16 - Ambiguous Genitalia | Smiths General Urology, Seventeenth Edition (LANGE Clinical Medicine)

Authors: Macfarlane, Michael T.

Title: Urology, 4th Edition

> Table of Contents > Part One - Chief Presentations > Chapter 16 - Ambiguous Genitalia

Chapter 16

Ambiguous Genitalia

Evaluation of the newborn with ambiguous genitalia is a medical and social emergency. Early sex assignment will help to resolve the social implications for the family. No other decision will have such a profound impact on the child and family. A clear understanding of the pathophysiology is essential if a correct decision is to be made expeditiously.

Mechanisms of Sexual Differentiation

The process of normal sexual differentiation is a series of staged modifications of bilateral tissue primordia. However, these modifications appear to be controlled by local factors, independent from one side to the other.

Development of Gonads

The genetic sex is determined at the time of fertilization by the delivery of an X or Y chromosome by the sperm. The normal female is 46XX and the normal male is 46XY. The medullary portion of the indifferent gonad develops into a testis under the influence of the protein product of the SRY (sex-determining region of the Y chromosome) gene, a product of the short arm of the Y chromosome, also known as the testis determining factor (TDF). In the absence of the SRY protein, the cortex of the indifferent gonad develops into an ovary by default. By the seventh week of gestation the gonadal sex has been established.

Development of Internal Ducts

By the sixth week of gestation, two paired internal duct systems derived from the mesonephric renal system exist side by side. The mesonephric (wolffian) duct will give rise to male structures, and the paramesonephric (m llerian) duct will

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become female structures. Male differentiation is dependent on testicular production of m llerian-inhibitory substance (MIS) from fetal Sertoli's cells and testosterone secretion by fetal Leydig's cells. Following regression of the m llerian duct under the influence of MIS, the wolffian duct will develop into the epididymis, vas deferens, and seminal vesicles under the influence of testosterone. In the absence of MIS and testosterone, the m llerian duct will evolve into the fallopian tubes, uterus, and upper third of the vagina, and the wolffian duct will passively degenerate.

Development of External Genitalia

The external genitalia develop from the urogenital sinus, genital tubercle, genital folds, and genital swellings. Male development is dependent on the ability of these tissues to convert testosterone into dihydrotestosterone by the enzyme 5- -reductase. Female differentiation is essentially the unmodified embryologic state that persists in the absence of these hormones.

Tissue Primordia	Female (Unmodified Differentiation)	Male (Requires 5- -reductase)
Urogenital sinus	Lower vagina and Skene's duct	Prostate
Genital tubercle	Clitoris	Glans penis
Genital folds	Labia minora	Urethra and shaft of penis
Genital swellings	Labia majora	Scrotum

Disorders of Sexual Differentiation

Not all disorders of intersexuality produce ambiguous genitalia. Numerous distinct disorders of chromosomal, gonadal, or phenotypic development have been described. Patients may present with infertility, delayed puberty, or primary amenorrhea. All disorders of ambiguous genitalia are the result of abnormal virilization (e.g., virilization of a genetic female, incomplete virilization of a genetic male, or partial virilization because of defective genetic assignment). Only those disorders that commonly present with ambiguous genitalia in the newborn are reviewed.

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Female Pseudohermaphroditism

The female pseudohermaphrodite is an example of virilization of a 46XX genetic female with normal ovaries secondary to excessive endogenous or exogenous intrauterine androgens. It is the most frequent etiology for ambiguous genitalia, and congenital adrenal hyperplasia is the most common reason for virilization.

Congenital adrenal hyperplasia occurs secondary to a defect in the glucocorticoid synthesis pathway (see figure on p. 176), resulting in decreased cortisol production and positive feedback on the anterior pituitary to increase adrenocorticotropic hormone (ACTH) release. Elevated ACTH levels cause adrenal hyperplasia and increased adrenal androgen synthesis. A defect in 21-hydroxylase with salt-losing symptoms accounts for about 90% of cases. The remaining 10% are due to a deficiency of 11- -hydroxylase with associated salt retention.
Other causes of excessive androgens include exogenous maternal ingestion of certain progestins or maternal virilizing tumors such as arrhenoblastomas or luteomas.

Mixed Gonadal Dysgenesis

Mixed gonadal dysgenesis is an abnormality of sex chromosome number, with the most common karyotype being 46XY/45X0 mosaic. Most patients are poorly virilized and infertile, so most are raised as females. Mixed gonadal dysgenesis is reported to be the second most frequent cause of ambiguous genitalia; 25% of patients will develop testicular gonadoblastomas if reared as males.

Male Pseudohermaphroditism

The male pseudohermaphrodite is an example of an incompletely virilized 46XY genetic male with normal testes. Causes include defective androgen synthesis, defective androgen action, deficient 5- -reductase activity (pseudovaginal perineoscrotal hypospadias), or deficient MIS (hernia uteri inguinale). When the androgen defect is severe, patients may have completely feminine external genitalia with intraabdominal testes (complete testicular feminization).

True Hermaphroditism

The true hermaphrodite is rare. These individuals have both testicular and ovarian elements; a uterus is usually present, as are

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internal ducts that correspond to the gonad on that side (e.g., testis, ovary, or ovotestis). The most common karyotype is 46XX (80%). Differentiation of the external genitalia is variable, and hypospadias is common.

Workup

History

Take a detailed family history of any abnormal sexual development, including unexplained fetal deaths, infertility, amenorrhea, and hirsutism. Question the mother about any medications or drugs taken during pregnancy (e.g., progestational agents are converted to androgens).

Physical Examination

Examine the infant carefully for a palpable gonad in the labioscrotal fold or scrotum that would exclude the diagnosis of female pseudohermaphroditism. Hyperpigmentation of the areola or labioscrotal folds suggests elevated levels of ACTH (ACTH shares a common subunit with melanocyte-stimulating hormone) and therefore congenital adrenal hyperplasia. Evidence of dehydration suggests a salt-losing (21-hydroxylase deficiency) congenital adrenal hyperplasia, whereas significant hypertension suggests sodium retention (11- -hydroxylase deficiency). Attempt to palpate a uterus in the lower abdomen. Document the size of the phallus and the position of the urethral meatus.

Biochemical Studies

Plasma Measurements

17-OH-progesterone elevation after the first 36 hours of life suggests 21-hydroxylase deficiency (upper limit of normal 200 ng/dL).
11-Deoxycortisol elevation suggests 11- -hydroxylase deficiency.
Testosterone levels before and after human chorionic gonadotropin (hCG) stimulation (2,000 IU/day for 4 days) in the male pseudohermaphrodite are helpful in differentiating androgen resistance from a defect in androgen synthesis.

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Testosterone and dihydrotestosterone levels are helpful in identifying 5- -reductase deficiency and androgen insensitivity syndromes.
Serum electrolytes should be obtained.

Urinary Measurements

17-Ketosteroids are metabolites of adrenal androgens (normal <15 mg/24 hours).
Pregnanetriol is a metabolite of 17-OH-progesterone.

Cultured Skin Fibroblasts

Cultured skin fibroblasts can be used to test for androgen resistance when necessary.

Special Studies

Genitography can be performed by injecting contrast into the urogenital sinus under fluoroscopic control.
Endoscopy can define the presence of a cervix and help perform genitography.
Ultrasonography can help document the presence of a uterus and fallopian tubes and thereby rule out male pseudohermaphroditism.
Exploratory laparotomy or laparoscopy and gonadal biopsy may become necessary.

Chromosome Studies

Buccal Smear

The presence of a Barr body (chromatin clumps on the nuclear membrane) within cells from the buccal mucosa can quickly suggest the genetic sex. The Barr body, which represents the second X chromosome, is found in more than 20% of the cells of a normal female and less than 2% of the cells of a normal male.

Karyotype Analysis

Karyotype analysis should be performed from cultured peripheral blood leukocytes arrested in metaphase. This will provide detailed chromosomal information; however, the results are usually not available for 3 to 4 days.

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Sex Assignment

No other medical intervention will have such a profound effect on the life of the patient. Sex assignment should be made with family consultation and only after all studies are complete. Every attempt should be made to rear children based on their genetic assignment.

Genital Reconstruction

Appropriate reconstruction of the external genitalia is best delayed until after some time for normal growth is allowed. Reconstruction between age 6 and 12 months is reasonable.