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