Premature Adrenarche - sepeap

Original Article
Premature
Adrenarche
Alexander K.C. Leung, MBBS, FRCPC, FRCP(UK &
Irel), FRCPCH, FAAP,
& Wm. Lane M. Robson, MD, FRCPC, FRCP(Glasg)
ABSTRACT
Premature adrenarche refers to the precocious secretion of adrenal androgens,
which results in the isolated development of pubic hair (pubarche) before the age
of eight years in girls and nine years in boys. The female to male ratio is
approximately 10:1. Dark, coarse and curly hair is limited initially to the labia
majora in girls and to the root of the penis in boys. The hair extends gradually into
the pubic region. Axillary hair, increased body odor, and acne can also be present.
Hirsutism, deepening of the voice, clitoral enlargement, breast development, and
phallic or testicular enlargement are characteristically absent. A transient acceleration
of growth is common but final height is usually not affected. The onset of
puberty usually occurs at the normal age. Premature adrenarche can be a forerunner
of polycystic ovary syndrome and/or syndrome X. Continued observation
and periodic re-evaluation is necessary. J Pediatr Health Care. (2008) 22, 230-233.
Key words: Premature adrenarche, pubarche, polycystic ovary syndrome, syndrome
X
Alexander K. C. Leung is Clinical Associate Professor of Pediatrics, the University of
Calgary, and Pediatric Consultant, the Alberta Children’s Hospital, Calgary, Alberta,
Canada.
Wm. Lane M. Robson is Medical Director, The Children’s Clinic, Calgary, Alberta,
Canada.
Correspondence: Alexander K. C. Leung, MBBS, FRCPC, FRCP(UK & Irel), FRCPCH,
FAAP, #200, 233 - 16th Ave NW, Calgary, Alberta, Canada T2M 0H5; e-mail:
aleung@ucalgary.ca.
0891-5245/$34.00
Copyright © 2008 by the National Association of Pediatric Nurse Practitioners.
doi:10.1016/j.pedhc.2007.07.002
www.jpedhc.org
INTRODUCTION
Adrenarche refers to the puberty
of the adrenal gland (Ibanez, DiMartino-Nardi,
Potau, & Saenger, 2000).
The condition is characterized by activation
of adrenal androgen production
and by impressive increases
in dehydroepiandrosterone (DHEA),
dehydroepiandrosterone sulfate
(DHEAS), androstenedione, and
testosterone (Guven, Cinaz, & Ayvali,
2005; Ibanez et al.). Adrenarche
is an enigmatic phenomenon
that occurs only in humans
and some higher primate species
such as the chimpanzee and gorilla
(Auchus & Rainey, 2004; Saenger
& DiMartino-Nardi, 2001). Premature
or precocious adrenarche refers
to an earlier than normal secretion
of adrenal androgens that
results in an isolated development
of pubic hair (pubarche) before 8
years of age in girls and 9 years in
boys, without the appearance of
other signs of sexual maturation
(Ibanez et al.; Saenger & DiMartino-Nardi).
Precocious development
of pubic hair can cause embarrassment
to the child and
anxiety to the parents. Clinicians
should be concerned because premature
adrenarche can be the first
overt sign of an androgen-secreting
tumor of a gonad or adrenal
gland, congenital adrenal hyperplasia,
or true precocious puberty.
Recent studies suggest that premature
adrenarche in some girls can
be a forerunner of polycystic ovary
syndrome and/or syndrome X
(Andiran, Yordam, & Kirazh, 2005;
Dorn & Rotenstein, 2004; Saenger
& DiMartino-Nardi, 2001).
EPIDEMIOLOGY
Premature adrenarche is uncommon.
In a cross-sectional study of
1231 school girls of Eastern European
origin, only 2 (0.8%) of 255
girls aged 7 to 7.9 years were
found to have premature adrenarche
(Zukauskaite, Lasiene, Lasas,
Urbonaite, & Hindmarch, 2005).
230 Volume 22 • Number 4 Journal of Pediatric Health Care

...premature adrenarche can be the first overt
sign of an androgen-secreting tumor of a
gonad or adrenal gland, congenital adrenal
hyperplasia, or true precocious puberty.
FIGURE 1. A 6-year-old girl
with isolated development of
pubic hair. This figure can be
viewed in color on the Web at
www.jpedhc.org.
Black children are affected much
more frequently than are White children
(Banerjee et al., 1998). The female-to-male
ratio is approximately
10:1 (Dorn & Rotenstein, 2004;
Saenger & DiMartino-Nardi, 2001).
Both prematurity and intrauterine
growth retardation might predispose
to premature adrenarche in a susceptible
individual (Charkaluk,
Trivin, & Brauner, 2004; Neville &
Walker, 2005). Excess weight gain
might be a trigger for adrenarche,
and obesity is reported to be associated
with a higher incidence of
premature adrenarche (Ibanez et
al., 2000; Leung & Robson, in
press; Neville & Walker, 2005; Remer,
2000). The occurrence of premature
adrenarche usually is sporadic,
although familial occurrence
also has been described (Leung,
1989).
PATHOGENESIS
Adrenarche begins several years
before the onset of gonadal maturation
and correlates with the appearance
of the zona reticularis of
the adrenal gland. Adrenarche is
independent of gonadarche and
proceeds even in persons with gonadal
dysgenesis. In normal puberty,
adrenarche and gonadarche
are closely linked. Premature adrenarche
is secondary to an early isolated
maturation of the zona reticularis
with an increase in adrenal
androgen secretion for the chronologic
age but with normal glucocorticoid
levels (Azziz et al.,
2004; Meas et al., 2002). Oversecretion
of adrenocorticotropic hormone
(ACTH) or corticotropin-releasing
hormone (CRH) per se
cannot account for premature
adrenarche because ACTH always
causes a greater increase in corticosteroids
than in androgens. In patients
with hyperadrenocorticotropism
and hypercortisolemia, DHEA
and DHEAS levels usually are not
elevated. Nevertheless, ACTH and
CRH might have a permissive role in
the modulation of adrenal androgen
secretion (Saenger & DiMartino-
Nardi, 2001). An increase of a central
androgen–stimulating proopiomelanocortin-derived
hormone might be
the primum movens of premature
adrenarche (Battaglia et al., 2002).
Increased sensitivity of the sexual
hair follicles to androgens also
has been suggested as a mechanism
because in some patients,
premature pubarche is associated
with normal androgen levels (Guven
et al., 2005; Ibanez et al., 2000).
This phenomenon might account
for the increased prevalence of premature
adrenarche among Black
children (Banerjee et al., 1998). The
association of premature adrenarche
with prematurity and intrauterine
growth retardation suggests
that premature adrenarche
might be a component of a fetal or
neonatal programming event (Auchus
& Rainey, 2004).
CLINICAL MANIFESTATIONS
The frequency of premature
adrenarche increases with age between
3 and 8 years of age in girls
and between 3 and 9 years of age
in boys, although cases have been
reported as early as 5 weeks of age
(Leung, 1989). Dark, coarse, and
often curly hair is the first clinical
sign. The hair is limited initially to
the labia majora in girls or to the
root of the penis in boys and then
extends gradually into the pubic
region (Figure 1). The amount and
thickness of the hair might
progress very slowly or not at all.
Axillary hair, increased body odor,
oily skin, and acne also might be
noted (Ghizzoni & Milani, 2000;
Ibanez et al., 2000). Acanthosis
nigricans is more common in patients
with premature adrenarche
(DiMartino-Nardi, 2000). Hirsutism,
deepening of the voice, clitoral
enlargement, breast development,
phallic or testicular enlargement,
and other evidence of virilization
or precocious puberty characteristically
are absent.
A transient acceleration of growth
is common, but final height usually
is not affected (Battaglia et al., 2002;
Ghizzoni & Milani, 2000). The onset
of puberty usually occurs at the normal
age (Battaglia et al.; Ibanez et al.,
2000).
DIFFERENTIAL DIAGNOSIS
Premature adrenarche is a diagnosis
of exclusion. The differential
diagnosis of premature development
of pubic hair is shown in the
Table. Pubic hair of infancy presumably
is due to transiently elevated
androgen levels in the first
few months of life and increased
sensitivity of sexual hair follicles to
androgens (Leung, Hedge, & Stephure,
2005; Nebesio & Eugster,
2006). Shortly after birth, a transient
surge of gonadotropins occurs
and leads to a sharp increase in testosterone
levels, which peaks at 1 to
Journal of Pediatric Health Care July/August 2008
231

TABLE. Differential diagnosis of premature development
of pubic hair
Condition
Pubic hair of infancy
Premature adrenarche
Precocious puberty
Virilizing tumors
Late-onset congenital
adrenal hyperplasia
Iatrogenic
3 months of age (Leung et al.).
Thereafter, the gonadotropin levels
fall, and by 6 months of age, serum
levels of testosterone decrease to
low prepubertal levels. In pubic
hair of infancy, pubic hair usually
occurs in an atypical location such
as the scrotum in boys and the
mons pubis in girls (Leung et al.;
Nebesio & Eugster). The growth of
the pubic hair is slowly progressive
in the first few months of life,
remains stationary for a few more
months, and then might regress.
Precocious puberty can be differentiated
by the concomitant appearance
of pubic hair with breast
development in girls or with testicular
enlargement in boys. Premature
adrenarche is extremely difficult,
if not impossible, to differentiate
from the early stage of constitutional
precocious puberty.
Sexual hair might be the first
sign of virilization due to an adrenocortical
or gonadal tumor. In
these conditions, other evidence of
excessive androgen secretion such
as acne, clitoral or phallic enlargement,
hirsutism, increased muscle
mass, markedly accelerated linear
growth, and deepening of the
voice usually appear at the same
time or shortly after the onset of
Characteristics
Pubic hair usually occurs in an atypical location such as
scrotum in boys and mons pubis in girls; the growth of pubic
hair is slowly progressive in the first few months of life,
remains stationary for a few months, and then might regress
Isolated development of pubic hair without the appearance of
other signs of sexual maturation; the onset of puberty is
normal
Concomitant appearance of pubic hair with breast
development in girls or with testicular enlargement in boys
Acne, clitoral or phallic enlargement, hirsutism, markedly
accelerated linear growth, and deepening of the voice at the
same time or shortly after the onset of pubic hair
development
In addition to premature development of sexual hair, hirsutism
and menstrual irregularities are usually present; in the male,
the testes usually remain infantile but other secondary sexual
characteristics are advanced; a positive family history is
suggestive
A history of androgen exposure will give a clue to the diagnosis
pubic hair development. In boys
with an adrenocortical tumor, the
testicular size is usually small,
whereas the reverse is true for
boys with a testicular tumor. Exogenous
androgen can cause development
of sexual hair as well as
other signs of virilization. Obtaining
a careful history about drug
exposure is important.
Congenital adrenal hyperplasia,
usually resulting from 21-hydroxylase
deficiency, classically produces
prenatal virilization in females
but can, in a late-onset
attenuated form, present with premature
development of sexual
hair, hirsutism, and menstrual irregularities.
In the male, the testes
usually remain infantile, but other
secondary sexual characteristics are
advanced. A positive family history
of congenital adrenal hyperplasia is
suggestive.
COMPLICATIONS
Girls with premature adrenarche
have a higher incidence of
polycystic ovary syndrome later in
life (Andiran et al., 2005; Auchus &
Rainey, 2004; Ibanez et al., 2002).
Polycystic ovary syndrome is characterized
by menstrual irregularities,
obesity, acne, hirsutism, and polycystic
ovaries (DiMartino-Nardi, 2000).
In some girls, premature adrenarche
may be a forerunner of syndrome X
(obesity, hypertension, insulin resistance,
type 2 diabetes, and dyslipidemia)
(Ibanez et al., 2000; Saenger &
DiMartino-Nardi, 2001). Affected
patients are at increased risk for
early atherosclerotic cardiovascular
disease (Saenger & DiMartino-
Nardi). In contrast, premature adrenarche
in boys is not associated with
an increased incidence of endocrine
or metabolic abnormalities (Dorn &
Rotenstein, 2004; Ibanez et al.).
DIAGNOSTIC STUDIES
Serum concentrations of DHEA,
DHEAS, androstenedione, and testosterone
and urinary 17-ketosteroids
should be measured. In premature
adrenarche, these levels
are usually increased for chronologic
age and are in the range of
those found in early puberty (Battaglia
et al., 2002). DHEAS levels,
however, might exceed those of
pubertal controls (Ibanez et al.,
2000). A bone age x-ray should be
preformed. In premature adrenarche,
the bone age is usually
within 2 standard deviations of
chronologic age.
Moderately elevated levels of serum
androgen other than DHEAS,
bone age advancement, or signs of
atypical premature pubarche such
as cystic acne or signs of systemic
virilization indicate the need for an
ACTH test to rule out congenital adrenal
hyperplasia (Ibanez et al.,
2000). An excessive increase in
serum 17-hydroxyprogesterone
level to 45 nmol/L after an
ACTH stimulation test suggests
late-onset congenital adrenal hyperplasia
(Battaglia et al., 2002).
Marked elevation of serum androgen
levels and advanced bone
age suggest the possibility of an
adrenocortical or gonadal tumor. A
patient with an androgen-producing
adrenocortical tumor does not respond
to ACTH stimulation or dexamethasone
suppression, whereas a
patient with congenital adrenal hyperplasia
does respond. Adrenal
232 Volume 22 • Number 4 Journal of Pediatric Health Care

Marked elevation of serum androgen levels and
advanced bone age suggest the possibility of an
adrenocortical or gonadal tumor.
computed tomography or ultrasonography
should be performed if
significant virilization occurs and
ACTH stimulation does not reveal
congenital adrenal hyperplasia (Rodriguez
& Pescovitz, 2003).
Pelvic ultrasonography should
be performed if polycystic ovary
syndrome is suspected. The presence
of an enlarged ovary and multiple
small follicles scattered around
an echogenic stroma establishes the
diagnosis (Battaglia et al., 2002).
Color Doppler flow measurements
might reveal significant vascular
changes within the intra-ovarian
vessels in patients with polycystic
ovary syndrome (Battaglia et al.).
Serum glucose, insulin, cholesterol,
and triglyceride levels should be measured
if syndrome X is suspected.
MANAGEMENT
Education and reassurance of
the patient and family as well as
psychological/emotional support
for the child and family are essential
to the clinical management of
such patients. The parents and
child should be reassured that, in
most cases, premature adrenarche
is a benign condition and that the
child will develop normally. Continued
observation and periodic
re-evaluation are necessary because
premature adrenarche might
be the first sign of precocious puberty.
In some girls, premature adrenarche
might be a forerunner of
polycystic ovary syndrome or syndrome
X. Girls with higher body
mass index warrant particularly
close follow-up (Miller, Emans, &
Kohane, 1996). Early identification
of these patients can allow early
treatment of the appropriate conditions
with reduction in risk for early
cardiovascular disease.
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