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Home , Cloacal membrane, Cloaca (embryology), Epoophoron, Gubernaculum, Mesonephric duct, Mesonephros

SECTION IV Genitourinary Tract Early of the Genitourinary Tract

Dale S. Huff

The embryology of the genital and urinary tracts are inextricably interrelated and will therefore be described together. The development of the genitourinary tract can be divided into three phases. First, the primitive genitourinary tract develops in the early part of the fifth postfertilization week. Second, in the middle of the fifth week even before the first phase is completed, the definitive urinary tract and the bipotential genital tract begin to be superimposed upon the primitive genitourinary tract. Before the second phase is completed, the third phase, of the bipotential genitourinary tract, begins when the bipotential genital tract begins to differentiate into either a male or definitive genital tract beginning in the sixth week, a process that is notcom- pleted until the 12th week. The postfertilization gestational ages are assigned following the revised data of O’Rahilly and Muller [1, Appendix 2].

Primitive Genitourinary Tract

General The primitive genitourinary tract is composed of the paired mesonephric bodies, the paired mesonephric ducts, and the midline . The cloaca first appears in the mid- dle of the fourth week when the caudal curl of the and the caudal intestinal portal define the from which the cloaca develops. The will divide the cloaca into a ventral half, which will become the , and a dorsal half, which will become the . The urogenital sinus will become the bladder and , and, in the female, the introitus. The mesonephric bodies are composed of mul- tiple mesonephric that are arranged in single file from rostral to caudal. Each mesonephric connects to the , also called the primary excre- tory duct, which connects to the ventral or urogenital part of the cloaca. The meso- nephric nephrons produce urine, which drains through the collecting ducts into the mesonephric duct and into the cloaca. A mesonephric body is also called the meso- nephros. The is the functional part of the primitive genitourinary tract and its development is described next.

95 Mesonephros and Mesonephric Duct

The mesonephros develops from the intermediate the embryo to the mid lumbar region at approximately . Its development is simultaneous with the the level of L2 to L3, where its most caudal attachment rostral to caudal wave of differentiation of the somites to the is located. From this point of attach- from the [2] and the differentiation ment it curves ventromedially away from the ectoderm of the overlying ectodermal ring within the ectoderm. and attaches to the urogenital portion of the cloaca, In the middle of the fourth week, the first somite appears at the level of L4 to L5, before the caudal growth of the in the paraxial mesoderm of the occipital region. Every mesonephros is completed. The caudal end of the few hours another pair of somites differentiates cau- mesonephros reaches only to the level of L2 to L3, the dally to the previous pair. Simultaneously, the adjacent site of the curve of the mesonephric duct and its differentiates into the nephro- attachment to the ectoderm. The mesonephric genic cord. By the end of the fourth week, the occipital nephrons are not metameric and there are more and upper cervical somites appear, and the nephro- nephrons than somites. As new nephrons are added genic cord adjacent to these somites differentiates into caudally, the rostral nephrons and mesonephric duct primitive nephric structures called , which degenerate. A total of over 80 nephrons develop but, rapidly disappear. The nephrotomes are somewhat due to the simultaneous degeneration of the rostral analogous to the of lower vertebrates, but nephrons, when the last nephron differentiates and a true pronephros does not exist in [3]. attaches to the curve of the mesonephric duct at the By the beginning of the fifth week, the middle and level L2 to L3 only approximately 32 nephrons remain. lower cervical somites appear. The mesonephric duct The mesonephric duct is attached to the mesonephros arises from the dorsolateral border of the nephrogenic by a common investing and the attach- cord adjacent to somite C4 at the level of the upper ments of the connecting of the mesonephric limb bud. The first mesonephric nephron immediately nephrons to the mesonephric duct. The attachment of differentiates within the adjacent to the caudal end of the mesonephros to the curve of the C6. Mesonephric nephrons are analogous to meta- mesonephric duct and the attachment of the curve of nephric nephrons and each is attached to the meso- the mesonephric duct to the ectoderm are the begin- nephric duct by its connecting [4]. The nings of the development of the and the mesonephric duct separates from the nephrogenic caudal gonadal . This coordinated rostral to cord and grows caudally between the dorsolateral caudal differentiation of somites, mesonephros, and border of the nephrogenic cord and the ectoderm by mesonephric duct is so rapid that within 1 to 2 days, elongation of its proliferating blind tip. Every few hours early in the middle of the fifth week, all of the thoracic a new somite differentiates caudal to its predecessor and lumbar somites have been added [6], the devel- [5] and new mesonephric nephrons differentiate cau- opment of the mesonephric bodies and mesonephric dally to their predecessors and attach to the indepen- duct is complete, the mesonephric duct has attached dently elongating mesonephric duct. The caudal to the cloaca, and the development of the inguinal growth of the mesonephric duct is faster than the ros- canal and caudal gonadal ligaments has begun [2] tral to caudal differentiation of mesonephric nephrons. (see Figs. IV-1 and IV-2). The continued development of As the duct elongates caudally, it is attached to the the inguinal region and the caudal gonadal ligaments ectoderm at multiple sites. It follows the caudal curl of is described below.

96 Color Atlas of Fetal and Neonatal Histology Otocyst Nasal disc Pharyngeal arches

Optic cup Ectodermal ring (shaded) Anterior neuropore Upper limb Level of C4 Mesonephric duct Midlumbar level Mesonephric vesicles Lower limb Mammary crest

Fi g u r e IV-1. Left lateral view of the embryo at the beginning of chyme, which invests the mesonephros and mesonephric duct, the fifth postfertilization week. The mesonephros extends from is not shown in this figure so that the individual mesonephric the midcervical to the midlumbar area and follows the caudal nephrons can be seen. The lower limb bud has appeared curl of the embryo. The caudal development of the meso- within the ectodermal ring at the midlumbar area in continuity nephros is complete and the caudal end of the mesonephros with the cloacal membrane. The precursors of the caudal is at the mid lumbar area. The mesonephric duct curves ven- attachments of the and gonadal ducts to the inguinal tromedially around the distal end of the mesonephros at the canal at the midlumbar area are already established. Several midlumbar area where it is attached to the ectodermal ring at developmental fields within the ectodermal ring are depicted the future site of the internal inguinal ring and canal. This is (shaded area). the first curve of the mesonephric duct. The ­common mesen-

AB

Midlumbar level Tail gut Cloaca (most caudal area of Cloacal attachment between membrane Lower limb mesonephric duct and ectodermal ring Cloaca Mesonephric * Allantois duct * Caudal end of Mesonephric Hind gut mesonephric duct * * vesicles Mesonephric vesicles Most caudal area of attachment between mesonephric duct and ectodermal ring

Fi g u r e IV-2. Closer views of the caudal end of the primitive of the mesonephric seen on end is attached the ectodermal genitourinary tract early in the fifth week. A, Left lateral view. ring at the asterisks at the future site of the internal inguinal ring The mesonephros follows the caudal curl of the embryo. At the and canal at the origin of the lower limb. The will midlumbar area, the first curve of the mesonephric duct is arise from the segment of the mesonephric duct between its attached to the overlying ectodermal ring (not shown) attachment to the ectodermal ring and its entrance into the between the asterisks at the future site of the internal inguinal cloaca. ring and canal. B, Dorsal view of the caudal curl. The first curve

Early Embryology of the Genitourinary Tract 97 Ectodermal Ring

The ectodermal ring is a placodal strip of thickened of the entire embryo of all vertebrates, both nonmamma- ectoderm that encircles the embryo in the boundary lian and mammalian [8]. Developmental fields arise within between the dorsal and ventral halves of the body. It the ectodermal ring and the underlying specialized first appears during the end of the fourth postfertilization mesoderm for the nose, eyes, ears, pharyngeal appara- week in the face and extends caudally on both sides of tus, upper limbs, mammary glands, lower limbs, inguinal the embryo like an inverted U to cover the lateral head, region, external genitalia, and anus (see Fig. IV-1). neck, thorax, abdomen, and the inguinal areas at the The mesonephric duct is in contact with the ectoder- same time as the somites, mesonephros, and meso- mal ring at various points from the midcervical to the nephric duct are differentiating [7]. The two limbs of the midlumbar regions. Its attachment to the ectodermal inverted U meet caudally in the ventral midline over the ring at the level of C4 through C8, the site of the upper cloacal membrane to complete the ring on the second limb bud, is so close that some believe the duct arises in day of the fifth week at the same time that the develop- whole or in part from the epithelium of that part of the ment of the somites, mesonephros, and mesonephric ectodermal ring rather than entirely from the nephro- duct reaches the midlumbar region. genic cord [9]. The most caudal attachment is the one The ectodermal ring is in intimate contact with the described above, between the first curve of the meso- underlying mesenchyme of the intermediate mesoderm, nephric duct (the future tail of the ) and the mesonephros, and especially the mesonephric duct. The ectodermal ring in the midlumbar region at the site of rich epithelial–mesenchymal connections between the the future inguinal ring. It is possible that the ­epithelial ectodermal ring and the underlying mesoderm are the mesenchymal interactions between the ectodermal histologic basis for molecular epithelial–mesenchymal ring and the first curve of the mesonephric duct at this interactions, which are features characteristic of devel- site induce the formation of a developmental field opmental fields. The ectodermal ring is thought to play an within which the , inguinal canal, and important role in directing the growth and development gonadal develop.

Inguinal Region and Caudal Gonadal Ligaments The inguinal region is defined as the junction between mesonephros and mesonephric duct. The mesen- the lower limb and the abdomen. The apical ectoder- chymal attachment of the caudal end of the mal ridge of the lower limb bud arises within the ecto- mesonephros to the first curve of the mesonephric dermal ring in the midlumbar area early in the fifth week. The caudal end of the lower limb bud is adjacent to the duct is the bipotential gonadal ligament. The ingui- cloacal membrane. The appearance of the lower limb nal crest becomes the gubernaculum. The abdom- bud establishes the embryonic inguinal region. inal wall develops around the gubernaculum The internal structures of the inguinal area are forming the inguinal canal. The first curve of the the inguinal canal and the bipotential caudal mesonephric duct is therefore attached to the gonadal ligaments. These structures develop rap- gubernaculum in the inguinal canal and to the idly beginning in the middle of the fifth week when caudal end of the ­mesonephros by the gonadal the mesoderm of the body wall grows between ligament. The will replace the mesonephros the ectodermal ring and the mesonephric duct, in the near future (see Fig. IV-4) and, during this breaking the epithelial mesenchymal attachments process, the attachment of the gonadal ligament between the ectodermal ring and the meso- to the caudal end of the mesonephros gradually nephric duct, beginning rostrally and progressing shifts to the caudal end of the gonad. caudally. The last attachment to be broken is the In the male the first curve of the mesonephric one between the first curve of the mesonephric duct becomes the tail of the epididymis, the duct and the ectodermal ring at the level of L2 to gonadal ligament becomes the testicular liga- L3. At the site of this broken attachment, a placode ment, and the gubernaculum remains as the of primitive mesenchyme forms a pyramidal nod- gubernaculum. In the female the parameso- ule within the mesoderm of the anterior abdominal nephric duct develops beside the mesonephric wall [10]. The tip of the nodule protrudes into the duct. The first curve of the peritoneal cavity. This mesenchymal nodule is the develops within the gonadal ligament. As the inguinal crest and it is located at the site of the mesonephric duct degenerates, the gonadal lig- inguinal canal. The mesenchyme around the first ament remains attached to the paramesonephric curve of the mesonephric duct attaches to the tip duct and becomes the . The of the inguinal crest (see Fig. IV-3). The caudal end gubernaculum becomes the round ligament and of the mesonephros, as described above, is the inguinal canal becomes the . attached to the first curve of the mesonephric Thus, by the middle of the fifth week the basic duct by the common mesenchyme investing the blue print of the primitive urinary tract is laid down

98 Color Atlas of Fetal and Neonatal Histology [11,12]. The mesonephric bodies are the largest a relationship that will never vary. The lower limb visceral organs of the embryo. They extend from bud is present. The mesonephric bodies will begin the midcervical to the midlumbar region as large to produce urine during the sixth week but will raised, parallel, parasagittal ridges protruding then degenerate in a rostral to caudal wave. The from the posterior abdominal wall near the mid- bodies will be replaced by the gonads and will line (see Fig. IV-5). They follow the line of the cau- disappear by the end of the eighth week [13]. At dal curl of the embryo. The precursors of the the middle of the fifth week, this primitive urinary caudal gonadal ligaments fix the caudal ends of system is ready for the beginning of the develop- the mesonephric bodies and the mesonephric ment of the bipotential genital tract and the ducts to the future inguinal ring and inguinal canal, definitive urinary tract.

A Tail gut B

Cloaca Common excretory duct Cloacal membrane Cloaca Ureter (ureteric bud) Allantois (ureteric bud) Lower limb Hind gut Caudal Common mesonephric excretory duct vesicles Inguinal crest Inguinal crest Mesonephric duct * Mesonephric ** Mesonephric duct Kidney vesicles

Fi g u r e IV-3. View of the caudal primitive genitourinary tract in future site of the inguinal ring and canal to which the first curve the middle of the fifth week approximately 2 days later than of the mesonephric duct is now attached. The segment of the Figure IV-2. A, Left lateral view. B, Dorsal view of the caudal curl. mesonephric duct between the inguinal crest and ureteric The ureteric bud and primitive kidney have appeared. The first bud will become the . The segment between the curve of the mesonephric duct has separated from the ecto- ureteric bud and the entrance to the cloaca is the common dermal ring. The inguinal crest (asterisks) has appeared in the excretory duct.

Early Embryology of the Genitourinary Tract 99 Pregenitalis Mesonephric duct

Mesonephric body Head Gonad

Epigenitalis C4 Upper limb

Mesonephric duct Mesonephric body

Paragenitalis * First curve L3 Fi g u r e IV-4. Left lateral view of the mesonephros and gonad at approximately the middle of the sixth postfertilization week. The individual mesonephric nephrons are hidden by the investing Lower limb mesenchyme of the mesonephros and mesonephric duct. The enlarging gonad gradually replaces the regressing mesoneph- L3 ros. The mesonephros extends from approximately T1 to L3. The ** Cloaca gonad extends from approximately T3 to T12. The caudal ends Tail of the mesonephros and gonad are not separated, and the Fi g u r e IV-5. Mesonephric bodies in the early to mid fifth week. caudal end of the gonad is indirectly attached to the first curve The investing mesenchyme of the mesonephros and meso- of the mesonephric duct through its continuity with the caudal nephric duct is included in this figure, and hide the underlying end of the mesonephros. The mesonephros is divided into three mesonephric nephrons. The mesonephric bodies are the larg- parts: the part cranial to the gonad, the pregenitalis; the part est organs in the embryo. They extend from the midcervical to adjacent to the gonad, the epigenitalis; and the part caudal the midlumbar area. The first curve of the mesonephric duct, to the gonad, the paragenitalis. The embryonic remnants of the future tail of the epididymis, and indirectly the caudal end the mesonephros and mesonephric duct are named accord- of the mesonephric bodies are attached to the inguinal crest, ing to this nomenclature. The asterisk is at the site of the devel- indicated by the asterisk, at the future site of the gubernacu- oping gubernaculum, inguinal ring, and inguinal canal. lum, internal inguinal ring, and inguinal canal.

100 Color Atlas of Fetal and Neonatal Histology Bipotential Genital Tract The bipotential genital tract is superimposed upon the differentiating mesoderm form the early gonadal primitive urogenital tract. It begins with development ridge on the ventromedial surface of the meso- of the bipotential gonad on the ventromedial surface nephric body [17]. of the mesonephros during the fifth week and ends The subsequent events are somewhat controversial. with completion of the ­paramesonephric duct at the One view proposes that primordial germ cells and end of the eighth week. The differentiation of the bipo- coelomic epithelium migrate into the differentiating tential gonads into testes and begins before mesoderm, and that these three ­components form the the development of the paramesonephric ducts is gonadal blastema [15]. The coelomic epithelium serves completed. as a scaffolding around which the other components of the gonadal blastema are organized. The mesodermal tissue forms a network of poorly defined, irregular gonadal cords in the deep portion of the gonad near its border with the mesonephric body. The coelomic epi- Bipotential Gonads thelium, primordial germ cells, and local mesenchyme lie between the cords. The development of the gonads begins with the primor- A recent study utilizing serial semithin sections of dial germ cells. The primordial germ cells may be first iden- Epon-embedded gonads from and tifiable in the inner cell mass of the blastocyst in the first fetuses proposes that gonadal cords arise from meso- postfertilization week [1,14]. There is good evidence that nephric glomerular and tubular epithelium. These cords they are in the amniotic ectoderm at the junction of the grow though the mesorchium into the hilum of the amnion with the epiblast at the caudal end of the bilami- gonad and, hence, into the cortex. These primitive nar disc early in the second week [15]. During the dissolu- mesonephric cords never intermingle with coelomic tion of the primary and the formation of the epithelium and give rise to the rete and definitive sex definitive yolk sac, they migrate by ameboid action cords [18]. through the extraembryonic mesenchyme of the body The gonadal blastema, whatever its origin, rapidly stalk and reach the of the caudal yolk sac near enlarges and forms a long oval gonad with a broad its junction with the allantois in the third week. During the attachment to the ventromedial surface of the meso- fourth week they continue to migrate through the wall and nephric body [11]. It does not reach either the upper or mesentery of the proximal hindgut and toward the adja- lower pole of the mesonephric body (see Fig. IV-4). At cent ventromedial side of the mesonephric bodies [16]. the junction between the gonad and the mesonephric In the middle of the fifth week, shortly after the body, the gonadal blastema pushes deeply into the mesonephros. appearance of the ureteric bud and crista ingui- By the middle of the sixth week, the bipotential period nalis, the primordial germ cells enter the ventro- of gonadal development ends. The mesonephros medial border of the mesonephric bodies. At the extends from the midcervical to the midlumbar regions same time, the mesonephric mesoderm prolifer- while the gonad extends from approximately T1 to T10 ates, differentiates into gonadal mesoderm, and (see Fig. IV-4). A groove forms along the length of the junction between the gonad and mesonephros, and induces the coelomic epithelium to proliferate the two begin to separate. This separation continues and form a thickened layer. The thick coelomic during the following period of testicular and ovarian epithelium and the enlarging underlying nest of differentiation.

Early Embryology of the Genitourinary Tract 101 Bipotential Mesonephric and Paramesonephric Ducts

The development of the bipotential mesonephric they are in contact. The paramesonephric ducts may (Wolffian) ducts is completed early in the fifth week arise in part from the mesonephric ducts. By the end of when they reach the cloaca. Subsequent remodeling the seventh week, the paramesonephric ducts reach occurs [2]. In the seventh week, the pelvis begins to the caudal ends of the mesonephric bodies and as form medial to the developing inguinal ring and guber- they follow the first curve of the mesonephric ducts naculum. As the developing urogenital sinus sinks into medially under the caudal end of the mesonephric the deepening pelvis, the mesonephric duct curves bodies they cross over the ­ventral surfaces of the meso- caudally over the lip of the pelvic inlet and into the pel- nephric ducts and come to lie medial to the meso- vis. This is the second mesonephric curve [6]. The two nephric ducts [12]. In the female the paramesonephric curves divide the mesonephric duct into three seg- duct replaces the mesonephric duct and assumes its ments. First, there is a rostral vertical segment attached caudal attachments. to the dorsolateral border of the mesonephros extend- At the start of the eighth week, the paramesonephric ing to the first curve at the caudal end of the meso- ducts meet in the midline and follow the second curve nephros. This will become the epididymis. The first curve of the mesonephric ducts caudally into the developing will become the tail of the epididymis. The second is a pelvis. Because of the crossing over, the parameso- horizontal segment extending from the first to the sec- nephric ducts are medial to the mesonephric ducts. ond curve and the third is a vertical segment from the They fuse to form a single solid duct. By the end of the second curve to the entrance of the duct into the uro- eighth week, the solid blind end of the fused parameso- genital sinus, which will become the vas deferens. nephric ducts meets the mesenchyme of the posterior The bipotential paramesonephric (Müllerian) ducts wall of urethral part of the vesicle urethral canal at the begin in the mid to late sixth postfertilization week as site of the sinual (Müllerian) tubercle between the open- invaginations of thickened areas of the coelomic epi- ings of the mesonephric ducts (see Fig. IV-6). This ends thelium at the rostral ends of the mesonephric bodies the period of the bipotential genital ducts. Sexual dif- and are probably under the inductive influence of the ferentiation of the ducts will begin shortly with the regres- mesonephric duct [6]. They grow caudally along the sion of the paramesonephric duct in the male and the lateral margins of the mesonephric ducts with which mesonephric duct in female.

Fate of the Paramesonephric Duct in the Male

In the 10th week, the Sertoli cells secrete Müllerian- inhibitory substance is local, not ­systemic, and does inhibiting substance, which diffuses along the meso- not effect the opposite paramesonephric­ duct. The nephric duct and causes the regression of the regression of the duct cranial to the cross-over point is ipsilateral paramesonephric duct beginning at the site complete except that a remnant may remain at which the paramesonephric duct crosses in front of attached to the upper pole of the testis as the appen- the mesonephric duct. The regression proceeds crani- dix testis. The caudal portion often persists as the pros- ally and caudally from this point. The action of Müllerian tatic utricle at the veru montanum.

102 Color Atlas of Fetal and Neonatal Histology Epigenitalis

GG

Paragenitalis

* B * Ureteral orifice

Bladder outlet

Urethra Müllerian tubercle Urogenital sinus, pelvic part

Fi g u r e IV-6. Bipotential genitourinary tract in the eighth week. from the bladder outlet to the rostral edge of the Müllerian The gonads (G) have replaced the mesonephric bodies. The tubercle becomes the proximal prostatic urethra and the mesonephric (red) and paramesonephric ducts (blue) are Müllerian tubercle becomes the veru montanum. In the female parallel, curve medially under the gonad (the first curve is at the urethra from the bladder outlet to the rostral edge of the the asterisks), curve caudally (the second curve is at the Müllerian tubercle greatly elongates and forms the entire arrows) over the pelvic inlet into the pelvis and fuse to the dor- length of the urethra except for its distal end and in the process sal wall of the urogenital sinus at the Müllerian tubercle. The the Müllerian tubercle migrates to the distal end of the urethra paramesonephric ducts cross in front of the mesonephric ducts and becomes the . The mesonephric nephrons have all at the first curve and fuse in the pelvic midline medial to the degenerated except for the remnants labeled epigenitalis mesonephric ducts. The caudal gonadal ligaments and ingui- and paragenitalis in this figure. In the male, the epigenitalis nal canal develop at the asterisks. The point of fusion of the becomes the efferent ductules and the paragenitalis persist as mesonephric and paramesonephric ducts with the urogenital embryonic remnants in the distal spermatic cord. In the female, sinus at the Müllerian tubercle marks the division of the urogeni- the epigenitalis remnants become the along the tal sinus into the vesicle urethral canal rostrally and the defini- hilum of the and the paragenitalis remnants become the tive urogenital sinus caudally. The vesicle urethral canal between the medial end of the ovary and the becomes the ­bladder and urethra. In the male the urethra . B—bladder.

Early Embryology of the Genitourinary Tract 103 References

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104 Color Atlas of Fetal and Neonatal Histology