Pxi

Normal female

Adrenal virilism

( Hormonal interactions along the ovarian and adrenal axes during normal female development, compared with adrenal virilism. Dashed arrows indicate low production of the hormone. Heavy arrows indicate increased hormone production. Plus and minus signs indicate positive and negative effects.

Normal male

Normal male

Adrenal VirilismGonadal Dysgenesis

lected cases and their manifestations are briefly discussed here, as are disorders of pubertal development (see also Chapters 37 and 38).

Gonadal dysgenesis refers to incomplete differentiation of the gonads and is usually associated with sex chromosome abnormalities. These result from errors in the first or second meiotic division and occur by chromosomal nondis-junction, translocation, rearrangement, or deletion. The two most common disorders are Klinefelter's syndrome (47,XXY) and Turner's syndrome (45,XO). Because of a Y chromosome, an individual with a 47,XXY karyotype has normal testicular function in utero in terms of testosterone and AMH production and no ambiguity of the genitalia at birth. The extra X chromosome, however, interferes with the development of the seminiferous tubules, which show extensive hyalinization and fibrosis, whereas the Leydig cells are hyperplastic. Such males have small testes, are azoospermic, and often exhibit some eunuchoidal features. Because of having only one X chromosome, an individual with a 45,XO karyotype will have no gonadal development during fetal life and is presented at birth as a phenotypic female. Given the absence of ovarian follicles, such patients have very low levels of estrogens, primary amenorrhea, and do not undergo normal pubertal development.

Female pseudohermaphrodites are 46,XX females with normal ovaries and internal genitalia but a different degree of virilization of the external genitalia, resulting from exposure to excessive androgens in utero. The most common cause is congenital adrenal hyperplasia, an inherited abnormality in adrenal steroid biosynthesis, with most cases of virilization resulting from 21-hydroxylase or 11 ^-hy-droxylase deficiency (see Chapter 34). In such cases, cortisol production is low, causing increased production of ACTH by activating the hypothalamic-pituitary axis (Fig. 39.15). The elevated ACTH levels induce adrenal hy-perplasia and an abnormal production of androgens and corticosteroid precursors. These infants are born with ambiguous external genitalia (i.e., clitoromegaly, labioscrotal fusion, or phallic urethra). The degree of virilization depends on the time of onset of excess fetal androgen production. When aldosterone levels are also affected, a life-threatening salt-wasting disease results. Untreated patients with congenital adrenal virilism develop progressive mas-culinization, amenorrhea, and infertility.

Male pseudohermaphrodites are 46,XY individuals with differentiated testes but underdeveloped and/or absent wolffian-derived structures and inadequate virilization of the external genitalia. These effects result from defects in testosterone biosynthesis, metabolism, or action. The 5a-reductase deficiency is an autosomal recessive disorder caused by the inability to convert testosterone to DHT. Such infants have ambiguous or female external genitalia and normal male internal genitalia (Fig. 39.16). They are often raised as females but undergo a complete or partial testosterone-dependent puberty, including enlargement of the penis, testicular descent, and the development of male psychosexual behavior. Azoospermia is common.

The testicular feminization syndrome is an X-linked recessive disorder caused by end-organ insensitivity to androgens, usually because of absent or defective androgen receptors. These 46,XY males have abdominal testes that secrete normal testosterone levels. Because of androgen in-sensitivity, the wolffian ducts regress, and the external genitalia develop along the female line. The presence of AMH

in utero causes regression of the mullerian ducts. These individuals have neither male nor female internal genitalia and phenotypic female external genitalia, with the vagina ending in a blind pouch. They are reared as females and undergo feminization during puberty because of the peripheral conversion of testosterone to estradiol.

Disorders of puberty are classified as precocious puberty, defined as sexual maturation before the age of 8 years, and delayed puberty, in which menses does not start by age 17 or testicular development is delayed beyond age 20. True precocious puberty results from premature activation of the hypothalamic-pituitary-gonadal axis, leading to the development of secondary sex characteristics as well as gametogenesis. The most frequent causes are CNS lesions or infections, hypothalamic disease, and hypothyroidism. Pseudoprecocious puberty is the early development of secondary sex characteristics without gametogenesis. It can result from the abnormal exposure of immature boys to androgens and of immature girls to estrogens. Augmented steroid production can be of gonadal or adrenal origin.

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