Figure 14.36 Development of the external genitalia in the female at 5 months (A) and in the newborn (B).
14.36A); urethral folds do not fuse, as in the male, but develop into the labia minora. Genital swellings enlarge and form the labia majora. The urogenital groove is open and forms the vestibule (Figs. 14.34C and 14.36B). Although the genital tubercle does not elongate extensively in the female, it is larger than in the male during the early stages of development (Fig. 14.34, A and B). In fact, using tubercle length as a criterion (as monitored by ultrasound) has resulted in mistakes in identification of the sexes during the third and fourth months of gestation.
Klinefelter syndrome, with a karyotype of 47,XXY (or other variants, e.g., XXXY), is the most common major abnormality of sexual differentiation, occurring with a frequency of 1/500 males. Patients are characterized by infertility, gynecomastia, varying degrees of impaired sexual maturation, and in some cases underandrogenization. Nondisjunction of the XX homologues is the most common causative factor.
In gonadal dysgenesis oocytes are absent and the ovaries appear as streak gonads. Individuals are phenotypically female but may have a variety of chromosomal complements, including XY. XY female gonadal dysgenesis (Swyer syndrome) results from point mutations or deletions of the SRY gene. Individuals appear to be normal females but do not menstruate and do not develop secondary sexual characteristics at puberty. Patients with Turner syndrome also have gonadal dysgenesis. They have a 45,X karyotype and short stature, high arched palate, webbed neck, shieldlike chest, cardiac and renal anomalies,
and inverted nipples (Fig. 14.37). Absence of oocytes in 45,X cases is due to increased oocyte loss and not to germ cell abnormalities.
Since sexual development of males and females begins in an identical fashion, it is not surprising that abnormalities in differentiation and sex determination occur. In some cases these abnormalities result in individuals with characteristics of both sexes, known as hermaphrodites. True hermaphrodites have both testicular and ovarian tissue, usually combined as ovotestes. In 70% of cases the karyotype is 46,XX, and there is usually a uterus. External genitalia are ambiguous or predominantly female, and most of these individuals are raised as females.
In pseudohermaphrodites, the genotypic sex is masked by a phe-notypic appearance that closely resembles the other sex. When the pseudohermaphrodite has a testis, the patient is called a male pseudohermaphrodite; when an ovary is present, the patient is called a female pseudohermaphrodite.
Female pseudohermaphroditism is most commonly caused by congenital adrenal hyperplasia (adrenogenital syndrome). Biochemical abnormalities in the adrenal glands result in decreased steroid hormone production and an increase in adrenocorticotropic hormone (ACTH). In most cases, 21-hydroxylation is inhibited, such that 17-hydroxyprogesterone (17-OHP) is not converted to 11-deoxycortisol. ACTH levels increase in response to defective cortisol production, which leads to ever-increasing amounts of 17-OHP. In turn, there is excessive production of androgens. Patients have a 46,XX chromosome complement, chromatin-positive nuclei, and ovaries, but excessive production of androgens masculinizes the external genitalia. This masculin-ization may vary from enlargement of the clitoris to almost male genitalia (Fig. 14.38). Frequently there is clitoral hypertrophy and partial fusion of
the labia majora, giving the appearance of a scrotum, and a small persistent urogenital sinus.
Male pseudohermaphrodites have a 46,XY chromosome complement, and their cells are usually chromatin-negative. Reduced production of an-drogenic hormones and MIS are responsible for this condition. Internal and external sex characteristics vary considerably, depending on the degree of development of external genitalia and the presence of paramesonephric derivatives.
Androgen insensitivity syndrome (formerly testicular feminization)
occurs in patients who have a 46,XY chromosome complement but have the external appearance of normal females (Fig. 14.39). This disorder results from a lack of androgen receptors or failure of tissues to respond to receptor-dihydrotestosterone complexes. Consequently, androgens produced by the testes are ineffective in inducing differentiation of male genitalia. Since these patients have testes and MIS is present, the paramesonephric system is suppressed, and uterine tubes and uterus are absent. The vagina is short and blind. The testes are frequently found in the inguinal or labial regions, but spermatogenesis does not occur. Furthermore, there is an increased risk of tumor formation in these structures, and 33% of these individuals develop malignancies prior to age 50. This syndrome is an X-linked recessive disorder that occurs in 1/20,000 live births.
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