Abnormalities Of Female Sexual Differentiation and Development
Structural anomalies of the uterus, cervix and vagina are the most common abnormalities of sexual differentiation seen in women. They arise from embryologic abnormalities of Müllerian system development (Chapters 5 and 6). The most severe form involves complete absence of the reproductive tract, including the vagina, uterus and fallopian tubes. Such agenesis of the Müllerian system is known as Mayer–Rokitansky–Kuster–Hauser syndrome, and is the second most common cause of primary amenorrhea (Chapter 30).
The remainder of the anomalies result from failure of the Müllerian system to fuse in the midline or to remodel in the midline after fusion to form a single uterine cavity (Fig. 27.1). The most dramatic form of fusion anomalies occurs when the Müllerian ducts fail to fuse along their entire length, resulting in the formation of two vaginas, two cervices and two separate uterine horns (double uterus or uterus didelphys). More commonly, only the upper portion of the uterus fails to fuse. The uterine body may then remain separated as two horns (bicornuate uterus or uterus bicornus) or, in milder cases, a dimple may be noted in the contour of the uterine fundus (arcuate uterus). Occasionally, only one side of the Müllerian system will develop, resulting in a hemi-uterus and a single fallopian tube (unicornuate uterus or uterus unicornus).
Failure to resorb the midline of the Müllerian ducts after fusion typically results in a uterine septum. A septum may be complete, running from the cervix to the fundus, or incomplete, involving only the uterine fundus (subseptate uterus). Occasionally, the vagina canalizes improperly and a vaginal septum will occur. This can occur in isolation or in conjunction with a uterine anomaly. Vaginal septa can be either longitudinal or horizontal. The longitudinal septum is reminiscent of those uterine anomalies resulting from failure of the Müllerian midline to resorb. Horizontal vaginal septa are thought to represent a failure of the vaginal plate to resorb at the site where it fuses with the Müllerian ducts.
Many women with structural anomalies of the reproductive tract are asymptomatic and never diagnosed. Others with Müllerian tract abnormalities may present with primary amenorrhea, recurrent miscarriages, preterm delivery and breech presentation at term. Because the mesonephros is closely involved in directing the development of the internal genitalia, the finding of a uterine anomaly should prompt an evaluation of the urinary system for an accompanying anomaly.
Exposure to diethylstilbestrol
In utero exposure to diethylstilbestrol (DES) occurred in individuals born between 1940 and 1971 whose mothers were given the synthetic estrogen in the hope of preventing a miscarriage. DES was subsequently shown to cause congenital abnormalities in women and, to a lesser degree, in men. The most frequently seen abnormalities in women are abnormally shaped cervices. These cervices have been described as coxcomb, hooded or hypoplastic. The uterine musculature may also be abnormally formed in DES-exposed women such that the uterine cavity assumes a T-shape on hysterosalpingography or saline-infusion sonohysterography. DES appears to cause these abnormalities via inappropriate activation of estrogen-dependent genes involved in differentiating the cervix and upper third of the vagina from the lower vagina. This results not only in the structurally abnormal cervices and uteri, but also in persistence of cervical glandular epithelium in the vagina (vaginal adenosis). In utero DES exposure is associated with an increased risk of reproductive failure, including infertility (likely from failed implantation), recurrent pregnancy loss and preterm delivery. DES daughters are also at increased risk for malignancies, specifically clear cell adenocarcinoma, arising in sites of vaginal adenosis. This is thought to result from exposure of the ectopic cervical glandular-type epithelia in the vagina to neoplastic inducers not usually accessible to the upper reproductive tract.
Occasionally, clinicians will observe cervical and uterine abnormalities that look exactly like those caused by in utero DES exposure in women never exposed to DES.
Congenital adrenal hyperplasia
Ambiguous genitalia in a newborn infant are most commonly caused by congenital adrenal hyperplasia (CAH). This diagnosis accounts for 40–50% of all cases of ambiguous genitalia. Depending on the degree of the defect and the particular steroidogenic enzyme that is dysfunctional, neonatal effects can be variable. Affected female infants may have a common urogenital sinus containing the vagina and urethra, which opens at the base of an enlarged phallus resembling a penis. The labia majora may be hypertrophied or fused and thus resemble an empty scrotum. Some female infants will appear like a male with hypospadias and cryptorchidism. Others will only exhibit mild to moderate clitoromegaly. Some of these infants will have accompanying hypertension (5%) or life-threatening salt wasting (30%) and this will aid in making the diagnosis soon after birth. Those carrying the most common defect, moderate 21β-hydroxylase deficiency, will have no other identifying characteristics. The finding of a normal female karyotype in a newborn assigned to the male gender in the delivery room requires an evaluation for CAH.
The primary defect in all types of CAH is the absence of one of the enzymes necessary for steroidogenesis. The most common forms involve the enzymes that convert androgens to the adrenal steroids (Table 27.1). In the absence of one of these enzymes, no steroidal end-product will be produced by the adrenal gland to feed back on the hypothalamic–pituitary axis and regulate adrenocorticotropic hormone (ACTH) secretion. Excess ACTH will continue to stimulate the adrenals to produce more of the steroid products prior to the enzymatic block. These products are then shunted toward androgen-forming pathways. Adrenal hyperplasia with excess androgen production will result. This is of little consequence in the male fetus but will result in masculinization of the androgen-sensitive external genitalia in a female fetus. Because the female fetus has neither testes nor Müllerian-inhibiting substance (MIS), females affected by CAH will have uteri and vaginas. The degree of hypertrophy and fusion of the external genitalia in CAH females will depend on the quantity of androgen involved and on the developmental timing of androgen exposure. Masculinized infants with ovaries and a 46XX karyotype are called female pseudohermaphrodites.
Therapy for female infants masculinized as a result of CAH includes glucocorticoid administration to suppress adrenal androgen secretion and genital reconstructive surgery. Infants who also have a defect in aldoster- one synthesis will also require mineralocorticoid replacement.
Virilization of female infants by maternal or exogenous androgen exposure occurs only when those androgens are unable to be converted to estrogens by placental aromatase. Therefore, infants born to mothers with CAH are not at risk unless the child has inherited the genetic defect from both parents and also carries the enzymatic deficiency. Infants born to mothers with an androgen-producing tumor may be virilized if the particular androgen produced cannot be aromatized (e.g., dihydrotestosterone, DHT) or it quantitatively exceeds the high aromatization capacity of the placenta. Maternal administration of synthetic progestins with androgenic activity has also been associated with virilization of the female neonate; use of synthetic progesterones is contraindicated in pregnant women. Female virilization that has resulted from in utero steroid exposure but has no accompanying risk for post- natal exposure can be treated with reconstructive surgery alone.
Women with Turner syndrome are often identified when the physical characteristics of short stature, webbed neck, shield chest and increased carrying angle accompany primary amenorrhea. The fundamental defect in Turner syndrome patients is the absence of a second sex chromosome(i.e., a 45X karyotype). In the absence of a functional second sex chromosome, the germ cells in the gonad do not survive past the embryonic period and a normal ovary or testis does not develop. Gonadal steroid synthesis and secretion do not occur during embryogenesis or at puberty. Systems other than reproduction are affected by Turner syndrome. Women with the disorder have an increased incidence of renal anomalies, autoimmune diseases and cardiac anomalies, particularly coarctation of the aorta and aortic aneurysms. Turner syndrome is the most common of a group of disorders known as gonadal dysgenesis.
Most individuals with gonadal dysgenesis have a female phenotype at birth. If the entirety of the second sex chromosome is missing, both the external and internal genitalia will be female. After puberty, these female structures will remain infantile because of the lack of ovarian estrogens from the nonfunctional gonad. If any remnant of a second sex chromosome is present in an individual with gonadal dysgenesis, the phenotype will depend on the specific genes retained. For instance, if the SRY locus is present and translocated onto another chromosome, signals to begin testicular differentiation will occur. MIS will be produced and the Müllerian duct system will regress. Despite MIS production, these individuals will have a rudimentary testis and lack androgen production. They will be born with female external genitalia, but lack a vagina and other female internal reproductive structures. Primordial Wolffian ducts may be identified at laparotomy along with ovotestes. These rare individuals are true hermaphrodites.
Sex chromosome mosaicism (multiple cell lines of different sex chromosomal composition) is not uncommon in Turner syndrome. Individuals carrying any portion of the Y chromosome, including SRY alone, may have a testicular component to their dysgenetic gonad. These patients are at risk for gonadal malignancies and may have functional testicular tissue that causes virilization at puberty. Therefore it is important to confirm any suspected diagnosis of Turner syndrome using karyotype analysis. Some experts recommend using a DNA probe against SRY as well. Individuals who possess a cell line containing a Y chromosome or who carry SRY should undergo bilateral gonadectomy prior to puberty to eliminate the possibility of virilization or cancer.
If sex chromosome mosaicism involves a second X chromosome, functional ovarian tissue may exist within the gonad. Women with such mosaicism may experience normal female puberty and even retain fertility for a brief period of time. Early menopause invariably occurs because the abnormal chromosomal constitution causes development of only a limited number of functional ovarian follicles. A woman with complete Turner syndrome or XX mosaicism can carry a pregnancy conceived through in vitro fertilization using donated oocytes. Her infantile uterus will require extensive hormonal priming.