Rev Endocr Metab Disord (2009) 10:63–76
DOI 10.1007/s11154-008-9096-y
Clinical spectrum of premature pubarche: Links
to metabolic syndrome and ovarian hyperandrogenism
Lourdes Ibáñez & Rubén Díaz & Abel López-Bermejo &
Maria Victoria Marcos
Published online: 26 August 2008
# Springer Science + Business Media, LLC 2008
Abstract Premature pubarche—defined as the appearance
of pubic hair before age 8 years in girls and 9 years in
boys—has been traditionally considered a benign entity.
However, recent evidence supports the notion that prema-
ture pubarche in girls may be a forerunner of the metabolic
syndrome, and may precede the development of clinical
ovarian androgen excess in adolescence. This sequence
seems to occur more frequently when premature pubarche
was preceded by reduced fetal growth and followed by
excessive postnatal catch-up in height and particularly in
weight; hyperinsulinemia appears to be a key factor in the
development of this sequence of events. In girls with
premature pubarche and a history of a low birth weight,
puberty tends to start earlier and to have a faster course, so
that final height may be moderately reduced. In these girls,
metformin therapy may reverse the progression to clinical
ovarian hyperandrogenism, normalize body composition
and excess visceral fat, and delay pubertal progression
L. Ibáñez (*) : R. Díaz
Endocrinology Unit, Hospital Sant Joan de Déu,
University of Barcelona,
08950 Esplugues, Barcelona, Spain
e-mail: libanez@hsjdbcn.org
A. López-Bermejo
Department of Pediatrics, Dr. Josep Trueta Hospital,
17007 Girona, Spain
M. V. Marcos
Endocrinology Unit, Hospital de Terrassa,
08227 Terrassa, Spain
L. Ibáñez : M. V. Marcos
CIBER de Diabetes y Enfermedades Metabólicas Asociadas,
Barcelona, Spain
without attenuating linear growth and bone mineralization,
suggesting that adult height may be improved. Long-term
follow-up of these patients is needed to fully determine the
ultimate effects of insulin sensitization as well as the main-
tenance of these benefits after discontinuation of therapy.
Keywords Premature pubarche . Low birth weight .
Ovarian hyperandrogenism . Metformin . Insulin .
Visceral fat
1 Introduction
Precocious or premature adrenarche refers to an early
increase in adrenal androgen production that usually results
in the development of pubic hair or pubarche before 8 years
in girls and 9 years in boys, and may include the
appearance of axillary hair and apocrine secretion, but is
independent of pubertal development [1]. The incidence of
premature pubarche due to premature adrenarche is almost
tenfold higher in girls than in boys [2].
Traditionally, premature pubarche has been considered an
extreme variation of normal [1, 3]. However, an increased
body of evidence support the notion that premature pubarche
can no longer be considered a benign condition in girls, and
may be indeed a forerunner of the metabolic syndrome and
may precede the development of clinical ovarian androgen
excess in adolescence [4–6]. This sequence seems to occur
more frequently when premature pubarche was preceded by
reduced fetal growth and followed by excessive postnatal
catch-up in height and particularly in weight [5].
In this review, the links among premature pubarche due
to early or exaggerated premature adrenarche, metabolic
syndrome and ovarian hyperandrogenism in girls are
discussed, as well as potential therapeutic strategies aimed
64
at preventing and/or reverting the endocrine-metabolic
abnormalities that may follow.
2 Premature pubarche
2.1 Pathophysiological basis
Premature development of pubic and/or axillary hair
without other signs of virilization or pubertal development
was first described by Wilkins and was descriptively named
“premature pubarche” [7]. Some years later, other inves-
tigators suggested that the adrenal glands could be involved
in the development of this condition and they named it,
therefore, “premature adrenarche” [8].
Most frequently, premature pubarche appears to be
secondary to an early or exaggerated variant of normal
maturation of adrenal gland function (premature adre-
narche) [9–11]. In this variant, known as typical or isolated
premature pubarche, androgens such as dehydroepiandros-
terone (DHEA), DHEA-sulfate (DHEAS), androstenedione
(Δ4-A) and testosterone (T) are usually moderately in-
creased for chronological age, but fall within the normal
range according to the Tanner stage for pubic hair [9, 10,
12]. In some cases, the early development of pubic hair is
associated with normal androgen levels for chronological
age, suggesting increased peripheral sensitivity to andro-
gens [3, 13]. Enzymatic defects of steroidogenesis are
pathological causes of premature pubarche, with reported
frequencies that vary among populations [12, 14–18].
The cause of the adrenal oversecretion in typical
premature pubarche is currently unclear. Hypersecretion of
a purported non-ACTH, pituitary secreted hormone sharing
amino acids 79–96 of human proopiomelanocortin, perhaps
in concert with ACTH, has been deemed responsible for
excessive adrenal androgen stimulation, but confirmatory
data are still lacking [19, 20]. Other theories postulate that
the development of the zona reticularis, the site of
production of adrenal androgens, is accelerated in prema-
Fig. 1 Serum dehydroepiandros-
terone-sulfate (DHEAS) levels in
girls with premature pubarche
DEAS (µmol / L)
compared to age-matched controls
of the same chronological age (left)
and of the same Tanner pubertal
stage (right). The enclosed areas
represent the mean 2SD levels in
controls. Redrawn with permis-
sion from Virdis et al. [31]
Rev Endocr Metab Disord (2009) 10:63–76
ture pubarche [21]. More recently, it has been proposed that
serine/threonine phosphorylation of cytochrome P450c17
(CYP17) by a cyclic AMP-dependent kinase, accounting
for a large increase in its 17,20 lyase activity, could be
responsible for the normal process of adrenarche; early
activation of this process might account for the premature
stimulation of adrenal androgen secretion [22]. Finally,
corticotropin-releasing hormone (CRH) has been found to
have immediate and possibly direct effects on adrenal
androgen release in both normal men and in girls with
premature pubarche, suggesting a potential physiopatho-
logical role of this hormone in both normal and premature
adrenarche [23, 24].
Nutritional status may be a regulator of adrenarche;
indeed, prenatal and postnatal weight gain appear to have
opposite influences on adrenarche, and within the range of
normal birth weights, small infants who gained weight
rapidly during childhood show the highest levels of
circulating adrenal androgens [25, 26].
2.2 Clinical features
Typically, the appearance of pubic hair, which is usually
dark, curly and coarse, is mostly limited to the labia majora
in girls and thus may elude detection on casual examination
in obese patients. The development of pubic hair is non- to
slowly progressive, and may spread throughout the pubic
area [3, 11]. Axillary hair, increased body odor, oily skin,
and acne, usually in form of a few microcomedones, may
also be present. In isolated premature pubarche, clitoral or
penile enlargement are absent, and testicular and breast
development remain prepubertal.
Premature pubarche children are usually taller than their
peers at diagnosis, and often show increased growth
beginning earlier in childhood [1, 27, 28]. Growth velocity
and bone maturation are moderately increased for chrono-
logical age but are concordant with height age [1, 27, 28].
In girls, these clinical features are accompanied by
increased circulating insulin-like growth factor (IGF-I)
7 7
6 6
DEAS (µmol / L)
5 5
4 4
3 3
2 2
1 1
2 4 6 8 10 12 14 P1 P2 P3 P4
Age Tanner
(yrs) stage
Rev Endocr Metab Disord (2009) 10:63–76
levels which persist throughout pubertal development and
into adolescence [29, 30].
2.3 Adrenal androgens
In most cases, premature pubarche is accompanied by
circulating steroid levels in the usual range for normal
adrenarche. This is typified by DHEAS levels above 40 μg/
dL, which are above average for 6- to 8-year-olds but
within normal limits for early puberty (Fig. 1). Increased
DHEAS levels are usually accompanied by mild elevations
of DHEA, T and Δ4-A [9, 10, 12]. Serum corticosteroid
responses to ACTH stimulation parallel these changes, with
increases of 17-hydroxypregnenolone and DHEA predom-
inating [6]. Some girls with premature pubarche may show
amplified or exaggerated adrenarche, a term usually applied
when circulating baseline DHEAS or Δ4-A levels and/or
17-hydroxypregnenolone and DHEA responses to ACTH
stimulation are above those of early pubertal girls [32, 33].
Exaggerated adrenarche is considered to be an early
manifestation of steroidogenic dysregulation of adrenal
P450c17 (CYP17) activity and is associated with increased
risks for persistent adrenal hyperandrogenism and for the
subsequent development of ovarian androgen excess [33,
34], as will be discussed below.
100
75
Cumulative Fraction of
Menarcheal Girls (%)
50
25
0
10 11 12
Age (yr)
PP + BW below -2 SD (n=50)
PP + BW from -2 to 0 SD (n=94)
PP + BW above 0 SD (n=43)
Fig. 2 Distributions of menarcheal age in birth weight (BW)
subgroups of girls with premature pubarche (premature pubarche).
Age at menarche was younger (p<0.001) in lower-BW vs upper-BW
girls; intermediate-BW girls showed an intermediate pattern. Median
age at menarche is 12.8 years in the reference population. Modified
from Ibáñez et al. [36]
65
2.4 Timing of puberty and final height
Girls with premature pubarche generally have age of onset
of true puberty early in the normal range, normal
progression of puberty and adult stature within target height
range [1]. However, when premature pubarche is preceded
by low birth weight (LBW), puberty starts earlier, the
transit through puberty is faster, menarche is advanced by
approximately 8–10 months, and adult height is decreased
an average of 6.5 cm (∼1 SD) compared with girls with
premature pubarche and normal birth weight [35]. In one
study, menarche before age 12.0 years was threefold more
prevalent (∼75% vs ∼25%) among LBW-premature
pubarche girls than in control subjects [36] (Fig. 2). The
acceleration of both the onset and the progression of
puberty has been ascribed to a stimulatory role of hyper-
insulinemia—a characteristic feature of both LBW girls and
premature pubarche girls [29, 35]—in the tempo of pubertal
progression. These findings remain to be confirmed in
larger and ethnically diverse populations. In boys, longitu-
dinal studies on final height are lacking.
2.5 Postpubertal follow-up
Girls with exaggerated adrenarche and premature pubarche
were found to be at high risk for ovarian hyperandrogenism
in adolescence [33]. The same authors later showed that
premature pubarche was linked to prepubertal, pubertal, and
postpubertal hyperinsulinemia, to low concentrations of
IGF-binding-protein 1 (IGFBP-1), and to other features of
metabolic syndrome including dyslipidemia, central fat
excess, and altered chronic inflammation markers [29, 37–
40]. Intrauterine growth retardation was subsequently
related to hyperinsulinemia and to exaggerated adrenarche,
and longitudinal data uncovered a sequence from reduced
fetal growth, to childhood catch-up in weight, to premature
pubarche, and to hyperinsulinemic hyperandrogenism in
adolescence [41–43].
3 Premature pubarche and metabolic risk factors
13 3.1 Insulin sensitivity
Hyperinsulinemia, increased early insulin responses to an
oral glucose load, increased glucose uptake rate in
peripheral tissues, elevated free androgen indexes [T
(nmol/L)/SHBG (nmol/L)×100], and decreased sex hor-
mone-binding globulin (SHBG) and IGFBP-1 levels have
been documented among lean Catalan girls with exagger-
ated adrenarche and premature pubarche. These features are
already present at premature pubarche diagnosis, persist
throughout pubertal development and seem to be related to
66
the degree of hyperandrogenemia [29, 37]. Fasting insulin
sensitivity—as assessed by the Homeostasis Model Assess-
ment (HOMA)—and the insulin area under the curve
following an oral glucose tolerance test (OGTT) were
strongly related to known cardiovascular risk factors such
as total cholesterol and central adiposity [44]. Significant
albeit less pronounced decreases in insulin sensitivity have
been described in prepubertal Northern European over-
weight girls with documented premature adrenarche with or
without premature pubarche [45]. Similarly, in another
series, nearly 50% of prepubertal Black African and
Caribbean girls with premature pubarche had significant
decreases in insulin sensitivity during frequently sampled
intravenous glucose tolerance tests [46].
First-degree relatives of girls with premature pubarche of
Northern Catalan descent are at a higher risk of impaired
glucose tolerance and type 2 diabetes. Hyperandrogenism
and an increased prevalence of gestational diabetes mellitus
are also frequent among female first degree relatives [47].
Available studies of boys with premature pubarche are
small and show inconsistent results. For example, decreased
insulin sensitivity after an OGTT, reduced circulating
SHBG and elevated IGF-I concentrations were described
in a prepubertal cohort of ethnically heterogeneous boys
with premature pubarche, whereas in lean boys of North-
ern-Catalan descent with premature pubarche, the same
parameters were found to be comparable to age-, sex- and
BMI-matched controls [27, 48].
3.2 Lipid profile and blood pressure
Girls with premature pubarche due to exaggerated adre-
narche have increased serum triglyceride levels and
low-density lipoprotein-cholesterol (LDL-C)/high-density
lipoprotein-cholesterol (HDL-C) ratios throughout pubertal
development [38]. In cross-sectional studies, both systolic
and diastolic blood pressure, total cholesterol (TC), very
low-density lipoprotein-cholesterol (VLDL-C), TC/HDL
and LDL-C/HDL-C ratios, and the atherogenic index were
significantly higher in girls with premature pubarche as
compared to control girls of the same population [49]. In
contrast, in girls selected on the basis of biochemical
premature adrenarche (with or without premature
pubarche), the weight-for-height adjusted blood pressure
and lipid levels were similar to those in normal population
controls [45].
3.3 Body composition
Central adiposity and excess visceral fat—even in the
absence of overweight or obesity—have been related to the
cluster of metabolic syndrome traits in children, including
abnormal concentrations of triglycerides, LDL-C and HDL-
Rev Endocr Metab Disord (2009) 10:63–76
C, and also to insulin resistance [50]. Girls with premature
pubarche have significantly greater waist circumference,
waist-to-hip ratio, total, truncal and abdominal fat mass [as
assessed by dual-energy X-ray absorptiometry (DXA)] than
age-, body mass index (BMI)- and pubertal stage-matched
control girls [39]. Abdominal fat mass is inversely related
to birth weight and positively related to the degree of
hyperandrogenemia and to fasting insulin and lipid levels
[39]. Excess androgens also seem to explain a concomitant
increase in bone mineral density, bone mineral content, and
circulating leptin [51, 52].
3.4 Inflammation markers
Adipose tissue has recently been recognized as an active
endocrine organ that secretes multiple bioactive factors
termed adipokines; these proteins may act locally or distally
as inflammatory, immune or hormonal signals and provide
a link between adipose tissue lipid accumulation and the
metabolic functions of other tissues such as liver and
muscle [53]. Dysregulation of adipokines is emerging as an
important mechanism by which adipose tissue contributes
to systemic insulin resistance and metabolic disease.
Among the so-called pro-inflammatory and pro-thrombotic
adipokines, are, for example, leptin, interleukin-6 (IL-6),
and plasminogen activator inhibitor-1 (PAI-1) [53–55]. In
contrast, circulating adiponectin levels—specifically those
of the high molecular weight (HMW) isoform, considered
the active form of the protein—correlate positively with
insulin sensitivity and seem to be protective for the
subsequent development of type 2 diabetes [54, 56].
A high leukocyte and/or neutrophil count and increased
neutrophil-to-lymphocyte ratios have been also related to
low-grade chronic inflammation and early cardiovascular
risk in women with ovarian hyperandrogenism [57, 58],
and also to be independent predictors of cardiovascular
events and mortality in subjects with coronary artery
disease [59].
Recent studies have disclosed that formerly LBW girls
with premature pubarche frequently have high neutrophil
counts, usually accompanied by proinflammatory shifts in
circulating IL-6 and in total and HMW adiponectin [40, 60–
62]. Hyperinsulinemic insulin resistance is a plausible
modulator of this leukocyte and adipocytokine profile,
which is in addition associated with central adiposity and
could be linked with subsequent cardiovascular risks [40].
In young girls with premature pubarche, circulating PAI-1
levels are increased compared with age-, sex-, and pubertal
stage-matched controls and are inversely related to birth
weight, so that PAI-1 levels are higher in LBW girls with
premature pubarche [63]. PAI-1 levels in early puberty
seem to predict the degree of post-menarcheal hyper-
insulinemia [63].
Rev Endocr Metab Disord (2009) 10:63–76
4 Premature pubarche and hyperinsulinemic
hyperandrogenism in adolescence
4.1 Premature pubarche and subsequent adrenal function
Reevaluation of adrenal function in adolescents and young
women with a history of premature pubarche followed
longitudinally since childhood revealed an increased inci-
dence of so-called “functional adrenal hyperandrogenism”,
a pattern of adrenal secretion resembling an exaggeration of
adrenarche, that does not imply an enzymatic abnormality.
This condition has been attributed to a dysregulation of
adrenal cytochrome P450c17, prominently in the Δ5-
pathway [13, 34, 64]. Fifty-five percent of these subjects
showed supranormal (>mean+2SD) levels after ACTH
stimulation of the 3β-hydroxysteroids 17-hydroxypregne-
nolone (17-OHPreg) and DHEA, with 50% of them also
showing excessive responses of Δ4-A and 17-hydroxypro-
gesterone (17-OHP) [64]. Neither baseline DHEAS, Δ4-A
nor post-ACTH 17-OHP values at diagnosis of premature
pubarche predicted the development of adrenal hyper-
androgenism in adolescence. Only low birth weight was
significantly associated with subsequent adrenal hyper-
Weight SDS at birth
1 In its classic form, PCOS is characterized by menstrual
0
-1
-2
-3
Non FAH FAH
n = 30 n = 16
p < 0.05 Mean
± SEM ± SD
Fig. 3 Weight at birth (SDS) in premature pubarche girls with (n=16)
or without (n=30) functional adrenal hyperandrogenism at adoles-
cence. A low weight at birth was found to be significantly associated
with subsequent functional adrenal hyperandrogenism. Modified from
Ibáñez et al. [63]
67
androgenism, pointing to the possibility of an endocrine
sequence of prenatal onset: low weight at birth, premature
pubarche in childhood and adrenal hyperandrogenism in
adolescence (Fig. 3) [64].
4.2 Premature pubarche and subsequent ovarian function
An increased incidence of hirsutism and polycystic appear-
ance of the ovaries on ultrasound in peripubertal and
postpubertal girls diagnosed with premature pubarche
during childhood had been pointed out by some authors
[65, 66]. In a group of postmenarcheal premature pubarche
girls [67], nine out of 27 had elevated scores of hirsutism
and elevated baseline androgen levels, and three also had
oligomenorrhea and polycystic ovaries on ultrasound.
Subsequently, postpubertal follow-up of girls with prema-
ture pubarche revealed a more than tenfold increased
prevalence of ovarian hyperandrogenism—the so-called
polycystic ovary syndrome (PCOS, 45% vs 3% in the
normal adolescent population); this entity seemed to occur
more frequently in girls with elevated DHEAS and/or Δ4-A
levels at diagnosis of premature pubarche (Fig. 4) [33].
4.2.1 Polycystic ovary syndrome: etiology
and pathophysiology
PCOS is the most common disorder associated with
hyperandrogenism in young females, the estimated preva-
lence being 3% in female adolescents and adults [13, 68].
abnormalities with anovulation, obesity, hyperandrogene-
mia, elevated plasma LH concentrations and ultrasono-
graphic evidence of polycystic ovaries [69]. However, PCOS
remains a controversial entity, partly due to the paucity of
knowledge of its pathogenesis, and partly because after two
consensus meetings there is still no agreement on the
diagnostic criteria [70, 71]. A significant percentage of
women with the clinical syndrome are not obese, do not have
the classic abnormalities in gonadotropin secretion, and lack
the sonographic features of PCOS [72–74].
The etiological hypotheses of PCOS are continuously
evolving to accommodate expanding knowledge on the
syndrome. Increased androgen synthesis, disrupted folliculo-
genesis and hyperinsulinemia have all been considered to be
part of the pathophysiological core of PCOS and are thought to
be triggered by genetic and/or environmental factors [75–91].
For example, several studies have investigated the contri-
bution of more than 70 candidate genes to the etiology of
PCOS [75]. Among them are polymorphic variants of genes
involved in the regulation of gonadotropin secretion, andro-
gen production and action, insulin signalling, and genes
involved in the development of diabetes and obesity [75].
Replication studies have been in some cases inconclusive—
68
Fig. 4 Correlation between
basal dehydroepiandrosterone
sulfate (DHEAS) and androste-
nedione (Δ4-A) levels at diag-
nosis of premature pubarche and
17-hydroxyprogesterone
(17-OHP) values after leuprolide
acetate challenge. Redrawn with
permission from Ibáñez et al.
[33]
for example, for the CYP11A gene encoding the cholesterol
side-chain cleavage enzyme (P450scc) and for a dinucleotide
repeat marker mapping to chromosome 19p13.2 (D19S884).
In some cases, associations could not be established between
candidate genes and PCOS traits in more than one
population; these include CAPN10, encoding calpain, and
the variable number of tandem repeats (VNTR) polymor-
phism flanking the insulin (INS) gene, which regulates its
transcription [76–79]. The role of genetic variants of the
androgen receptor (AR) gene and X-inactivation in PCOS
has yielded conflicting results. Several studies demonstrated
an inverse relationship between the length of the CAG repeat
encoding the polyglutamine tract in the N-terminal trans-
activation domain of the AR and receptor activity, and thus,
sensitivity to androgens [80, 81]. However, as the AR gene is
X-linked and one copy of the X chromosome is inactivated
in women, the pattern of X-inactivation could influence AR
activity, and thus PCOS phenotype [82].
Increasing evidence suggests that the origins of PCOS
occur in utero or in early postnatal life, a concept supported
by prenatally androgenized animal models [83]. Timing of
gestational androgen excess is important because different
PCOS-associated characteristics arise when the hormonal
insult is administered at various stages of fetal organogenesis
[83, 84]. In humans, prenatal androgenization could be
induced by genetic or environmental factors, might be
enhanced by epigenetic contributions, and might subsequent-
ly program differentiating target tissues toward the develop-
ment of the PCOS phenotype in adult life [82, 83, 85].
Intrinsic abnormalities in folliculogenesis, and/or an
abnormal endocrine environment, have been deemed
responsible for PCOS-associated dysfunctional ovulation
[86, 87]. Intra-ovarian hyperandrogenism combined with
hyperinsulinemia may promote early follicular growth,
inhibition of the follicle selection process, lack of matura-
Rev Endocr Metab Disord (2009) 10:63–76
tion of the preantral and antral follicles, and thus interfere in
the FSH-induced differentiation of granulosa cells [87].
The combination of several of these factors may result in
functional ovarian hyperandrogenism, an entity characterized
by a distinct ovarian 17-OHP hyperresponse to acute GnRH
agonist challenge, and commonly encountered in non-obese
adolescent girls with a history of premature pubarche and
exaggerated adrenarche. This entity is currently considered a
form of PCOS [4, 33, 34]. Functional ovarian hyper-
androgenism is usually associated with hyperinsulinemia
and/or insulin resistance, which are thought to be main
contributors to the ovarian—and also to the usually
accompanying adrenal–androgen excess, together with ex-
cess LH and abnormal, androgen-induced negative-feedback
of progesterone on LH secretion [88–91].
4.2.2 Polycystic ovary syndrome: diagnostic criteria
PCOS is most commonly defined according to the
proceedings of an expert conference sponsored by the
National Institutes of Health (NIH) in April 1990, which
noted the disorder as having: (1) clinical hyperandrogenism
and/or hyperandrogenemia, (2) oligoovulation, and (3)
exclusion of known disorders [92]. Another expert confer-
ence held in Rotterdam in May 2003 defined it, after the
exclusion of related disorders, by two of the following three
features: (1) oligo- or anovulation, (2) clinical and/or
biochemical signs of hyperandrogenism, or (3) polycystic
ovaries on ultrasound [93, 94]. The latter criterion has
proved to be controversial, and is considered by some to be
a late epiphenomenon of an early-onset disorder related to
prenatal growth [74, 95]. For example, among non-obese
adolescents with functional ovarian hyperandrogenism,
those with LBW appear to be at lower risk for having
polycystic ovarian morphology [95] (Fig. 5). These find-
Rev Endocr Metab Disord (2009) 10:63–76
100
75
Birthweight centile
Non PCO
50
PCO
25
0
1,5 2,0 2,5 3,0
, 3,5
Birthweight (kg)
Non-PCO (n=53) PCO (n=33)
Fig. 5 Distribution of birth weights in non-obese adolescents and
young women with ovarian androgen excess. Birth weights in patients
without polycystic ovaries (PCO) are lower (p<0.0005) than in
patients with PCO. The birth weight distribution of the PCO patients
compares to that of the general population, the birth weight centiles,
25, 50 and 75 in Catalunya being 3.1, 3.3 and 3.5. Redrawn with
permission from Ibáñez et al. [95]
ings imply that the introduction of polycystic ovarian
morphology as a diagnostic criterion [96] of PCOS will
reduce the fraction of women with a low-normal birth
weight among women with “PCOS” [43, 97], and will draw
even more attention to risk factors such as obesity.
Furthermore, these observations suggest that there are
differing developmental pathways to PCOS [43, 97], thus
calling into question the relevance of polycystic ovarian
morphology for PCOS diagnosis.
4.2.3 Polycystic ovary syndrome: syndrome X
It is now well accepted that PCOS is associated with
increased risk of cardiovascular comorbidities [98, 99].
Women with PCOS have an increased prevalence of several
established cardiovascular risk factors such as hyperinsuli-
nemia and glucose intolerance, increased abdominal adipos-
ity—specifically an increase in visceral fat—even if not
obese [100–102], dyslipidemia, hypertension, endothelial
dysfunction, and a prolonged state of low-grade inflamma-
tion [57, 58, 100]. These abnormalities are among the
components of the metabolic syndrome, and this has led to
inclusion of PCOS as part of the cluster of this disorder.
Abdominal fat excess, endothelial dysfunction and impaired
insulin sensitivity have each been related to the circulating
levels of adiponectin and other adipocytokines, as well as to
inflammatory markers such as IL-6, tumor necrosis factor-α
(TNF-α), C-reactive protein (CRP) and the neutrophil count
[57, 58, 100, 103]. Insulin resistance appears to be a key
factor linking these features to coronary artery disease.
69
4.2.4 Premature pubarche and ovarian hyperandrogenism
The development of functional ovarian hyperandrogenism
after premature pubarche in girls seems to be preceded by
an apparently normal phase with regular cycles lasting for
about 3 to 5 years after menarche, during which ovulatory
function may already be deteriorating [104]. Anovulation
seems to be more frequent in those girls with a high 17-
OHP response to ACTH testing at prepubertal diagnosis of
premature pubarche [104].
Studies of ovarian steroid secretion during puberty
indicate that girls with premature pubarche have exagger-
4,0
ated ovarian androgen synthesis compared with age,
Tanner-stage and BMI-matched control girls [105]. The
ovarian androgen hyperresponsiveness is detectable by
early puberty, but is most evident during mid- and late
puberty, and is characterized by higher basal, peak, and
incremental responses of most steroid precursors to GnRH
agonist challenge [105]. This pattern resembles the adrenal
hyperresponsiveness to ACTH typical of exaggerated
adrenarche, and is suggestive of abnormal regulation of
ovarian cytochrome P450c17 (CYP17). As the same
enzyme catalyzes androgen synthesis in the adrenals
[106], it has been proposed that there may be increased
CYP17 expression or activity in both the adrenals and the
ovaries. The ensuing hyperfunction might be first detect-
able in the adrenal gland during childhood, being unmasked
by premature pubarche, and later become evident in the
ovary through the clinical and biochemical pattern of
functional ovarian hyperandrogenism [33]. In some subsets
of patients in which genetic or environmental predisposing
factors coexist (see below), disordered regulation of CYP17
might persist postpubertally, leading to the clinical and
biochemical pattern typical of functional ovarian hyper-
androgenism.
4.2.5 Premature pubarche and ovarian hyperandrogenism:
the role of hyperinsulinemia
Girls with premature pubarche have increased insulin levels
from prepuberty that persist throughout pubertal develop-
ment and into adolescence [29, 37]. The hyperinsulinemia
is related to the degree of ovarian hyperandrogenism and to
the free androgen index (equivalent to free testosterone)
levels [37]. Hyperinsulinemia has been proposed as a
trigger in the development of adrenal and ovarian hyperse-
cretion of androgens [34]. Indeed, both insulin and IGF-I
are capable of stimulating androgen production by thecal–
interstitial cells and to augment the steroidogenesis and
ACTH responsiveness of human adrenocortical cells in
culture [107–109]. Insulin also modulates IGF-I and
insulin-like growth factor binding protein-1 (IGFBP-1)
70
action and inhibits sex hormone-binding globulin (SHBG)
production in human hepatoma cell lines [110].
Further modulation of these actions can be exerted by
genetic polymorphisms related to the secretion and/or
action of insulin and androgens, such as the INS VNTR,
the androgen receptor CAG repeat polymorphism, the
aromatase receptor haplotype, and SNPs of the IGF-I
receptor, insulin receptor substrate-1 (IRS-1) and PAI-1
genes, among others [111–116]. Obesity in pre- and early
puberty favors an additional increase in androgen synthesis
from circulating precursors and may further enhance LH
secretion and ovarian androgen production [117].
4.2.6 Low birth weight as a marker linking premature
pubarche, ovarian hyperandrogenism and hyperinsulinism
Reduced fetal growth was first related to non-insulin-
dependent diabetes mellitus in older adults [118]. Subse-
quently, reduced fetal growth was found to be associated
with insulin resistance in short prepubertal children [119],
and to pronounced adrenarche in adolescent girls [42].
Girls with premature pubarche have lower birth weight
SD scores than control girls [43]. Those girls with
premature pubarche who subsequently develop functional
ovarian hyperandrogenism have even lower birth weight.
Finally, the lowest birth weights were found in girls with—
in addition—pronounced hyperinsulinism (after an oral
glucose load, mean serum insulin levels greater than the
mean+2SD of girls with normal birth weights—between −1
and +1SD) [43] (Fig. 6).
Birthweight
SDS
*
* exerted by genetic polymorphisms [111–116]. Weight
1
* excess aggravates the phenotype or accelerates its emer-
0
-1
-2
-3
Precocious Pubarche - + + +
Ovarian Hyperandrogenism - - + +
Hyperinsulinism - - - +
n = 31 n = 25 n = 12 n = 11
* p ≤ 0.01 ± Std. Dev. ± Std. Err. Mean
Fig. 6 Birth weight scores of postmenarcheal control girls (−, − and −)
and postmenarcheal girls with a history of precocious pubarche without
ovarian hyperandrogenism and without hyperinsulinemia
(+, − and −); with ovarian hyperandrogenism and without hyper-
insulinemia (+,+ and −), and with both ovarian hyperandrogenism and
hyperinsulinemia (+,+ and +). Redrawn with permission from Ibáñez et
al. [43]
Rev Endocr Metab Disord (2009) 10:63–76
Fasting serum lipids, lipoproteins and IGFBP-1 concen-
trations were measured in a similar cohort of controls and
girls with premature pubarche [41]. Among the girls with
premature pubarche, those with dyslipidemia and with low
IGFBP-1 in adolescence had lower (p<0.0001) birth weight
SD scores than those with normal lipids, lipoproteins and
IGFBP-1, whereas girls with an intermediate number of
abnormalities had intermediate birth weight SD scores.
Thus, dyslipidemia and low IGFBP-1 in girls with
premature pubarche were related to prenatal growth
retardation.
Thus, postnatal endocrine functions apparently differ in
their susceptibility to modulation by prenatal growth
conditions. Premature pubarche with pronounced adre-
narche, ovarian hyperandrogenism, dyslipidemia and hy-
perinsulinism may all have a common prenatal origin,
rather than a direct causal relationship initiated in late
childhood or adolescence. The three “cornerstones” of this
syndrome (low birth weight, premature pubarche and
ovarian hyperandrogenism) serve to identify other markers
along the pathway: premature pubarche was found to be
preceded by central fat excess and a lean mass deficit, to be
accompanied by dyslipidemia and low SHBG levels, by an
abnormal adipokine pattern, by a high neutrophil count, and
followed by an early and fast-progressing puberty and
menarche, and by postmenarcheal adrenal hyperandrogen-
ism and anovulation [36, 58, 60, 64, 104].
Longitudinal data in girls show that the endocrine-
metabolic risk conferred by prenatal growth retardation is
not readily detectable until puberty or even post menarche,
and that it is not attributable to a higher BMI [5]. Further
modulation of the endocrine-metabolic phenotype is
gence. The true prevalence of this pathway to ovarian
hyperandrogenism will be known when birth weights have
been reported in women with ovarian hyperandrogenism
with and without obesity, hyperinsulinemia, or a polycystic
appearance of the ovaries on ultrasound.
5 Premature pubarche: novel therapies to prevent
the progression to ovarian hyperandrogenism
and to modulate the transit through puberty
Whereas low birth weight confers additional risk for
progression to adolescent ovarian hyperandrogenism in
girls with premature pubarche, the early post-menarcheal
phase has been identified as the critical period in which
concomitant amplification of hyperinsulinemia, dyslipide-
mia, fat excess, and lean mass deficit occur [5, 39].
Hyperinsulinemic insulin resistance is thought to be a key
pathogenetic factor [120–122].
Rev Endocr Metab Disord (2009) 10:63–76 71

Fig. 7 Serum testosterone, LDL- Testosterone (ng/dL) LDL-cholesterol (mg/dL) HDL-cholesterol (mg/dL)
and HDL-cholesterol, together 100 120 70
with body composition indices
(by dual-energy x-ray absorpti-
80 100 60
ometry) in 24 post-menarcheal ***
***
girls (mean age 12.4 years) who ***
had a small size at birth, followed 60 80 50
by precocious pubarche in child-
hood. Girls were randomized to 40 60 40
remain untreated (n=12; open
dots) or to receive metformin
(850 mg/day; n=12; closed dots) Truncal Fat Mass (Kg) Body Fat Mass (Kg) Lean Body Mass (Kg)
for 12 months. Means±SEM are
12 24 38
displayed. **p<0.005; ***p<
0.0001; broken lines indicate
mean reference values. Redrawn 10 20 36
with permission from Ibáñez et ** ***
***
al. [125] 8 16 34

6 12 32

0 6 12 0 6 12 0 6 12 months

30 6
Fig. 8 Gain in height, body
mass index, lean mass and body
fat in girls with premature 25 5

Body mass index (Kg/m 2 )

pubarche and history of low
birth weight, who were ran- 20 4
Height (cm)

domized to remain untreated

(n=19), or to receive metformin
**
15 3
(n=19) for 4 years. Metformin
treatment was accompanied by a
lower increment of body fat. 10 2
Means±95% confidence interval
(CI) are shown. **p<0.005 for 5 1
longitudinal differences between
subgroups. Redrawn with per- 0 0
mission from Ibáñez et al. [61]

14 14

12 12

10
Lean body mass (Kg)

10
Body fat (Kg)

8 8
**
6 6

4 4

2 2

0 0
0 2 4 0 2 4
Year Year
Mean

Untreated Metformin 95% CI

72
Insulin sensitization with metformin decreases hyperinsu-
linemia and hyperandrogenism in women with PCOS,
restores eumenorrhea and increases the rate of spontaneous
ovulation; the same effects have been observed in non-obese
adolescents with premature pubarche [120–124]. We ex-
plored the preventive use of insulin sensitization to disrupt
progression from premature pubarche to PCOS in formerly
lean girls of low birth weight, who were 6–12 months
postmenarche (age 12.4 years), with hyperinsulinemia,
hyperandrogenemia, dyslipidemia, excess truncal and body
fat, and reduced lean body mass, but without clinical signs or
symptoms of androgen excess [125]. These girls were
randomized to receive metformin [850 mg/day] or no
treatment for 12 months. In untreated girls, insulin sensitiv-
ity, serum androgens, lipids, total and truncal fat mass, and
lean body mass each deviated further from normal. In
metformin-treated girls, each of these abnormalities reversed
within 6 months, and body composition continued to
improve between 6–12 months (Fig. 7). Most benefits of
metformin were lost as soon as therapy was discontinued
[125]. These results were subsequently replicated in another
cohort of low birth weight girls with premature pubarche
from the same population [40]; the addition of flutamide was
beneficial only in a subset of girls identified by genetic
markers as having greater androgen receptor activity [126].
In low birth weight, prepubertal premature pubarche girls at
risk for PCOS, insulin sensitization with metformin (425 mg/
day) also had normalizing effects on SHBG, Δ4-A,
DHEAS, LDL- and HDL-cholesterol, triglycerides, IL-6,
adiponectin, total and abdominal fat mass, and lean body
mass [40].
As discussed, premature pubarche girls with a history of
low birth weight tend to have an early and often rapidly
progressive puberty, mainly if low birth weight is followed by
postnatal catch-up with an excess gain in weight [127, 128].
This risk seems to exist even in the absence of frank obesity;
therefore, we hypothesized that insulin resistance substan-
tially contributes to this outcome. We therefore explored the
puberty-delaying effects of insulin sensitization with metfor-
min initiated shortly after diagnosis of premature pubarche
(age ∼8 years). Metformin treatment was associated with
lower body fat and serum leptin levels, with a 0.4-year delay
in the clinical onset of puberty; and with preserved linear
growth rate [129] (Fig. 8). After 4 years, metformin-treated
girls gained on average 5.5 kg (or approximately 50%) less
fat, particularly less visceral fat, were less insulin resistant
and less hyperandrogenic, had lower IGF-I levels and a less
atherogenic lipid profile, and were less likely to be post-
menarcheal than untreated girls. However, their gains in
height, lean mass and bone mineral density were similar
[61]. The mechanisms underlying these effects are poorly
understood; they may be partly exerted, for example, through
metformin-associated improvement of insulin sensitivity in
Rev Endocr Metab Disord (2009) 10:63–76
muscle and liver, and partly by direct metformin action on
ovarian steroidogenesis [61].
6 Conclusions
Premature pubarche in girls is not necessarily a normal
phenomenon; i.e. it is not simply the earlier occurrence of
adrenarche. Long-term follow-up of these girls support the
notion that premature pubarche may be a forerunner of the
metabolic syndrome and precede the development of
clinical ovarian androgen excess in adolescence. This
sequence occurs more frequently when premature pubarche
is preceded by reduced fetal growth and followed by
excessive postnatal catch-up in height and mainly in
weight; in these girls, puberty may begin earlier, the transit
through puberty is faster, and final height may be
moderately reduced.
An unfavorable metabolic environment in which hyper-
insulinemia appears to be the key factor may unmask
genetic traits—still to be fully defined—predisposing to
ovarian dysfunction, and the unfolding endocrine abnor-
malities may further aggravate the metabolic disarray.
In formerly low birth weight girls with premature
pubarche, particularly those who are more hyperinsuline-
mic, metformin therapy may reverse the progression of
premature pubarche to clinical ovarian hyperandrogenism,
may normalize body composition and excess visceral fat,
and may delay pubertal progression without attenuating
linear growth. These findings suggest that in this subpop-
ulation of girls with premature pubarche, adult height may
be increased. Long-term follow up of these patients is
needed to fully determine the ultimate effects of insulin
sensitization as well as the maintenance of these benefits
after discontinuing therapy.
Acknowledgements LI and MVM are Clinical Investigators of
CIBERDEM (FIS, Instituto de Salud Carlos III, Madrid, Spain).
ALB is an Investigator of the Fund for Scientific Research I3
(Ministry of Education and Science, Spain).
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