Masculinization of the external genitalia of genotypic females (except for isolated enlargement of the clitoris, which can occur from later androgen exposure) is always caused by the presence of excessive androgens during the critical period of development (8 to 13 weeks of gestation) (Table 177-1). The degree of virilization can range from mild clitoral enlargement to the appearance of a male phallus with a penile urethra and fused scrotum with raphe. Congenital virilizing adrenal hyperplasia is the most common cause of female ambiguous genitalia; it is most commonly the result of an enzyme deficiency that impairs synthesis of glucocorticoids but does not affect androgen production. The impaired cortisol secretion leads to adrenocorticotropic hormone (ACTH) hypersecretion, which stimulates hyperplasia of the adrenal cortex and excessive adrenal production of androgens (see Chapter 178).
46,XY Disorders of Sexual Development
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Underdevelopment of the male external genitalia occurs because of a relative deficiency of testosterone production or action (Table 177-2). The penis is small, with various degrees of hypospadias (penile or perineal) and associated chordee or ventral binding of the phallus; unilateral, but more often bilateral, cryptorchidism may be present. The testes should be sought carefully in the inguinal canal or labioscrotal folds by palpation or ultrasound. Rarely a palpable gonad in the inguinal canal or labioscrotal fold represents a herniated ovary or an ovotestis. The latter patients have ovarian and testicular tissue and usually ambiguous external genitalia. Production of testosterone by a gonad implies that testicular tissue is present and that at least some cells carry the SRY gene.
Testosterone production can be reduced by specific deficiencies of the enzymes needed for androgen biosynthesis or by dysplasia of the gonads. In the latter, if müllerian-inhibiting substance production also is reduced, a rudimentary uterus and fallopian tubes are present.
The complete form of androgen resistance or androgen insensitivity syndrome is the most dramatic example of resistance to hormone action by defects in the androgen receptor. Affected patients have a 46,XY karyotype, normally formed testes (usually located in the inguinal canal or labia majora), and female external genitalia with a short vagina and no internal müllerian structures. At the time of puberty, testosterone concentrations increase to normal or above normal male range. Because a portion of the testosterone is normally converted to estradiol in peripheral tissues and the estrogen cannot be opposed by the androgen, breast development ensues at the normal age of puberty without growth of pubic, facial, or axillary hair or the occurrence of menstruation.
5α-Reductase deficiency presents at birth with predominantly female phenotype or with ambiguous genitalia, including perineoscrotal hypospadias. The defect is in 5α reduction of testosterone to its metabolite DHT. At puberty spontaneous secondary male sexual development occurs. Gender identity and gender role are significant psychological issues with these patients if diagnosed at puberty.
Isolated P-450c17 deficiency with Adrenal function normal 17,20-desmolase deficiency possible mutations in DAX1,
SOX9, GATA4, WT1
Complete androgen insensitivity Female external genitalia, absence of müllerian structures
Partial androgen insensitivity As previous with ambiguous external genitalia 5α-Reductase deficiency Autosomal recessive, virilization at puberty
StAR, Steroid acute regulatory protein.
Sex Chromosome and Ovotesticular Disorders of Sexual Development
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