CHAPTER 18: Anatomic Disorders

Early in life, embryos of male and female sex are indistinguishable from one another (Table 18-1). At critical stages of embryonic development, insults can lead to congenital anatomic disorders of the reproductive tract. Influences include genetic mutation, epigenetic factors, developmental arrest, or abnormal hormonal exposures. Disorders range from congenital absence of the vagina and uterus, to lateral or vertical fusion defects of the müllerian ducts, to external genitalia that are ambiguous. Sexual differentiation is complex and requires both hormonal pathways and morphologic development to be normal and correctly integrated. Thus, it is not surprising that neonates with genital anomalies often have multiple other malformations. Associated urinary tract defects are especially frequent and are linked to the concurrent embryonic development of both reproductive and urinary tracts (Hutson, 2014).

The urogenital tract is functionally divided into the urinary system and genital system. The urinary organs include the kidney, ureters, bladder, and urethra. The reproductive organs are the gonads, ductal system, and external genitalia. Like most organ systems, the female urogenital tract develops from multiple cell types that undergo important spatial growth and differentiation. These develop during relatively narrow time windows and are governed by time-linked patterns of gene expression (Park, 2005).

Both the urinary and genital systems develop from intermediate mesoderm, which extends along the entire embryo length. During initial embryo folding, a longitudinal ridge of this intermediate mesoderm develops along each side of the primitive abdominal aorta and is called the urogenital ridge. Subsequently, the urogenital ridge divides into the nephrogenic ridge and the genital ridge, also called the gonadal ridge (Fig. 18-1).

At approximately 60 days of gestation, the nephrogenic ridges develop into the mesonephric kidneys and paired mesonephric ducts, also termed wolffian ducts. These mesonephric ducts connect the mesonephric kidneys (destined for resorption) to the cloaca, which is a common opening into which the embryonic urinary, genital, and alimentary tracts join (Fig. 18-2A). Recall that evolution of the renal system passes sequentially through the pronephric and mesonephric stages to reach the permanent metanephric system. The ureteric bud arises from the mesonephric duct at approximately the fifth week of fetal life. It lengthens to become the metanephric duct (ureter) and induces differentiation of the metanephros, which will eventually become the final functional kidney.

The paired paramesonephric ducts, also termed the müllerian ducts, develop from invagination of the intermediate mesoderm at approximately the sixth week and grow alongside the mesonephric ducts (Figs. 18-1B and 18-2B). The caudal portions of the müllerian ducts approximate one another in the midline and end behind the cloaca (Fig. 18-2C). The cloaca is divided by formation of the urorectal septum by the seventh week and is separated to create the rectum and the urogenital sinus (Fig. 18-2D). The urogenital sinus is considered in three parts: (1) the cephalad or vesicle portion, which will form the urinary bladder; (2) the middle or pelvic portion, which creates the female urethra; and (3) the caudal or phallic part, which will give rise to the distal vagina and the greater vestibular (Bartholin), urethral, and paraurethral (Skene) glands. During differentiation of the urinary bladder, the caudal portion of the mesonephric ducts is incorporated into the trigone of the bladder wall. Consequently, the caudal portion of the metanephric ducts (ureters) penetrates the bladder with distinct and separate orifices (see Fig. 18-2D).

The close association between the mesonephric (wolffian) and paramesonephric (müllerian) ducts has important clinical relevance because developmental insult to either system is often associated with anomalies that involve the kidney, ureter, and reproductive tract. For example, Kenney and colleagues (1984) noted that up to 50 percent of females with uterovaginal malformations have associated urinary tract anomalies.

Gonadal Determination

Mammalian sex is determined genetically. Individuals with X and Y chromosomes normally develop as males, whereas those with two X chromosomes develop as females. Before 7 weeks of embryonic development, embryos of male and female sex are indistinguishable from one another.

During this indeterminate time, the genital ridge begins as coelomic epithelium with underlying mesenchyme. The epithelium proliferates, and cords of epithelium invaginate into the mesenchyme to create primitive sex cords. In both 46,XX and 46,XY embryos, the primordial germ cells are first identified as large polyhedral cells in the yolk sac. These germ cells migrate by amoeboid motion along the hindgut dorsal mesentery to populate the undifferentiated genital ridge (see Fig. 18-1). Thus, the major cellular components of the early genital ridge include primordial germ cells and somatic cells.

At this point, the presence or absence of gonadal determinant genes directs fetal gender development (Taylor, 2000). Sexual determination is the development of the genital ridge into either an ovary or testis. This depends on the genetic sex produced at fertilization, when the X-bearing oocyte is penetrated by either an X- or Y-chromosome-bearing sperm. In humans, the gene named the sex-determining region of the Y (SRY) is the testis-determining factor. In the presence of SRY, gonads develop as testes. Other genes are important for normal gonad development and include SOX9, SF-1, DMRT1, GATA4, WNT4, WT1, DAX1, and RSPO1 (Arboleda, 2014; Blaschko, 2012). Not surprisingly, mutations in any of these genes may lead to abnormal sexual determination. Moreover, gene dosage and relative expression levels play an important role (Ocal, 2011).

In males, cells in the medullary region of the primitive sex cords differentiate into Sertoli cells, and these cells organize to form the testicular cords (Fig. 18-3A). Testicular cords are identifiable at 6 weeks and consist of these Sertoli cells and tightly packed germ cells. Early in the second trimester, the cords develop a lumen and become seminiferous tubules. Development of a testis-specific vasculature is crucial for normal testicular development (Ross, 2005).

During this early development, Sertoli cells begin secreting antimüllerian hormone (AMH), also called müllerian inhibitory substance (MIS). This gonadal hormone causes regression of the ipsilateral paramesonephric (müllerian duct) system, and this involution is completed by 9 to 10 weeks’ gestation (Marshall, 1978). AMH also controls the rapid gubernacular growth necessary for the transabdominal descent of the testis. Serum AMH levels remain elevated in boys during childhood and then decline at puberty to the low levels seen in adult men. In contrast, girls have undetectable AMH levels until puberty, when serum levels become measurable. Clinically, AMH levels in mature women reflect ovarian follicle reserve and are used in fertility aspects of reproductive medicine (Chap. 19).

In the testes, Leydig cells arise from the original mesoderm of the genital ridge and lie between the testicular cords. Their differentiation begins approximately 1 week after Sertoli cell development. The Leydig cells begin to secrete testosterone by 8 weeks’ gestation due to stimulation of the testes by human chorionic gonadotropin (hCG). Testosterone acts in a paracrine manner on the ipsilateral mesonephric (wolffian) duct to promote virilization of the duct into the epididymis, vas deferens, and seminal vesicle. In addition, the androgens testosterone and dihydrotestosterone (DHT) are essential for male phenotype development. These androgens control differentiation and growth of the internal ducts and external genitalia and also prime male differentiation of the brain.

In the female embryo, without the influence of the SRY gene, the bipotential gonad develops into the ovary. The pathways regulating female sex determination have remained incompletely defined, but WNT4, WT1, FoxL2, and DAX1 genes are important for normal development (Arboleda, 2014; MacLaughlin, 2004). Compared with testicular development, ovarian determination is delayed by approximately 2 weeks. Development is first characterized by the absence of testicular cords in the gonad. The primitive sex cords degenerate, and the mesothelium of the genital ridge forms secondary sex cords (Fig. 18-3B). These secondary cords become the granulosa cells that band together to form the cell layer that surrounds the germ cells. Oocytes and the surrounding granulosa cells begin communication when the resting primordial follicles are stimulated to grow under the influence of follicle-stimulating hormone (FSH) at puberty. The medullary portion of the gonad regresses and forms the rete ovarii within the ovarian hilum.

Germ cells that carry two X chromosomes undergo mitosis during their initial migration to the female genital ridge. They reach a peak number of 5 to 7 million by 20 weeks’ gestation. At this time, the fetal ovary demonstrates mature organization of stroma and primordial follicles containing oocytes. During the third trimester, oocytes begin meiosis but arrest during meiosis I until the oocyte undergoes ovulation after menarche. Atresia of the oocytes starts in utero, leading to a reduced number of germ cells at birth.

Ductal System Development

Sexual differentiation of the mesonephric (wolffian) and paramesonephric (müllerian) ducts begins in week 7 from the influence of gonadal hormones (testosterone and AMH) and other factors. In the male, AMH forces paramesonephric regression, and testosterone prompts mesonephric duct differentiation into the epididymis, vas deferens, and seminal vesicles.

In the female, a lack of AMH allows müllerian ducts to persist. Early, these ducts grow caudally along with the mesonephric ducts. During paramesonephric duct elongation, homeobox (Hox) genes, specifically in groups 9–13, play a role in determining positional identity along the long axis of the developing duct. For example, HoxA9 is one such gene that is expressed at high levels in areas destined to become the fallopian tube (Park, 2005). HoxA10 and HoxA11 are expressed in the developing uterus and in the adult uterus. These and other ovarian determinant genes play an active role in gonadal and reproductive tract morphogenesis, but mechanisms are yet to be elucidated fully (Massé, 2009; Taylor, 2000).

During their elongation, both mesonephric and paramesonephric duct systems become enclosed in peritoneal folds that later give rise to the broad ligaments of the uterus. At approximately 10 weeks’ gestation and during their caudal migration, the two distal portions of the müllerian ducts approach each other in the midline and fuse even before they reach the urogenital sinus. The fused ducts form a tube called the uterovaginal canal. This tube then inserts into the urogenital sinus at Müller tubercle (Fig. 18-4).

By 12 weeks, mesonephric ducts regress from lack of testo­sterone. The uterine corpus and cervix differentiate, and the uterine wall thickens. Initially, the upper pole of the uterus contains a thick midline septum that undergoes dissolution to create the uterine cavity. Dissolution of the uterine septum is usually completed by 20 weeks. The unfused cephalad portions of the müllerian ducts become the fallopian tubes (Fig. 18-2F). Any failure of lateral fusion of the two müllerian ducts or failure to reabsorb the septum between them results in separate uterine horns or some degree of persistent midline uterine septum.

Most investigators suggest that the vagina develops under influence from the müllerian ducts and estrogenic stimulation. The vagina forms partly from the müllerian ducts and partly from the urogenital sinus (Massé, 2009). Specifically, the upper two thirds of the vagina derive from the fused müllerian ducts. The distal third of the vagina develops from the bilateral sinovaginal bulbs, which are cranial evaginations of the urogenital sinus.

During vaginal development, the müllerian ducts reach the urogenital sinus at Müller tubercle (Fig. 18-4A). Here, cells in the sinovaginal bulbs proliferate cranially to lengthen the vagina and create a solid vaginal plate (Fig. 18-4B). During the second trimester, these cells desquamate, allowing full canalization of the vaginal lumen (Fig. 18-4C). The hymen is the partition that remains to a varying degree between the dilated, canalized, fused sinovaginal bulbs and the urogenital sinus. The hymen usually perforates shortly before or after birth. An imperforate hymen represents persistence of this membrane.

External Genitalia

Early development of the external genitalia is similar in both sexes. By 6 weeks’ gestation, three external protuberances have developed surrounding the cloacal membrane. These are the left and right cloacal folds, which meet ventrally to form the genital tubercle (Fig. 18-5A). With division of the cloacal membrane into anal and urogenital membranes, the cloacal folds become the anal and urethral folds, respectively. Lateral to the urethral folds, genital swellings arise, and these become the labioscrotal folds. Between the urethral folds, the urogenital sinus extends onto the surface of the enlarging genital tubercle to form the urethral groove. By week 7, the urogenital membrane ruptures, exposing the cavity of the urogenital sinus to amnionic fluid.

The genital tubercle elongates to form the phallus in males and the clitoris in females. However, one is not is able to visually differentiate between male and female external genitalia until week 12. In the male fetus, dihydrotestosterone (DHT) forms locally by the 5α reduction of testosterone. DHT prompts the anogenital distance to lengthen, the phallus to enlarge, and the labioscrotal folds to fuse and form the scrotum. Sonic hedgehog (SHH) is a gene that regulates urethral tubularization in males at 14 weeks’ gestation (Shehata, 2011). Specifically, DHT and SHH expression promote the urethral folds to merge and enclose the penile urethra (Fig. 18-5B). In the female fetus, without DHT, the anogenital distance does not lengthen, and the labioscrotal and urethral folds do not fuse (Fig. 18-5C). The genital tubercle bends caudally to become the clitoris, and the urogenital sinus becomes the vestibule of the vagina. The labioscrotal folds create the labia majora, whereas the urethral folds persist as the labia minora.

Definitions

As evident from the prior discussion, abnormal sex development may involve the gonads, internal duct system, or external genitalia. Rates vary and approximate 1 in every 1000 to 4500 births (Murphy, 2011; Ocal, 2011).

Formerly, intersex disorders were subdivided as those: (1) associated with gonadal dysgenesis, (2) associated with undervirilization of 46,XY individuals, and (3) associated with prenatal virilization of 46,XX subjects. The nomenclature used to describe atypical sexual differentiation has evolved. Instead of the terms “intersex,” “hermaphroditism,” and “sex reversal,” consensus recommends a new taxonomy based on the umbrella term, disorder of sex development (DSD) (Lee, 2006). Proposed classification of DSDs are: (1) sex chromosome DSDs, (2) 46,XY DSDs, and (3) 46,XX DSDs (Table 18-2)(Hughes, 2006).

Other terms describe the abnormal phenotypic findings that can be found. First, some DSDs are associated with abnormal, underdeveloped gonads, that is, gonadal dysgenesis. With this, if a testis is poorly formed, it is called a dysgenetic testis, and if an ovary is poorly formed, it is called a streak gonad. In affected patients, the underdeveloped gonad ultimately fails, which is indicated by elevated gonadotropin levels. Another important clinical sequela is that patients bearing a Y chromosome are at high risk of developing a germ cell tumor in the dysgenetic gonad.

A second term, ambiguous genitalia, describes genitalia that do not appear clearly male or female. Abnormalities may include hypospadias, undescended testes, micropenis or enlarged clitoris, labial fusion, and labial mass.

Last, ovotesticular defines conditions characterized by ovarian and testicular tissue in the same individual. It was formerly termed true hermaphroditism. In these cases, the morphology of the paired gonads can vary, and options that may be paired include a normal testis, a normal ovary, a streak gonad, a dysgenetic testis, or an ovotestis. In the last, both ovarian and testicular elements are combined within the same gonad. The gonadal location varies from abdominal to inguinal to scrotal. With ovotesticular DSDs, the internal ductal system structure depends on the ipsilateral gonad and its degree of determination. Specifically, the amount of AMH and testosterone determines the degree to which the internal ductal system is masculinized or feminized. External genitalia are usually ambiguous and undermasculinized due to inadequate testosterone.

Sex Chromosome Disorders of Sex Development

Turner and Klinefelter Syndromes

Sex chromosome DSDs typically arise from an abnormal number of sex chromosomes. Of these, Turner and Klinefelter syndromes are most frequently encountered. Turner syndrome is caused by de novo loss or severe structural abnormality of one X chromosome in a phenotypic female. It is the most common form of gonadal dysgenesis that leads to primary ovarian failure.

Most affected fetuses are spontaneously aborted. However, in girls with Turner syndrome who survive, phenotype varies widely, but nearly all affected patients have short stature. This results from lack of one copy of the SHOX gene, which resides on the short arm of the X chromosome (Hutson, 2014). The classic stigmata of Turner syndrome are listed in Table 18-3. Of these, cubitus valgus is an elbow deformity that deviates the forearm greater than 15 degrees when the arm is extended at the side. Associated problems include cardiac anomalies (especially coarctation of the aorta), renal anomalies, hearing impairment, otitis media and mastoiditis, and an increased incidence of hypertension, achlorhydria, diabetes mellitus, and Hashimoto thyroiditis. This syndrome may be recognized in childhood. However, some patients are not diagnosed until adolescence, when they present with prepubertal female genitalia and primary amenorrhea, both stemming from gonadal failure, and with short stature. The uterus and vagina are normal and capable of responding to exogenous hormones.

Those with a Turner variant have a structural abnormality of the second X chromosome or have a mosaic karyotype, such as 45,X/46,XX. Indeed, more than half of the girls with this syndrome have chromosomal mosaicism. Those with a Turner variant may exhibit some or all of the syndrome signs. Patients with mosaicism are more likely to have some pubertal maturation.

For patients with 45,X DSD, hormone treatment is needed to effect breast development. Our protocol uses estradiol, 0.25 mg orally daily for approximately 6 months. This begins near age 12 or at the time of delayed puberty diagnosis. The daily estradiol dose is sequentially increased each 6 months to 0.5 mg, 0.75 mg, 1 mg, and then 2 mg daily. We colloquially term this the “start low and go slow” protocol. Progesterone is begun after approximately 1 year of unopposed estrogen treatment. Each month, micronized progesterone, 200 mg orally nightly, is given for 12 nights and then stopped to permit withdrawal bleeding. This method mimics normal pubertal hormonal stimulation of breast tissue. The patient is then maintained on 2 mg of oral estradiol and monthly withdrawal to progesterone. Alternatively, a low-dose combination oral contraceptive would also be acceptable maintenance after adequate breast development has been effected.

Another sex chromosome DSD is Klinefelter syndrome (47,XXY), which occurs in one in 600 births or in 1 to 2 percent of all males. These individuals tend to be tall, undervirilized males with gynecomastia and small, firm testes. They have significantly reduced fertility from hypogonadism due to gradual testicular cell loss that begins shortly after testis determination (Nistal, 2014). These men are at increased risk for germ cell tumors, osteoporosis, hypothyroidism, diabetes mellitus, breast cancer, and cognitive and psychosocial problems (Aksglaede, 2013). The most common genotype of Klinefelter syndrome is XXY, although variants exist with differing numbers of X chromosomes.

Chromosomal Ovotesticular DSD

Several karyotypes can create a coexistent ovary and testis, and thus ovotesticular DSD is found in all three DSD categories (see Table 18-2). In the sex chromosome DSD group, ovotesticular DSD may arise from a 46,XX/46,XY karyotype. Here, an ovary, testis, or ovotestis may be paired. The phenotype mirrors that for ovotesticular DSDs in general described earlier on this page.

For others in the sex chromosome DSD group, ovotesticular DSD arises from a chromosomal mosaic such as 45,X/46,XY. With this karyotype, a picture of mixed gonadal dysgenesis shows a streak gonad on one side and a dysgenetic or normal testis on the other. The phenotypic appearance ranges from undervirilized male to ambiguous genitalia to Turner stigmata.

46,XY Disorders of Sex Development

Insufficient androgen exposure of a fetus destined to be a male leads to 46,XY DSD, formerly called male pseudohermaphroditism. The karyotype is 46,XY, and testes are frequently present. The uterus is generally absent as a result of normal embryonic AMH production by Sertoli cells. These patients are most often sterile from abnormal spermatogenesis and have a small phallus that is inadequate for sexual function. As seen in Table 18-2, etiology of 46,XY DSD may stem from abnormal testis development or from abnormal androgen production or action.

46,XY Gonadal Dysgenesis

This spectrum of abnormal gonad underdevelopment includes pure or complete, partial, or mixed 46,XY gonadal dysgenesis (see Table 18-2). These are defined by the amount of normal testicular tissue and by karyotype.

Of these, pure gonadal dysgenesis results from a mutation in SRY or in another gene with testis-determining effects (DAX1, SF-1, CBX2) (Hutson, 2014). This leads to underdeveloped dysgenetic gonads that fail to produce androgens or AMH. Formerly named Swyer syndrome, the condition creates a normal prepubertal female phenotype and a normal müllerian system due to absent AMH.

Partial gonadal dysgenesis defines those with gonad development intermediate between normal and dysgenetic testes. Depending on the percentage of underdeveloped testis, wolffian and müllerian structures and genital ambiguity are variably expressed.

Mixed gonadal dysgenesis is one type of ovotesticular DSD. As discussed, with mixed gonadal dysgenesis, one gonad is streak and the other is a normal or a dysgenetic testis. Of affected individuals, a 46,XY karyotype is found in 15 percent (Nistal, 2015). The phenotypic appearance is wide ranging as with partial gonadal dysgenesis.

Last, testicular regression can follow initial testis development. A broad phenotypic spectrum is possible and depends on the timing of testis failure.

Because of the potential for germ cell tumors in dysgenetic gonads and intraabdominal testes, affected patients are advised to undergo gonadectomy (Chap. 36).

Abnormal Androgen Production or Action

In some cases, 46,XY DSD may stem from abnormalities in: (1) testosterone biosynthesis, (2) luteinizing hormone (LH) receptor function, (3) AMH function, or (4) androgen receptor action. First, as evident from Table 15-5,, the sex steroid biosynthesis pathway can suffer enzymatic defects that block testosterone production. Depending on the timing and degree of blockade, undervirilized males or phenotypic females may result. Potential defective enzymes include steroid acute regulatory protein (StAR), cholesterol side-chain cleavage enzyme (P450scc), 3β-hydroxysteroid dehydrogenase type II, 17α-hydroxylase/17,20 desmolase (P450c17a), and 17β-hydroxysteroid dehydrogenase. The last two enzyme deficiencies can also cause congenital adrenal hyperplasia, and hypertension is a common feature in P450c17a deficiency. In addition to these central enzymatic defects, peripherally, abnormal 5α-reductase type 2 enzyme action leads to impaired conversion of testosterone to DHT. DHT is the active androgen in peripheral tissues, and undervirilization results.

Second, hCG/LH receptor abnormalities within the testes can lead to Leydig cell aplasia/hypoplasia and impaired testosterone production. In contrast, disorders of AMH and AMH receptors result in persistent müllerian duct syndrome (PMDS). Affected patients appear as males but have a persistent uterus and fallopian tubes due to failed AMH action.

Finally, the androgen receptor may be defective and result in androgen insensitivity syndrome (AIS). The estimated incidence of AIS ranges from 1 in 13,000 to 1 in 41,000 live births (Bangsboll, 1992; Blackless, 2000). Mutations produce a nonfunctional receptor that will not bind androgen or is unable to initiate full transcription once bound. As a result, resistance to androgens may be complete and female external genitalia are found. Alternatively, an incomplete form is associated with varying degrees of virilization and genital ambiguity. Milder forms of AIS have been described in men with severe male factor infertility and poor virilization. For those with male gender assignment, testosterone therapy via patch or injection may be needed for continued masculine response.

Patients with complete androgen-insensitivity syndrome (CAIS) appear as phenotypically normal females at birth. They often present at puberty with primary amenorrhea. External genitalia appear normal; scant or absent pubic and axillary hair is noted; the vagina is shortened or blind ending; and the uterus and fallopian tubes are absent. However, these girls develop breasts during pubertal maturation due to abundant androgen-to-estrogen conversion. Testes may be palpable in the labia or inguinal area or may be found intraabdominally.

In CAIS patients, surgical excision of the testes after puberty is recommended to decrease the associated risk of germ cell tumors, which may be as high as 20 to 30 percent (Chap. 36) (Chavhan, 2008). Additionally, estrogen is replaced to reach physiologic levels, and a functional vagina is created either by dilation or by surgical vaginoplasty. Adequate estrogen replacement in these patients is important to maintain breast development and bone mass and to provide relief from vasomotor symptoms.

46,XX Disorders of Sex Development

As seen in Table 18-2, etiology of 46,XX DSD may stem from abnormal ovarian development or from excess androgen exposure.

Abnormal Ovarian Development

Disorders of ovarian development in those with a 46,XX complement include: (1) gonadal dysgenesis, (2) testicular DSD, and (3) ovotesticular DSD.

With 46,XX gonadal dysgenesis, similar to Turner syndrome, streak gonads develop. These lead to hypogonadism, prepubertal normal female genitalia, and normal müllerian structures, but other Turner stigmata are absent.

With 46,XX testicular DSD, several possible genetic mutations lead to testis–like formation within the ovary (streak gonad, dysgenetic testis, or ovotestis). Defects may stem from SRY translocation onto one X chromosome. In individuals without SRY translocation, other genes with testis-determining effects are most likely present or activated. These include WNT4, RSPO1, or CTNNB1 gene defects or SOX9 gene duplication (Ocal, 2011). SRY guides the gonad to develop along testicular lines, and testicular hormone function is near normal. Production of AMH prompts müllerian system regression, and androgens promote development of the wolffian system and external genitalia masculinization. Spermatogenesis, however, is absent due to a lack of certain genes on the long arm of the Y chromosome. These individuals are not usually diagnosed until puberty or during infertility evaluation.

With 46,XX ovotesticular DSD, individuals possess a unilateral ovotestis with a contralateral ovary or testis, or bilateral ovotestes. Phenotypic findings depend on the degree of androgen exposures and mirror those for other ovotesticular DSDs.

Androgen Excess

Discordance between gonadal sex (46,XX) and the phenotypic appearance of external genitalia (masculinized) may result from excessive fetal androgen exposure. This was previously termed female pseudohermaphroditism. In affected individuals, the ovaries and female internal ductal structures such as the uterus, cervix, and upper vagina are present. Thus, patients are potentially fertile. The external genitalia, however, are virilized to a varying degree depending on the amount and timing of androgen exposure. The three embryonic structures that are commonly affected by elevated androgen levels or ovarian development disorders are the clitoris, labioscrotal folds, and urogenital sinus. As a result, virilization may range from modest clitoromegaly to posterior labial fusion and development of a phallus with a penile urethra. Degrees of virilization can be described by the Prader score, which ranges from 0 for a normal-appearing female to 5 for a normal, virilized male.

Fetal, placental, or maternal sources may provide the excessive androgen levels. Maternally derived androgen excess may come from virilizing ovarian tumors such as luteoma and Sertoli-Leydig cell tumor or from virilizing adrenal tumors. Fortunately, these neoplasms infrequently cause fetal effects because of the tremendous ability of placental syncytiotrophoblast to convert C19 steroids (androstenedione and testosterone) to estradiol via the enzyme aromatase (Cunningham, 2014c). As another source, drugs such as testosterone, danazol, norethindrone, and other androgen derivatives may cause fetal virilization.

Of fetal sources, exposure can also arise from fetal congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency from CYP21 mutation. This is a frequent cause of virilization and has an incidence approximating 1 in 14,000 live births (White, 2000). In many cases, CAH can be diagnosed antenatally, and early maternal dexamethasone therapy can ameliorate the masculine phenotype (New, 2012). In addition, androgen excess and ambiguous genitalia can also be seen with fetal 11-beta hydroxylase and 3β-hydroxysteroid dehydrogenase deficiencies, from CYP11B1 and HSD3B2 gene mutations, respectively (Fig. 15-5). Mutations of POR gene can also disorder steroidogenesis. Cytochrome POR is a protein that transfers electrons to important cytochrome P450 enzymes and steroidogenic enzymes. Severely affected female neonates with POR gene mutations are virilized because of defective aromatase activity and because of the diversion of 17-hydroxyprogesterone to DHT by a “backdoor” androgen pathway (Fukami, 2013).

Of placental sources, placental aromatase deficiency from fetal CYP19 gene mutation causes an accumulation of placental androgen and underproduction of placental estrogens. Consequently, both the mother and the 46,XX fetus are virilized (Murphy, 2011).

Gender Assignment

At birth, gender assignment to the normal newborn usually involves a simple assessment of the external genitalia and a straightforward joyful declaration of male or female by the obstetrician. Delivery of a newborn with DSD is a potential medical emergency and presents a serious psychosocial, diagnostic, medical, and possibly surgical challenge for a multispecialty medical team. For the unprepared obstetrician in the labor room, ambiguous external genitalia in a newborn can create possible long-lasting psychosexual and social ramifications for the individual and family. Ideally, as soon as the neonate with ambiguous genitalia is stable, parents are encouraged to hold the child. The newborn is referred to as “your baby” and not as “it” or “he/she.” When discussing ambiguous development, other suggested terms used include “phallus,” “gonads,” “folds,” and “urogenital sinus” to reference underdeveloped structures. The obstetrician explains that the genitalia are incompletely formed and emphasizes the seriousness of the situation and the need for rapid consultation and laboratory testing see (Fig. 18-6). During family education, the need for accurate determination of gender and sex of rearing is emphasized.

Because similar or identical phenotypes may have several etiologies, diagnosis of a specific DSD may require several diagnostic tools (Ocal, 2011). Relevant neonatal physical examination evaluates: (1) ability to palpate gonads in the labioscrotal or inguinal regions, (2) ability to palpate uterus during rectal examination, (3) phallus size, (3) genitalia pigmentation, and (4) presence of other syndromic features. The newborn’s metabolic condition is assessed, as hyperkalemia, hyponatremia, and hypoglycemia may indicate congenital adrenal hyperplasia. The mother is examined for signs of hyperandrogenism (Thyen, 2006).

Pediatric endocrinologists and reproductive endocrinologists are consulted as soon as possible. The diagnostic evaluation of DSD includes hormone measurements, imaging, cytogenetic studies, and in some cases endoscopic, laparoscopic, and gonadal biopsy. Sonography shows the presence or absence of müllerian/wolffian structures and can locate the gonads. Sonography also can identify associated malformation such as renal abnormalities. The genetic evaluation includes karyotype, fluorescent in situ hybridization (FISH), and more recently, specific molecular studies to screen for mutations or gene dosage imbalance.

The psychologic and social implications of gender assignment and those relating to treatment are important and require a multidisciplinary approach. The current intense debate on the management of patients with DSD focuses on four major issues, namely, etiologic diagnosis, gender assignment, indications for and timing of genital surgery, and disclosure of medical information to the patient (Daaboul, 2001; de Vries, 2007). Discussions include the possible need for hormonal stimulation at puberty and potential later surgical reconstruction.

The bilaminar cloacal membrane lies at the caudal end of the germinal disc and forms the infraumbilical abdominal wall. Normally, an ingrowth of mesoderm between the ectodermal and endodermal layers of the cloacal membrane leads to formation of the lower abdominal musculature and the pelvic bones. Without reinforcement, the cloacal membrane may prematurely rupture. Bladder exstrophy is a complex and severe pelvic malformation due to premature rupture of this cloacal membrane and subsequent failure of the membrane to be reinforced by an ingrowth of mesoderm. Depending on the infraumbilical defect size and developmental stage at rupture, bladder exstrophy, cloacal exstrophy, or epispadias results.

Of these, bladder exstrophy has an estimated incidence of 1 in 50,000 newborns and is equally prevalent in males and females (Lloyd, 2013). Exstrophy is characterized by an exposed bladder lying outside the abdomen. Associated findings commonly include abnormal external genitalia and a widened symphysis pubis, caused by the outward rotation of the innominate bones. Stanton (1974) noted that 43 percent of 70 females with bladder exstrophy had associated reproductive tract anomalies. The urethra and vagina are typically short, and the vaginal orifice is frequently stenotic and displaced anteriorly. The clitoris is duplicated or bifid, and the labia, mons pubis, and clitoris are divergent. The uterus, fallopian tubes, and ovaries are typically normal except for occasional müllerian duct fusion defects.

A complex approach is required to achieve acceptable urinary continence and external genitalia reconstruction (Laterza, 2011). Surgical closure of the exstrophy is currently performed in the first 4 years of life in stages (Massanyi, 2013). Vaginal dilatation or vaginoplasty may be required to allow satisfactory intercourse in mature females (Jones, 1973). Long term, the defective pelvic floor may predispose women to uterine prolapse (Nakhal, 2012).

Congenital abnormalities of the clitoris are unusual but include clitoral duplication, clitoral cysts, and clitoral enlargement from excess androgen exposure. Clitoral duplication, also known as bifid clitoris, usually develops in association with bladder exstrophy or epispadias. The disorder is rare, and the incidence approximates 1 in 480,000 females (Elder, 1992).

In those with epispadias but without bladder exstrophy, visibly apparent anomalies include a widened, patulous urethra; absent or bifid clitoris; flattened mons pubis; and labia that do not fuse anteriorly. Vertebral abnormalities and diastases of the pubic symphysis are also commonly associated. Female epispadias can be divided into three types—vestibular, subsymphyseal, and retrosymphyseal—which are differentiated by the type of urethral involvement (Schey, 1980).

Female phallic urethra is another clitoral anomaly, and the phallic urethra opens at the clitoral tip (Sotolongo, 1983). This anomaly affects 4 to 8 percent of girls with persistent cloaca and has been associated with embryonic exposure to cocaine (Karlin, 1989).

Epidermal cysts may be found on the clitoris, and inversion of epidermal cells beneath the dermis or subcutaneous tissue is the presumed pathogenesis. Cysts can reach 1 to 5 cm in diameter. Surgical removal of the cyst is the preferred treatment. Vasculature and nerve supply preservation during this procedure is important to sexual health (Johnson, 2013).

Clitoromegaly noted at birth is suggestive of fetal exposure to excessive androgens. Clitoromegaly is defined as a clitoral index greater than 10 mm². This index is determined by the glans length times the width. Moreover, early androgen exposure may lead to fusion of the labioscrotal folds and findings of a single perineal opening, the urogenital sinus. Labia are rugated and scrotum-like. A gonad found in the groin or labia majora, however, raises concern for 46,XY DSD.

Frequently in premature neonates, the clitoris may appear large, but it does not change size and appears to regress as the infant grows. Other causes of newborn clitoromegaly include breech presentation with vulvar swelling, chronic severe vulvovaginitis, and neurofibromatosis (Dershwitz, 1984; Greer, 1981). Clitoral reduction surgery is done typically by skilled pediatric urologists, and preservation of vasculature and nerve supply is essential.

The hymen is the membranous vestige of the junction between the sinovaginal bulbs and the urogenital sinus (see Fig. 18-4). It generally perforates during fetal life to establish a connection between the vaginal lumen and the perineum. Various hymeneal abnormalities include imperforate, microperforate, annular, septate, cribriform (sievelike), naviculate (boatlike), or septate types (Fig. 18-7) (Breech, 1999). Imperforate hymen follows failure of the inferior end of the vaginal plate to canalize, and its incidence approximates 1 in 1000 to 2000 females (Parazzini, 1990). Although typically sporadic, imperforate hymen in multiple family members has been reported (Stelling, 2000; Usta, 1993).

If the hymen is imperforate, blood from endometrial sloughing or mucus accumulates in the vagina. During the neonatal period, significant amounts of mucus can be secreted secondary to maternal estradiol stimulation. The newborn may have a bulging, translucent yellow-gray mass at the vaginal introitus. This condition is termed hydro/mucocolpos. Most cases are asymptomatic and resolve as the mucus is reabsorbed and estrogen levels decline. However, large hydro/mucocolpos may cause respiratory distress or may obstruct the ureters, resulting in hydronephrosis or life-threatening acute renal failure (Breech, 2009; Nagai, 2012).

After menarche, adolescents with imperforate hymen present with trapped menstrual blood behind the hymen, which creates a bluish bulge at the introitus (Fig. 14-5B). With cyclic menstruation, the vaginal canal greatly distends, and the cervix may dilate and allow formation of a hematometra and hematosalpinx. Cyclic pain, amenorrhea, abdominal pain mimicking acute abdomen, and difficulty with urination or defecation may be presenting symptoms (Bakos, 1999). Moreover, retrograde menstruation can lead to development of endometriosis. Other obstructive reproductive tract anomalies that are located more cephalad, such as transverse vaginal septum, may present similarly.

Patients with microperforate, cribriform, or septate hymen will typically complain of menstrual irregularities or difficulty with tampon placement or intercourse. Microperforate or imperforate hymen may be corrected when diagnosed and is illustrated in Section 43-17. Breech and Laufer (1999) advocate repair when estrogen is present to improve tissue healing, either in infancy or after thelarche, but before menarche. This timing avoids the formation of hematocolpos and possible hematometra. Laparoscopy is often performed concurrently with hymenectomy to exclude endometriosis. Importantly, clinicians should avoid needle aspiration of a hematocolpos for diagnosis or treatment. Aspiration may seed the retained blood with bacteria and increase infection risks. Moreover, recurrent hematocolpos secondary to inadequate drainage is common following needle aspiration alone.

Hymeneal cysts in the newborn must be differentiated from an imperforate hymen with hydro/mucocolpos (Nazir, 2006). These cysts typically have an opening and may regress spontaneously (Berkman, 2004). They may also be treated by incision and drainage. Simple puncture without anesthesia has also been successfully performed.

Transverse vaginal septa are believed to arise from failed müllerian duct fusion or failed canalization of the vaginal plate (Fig. 18-8). The anomaly is uncommon, and Banerjee (1998) reported an incidence of 1 in 70,000 females. A septum may be obstructive, with mucus or menstrual blood accumulation, or nonobstructive, with mucus and blood egress.

Transverse vaginal septum can develop at any level within the vagina (Williams, 2014). Those in the upper vagina correspond to the junction between the vaginal plate and the caudal end of the fused müllerian ducts (see Fig. 18-4). Septal thickness may vary but typically is thin (1 cm). Thicker septa can measure 5 to 6 cm, and these tend to lie nearer the cervix (Rock, 1982).

In neonates and infants, obstructive transverse vaginal septum has been associated with fluid and mucus collection in the upper vagina. The resulting mass may be large enough to compress abdominal or pelvic organs. In addition, pyomucocolpos, pyometria, and pyosalpinges may develop from ascension of vaginal or perineal bacteria through small perforations within a septum (Breech, 1999). In contrast to other müllerian duct defects, transverse vaginal septum is associated with few urologic abnormalities.

Patients with transverse vaginal septum usually present with symptoms similar to those of imperforate hymen. The diagnosis is suspected when an abdominal or pelvic mass is palpated or when a foreshortened vagina and inability to identify the cervix is encountered. Diagnosis is confirmed by either sonography or magnetic resonance (MR) imaging. MR imaging is most helpful prior to surgery to determine the septal thickness and depth (Fig. 18-9). In addition, MR imaging may identify whether a cervix is present, and thereby allow differentiation of a high vaginal septum from cervical agenesis.

Surgical repair technique is dependent on septal thickness, and skin grafts or buccal mucosal grafts may occasionally be necessary to cover the defect left by excision of very thick septa. Smaller septa may be removed by excision followed by end-to-end anastomosis of the upper and lower vagina as described in Section 43-24. Sanfilippo (1986) recommends laparoscopy concurrently with transverse vaginal septum excision because of the high rate of endometriosis due to retrograde menstruation from outflow tract obstruction.

A longitudinal vaginal septum results from defective lateral fusion or incomplete reabsorption of the caudal central portion of the müllerian ducts. These septa may be partial or extend the complete vaginal length. Longitudinal septa are generally seen with partial or complete duplication of the cervix and uterus. They may also accompany anorectal malformations, and renal abnormalities are common.

Affected individuals complain of difficulty with intercourse. Vaginal bleeding may occur despite placement of a tampon, because the tampon is placed in only one of the duplicated vaginas. Nonobstructed forms can be managed conservatively unless dyspareunia develops. However, there are obstructive longitudinal vaginal septa (Fig. 18-10). Typically, the patient presents in adolescence with normal menarche, but reports worsening, monthly unilateral vaginal and pelvic pain from outflow obstruction (Carlson, 1992). During examination, a patent vagina and cervix are noted, but a unilateral vaginal and pelvic mass can be palpated. Obstructed hemivagina is almost universally associated with ipsilateral renal agenesis. The triad of uterine didelphys, obstructed hemivagina, and ipsilateral renal anomaly is the OHVIRA syndrome, also known as Herlyn-Werner-Wunderlich syndrome.

Surgical correction of a longitudinal vaginal septum consists of excision of the obstructing septum, taking precautions to avoid the urethra/bladder and rectum. With obstructive cases, sonographic guidance during excision can help in identifying the distended upper vagina (Breech, 2009). Joki-Erkkila and Heinonen (2003) followed 26 females after surgical repair of obstructive outflow tract anomalies. They found a high rate of vaginal stricture requiring reoperation, as well as abnormal uterine bleeding, dyspareunia, and dysmenorrhea.

Although in each sex the müllerian or wolffian ducts marked for degeneration normally do regress, vestigial remnants can be found and may become clinically apparent. Thus, laterally located cysts may be mesonephric (wolffian) duct remnants. The lowermost portion of the vagina derives from the urogenital sinus, which may give rise to congenital vestibular cysts (Heller, 2012).

Remnant cysts are typically located in the anterolateral wall of the vagina, although they may be found at various locations along its length. Most are asymptomatic and benign, measure 1 to 7 cm in diameter, and do not require surgical excision. Deppisch (1975) described 25 cases of symptomatic vaginal cysts and reported a wide range of symptoms. These included dyspareunia, vaginal pain, difficulty with tampon use, urinary symptoms, and palpable mass. If these cysts become infected and intervention is required during the acute phase, cyst marsupialization is preferred.

Occasionally, a remnant cyst may cause chronic symptoms and warrant excision. Pelvic MR imaging can assist prior to surgery to determine the extent of the cyst and its anatomic relationship to the ureter or bladder base (Hwang, 2009). Of note, complete vaginal cyst excision may be more difficult than anticipated, as some may extend up into the broad ligament and anatomically approximate the distal course of the ureter.

Abnormalities of the uterus may be congenital or acquired and typically present with menstrual dysfunction, pelvic pain, infertility, or pregnancy wastage. Congenital anomalies have a heterogeneous genetic basis, and WT1, Pax2, WNT2, PBX1, and HOX genes are potentially involved (Hutson, 2014).

Various classification schemes for female reproductive tract anomalies exist, but the most commonly used system was proposed by Buttram and Gibbons (1979) and adapted by the American Society for Reproductive Medicine (former American Fertility Society, 1988). Within this system, six categories organize similar embryonic developmental defects (Table 18-4). Acien (2009) and Rock (2010) have described types of uterovaginal and cervical malformations that do not adapt to the usual classification systems. Such anomalies are best described and drawn in detail in a patient’s medical record for future reference.

Most cases are diagnosed during evaluation for obstetric or gynecologic problems, but in the absence of symptoms, most anomalies remain undiagnosed. Because nearly 57 percent of women with uterine defects have successful fertility and pregnancy, the true incidence of congenital müllerian defects may be significantly understated. Nahum (1998) found that the prevalence of uterine anomalies in the general population was 1 in 201 women or 0.5 percent. Dreisler and colleagues (2014) found uterine anomalies in nearly 10 percent of 622 women from the general population undergoing saline infusion sonography.

Anatomic uterine defects have long been recognized as a cause of obstetric complications. Recurrent pregnancy loss, preterm labor, abnormal fetal presentation, and prematurity constitute the major reproductive problems encountered. Cunningham and colleagues (2014a) provide a full discussion of specific müllerian abnormalities and their obstetric importance. Müllerian defects are also associated with renal anomalies in 30 to 50 percent of cases, and defects include unilateral renal agenesis, severe renal hypoplasia, horseshoe kidney, pelvic kidney, and ectopic or duplicate ureters (Sharara, 1998). Spinal anomalies have been reported in 10 to 12 percent of cases and include wedge, supernumerary, or asymmetric and rudimentary vertebral bodies (Kimberley, 2011). The combination of müllerian and renal aplasia and cervicothoracic somite dysplasia has been described as MURCS association (Duncan, 1979). An association with Klippel-Feil syndrome has also been reported. Other anomalies associated with vaginal agenesis include ear anomalies and hearing loss, with the latter reported to be as high as 25 percent. The pattern of associated anomalies suggests an embryologic link (Kimberley, 2011).

Müllerian anomalies may be discovered during routine pelvic examinations, infertility evaluation, or surgery for other indications. Depending on clinical presentation, diagnostic tools may include hysterosalpingography (HSG), sonography, MR imaging, laparoscopy, and hysteroscopy. Each tool has limitations, but they may be used in combination to completely define anatomy. In women undergoing fertility evaluation, HSG is commonly selected for uterine cavity and tubal patency assessment. That said, HSG poorly defines the external uterine contour and can delineate only patent cavities. In other clinical settings, sonography is initially performed. Transabdominal views may help to maximize the viewing field, but transvaginal sonography (TVS) provides better image resolution. Saline infusion sonography (SIS) improves delineation of the endometrium and internal uterine morphology, but only with a patent endometrial cavity. Three-dimensional (3-D) sonography can provide uterine images from virtually any angle. Thus, coronal images can be constructed and are essential in evaluating both internal and external uterine contours. Sonography is ideally completed during the luteal phase when the secretory endometrium provides contrast from increased thickness and echogenicity (Caliskan, 2010). Several investigators have reported good concordance between 3-D TVS and MR imaging of müllerian anomalies, but MR imaging is currently preferred for imaging complex defects (Bermejo, 2010; Ghi, 2009). MR imaging provides clear delineation of both the internal and external uterine anatomy and has a reported accuracy of up to 100 percent in the evaluation of müllerian anomalies (Fedele, 1989; Pellerito, 1992). Moreover, complex anomalies and commonly associated secondary diagnoses such as renal or skeletal anomalies can be concurrently evaluated. In some women undergoing an infertility evaluation, hysteroscopy and laparoscopy may be selected to assess for müllerian anomalies; screen for endometriosis, which is often coexistent; and exclude other tubal or uterine cavity pathologies (Puscheck, 2008; Saravelos, 2008).

Segmental Müllerian Hypoplasia or Agenesis

Some form of müllerian aplasia, hypoplasia, or agenesis affects 1 in every 4000 to 10,000 females and is a common cause of primary amenorrhea (American College of Obstetricians and Gynecologists, 2009). Uterine agenesis follows failed development of the lower portion of the müllerian ducts during embryogenesis and usually leads to absence of the uterus, ­cervix, and upper part of the vagina (Oppelt, 2006). Variants may display absence of the upper vagina but presence of the uterus. Normal ovaries are found, and affected individuals otherwise develop as phenotypically normal females and present with primary amenorrhea.

Vaginal Atresia

Females with vaginal atresia lack the lower portion of the vagina, but otherwise have normal pubertal maturation and external genitalia (Fig. 18-11). Embryologically, the urogenital sinus fails to contribute its expected caudal portion of the vagina (Simpson, 1999). As a result, the lower portion of the vagina, usually one-fifth to one-third of the total length, is replaced by 2 to 3 cm of fibrous tissue. In some individuals, however, vaginal atresia may extend to near the cervix.

Since most affected women have normal external genitalia and upper reproductive tract organs, vaginal atresia does not often become apparent until menarche. Adolescents generally present shortly after physiologic menarche with cyclic pelvic pain due to hematocolpos or hematometra. On physical examination, the hymeneal ring is normal. But proximal to the ring, only a vaginal dimple or small pouch is found. A rectoabdominal examination confirms midline organs. Additionally, sonographic or MR imaging will display upper reproductive tract organs. Of these, MR imaging is the most accurate diagnostic tool, as the length of the atresia, the amount of upper vaginal dilatation, and the presence of the cervix can be identified. Presence of the cervix in such cases distinguishes vaginal atresia from müllerian agenesis. Laparoscopy, however, is often necessary when anatomy cannot be fully evaluated with radiographic studies. Treatment follows that for müllerian agenesis.

Cervical Agenesis

Because of the common müllerian source, women with congenital absence of the cervix typically also lack the upper vagina. The uterus, however, usually develops normally (see Fig. 18-11). In addition to agenesis, Rock (2010) has described various forms of cervical dysgenesis.

Women with cervical agenesis initially present similarly to patients with other reproductive tract obstructive anomalies, that is, with primary amenorrhea and cyclic abdominal or pelvic pain. If a functional endometrium is present, a patient may have a distended uterus, and endometriosis may have developed secondary to retrograde menstrual flow. A single midline uterine fundus is the norm, although bilateral hemiuteri have also been described (Dillon, 1979).

Radiographic studies, sonography, and MR imaging aid anatomy delineation. If imaging demonstrates an obstructed uterus, hysterectomy has been recommended by some (Rock, 1984). In contrast, Niver (1980) and others report creation of an epithelialized endocervical tract and vagina. Significant morbidity, including infection, recurrent obstruction requiring hysterectomy, and death due to sepsis, however, has been reported with establishment of such a vaginal-uterine connection (Casey, 1997; Rock, 2010). Alternatively, conservative management with GnRH antagonists or agonists or with combination oral contraceptive pills may be used to suppress retrograde menses and possible endometriosis until a patient is ready for reproduction options (Doyle, 2009). Thus, the uterus may be retained for possible reproductive potential. Thijssen and associates (1990) reported a successful pregnancy using zygote intrafallopian tube transfer in a patient with cervical agenesis. Gestational surrogacy offers another viable option for these women.

Müllerian Agenesis

Congenital absence of both the uterus and vagina is termed müllerian aplasia, müllerian agenesis, or Mayer-Rokitansky-Küster-Hauser syndrome (MRKHS). In classic müllerian agenesis, patients have a shallow vaginal pouch, measuring only 1 to 2 inches deep. In addition, the uterus, cervix, and upper part of the vagina are absent. Typically, normal ovaries persist, given their separate embryonic source, and a portion of the distal fallopian tubes is present. Most patients with müllerian agenesis have only small rudimentary müllerian bulbs without endometrial activity. However, in 2 to 7 percent of women with this condition, active endometrium develops and patients typically present with cyclic abdominal pain (American College of Obstetricians and Gynecologists, 2009). Surgical excision of symptomatic rudimentary bulbs is required. With müllerian agenesis, traditional conception is impossible, but pregnancy may be achieved using oocyte retrieval, fertilization, and gestational surrogacy.

Evaluation for associated congenital renal or other skeletal anomalies is essential in individuals with müllerian hypoplasia or agenesis. As noted, approximately 15 to 36 percent of women with uterine agenesis also have defects of the urinary system, and 12 percent may have scoliosis. Skeletal malformations observed include spina bifida, sacralization (partial fusion of L5 to the sacrum), sacral bone lumbarization (nonfusion of the first and second sacral segments), and cervical vertebral anomalies. As noted earlier, MURCS syndrome displays müllerian duct aplasia, renal aplasia, and cervicothoracic somite dysplasia (Oppelt, 2006). Cardiac malformations and neurologic disturbances play a lesser role and include ventricular septal defects and unilateral hearing problems. Fifty to 60 percent of women with müllerian agenesis have secondary malformations and thus are regarded as having a complex multiorgan and multisystem syndrome.

Treatment

One treatment goal for most of these women is creation of a functional vagina. This may be accomplished conservatively or surgically. There are several conservative approaches, and each attempts to progressively invaginate the vaginal dimple to create a canal of adequate size. Graduated hard glass dilators were initially recommended by Frank (1938). Ingram (1981) modified the Frank method by affixing the dilators to a bicycle seat mounted upon a stool. This affords patients hand mobility for other activities during the 30 minutes to 2 hours spent each day for passive dilation (American College of Obstetricians and Gynecologists, 2009). Currently, firm silicon dilators are available through several medical vendors. A vagina may also be created with repeated coitus. Overall, vaginal dilatation techniques are successful in forming a functional vagina in as many as 90 percent of cases (Croak, 2003; Roberts, 2001).

Surgical procedures are seen by many as a more immediate solution to creation of a neovagina, and several methods have been reported. The method used most commonly by gynecologists is the McIndoe vaginoplasty (McIndoe, 1950). As illustrated in Section 43-25, a canal is created within the connective tissue between the bladder and rectum. A split-thickness skin graft obtained from the patient’s buttocks or thigh is then used to line the neovagina.

Modifications of the McIndoe procedure include substitution of buccal mucosa, human amnion, or absorbable adhesion barriers as the neovaginal lining (Ashworth, 1986; Lin, 2003; Motoyama, 2003). Similarly, cutaneous or musculocutaneous flaps have been employed to line the neovagina (Williams, 1964). Also, the Davydov procedure pulls pelvic peritoneum from the pelvis into the newly created vaginal space and then to the introitus. However, bladder and ureteric injuries and vesicovaginal fistula are potential complications (Davydov, 1969).

All of these methods require a commitment to scheduled postoperative dilatation to avoid significant vaginal stricture (Breech, 1999). Accordingly, these procedures should be considered only if the patient is mature and willing to adhere to a postoperative regimen of regular intercourse or manual dilatation with dilators.

To avoid these postoperative requirements, pediatric surgeons more frequently use a segment of bowel to create the vagina. These colpoplasties most commonly use sigmoidal or ileal segments and require abdominal entry and bowel anastomosis. Many patients complain of a persistent vaginal discharge from the gastrointestinal mucosa. Kapoor (2006) reported on 14 such sigmoid vaginoplasties and noted good cosmetic results and no cases of colitis, stenosis, or excessive mucus.

Alternatively, the Vecchietti procedure uses an initial abdominal surgery to create an apparatus for passive vaginal dilatation. A synthetic sphere, attached to two wires, is placed in the vagina dimple. The wires are guided through the potential neovaginal space and into the peritoneal cavity, and then exit onto the anterior abdominal wall. The wires are placed on continuous tension, which is increased daily to stretch the blind vaginal pouch (Vecchietti, 1965).

To address uterine agenesis, uterine transplantation from a deceased donor has been described and entailed uterine harvest and revascularization. The donor uterus was supplied by its uterine and internal iliac vessels, which were anastomosed to the recipient’s external iliac vessels (Ozkan, 2013). This patient with MRKH syndrome resumed menses, conceived following in vitro fertilization, but failed to sustain the gestation (Erman Akar, 2013). More work is likely to come in this area of research.

Unicornuate Uterus

Failure of one müllerian duct to develop and elongate results in a unicornuate uterus. This anomaly is common, and Zanetti (1978) found an incidence of 14 percent in a series of 1160 uterine anomalies. With unicornuate uterus, a functional uterus, normal cervix, and normal round ligament and fallopian tube are found on one side. On the contralateral side, müllerian structures develop abnormally, and agenesis or more frequently a rudimentary uterine horn is identified. A rudimentary horn may communicate or more commonly not communicate with the unicornuate uterus. In addition, the endometrial cavity of the rudimentary horn may be obliterated or may contain some functioning endometrium. Active endometrium in a noncommunicating horn will eventually be symptomatic with cyclic unilateral pain and possibly with hematometra.

Women with a unicornuate uterus have an increased incidence of infertility, endometriosis, and dysmenorrhea (Fedele, 1987, 1994; Heinonen, 1983). On physical examination, the uterus is often markedly deviated, but imaging is frequently needed to further define horn anatomy. In addition, renal sonography is performed, as 40 percent of women with a unicornuate uterus also have some degree of renal agenesis, usually ipsilateral to the anomalous side (Rackow, 2007). If anatomy is unclear, then MR imaging is selected to add information.

Women with unicornuate uterus have impaired pregnancy outcomes. A review of studies reveals a spontaneous abortion rate of 36 percent, a preterm delivery rate of 16 percent, and a live birth rate of 54 percent (Rackow, 2007). Other obstetric risks include malpresentation, fetal-growth restriction, fetal demise, and prematurely ruptured membranes (Chan, 2011; Reichman, 2009).

The pathogenesis of pregnancy loss associated with unicornuate uterus is incompletely understood, but reduced uterine capacity or anomalous distribution of the uterine artery has been suggested (Burchell, 1978). Moreover, cervical incompetence may contribute to the risk for premature delivery and second-trimester abortion. Accordingly, a unicornuate uterus is suspected in any woman with a history of pregnancy loss, premature delivery, or abnormal fetal lie.

No surgeries are currently available to enlarge the unicornuate uterus cavity. Some obstetricians recommend prophylactic cervical cerclage, but adequate trials assessing outcome are lacking. Selection of a gestational surrogate may circumvent these anatomic limitations. Other patients, however, seem to carry their pregnancies longer with each subsequent gestation and may eventually reach fetal viability prior to labor.

Pregnancy may also occur in the rudimentary horn. In noncommunicating horns, this is thought to result from the intraabdominal transit of sperm from the contralateral fallopian tube. Pregnancy in a cavitary horn regardless of communication is associated with a high rate of uterine rupture, typically prior to 20 weeks (Rolen, 1966). Because of the high maternal morbidity secondary to intraperitoneal hemorrhage, preconceptional excision of a cavitary rudimentary horn is reasonable (Heinonen, 1997; Nahum, 2002). With a rudimentary horn pregnancy, excision is indicated. Lapa­rotomy is typical, but laparoscopy is feasible with suitable skills and well-selected cases (Kadan, 2008; Spitzer, 2009).

If the rudimentary horn is obliterated, removal is not routinely recommended. Salpingectomy or salpingo-oophorectomy on the side with the rudimentary horn, however, has been suggested to prevent ectopic pregnancy in women with a unicornuate uterus, although the ectopic pregnancy risk is low.

Uterine Didelphys

A didelphic uterus results from failed fusion of the paired müllerian ducts. This anomaly is characterized by two separated uterine horns, each with an endometrial cavity and uterine cervix. A longitudinal vaginal septum runs between the two cervices in most cases. Heinonen (1984) reported that all 26 women with uterine didelphys in his series had a longitudinal vaginal septum. Occasionally, one hemivagina is obstructed by an oblique or transverse vaginal septum (see Fig. 18-10) (Hinckley, 2003).

Uterine didelphys should be suspected if a longitudinal vaginal septum or if two separate cervices are discovered. Imaging is recommended to confirm the diagnosis as outlined on page 418.

Pregnancies develop in one of the two horns, and of the major uterine malformations, the didelphic uterus has a good reproductive prognosis. Compared with the unicornuate uterus, although the potential for uterine growth and capacity appears similar, uterine didelphys probably has an improved blood supply from collateral connections between the two horns. Alternatively, improved fetal survival may be secondary to earlier diagnosis, which favors earlier and more intensive prenatal care (Patton, 1994). Heinonen (2000) followed 36 women with uterus didelphys long term and found that 34 of 36 women (94 percent) who wanted to conceive had at least one pregnancy, and they produced 71 pregnancies. Of these pregnancies, 21 percent were spontaneously aborted, and 2 percent were ectopic. The rate for fetal survival was 75 percent; for prematurity, 24 percent; for fetal-growth restriction, 11 percent; for perinatal mortality, 5 percent; and for cesarean delivery, 84 percent. In this series, pregnancy located more often (76 percent) in the right horn than in the left. Because the spontaneous abortion rate mirrors that of women with normal uterine cavities, surgical procedures in response to pregnancy loss are rarely indicated. Thus, surgery should be reserved and only considered for highly selected patients in whom repeated late-trimester losses or premature delivery has occurred with no other apparent etiology.

Bicornuate Uterus

This anomaly is caused by incomplete fusion of the müllerian ducts. It is characterized by two separate but communicating endometrial cavities and a single uterine cervix. Failed fusion may extend to the cervix, resulting in a complete bicornuate uterus, or may be partial, causing a milder abnormality. Women with a bicornuate uterus can expect reasonable success—approximately 60 percent—in delivering a living child. As with many uterine anomalies, premature delivery is a substantial obstetric risk. Heinonen and colleagues (1982) reported a 28-percent abortion rate and a 20-percent incidence of premature labor in women with a partial bicornuate uterus. Women with a complete bicornuate uterus had a 66-percent incidence of preterm delivery and a lower fetal survival rate.

Radiologic discrimination of bicornuate uterus from the septate uterus can be challenging, however, it is important because septate uterus is easily treated with hysteroscopic septal resection. Widely diverging horns seen on HSG may suggest a bicornuate uterus. An intercornual angle >105 degrees suggests bicornuate uterus, whereas one <75 degrees indicates a septate uterus. However, MR imaging is necessary to define fundal contour. With this, an intrafundal downward cleft measuring ≥1 cm is indicative of bicornuate uterus, whereas a cleft depth <1 cm indicates a septate uterus. Use of 3-D sonography also allows internal and external uterine assessment. Thus, sonography and HSG seem acceptable imaging techniques in the initial investigation. When the presumptive diagnosis is a septate uterus, laparoscopy may be performed for a definitive diagnosis and before hysteroscopic resection of the septum is initiated.

Surgical reconstruction of the bicornuate uterus is infrequently done but has been advocated in women with multiple spontaneous abortions in whom no other causative factors are identified. Strassman (1952) described the surgical technique that unified equal-sized endometrial cavities (Fig. 18-12). Reproductive outcome after unification generally has been good. In 289 women, preoperative pregnancy loss was more than 70 percent. Following surgery, more than 85 percent of pregnancies resulted in delivery of a viable infant. The actual benefit of metroplasty for a bicornuate uterus, however, has not been tested in a controlled clinical series. As in surgery for uterine didelphys, metroplasty is reserved for women in whom recurrent pregnancy loss occurs with no other identifiable cause.

Septate Uterus

Following fusion of the müllerian ducts, failure of their medial segments to regress can create a permanent septum within the uterine cavity. Its contours can vary widely and depend on the amount of persistent midline tissue. The septum can project minimally from the uterine fundus or can extend completely to the cervical os. Moreover, septa can develop segmentally, resulting in partial communications of the partitioned uterus (Patton, 1994). The histologic structure of septa ranges from fibrous to fibromuscular.

The true incidence of these anomalies is not known because they are usually detected only in women with obstetric complications. Although this defect does not predispose to increase rates of preterm labor or cesarean delivery, septate uterus is associated with a marked increase in spontaneous abortion rates (Heinonen, 2006). Woelfer and associates (2001) reported a first-trimester spontaneous abortion rate for septate uterus of 42 percent. Moreover, early pregnancy loss is significantly more common with a septate than with a bicornuate uterus (Proctor, 2003).

This extraordinarily high pregnancy wastage likely results from partial or complete implantation on a largely avascular septum, from distortion of the uterine cavity, and from associated cervical or endometrial abnormalities. Based on operative experience for septal defects, the blood supply to the fibromuscular septum appears markedly reduced compared with normal myometrium. In addition to spontaneous abortion, septate uterus may rarely cause fetal malformation, and Heinonen (1999) described three newborns with a limb-reduction defect born to women with septate uterus.

Diagnosis of the septate uterus follows guidelines established for the bicornuate uterus and includes HSG and/or sonography. Historically, abdominal metroplasty for septate uterus was shown to dramatically decrease fetal wastage and ultimately improve fetal survival rates (Rock, 1977; Blum, 1977). Two main disadvantages to metroplasty include the requirement of cesarean delivery to prevent uterine rupture in subsequent pregnancy and the high rate of postoperative pelvic adhesion formation and subsequent infertility.

Currently, hysteroscopic septum resection is an effective and safe alternative to treat women with septate uterus (Section 44-17). Typically, operative hysteroscopy is combined with concurrent laparoscopic surveillance to reduce the risk of uterine perforation. After the initial case reports by Chervenak and Neuwirth (1981), many investigators have confirmed satisfactory live birth rates with the procedure (Daly, 1983; DeCherney, 1983; Israel, 1984). In a retrospective review, Fayez (1986) evaluated reproductive outcome in women who had either an abdominal metroplasty or hysteroscopic septoplasty. They noted an 87-percent live birth rate in the hysteroscopic group compared with a 70-percent rate in the abdominal group. Similarly, Daly and associates (1989) reported impressive results after hysteroscopic surgery. Proponents of hysteroscopic resection describe reduced rates of pelvic adhesions, shortened postoperative convalescence, lowered operative morbidity, and avoidance of mandatory cesarean delivery (Patton, 1994).

Arcuate Uterus

An arcuate uterus displays only mild deviation from normal uterine development. Anatomic hallmarks include a slight midline septum within a broad fundus, sometimes with minimal fundal cavity indentation. Most clinicians report no impact on reproductive outcomes. Conversely, Woelfer and colleagues (2001) found excessive second-trimester losses and preterm labor. Surgical resection is indicated only if excessive rates of pregnancy loss are encountered and other etiologies for recurrent spontaneous abortion have been excluded.

Diethylstilbestrol-Induced Reproductive Tract Abnormalities

Diethylstilbestrol (DES), a synthetic nonsteroidal estrogen, was prescribed to an estimated 3 million pregnant women in the United States from the late 1940s through the early 1960s. Early reports claimed the drug was useful in treating abortion, preeclampsia, diabetes, hot flushes, and preterm labor (Massé, 2009). It was ineffective for these indications. Almost 20 years later, Herbst and coworkers (1971) found that DES exposure in utero was linked to the development of a “T-shaped” uterus and an increased incidence of clear cell adenocarcinomas of the vagina and cervix. The risk of this vaginal malignancy approximates 1 in 1000 exposed daughters. Daughters also have increased risks of developing vaginal and cervical intraepithelial neoplasia, suggesting that DES exposure could affect gene regulation (Herbst, 2000). DES has also been shown to suppress the WNT4 gene and alter Hox gene expression in mouse müllerian ducts. This provides a plausible molecular mechanism for the uterine abnormalities, vaginal adenosis, and rarely, carcinoma observed in exposed patients (Massé, 2009).

During normal development, the vagina is originally lined by a glandular epithelium derived from the müllerian ducts. By the end of the second trimester, this layer is replaced by squamous epithelium extending up from the urogenital sinus. Failure of the squamous epithelium to completely line the vagina is termed adenosis. Although variable, it typically appears red, punctate, and granular. Common symptoms include vaginal irritation, discharge, and metrorrhagia—in particular, postcoital bleeding. Moreover, adenosis is frequently associated with vaginal clear cell adenocarcinoma.

Genitourinary malformations following DES exposure in utero have also been noted and include those of the cervix, vagina, uterine cavity, and fallopian tubes. Transverse septa, circumferential ridges involving the vagina and cervix, and cervical collars (“cockscomb cervix”) have been found. Women with cervicovaginal abnormalities are more likely to have uterine anomalies, such as smaller uterine cavities, shortened upper uterine segments, and “T-shaped” and irregular cavities (Barranger, 2002). Fallopian tube abnormalities include shortened and narrowed dimensions and absent fimbria.

Males exposed to DES in utero also have structural abnormalities. Cryptorchidism, testicular hypoplasia, microphallus, and hypospadias have been reported (Hernandez-Diaz, 2002).

Women exposed to DES, in general, have impaired conception rates (Senekjian, 1988). Reduced fertility in these women is poorly understood but is associated with cervical hypoplasia and atresia. Of those who do conceive, the incidences of spontaneous pregnancy loss, ectopic pregnancy, and preterm delivery are increased, again particularly in those with associated structural abnormalities (Goldberg, 1999). Now, more than 50 years after DES use was proscribed, most affected women are past childbearing age, but higher rates of earlier menopause and breast cancer have been reported (Hatch, 2006; Hoover, 2011).

The fallopian tubes develop from the unpaired cephalad ends of the müllerian ducts. Congenital anomalies of the fallopian tube include accessory ostia, complete or segmental absence of the fallopian tube, and several embryonic cystic remnants. The remnants of the mesonephric duct in the female include a few blind tubules, the epoophoron, in the mesovarium, and similar ones, collectively called the paroophoron, adjacent to the uterus (see Fig. 18-2F) (Moore, 2013). The epoophoron or paroophoron may develop into clinically identifiable cysts. Remnants of the müllerian duct may be found along its embryologic course. The most common is a small, blind cystic structure attached by a pedicle to the distal end of the fallopian tube, the hydatid of Morgagni (Zheng, 2009).

Paratubal cysts are frequent incidental discoveries during gynecologic operations for other abnormalities or are found on sonographic examination (Chap. 9). They may be of mesonephric, paramesonephric, or mesothelial origin. Most cysts are asymptomatic and slow growing and are discovered during the third and fourth decades of life.

In utero exposure to DES has been associated with various tubal abnormalities. Short, tortuous tubes or ones with shriveled fimbria and small ostia have been linked to infertility (DeCherney, 1981).

A supernumerary ovary is an ectopic ovary that has no connection with the broad, uteroovarian, or infundibulopelvic ligaments (Wharton, 1959). This rare gynecologic anomaly may be located in the pelvis, retroperitoneum, paraaortic area, colonic mesentery, or omentum. Aberrant migration of part of the genital ridge after incorporation of germ cells describes one theory (Printz, 1973).

In contrast, the term accessory ovary describes excess ovarian tissue nearby and connected to a normally placed ovary. Wharton (1959) estimated that both accessory ovary and supernumerary ovary were rare, finding approximately 1 case of accessory ovary in 93,000 patients and 1 case of supernumerary ovary in 29,000 autopsies. In Wharton’s review, 3 of 4 patients with supernumerary ovary and 5 of 19 patients with accessory ovary had additional congenital defects, most frequently involving the genitourinary tract.

An absent ovary, with or without an associated tube, may result from congenital agenesis or from ovarian torsion with necrosis and reabsorption (Eustace, 1992; James, 1970). The incidence has been suggested to be approximately 1 in 11,240 women (Sivanesaratnam, 1986).