Key points
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Gender identification in a newborn infant has emotional and psychological implications and should be performed as accurately as possible. However, in the setting of ambiguous genitalia, gender assignment should not be considered without definitive testing and multidisciplinary participation.
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Congenital adrenal hyperplasia is an autosomal recessive condition, most commonly the result of an inborn error of metabolism involving the enzyme 21-hydroxylase. Homozygous individuals account for 1 of every 490 to 67,000 births, averaging 1 in 14,000, and are at risk of moderate to severe manifestations. Approximately 1 in 20 to 1 in 250 individuals are heterozygotes (carriers), and they can have a more mild presentation. Differences in incidence depend on the ethnic background of the population tested.
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Vaginal agenesis is most often associated with Mayer-Rokitansky-Küster-Hauser syndrome, also known as müllerian agenesis. Up to 50% of these women have urologic abnormalities, and approximately one in eight have skeletal abnormalities as well.
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Approximately 15% of women with a history of first-trimester recurrent miscarriage and 25% of those with a second-trimester miscarriage may have a uterine anomaly.
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The uterine septum is the only uterine anomaly that can be easily corrected with a surgical procedure. In women with poor reproductive outcomes, surgery can normalize their chances of miscarriage and live birth.
Congenital abnormalities of the female reproductive tract are common and can affect the external genitalia and müllerian structures. These abnormalities can be caused by genetic errors or by teratogenic events during embryonic development . Minor abnormalities may be of little consequence, but major abnormalities may lead to severe impairment of menstrual and reproductive functions and can be associated with anomalies of the urinary tract. This chapter reviews a number of such abnormalities and discusses diagnosis and treatment. Anomalies can present at varying times in a woman’s life—at birth, before puberty, with the onset of menses, and during a pregnancy with adverse pregnancy outcomes—but many women with congenital anomalies of the reproductive tract are asymptomatic . Based on large studies, the incidence of müllerian anomalies is considered to be 1% to 3% ( ), and the prevalence of uterine anomalies is suggested to be 5% to 8% ( ). Because of the profound psychological effects such abnormalities can have, the gynecologist must approach the problems of genital and müllerian anomalies with sensitivity and an understanding of the effects on the woman and her family. Most tertiary centers have a diverse multidisciplinary team available for the evaluation, treatment, and support of the patient with a serious disorder of sexual development.
Ambiguous genitalia
After delivery, the obstetrician is often the provider who identifies the gender of the neonate. Thereafter, a more detailed assessment of the neonate’s genital anatomy is necessary. The physician should systematically observe the newborn’s perineum, beginning with the mons pubis. The clitoris should be examined for any obvious enlargement, the opening of the urethra should be identified, and the labia should be gently separated to see if the introitus can be visualized. If it is possible to separate the labia, the hymen might be observed. Generally the hymen is perforate, revealing the entrance to the vagina. At times the labia are joined by filmy adhesions, which usually separate during childhood but can be treated with the application of estrogen cream when medically indicated. Posteriorly the labia fuse in the midline at the posterior fourchette of the perineum. Posterior to the perineal body the rectum can be visualized, and it should be tested to be sure that it is perforate. Meconium staining around the rectum is evidence of perforation. If there is doubt, the rectum may be penetrated with a moistened cotton-tipped swab. Palpation of the inguinal area and labia for any masses is also important.
In newborns with ambiguous genitalia, a range of abnormalities involving the clitoris, urethra, labia, and introitus can be identified, and immediate evaluation is necessary. The current diagnostic terminology for individuals with abnormal external genitalia and associated issues is disorder of sexual development (DSD), and these disorders can be related to in utero androgen exposure (too much or too little) that has affected development of the external genitalia. Women (individuals with XX karyotypes) with masculinized or virilized external genitalia are identified as 46,XX DSD, and men (with 46,XY karyotypes) with undervirilized external genitalia are identified as 46,XY DSD ( ). For women, the timing of antenatal (embryonic) exposure to androgen influences the degree of masculinization ( Fig. 11.1 ) ( ). The vaginal plate separates from the urogenital sinus at about 12 weeks of fetal development. Androgen exposure before 12 weeks can result in labioscrotal fusion and retention of the urogenital sinus , which creates a single tract that the urethra and vagina empty into before reaching the perineum. Androgen exposure after 12 weeks primarily presents with clitoral hypertrophy ( ).
The finding of ambiguous genitalia occurs in a wide spectrum of possibilities, from labioscrotal fusion and an enlarged clitoris with a penile urethra to a urogenital sinus to clitoromegaly and a normal introitus. With labial fusion, the physician should palpate the groins and labial folds for evidence of gonads. Gonads palpable in the inguinal canal, labioinguinal region, or labioscrotal folds are usually testes, and this finding is typically seen in a male with ambiguous genitalia rather than a virilized woman. Conversely, an infant with ambiguous genitalia but without palpable testes in the scrotum is more likely to be a virilized woman, most often the result of congenital adrenal hyperplasia. A rectal examination may allow palpation of a cervix and uterus, thus helping with gender assignment. If a bifid clitoris and labial fusion are noted, this anomaly is usually associated with extrophy of the bladder. As with any congenital anomaly, the neonate should be thoroughly evaluated for other congenital anomalies.
The initial evaluation of ambiguous genitalia involves checking a karyotype, performing a transabdominal pelvic ultrasound to assess pelvic anatomy, and obtaining blood for serum electrolytes and steroid hormone levels . In a female neonate an ultrasound can easily identify a uterus because the estrogenized tissue is easy to visualize. If further evaluation of neonatal pelvic anatomy is necessary, cystoscopy and vaginoscopy can be performed with a pediatric cystoscope to assess the pelvic structures, including the location of the urethra and vagina and the presence of a cervix. Possible causes of 46,XX DSD include congenital adrenal hyperplasia, other genetic mutations that affect the steroid pathway, maternal ingestion of androgens, and maternal production of excess androgens ( Box 11.1 ) ( ).
I. Androgen-induced
A. Fetal source
- 1.
Congenital adrenal hyperplasia
- a.
Virilism only, defective adrenal 21-hydroxylation (CYP21)
- b.
Virilism with salt-losing syndrome, defective adrenal 21-hydroxylation (CYP21)
- c.
Virilism with hypertension, defective adrenal 11β-hydroxylation (CYP11B1)
- d.
Virilism with adrenal insufficiency, deficient 3β-HSD 2 (HSD3B 2)
- a.
- 2.
P450 aromatase (CYP19) deficiency
- 3.
Glucocorticoid receptor gene mutation
B. Maternal source
- 1.
Iatrogenic
- a.
Testosterone and related steroids
- b.
Certain synthetic oral progestogens and, rarely, diethylstilbestrol
- a.
- 2.
Virilizing ovarian or adrenal tumor
- 3.
Virilizing luteoma of pregnancy
- 4.
Congenital virilizing adrenal hyperplasia in mother *
* In pregnant patient whose disease is poorly controlled or who is noncompliant, especially during the first trimester.
C. Undetermined source
- 1.
Virilizing luteoma of pregnancy
II. Non–androgen-induced disturbances in differentiation of urogenital structures
It is important to systematically evaluate the newborn’s genitalia to make the appropriate gender assignment when possible. In the past, gender was assigned primarily on the principle of “phallic adequacy,” meaning neonates with an ambiguous phallus were assigned female gender. In contrast, the current approach is to initiate a thorough evaluation of the neonate and to defer gender assignment until the clinical picture is clear . Most tertiary centers use a multidisciplinary team for the evaluation and management of an individual with DSD, including specialists in medical genetics, pediatric urology, pediatric endocrinology, gynecology, and psychiatry ( ).
Perineal and hymenal anomalies
Clitoral anomalies
In an adult woman the clitoris is generally 1 to 1.5 cm long and 0.5 cm wide in the nonerect state. The glans is partially covered by a hood of skin, and the urethra opens near the base of the clitoris. Abnormalities of the clitoris are unusual, although it may be enlarged as a result of androgen stimulation. In such circumstances the shaft of the clitoris may be quite enlarged and partial development of a penile urethra may have occurred ( Fig. 11.2 ) ( ). Extreme cases of androgen stimulation are generally associated with fusion of the labia. These findings occur in infants with congenital adrenal hyperplasia and in those with in utero exposure to exogenous or endogenous androgens ( Fig. 11.3 ) ( ). Similar in appearance to infants with congenital adrenal hyperplasia, men with partial androgen insensitivity syndrome have underdeveloped male external genitalia and a small phallus that appears as clitoral hypertrophy ( Fig. 11.4 ) ( ).
A bifid clitoris ( Fig. 11.5 ) is usually seen in association with extrophy of the bladder, which occurs rarely (1 per 30,000 births) and has a male predominance (3:1). However, when it occurs in women, it is often associated with a bifid clitoris. Approximately half of female patients with bladder extrophy may have associated reproductive tract anomalies such as vaginal anomalies and müllerian duct fusion disorders. In such cases an anterior rotation and a shortening of the vagina with labial fusion are quite common.
Labial fusion
Labial fusion may occur without clitoromegaly. The resultant ambiguous genitalia implies a form of DSD. The diagnoses 46,XX DSD and 46,XY DSD apply to individuals with a pure XX or XY karyotype but with the external genitalia of the opposite sex of the karyotype or ambiguous genitalia. The term hermaphrodite was derived from the child of the Greek gods Hermes and Aphrodite, Hermaphroditus, who was part female and part male. It is no longer used. True hermaphroditism is now called ovotesticular DSD ; a person with this condition has both ovarian (including follicular elements) and testicular tissue, either in the same or opposite gonads . Ovotesticular DSD is extremely rare in North and South America but more common (though still very rare) in Africa.
Ovotestes are present in individuals with ovaries that usually have both an SRY antigen and testicular tissue present . The degree to which müllerian and wolffian development occurs depends on the amounts of testicular tissue present in the ovotestes and the proximity to the developing duct system. When considerable amounts of testicular tissue are present within the organ, there is a tendency for descent toward the labial/scrotal area. Thus palpation of the gonad in the inguinal canal or within the labial scrotal area is fairly common. Ovulation and menstruation may occur if the müllerian system is appropriately developed. In a similar fashion, spermatogenesis may occur as well. When testicular tissue is present, there is an increased risk for malignant degeneration, and these gonads should be removed after puberty . Germ cell tumors, such as gonadoblastomas and dysgerminomas, have been reported in the ovarian portion of ovotestes.
Congenital adrenal hyperplasia
Although labial fusion may result from exposure to exogenous androgens or be associated with defects of the anterior abdominal wall, by far the most common cause is congenital adrenal hyperplasia. The most common form of congenital adrenal hyperplasia results from an inborn error of metabolism involving deficiency of the 21-hydroxylase enzyme ( Fig. 11.6 ). This condition is transmitted as an autosomal recessive gene coded on chromosome 6, and both severe and mild gene mutations have been identified. With the severe mutation, because of the absence of the 21-hydroxylase enzyme, the major biosynthetic pathway to cortisol is blocked; instead, 17-OH-progesterone is produced and then converted to the androgen androstenedione. The fetal hypothalamic-pituitary axis senses inadequate levels of cortisol and secretes excess adrenocorticotropic hormone (ACTH), which leads to increasing levels of androstenedione from the female adrenal gland and subsequent masculinization of the external genitalia. Homozygous individuals occur with an incidence as high as 1 per 490, depending on the geographic location and population studied. Screening programs have noted the incidence to be approximately 1 in 14,500 births ( ). Depending on the population, carriers of the gene (heterozygotes) are present in a frequency ranging from 1 per 20 to 1 per 250. Two other less common enzyme defects, also transmittable as autosomal recessive traits, may produce similar abnormal findings: the 11-hydroxylase deficiency and the 3b-hydroxysteroid dehydrogenase deficiency . These two enzyme defects and 21-hydroxylase deficiency may cause ambiguous genitalia with masculinized women.
Congenital adrenal hyperplasia (CAH) may be demonstrated at birth by the presence of ambiguous genitalia in 46,XX individuals or may present later in childhood. The majority of newborns (75%) who are homozygous for a CAH mutation are at risk for the development of a life-threatening neonatal adrenal crisis as a result of sodium loss because of lack of aldosterone production . In individuals with a milder disease presentation, delayed diagnosis may result in accelerated bone maturation because of high levels of androgens being aromatized to estradiol, thus leading to premature closure of the epiphyseal plates and short stature. The development of premature secondary sexual characteristics in men and further virilization in women may also occur ( Fig. 11.7 ) ( ). Most U.S. states have mandatory neonatal 17-OH progesterone testing to screen for CAH.
Treatment of congenital adrenal hyperplasia involves cortisol replacement . This suppresses ACTH output, decreasing the stimulation of the cortisol-producing pathways of the adrenal cortex and subsequently decreasing androgen production. For women known to be at risk, those diagnosed with CAH, and those who have had children with CAH, antenatal therapy may be offered, but this remains controversial. After a positive pregnancy test, daily administration of dexamethasone suppresses the fetal adrenal glands until the fetal gender can be verified with prenatal diagnosis. Although this intervention remains an option, it should not be carried out routinely and is still considered experimental by the major societies (e.g., the Endocrine and Pediatric Endocrine Societies). Many female infants exposed to high levels of androgens in utero may need corrective surgery. Children who have had initial corrective surgeries may need follow-up vaginoplasty as teenagers because of vaginal stenosis. Furthermore, because of the profound gender identity issues related to ambiguous genitalia in women with CAH, and also for women with other DSDs, ongoing psychological support and counseling are important . When available, multidisciplinary team support is recommended for the gynecologic, urologic, endocrinologic, and psychological care of these individuals.
Hymenal anomalies
The hymen represents the junction of the sinovaginal bulbs with the urogenital sinus and is composed of endoderm from the urogenital sinus epithelium. The hymen is initially a solid membrane of tissue, and the central cells of the membrane typically dissolve during late fetal development to establish a connection between the lumen of the vaginal canal and the vestibule. If this perforation does not take place, the hymen is imperforate ( ) ( Fig. 11.8 ). The incidence of an imperforate hymen is thought to be approximately 1 in 1000 live-born female infants ( ). Occasionally, a hydrocolpos or mucocolpos may occur in neonates or infants when fluid or vaginal secretions build up behind an imperforate hymen. Although this fluid collection may spontaneously resolve, if it forms a mass that obstructs the urinary tract, then the hymen must be incised to release the obstructing fluid.
Menarche typically occurs within 2 to 3 years from the start of thelarche (breast development), and young women with an imperforate hymen may experience cyclic cramping but no menstrual flow. An imperforate hymen is commonly diagnosed after puberty in the setting of primary amenorrhea, hematocolpos, and possibly hematometra, which can cause pelvic pain, urinary retention, and difficulty with bowel movements . In more advanced cases, because of retrograde menstruation, the menstrual blood may distend the fallopian tubes and form endometrial implants in the peritoneal cavity. Surprisingly, some women have minimal symptoms with this condition.
The diagnosis can be determined by history and physical examination; a bulging membrane with a bluish hue is appreciated at the introitus, and a vaginal mass is palpable on rectal examination. Surgical intervention is necessary to relieve the obstruction of the reproductive tract. Under anesthesia, a cruciate incision is made into the hymen extending from 10 to 4 o’clock and 2 to 8 o’clock. Once the imperforate hymen has been carefully incised and the hematocolpos drained, the excess hymenal tissue is trimmed and hemostasis is achieved with interrupted fine absorbable sutures. The tissue often heals quickly and well, leaving a patent hymen.
Several variations of partial hymenal perforation exist: microperforate, cribriform and septate hymen, and incomplete perforate hymen ( Fig. 11.9 ) ( ). Women with partial hymenal perforation commonly present with difficulty inserting a tampon or difficulty with sexual activity. Occasionally a young woman is able to insert a tampon past the hymen anomaly, but once the tampon expands with blood, it cannot be removed because of the partial hymenal obstruction. Surgical correction may be necessary to remove the excess hymenal tissue and restore normal hymenal anatomy.
Müllerian anomalies
Müllerian anomalies, otherwise known as congenital anomalies of the female reproductive tract, occur as a result of defects in development of the müllerian ducts, which are the embryologic origin of the fallopian tubes, uterus, cervix, and a portion of the vagina. Before reviewing these disorders, it is important to understand the development of the female reproductive tract.
Embryology
Although genetic sex is determined when sperm fertilizes the oocyte, male or female phenotype is not defined until after the sixth week of development . Between the third and fifth weeks of embryologic development, both the wolffian (mesonephric) and müllerian (paramesonephric) ducts are present. The müllerian ducts form from clefts between the mesonephros and the developing gonad. The paired wolffian ducts connect the embryologic kidney (mesonephros) to the cloaca between 5 and 10 weeks of gestation; development of the functional kidney (metanephros) is stimulated by an outgrowth of the wolffian duct known as the ureteric bud. The fate of these various embryonic elements is closely entwined; an insult to or abnormal development of one embryonic element usually affects the others.
The subsequent steps of müllerian duct development are elongation, fusion, canalization, and septal resorption. The müllerian ducts elongate caudally and eventually fuse in the midline as they descend into the pelvis, reaching the urogenital sinus at an elevation known as the müllerian tubercle. At this point the ducts are two solid tubes of tissue that are fused medially; this occurs by 10 weeks’ gestation. Next, central absorption of the cells occurs, leading to two hollow tubes of tissue that remain fused medially. Last, the midline septum between the two tubes of tissue undergoes resorption; this process commonly occurs in a caudal to cephalad direction, leading to a midline unified structure. The inferior portion of the müllerian ducts becomes the upper vagina, followed by the cervix and uterus, and the cephalad unfused portion of the ducts develops into the fallopian tubes. This process is completed by week 20 of embryologic development . Although this is the common theory of müllerian duct development, based on the variety of anomalies that arise from this process, many variations can occur.
The vagina develops from both müllerian duct tissue and the urogenital sinus. Once the müllerian ducts reach the urogenital sinus at approximately 10 weeks’ gestation, cells proliferate from the upper portion of the urogenital sinus to form solid aggregates known as the sinovaginal bulbs. These cell masses develop into a cord, the vaginal plate, which extends from the müllerian ducts to the urogenital sinus. This plate canalizes, starting at the hymen, which is where the sinovaginal bulb attaches to the urogenital sinus, and proceeding cranially to the developing cervix, which by this time has already canalized. The process is completed by 20 weeks’ gestation.
As previously mentioned, abnormalities in any or multiple parts of müllerian and urogenital sinus development can occur and lead to a constellation of structural defects of the female reproductive tract. Anomalies in müllerian duct elongation, fusion, canalization, and septal resorption have been identified, as have anomalies in vaginal plate resorption. Common müllerian anomalies are discussed in the next few sections.
Anomalies of müllerian duct development
Müllerian anomalies are commonly classified into three categories of disordered duct development: agenesis and hypoplasia, lateral fusion defects, and vertical fusion defects. Reproductive tract abnormalities caused by in utero exposure to diethylstilbestrol (DES), a synthetic estrogen that has not been used for several decades, constitute a fourth group of anomalies. Agenesis and hypoplasia can occur for a portion of or an entire müllerian duct or for both ducts, affecting one or multiple müllerian-derived structures. Lateral fusion defects are the most common category of müllerian defects and originate from failure of migration of one or both ducts, midline fusion of the ducts, or absorption of the midline septum between the ducts. A range of anomalies can occur, including symmetric or asymmetric and nonobstructed or obstructed müllerian structures. Vertical fusion defects occur as a result of disordered fusion of the müllerian ducts with the urogenital sinus or abnormal vaginal canalization, and they may present with menstrual flow obstruction. The next sections discuss specific abnormalities of müllerian duct development.
Vaginal agenesis
Vaginal agenesis, also called müllerian agenesis or müllerian aplasia, occurs as a result of failure of müllerian duct development or marked aberrations in the typical steps of müllerian development. This condition is also known as the Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome, named after the four physicians who discovered the syndrome ( Fig. 11.10 ) ( ). Vaginal agenesis is characterized by a congenital abnormality of the vagina, ranging from an absent vagina to a shortened one, and variable development of the uterus; 7% to 10% of women with vaginal agenesis have rudimentary uterine tissue present ( ). The syndrome occurs in approximately 1 in 5000 women . These individuals have normal pubertal development, normal ovarian function, and a 46,XX karyotype, and they commonly present with primary amenorrhea at age 15 to 16 years. The cause of this disorder is currently unknown, but research into possible genetic disorders leading to MRKH syndrome is ongoing.
