Disorders of sexual differentiation, such as virilization or feminization, can be caused by primary
gonadal disorders ( Chapter 22 ) and several primary adrenal disorders.
The adrenal cortex
secretes two compounds—______________and ______________—that can be
converted to testosterone in peripheral tissues.
dehydroepiandrosterone and androstenedione
Unlike gonadal androgens, ACTH regulates
adrenal androgen formation ( Fig. 24-45 ); thus, excess secretion can occur either as a _________________
. The adrenal causes of androgen excess
include adrenocortical neoplasms and a group of disorders that have been designated
congenital adrenal hyperplasia (CAH) .
syndrome or as a component of Cushing disease
Adrenocortical neoplasms associated with virilization are more likely to be androgen-secreting
adrenal carcinomas than adenomas. Such tumors are often also associated with
hypercortisolism (“mixed syndrome”). They are morphologically identical to other cortical
neoplasms and will be discussed later.
CAH represents a group of autosomal-recessive, inherited metabolic errors, each characterized
by a deficiency or total lack of a particular enzyme involved in the biosynthesis of cortical
steroids, particularly cortisol.
Steroidogenesis is then channeled into other pathways, leading to
increased production of androgens, which accounts for virilization.
deficiency of cortisol results in increased secretion of ACTH, resulting in adrenal hyperplasia.
Certain enzyme defects may also impair aldosterone secretion, adding salt wasting to the
virilizing syndrome. Other enzyme deficiencies may be incompatible with life or, in rare instances, may involve only the aldosterone pathway without involving cortisol synthesis. Thus,
there is a spectrum of these syndromes; the following remarks focus on the most common.
The defective conversion of progesterone to 11-deoxycorticosterone by 21-hydroxylase (the
product of CYP21A2) accounts for over 90% of cases of CAH. Figure 24-45 illustrates normal
adrenal steroidogenesis and the consequences of 21-hydroxylase deficiency, which may range
from a total lack to a mild loss, depending on the nature of the CYP21A2 mutation.
distinctive syndromes have been described
: (1) salt-wasting (classic) adrenogenitalism,
(2)simple virilizing adrenogenitalism, and
(3) nonclassic adrenogenitalism, a mild disease that may
be entirely asymptomatic or associated only with symptoms of androgen excess during
childhood or puberty.
The carrier frequency of the classic form is approximately 1 in 120, while the carrier frequency
of the nonclassic or mild form may be higher, depending on the ethnic group; Hispanics and
Ashkenazi Jewish populations have the highest carrier frequencies. The incidence of classic 21-
hydroxylase deficiency varies somewhat between populations, with a worldwide mean of around
1 in 13,000 newborns. The mechanism of CYP21A2 gene inactivation in 21-hydroxylase
deficiency involves recombination with a neighboring pseudogene on chromosome 6p21 called
____________ (a pseudogene is an inactive homologous gene created by ancestral duplication in a
localized region of the genome).  In the majority of cases of CAH, portions of the CYP21A1
pseudogene replace all or part of the active CYP21A2 gene. The introduction of nonfunctional
sequences from CYP21A1 into the CYP21A2 sequence has the same effect as inactivating
mutations in CYP21A2.
The_______________results from an inability to convert progesterone into
deoxycorticosterone because of a total lack of the hydroxylase. Thus, there is virtually no
synthesis of mineralocorticoids, and concomitantly, there is a block in the conversion of
hydroxyprogesterone into deoxycortisol resulting in deficient cortisol synthesis.
usually comes to light soon after birth, because in utero the electrolytes and fluids can be
maintained by the maternal kidneys.
There is salt wasting, hyponatremia, and hyperkalemia,
which induce acidosis, hypotension, cardiovascular collapse, and possibly death.
concomitant block in cortisol synthesis and excess production of androgens, however, lead to
virilization, which is easily recognized in the female at birth or in utero but is difficult to recognize
in the male. Males with this disorder are generally unrecognized at birth but come to clinical
attention 5 to 15 days later because of some salt-losing crisis.
Simple virilizing adrenogenital syndrome without salt wasting (presenting as genital ambiguity)
occurs in approximately a third of patients with 21-hydroxylase deficiency.
generate sufficient mineralocorticoid for salt reabsorption and prevent a salt-wasting “crisis.”
However, the lowered glucocorticoid level fails to cause feedback inhibition of ACTH secretion.
Thus, the level of testosterone is increased, with resultant progressive virilization.
Nonclassic or late-onset adrenal virilism is significantly more common than the classic patterns
There is only a_________________, which accounts for the later onset.
Individuals with this syndrome may be virtually asymptomatic or have mild
manifestations, such as hirsutism, acne, and menstrual irregularities.
Nonclassic CAH cannot be
diagnosed on routine newborn screening, and the diagnosis is usually rendered by
demonstration of biosynthetic defects in steroidogenesis.
partial deficiency in 21-hydroxylase function
In all cases of CAH the adrenals are bilaterally hyperplastic, sometimes increasing to 10 to 15 times their normal weights because of the sustained elevation in
The adrenal cortex is thickened and nodular, and on cut section the widened cortex
appears brown, because of total depletion of all lipid.
The proliferating cells are mostly
compact, eosinophilic, lipid-depleted cells, intermixed with lipid-laden clear cells.
of corticotroph (ACTH-producing) cells is present in the anterior pituitary in most persons
The clinical features of these disorders are determined by the specific enzyme deficiency and
include abnormalities related to androgen excess, with or without aldosterone and
glucocorticoid deficiency .
CAH affects not only adrenal cortical enzymes but also products
synthesized in the medulla. High levels of intra-adrenal glucocorticoids are required to facilitate
medullary catecholamine (epinephrine and norepinephrine) synthesis. In patients with severe
salt-wasting 21-hydroxylase deficiency, a combination of low cortisol levels and developmental
defects of the medulla (adrenomedullary dysplasia) profoundly affects catecholamine secretion,
further predisposing these individuals to hypotension and circulatory collapse