rro u n d e d b y f o l­ lic u la r cells. XX sex chromosome configuration, medullary Cranially, the duct opens into the abdominal cords of the gonad regress, and a secondary gen- cavity with a funnel-like structure. Caudally, eration of cortical cords develops (Figs. 16.21 it first runs lateral to the mesonephric duct, and 16.22). In embryos with an XY sex chromo- then crosses it ventrally to grow caudomedially some complex, medullary cords develop into (Fig. 16.23). In the midline, it comes in cióse testis cords, and secondary cortical cords fail to contact with the paramesonephric duct from the develop (Figs. 16.20 and 16.21). opposite side. The caudal tip of the combined ducts projects into the posterior wall of the uro­ Genital Ducts genital sinus, where it causes a small swelling, the sinus tubercle (Fig. 16.24A). The mesoneph­ In d iffe re n t Stage ric ducts open into the urogenital sinus on either Initially, both male and female embryos have two side of the sinus tubercle. pairs of genital ducts: mesonephric (Wolffian) ducts and paramesonephric (Müllerian) ducts. Genital Ducts in the Male The paramesonephric duct arises as a longitudi­ Genital ducts in the male are stimulated to develop nal invagination of the epithelium on the antero- by testosterone and are derived from parts of the lateral surface of the urogenital ridge (Fig. 16.23). mesonephric kidney system (Fig. 16.25). Some of FIGURE 16.23 G e n ita l d u c ts in th e Degenerating excretory tubules s ix th w e e k in th e m a le (A) a n d fe ­ of the mesonephros m a le ÍB). T h e m e s o n e p h ric a n d Degenerating p a ra m e s o n e p h ric d u c ts a re p re s e n t medullary cords in b o th. N o te th e e x c re to ry tu b u le s o f th e m e s o n e p h ro s a n d th e ir re - la tio n to th e d e v e lo p in g g o n a d in Rete testis Cortical cords b o th sexes. Testis cords of the ovary Túnica albugínea Mesonephros Mesonephric duct Paramesonephric duct B  Chapter16 Urogenital System A b d om in a l ostium o f uterine tube S u spe nso ry ligam ent o f o v a ty L igam ent o f o v a ty proper F im briae E poophoron C ortical cords o f o v a ty C orpus uteri R ound ligam ent o f uterus M esonephric- U terine c anal G a rtn e r cyst du ct S inus tu b e rc le B FIGURE 16.24 A. G e n ita l d u c ts in th e fe m a le a t th e e n d o f th e s e c o n d m o n th. N o te th e p a ra m e s o n e p h ric [M ü lle ria n ] tu b e rc le a n d fo rm a tio n o f th e u te rin e c a n a l. B. G e n ita l d u c ts a fte r d e s c e n t o f th e o v a ry. T he o n iy p a rts re m a in in g fro m th e m e s o n e p h ric s y s te m are th e e p o o p h o ro n , p a ro o p h o ro n , a n d G a rtn e r c y s t. N o te th e s u s p e n s o ry lig a m e n t o f th e o v a ry , lig a m e n t o f th e o v a ry p ro p e r, a n d ro u n d lig a m e n t o f th e u te ru s. Testis M üllerian- Testosterone inhibitin g sub sta n ce (Leydig cells) (S erto li cells) M e so n e p h ric ducts stim ulated (efferent ductules, epididym is, vas deferens, se m inal vesicles) P a ram e so ne ph ric du cts suppressed D ihydro testosterone E xternal g e n ita lia stim ula ted G row th o f penis, scrotum , and prostate Ovary E strogens (including m aternal and placental sources) P a ram esonephric du cts stim ula ted E xternal g e n italia stim ulated (u te rin e tube, uterus, upper (labia, clitoris, low er portion po rtio n o f vagina) of vagina) FIGURE 16.25 In flu e n c e o f th e s e x g la n d s o n fu rth e r s e x d iffe re n tia tio n.  Part II Systems-Based Embryology Seminal vesicle Utriculus prostaticus Rete testis Epigenital tubules Testis cords Túnica albugínea Appendix epididymis Vas deferens -Appendix testis Paragenital tubules Testis cord Efferent Rete testis ductules Epididymis Paradidymis Sinus tubercle A FIGURE 16.26 A. G e n ita l d u c ts in th e m a le in th e fo u rth m o n th. C ra n ia l a n d c a u d a l [p a ra g e n ita l tu b u le ] s e g m e n ts o f th e m e s o n e p h ric s y s te m re g re ss. B. G e n ita l d u c ts a fte r d e s c e n t o f th e te s tis. N o te th e h o rs e - s h o e -s h a p e d te s tis c o rd s , re te te s tis , a n d e ffe re n t d u c tu le s e n te rin g th e d u c tu s d e fe re n s. T he p a ra d id y m is is fo rm e d b y re m n a n ts o f th e p a ra g e n ita l m e s o n e p h ric tu b u le s. T he p a ra m e s o n e p h ric d u c t has d e g e n e ra te d e x c e p t fo r th e a p p e n d ix te s tis. T he p ro s ta tic u tric le is an o u tp o c k e tin g fro m th e u re th ra. the original excretoiy tubules, the epigenital recognized in each duct: ( 1) a cranial vertical tubules, estabüsh contact with cords of the rete portion that opens into the abdominal cavity, testis and form the efferent ductules of the testis ( 2 ) a horizontal part that crosses the meso­ (Fig. 16.26). Excretory tubules along the caudal nephric duct, and (3) a caudal vertical part that pole of the testis, the paragenital tubules, do not fuses with its partner from the opposite side join the cords of the rete testis (Fig. 16.26). Their (Fig. 16.24A). With descent of the ovary, the vestiges are coUectively known as the paradidymis. first two parts develop into the uterine tube Except for the most cranial portion, the (Fig. 16.24B), and the caudal parts fuse to form appendix epididymis, the mesonephric ducts per- the uterine canal. When the second part of the sist and form the main genital ducts (Fig. 16.26). paramesonephric ducts moves mediocaudally, Immediately below the entrance of the efferent the urogenital ridges gradually come to lie in a ductules, the mesonephric ducts elongate and transverse plañe (Fig. 16.27A,B). After the ducts become highly convoluted, forming the (ductus) fuse in the midline, a broad transverse pelvic fold epididymis. From the tail of the epididymis to the is established (Fig. 16.27C). This fold, which ex- outbudding of the seminal vesicle, the mesoneph­ tends from the lateral sides of the fused parame­ ric ducts obtain a thick muscular coat and form sonephric ducts toward the wall of the pelvis, is the ductus deferens. The región of the ducts be- the broad ligament of the uterus. The uterine yond the seminal vesicles is the ejaculatory duct. tube lies in its upper border, and the ovary lies Under the influence of anti-MüUerian hormone on its posterior surface (Fig. 16.27C). The uterus (AMH; also caUed Müllerian inhibiting sub- and broad ligaments divide the pelvic cavity stance [MIS]) produced by Sertoli cells, parame­ into the uterorectal pouch and the uterovesi- sonephric ducts in the male degenerate except for cal pouch. The fused paramesonephric ducts a small portion at their cranial ends, the appendix give rise to the corpus and cervix of the uterus testis (Figs. 16.25 and 16.26B). and the upper portion of the vagina. The uterus Genital Ducts in the Femafe is surrounded by a layer of mesenchyme that In the presence of estrogen and the absence of forms both its muscular coat, the myometrium, testosterone and AMH (MIS), paramesonephric and its peritoneal covering, the perimetrium. In ducts develop into the main genital ducts of the the absence of testosterone, mesonephric ducts female (Fig. 16.25). Initially, three parts can be in the female degenerate.  Chapter16 Urogenital System U rogenital ridge U terorectal M e son e ph ric e xcretory pouch tu b u le O vary M esor^ephric duct Broad P a ra m esonephric Fused ligam ent d uct p a ram esone phric o f uterus ducts U terovesical pouch FIGURE 16.27 T ra n s v e rs e s e c tio n s th ro u g h th e u ro g e n ita l rid g e a t p ro g re s s iv e ly lo w e r le ve ls. A,B- The p a ra m e s o n e p h ric d u c ts a p p ro a c h e a ch o th e r in th e m id lin e a n d fu s e. C. A s a re s u lt o f fu s ió n , a tra n s v e rs e fo ld , th e b ro a d lig a m e n t o f th e u te ru s , fo rm s in th e p e lv is. T he g o n a d s c o m e to lie a t th e p o s te rio r a s p e c t o f th e tra n s v e rs e fo ld. M olecular Regulation o f Genital Duct by these tubules, diíFerentiation of the testes does Development not continué. Next, SRY either directly or indi- SRY is a transcription factor and the master rectly (through S0X9) upregulates production of gene for testes development. It appears to act STEROIDOGENESIS FACTOR 1 (SF l) that in conjunction with the autosomal gene S0X9, stimulates differentiation of Sertoli and Leydig a transcriptional regulator, that can also induce ceUs. SFl working with S0X 9 elevates the con- testes diíFerentiation (see Fig. 16.28 for a poten- centration of AMH leading to regression of the tial pathway for these genes). S0X 9 is known to paramesonephric (Müllerian) ducts. In Leydig bind to the promoter región of the gene for AMH ceUs, SFl upregulates the genes for enzymes that (MIS) and probably regulates this gene’s expres- synthesize testosterone. Testosterone enters sion. Initially, SRY and/or S0X 9 induce the testes ceUs of target tissues where it may remain in- to secrete FGF9 that acts as a chemotactic factor tact or be converted to dihydrotestosterone by that causes tubules from the mesonephric duct to a 5-ot reductase enzyme. Testosterone and dihy­ penetrate the gonadal ridge. Without penetration drotestosterone bind to a specific high-aíRnity MALES (XY) FEMALES (XX) ^ ^ e s te s ^ ( l^ v a r ie s ^ FIGURE 16.28 S c h e m a tic s h o w in g g e n e s re s p o n s ib le fo r d iffe re n tia tio n o f th e te s te s a n d o v a rle s. In b o th m a le s a n d fe m a le s , S0X9 a n d WNT4 a re e x p re s s e d in th e g o n a d a l rid g e s. In m a le s , th e e x p re s s io n o f SRY u p re g u la te s S 0 X 9 , w h ic h in tu rn a c tiv a te s e x p re s s io n o f SFl a n d o th e r g e n e s re s p o n s ib le fo r te s te s d iffe r ­ e n tia tio n , w h ile in h ib itin g e x p re s s io n o f WNT4. In fe m a le s , th e u n in h ib ite d e x p re s s io n o f WNT4 u p re g u la te s DAXl th a t in tu rn in h ib its S 0 X 9 e x p re s s io n. T h en, u n d e r th e c o n tin u e d in flu e n c e o f WNT4, o th e r d o w n s tre a m ta r g e t g e n e s (p e rh a p s TAFinOB] in d u c e o v a ría n d iffe re n tia tio n.  Part II Systems-Based Embryology intracellular receptor, and this hormone recep­ (Figs. 16.29A and 16.30A), two solid evagina- tor complex is transported to the nucleus where tions grow out from the pelvic part of the sinus it binds to DNA to regúlate transcription of (Figs. 16.29B and 16.30B). These evaginations, tissue-specific genes and their protein producís. the sinovaginal bulbs, proliferate and form a Testosterone receptor complexes medíate dif- solid vaginal píate. Proliferation continúes at ferentiation of the mesonephric ducts to form the cranial end of the píate, increasing the dis- the vas deferens, seminal vesicles, eíferent duct- tance between the uterus and the urogenital ules, and epididymis. Dihydrotestosterone re­ sinus. By the fifth month, the vaginal outgrowth ceptor complexes modulate diíferentiatíon of is entirely canalized. The wing-like expansions the male external genitalia (Fig. 16.25). of the vagina around the end of the uterus, the WNT4 is the ovary-determining gene. This vaginal fornices, are of paramesonephric origin gene upregulates D A X l, a member of the nuclear (Fig. 16.30C). Thus, the vagina has a dual origin, hormone receptor family, that inhibits the with the upper portion derived from the uterine function of 50X9. In addition, WNT4 regulates canal and the lower portion derived from the expression of other genes responsible for ovarían urogenital sinus. diíferentiatíon, but these target genes have not The lumen o f the vagina remains sepa- been ídentífied. One target may be the TAFII105 rated from that o f the urogenital sinus by a gene, whose protein product is a subunit for the thin tissue píate, the hymen (Figs. 16.29C and TATA-binding protein for RNA polymerase in 16.30C), which consists o f the epithelial lining ovarían follicular cells. Female mice that do not o f the sinus and a thin layer of vaginal cells. synthesíze this subunit do not form ovaries. It usually develops a small opening during Estrogens are also involved in sexual dííferen- perinatal life. tiation, and under their influence, the parameso- The female may retain some remnants of nephric (Müllerian) ducts are stimulated to form the cranial and caudal excretory tubules in the the uterine tubes, uterus, cervix, and upper v ^ n a. mesovarium, where they form the epoophoron In addition, estrogens act on the extemal genitalia and paroophoron, respectively (Fig. 16.24B). at the indifferent stage to form the labia majora, The mesonephric duct disappears except for a labia minora, clitoris, and lower vagina (Fig. 16.25). small cranial portion found in the epoopho­ ron and occasionally a small caudal portion Vagina that may be found in the wall o f the uterus or Shortly after the solid tip of the parameso- vagina. Later in life, it may form Gartner cyst nephric ducts contacts the urogenital sinus (Fig. 16.24B). Lum en o f uterus U terine tu be U terine septum C au da l tip o f p a ra m e son e ph ric du cts S inus tu b e rcle Tissue o f s in o va g in a bulbs U rogential sinus (vaginal p la te )^ ^ j;;ílírii:5^ A B FIGURE 16.29 F o rm a tio n o f th e u te ru s a n d v a g in a. A. 9 w e e k s. N o te th e d is a p p e a ra n c e o f th e u te rin e s e p tu m. B. A t th e e n d o f th e th ird m o n th. N o te th e tis s u e o f th e s in o v a g in a l b u lb s. C. N e w b o rn. T he fo rn ic e s a n d th e u p p e r p o rtio n o f th e v a g in a a re fo rm e d b y v a c u o liz a tio n o f th e p a ra m e s o n e p h ric tis s u e , a n d th e lo w e r p o rtio n o f th e v a g in a is fo rm e d b y v a c u o liz a tio n o f th e s in o v a g in a l bulbs.  Chapter16 Urogenital System U rin ary bla dd er U terine S y m p h y s i^ canal \ S in u s tubercle FIGURE 16.30 S a g itta l s e c tio n s s h o w in g fo rm a tio n o f th e u te ru s a n d v a g in a a t v a rio u s s ta g e s o f d e v e lo p - m e n t. A. 9 w e e k s. B. End o f th ird m o n th. C. N e w b o rn. Clinical Correlates uterine and Vaginal Defects r u d im e n t a r y p a r t lie s a s a n a p p e n d a g e to Duplications of the uterus re s u lt fr o m la c k o f f u ­ t h e w e ll- d e v e lo p e d s id e. B e c a u s e it s lu m e n s ió n o f th e p a ra m e s o n e p h ric d u c ts in a lo c a l a re a u s u a lly d o e s n o t c o m m u n ic a t e w it h th e o r t h r o u g h o u t th e ir n o rm a l lin e o f fu s ió n. In its e x ­ v a g in a , c o m p lic a t io n s a r e c o m m o n [u t e r u s tr e m e fo rm , th e u te ru s is e n tire ly d o u b le (uterus b ic o r n is u n ic o llis w it h o n e r u d im e n t a r y h o r n ] didelphys) (Fig. 16.31-4]; in th e le a s t s e v e re fo rm , (F ig. 1 6.3 1 D ]. I f t h e a tr e s ia in v o lv e s b o th it is o n iy s lig h tiy in d e n te d in th e m id d ie (uterus s id e s , a n a t r e s ia o f t h e c e r v ix m a y r e s u lt arcuatus) (Fig. 16.31S]. O n e o f th e re la tiv e ly c o m - (F ig. 1 6.3 1 f]. I f t h e s in o v a g in a l b u lb s f a il to m o n a n o m a lie s is th e uterus bicornis, in w h ic h f u s e o r d o n o t d e v e lo p a t a ll, a d o u b le v a g in a th e u te ru s h a s tw o h o rn s e n te rin g a c o m m o n o r a t r e s ia o f t h e v a g in a , r e s p e c t iv e ly , r e s u lt s v a g in a (Fig. 16.31C). T h is c o n d itio n is n o rm a l in (F ig. 1 6.3 1 4 ,F ]. In t h e la t t e r c a s e , a s m a ll v a g ­ m a n y m a m m a ls b e lo w th e p rim a te s. in a l p o u c h o r ig in a t in g f r o m t h e p a r a m e s o ­ In p a t ie n t s w it h c o m p le t e o r p a r t ia l a t r e - n e p h r ic d u c t s u s u a lly s u r r o u n d s t h e o p e n in g s ia o f o n e o f t h e p a r a m e s o n e p h r ic d u c ts , th e o f t h e c e r v ix. Indentatlon U terus d id e lp h ys U te ru s a rcu a tu s U terus bicornis w ith d o u b le v a g in a _ I I ^ o f vagina D n E , f V U teru s b ico rn is unicollis C ervical atresia V a gina l atresia 1 ru d e m e n ta ry horn FIGURE 16.31 M ain a b n o rm a litie s o f th e u te ru s a n d v a g in a , c a u s e d b y p e rs is te n c e o f th e u te rin e s e p tu m o r o b lite ra tio n o f th e lu m e n o f th e u te rin e ca n a l.  Part II Systems-Based Embryology G enital tubercle G ^ it a l tubercle G enital sw eiling C lo a cal m em brane A B FIGURE 16.32 In d iffe re n t s ta g e s o f th e e x te rn a l g e n ita lia. A. A p p ro x im a te ly 4 w e e k s. B. A p p ro x im a te ly 6 w ee ks. External Genitalia E xternal G enitalia in the Male In d iffe re n t Stage Development of the external genitalia in the male In the third week of development, mesenchyme is under the influence of androgens secreted by cells originating in the región of the primitive the fetal testes and is characterized by rapid elon- streak migrate around the cloacal membrane gation of the genital tubercle, which is now called to form a pair of slightly elevated cloacal folds the phallus (Figs. 16.33A). During this elonga- (Fig. 16.32A). Cranial to the cloacal membrane, the tion, the phallus pulís the urethral folds forward folds unite to form the genital tubercle. Caudally, so that they form the lateral walls of the urethral the folds are subdivided into urethral folds an- groove. This groove extends along the caudal as- teriorly and anal folds posteriorly (Fig. 16.325). pect of the elongated phallus but does not reach In the meantime, another pair of elevations, the the most distal part, the glans. The epithelial lin- genital swellings, becomes visible on each side of ing of the groove, which originates in the endo- the urethral folds. These swellings later form the derm, forms the urethral píate (Fig. 16.335). scrotal swellings in the male (Fig. 16.33A) and At the end of the third month, the two ure­ the labia majora in the female (Fig. 16.355). At thral folds cióse over the urethral píate, forming the end of the sixlh week, however, it is impos- the penile urethra (Figs. 16.335). This canal does sible to distinguish between the two sexes. not extend to the tip of the phallus. This most U rethral outlet P hallus U rethral píate Penile urethra G lans penis U rethral groove Line o f fusión Solid epithelial cord o f urethral folds U rethral fold Line of fu sió n o f S crotal scrotal sw e llin gs G la n d u la r part s w e llin g s P e rin eum of urethra (scrotal septum ) Lum en o f A n al folds P erineum p enile urethra Anus A B D FIGURE 16.33 A. D e v e lo p m e n t o f e x te rn a l g e n ita lia in th e m a le a t 10 w e e k s. N o te th e d e e p u re th ra l g ro o v e fla n k e d b y th e u re th ra l fo ld s. B. T ra n s v e rs e s e c tio n s th ro u g h th e p h a llu s d u rin g fo rm a tio n o f th e p e n ile u re ­ th ra. T h e u ro g e n ita l g ro o v e is b rid g e d b y th e u re th ra l fo ld s. C. D e v e lo p m e n t o f th e g la n d u la r p o rtio n o f th e p e n ile u re th ra. D. N e w b o rn.  Chapter16 Urogenital System distal portion of the urethra is formed during The genital swellings, known in the male the fourth month, when ectodermal cells from as the scrotal swellings, arise in the inguinal the tip of the glans penetrate inward and form región. With further development, they move a short epithehal cord. This cord later obtains caudally, and each swelling then makes up half a lumen, thus forming the external urethral of the scrotum. The two are separated by the meatus (Fig. 16.33C). scrotal septum (Figs. 16.33D). Clinical Correlates Defects in th e Male Genitalia o r n e a r th e b a s e o f th e p e n is (F ig. 1 6.3 4 ). In In hypospadias, fu s ió n o f t h e u r e th r a l fo ld s ra re c a s e s , th e u r e th r a l m e a tu s e x te n d s a lo n g is in c o m p le te , a n d a b n o r m a l o p e n in g s o f th e t h e s c r o ta l ra p h e. W h e n fu s ió n o f th e u r e ­ u r e th r a o c c u r a lo n g t h e in f e r io r a s p e c t o f th e t h r a l fo ld s fa ils e n tir