Adrenal Hyperandrogenism in Children
Lucia Ghizzoni,
George Mastorakos and
Alessandra Vottero
Department of Pediatrics (L.G., A.V.), University of Parma, 43100
Parma, Italy; and Endocrine Unit (G.M.), Evgenidion Hospital, Athens
University, 11528 Athens, Greece
Address correspondence and requests for reprints to: Lucia Ghizzoni, M.D., Clinica Pediatrica, Universita degli Studi di Parma, Via Gramsci 14, 43100 Parma, Italy. E-mail: lughizzo{at}unipr.it
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Introduction
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HYPERANDROGENISM of a mild-to-moderate
degree is probably the most common abnormality in normoestrogenic
menstrual disturbances. Androgen excess arises from abnormal ovarian or
adrenal sources. The adrenal androgens, normally secreted by the fetal
adrenal zone or the zona reticularis, are steroid hormones
with weak androgen activity. Although adrenal androgens do not seem to
play a major role in the fully androgenized adult men, they seem to
play a role in the adult woman and in both sexes before puberty. Girls,
women, as well as prepubertal boys may be negatively affected by
adrenal androgen hypersecretion in contrast to adult men.
In this review, we examine the roles and effects of adrenal androgens
and analyze the clinical significance of their hypersecretion during
childhood.
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Adrenal Androgen Physiology
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The adrenal cortex is divided into three histological and
functional zones: the outer, aldosterone-secreting zona
glomerulosa; the intermediate, cortisol-secreting, zona
fasciculata; and the inner, androgen-secreting, zona
reticularis. In the fetus, the adrenal cortex consists of the two
adult adrenal zonae glomerulosa and fasciculata
and an inner large fetal adrenal zone, which virtually disappears
within weeks after birth. Remaining cell foci from the fetal adrenal
zone presumably give rise to the adrenal zona reticularis
starting at the age of 45 yr in both sexes. This zone continues to
grow until young adulthood (2025 yr), remains at a plateau for 510
yr, and regresses gradually after the age of 35 yr.
The major androgens secreted by the adrenals are dehydroepiandrosterone
(DHEA), DHEA sulfate (DHEA-S), and
androstenedione (
4-A). Production of testosterone (T) by these
glands is minimal (1). DHEA and DHEA-S are mainly the
products of zona reticularis,
4-A and testosterone T are
secreted by both zona reticularis and zona
fasciculata (2, 3). Adrenal androgens are secreted in small
amounts during infancy and early childhood, and their secretion
gradually increases with age, paralleling the growth of the zona
reticularis (4). The mechanism(s) by which this zone develops with
age and the regulation of its secretion are not fully known. During
this process, plasma concentrations of the adrenal androgens increase,
whereas those of cortisol remain stable, suggesting that factors other
than corticotropin are involved. These may include the elusive
androgen-stimulating factor (AASF) (Fig. 1
), the existence of which has
been repeatedly questioned (5, 6). A programmed shift in production of
intradrenal regulatory factors associated with differentiation of
adrenal cells and changes in steroid biosynthesis might also take place
independently of circulating factors.
Adrenal androgens are secreted by the adrenal glands in response to
their tropic hormone ACTH (2) (Fig. 1
). This is a 39-amino acid peptide
synthesized and secreted by the anterior pituitary under the regulatory
control of CRH and arginine-vasopressin (7, 8). Under ACTH regulation,
adrenal androgens are secreted synchronously with cortisol, in both the
secretory episodes and the circadian pattern (9, 10).
Corticotropin-stimulated cortisol exerts major feedback inhibitory
influences at the level of both the hypothalamus and the anterior
pituitary by suppressing CRH, arginine-vasopressin, and ACTH synthesis
and secretion. Furthermore, the hypothalamic-pituitary-adrenal (HPA)
axis exerts both negative and positive influences on GH secretion (11),
as well as a primarily negative influence on the secretion of TSH (12).
Under physiological conditions, the HPA axis has also a prevailing
inhibitory effect on leptin secretion (Ghizzoni, L., personal
communication).
Steroid precursors and the adrenal androgens themselves may be
respectively converted to androgens or more potent androgens in
peripheral tissues, such as hair follicles, sebaceous glands, prostate,
and external genitalia (13). Major conversions are those of
4-A to T
and T to dihydrotestosterone by the enzymes 17-ketosteroid reductase
and 5
-reductase, respectively. Active uptake of androgens and
in situ estrogen synthesis occur in peripheral adipose
tissue, where the aromatization of
4-A and T to estrone and
estradiol, respectively, occurs. The adrenal androgens and their
metabolites are inactivated at various tissues, including the liver and
kidney (14).
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Etiology of Adrenal Androgen Hypersecretion (Table 1 )
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Primary adrenal causes
Premature pubarche.Premature pubarche refers to the
appearance of pubic hair before age 8 yr in girls and 9 yr in boys,
without other signs of puberty or virilization (15). Axillary hair,
apocrine odor, and acne may or may not be present. Growth velocity may
be increased, and slightly advanced bone maturation is often present
and is usually well correlated with the height age. The transient
acceleration of growth and of bone maturation have no negative effects
on the onset and progression of puberty and on final height (16). The
precise etiology of premature pubarche is not known. Generally, it has
been attributed to the early maturation of the zona
reticularis, which leads to an increase of adrenal androgens to
levels normally seen in early puberty (17, 18). It has also been
proposed that an increase in androgen biosynthesis might be due to the
preferential hyperphosporylation of the enzyme P450c17 due to an
autosomal dominant activating mutation of the kinase responsible for
the serine/threonine phosphorylation of the enzyme (19). Because serine
phosphorylation of P450c17, the key regulatory enzyme controlling
androgen biosynthesis, has been shown in vitro to
increase its activity (19), it is possible that the same mechanism can
cause in vivo increased androgen production. Adrenal
steroid, cortisol, ACTH, and ß-endorphin-immunoreactivity responses
to human CRH stimulation test are similar in normal children and
children with premature pubarche, suggesting that CRH does not seem to
play a role in premature pubarche
(20).
The diagnosis is based on the exclusion of true precocious puberty and
the nonclassic forms of congenital adrenal hyperplasia. The incidence
of defective steroidogenesis in children with premature pubarche
is extremely variable, ranging from 0% in some reports (21) to 40% in
others (22), probably due to the varying ethnic background of the
populations studied. Recently (23), a high incidence of molecular
defects of the CYP21 gene was reported in Greek children with premature
pubarche, the majority of whom were heterozygotes for 9 different
molecular defects. Whether this finding has any general clinical
relevance, only long-term prospective studies will be able to establish
it. Since idiopathic precocious puberty is generally characterized
by pubertal progression of the hypothalamic-pituitary-gonadal
axis,it can usually be clinically distinguished from premature
pubarche. The plasma concentrations of DHEA, DHEA-S, and
4-A, as well as the levels of the 17-ketosteroids and their urinary
metabolites, are increased for age and similar to those normally found
in pubertal children with Tanner stage II of pubertal development (4, 24). ACTH stimulation test rules out nonclassic congenital adrenal
hyperplasia, but not the carrier state (4). Gonadotropin levels are in
the prepubertal normal range both at basal state and after stimulation
with gonadotropin-releasing hormone.
Once precocious puberty and nonclassic congenital adrenal hyperplasia
are excluded, no treatment is needed. However, a long-term follow-up of
these patients is warranted. Recent data, in fact, indicate that girls
with premature pubarche may not have a benign outcome. Postpubertal
girls diagnosed with premature pubarche during childhood have an
increased frequency of functional ovarian hyperandrogenism (25).
Furthermore, hyperinsulinemia is a common feature in adolescent
patients with premature pubarche and functional ovarian
hyperandrogenism and is directly related to the degree of androgen
excess (26, 27, 28). Although the mechanisms interlinking the triad of
hyperinsulinemia, premature pubarche, and ovarian hyperandrogenism
remain enigmatic, this frequent concurrence may result, at least in
part, from a common genetic or early origin, as the result of in
utero growth retardation (29).
In polycystic ovary syndrome, the insulin resistance has been
shown to be the result of a postbinding defect in insulin receptor
signal transduction that seems to be due to a constitutively increased
receptor serine phosphorylation that inhibits the receptor tyrosine
kinase activity (30). Serine phosphorylation of P450c17, the key
regulatory enzyme controlling androgen biosynthesis has also been shown
in vitro to increase its activity (19). This could
result in increased androgen production. Thus, the same factor could
lead to insulin resistance in adulthood and hyperandrogenism by
serine-phosphorylation-mediated changes in different enzymatic
activities.
Adrenal tumors.Adrenal tumors are divided into benign and
malignant groups (adenomas and carcinomas, respectively) and can be
hormone secreting or nonsecreting (31, 32, 33). The exact incidence of
these tumors in children is not known; they are relatively rare, but
most often malignant. The age of appearance is usually during the 1st
decade of life (34). Females are more frequently affected than males
(2.5:1) (35). Primary adrenal tumors may autonomously hypersecrete
androgens and/or other hormones (31). Generally, the supraphysiologic
amount of androgens secreted by these tumors is characterized by
extremely elevated circulating DHEA and DHEA-S levels.
Other androgens, such as
4-A and T, may also be elevated by either
direct secretion or peripheral conversion of DHEA and
DHEA-S.
The clinical manifestations of patients with androgen-secreting adrenal
tumors depend on the nature of the hormones secreted; most frequently,
however, children with adrenocortical cancers present with virilization
in females and early puberty in males (32). Glucocorticoid
overproduction occurs occasionally in conjunction with virilizing
tumors, but patients may not present with Cushingoid features. The
onset of the disease is sudden, and hormonal symptoms are rapidly
progressive. Because of the anatomic location of the adrenal tumors, as
well as the nonsecreting nature of some of them, adrenal adenomas or
carcinomas may remain undiagnosed for a considerable period of
time.
Benign virilizing adrenocortical adenomas are usually small (diameter
<5 cm) and not visible on ultrasound, but are visible on computed
tomographic or magnetic resonance imaging (MRI) scans. These tumors do
not show enhancement at the T2 relaxation time of MRI. Plasma
concentrations of adrenal androgens and/or T are elevated and usually
not suppressed by dexamethasone.
Malignant virilizing adrenocortical carcinomas are generally larger
than 5 cm in diameter and have already invaded the capsule of the gland
or neighboring tissues by the time they are discovered. They can
produce several steroid intermediates, adrenal androgens, and/or T, as
well as compounds with glucocorticoid and mineralocorticoid activity
(31). These steroids are nonsuppressible by dexamethasone. These tumors
are frequently palpable or visible on ultrasound and, unlike benign
adenomas, their MRI shows enhancement at the T2 relaxation time.
Potential mechanisms that could be particularly important in
adrenocortical tumorigenesis include abnormalities in recently
described factors specific to the adrenal cortex. These include the
steroidogenic acute regulatory protein (36), which enhances the
mitochondrial conversion of cholesterol into pregnenolone by the
cholesterol side-chain cleavage enzyme, steroidogenic factor I (37), an
orphan nuclear receptor that is a key regulator of the steroid
hydroxylase in adrenocortical cells, and a new member of the nuclear
receptor superfamily called DAX-I (38). The product of the latter acts
as a dominant negative regulator of transcription mediated by the
retinoic acid receptor. Recently, steroidogenic acute regulatory
protein mRNA has been found expressed at high levels in normal human
adrenals and adrenocortical tumors (36). On the other hand, whether
abnormalities in the gene encoding for steroidogenic factor I or in the
DAX-1 gene might be associated with human adrenocortical tumorigenesis
remains unknown.
Complete surgical excision with replacement steroid therapy provides
the best therapeutic choice for patients with primary adrenal tumors
(33). For inoperable or partially resectable carcinoma, combination
chemotherapy may offer an alternative management approach (39).
However, the experience with pediatric patients is largely anedoctal.
Occasionally, for the correction of hyperandrogenism, hypercortisolism,
and/or hypermineralocorticoidism, steroid synthesis inhibitors such as
ketoconazole and androgen, glucocorticoid, or mineralcorticoid
antagonists may be required. Radiation therapy is occasionally helpful
for palliation of bone metastases.
Glucocorticoid resistance
Corticotropin hypersecretion. The syndrome of
glucocorticoid resistance is a rare condition resulting from partial,
albeit generalized, inability of glucocorticoids to exert their effects
on target tissues. The loss-of-function glucocorticoid receptor (hGR)
mutation results in compensatory elevation of circulating ACTH and
cortisol. Although adequate compensation is apparently achieved by
elevated cortisol concentrations in the great majority of the patients
described, excess ACTH secretion also results in increased production
of adrenal steroids with salt-retaining activity (mineralocorticoid
excess) and enhanced secretion of adrenal androgens (hyperandrogenism).
Since the syndrome of familial glucocorticoid resistance was first
described in 1976 (40), over 10 kindreds and few sporadic cases have
been reported; however, the molecular defects of only 4 kindreds and
one sporadic case have been elucidated so far (41, 42, 43, 44). Abnormalities
of the hGR, primarily inactivating mutations of the ligand-binding
domain or mutations leading to functional knockout of one of the two GR
gene alleles, have been described (45). Recently, the genetic study of
a fifth case/kindred with symptoms of hyperandrogenism and signs of
marked glucocorticoid resistance, having a heterozygotic hGR mutation
in the ligand-binding domain, has been carried out (46). The mutant
receptor had reduced affinity for dexamethasone and decreased
transcriptional activity; interestingly, it also had dominant negative
activity on the wild-type receptor. Furthermore, a
genetically-determined imbalanced expression of the glucocorticoid
receptor isoforms (hGR
and hGRß) has been found in cultured
lymphocytes from a patient with congenital generalized glucocorticoid
resistance and chronic leukemia (47). Although the mechanism of action
of hGR
has been extensively studied, the role of hGRß in the
modulation of glucocorticoid actions remains uncertain. However, it has
been recently postulated that hGRß might exert a specific dominant
negative effect on transcriptional activation induced by hGR
(48, 49). Therefore, the markedly reduced hGR
and normal hGRß
expression resulting in a low hGR
/hGRß ratio might be compatible
with glucocorticoid resistance in this patient (47).
The spectrum of clinical manifestations of this syndrome is quite
broad, varying from asymptomatic to chronic fatigue syndrome (perhaps
reflecting glucocorticoid deficiency) (50) to symptoms and signs of
mineralocorticoid excess, such as hypertension and/or hypokalemic
alkalosis (40, 51) and hyperandrogenism. The latter can manifest as
precocious puberty in children and as acne, hirsutism, menstrual
irregularities, oligo, or anovulation in women and adolescents.
Recently, a female newborn with ambiguous genitalia due to a combined
defect of the glucocorticoid receptor and the 21-hydroxylase genes has
been reported (52). In men, oligospermia and infertility have been
observed, possibly as a result of disturbances in FSH regulation caused
by excessive adrenal androgens (51).
The criteria for the diagnosis of primary glucocorticoid resistance
are: 1) increased serum cortisol and free cortisol levels in urine
without features of Cushings syndrome; 2) normal or increased plasma
ACTH concentrations despite cortisol excess; 3) resistance to single or
multiple doses of dexamethasone; 4) preservation of the normal cortisol
diurnal rhythm and a stress-responsive pattern of HPA axis activity,
albeit at elevated levels; and 5) evidence of glucocorticoid resistance
in relatives (53).
Asymptomatic, normotensive subjects with primary glucocorticoid
resistance require no treatment. Symptomatic patients should be treated
with a synthetic, potent, long-acting glucocorticoid, with minimal
intrinsic mineralocorticoid activity, such as dexamethasone, at a dose
that would be pharmacologic for the normal population (13 mg/day).
Untreated patients have no risk of adrenal insufficiency and do not
need special precautions during surgery, illness, or other stress
(53).
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Conclusion
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Excess of adrenal androgens before puberty is responsible for
clinical manifestations that vary with sex. In prepubertal boys the
excess of adrenal androgens leads to virilization manifested as penile
enlargment, hair development in androgen-dependent areas of the skin,
and development of other seconadary sexual characteristics. This is
defined as peripheral isosexual precocious puberty. In prepubertal
girls, excess androgen leads to inappropriate virilization manifested
as acne, hirsutism, and clitoromegaly. This is defined as peripheral
heterosexual precocity. In both sexes, androgen excess increases height
velocity and somatic development, as well as the rate of skeletal
maturation. Premature epiphyseal fusion in these children frequently
leads to short adult height. Thus, in children with hyperandrogenism, a
prompt diagnosis is extremely important not only to achieve a rapid
regression of the clinical signs of virilization, but also to prevent
the late androgen-related effects on growth. In premature pubarche, the
most frequent cause of adrenal hyperandrogenism in children, androgen
levels are only mildly elevated and, therefore, are not accompanied by
severe symptoms of androgen excess. Even in this condition, however, a
careful and prolonged follow-up is necessary to monitor the eventual
appearance of signs and symptoms of hyperandrogenism.
Received October 14, 1999.
Accepted October 20, 1999.
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