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THE EXTERNAL GENITALIA
Saturday, August 16, 2008
Undifferentiated Stage
The external genitalia begin to form early in the embryonic period, shortly after development of the cloaca. The progenitory tissues of the genitalia are common to both sexes, and the early stage of development is virtually the same in females and males. Although differentiation of the genitalia can begin around the onset of the fetal period if testicular differentiation is initiated, definitive genital sex is usually not clearly apparent until the 12th week. Formation of external genitalia in the male involves the influence of androgen on the interaction of subepidermal mesoderm with the inferior parts of the endodermal urogenital sinus. In the female, this androgenic influence is absent.
The external genitalia form within the initially compact area bounded by the umbilical cord (anteriorly), the developing limb buds (laterally), the embryonic tail (posteriorly), and the cloacal membrane (centrally). Two of the primordia for the genitalia first appear bilaterally adjacent to the cloacal membrane (a medial pair of cloacal folds and a lateral pair of genital [labioscrotal] swellings). The cloacal folds are longitudinal proliferations of caudal mesenchyme located between the ectodermal epidermis and the underlying endoderm of the phallic part of the urogenital sinus. Proliferation and bilateral anterior fusion of these folds create the genital tubercle, which protrudes near the anterior edge of the cloacal membrane by the sixth week (Fig 4–24, Fig 4–25 and Fig 4–26). Extension of the tubercle forms the phallus, which at this stage is the same size in both sexes.
By the seventh week, the urorectal septum subdivides the bilayered (ectoderm and endoderm) cloacal membrane into the urogenital membrane (anteriorly) and the anal membrane (posteriorly). The area of fusion of the urorectal septum and the cloacal membrane becomes the primitive perineum, or perineal body. With formation of the perineum, the cloacal folds are divided transversely as urogenital folds adjacent to the urogenital membrane and anal folds around the anal membrane. As the mesoderm within the urogenital folds thickens and elongates between the perineum and the phallus, the urogenital membrane sinks deeper into the fissure between the folds. Within a week, this membrane ruptures, forming the urogenital orifice and, thus, opening the urogenital sinus to the exterior. Similar thickening of the anal folds creates a deep anal pit, in which the anal membrane breaks down to establish the anal orifice of the anal canal (Fig 4–24 and Fig 4–25).
Subsequent masculinization or feminization of the external genitalia is a consequence of the respective presence or absence of androgen and the androgenic sensitivity or insensitivity of the tissues. The significance of both of these factors (availability of hormone and sensitivity of target tissue) is exemplified by the rare condition (about 1 in 50,000 “females”) of testicular feminization, wherein testes are present (usually ectopic) and produce testosterone and anti-müllerian hormone. The anti-müllerian hormone suppresses formation of the uterus and uterine tubes (from the paramesonephric ducts), whereas testosterone supports male differentiation of the mesonephric ducts to form the epididymis and ductus deferens. The anomalous feminization of the external genitalia is considered to be due to androgenic insensitivity of the precursor tissues consequent to an abnormal androgen receptor or postreceptor mechanism set by genetic inheritance.
Male
Early masculinization of the undifferentiated or indifferent genitalia takes place during the first 3 weeks of the fetal period (weeks 9–12) and is caused by androgenic stimulation. The phallus and urogenital folds gradually elongate to initiate development of the penis. The subjacent endodermal lining of the inferior part (phallic) of the urogenital sinus extends anteriorly along with the urogenital folds, creating an endodermal plate, the urethral plate. The plate deepens into a groove, the urethral groove, as the urogenital folds (now called urethral folds) thicken on each side of the plate. The urethral groove extends into the ventral aspect of the developing penis, and the bilateral urethral folds slowly fuse in a posterior to anterior direction over the urethral groove to form the spongy (penile) urethra, thereby closing the urogenital orifice (Fig 4–17 and Fig 4–24). The line of fusion becomes the penile raphe on the ventral surface of the penis.
As closure of the urethral folds approaches the glans, the external urethral opening on this surface is eliminated. Concurrently, an ectodermal glandular plate invaginates the tip of the penis. Canalization of the plate forms the distal end of the penile urethra, the glandular urethra. Thus, the external urethral meatus becomes located at the tip of the glans when closure of the urethral folds is completed (Fig 4–24). The prepuce is formed slightly later by a circular invagination of ectoderm at the tip of the glans penis. This cylindric ectodermal plate then cleaves to leave a double-layered fold of skin extending over the glans.
While the cloacal folds and phallic urogenital sinus were differentiating into the penis and the urethra, the genital (labioscrotal) swellings of the undifferentiated stage were enlarging lateral to the cloacal folds. Medial growth and fusion of the scrotal swellings to form the scrotum and scrotal raphe around the 12th week virtually complete the differentiation of the male external genitalia (Fig 4–24 and Fig 4–26).
Female
A. DEVELOPMENT OF EXTERNAL GENITALIA
Feminization of the external genitalia proceeds in the absence of androgenic stimulation (or nonresponsiveness of the tissue). The 2 primary distinctions in the general process of feminization versus masculinization are (1) the lack of continued growth of the phallus and (2) the near absence of fusion of the urogenital folds and the labioscrotal swellings. Female derivatives of the indifferent sexual primordia for the external genitalia are virtually homologous counterparts of the male derivatives. Formation of the female genitalia is schematically presented in Fig 4–25.
The growth of the phallus slows relative to that of the urogenital folds and labioscrotal swellings and becomes the diminutive clitoris. The anterior extreme of the urogenital folds fuses superior and inferior to the clitoris, forming the prepuce and frenulum of the clitoris, respectively. The midportions of these folds do not fuse but give rise to the labia minora. Lack of closure of the folds leaves the urogenital orifice patent and results in formation of the vestibule of the vagina from the inferior portion of the pelvic part and the phallic part of the urogenital sinus at about the fifth month (Fig 4–25). Derivatives of the vesical part of the sinus (the urethra) and the superior portion of the pelvic part of the sinus (vagina and greater vestibular glands) then open separately into the vestibule. The frenulum of the labia minora is formed by fusion of the posterior ends of the urogenital folds. The mesoderm of the labioscrotal swellings proliferates beneath the ectoderm and remains virtually unfused to create the labia majora lateral to the labia minora. The swellings blend together anteriorly to form the anterior labial commissure and the tissue of the mons pubis, while the swellings posteriorly less clearly define a posterior labial commissure. The distal fibers of the round ligament of the uterus project into the tissue of the labia majora.
B. ANOMALIES OF THE LABIA MINORA
In otherwise normal females, 2 somewhat common anomalies occur—labial fusion and labial hypertrophy. True labial fusion as an early developmental defect in the normally unfused midportions of the urogenital folds is purportedly less frequent than “fusion” due to inflammatory-type reactions. Labial hypertrophy can be unilateral or bilateral and may require surgical correction in extreme cases.
C. ANOMALIES OF THE LABIA MAJORA
The labia majora are derived from the bilateral genital (labioscrotal) swellings, which appear early in the embryonic period and remain unfused centrally during subsequent sex differentiation in the fetal period. Anomalous conditions include hypoplastic and hypertrophic labia as well as different gradations of fusion of the labia majora. Abnormal fusion (masculinization) of labioscrotal swellings in genetic females is most commonly associated with ambiguous genitalia of female pseudohermaphroditism consequent to congenital adrenal hyperplasia (adrenogenital syndrome). Over 90% of females with congenital adrenal hyperplasia have a steroid 21-hydroxylase deficiency (autosomal recessive), resulting in excess adrenal androgen production. This enzyme deficiency has been reported to be “the most common cause of ambiguous genitalia in genetic females.” Associated anomalies include clitoral hypertrophy and persistent urogenital sinus. Formation of a penile urethra is extremely rare.
D. ANOMALIES OF THE CLITORIS
Clitoral agenesis is extremely rare and is due to lack of formation of the genital tubercle during the sixth week. Absence of the clitoris could also result from atresia of the genital tubercle. The tubercle forms by fusion of the anterior segments of the cloacal folds. Very rarely, these anterior segments fail to fuse, and a bifid clitoris forms. This anomaly also occurs when unification of the anterior parts of the folds is restricted by exstrophy of the cloaca or bladder. Duplication of the genital tubercle with consequent formation of a double clitoris is equally rare. Clitoral hypertrophy alone is not common but may be associated with various intersex disorders.
E. ANOMALIES OF THE PERINEUM
The primitive perineum originates at the area of contact of the mesodermal urorectal septum and the endodermal dorsal surface of the cloacal membrane (at 7 weeks). During normal differentiation of the external genitalia in the fetal period, the primitive perineum maintains the separation of the urogenital folds and ruptured urogenital membrane from the anal folds and ruptured anal membrane, and later develops the perineal body. Malformations of the perineum are rare and usually associated with malformations of cloacal or anorectal development consequent to abnormal development of the urorectal septum. Imperforate anus has an incidence of about 0.02%. The simplest form (rare) is a thin membrane over the anal canal (the anal membrane failed to rupture at the end of the embryonic period). Anal stenosis can arise by posterior deviation of the urorectal septum as the septum approaches the cloacal membrane, causing the anal membrane to be smaller (with a relatively increased anogenital distance through the perineum). Anal agenesis with a fistula detected as an ectopic anus is considered to be a urorectal septal defect. The incidence of agenesis with a fistula is only slightly less than that without a fistula. In females, the fistula commonly may be located in the perineum (perineal fistula) or may open into the posterior aspect of the vestibule of the vagina (anovestibular fistula; see Cloacal Dysgenesis).
* Embryonic or fetal ages given in this chapter are relative to the time of fertilization and should be considered estimates rather than absolutes.
The external genitalia begin to form early in the embryonic period, shortly after development of the cloaca. The progenitory tissues of the genitalia are common to both sexes, and the early stage of development is virtually the same in females and males. Although differentiation of the genitalia can begin around the onset of the fetal period if testicular differentiation is initiated, definitive genital sex is usually not clearly apparent until the 12th week. Formation of external genitalia in the male involves the influence of androgen on the interaction of subepidermal mesoderm with the inferior parts of the endodermal urogenital sinus. In the female, this androgenic influence is absent.
The external genitalia form within the initially compact area bounded by the umbilical cord (anteriorly), the developing limb buds (laterally), the embryonic tail (posteriorly), and the cloacal membrane (centrally). Two of the primordia for the genitalia first appear bilaterally adjacent to the cloacal membrane (a medial pair of cloacal folds and a lateral pair of genital [labioscrotal] swellings). The cloacal folds are longitudinal proliferations of caudal mesenchyme located between the ectodermal epidermis and the underlying endoderm of the phallic part of the urogenital sinus. Proliferation and bilateral anterior fusion of these folds create the genital tubercle, which protrudes near the anterior edge of the cloacal membrane by the sixth week (Fig 4–24, Fig 4–25 and Fig 4–26). Extension of the tubercle forms the phallus, which at this stage is the same size in both sexes.
By the seventh week, the urorectal septum subdivides the bilayered (ectoderm and endoderm) cloacal membrane into the urogenital membrane (anteriorly) and the anal membrane (posteriorly). The area of fusion of the urorectal septum and the cloacal membrane becomes the primitive perineum, or perineal body. With formation of the perineum, the cloacal folds are divided transversely as urogenital folds adjacent to the urogenital membrane and anal folds around the anal membrane. As the mesoderm within the urogenital folds thickens and elongates between the perineum and the phallus, the urogenital membrane sinks deeper into the fissure between the folds. Within a week, this membrane ruptures, forming the urogenital orifice and, thus, opening the urogenital sinus to the exterior. Similar thickening of the anal folds creates a deep anal pit, in which the anal membrane breaks down to establish the anal orifice of the anal canal (Fig 4–24 and Fig 4–25).
Subsequent masculinization or feminization of the external genitalia is a consequence of the respective presence or absence of androgen and the androgenic sensitivity or insensitivity of the tissues. The significance of both of these factors (availability of hormone and sensitivity of target tissue) is exemplified by the rare condition (about 1 in 50,000 “females”) of testicular feminization, wherein testes are present (usually ectopic) and produce testosterone and anti-müllerian hormone. The anti-müllerian hormone suppresses formation of the uterus and uterine tubes (from the paramesonephric ducts), whereas testosterone supports male differentiation of the mesonephric ducts to form the epididymis and ductus deferens. The anomalous feminization of the external genitalia is considered to be due to androgenic insensitivity of the precursor tissues consequent to an abnormal androgen receptor or postreceptor mechanism set by genetic inheritance.
Male
Early masculinization of the undifferentiated or indifferent genitalia takes place during the first 3 weeks of the fetal period (weeks 9–12) and is caused by androgenic stimulation. The phallus and urogenital folds gradually elongate to initiate development of the penis. The subjacent endodermal lining of the inferior part (phallic) of the urogenital sinus extends anteriorly along with the urogenital folds, creating an endodermal plate, the urethral plate. The plate deepens into a groove, the urethral groove, as the urogenital folds (now called urethral folds) thicken on each side of the plate. The urethral groove extends into the ventral aspect of the developing penis, and the bilateral urethral folds slowly fuse in a posterior to anterior direction over the urethral groove to form the spongy (penile) urethra, thereby closing the urogenital orifice (Fig 4–17 and Fig 4–24). The line of fusion becomes the penile raphe on the ventral surface of the penis.
As closure of the urethral folds approaches the glans, the external urethral opening on this surface is eliminated. Concurrently, an ectodermal glandular plate invaginates the tip of the penis. Canalization of the plate forms the distal end of the penile urethra, the glandular urethra. Thus, the external urethral meatus becomes located at the tip of the glans when closure of the urethral folds is completed (Fig 4–24). The prepuce is formed slightly later by a circular invagination of ectoderm at the tip of the glans penis. This cylindric ectodermal plate then cleaves to leave a double-layered fold of skin extending over the glans.
While the cloacal folds and phallic urogenital sinus were differentiating into the penis and the urethra, the genital (labioscrotal) swellings of the undifferentiated stage were enlarging lateral to the cloacal folds. Medial growth and fusion of the scrotal swellings to form the scrotum and scrotal raphe around the 12th week virtually complete the differentiation of the male external genitalia (Fig 4–24 and Fig 4–26).
Female
A. DEVELOPMENT OF EXTERNAL GENITALIA
Feminization of the external genitalia proceeds in the absence of androgenic stimulation (or nonresponsiveness of the tissue). The 2 primary distinctions in the general process of feminization versus masculinization are (1) the lack of continued growth of the phallus and (2) the near absence of fusion of the urogenital folds and the labioscrotal swellings. Female derivatives of the indifferent sexual primordia for the external genitalia are virtually homologous counterparts of the male derivatives. Formation of the female genitalia is schematically presented in Fig 4–25.
The growth of the phallus slows relative to that of the urogenital folds and labioscrotal swellings and becomes the diminutive clitoris. The anterior extreme of the urogenital folds fuses superior and inferior to the clitoris, forming the prepuce and frenulum of the clitoris, respectively. The midportions of these folds do not fuse but give rise to the labia minora. Lack of closure of the folds leaves the urogenital orifice patent and results in formation of the vestibule of the vagina from the inferior portion of the pelvic part and the phallic part of the urogenital sinus at about the fifth month (Fig 4–25). Derivatives of the vesical part of the sinus (the urethra) and the superior portion of the pelvic part of the sinus (vagina and greater vestibular glands) then open separately into the vestibule. The frenulum of the labia minora is formed by fusion of the posterior ends of the urogenital folds. The mesoderm of the labioscrotal swellings proliferates beneath the ectoderm and remains virtually unfused to create the labia majora lateral to the labia minora. The swellings blend together anteriorly to form the anterior labial commissure and the tissue of the mons pubis, while the swellings posteriorly less clearly define a posterior labial commissure. The distal fibers of the round ligament of the uterus project into the tissue of the labia majora.
B. ANOMALIES OF THE LABIA MINORA
In otherwise normal females, 2 somewhat common anomalies occur—labial fusion and labial hypertrophy. True labial fusion as an early developmental defect in the normally unfused midportions of the urogenital folds is purportedly less frequent than “fusion” due to inflammatory-type reactions. Labial hypertrophy can be unilateral or bilateral and may require surgical correction in extreme cases.
C. ANOMALIES OF THE LABIA MAJORA
The labia majora are derived from the bilateral genital (labioscrotal) swellings, which appear early in the embryonic period and remain unfused centrally during subsequent sex differentiation in the fetal period. Anomalous conditions include hypoplastic and hypertrophic labia as well as different gradations of fusion of the labia majora. Abnormal fusion (masculinization) of labioscrotal swellings in genetic females is most commonly associated with ambiguous genitalia of female pseudohermaphroditism consequent to congenital adrenal hyperplasia (adrenogenital syndrome). Over 90% of females with congenital adrenal hyperplasia have a steroid 21-hydroxylase deficiency (autosomal recessive), resulting in excess adrenal androgen production. This enzyme deficiency has been reported to be “the most common cause of ambiguous genitalia in genetic females.” Associated anomalies include clitoral hypertrophy and persistent urogenital sinus. Formation of a penile urethra is extremely rare.
D. ANOMALIES OF THE CLITORIS
Clitoral agenesis is extremely rare and is due to lack of formation of the genital tubercle during the sixth week. Absence of the clitoris could also result from atresia of the genital tubercle. The tubercle forms by fusion of the anterior segments of the cloacal folds. Very rarely, these anterior segments fail to fuse, and a bifid clitoris forms. This anomaly also occurs when unification of the anterior parts of the folds is restricted by exstrophy of the cloaca or bladder. Duplication of the genital tubercle with consequent formation of a double clitoris is equally rare. Clitoral hypertrophy alone is not common but may be associated with various intersex disorders.
E. ANOMALIES OF THE PERINEUM
The primitive perineum originates at the area of contact of the mesodermal urorectal septum and the endodermal dorsal surface of the cloacal membrane (at 7 weeks). During normal differentiation of the external genitalia in the fetal period, the primitive perineum maintains the separation of the urogenital folds and ruptured urogenital membrane from the anal folds and ruptured anal membrane, and later develops the perineal body. Malformations of the perineum are rare and usually associated with malformations of cloacal or anorectal development consequent to abnormal development of the urorectal septum. Imperforate anus has an incidence of about 0.02%. The simplest form (rare) is a thin membrane over the anal canal (the anal membrane failed to rupture at the end of the embryonic period). Anal stenosis can arise by posterior deviation of the urorectal septum as the septum approaches the cloacal membrane, causing the anal membrane to be smaller (with a relatively increased anogenital distance through the perineum). Anal agenesis with a fistula detected as an ectopic anus is considered to be a urorectal septal defect. The incidence of agenesis with a fistula is only slightly less than that without a fistula. In females, the fistula commonly may be located in the perineum (perineal fistula) or may open into the posterior aspect of the vestibule of the vagina (anovestibular fistula; see Cloacal Dysgenesis).
* Embryonic or fetal ages given in this chapter are relative to the time of fertilization and should be considered estimates rather than absolutes.
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