Specific Disorders of Ambiguous Genitalia
By definition, a female pseudohermaphrodite is a genetic female with ovaries but virilized external genitalia. This may arise from either endogenous production of androgens or exogenous androgen exposure such as from a maternal source. The most common variant of classic ambiguous genitalia is the female pseudohermaphrodite secondary to congenital adrenal hyperplasia. Figure 2 shows the pathways of corticosteroid biosynthesis that are involved in congenital adrenal hyperplasia. The most common defect that leads to ambiguous genitalia and female pseudohermaphroditism is a defect in the enzyme 21hydroxylase. Other enzymatic defects in the process may also lead to both male and female pseudohermaphroditism. Starting in the upper left hand corner, cholesterol is synthesized in the adrenal into androgens, mineralocorticoids, and cortisol. Cortisol levels drive the process through feedback loops in the hypothalamus and pituitary. If cortisol levels are low because of an enzymatic defect preventing its production, such as when there is a 21-hydroxylase deficiency, then the pituitary responds by increased ACTH secretion leading to further stimulation of the system and a buildup of the precursor molecules. Such a shift leads to overproduction of androgens leading to virilization and underproduction of the mineralocorticoids leading to salt wasting.
The elevation of serum levels of precursors also provides a means of diagnosis. Both serum and urinary levels of 17-hydroxy-progesterone will be elevated in patients with 21-hydroxylase deficiency and 17-hydroxypreg-nenolone will be elevated in patients with 3ß-steroid dehydrogenase defect. Also associated with male pseudohermaphrodites may be 3ß-steroid dehydrogenase deficiency. Patients with the uncommon 11ß- hydroxylase deficiency will have both virilism and hypertension from the elevation of androgens and the elevation of the mineralocorticoid 11-deoxycorticosterone.
Congenital adrenal hyperplasia is alone among the causes of ambiguous genitalia as being potentially life threatening in the newborn, because of the potential for mineralocorticoid deficiency leading to hyponatremia, hyperkalemia, dehydration, and circulatory collapse during the 2nd week of life.
A male pseudohermaphrodite has a 46XY karyotype but deficient masculinization of the external genitalia. There are three basic mechanisms of undervirilism that lead to male pseudohermaphroditism. It may occur through inadequate testosterone production, inadequate testosterone metabolism, or through an androgen receptor defect.
Inadequate testosterone production may occur from Leydig cell deficiency. This may be from testicular hypoplasia or absence. Testicular absence is thought to occur most commonly as testicular regression rather than primary agenesis. It is surmised that a fetal mishap such as bilateral prenatal torsion leads to loss of testicular tissue. More commonly, inadequate production is due to an inborn error in androgen biosynthesis. Figure 2 shows certain enzymatic defects in congenital adrenal hyperplasia that may lead to underproduction of cortisol and mineralocorticoids; in a similar manner, different enzymatic blocks may cause underproduction of androgens. Location of the block will influence mineralocorticoid under or overproduction. Patients may be hypertensive from salt retention induced from excessive mineralocorticoids. This may be the presenting finding in females. In the male, they too may be hypertensive, but they tend to present earlier due to undervirilism. Examples of enzymatic defects which may lead to male pseudohermaphroditism are 3ß-hydroxysteroid dehydrogenase, 17-hydroxylase, 17,20 desmolase, and 17ßhydroxysteroid dehydrogenase deficiencies. The level of under-virilism will vary in each of these conditions depending on the degree of enzymatic block, level of the block, and time of diagnosis. Some conditions such as 17ßhydroxysteroid dehydrogenase deficiency are initially associated with nearly complete lack of virilization until puberty when they may present as severe late virilization in a phenotypic female (Forest, 2001).
Male pseudohermaphroditism from inadequate testosterone metabolism is secondary to 5α-reductase deficiency. Testosterone production is normal but they are unable to produce DHT, which is responsible for virilization of the external genitalia. These patients have a 46XY karyotype, regression of müllerian ducts, normal wolffian duct structures, hypoplastic prostates, and varying degrees of undervirilism of the external genitalia. The typical patient is a phenotypic female at birth with normal male internal genitalia. Most are raised as females. At puberty, they will exhibit virilization, phallic growth, testicular descent, and deepening of the voice. Because brain receptors respond to testosterone, not DHT, these patients may have a male gender identity (Forest, 2001).
Androgen receptor defects may be total or incomplete. The former condition is commonly referred to as testicular feminization syndrome. These patients often present at puberty as phenotypic females with amenorrhea. Or, they may present earlier as a phenotypic female with an inguinal hernia containing a palpable gonad, which turns out to be a testis. Often these patients have a normal female habitus, breast development, sparse pubic hair, and a short blind-ending vagina, which may be adequate for intercourse. They are sterile, but otherwise physically and mentally female and are always reared as such. Because of the risk of gonadal tumors, testes should be removed.
Patients with partial androgen insensitivity will present with incomplete masculinization of varying degree. These patients may have a small phallus with proximal hypospadias, a bifid scrotum with penoscrotal transposition, and at times a small blind-ending vaginal pouch. More severe forms will resemble an overvirilized female more than an undervirilized male. Management is individualized to the patient. Because there is minimal response to testosterone, androgen treatment may be unsatisfactory to produce adequate phallic growth. Consideration should be given towards female gender assignment in those patients thought to have an inadequate phallus.
A rare disorder called hernia uteri inguinalis is seen with inadequate Sertoli cell production of MIS, leading to persistent müllerian ductal structures. These patients are normally masculinized; however, at the time of hernia or correction of undescended testis, a uterus and fallopian tube may be found. Treatment includes orchidopexy and hysterectomy with care being taken to preserve the testicular blood supply, which may be related to the uterus and fallopian tube.
Pure gonadal dysgenesis refers to a primary defect in gonadal formation. It may occur in patients with both 46XX and 46XY karyotype. Females with 46XX will have a normal stature, sexual infantilism, and bilateral streak gonads. They will often present with delayed puberty and amenorrhea and will be sterile but physically responsive to estrogen replacement. A 46XX karyotype is not associated with gonadal neoplasia.
The 46XO karyotype is found in patients with Turner's syndrome. It is a frequent malformation found in approximately 1 out of every 2,500 live female births. The physical findings of bilateral streak gonads, short stature, webbed neck, facial dystrophism, and sexual infantilism are due to the total or partial loss of the chromosomal information from one of the two X chromosomes. Renal anomalies are common with horseshoe kidney being the most common. Cardiovascular anomalies found with this syndrome include bicuspid mitral valve and aortic coarctation. Management is directed at correcting physical anomalies. Short stature may respond to human growth hormone. Most will require hormone replacement therapy at puberty to develop secondary sexual characteristics. Fertility is rare but reported.
Patients with pure gonadal dysplasia and a 46XY karyotype will display variable degrees of undermasculinization dependent upon the amount of testicular dysplasia. Because testicular secretion of MIS may also be deficient, retained müllerian ductal structures are also common. Patients with 46XY karyotype are at an increased risk of gonadoblastoma occurrence. As a general rule, patients found early are reared as females with gonadectomy, clitoral reduction, vaginoplasty, and estrogen/prog-esterone replacement starting at puberty. In patients who present late and are committed to male gender assignment, they can undergo hypospadias repair, removal of müllerian duct structures, and gonadectomy. They should receive androgen therapy starting at puberty.
Patients with mixed gonadal dysgenesis have been categorized as having "partial gonadal dysgenesis" secondary to Y chromosome mosaicism (Kim et al., 2002). The majority of patients will have a 45 XO/46XY karyotype, and it is characterized by a unilateral testis, a contralateral streak gonad, persistent müllerian ductal structures ipsilateral with the streak gonad, and varying levels of external genitalia undervirilization (Diamond, 2002). In the newborn period, mixed gonadal dysgenesis is the second most common cause of ambiguous genitalia, after congenital adrenal hyperplasia. There is an estimated incidence of gonadal tumor (gonadoblastoma or dysgerminoma) of approximately 15% to 20%. Most commonly, this occurs in the dysgenetic testis. These patients also have an increased incidence of Wilms' tumor and Denys-Drash syndrome characterized by progressive nephropathy (Diamond, 2002). The management of patients with mixed gonadal dysgenesis consists of Wilms' tumor screening, gender assignment, appropriate gonadectomy, and genital reconstruction. Two-thirds of patients are reared as females. If the patient is highly masculinized and the decision is made to rear the child as a male with testis preservation, careful periodic screening of the testis must be undertaken due to the risk of malignancy.
The phenotype associated with true hermaphrodites varies between the extremes of female/male differentiation. However, the majority of patients show some signs of virilization. There are regional differences in the incidence, time of diagnosis, and karyotype of true hermaphrodites. While it is rare in the West, it is one of the more common types of intersex in Africa (Kuhnle, Krob, & Maier, 2003). Most children are found at birth because of this partial virilization; however, in the Third World, late presentation is common. Regional variation in karyotype show that in Africa, 46XX is most common, in Europe and North America, mosaicism is more common (46XX/46XY and 47XXX/46XY), and in Japan, 46XY is common.
The hallmark of true hermaphroditism is the finding of gonads with both testicular and ovarian tissue; the latter being different from a streak by the presence of a well-formed follicle. Ovarian tissue generally matures normally with follicular maturation at puberty. Testicular tissue by contrast, will often have progressive fibrosis with age and spermatogenesis is rare. Hormonal production usually follows histologic changes. At birth, the ability to produce testosterone may be normal, but it becomes progressively impaired later in adolescence as testicular fibrosis becomes more evident. Internal ducts follow ipsilateral gonadal histology. Tumors may arise, most commonly gonadoblastoma and dysgerminoma; however, in patients diagnosed and managed early, malignant degeneration is rare.
The diagnosis of true hermaphroditism is via chromosomal analysis, imaging, and hormonal studies which usually precede open or laparoscopic exploration. Imaging with sonography may reveal uterine and ovarian structures. Genitogram may outline a vagina, cervix, uterine cavity, and fallopian tubes. Endocrine studies include a HCG stimulation test in which a rise in serum testosterone following HCG administration is indicative of functioning testicular tissue. Histologic confirmation of the condition rests with gonadal biopsy. Management consists of removing the conflicting gonadal tissue, genital reconstruction that best agrees with the sex of rearing, and potential hormonal supplementation at puberty.
Urol Nurs. 2005;25(1):11-18, 23-24. © 2005 Society of Urologic Nurses and Associates
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