Disorders of sexual differentiation

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CHAPTER 42

Disorders of sexual differentiation

1. Describe the first level of sexual differentiation.

2. What is the next level of sex determination?

3. Discuss the development of the external genitalia.

4. What is testis-determining factor (TDF)?

5. Describe the Lyon hypothesis. In which cells are two X chromosomes necessary for normal development?

6. Discuss normal male sexual differentiation.

The fetus is sexually bipotential. Figure 42-1 shows schematically how male development is accomplished. The undifferentiated gonad is derived from coelomic epithelium, mesenchyme, and germ cells, which, in the presence of SRY, give rise to Leydig cells, Sertoli cells, seminiferous tubules, and spermatogonia. Testes are formed at 7 weeks. Testicular production of testosterone (Leydig cells) leads to wolffian duct development, whereas MIF (Sertoli cells) leads to müllerian duct regression. Masculinization of the external genitalia is mediated by DHT, which is produced from testosterone by the action of the enzyme 5-alpha-reductase.

7. Describe normal female sexual differentiation.

8. How is external genital development determined?

9. The differential diagnosis of disorders of sexual differentiation (DSD) is complex, but it may be simplified by an approach based on an understanding of the process of sexual differentiation. Can you devise such a classification?

10. What is a virilized female?

A virilized female (previously called female pseudohermaphroditism) is characterized by a 46,XX karyotype, ovaries, normal müllerian duct structures, absent wolffian duct structures, and virilized genitalia resulting from exposure to androgens during the first trimester. See Table 42-2.

TABLE 42-2.

PRADER CLASSIFICATION: DEGREE OF VIRILIZATION OF EXTERNAL GENITALIA

Type 1 Clitoral hypertrophy
Type 2 Clitoral hypertrophy, urethral and vaginal orifices present, but very near
Type 3 Clitoral hypertrophy, single urogenital orifice, posterior fusion of the labia majora
Type 4 Penile clitoris, perineoscrotal hypospadias, complete fusion of the labia majora
Type 5 Complete masculinization (normal-looking male genitalia) but no palpable testes

11. What is the most common cause of a virilized female?

The most common cause is congenital adrenal hyperplasia (CAH) resulting from 21-hydroxylase deficiency. In fact, this disorder is the single most common cause of sexual ambiguity. In this condition, the gene responsible for encoding the 21-hydroxylase enzyme is inactive. This enzyme blockage occurs along the pathway to cortisol and aldosterone. Because of low or absent levels of cortisol, the feedback mechanism produces increased adrenocorticotropic hormone (ACTH), which drives the pathway further and results in accumulation of precursor hormones, the measurement of which is useful for making a diagnosis. Increased ACTH also drives the production of excess adrenal androgens, which result in virilization. Virilization may also be caused by maternal ingestion of androgens or synthetic progesterones during the first trimester of pregnancy.

12. How do virilized female infants present?

13. What is an undervirilized male?

14. Which boys with hypospadias should be evaluated for sexual ambiguity?

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