Penis, the Yard, made up of two nervous Bodies, the Channel, Nut, Skin, and Fore-skin, etc. BPD (ed.2) 1693.
Development of the penis and urethra
Early stages of genital development
Cloacal membrane and genital tubercle
The cloacal membrane is the inducer of developmental processes in the perineal region in early embryonic life. It is a patch of thickened endoderm and closely applied ectoderm without the usual intervening mesoderm that is positioned strategically at the caudal end of the embryo between the umbilical cord and the base of the tail. The outer, depressed region comprises the ectodermal cloaca, and the endodermal cloaca is the portion within the cloaca proper.
At 6 weeks, the genital tubercle appears as a wide cone. It has a gradual slope caudally where it is further amplified by lateral buttresses, structures destined to become the corporal bodies ( Fig. 16-1 A). The genital tubercle arises between the coccygeal tubercle at the end of the embryo and the umbilical cord at the umbilicus, from which it is separated by the umbilicophallic groove ( Fig. 16-1 B).
The descending urorectal septum will divide the cloaca into a urogenital sinus and an anal canal and, on contact with the cloacal membrane, stimulate it to divide into a urogenital membrane extending onto the undersurface of the genital tubercle and an anal membrane caudally (see Fig. 16-3 ). The anterior extent of development of the urogenital membrane is limited by the proximity of the genital tubercle to the umbilicus.
Genital swellings, tubercles, and grooves
Paired genital (labioscrotal) swellings soon arise by the encroachment of the most caudal rim of mesoderm on either side of the urogenital membrane, forming thickened areas beside the genital tubercle that are separated from it by the lateral phallic grooves ( Fig. 16-2 ).
The shallow primitive urethral groove forms on the caudal slope of the genital tubercle, flanked by the slightly elevated urethral (genital) folds. The tubercle is pushed into a vertical position by the widening umbilicophallic groove and is enlarged by incorporation of the lateral buttresses. Caudal to the urogenital membrane are two swellings, the anal hillocks (tubercles). These lie medial to the gluteal folds and are oriented about the anal pit. They are continuous with the urethral folds except for the intervening perineal body.
The lower abdominal wall is formed by further growth of mesodermal cells between the endoderm and ectoderm and will later acquire muscle cells from ingrowth of the mesodermal somites. This ventrally directed growth has the effect of rotating the plane of the urogenital membrane more into the long axis of the body.
In the interior during this time, the urogenital sinus, derived from the ventral part of the endodermal cloaca, becomes separated by the descent and coaptation of the urorectal septum (see Figure 13-7 ). The vesicourethral canal has been formed from the anterior portion of the urogenital sinus. The urogenital sinus develops into a short tubular pelvic part and a flattened phallic part . The pelvic part is the future site of the prostate; the phallic portion makes up the distal portion of the urethra. The overlying urogenital membrane becomes perforated in the urethral groove to form the urogenital orifice so that as the urethral groove deepens, it is in communication with the phallic portion of the urogenital sinus.
Up to this point, the male and female genitalia are essentially indistinguishable. One of the first signs of masculinization is an increase in the distance between the anus and the genital structures.
Genetic information from the short arm of the Y chromosome (the testis-determining factor gene) operating through the H-Y antigen influences the indifferent gonad in the second month to develop into a testis. In the absence of the Y chromosome, the gonad becomes an ovary. The testis, in turn, produces testosterone and müllerian-inhibiting substance, agents that influence development of the sexual ducts in the male direction. The testosterone produced by the interstitial (Leydig) cells causes the nearby wolffian (mesonephric) duct to form the epididymis, vas deferens, and seminal vesicles. The müllerian-inhibiting substance, coming from the Sertoli cells at the end of the second month, blocks the development of the müllerian ducts, which were destined to form the fallopian tubes, uterus, and the upper portion of the vagina.
Second, testosterone, produced by the interstitial cells in response to a surge of luteinizing hormone from the pituitary from the 6th to the 14th weeks, is converted to 5-dihydrotestosterone by the enzyme 5-alpha reductase, which is present in the cells of the external genitalia and urogenital sinus. This hormone, transported to the nucleus after binding to cytosol receptors, causes translation and transcription of the genetic material to promote male development of the genital swellings and folds and the genital tubercle. Later, testosterone itself, its production stimulated by maternal chorionic gonadotropin, enlarges the penis.
After significant elongation of the phallus, the first steps toward masculinization are the formation of the penile urethra from the urethral groove and the development of the prepuce.
Growth of the genital tubercle and formation of the urethral plate
The genital tubercle grows over the ventral part of the urogenital membrane during the eighth week by the insertion of rapidly proliferating mesoderm in paired masses between its endodermal and ectodermal layers ( Fig. 16-3 A). The phallus is a simple tubular structure up to 9 weeks of gestation, at which time a circumferential depression appears that marks the site of demarcation of the glans. The depression deepens into the coronal sulcus, to be followed in 4 days by formation of the scrotal swellings from the genital swellings at the base of the phallus. As the phallus enlarges, its floor is formed by the urogenital membrane, beneath which is the phallic part of the urogenital sinus.
The urethral plate forms at the same time by the forward invasion of a strip of sagittally stacked endodermal cells into the solid mesodermal core of the genital tubercle. These come to lie just beneath the ectodermal surface epithelium.
A cut through x–x′ shows the sagittally oriented endodermal urethral plate extending into the mesodermal body of the genital tubercle under the ectoderm over the phallic part of the urogenital sinus that is still closed by the urogenital membrane ( Fig. 16-3 B).
Enlargement of the urethral folds
Proliferation of mesenchyme on either side of the urethral plate raises the primitive urethral folds. The urethral groove develops between them as they become more prominent ( Fig. 16-4 ). The folds also extend caudally alongside the cloacal membrane that lies in the depression of the external, ectodermal cloaca. By this time, the internal, endodermal cloaca is divided by the formation of the urorectal septum (see Figure 13-7 ).
The genital swellings, destined to form the scrotum, enlarge and appear to move caudally.
Formation of the primary urethral groove, transverse sections
The endodermal urethral plate invades the mesodermal core of the primitive phallus that is covered by the ectodermal surface epithelium ( Fig. 16-5 A).
The primary urethral groove indents the urethral plate ( Fig. 16-5 B).
The overlying ectoderm in the groove regresses to expose the endoderm of the urethral plate ( Fig. 16-5 C).
The edges of the urethral plate become attached to the ectodermal margin of the groove. The breakdown of the central endoderm of the plate increases the depth of the groove, forming the secondary (definitive) urethral groove, which is lined by endoderm and flanked by the ectodermal urethral folds ( Fig. 16-5 D).
Developing urethral groove
The urethral plate extends within the mesenchyme of the phallus. Its partial degeneration forms the secondary urethral groove ( Fig. 16-6 ).
Enclosure of the urethra
The ectoderm lying over the urethral plate regresses, exposing the secondary urethral groove lined by the endodermal urethral plate ( Fig. 16-7 A). Beginning near the anus, the adjacent ectodermal urethral folds fuse over the urethral plate to form the penile urethra, with the distal urethra (at the coronal sulcus) being the last to close.
In a section through x–x′ in Figure 16-7 A, the endodermal urethral plate is seen enclosed as the lining of the penile urethra ( Fig. 16-7 B). The site of fusion of the urethral folds forms the perineal raphe, an ectodermal formation ( Figs. 16-8 and 16-9 ). The endodermal urethra now lies within the mesoderm, which, in turn, is enclosed in ectoderm.
The mesenchyme within the urethral folds forms the corpus spongiosum after their fusion. It develops separately from the erectile tissue of the glans.
Formation of the glanular urethra
The glanular segment of the urethra that will be part of the fossa navicularis is formed later than the urethra in the shaft and by a different mechanism.
A groove does form on the undersurface of the glans, but only the proximal part of it is reached by the endodermal urethral plate as it progresses down the shaft ( Fig. 16-10 A). Thus, because the plate does not extend all the way to the tip of the glans, it will form only the proximal portion of the glanular urethra, leaving the terminal portion to be formed differently.
A plug of ectoderm from the tip of the glans invades the mesenchyme as an ectodermal intrusion.
As the ectoderm invades more deeply into the glans, it develops a lumen at the same time that the urethral folds enclose more of the urethral plate ( Fig. 16-10 B). The ventral segment (marked VS ) of the proximal end of the invading ectodermal intrusion comes to lie dorsal to the distal extremity of the advancing urethral plate.
The primary urethral folds proliferate and close over the groove ( Fig. 16-10 C). The floor of the ectodermal intrusion makes contact with the end of the urethral plate that forms the roof of the advancing urethra and the intervening double wall breaks down. This places the new ectodermal lumen in continuity with the proximal, endodermal portion of the urethra.
In this way, the dorsal wall of the fossa navicularis is composed of ectoderm and the ventral wall, endoderm, an explanation of why stratified squamous epithelium (from ectoderm) is found in this most distal portion, even though transitional epithelium (of endodermal origin) lines most of the urethra. The abortive urethral depression seen at the normal meatal site in hypospadias and the fish-mouth meatus may be explained by abnormalities of ectodermal intrusion.
Should the tissue lying between the ectodermal ingrowth and the outgrowth of the urethral plate be incompletely resorbed, a diverticulum is left on the anterior wall. This will form the lacuna magna or sinus of Guérin. The sinus lies under a flap, the valve of Guérin, that is covered on both sides by squamous epithelium.
The urethral folds are continuous with the glandar lamella that initiates development of the prepuce. As the folds join at the base of the glans, the margins of the lamella are fused to the preputial folds, forming the frenulum.
During the third month, the primitive mesenchyme that produced phallic growth begins differentiation into the corporal bodies. The corpora cavernosa of the penis develop from densely packed cells of the initially paired genital tubercles, and the corpus spongiosum and glans are formed from the caudal end of the urogenital sinus and the paired urethral folds. These bodies later become perforated by vascular passages that form erectile tissue.
Until the 14th week, no difference is noted between the phallus of the male and female fetus, even though appreciable sexual differentiation has already occurred. After that time, the penile growth rate in males becomes linear, so that at birth the stretched length of the penis is 3.5 cm, with a diameter of 1.1 cm.
Origin of the prepuce
Formation of the preputial folds
At about 8 weeks of gestation, low preputial folds appear on both sides of the penile shaft, which join dorsally to form a flat ridge at the proximal edge of the corona. The ridge does not entirely encircle the glans because it is blocked on the ventrum by the incomplete development of the glandar urethra ( Fig. 16-11 A). Simultaneously with the formation of the ridge, epithelium proliferates into the base of the fold. This is the so-called glandar lamella , which is an actively proliferating layer many cells thick at its proximal margin ( Fig. 16-11 B).
Within a week, proliferation of the lamella rolls the preputial folds progressively over the base of the glans to form a preputial groove between the corona and the nascent prepuce.
Proliferation of the glandar lamella
In the proximal part of the preputial groove, epithelial cells of the glandar lamella (stippled) grow to form a shelf between the preputial fold and the glans ( Fig. 16-12 A).
As the preputial folds are pushed distally, the epithelial tissue of the lamella remains most active at the proximal end, the base of the groove ( Fig. 16-12 B). That the process is not one of fusion is shown by the fact that the more proximal part of the glandar lamella is always less differentiated than the more distal parts.
The mesenchyme lying between the epithelium of the preputial fold and the glandar lamella becomes active in conjunction with the lamellar epithelium and is incorporated between the margins of the glandar lamella as the preputial fold and the ventral margin of the glandar lamella are carried onto the glans with it ( Fig. 16-12 C). Thus, the preputial fold is transported distally by active growth of the mesenchyme between the folds as well as by the rapid proliferation of the ectoderm of the glandar lamella. The process continues until the preputial fold covers all of the glans except for the ventral portion, which is blocked by the late closure of the urethral groove.
Covering of the glans
By the time the fetus reaches 12 weeks of age, the distal urethra has formed and the flattened preputial fold not only covers the entire glans but, because of continued mesenchymal proliferation, extends beyond it ( Fig. 16-13 ).
Separation of prepuce and glans
The single epithelial layer between the prepuce and the glans forms epithelial pearls that start its degeneration into two layers ( Fig. 16-14 A).
The separation starts distally, forming the glandopreputial space and it continues to the time of birth ( Fig. 16-14 B).
Development of the corpora
The corpus spongiosum is formed from the mesenchyme carried ventrally with the urethral folds and remaining after their fusion.
The unorganized mesenchyme of the paired bodies of the corpora cavernosa at first is supplied by capillaries. Dorsal vessels develop from the capillaries to become recognized as the dorsal arteries and deep dorsal vein by the 13th week. Two weeks later, the peripheral cells differentiate into the tunica albuginea, and those centrally distributed become organized into trabeculae. The erectile tissue of the glans itself is formed separately. The adult structure of the penis is formed in the newborn period, with the aggregation of smooth muscle and elastic tissue around the cavernous spaces.
Female genital differentiation
Differentiation of female external genitalia
Other than an increase in the distance between the anus and the genital structures, the most certain sign of male differentiation in the genitalia is the appearance of a longer urethral groove on the caudal slope of the male genital tubercle. The end of the indifferent stage at about 9 weeks also may be indicated by the formation of the perineal raphe through fusion of the urethral folds at the junction of the penis and scrotum and by the caudal migration of the genital swellings to form the scrotum. The formation of the posterior commissure is the comparable event in the female. Female sex may be even more definitely determined at about 10 weeks when the caudal curvature of the clitoris is apparent and no perineal raphe has developed. Compared with those in the male, the homologous genital structures in the female undergo relatively little change after the indifferent stage.
In the indifferent stage, the noncurved phallus has a recess at the site of the future coronal sulcus ( Fig. 16-15 A). The urethral folds are present on either side of the urethral groove. The glanular portion has an epithelial tag. The genital swellings lie midway between the phallus and the perineum.
By 8 weeks, the phallus appears to recede as the genital (labioscrotal) swellings surround it and as greater growth of cavernous tissue compared with that of urethral tissue produces downward curvature ( Fig. 16-15 B). The urethral groove ends at the posterior commissure.
The caudal ends of the genital swellings that are to become the labia majora fuse to form the posterior commissure, and the urethral folds elongate to become the labia minora ( Fig. 16-15 C). The persisting primary urogenital opening remains as the urethrovaginal orifice. Differentiation is virtually complete by 20 weeks.
The development of the female prepuce is similar to that in the male, although it is formed more slowly and in more complicated steps. One difference is that, although three glandar lamellae are formed, only the middle one evolves like the male counterpart, and then it does not extend over more than half the circumference. For that reason, the frenulum is very wide. The urethral groove prevents fusion of the urethral folds with the glandar lamella, leaving the prepuce covering only the dorsum of the clitoris.
Table 16-1 presents a comparison of male and female genital differentiation.
Female and male genital homologies
At 9 weeks , the urethral and genital swellings and the phallic tubercle in the female have evolved to a degree similar to that of the male ( Fig. 16-16 A).
The phallic tubercle develops at a slower rate in the female than in the male and develops into a clitoris at term ( Fig. 16-16 B). The clitoris bends downward, in contrast to the perpendicular stance of the male phallus. It contains corpora cavernosa, but the corpus spongiosum remains vestigial except for the divided posterior portion, which remains as erectile tissue on either side of the vagina. The posterior ends of the urethral folds fuse, and the remaining portion develops into the labia minora. Incomplete fusion of the labia minora is occasionally seen. The labioscrotal folds from the genital swellings do not grow and fuse as in the male, but remain smaller and separated to form the labia majora joined only at the posterior commissure.
Epispadias results from failure of the mesodermal swellings to fuse in the midline in time, leaving a portion of the cloacal membrane exposed ventral to the genital tubercle. The defect in the urethra may be restricted to the dorsum of the penis ( Fig. 16-17 A). Rarely, the penile urethra and even the posterior urethra may be absent so that the opening lies at the neck of the bladder ( Fig. 16-17 B; Table 16-2 ).
|Anomaly||Gestational Age (Weeks)|
|Agenesis of the penis||4|
|Agenesis of the glans penis||16|
|Defects of the corpus spongiosum and corpora cavernosa||12|
|Duplication of the penis||Various|
|Transposition of the penis and scrotum||9|
|Duplications of the penile urethra||10–14|
|Atresia and stenosis of the urethra||Various|
|Hypospadias||8 or later|
Superior duplication of the urethra may be due to late fusion of the margins of an epispadiac urethral groove.
Exstrophy of the bladder and cloacal exstrophy are described in the chapter on the bladder in Figures 13-37 to 13-41 , and bladder exstrophy is also illustrated in Fig. 10-5 ). Briefly, compared with epispadias, vesical exstrophy is the result of greater displacement and persistence of an abnormally large cloacal membrane that prevents ingrowth of mesenchyme.
Duplication of the clitoris is the rule in the female with vesical exstrophy, and failure of fusion of the müllerian ducts is commonly seen with more severe forms of cloacal exstrophy. In the male, the effects are more extreme. The penis is markedly bifid in cloacal exstrophy, although in milder cases of the anomaly, the findings are a short penis resulting from separation of the pubic rami and dorsal chordee secondary to a short urethra or urethral plate.
Hypospadias is a form of incomplete male differentiation that leaves the meatus lying proximal to its normal terminal position secondary to failure of the urethral groove to form or from its failure to close completely. The result is the exposure of the urethral plate that is covered with endodermal transitional epithelium. The short terminal portion that is lined by stratified squamous epithelium forms the blind pit that is found on the glans at the site of the normal meatus, a remnant of the intrusion of epithelium that normally occurs to form the distal part of the fossa navicularis ( Fig. 16-18 ) (see also Fig. 16-10 ). In hypospadias, the urethra derived from the urethral plate has not been closed by the urethral folds far enough distally to reach this ingrowth.