Embryology
Formation of the mesoderm
The period of organogenesis, also called the embryonic period, spans the third to the eighth week of development. At approximately 15 days after fertilization, invagination and lateral migration of mesodermal cells occur between the ectodermal and endodermal layers of the embryo. At about the sixteenth day of development, the posterior wall of the yolk sac forms a small diverticulum, the allantois, which extends into the connecting stalk. The hindgut undergoes slight dilation to form the cloaca; it receives the allantois ventrally and the two mesonephric ducts laterally. By the seventeenth day of development, the endoderm and ectoderm layers are separated entirely by the mesoderm layer, with the exception of the prochordal plate cephalad and the cloacal plate caudal. The cloacal plate consists of tightly adherent endodermal and ectodermal layers. With ventral bending of the embryo, the connecting stalk and contained allantois, as well as the cloacal membrane, are displaced onto the ventral aspect of the embryo.
A spur of mesodermal tissue migrates from the base of the allantois toward the cloacal membrane around 28 days after fertilization, forming the urorectal septum ( Fig. 2.1 ). This structure partitions the cloaca into a ventral urogenital sinus and a dorsal rectum. Following this, each of the three germ layers, the endoderm, mesoderm, and ectoderm, give rise to specific tissues and organs. The intermediate mesoderm differentiates into the urogenital structures. Other portions of the mesoderm form multiple structures, including the vascular system, the spleen, the connective tissue, and the wall of the gut tube.
At birth, the urogenital system can be divided functionally into two different systems: the urinary system and the genital system. However, embryologically and anatomically they are intimately connected because both develop from a common mesodermal ridge known as the intermediate mesoderm. Both systems share a common origin, with significant interaction between the components of each system during the later stages of development. Epithelial-mesenchymal interactions are primarily responsible for the maintenance and differentiation of many of the structures of the urogenital system. Furthermore, male and female sexual differentiation is dependent on the presence of specific promoting or inhibiting factors.
This chapter will explore the embryology and basic congenital anomalies of the urinary tract, rectum, and anal sphincters. It will detail the embryology of female genital organs and discuss congenital anomalies and their treatments.
Urinary system
Kidney and ureter.
The urinary system begins to take shape before any gonadal development is evident. The kidney exists in three distinct but slightly overlapping forms during development. The first is the pronephros, which is present at approximately 22 days of gestation and is rudimentary and nonfunctioning. The second form, the mesonephros, likely functions for a short time during the early fetal period. The excretory tubules of the mesonephros enter the longitudinal collecting duct (primary nephric duct). These formations go on to form the mesonephric duct, which is crucial in the formation of the male genital system but disappears in the female. By the end of the fourth week, the mesonephric ducts attach to the cloaca, and a continuous lumen is present. The ureteric bud is an epithelial outgrowth of the mesonephric duct near the attachment to the cloaca that penetrates the mesodermal tissue and ultimately forms the renal calyces, ureter, renal pelvis, and collecting tubules. Interactions between the mesoderm and ureteric bud form the third and permanent form of kidney, the metanephros ( Fig. 2.2 ). The excretory units of the kidney develop from the metanephric mesoderm.
The definitive kidney, formed from the metanephros, begins to function around the twelfth week of development. Urine is passed and mixes with amniotic fluid. The fetus swallows this and recycles it through the kidney. During fetal life, the placenta is responsible for waste excretion, not the kidney.
Initially the kidney is positioned in the pelvic region, but it begins a caudal ascent secondary to lumbar and sacral body growth in the late embryonic and early fetal periods. If a kidney fails to ascend, it remains close to the iliac vessels and is known as a pelvic kidney. Occasionally, the kidneys are so close in proximity that the lower poles fuse, leading to development of a horseshoe kidney. This structure often cannot ascend completely, as it cannot pass the inferior mesenteric artery root.
Bladder, trigone, and urethra.
During the fourth to seventh week of development, the cloaca divides into two separate structures: the urogenital sinus (anteriorly) and the anal canal (posteriorly). These structures are separated by a mesodermal structure, the urorectal septum. The tip of this septum eventually forms the perineal body. The upper and largest portion of the urogenital sinus forms the urinary bladder, which is of endodermal origin. Initially, the bladder is continuous with the allantois (rudimentary structure primarily involved in nutrition and waste excretion in the embryo), but the lumen of the allantois becomes obliterated and forms a fibrous cord called the urachus, which runs from the bladder dome to the umbilicus and is called the median umbilical ligament in the adult. The middle portion of the urogenital sinus forms the prostatic and membranous parts of the urethra, and the distal portion forms the phallic portion.
The expanding wall of the bladder grows and incorporates the mesonephric ducts and ureteric buds, forming the bladder trigone. This structure provides a mesodermal contribution to the endodermal wall of the vesicourethral canal. At about 42 days after fertilization, the trigone may be defined as the region of the vesicourethral canal lying between the ureteric orifices and the termination of the mesonephric ducts (see Fig. 2.2 ). The caudal portion of the vesicourethral canal remains narrow and forms the entire urethra. The urethra consists of epithelium that is derived from endoderm, whereas the surrounding connective tissue and smooth muscle are mesodermal in origin. In females, the cranial portion of the urethra gives rise to the urethral and paraurethral glands. A timetable and schematic representation of the embryologic contributions of the various structures of the urogenital system are shown in Table 2.1 and Fig. 2.3 , respectively.
| Time After Fertilization | Event |
|---|---|
| 15 days | Ingrowth of intraembryonic mesoderm |
| 16–17 days | Allantois appears |
| 17 days 22 days 28 days | Cloacal plate forms Pronephros present Mesonephric duct reaches cloaca; ureteric bud appears |
| 28–49 days | Partitioning of cloaca by urorectal septum |
| 30–37 days | Ureteric bud initiates formation of metanephros (permanent kidney) |
| 41 days | Lumen of urethra is discrete; genital tubercles prominent |
| 42–44 days | Urogenital sinus separates from rectum; mesonephric ducts and ureters drain separately into urogenital sinus, defining boundaries of trigone |
| 51–52 days | Kidneys in lumbar region; glomeruli appear in kidney |
| 12 weeks | Renal function initiates |
| 13 weeks | Bladder becomes muscularized |
| 20–40 weeks | Further growth and development complete the urogenital organs |
The separate development of the trigone and bladder may explain why the muscle laminae of the trigone are contiguous with the muscle of the ureter, but not with the detrusor muscle of the bladder. This separate development also may account for pharmacologic responses of the musculature of the bladder neck and trigone, which differ partially from those of the detrusor. Because of its embryonic origins (mesonephric ducts and ureters), initially the bladder mucosa is mesodermal, but with time this lining is replaced by endodermal epithelium from the hindgut.
Congenital anomalies of the urinary tract.
Anomalies of the urinary system are common (3%–4% of live births). Knowledge of the embryology of the genitourinary system is necessary for understanding the causes of the multiple congenital anomalies of the upper and lower urinary tracts. Selected congenital anomalies of the urinary tract and their embryologic causes are shown in Table 2.2 .
| Condition | Embryologic Cause |
|---|---|
| Renal agenesis | Faulty interaction between the ureteric bud and metanephrogenic mesenchyme |
| Pelvic kidney | Failure of kidney to ascend to the lumbar region |
| Horseshoe kidney | Fusion of lower poles of both kidneys; ascent to lumbar region prevented by root of inferior mesenteric artery |
| Urachal fistula, cyst, sinus | Variable persistence of the intraembryonic portion of allantois, from bladder to umbilicus |
| Double ureter | Early splitting of the ureteric bud |
| Ectopic ureter | Two ureteric buds develop from one mesonephric duct. One bud is in normal position; the abnormal bud moves downward with the mesonephric duct to enter into the urethra, vagina, vestibule, or uterus |
| Bladder exstrophy | Insufficiency of mesoderm of the ventral abdominal wall leading to abdominal ectodermal breakdown and degeneration of the anterior bladder wall; the bladder opens broadly onto the abdominal wall |
Rectum and anal sphincters
Normal development of the hindgut.
In the early embryo, the caudal portion of the primitive gut forms the hindgut. The hindgut extends from the posterior intestinal portal to the cloacal membrane and gives rise to the distal third of the transverse colon, the descending colon, the sigmoid, the rectum, and the upper part of the anal canal. The terminal portion of the hindgut enters into the cloaca, an endoderm-lined cavity that is in direct contact with the surface ectoderm. This boundary between the endoderm and ectoderm forms the cloacal membrane.
During further development, a transverse ridge called the urorectal septum arises from mesoderm between the allantois and the hindgut. This septum gradually grows caudad, thereby dividing the cloaca into an anterior portion, the primitive urogenital sinus, and a posterior portion, the anorectal canal. The primitive perineum is formed when the urorectal septum reaches the cloacal membrane when the embryo is 7 weeks old. At this time, the cloacal membrane ruptures, creating an anal opening for the hindgut and a ventral opening for the urogenital sinus.
Ectoderm on the surface portion of the cloaca proliferates and invaginates to create the anal pit. Degeneration of the anal membrane (formerly cloacal membrane) establishes continuity between the upper and lower anal canal. The upper part of the anal canal is thus endodermal in origin; the lower third of the anal canal is ectodermal. The junction between these regions is delineated by the pectinate line. The embryologic origin of the anus explains the differing blood and nerve supplies and epithelial cell types of the upper and lower anal canal.
The external anal sphincter appears in human embryos at approximately 7 to 8 weeks. This sphincter, together with the levator ani, is believed to originate from hypaxial myotomes. Although the anal sphincter and levator ani may arise from distinct primordia, their relationship is very close.
Congenital anomalies of the rectum and anal sphincters.
Imperforate anus is one of the more common abnormalities of the hindgut. In simple cases, the anal canal ends blindly at the anal membrane, which then forms a diaphragm between the endodermal and ectodermal portions of the anal canal. This occurs when the anal membrane fails to break down. In more severe cases, a thick layer of connective tissue may be found between the terminal end of the rectum and the surface because of either a failure of the anal pit to develop or atresia of the rectal ampulla. Vascular accidents in this region are the likely cause of rectoanal atresias. These vary greatly and present as a fibrous remnant or loss of a segment of the rectum or anus.
Rectourethral and rectovaginal fistulas are likely caused by abnormalities in the formation of the cloaca or urorectal septum. If the urorectal septum does not extend far enough caudally or shifts anteriorly, then the hindgut opens into the urethra or vagina, creating a fistula.
Female genital system
Gonads.
Gonads appear in early development as a pair of longitudinal ridges of steroidogenic mesoderm called the genital or gonadal ridges, which are formed by proliferation of the epithelium and condensation of the underlying mesenchyme. These initially do not contain germ cells. Primordial germ cells originate in the epiblast, migrate through the primitive streak, and by the third week reside in the posterior wall of the yolk sac ( Fig. 2.4 ). They then migrate along the dorsal mesentery of the hindgut and arrive at the primitive gonads at the beginning of the fifth week and invade the genital ridges in the sixth week. Approximately 1000 to 2000 primordial germ cells enter the genital ridges. If the primordial germ cells fail to reach the genital ridge, the gonads do not develop. In the female, once the primordial germ cells reach the genital ridge, they are called oogonia. Oogonia begin to proliferate at this stage and continue into the fourth month. Once these cells proliferate via mitosis, they are called oocytes.
In the absence of the Y chromosome (XX or XO) and in the presence of the appropriate somatic cell environment, primitive sex cords (medullary cords) regress ( Fig. 2.5 A). However, the surface epithelium continues to proliferate and develops a second generation of cords called cortical cords. Cells in these cords surround each oocyte with a layer of epithelial cells called follicular cells. Together, the oocyte and follicular cells constitute a primary follicle ( Fig. 2.5 B). These enter meiosis until prophase I, when meiosis is arrested. The oocytes remain in this phase until ovulation, which may occur up to 50 years later.
Genital ducts, sexually indifferent stage.
As in gonadal development, the embryo genital ducts go through a sexually indifferent stage. Until approximately 8 weeks, both male and female embryos contain two pairs of genital ducts: paramesonephric (Müllerian) ducts and mesonephric (Wolffian) ducts. The paramesonephric ducts are a longitudinal invagination of the epithelium of the urogenital ridge. The ducts open cranially into the intraabdominal cavity and extend caudally. The paramesonephric ducts travel lateral to the mesonephric ducts and move medially, crossing the mesonephric ducts ventrally and coming into close contact in the midline. The paired paramesonephric ducts initially are separated by a septum but later fuse to form the uterine canal. Once these ducts are combined, the fused tip projects into the posterior wall of the urogenital sinus, where it causes a small swelling called the paramesonephric tubule. The mesonephric ducts open into the urogenital sinus on either side of this tubercle.
Sexual differentiation.
Sexual differentiation is determined genetically at the time of fertilization, but the gonads do not acquire sex-specific morphologic characteristics until the seventh week of development. Sexual differentiation is a complex process that depends on the presence or absence of the Y chromosome, which contains the testis-determining gene, SRY (sex determining region on Y). Under its influence male development occurs, and in its absence female development occurs.
The way in which the genital ducts undergo sexual differentiation is an intricate process that involves multiple levels of molecular regulation, of which is only partially understood. SRY , autosomal gene SOX9 , and Müllerian inhibiting substance (MIS) all play important roles. SRY is a transcription factor that acts in conjunction with SOX9. When the Y chromosome is present, SRY and SOX9 influence multiple pathways that lead to testes development and testosterone production in the male. SOX9 is also known to bind to the promoter region of the gene encoding MIS. MIS is critical in sexual differentiation, as its presence leads to regression of the paramesonephric ducts ( Fig. 2.6 ). When the Y chromosome is not present, WNT4, which is encoded by a gene called the ovary-determining gene, inhibits the function of SOX9 and regulates the expression of other genes responsible for ovarian differentiation. Estrogens are also important in sexual differentiation, as they stimulate the paramesonephric ducts to form the uterus, fallopian tubes, cervix, and upper vagina. They also act on external genitalia.
Once sexual differentiation begins, at approximately 7 to 8 weeks, the paramesonephric ducts develops into three main sections: the cranial portion that opens into the abdominal cavity, the horizontal portion that crosses the mesonephric duct, and the fused caudal portion located medial to the mesonephric duct ( Fig. 2.7 A). As the paramesonephric ducts move medially, a pelvic fold is formed from the pelvis to the fused paramesonephric ducts, forming the broad ligament. The two most cranial portions develop into the fallopian tubes and the fused distal portion forms the uterus and cervix ( Fig. 2.7 B).
Vagina.
After the solid tip of the paramesonephric ducts reaches the urogenital sinus, two solid evaginations known as the sinovaginal bulbs grow out from the pelvic part of the sinus ( Fig. 2.8 A). These bulbs proliferate and form the solid vaginal plate. Proliferation continues at the cranial plate, which increases the distance between the uterus and urogenital sinus ( Fig. 2.8 B). The solid plate becomes canalized by the fifth month of development ( Fig. 2.8 C). This demonstrates that the vagina has two origins: the upper vagina originates from the paramesonephric ducts, and the lower vagina from the urogenital sinus. The lumen of the vagina remains separated from the urogenital sinus by the hymen, which consists of the epithelial lining of the sinus and a thin layer of vaginal cells.
Though the mesonephric ducts regress in a developing female embryo, in some females a remnant of these ducts persists. If a small cranial portion persists, it forms the epoohoron, whereas the caudal portion forms the paroophoron. Most of these regress during further embryonic development, but the most cranial portion (found in the epoophoron) and most caudal portion (found in wall of uterus or vagina and called Gartner’s cyst) may be found in adult women (see Fig. 2.7 B).
External genitalia.
Cloacal folds form around the cloacal membrane in the third week of development. Cranial to the cloacal membrane, these folds fuse to form the genital tubercle ( Fig. 2.9 A). Caudally, the folds are subdivided into urogenital folds anteriorly and anal folds posteriorly. A second set of tissue elevations, the genital swellings, becomes visible on each side of the urogenital folds ( Fig. 2.9 B). When the original cloacal membrane breaks down during the eighth week, the urogenital sinus opens between the genital folds directly to the outside. Estrogens further stimulate development of the external genitalia. The genital tubercle elongates and forms the clitoris. The urogenital folds form the labia minora, and the genital swellings form the labia majora. The urogenital sinus remains open and forms the vestibule, into which the urethra and vagina open ( Fig. 2.9 C). Table 2.3 delineates the embryologic origin of the major female genital structures. 
provides an overview of the embryology and congenital anomalies of the lower urogenital tract.
| Indifferent Structure | Female Derivative |
|---|---|
| Genital ridge | Ovary |
| Primordial germ cells | Ova |
| Sex cords | Follicular (granulosa) cells |
| Mesonephric tubules | Oophoron |
| Paroophoron | |
| Mesonephric ducts | Appendix of ovary |
| Gartner’s duct cyst | |
| Paramesonephric ducts | Fallopian tubes |
| Uterus | |
| Upper vagina | |
| Definitive urogenital sinus (lower part) | Lower vagina |
| Vulvar vestibule | |
| Early urogenital sinus (upper part) | Urinary bladder |
| Urethra | |
| Genital tubercle | Clitoris |
| Genital folds | Labia minora |
| Genital swellings | Labial majora |
Congenital anomalies of the female genital system
Congenital anomalies of the female genital system presenting as congenital absence of the vagina and uterus
Malformations of the Müllerian ducts and the external genitalia can have significant impact on both reproductive potential and sexual function. When a patient presents with such an abnormality, it is important to put significant thought and time into determining the correct diagnosis and subsequent treatment.
The literature reports the rate of female congenital anomalies at between 0.2% to 0.4% of the general population. However, the prevalence of female congenital anomalies may be as high as 7% when using some of the newer diagnostic methods. These rates are much higher when looking at subgroups of patients with recurrent pregnancy loss and infertility. However, in many instances women with these anomalies are asymptomatic.
Though sex steroid receptor abnormalities and enzyme deficiencies are not considered malformations of the Müllerian ducts, they often have similar clinical presentations and should be considered in the differential. The workup and diagnosis of these disorders are beyond the scope of this chapter; however, treatments are often similar.
Classification.
The classification of Müllerian anomalies helps with both the diagnosis and the comparison of outcomes after various treatment modalities. However, there is no single classification that encompasses all anomalies that have been reported in the literature.
Although the direct cause of the majority of these anomalies is not known, on the basis of our embryological knowledge the pathogenesis of many of these anomalies can be understood. On the basis of pathophysiology, Müllerian anomalies can be broadly classified as being related to (1) agenesis, (2) vertical fusion defects, or (3) lateral fusion defects. Compared with other anomalies, agenesis of the uterus and agenesis of the vagina are relatively common anomalies. Vertical fusion defects are usually the result of abnormal canalization of the vaginal plate and result in defects such as a transverse vaginal septum and imperforate hymen. Lateral fusion defects can be symmetrical or asymmetrical and include septum of the uterus and vagina, as well as unicornuate and bicornuate uteruses and related abnormalities.
There are endless variations to Müllerian and vaginal anomalies. It is impossible to note these variations effectively in any one classification system. Consequently, many investigators are still searching for that elusive classification system that can not only encompass all the anomalies noted in the vagina, cervix, uterus, and adnexa, but also translate into accurate comprehension and visualization of the defect by other colleagues.
The most accepted classification of uterine anomalies, published by the American Society of Reproductive Medicine (ASRM), places uterine anomalies into distinct groups based on anatomic configuration ( Table 2.4 ). Because vaginal anomalies are not included in this classification, they must be described along with the uterine anomaly. This classification does not give insight into pathophysiology but is an effective way to communicate observations for purposes of treatment and prognosis.
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Müllerian agenesis (Mayer Rokitansky Kuster Hauser syndrome).
Müllerian agenesis (i.e., Mayer Rokitansky Kuster Hauser syndrome) was first described in 1829. Its incidence is reported to be 1 in every 5000 newborn females. The etiology of Müllerian agenesis remains unknown. It appears to be influenced by multifactorial inheritance, and rare familial cases have been reported. It does not appear to be transmitted in an autosomal dominant manner, because none of the female offspring of women with Müllerian agenesis (born via in vitro fertilization and surrogacy) have shown evidence of Müllerian agenesis. Because the vagina and associated uterine structures do not develop with this disorder, it is an ASRM class IA Müllerian anomaly. Patients typically present during their adolescent years with concerns of primary amenorrhea. As a cause of primary amenorrhea, Müllerian agenesis is second only to gonadal dysgenesis.
Patients with Müllerian agenesis will present with normal onset of puberty and appropriate secondary sexual characteristics, but apparently delayed menarche. They do not complain of cyclic pelvic pain, unlike patients with obstructive Müllerian anomalies. The external genitalia appear completely normal, with normal pubic hair growth and normally-sized labia minora, which is in contrast to patients with complete androgen insensitivity syndrome. Hymenal fringes may be evident, but the vaginal opening is absent. No pelvic masses suggestive of hematocolpos will be evident, which is in contrast to cases of complete transverse septum. Because these patients have a 46XX karyotype, normal ovaries will be present in the pelvis. Ovulation can be documented as a shift in basal body temperature. These patients’ hormonal levels are normal, and their cycle length based on hormonal studies varies from 30 to 34 days. In addition, they may experience monthly pain (mittelschmerz) that is indicative of ovulation.
Müllerian agenesis is associated with renal and skeletal system anomalies. Renal abnormalities are noted in 40% of these patients. These include complete agenesis of a kidney, malposition of a kidney, and changes in renal structure. Skeletal abnormalities are noted in 12% of patients and include primarily spine defects and limb and rib defects. Patients with Müllerian agenesis should be actively assessed for these associated anomalies. Hearing difficulties have also been reported in patients with Müllerian agenesis. A higher rate of auditory defects has been noted in general in patients with Müllerian anomalies compared with those with normal Müllerian structures.
The diagnosis of Müllerian agenesis is confirmed via imaging techniques. Abdominal ultrasonography will demonstrate the lack of uterus and the existence of ovaries. The presence of a midline mass consistent with a blood collection usually indicates an obstructive Müllerian anomaly. The distinction between Müllerian agenesis and obstruction is extremely important, because an incorrect diagnosis can jeopardize appropriate management. With the advent of magnetic resonance imaging (MRI), laparoscopy is no longer considered necessary to make this diagnosis. Typical findings in the pelvis include portions of the fallopian tubes, normal ovaries, and usually small Müllerian remnants attached to the proximal portion of the fallopian tubes that may be solid or have functioning endometrial tissue. Direct communication with the radiologist about the differential diagnosis before imaging studies is important. On occasion, the unsuspecting radiologist may interpret the small uterine remnants as a uterus. Careful attention to the very small dimensions of this structure will alert the physician to this possibility. MRI is also important to evaluate coexisting anomalies of the urinary tract, such as renal agenesis and other renal malformations. It is critical to diagnose these before surgical treatment.
The diagnosis, usually made in early adolescence, must be explained to the patient with great sensitivity. At a time when being like her peers is extremely important, knowledge of this diagnosis can be psychologically devastating. Each patient must be reassured that her external genitalia appear normal, and that she will be able to have a normal sex life after the creation of a normally functioning vagina. Although usually not voiced, the inability to subsequently bear children is a major disappointment to teenagers. Fortunately, with assisted reproductive technology procedures including in vitro fertilization, surrogacy, and uterine transplantation ( ), having their own genetic child will be an option for many of these young women.
Receptor abnormalities and enzyme deficiencies.
These genetic disorders are secondary to enzyme deficiencies or defects in the hormone receptors of the sex steroid pathways. Because these affect sex steroid production during embryogenesis, development of the embryo and fetus can be greatly affected. Often affecting the embryo during the sexually indifferent stage, the absence of specific receptors or enzymes can completely change the hormonal environment, which leads to discrepancies between genotype and phenotype. The most common syndromes include complete androgen insensitivity syndrome, 5-alpha-reductase deficiency, 17-alpha-hydroxylase deficiency, vanishing testes syndrome, and absent testis determining factor.
Incomplete androgen insensitivity syndrome (partial testosterone resistance), 5-alpha-reductase deficiency, 17-alpha-hydroxylase deficiency, vanishing testes syndrome, and absent testis determining factor often have variable presentations, including ambiguous genitalia at birth, inappropriate virilization at puberty, and/or lack of pubertal development. These are rare, complex disorders that require the attention of a subspecialist for proper diagnosis.
Complete androgen insensitivity syndrome.
This is an x-linked recessive disorder in which there is a defect in the androgen receptor leading to testosterone resistance. This resistance leads to a failure of male sexual characteristic development. These individuals have a karyotype of XY and have a normal, functioning SRY . The testes develop normally during embryogenesis and produce normal levels of testosterone. However, because the receptor is defective, all downstream development dependent on testosterone does not occur. Specifically, the active development of the mesonephric ducts does not take place, leading to absence of the seminal vesicle, prostate, ductus deferens, epididymis, and maturation and descent of the testes. Because the embryo testis is normal, it produces MIS, also known as anti-Müllerian hormone, leading to active regression of the paramesonephric ducts. This prevents further development of the uterus, fallopian tubes, and upper vagina (see Fig. 2.6 ). These individuals are genetically male and have testes but are typically female in appearance. The testes are not fully developed, and often are located in the abdomen, inguinal canal, or labia. The external genitalia appear normal for a female infant at birth. At puberty, the testes make normal or high levels of testosterone, which is aromatized to estrogen in the cell, leading to normal female secondary sexual characteristics. At puberty, breast development occurs, but the areolas are pale, and the pubic and axillary hair is sparse. Similar to those with Müllerian agenesis, these patients often present with primary amenorrhea. The diagnosis of complete androgen insensitivity syndrome is made with physical examination and imaging demonstrating normal female external genitalia, absence of the upper vagina, uterus, ovaries, and fallopian tubes, high serum testosterone concentrations, and 46 XY karyotype. Please see Table 2.5 for the differences between complete androgen insensitivity syndrome and Müllerian agenesis. Because both disorders present without a vagina, the treatment options are the same. However, patients with complete androgen insensitivity syndrome should undergo surgical excision of the testes after puberty because of the increased risk of developing testicular cancer after age 25 years.
