Developmental Cognitive Neuroscience 25 (2017) 1228 [619041]

Developmental Cognitive Neuroscience 25 (2017) 12–28
Contents lists available at ScienceDirect
Developmental Cognitive Neuroscience
jo ur nal ho me pag e: http://www.elsevier.com/locate/dcn
A systematic review of adrenarche as a sensitive period in
neurobiological
development and mental health
Michelle L. Byrnea, Sarah Whittleb, Nandita Vijayakumara, Meg Dennisonc,
Julian G. Simmonsb,d, Nicholas B. Allena,d,∗
aDepartment of Psychology, University of Oregon, Eugene, OR, USA
bMelbourne Neuropsychiatry Centre, The University of Melbourne and Melbourne Health, Victoria, Australia
cDepartment of Psychology, University of Washington, Seattle, WA, USA
dMelbourne School of Psychological Sciences, The University of Melbourne, Victoria, Australia
a r t i c l e i n f o
Article history:
Received
18 April 2016
Received
in revised form
17
September 2016
Accepted
12 December 2016
Available
online 21 December 2016
Keywords:PubertyAdrenarcheSensitive periods
Mental
health
Brain
developmenta b s t r a c t
Substantial hormonal and neurobiological changes occur during puberty, and are widely argued to ren-
der this period of life a sensitive period in terms of risk for mental health problems. However, there is
a paucity of research focusing on adrenarche, the earlier phase of pubertal development. Furthermore,
there is a limited understanding of the association between adrenarche and neural development during
this phase of life. We systematically reviewed research examining human adrenarcheal development as
operationalized by hormonal levels of DHEA and DHEA-S, in relation to indices of mental health (Sys-
tematic Review 1). We then reviewed the limited amount of literature that has examined the association
between adrenarcheal development and brain structure or function (Systematic Review 2). In general,
studies showed that earlier timing of adrenarche was associated with greater mental health symptoms,
and there is emerging support that brain development plays a role in this relationship. However, sev-
eral methodological inconsistencies were noted. We propose that future research in this area test a
theoretical model of adrenarche as a sensitive period of neurobiological development, whereby timing
of exposure to hormones interacts with brain development, biological sex, and psychosocial stress to
influence environmental sensitivity and risk for mental health problems through adolescence.
© 2016 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND
license (http://creativecommons.org/licenses/by-nc-nd/4.0/ ).
Contents
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
1.1. Adrenarche in human development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
1.2. Possible links between adrenarcheal and brain development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
1.3. The case for adrenarche as a sensitive period in mental health development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
1.4. The aim of this review. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .14
2. Material and methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
2.1. Methods of systematic review (SR) 1: adrenarcheal development and mental health . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
2.1.1. Literature search of SR1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
2.1.2. Inclusion and exclusion criteria of SR1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .14
2.2. Methods of SR2: adrenarcheal development and brain structure or function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
2.2.1. Literature search of SR2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
2.2.2. Inclusion and exclusion criteria of SR2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .16
3. Results. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .17
3.1. Results of SR1: adrenarcheal development and mental health. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .17
3.1.1. Methods of measuring adrenarche in SR1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
3.1.2. Summary of overall patterns of results in SR1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
∗Corresponding author at: Department of Psychology, 122 The University of Oregon, Eugene, OR 97403, USA.
E-mail address: nallen3@uoregon.edu (N.B. Allen).
http://dx.doi.org/10.1016/j.dcn.2016.12.004
1878-9293/© 2016 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.
0/).

M.L. Byrne et al. / Developmental Cognitive Neuroscience 25 (2017) 12–28 13
3.1.3. Summary of patterns by sex in SR1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
3.1.4. Summary of patterns by measurement of mental health in SR1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
3.2. Results of SR 2: adrenarcheal development and brain structure or function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
4. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
5. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
Conflicts of interest and source of funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
1. Introduction
Substantial changes occur during puberty, including social and
physical development, increases in hormones and hormonal reac-
tivity, and related neurobiological development. These changes are
widely argued to render this period of life a sensitive period in
terms of risk for mental health problems (Ladouceur et al., 2012;
Paus et al., 2008 ). However, there are two separate phases in
pubertal development: adrenarche , which is triggered by the mat-
uration of the zona reticularis of the adrenal gland, and gonadarche ,
associated
with the maturation of the hypothalamic-pituitary-
gonadal axis. A link between puberty and mental health has been
mainly demonstrated with respect to the second phase of puber-
tal development, gonadarche, which begins with the secretion of
gonadotropin-releasing hormone (GnRH) from the hypothalamus
at approximately 10–11 years of age, and triggers a rise in testos-
terone and estradiol, the maturation of primary and secondary
sexual characteristics, and menarche in girls (Dorn, 2006 ). Individ-
ual differences in puberty can be measured in three ways. First,
pubertal status, the developmental stage at which an individual is
at a given point of time, can be measured by physical characteristics
such as Tanner stage. Tanner stage can be assessed via self-report,
parent-report, or a physical examination by a physician. Second,
pubertal timing, which is pubertal status relative to same-age and
−sex peers, can be measured by comparing stage/status via physical
characteristics to peers, or by comparing levels of pubertal hor-
mones to peers. Third, pubertal tempo, which is how quickly an
individual passes through pubertal stages, can be measured over
time (i.e., longitudinally) to examine the rate of maturation via
physical characteristics or levels of hormones. We note that there
is a paucity of studies that examine pubertal tempo in relation to
mental health. Pubertal stage (gonadarche), on the other hand, has
shown to be associated with mental health (Angold et al., 1998;
Oldehinkel et al., 2011 ), and, in particular, it is pubertal timing that
appears to be especially salient in predicting the onset of mental
health problems (e.g., Angold and Costello, 2006; Kaltiala-Heino
et al., 2003b; Mendle et al., 2010 ), and may be associated with
different symptoms compared to pubertal stage alone (Oldehinkel
et al., 2011 ). Early timing of gonadarche has been associated with
depression (Copeland et al., 2010; Graber et al., 2004 ), anxiety
(Hayward et al., 1992; Patton et al., 1996; Zehr et al., 2007 ), and
eating (Zehr et al., 2007 ) and behavioral disorders (Copeland et al.,
2010; Lynne et al., 2007; Stattin and Magnusson, 1990 ), especially
for girls (Ge et al., 2001b ), while the evidence for boys is more mixed
(Ge et al., 2001a; Graber et al., 1997; Kaltiala-Heino et al., 2003a ).
1.1. Adrenarche in human development
Considerably less work has focused on how adrenarche, the
earlier phase of pubertal development associated with a dramatic
increase in the level of androgens secreted by the adrenal cor-
tex, affects psychological and neural functioning. This is surprising
given that 1) early timing of adrenarche is a known risk factor
for poor physical health later in life (Ibá˜nez et al., 2006 ), and 2)
adrenarche does not occur in species other than human beings
and some higher primates (Conley et al., 2012 ), and thereforemay have specific evolutionary significance that might be asso-
ciated with patterns of neural development particular to these
species. Adrenarche typically begins around five to seven years of
age when levels of the androgens dehydroepiandrosterone (DHEA)
and its sulfate (DHEA-S), secreted from the adrenal glands, begin
to increase, before the hypothalamic-pituitary-gonadal axis is re-
activated (Parker et al., 1978; Rainey et al., 2002; Remer et al., 2005 ).
DHEA is converted to DHEA-S through a sulfation process and is
also more stable as DHEA-S (Maninger et al., 2009 ). Adrenarche and
gonadarche are separate periods that are activated and controlled
by
independent mechanisms (Counts et al., 1987 ). Importantly, the
external physical changes associated with adrenarche (increased
skin oil production, body odor, and skeletal maturation; Dorn and
Chrousos, 1997 ) may not be obvious until well after the initial rise in
adrenarcheal hormones has begun (Wan, 2012 ) and as of yet there
are no references values for DHEA/DHEA-S that match the physical
manifestations of adrenarche (Uc¸ ar, 2015 ). This means that mea-
surement of these hormones as objective indications of this phase
is vital for research examining adrenarche.
1.2. Possible links between adrenarcheal and brain development
Moreover, there is limited understanding of the association
between adrenarche and neural development during this phase
of life. However, it has been proposed that adrenarche serves an
evolutionary purpose for humans to extend brain development
and promote synaptogenesis for social learning that is neces-
sary starting from this age (Campbell, 2006 ). Indeed, there is
evidence suggesting that adrenarcheal hormones may be key fac-
tors in brain development during the transition from childhood
to early adulthood. For example, animal research has demon-
strated that DHEA and DHEA-S have pleiotropic roles in the brain
including stimulating neurite growth and neurogenesis, modify-
ing neural activity via direct and indirect effects (via conversion to
testosterone, di-hydrotestosterone and estrogen) on pre- and post-
synaptic receptor and binding sites, and neuroprotective effects
(via anti-glucocorticoid, anti-oxidant and inhibition of apoptosis;
Maninger et al., 2009 ). Rodent work has demonstrated that DHEA
administration decreases cognitive impairments and putatively
depressive behaviors by enhancing neurogenesis in the hippocam-
pus (Moriguchi et al., 2013, 2011 ). In adults, administration of
DHEA appears to reduce activity in the amygdala and hippocampus,
enhance connectivity between the amygdala and hippocampus,
and enhance activity in the rostral anterior cingulate cortex (rACC)
during emotional processing and regulation (Sripada et al., 2013 ).
Furthermore, the timing of adrenarcheal hormones may follow
patterns in brain development, suggesting that these hormones
may have organizational and activation roles in the brain, although
more research is needed. For example, DHEA-S levels are high
at birth, decrease rapidly after birth, begin to increase again at
the beginning of adrenarche around five to six years of age, and
peak in the mid-20s (Rainey et al., 2002; Sulcová et al., 1997 ) –
although it should be noted that other research has shown that
DHEA begins to increase closer to seven years of age (Remer et al.,
2005 ), or later depending on sex (Sulcová et al., 1997 ). Timing of
adrenarche is variable, and in particular, consensus regarding def-

14 M.L. Byrne et al. / Developmental Cognitive Neuroscience 25 (2017) 12–28
initions of premature adrenarche (PA) vary (Idkowiak et al., 2011;
Utriainen et al., 2015 ), although the consensus as of yet is that PA
is defined by increasing levels of adrenarcheal hormones before
age 8 in girls and 9 in boys in conjunction with physical signs such
as pubarche (Idkowiak et al., 2011 ). Little is known about under-
lying causes of variation in the timing of adrenarche, although it
has been associated with sex, ethnicity and body mass (for review,
see Utriainen et al., 2015 ), and prenatal stress (Belsky et al., 2015 ).
Therefore, further longitudinal research following children from
ages five through to gonadarche is needed to determine the average
age, range, and individual differences associated with the onset of
adrenarche.
Nevertheless, this timing of the onset of adrenarche, as mea-
sured by DHEA-S, appears to be similar to that observed for cortical
glucose utilization rates, which peak from four to eight years of age
(with one study showing a single peak at 7.8 years; Muzik et al.,
1999 ), and is also similar to when the brain reaches its adult volume
(for review see Campbell, 2011 ). Furthermore, maturation of grey
matter in the cerebral cortex continues into the early 20s (Gogtay
et al., 2004 ), and as stated earlier, levels of DHEA-S peak after age 20
(Rainey et al., 2002; Sulcová et al., 1997 ). In sum, similar patterns in
the increase in DHEA and DHEA-S and indices of brain maturation,
which are nicely visualized in a review by Campbell (2011) , are sug-
gestive of the hypothesis that adrenarche may have salient effects
on brain development beginning from childhood and throughout
adolescence and early adulthood.
1.3. The case for adrenarche as a sensitive period in mental health
development
Although studies of child and adolescent brain development
have mainly focused on changes associated with chronological age
(Mutlu et al., 2013; Tamnes et al., 2010; Vijayakumar et al., 2016;
Wierenga et al., 2014 ), it has been suggested that patterns of brain
development might be better explained by pubertal (particularly
gonadal) development (Crone and Dahl, 2012; Giedd et al., 1999 ).
Further, it has been suggested that periods of marked brain devel-
opment during the transition from childhood to adolescence might
render the brain particularly sensitive to factors that contribute
to the development of mental health problems (Blakemore et al.,
2010 ). We posit that in addition to gonadarche, the adrenarcheal
period may be a particularly sensitive period of development when
hormones, neurobiological maturation, and environmental risk fac-
tors interact to influence psychosocial development. This sensitive
period may begin as early as age five, when levels of adrenar-
cheal hormones rise, but more research measuring adrenarcheal
hormones over time is needed to confirm this. However, during
the transition from childhood to adolescence, the brain contin-
ues to experience rapid growth and reorganization, second only
to infancy in terms of its significance (Spear, 2000 ). It becomes
more plastic and hence sensitive to internal and external factors
that may influence neurodevelopmental trajectories (Andersen and
Teicher, 2008 ). The period of adrenarche, starting in childhood, is
characterized by significant changes across the cortex, including
development of prefrontal and limbic regions that support emo-
tional and behavioral regulation (Kesek et al., 2009 ), as well as the
connections between these regions (Cunningham et al., 2002 ).
Therefore, neurodevelopmental mechanisms are likely to be
important mediators of the association between adrenarche and
mental health outcomes. A review of the extant research on
adrenarche and both mental health and brain development is
timely to establish whether there are consistent patterns and asso-
ciations. This review will also highlight research directions and
methodological issues that require further investigation.1.4. The aim of this review
In this review paper, we will use PRISMA guidelines to system-
atically review research that has examined human adrenarcheal
development, as measured by levels of the adrenarcheal hormones
DHEA and DHEA-S, in relation to indices of mental health (Sys-
tematic Review 1). We will then review the more limited amount
of literature (including a series of studies by our group) that has
examined the association between adrenarcheal development and
brain structure or function (Systematic Review 2). We will com-
ment on potentially important factors that influence associations
between adrenarcheal development, brain structure/function, and
mental health, such as timing of exposure to adrenal hormones, and
biological sex. Finally, we propose a theoretical model of adrenar-
che as a sensitive period of neurobiological development, whereby
brain development can either interact with, or mediate the asso-
ciation between timing of exposure to hormones, environmental
sensitivity, and risk for mental health problems through adoles-
cence. In addition to exploring the prospective effects of adrenarche
on subsequent neurobiological and psychosocial development, we
will explore factors associated with earlier timing of adrenarche,
such as psychosocial stress (e.g., Ellis and Essex, 2007 ), to build a
theoretical framework that can guide future investigation.
2. Material and methods
2.1. Methods of systematic review (SR) 1: adrenarcheal
development and mental health
The systematic reviews were conducted according to the
PRISMA guidelines (Moher et al., 2009 ). Online searches of the
PubMed, MEDLINE (EBSCO host), and PsycINFO (APA PsycNET)
databases were performed in August 2016. Fig. 1 presents a
flowchart and details of the procedure for SR1.
2.1.1. Literature search of SR1
Abstracts were reviewed for references to measurement of
DHEA/DHEA-S during puberty and mental health. If the study
was relevant, the full text was retrieved. Additional studies were
retrieved through other methods, including reviewing bibliogra-
phies of articles identified through the search terms.
2.1.2. Inclusion and exclusion criteria of SR1
Journal articles were included in SR1 if they reported on studies
that 1) measured adrenarche from five years (Rainey et al., 2002 )
onwards1through basal levels of adrenarcheal hormones DHEA or
DHEA-S, and 2) measured any Axis-I mental health symptoms or
diagnosis of a mental illness either through self-report question-
naires, parent or teacher questionnaires, or researcher observed
scales. We included studies that either 1) conducted analyses
between continuous levels of adrenarcheal hormones and men-
tal health problems, or 2) placed participants into adrenarcheal
groups based on levels of adrenarcheal hormones and examined
group differences in mental health. The age range for mental health
measurement was not limited to allow for the inclusion of longitu-
dinal studies that investigated long term mental health outcomes
associated with adrenarche. Studies that measured overall puber-
tal development (status, timing, or tempo) but did not differentiate
between adrenarche and gonadarche (i.e., studies that only mea-
sured total score on the Pubertal Development Scale or Tanner
staging and did not measure levels of DHEA or DHEA-S) were not
1We did not include a specific upper age limit to define the end of adrenarche
because there is currently no consensus on the end status of adrenarche.

M.L. Byrne et al. / Developmental Cognitive Neuroscience 25 (2017) 12–28 15
Fig. 1. Procedure used for study selection in Systematic Review 1 (Adrenarche and mental health).
included. Further inclusion and exclusion criteria for SR1 are pre-
sented in Fig. 1.
2.2. Methods of SR2: adrenarcheal development and brain
structure or function
Fig. 2 presents a flowchart and details of the procedure for SR2.2.2.1. Literature search of SR2
Abstracts were reviewed for references to measurement of
DHEA/DHEA-S during puberty and brain structure or function. If the
study was relevant, the full text was retrieved. Additional studies
were retrieved through other methods, including reviewing bibli-
ographies of articles identified through the search terms.

16 M.L. Byrne et al. / Developmental Cognitive Neuroscience 25 (2017) 12–28
Fig. 2. Procedure used for study selection in Systematic Review 2 (Adrenarche and Brain Structure/Function).
2.2.2. Inclusion and exclusion criteria of SR2
Journal articles were included in SR2 if they reported on studies
that 1) measured adrenarche from five years onwards through basal
levels of adrenarcheal hormones DHEA or DHEA-S, and 2) measured
brain structure using MRI, or brain function during emotional or
social processing using fMRI or PET. We did not include EEG studies
in our review as they would not be as informative as to the specificcircuits and regions involved during adrenarche. Again, studies that
measured overall pubertal development (stage, timing, or tempo)
but did not differentiate between adrenarche and gonadarche (i.e.,
studies that only measured total score on the Pubertal Develop-
ment Scale or Tanner staging and did not measure levels of DHEA or
DHEA-S) were not included. Further inclusion and exclusion criteria
for SR2 are presented in Fig. 2.

M.L. Byrne et al. / Developmental Cognitive Neuroscience 25 (2017) 12–28 17
3. Results
3.1. Results of SR1: adrenarcheal development and mental health
3.1.1. Methods of measuring adrenarche in SR1
A summary of each study is presented in Table 1. Studies mea-
sured adrenarche in different ways. First, five studies measured
levels of adrenarcheal hormones (DHEA and/or DHEA-S) alone
(Belsky et al., 2015; Constantino et al., 1993; Goodyer et al., 2000,
1996; Van Goozen et al., 1998 ), and twelve studies measured both
hormones and physical characteristics associated with adrenarche,
such as Tanner stage of pubic hair development (Dorn et al., 2008,
1999; Klauser et al., 2015; Mundy et al., 2015; Murray et al., 2016;
Nottelmann et al., 1987; Shirtcliff et al., 2007; Sontag-Padilla et al.,
2012; Susman et al., 1996, 1987; van Goozen et al., 2000; Whittle
et al., 2015 ). Amongst the latter, three compared groups of children
with “premature adrenarche” (PA) with on-time children based on
Tanner pubic hair stage, but then confirmed PA status by showing
that levels of adrenarcheal hormones were significantly higher in
the PA compared to the on-time group (Dorn et al., 2008, 1999;
Sontag-Padilla et al., 2012 ), consistent with the definition of PA
(Idkowiak et al., 2011 ). We considered these studies to be mea-
suring differences in adrenarcheal hormones in a similar way that
Klauser et al. (2015) placed participants into early vs. late adrenar-
cheal timing based on levels of DHEA and testosterone, or Belsky
et al. (2015) defined a pre-adrenarcheal group as DHEA below a
detection threshold.
Second, studies handled the issue of adrenarcheal timing in
different ways. For example, some measured levels of hormones
across different ages and did not control for exact age, which
could be seen as measuring adrenarcheal stage instead of tim-
ing (Constantino et al., 1993; Dorn et al., 2008, 1999; Goodyer
et al., 2000, 1996; Sontag-Padilla et al., 2012; Susman et al., 1996,
1987; Van Goozen et al., 1998 ). Although two of these studies lim-
ited the age range of the participants to approximately two to
three years (Dorn et al., 2008; Sontag-Padilla et al., 2012 ), most
had wider age ranges (Constantino et al., 1993; Goodyer et al.,
2000, 1996; Susman et al., 1996, 1987; Van Goozen et al., 1998 ).
Furthermore, one of these studies compared a group of children
aged six to nine years with PA to those with on-time adrenar-
che, and although the authors did not statistically control for age,
they found no significant age difference between groups (Dorn
et al., 1999 ). Another two similar studies age-matched on-time
children with PA children within six months (Dorn et al., 2008;
Sontag-Padilla et al., 2012 ), and these could be argued to have mea-
sured adrenarcheal timing instead of stage. Three studies (Mundy
et al., 2015; Nottelmann et al., 1987; van Goozen et al., 2000 ) mea-
sured levels of hormones but controlled for chronological age in
their statistical models, which could therefore be considered to
be adrenarcheal timing (i.e., developmental differences standard-
ized by age;), although one of these studies controlled for both
age and Tanner stage pubertal development (Nottelmann et al.,
1987 ). Another study measured Tanner stage in addition to DHEA
levels but, rather than controlling for Tanner stage, this variable
was examined as a separate dependent variable in the association
with DHEA levels (Shirtcliff et al., 2007 ). Yet, other studies mea-
sured adrenarcheal timing explicitly by design by restricting the
age range and classifying early vs. late timing based on compar-
ative levels of adrenarcheal hormones. For example, Belsky et al.
(2015) measured DHEA in salvia in Grade 1 girls aged 6.8–7.8 years
and classified girls with six out of eight undetectable assays as pre-
adrenarcheal. A further three studies (Klauser et al., 2015; Murray
et al., 2016; Whittle et al., 2015 ) included data from the “Imag-
ing brain development in the Childhood to Adolescence Transition
Study” (iCATS). This study recruited children from a larger cohort(CATS; Mundy et al., 2015, 2013 ) based on earlier or later timing of
adrenarche by measuring levels of salivary DHEA and testosterone
in children approximately nine years of age, with the crossover area
of the upper tertiles of DHEA/testosterone characterized as rela-
tively earlier development, and the lower tertiles as relatively later
development (Simmons et al., 2014 ).
3.1.2. Summary of overall patterns of results in SR1
In many studies, children with higher levels of DHEA or DHEA-
S (or earlier timing of adrenarche based on higher levels of these
hormones compared to peers) had higher levels of mental health
symptoms or a greater likelihood of having a mental disorder
(Belsky et al., 2015; Dorn et al., 2008, 1999; Mundy et al., 2015;
Sontag-Padilla et al., 2012; Susman et al., 1996, 1987; van Goozen
et al., 2000; Van Goozen et al., 1998; Whittle et al., 2015 ). However,
there were a significant number of studies that showed opposite
associations, that lower levels of DHEA/DHEA-S were associated
with mental health problems (Nottelmann et al., 1987; Shirtcliff
et al., 2007; Goodyer et al., 1996 ). Further breakdown of these find-
ings based on mental health problems are presented in section
3.1.4 . Interestingly, of the studies that found a negative association,
Goodyer et al. (1996) found that it was specifically morning DHEA
(measured at 08:00 h) that was lower in a group of adolescents with
MDD, suggesting that the diurnal variation in DHEA is a method-
ological concern for future research. Furthermore, Nottelmann et al.
(1987) found that when controlling for Tanner pubertal status and
chronological age, only the negative association between DHEA-
S and social self-image problems in girls survived. A few studies
found no significant associations between DHEA/DHEA-S and men-
tal health (Constantino et al., 1993; Goodyer et al., 2000; Murray
et al., 2016 ). Of these, Goodyer et al. (2000) only measured DHEA to
predict if participants developed MDD over a 12 month follow-up,
but did not conduct cross-sectional analyses of DHEA and self-
report symptoms at baseline. Another study found no associations
between anxiety symptoms and levels of DHEA or DHEA-S, but
found that earlier Tanner stage within a cohort (which could be
interpreted as later pubertal timing) was associated with higher
obsessive compulsive disorder symptoms (Murray et al., 2016 ).
3.1.3. Summary of patterns by sex in SR1
Studies that differentiated by sex mainly showed that higher
levels of DHEA and DHEA-S (or earlier timing of adrenarche) was
associated with higher levels of mental health symptoms (including
externalizing) amongst girls (Dorn et al., 2008; Mundy et al., 2015;
Sontag-Padilla et al., 2012; Whittle et al., 2015 ), although one study
found that higher levels of internalizing symptoms were associated
with lower levels of DHEA in girls only (Shirtcliff et al., 2007 ), two
studies found similar negative associations between DHEA-S and
externalizing symptoms (Susman et al., 1996, 1987 ), and one found
negative associations between DHEA-S and both internalizing and
externalizing symptoms (only when not controlling for age and
Tanner pubertal status; Nottelmann et al., 1987 ). For boys, results
were similar; one study found that higher levels of DHEA were asso-
ciated with higher levels of anxiety symptoms (Susman et al., 1996 ),
and another found the same for self-reported sadness (Susman
et al., 1987 ), in boys only and not girls. Another found that boys with
conduct disorder or ODD had higher levels of DHEA-S than controls,
and DHEA-S was positively associated with symptoms of delin-
quency and aggression (Van Goozen et al., 1998 ). However, one
study found that levels of DHEA-S were negatively associated with
self-reported impulse control and parent-reported delinquency in
boys (Susman et al., 1987 ). Finally, two studies found no significant
associations for boys: one study found no significant differences in
depressive or anxiety symptoms between early and late develop-
ers (based on hormone levels), for girls and boys together, or for
boys and girls separately (Klauser et al., 2015 ); another study of

18 M.L. Byrne et al. / Developmental Cognitive Neuroscience 25 (2017) 12–28Table 1
Summary of studies from Systematic Review 1 (SR1).
Authors (year);
PubMed IDSample Measure(s) of adrenarche Measure(s) of mental health Summary of findings
Murray et al.
(2016)
PMID: 26600008100
children who completed
an MRI scan, out of 128
9-year-old children, selected
based on high vs. low DHEA
and testosterone levels in
saliva 6 months priorContinuous levels of DHEA,
DHEA-S, and testosterone were
measured again in saliva
(averaged across 2 mornings)Self-reported SCAS (anxiety
symptoms)SCAS scores were not significantly associated with hormone measures
Note: Associations between adrenarche and brain structure were found,
reported in SR2.
Whittle et al.
(2015)
PMID: 2567854883 children who completed an
fMRI task, out of 128
9-year-old children, selected
based on high vs. low DHEA
and testosterone levels in
saliva 6 months priorContinuous levels of DHEA and
testosterone were measured
again in saliva (averaged across
2 mornings)Parent-report CBCL
(externalizing symptoms only),
self-reported CDI (depressive
symptoms), and self-reported
SCAS (anxiety symptoms)In females only, CBCL externalizing score was positively associated with
DHEA (r = 0.364, p < 0.05). There were no significant associations between
DHEA and mental health in males.
Note: Associations between adrenarche and brain function were found,
reported in SR2.
Klauser et al.
(2015)
PMID: 2545989741 early developing (mean age
9.64 ± 0.35) and 44 late
developing (9.48 ± 0.30)
children based on DHEA and
testosterone levelsEarly
vs. late adrenarche based
on levels of DHEA and
Testosterone approximately 6
months earlier; Tanner stage
based on parent-report Sexual
Maturity Status line drawingsSelf-reported CDI (depressive
symptoms) and self-reported
SCAS (anxiety symptoms)Controlled for Tanner stage to exclude effect of early gonadarche, and for
age.No
significant differences between early and late children were found for
CDI or SCAS scores, for boys and girls together, or for boys or girls
separately.
Note:
Associations between adrenarche and brain structure were also found,
reported in SR2.
Belsky et al. (2015)
PMID: 2591559273
females in Grade 1 (aged
6.8–7.8 years, mean
age = 7.25 years)DHEA measured in saliva 4
times at home visit following
Grade 1. Preadrenarcheal (41%
of sample) = 6/8 assays below
detection threshold of 10 pg/ml
and all <16 pg/mlAt
age 18 (mean age 17.84 yrs),
self-report MacArthur Health
and Behavior Questionnaire
(internalizing and
externalizing)Longitudinal study found path for prenatal stress → maternal depression &
negative parenting in infancy → increased cortisol at 4.5 yrs → accelerated
adrenarcheal development → more physical and mental health problems
age 18. Adrenarche & mental health correlated at 0.32 (p < = 0.01)
Mundy et al. (2015)
PMID: 26592329Population based study of 1124
children aged 8–9.DHEA, DHEA-S, and
testosterone measured in
saliva. Hormone levels were
standardized by age
(separately by sex), then
categorized into minimal,
intermediate, and advanced
development.Parent-report Strengths and
Difficulties Questionnaire
(Difficulties scales: Emotional
symptoms, conduct problems,
hyperactivity/inattention, peer
problems; Other scale:
prosocial behavior)In
females, only higher levels of DHEA-S were positively associated with
peer problems only.
In males: higher levels of DHEA were associated with more peer problems
and emotional symptoms; higher levels of DHEA-S were associated with
more total difficulties, conduct problems, hyperactivity/inattention, and
peer problems; higher levels of testosterone were associated with more
total difficulties, peer problems, and emotional symptoms.
Sontag-Padilla
et al. (2012)
PMID: 2229300576
girls mean age 7.50 years,
SD = 0.85. Two groups: 40 with
PA (recruited from pediatric
endocrine clinics), 36 on time
(recruited via community)Premature adrenarche (PA) vs.
on-time adrenarche. PA
documented by a pediatric
endocrinologist, Tanner 1
breast, Tanner 2 or greater
pubic hair (On-time were
Tanner 1 breast and Tanner 1
pubic
hair).
Adrenal hormones DHEA-S and
androstendione were
measured in serum to confirm
PA status.Parent report of the CBCL
(internalizing and
externalizing); Child
self-report CDI (depressive
symptoms), child self-report
STAI-C (anxiety symptoms)Main effects – PA girls had higher levels of CBCL internalizing scores [50.70
(10.45) vs. 46.06 (8.99), t = −2.01, d = 0.48, p < 0.05], and higher CBCL
externalizing scores [50.28 (9.02) vs. 45.00 (8.67), t = −2.53, d = 0.60, <0.01]
Interactions – PA interacted with: lower levels of executive functioning to
predict higher externalizing and anxiety symptoms; increased cortisol to
predict externalizing symptoms; and decreased cortisol to predict
depressive symptoms

M.L. Byrne et al. / Developmental Cognitive Neuroscience 25 (2017) 12–28 19Dorn et al. (2008)
PMID: 18655525Same
sample as Sontag-Padilla
et al. (2012)See Sontag-Padilla et al. (2012) .
This study also examined
testosterone in bloodDISC
(diagnostic interview);
teacher and parent report CBCL
(internalizing and
externalizing); child self-report
CDI (depressive symptoms),
child self-report STAI-C
(anxiety symptoms), child
self-report relational
aggressionCompared to on-time girls, PA girls had:
− higher rate of diagnosis of ODD in the past year (20% vs 3.1%; p = 0.04),
past month (17.5% vs 0%; p = 0.02), and lifetime (20% vs 3.1%; p = 0.04);
− higher symptoms scores for separation anxiety (3.13 ± 2.43 vs.
1.77 ± 1.93), specific phobia (1.40 ± 1.13 vs. 0.59 ± 0.S4), GAD (3.08 ± 2.38
vs. 1.59 ± 1.74), panic disorder, OCD (0.48 ± 0.91 vs. 0.03 ± 0.18), MDD
(4.93 ± 3.71 vs. 2.09 ± 1.91), ADHD (5.10 ± 4.87 vs. 2.59 ± 3.23), and ODD
(6.45 ± 3.07 vs. 4.59 ± 3.10);
− higher scores of parent-report Social Problems (55.2 ± 7.3 vs. 51.8 ± 4.6),
Anxious/Depressed (54.2 ± 5.3 vs. 51.8 ± 3.4), Aggressive Behavior
(54.0 ± 5.4 vs. 51.5 ± 3.2), total Externalizing Behavior (50.3 ± 9.0*
45.0 ± 8.7), total Internalizing Behavior (50.7 ± 10.5* 46.1 ± 9.0) and total
Behavior Problems (50.0 ± 11.2** 4l.S ± 14.3) on the CBCL;
− and higher scores of teacher-report aggressive behavior on the CBCL
(p = 0.03)
Shirtcliff et al.
(2007)
PMID: 17537074106 boys and 107 girls, mean
age 13.7 years (SD = 1.7)Continuous
baseline levels
(prior to a stress task) of DHEA
in saliva (also measured
pubertal development via
Tanner stage)Internalizing and externalizing
symptoms with the parent-
and child-report CBCL and DISC
interviewGirls with more internalizing problems had lower levels of baseline DHEA.
No significant associations between baseline DHEA and symptoms for boys.
Goodyer et al.
(2000)
PMID: 1110232373
boys, 107 girls, mean age
13.5 years (range 12.2–16.5) at
high risk for psychopathology
(due to recent negative life
events, high emotionality, or
parental history)DHEA
in saliva at 08:00 and
20:00, averaged across 4 days,
i.e., mean morning DHEA and
mean evening DHEA.Self-report depressive
symptoms (Mood and Feelings
Questionnaire); DSM-IV
criteria for MDD with the
K-SADS interview at a 12
month follow-up.Mean
DHEA (either morning or evening) did not predict if participants
developed MDD at follow-up; however, associations between mean
DHEA and self-report symptoms at baseline were not measured.
van Goozen et al.
(2000)
PMID: 110689013 groups of children, 24 with
ODD, 42 psychiatric controls
(PC), and 30 normal controls
(NC; 16 boys), aged between 6
and 12 (ODD mean = 10.1, PC
mean = 9.3, NC mean = 10.1).DHEA-S
measured in plamsa.
Tanner stage measured for
pubic hair and breast or male
gential developmentDSM-IV
criteria via
semistructured diagnostic
interview for ODD and other
psychiatric disordersDHEA-S : Controlling for age and Tanner stage, there was a main effect of
group [F (2,76) = 5.65, p < 0.01], with the ODD group having higher levels of
DHEA-S (ODD = 3.01 /H9262mol/L ± 1.7, PC = 1.63 ± 1.4, NC = 2.03 ± 1.1).
Dorn et al. (1999)
PMID: 9988243Pilot
study of children 6–9
years old. 9 PA (8 girls, enrolled
from pediatric endocrine
clinics), 20 on-time (8 girls,
recruited from the
community).Premature adrenarche (PA) vs.
on-time adrenarche. PA
documented by a pediatric
endocrinologist, Tanner 2 or 3
pubic hair (On-time were
Tanner 1 breast or genital and
Tanner 1 pubic hair).
Adrenal hormones DHEA,
DHEA-S and
delta-4-androstenedione were
measured in serum and were
higher in PA group.Parent-report
DISC interview
for DSM-III disorders,
parent-report CBCL, self-report
CDI (depressive symptoms),
and self-report STAI-C (anxiety
symptoms)PA children had higher CDI scores at the trend level only [10.2 ± 5.1 vs.
5.4 ± 5.1, t(24) = 2.03, p = 0.05]. PA children had higher scores on the
parent-report CBCL for Somatic complaints (56.8 ± 8.5 vs. 51.4 ± 3.4,
t = 2.42, p = 0.02), Withdrawal (56.9 ± 10.4 vs. 51.3 ± 3.9, t = 2.13, p = 0.04),
Social Problems (54.9 ± 6.2 vs. 50.9 ± 2.6, t = 2.50, p = 0.02), total
Internalizing (52.6 ± 13.5 vs. 42.5 ± 9.9, t = 2.20, p = 0.04), total
Externalizing (54.1 ± 9.7 vs. 42.8 ± 9.6, t = 2.83, p = 0.01), and total Behavior
Problems (53.5 ± 11.9 vs. 40.3 ± 10.7, t = 2.86, p = 0.01). 44% of children in
the PA group had 1 or more diagnoses, while only 1 child in the on-time
group had a diagnosis.

20 M.L. Byrne et al. / Developmental Cognitive Neuroscience 25 (2017) 12–28Table 1 (Continued )
Authors (year);
PubMed IDSample Measure(s) of adrenarche Measure(s) of mental health Summary of findings
Van Goozen et al.
(1998)
PMID: 94744482
groups of boys, 15 with
conduct or oppositional defiant
disorder and 25 controls, aged
8–12 years (mean age CD: 10.2,
controls: 9.6)Androstenedione,
testosterone,
and DHEA-S measured in
plasmaDSM-IV criteria for CD or ODD;
Parent- and teacher-report
CBCL (Aggression and
Delinquency scales)CD participants had a significantly higher level of DHEA-S
[2.85 nmol/l ± 1.1 vs. 1.46 ± 0.8, F (1,38) = 22.68, p < 0.0001] and a higher
level of androstenedione at trend level [1.03 ± 0.4 vs. 0.81 ± 0.3, F
(1,38) = 3.82, p < 0.06], but no difference in testosterone [0.90 ± 1.1 vs.
0.86 ± 1.5, F (1,38) = 0.01, NS].
DHEA-S was significantly associated with parent-report Delinquency
(rho = 0.33) and Aggression (rho = 0.46) and teacher-report Delinquency
(rho = 0.39) and Aggression (rho = 0.48).
Goodyer et al.
(1996)3 groups of adolescents aged
8–16, 82 with MDD, 25
non-MDD psychiatric controls,
and 40 healthy controlsDHEA in saliva, averaged over
2 days at 08:00, 12:00, and
20:00.DSM-II criteria using the
K-SADS diagnostic interview:
1) for MDD, 2) other psychiatric
disorder, or 3) no disorder.MDD group had lower morning DHEA than the other groups. No group
differences in DHEA-S.
Susman et al.
(1996)
PMID: 8853589108
healthy adolescents, 56
ten- to 15-year-old boys (mean
age 12.7), 52 nine- to 15-year
old girls (mean age 11.9)Plasma concentrations of
DHEA, DHEA-S, and other
gonadal hormonesExternalizing:
CBCL, Anxiety:
total number of anxiety
symptoms from the DISCExternalizing
symptoms and DHEA-S were significantly negatively
associated in girls.
Anxiety symptoms and DHEA were significantly positively associated in
boys.
Constantino et al.
(1993)
PMID: 828266718 boys, aged 4–10 years, that
were hospitalized for
aggressive behavior and had
Conduct Disorder, and 18 age-
and race-matched controlsSerum concentrations of DHEA
and DHEA-S, and other
hormones.Boys in the aggressive group
met DSM-III criteria for
Conduct Disorder and scored
>98th percentile on the
aggression subscale of the CBCLThere were no significant group differences in concentrations of any
hormones.
Susman et al.
(1987)
PMID: 360866056
boys and 52 girls, aged 9–14
years (all 5 stages of gonadal
development)Serum levels of gonadotropins,
gonadal steroids, adrenal
androgens (including DHEA
and DHEA-S), and
testosterone-estradiol binding
globulinEmotional dispositions:
self-reported anger,
nervousness, sadness, and
impulse control.
Aggressive attributes:
mother-reported acting out,
aggressive behavior problems,
and rebellious and nasty
characteristicsFor DHEA/DHEA-S only:
Girls: DHEA-S positively associated with self-reported calmness, and
negatively associated with parent-reported aggressiveness and nasty
behavior.Boys:
DHEA positively associated with self-reported sadness and
parent-reported rebelliousness, and DHEA-S negatively associated with
self-reported impulse control and parent-reported delinquency
Nottelmann et al.
(1987)
PMID: 3819952Same sample as Susman et al.
(1987) .See Susman et al. (1987) . “Self-image
problems”/adjustment from
the self-report Offer Self-Image
Questionnaire for Adolescents.
Mother-report of internalizing
and externalizing symptoms
on the CBCL.For DHEA/DHEA-S only (analyses only reported separately by sex):
Girls: Negative association between DHEA-S and social self-image
problems (controlling for age and pubertal status), and internalizing and
externalizing symptoms (not controlling for age and pubertal status).
Boys: No significant associations between DHEA/DHEA-S and self-image
problems,
but a negative association between DHEA-S and hyperactive
symptoms (only when not controlling for chronological age and Tanner
pubertal status).

M.L. Byrne et al. / Developmental Cognitive Neuroscience 25 (2017) 12–28 21
boys with conduct disorder and controls showed no group differ-
ences in levels of DHEA(S) (Constantino et al., 1993 ). It should be
noted that the latter study had a wide range of ages (4–10 years)
and was not designed to measure DHEA as a marker of pubertal
development specifically.
3.1.4. Summary of patterns by measurement of mental health in
SR1
The measurement of mental health also varied. Some stud-
ies measured symptoms: six studies measured anxiety symptoms
(Dorn et al., 2008, 1999; Murray et al., 2016; Sontag-Padilla et al.,
2012; Susman et al., 1996; Whittle et al., 2015 ); four measured
depressive symptoms (Dorn et al., 2008, 1999; Sontag-Padilla et al.,
2012; Whittle et al., 2015 ); eight measured internalizing symp-
toms more broadly (Belsky et al., 2015; Dorn et al., 2008, 1999;
Mundy et al., 2015; Nottelmann et al., 1987; Shirtcliff et al., 2007;
Sontag-Padilla et al., 2012; Susman et al., 1987 ); and 11 measured
externalizing symptoms (Belsky et al., 2015; Dorn et al., 2008, 1999;
Mundy et al., 2015; Nottelmann et al., 1987; Shirtcliff et al., 2007;
Sontag-Padilla et al., 2012; Susman et al., 1996, 1987; Van Goozen
et al., 1998; Whittle et al., 2015 ). Of the studies that measured inter-
nalizing symptoms, two found that they were not associated with
hormones (Klauser et al., 2015; Murray et al., 2016 ), one found a
negative association (Shirtcliff et al., 2007 ), and seven found a posi-
tive association (Belsky et al., 2015; Dorn et al., 2008, 1999; Mundy
et al., 2015; Sontag-Padilla et al., 2012; Susman et al., 1996, 1987 ).
Of the studies measuring externalizing symptoms, seven found that
they were positively associated with hormones (Belsky et al., 2015;
Dorn et al., 2008, 1999; Mundy et al., 2015; Sontag-Padilla et al.,
2012; Van Goozen et al., 1998; Whittle et al., 2015 ), and two found
a negative association (Susman et al., 1996, 1987 ). Some studies
measured diagnosis of a mental disorder from DSM criteria: three
measured a large range of diagnoses (Dorn et al., 2008, 1999; van
Goozen et al., 2000 ), two measured Conduct or Oppositional Defi-
ant Disorder (Constantino et al., 1993; Van Goozen et al., 1998 ),
and two measured MDD (Goodyer et al., 2000, 1996 ). Several stud-
ies overlapped across measurement of diagnoses and/or types of
symptoms.
We totaled studies that measured symptoms (internalizing vs.
externalizing) by biological sex. We did not include studies that
only measured diagnoses since there were not enough of those to
ascertain patterns. If studies did not differentiate results by sex, but
included both sexes, we counted the study as a result for males and
females. The totals and the citations are listed in Table 2. For both
males and females, a slight majority of studies found a positive
association between hormones and both internalizing and exter-
nalizing symptoms. However, there were a significant number of
conflicting studies that may be due to differences in age ranges and
the method of measuring adrenarcheal status or timing compared
to peers.
3.2. Results of SR 2: adrenarcheal development and brain
structure or function
Seven studies measured adrenarche or DHEA/DHEA-S during
puberty and brain structure or function, summarized in Table 3
One study measured cortical thickness (CTh; Nguyen et al., 2013 ),
one measured white and gray matter volume (Klauser et al., 2015 ),
one measured pituitary volume (Murray et al., 2016 ), one mea-
sured white matter mean diffusivity using DTI (Menzies et al.,
2015 ), and three measured brain activity during emotional tasks
using fMRI (Goddings et al., 2012; Klapwijk et al., 2013; Whittle
et al., 2015 ). Of note, Klapwijk et al. (2013) specifically measured
functional connectivity during an emotional task. In these stud-
ies, levels of adrenarcheal hormones were positively associated
with CTh in prefrontal areas (Nguyen et al., 2013 ) and volume ofTable 2
Cross
tab description of studies measuring internalizing and externalizing symp-
toms
by biological sex – direction of association with levels of adrenarcheal
hormones.
Internalizing Symptoms Externalizing Symptoms
Males Positive association: 4
studies(
Dorn et al., 1999; Mundy
et
al., 2015; Susman et al.,
1996,
1987 )
Null association: 3 studies
(Klauser et al., 2015;
Murray
et al., 2016;
Whittle
et al., 2015 )Positive association: 3
studies(
Dorn et al., 1999; Mundy
et
al., 2015; Van Goozen
et
al., 1998 )
Negative association: 2
studies(
Nottelmann et al., 1987;
Susman
et al., 1987 )
Null
association: 2 studies
(Shirtcliff et al., 2007;
Whittle et al., 2015 )
Females Positive association: 4
studies(
Belsky et al., 2015; Dorn
et
al., 2008, 1999;
Sontag-Padilla et al., 2012 )
Negative
association: 2
studies(
Nottelmann et al., 1987;
Shirtcliff
et al., 2007 )
Null association: 3 studies
(Klauser et al., 2015;
Murray
et al., 2016;
Whittle
et al., 2015 )Positive association: 5
studies(
Belsky et al., 2015; Dorn
et
al., 2008, 1999; Mundy
et al., 2015; Sontag-Padilla
et
al., 2012; Whittle et al.,
2015 )
Negative
association: 2
studies(
Nottelmann et al., 1987;
Susman
et al., 1996 )
the pituitary (Murray et al., 2016 ), but negatively correlated with
white matter volume in prefrontal areas (Klauser et al., 2015 ).
Hormones were also positively associated with activity during an
emotional face-viewing task in several prefrontal areas, the insula,
and the striatum, especially for females (Whittle et al., 2015 ), and
during social emotional processing compared to basic emotion
processing in the left anterior temporal cortex (Goddings et al.,
2012 ). However, two studies found no association between levels
of DHEA/DHEA-S and either white matter diffusivity or functional
connectivity (Klapwijk et al., 2013; Menzies et al., 2015 ). It should
be noted that three studies (Klauser et al., 2015; Murray et al., 2016;
Whittle et al., 2015 ) are all separate analyses from the same study of
adrenarcheal timing discussed in the Results of SR 1 above (iCATS;
Simmons et al., 2014 ). These three studies measured adrenarcheal
timing by design, whereas the study by Nguyen et al. (2013) mea-
sured basal levels of hormones over the course of four years in
participants aged four to 22 years of age, although the authors
controlled for the effects of age in the regression models and also
tested group differences at each age. Three studies (Goddings et al.,
2012; Klapwijk et al., 2013; Menzies et al., 2015 ) did not specif-
ically measure adrenarche (participants were aged 11–16 years
and differences in puberty were likely measuring differences in
gonadarche), however, results from Goddings et al. (2012) showed
positive associations between levels of DHEA and brain activity
during social emotional processing.
As mentioned above, two out these five studies (Murray et al.,
2016; Whittle et al., 2015 ) also measured mental health symptoms
in relation to adrenarche and brain development (discussed in SR1).
In particular, these studies assessed whether brain structure or
function mediated the association between adrenarche and mental
health symptoms. One of these studies (Whittle et al., 2015 ) found
that, for females, higher levels of externalizing symptoms were
associated with a medium to large effect on decreased activation
in the anterior insula and a medium effect on increased activation
in the ventromedial prefrontal cortex while viewing happy faces.
Also, decreased activity in the insula while viewing happy faces
partially mediated the association between higher levels of DHEA
and higher levels of externalizing symptoms in females. The other

22 M.L. Byrne et al. / Developmental Cognitive Neuroscience 25 (2017) 12–28Table 3
Summary of studies from Systematic Review 2 (SR2).
Authors (year);
PubMed IDSample Measure(s) of adrenarche Measure(s) of brain structure
or functionSummary
of findings
Murray et al.
(2016)
PMID: 26600008100 children who completed
an MRI scan, out of 128
9-year-old children, selected
based on high vs. low DHEA
and testosterone levels in
saliva 6 months priorContinuous levels of DHEA,
DHEA-S, and testosterone were
measured again in saliva
(averaged across 2 mornings);
Tanner stage based on
parent-report Sexual Maturity
Status line drawingsStructural MRI to measure
pituitary gland.Pituitary
volume was positively associated with levels of DHEA (r = 0.28,
p < 0.01), DHEA-S (r = 0.32, p < 0.01), and testosterone (r = 0.24, p < 0.05).
Note: Associations between adrenarche and anxiety symptoms were also found,
reported in SR1.
Whittle et al.
(2015)
PMID: 2567854883 children who completed an
fMRI task, out of 128
9-year-old children, selected
based on high vs. low DHEA
and testosterone levels in
saliva 6 months priorContinuous levels of DHEA
were measured again in saliva
(averaged across 2 mornings);
Tanner stage (nuisance factor)
based on parent-report Sexual
Maturity Status line drawingsfMRI during an emotional
face-viewing task. ROIs:
amygdala, hippocampus,
cingulate cortex, insula, dlPFC,
and striatumLevels of DHEA were negatively associated with activity in the right insula and
mid-cingulate cortex during fear compared to calm faces, in the right
mid-cingulate during angry compared to calm faces, and in the left dorsal
cingulate during happy compared to calm faces.
For females, these associations were present in the insula, cingulate, and dlPFC
for
fear faces, right mid-cingulate and putamen for angry faces, and insula and
right cingulate for happy faces. Females also had a positive association
between DHEA and activity in the left subgenual and right vmPFC for happy
faces.No
associations for males.
Note: Associations between adrenarche and mental health symptoms were also
found,
reported in SR1.
Klauser et al.
(2015)
PMID: 2545989741 early developing (mean age
9.64 ± 0.35) and 44 late
developing
(9.48 ± 0.30)
children based on DHEA and
testosterone levelsEarly vs. late adrenarche based
on levels of DHEA and
Testosterone approximately 6
months earlier; Continuous
levels of DHEA and
testosterone were measured
again in saliva (averaged across
2 mornings); Tanner stage
based on parent-report Sexual
Maturity Status line drawingsStructural MRI to measure gray
and white matter volumeControlled for age, and for Tanner stage to exclude effect of early gonadarche.
No group differences in total brain volume, total gray matter volume, total
white
matter volume, or regional gray matter volume in the whole sample, or
for boys and girls separately.
The early group had decreased white matter volume on left anterior corona
radiata (frontal lobe) for the whole sample (peak t = 4.21, corrected p = 0.046),
and in a subsample of males (peak t = 4.43, corrected p = 0.019), but not
females.Current
DHEA levels were also negatively correlated with white matter volume
in left corona radiata in the whole sample (peak t = 3.98, corrected p = 0.022).
Menzies et al.
(2015)
PMID: 2545441661 boys aged 12.7–16.0 years Levels of DHEA (as well as
testosterone and estradiol) in
saliva (for post hoc analyses).
Authors also grouped boys into
early-mid puberty
(gonadarche) and late-post
puberty via Tanner stage (for a
priori analyses).White matter microstructure
(DTI): white matter mean
diffusivity (MD) and fractional
anisotropy (FA)There were no associations between FA and gonadarche status based on
Tanner stage, so no post hoc analyses were conducted for FA. For MD, there
were no significant associations with DHEA (but there was a significant
negative association with testosterone)

M.L. Byrne et al. / Developmental Cognitive Neuroscience 25 (2017) 12–28 23Nguyen et al.
(2013)
PMID: 23804104Longitudinal study of 255
healthy children from 4 to 22
years old (143 females, 112
males)Levels DHEA (and testosterone
for 234 participants) measured
in saliva over the course of 4
years at each MRI visit;
Self-report PDS used to
differentiate between pre- and
post-gonadarche participantsRepeated MRI scans every 2
years – measured cortical
thickness (CTh).DHEA associated with increased CTh in left frontal, right temporal, and right
parietal lobes in the pre-gonadarche group (r = 0.15). No significant DHEA-CTh
associations in the post-gonadarche group. Age analysis showed DHEA
associated with increased CTh between 4–13 years (all rs = 0.2): in the DLPFC
from 4 to 8, right premotor cortex from 5 to 11, right temporoparietal junction
from 7 to 12, and right entorhineal/perirhinal cortex from 4 to 13. After age 13,
no significant associations.
In the complete sample, significant interaction between DHEA and
testosterone for the right ACC (r = 0.2). In the pre-gonadarche group,
significant interaction between DHEA and testosterone in the right posterior
cingulate gyrus and occipital pole (r = 0.3 for both). No significant interaction
between DHEA and testosterone in the post-gonadarche group.
No interactions with sex.
Klapwijk et al.
(2013)
PMID: 2399867435 female adolescents aged
11.1–13.7 years (mean 12.6; SD
0.7), 33 of which also had
DHEA measured in salivaLevels
of DHEA in saliva (as
well as testosterone and
estradiol). Other separate
indicators of puberty were
Tanner stages and
self-reported menarcheal
status, and the latter two were
combined to create early and
late groups.fMRI
during an emotion
evocation task (two social and
two basic emotions);
functional connectivity
between the dmPFC and other
social brain regions (pSTS, TPJ
and ATC)No associations between DHEA and functional connectivity.
Goddings et al.
(2012)
PMID: 2310673442 female adolescents mean
age 12.5 years, range 11.1–13.7
years.This study did not measure
adrenarche specifically
(early/late pubertal groups
were based on Tanner stages
and menarche – likely
measures of pre/post
gonadarche, especially in the
age range of the sample), but
they did measure salivary
levels of testosterone, estradiol,
and DHEA. Results are shown
for DHEA
associations only.fMRI during emotional
evocation (social vs. basic
emotions). ROIs: MPFC,
precuneus, right pSTS/TPJ, left
ATC, left DMPFC.Levels of DHEA positively associated with activity in the left anterior temporal
cortex (ATC) during the social emotion tasks compared to the basic emotion
tasks.

24 M.L. Byrne et al. / Developmental Cognitive Neuroscience 25 (2017) 12–28
study (Murray et al., 2016 ) found that larger pituitary volumes were
associated with a medium effect on higher levels of social anxi-
ety symptoms. Mediation analyses showed that when controlling
for age, sex, and BMI, larger pituitary volumes partially mediated
the association between higher levels of DHEA/DHEA-S and higher
levels of social anxiety symptoms.
4. Discussion
Overall, this review suggests that measures of adrenarche are
associated with mental health symptoms or diagnoses. Brain devel-
opment may play a role in this association, but studies are limited.
However, future research may be justified in testing a model by
which changes in brain development might mediate this associ-
ation between adrenarche and mental health. In general, studies
showed that earlier timing of adrenarche and higher levels of
adrenarcheal hormone levels were associated with more mental
health problems, but there were a number of conflicting studies
that may be due to differences in methodology. For studies that
examined results by sex, a pattern of results is beginning to emerge
for females whereby earlier timing of adrenarche (or higher lev-
els of adrenarcheal hormones) is associated with greater mental
health problems. There is less research on males, but findings thus
far are similar. Some studies found that higher levels of adrenar-
cheal hormones were associated with higher levels of internalizing
symptoms, either anxiety symptoms (Susman et al., 1996 ) or emo-
tional symptoms more broadly (Mundy et al., 2015 ). Other studies
found that higher levels of hormones were associated with exter-
nalizing disorders and symptoms (Mundy et al., 2015; Van Goozen
et al., 1998 ), although not always in the expected direction (Susman
et al., 1987 ). More studies that include both boys and girls and
examine sex differences will help to elucidate if patterns remain
similar across sexes.
Only seven studies measured adrenarche and brain structure or
function, and each study measured a different aspect of the brain
(function (ROI or connectivity), volume, diffusion, or CTh). There-
fore, strong amalgamation of findings is not possible; however,
patterns are beginning to emerge. The limited data from these stud-
ies of adrenarcheal hormones, brain structure and function, and
mental health symptoms shows that associations between these
variables are likely to be present and suggest that further work in
this area is justified. In particular, both studies that examined medi-
ational paths (albeit cross-sectional) found that measures of brain
structure and function mediated the association between adrenar-
che and mental health symptoms (Murray et al., 2016; Whittle et al.,
2015 ).
There are several methodological issues that need to be
addressed in future research on adrenarche, brain development,
and mental health. First, as discussed above, studies should have
enough power to analyze results by sex. There is some suggestion
that the prevalence of PA (Utriainen et al., 2015 ) and the gen-
eral timing of adrenarche may be different for girls and boys (e.g.,
the increase in DHEA appears to continue longer into adulthood
for males compared to females; Worthman, 1999 ), and previous
research has also suggested that risk for mental health prob-
lems is sex differentiated, especially for depression (for review,
see Piccinelli and Wilkinson, 2000 ), and that this differentiation
emerges at gonadarche (Angold et al., 1998; Patton et al., 1996 ).
Therefore, given these possible differences in developmental tim-
ing, examining effects uniquely by sex is critical to understanding
unique risk trajectories for mental health problems.
Second, as outlined in the results, some studies measured stage
and others measured timing (stage compared to same age- and
sex-peers). Within those that measured timing, studies defined
timing in different ways – either by comparing levels of hormonesin a restricted age range, or by controlling for age a covariate in
statistical models. Relatedly, the issue of clinical vs. normal varia-
tion in adrenarcheal development needs to be considered. Some
studies measured normal variations in adrenarche while others
included participants that had been clinically diagnosed with PA
and compared them to normally developing controls. None mea-
sured tempo of adrenarche, which is the rate of maturation. Studies
of pubertal (gonadarche) tempo have shown that faster tempo
are associated with more mental health symptoms in both boys
(Mendle et al., 2010 ) and girls (Marceau et al., 2011 ). Therefore,
tempo may also be an especially salient factor in the association
between adrenarche and mental health.
Third, it is not yet clear if it is better to measure adrenarche
with physical characteristics (e.g., physical signs such as presence
of pubic hair), with biological hormones such as DHEA/DHEA-S, or
a combination of both. For example, of those studies that measured
hormones and Tanner stage, most found conflicting results for asso-
ciations with mental health. Murray et al. (2016) found that anxiety
was associated with earlier Tanner stage (i.e., less developed) but
not with levels of hormones. Whittle et al. (2015) found that for
females, both later Tanner stage and higher levels of hormones
(i.e., more developed) were associated with more externalizing
symptoms, but for males, only earlier Tanner stage (i.e., less devel-
oped) was associated with more internalizing symptoms. Klauser
et al. (2015) controlled for Tanner stage and found no associations
between mental health symptoms and levels of hormones. van
Goozen et al. (2000) found earlier Tanner stage (i.e., less developed)
to be associated with externalizing disorder, but when controlling
for age and Tanner stage, higher levels of hormones were associated
with externalizing disorder. On the other hand, several studies that
selected PA vs. on-time children based on Tanner pubic hair stage
confirmed that PA children had higher levels of adrenarcheal hor-
mones (Dorn et al., 2008, 1999; Sontag-Padilla et al., 2012 ). It is
likely that adrenarcheal hormones do not produce some physical
changes until gonadarche (Wan, 2012 ), and therefore it is not possi-
ble to separate adrenarche and gonadarche by measuring physical
changes alone. On the other hand, although cutoff values for DHEA-
S in serum have recently been proposed to match age of onset
of biochemical adrenarche with the physical manifestation (pub-
arche; Guran et al., 2015 ), others have suggested that these DHEA-S
reference values cannot be validated without longitudinal research
(see commentary by Uc¸ ar, 2015 ). Future studies should measure
both adrenarcheal hormones and physical characteristics (espe-
cially pubic hair stage) in order to further understand how these
two variables are related to development.
Fourth, concurrent DHEA/DHEA-S and mental health assess-
ment may show DHEA/DHEA-S reactivity to stress and mental
health disorder, rather than the measurement of adrenarcheal lev-
els being indicative of a pubertal process alone. For example, animal
research has shown that both acute and chronic stress are associ-
ated with increases in DHEA-S (Maninger et al., 2010 ). Much of
the earlier work in this area was not necessarily designed to mea-
sure DHEA/DHEA-S as a marker of adrenarcheal development, and
the vast majority of studies reviewed here measured adrenarcheal
hormones and mental health symptoms or disorder at the same
time (Constantino et al., 1993; Dorn et al., 2008, 1999; Goodyer
et al., 1996; Klauser et al., 2015; Mundy et al., 2015; Murray et al.,
2016; Nottelmann et al., 1987; Shirtcliff et al., 2007; Sontag-Padilla
et al., 2012; Susman et al., 1996, 1987; van Goozen et al., 2000; Van
Goozen et al., 1998; Whittle et al., 2015 ). Indeed, only two stud-
ies measured mental health outcomes longitudinally. One found
that in girls, earlier adrenarcheal timing at ages six to seven was
associated with more internalizing and externalizing symptoms at
age 18 (Belsky et al., 2015 ). Interestingly, this study also found that
prenatal stress predicted earlier timing in these girls at age six to
seven. However, another study found that baseline DHEA levels

M.L. Byrne et al. / Developmental Cognitive Neuroscience 25 (2017) 12–28 25
Fig. 3. Proposed model of adrenarche as a potential sensitive period of neurobiological and psychosocial development.
did not predict the emergence of MDD over a year-long follow-
up (Goodyer et al., 2000 ). Further longitudinal research is needed
to
elucidate the associations between stress, mental health, and
adrenarcheal hormones.
Fifth, there is currently no consensus on an “end point” of
adrenarche. This is due to the gradual increase of adrenarcheal hor-
mones, ending in early adulthood. Therefore, it is difficult to assess
when a sensitive period for brain development may end. It is possi-
ble that adrenarche “ends” in early adulthood; however, a sensitive
period for brain development and the onset of mental illness may
end earlier than that. For example, the most sensitive period for
brain development may be closer to the onset of adrenarche, espe-
cially if adrenarche is seen as an event (i.e., when the sharp increase
in adrenarcheal hormones begins) rather than a period of time.
In other words, although DHEA and DHEA-S continue to increase
steadily across adolescence and into early adulthood, it is possible
that the initial increase of these hormones is more salient for brain
and psychological development. However, this has not been empir-
ically tested. Again, longitudinal research could measure levels of
hormones, brain development, and mental health across childhood
(from age five) and adolescence (up to the early 20s) to answer some
of these questions.
Sixth, these studies measured different types of adrenarcheal
hormone(s). Although adrenarche is most commonly defined as
increases in secretion of DHEA and DHEA-S, there are other metabo-
lites of this process that are related to adrenarcheal development,
such as testosterone, that may also be associated with brain
development and mental health. Furthermore, although DHEA
and DHEA-S are associated, there is a diurnal variation in DHEA
(Hucklebridge et al., 2005 ) that does not appear to be synchronous
with variation in DHEA-S (Carlström et al., 2002 ). Therefore, stud-
ies that measure one of these hormones without the other may
not be directly comparable, and the reasons for measuring one or
the other are not clear from many of the research studies reviewed
here. Future research should either measure both DHEA and DHEA-
S or have clear, justified hypotheses about one of the hormones. It
is not yet clear from the synthesized research if one or the other is
more salient in brain or mental health development. Furthermore,
as with cortisol, there is evidence that diurnal DHEA hyper-/hypo-
secretion may be important: one study reviewed here found that
low morning levels of DHEA were associated with MDD in children
eight to 16 years of age (Goodyer et al., 1996 ). Additionally, interac-
tions between hormones may be important. For example, research
has shown that DHEA/DHEA-S and cortisol interact to predict
mental health symptoms in adults (Goodyer et al., 1998; Michael
et al., 2000 ). Interactions between hypothalamic–pituitary–adrenal
(HPA) and hypothalamic–pituitary–gonadal (HPG) axes seem to
be especially salient for adolescent mental health (for review, see
Marceau et al., 2015 ). In the current review, Nguyen et al. (2013)
found that levels of DHEA interacted with levels of testosterone topredict cortical thickness of the right cingulate cortex and occipital
pole, especially in participants that were pre-pubertal on measures
of
physical development. Therefore, future studies should consider
measuring how adrenarcheal hormones interact with other hor-
mones such as cortisol or testosterone.
Seventh, the term “mental health problems” is broad. Some of
the results differed depending on the type of psychopathology,
especially regarding internalizing compared to externalizing symp-
toms (e.g., Susman et al., 1996, 1987 ). Furthermore, it is unclear
whether adrenarche is associated with threshold, clinical-level
diagnoses of a mental illness, or if it is associated with subclinical
variations in mental health symptoms. Subclinical symptoms for
many mental illnesses in adolescence, such as depressive symp-
toms, often predict the development of clinical episodes later in
life (Pine et al., 1999 ). However, future research should exam-
ine both levels of symptoms, which can be measured via self- or
parent-report questionnaires, and clinical diagnoses, which can
be measured via established clinical cut off scores on question-
naires, or by semi-structured diagnostic interviews administered
by trained researchers (usually considered the gold standard).
Finally, longitudinal studies in this area are especially critical.
Only studies that measure changes in adrenarche over time are able
to assess the importance of adrenarcheal tempo compared to stage
or timing. Also, in order to formally test brain development as a
mediator of the association between adrenarche and mental health,
longitudinal studies that measure adrenarcheal development, brain
structure and function, and mental health across time are needed.
Although we reviewed two longitudinal studies (Belsky et al., 2015;
Nguyen et al., 2013 ), neither examined all three variables.
Nevertheless, based on an integration of the literature reviewed
here, we propose a hypothetical model of adrenarche as a poten-
tially sensitive period of neurobiological development (refer to
Fig. 3). In this model, timing of exposure to adrenarcheal hormones
interacts with biological sex to influence changes in brain develop-
ment (a), which, in turn, are associated with risk for mental health
problems (b), the type of which can also interact with sex. We note
that brain development might only be one of many indirect path-
ways from adrenarcheal timing to mental health outcomes, but we
argue that the existing evidence justifies this as the next step for
research to test empirically. Importantly, this model also indicates
that these processes could potentially be both influenced by stress,
especially early stressful family environments (c), as well as influ-
ence environmental sensitivity to psychosocial stress and increase
risk for mental health problems (d). For example, for path c in the
model, life history theory suggests that humans are sensitive espe-
cially to early childhood experiences and environments such that
increased stress early in life may alter biological processes to pro-
duce different reproductive strategies (Charnov, 1993; Roff, 1992;
Stearns, 1992 ). This environmental stress early in life may act as
a cue to biological systems to favor earlier reproduction. Indeed,

26 M.L. Byrne et al. / Developmental Cognitive Neuroscience 25 (2017) 12–28
one longitudinal study showed that more stressful early childhood
environments were associated with earlier timing of adrenarche
as measured by adrenal hormones (Ellis and Essex, 2007 ). Further-
more, for path d in the model, early timing of adrenarche could
render an individual sensitive to stress via effects on brain devel-
opment, especially psychosocial stress, as one study showed that
levels of adrenarcheal hormones were associated with brain activ-
ity specifically during social emotional processing (Goddings et al.,
2012 ). Earlier timing could be related to potentially maladaptive
patterns of brain development, and therefore result in greater sen-
sitivity to stress. However, this hypothetical pathway remains to
be empirically tested.
To comprehensively test this model, future research should be
longitudinal and prospective in nature, and should objectively mea-
sure early family environments and ongoing psychosocial stress.
Multiple measurements of adrenarcheal hormones and physical
characteristics across time are needed to assess both timing and
tempo of development. Measures of brain structure and function,
and of mental health problems, should also be assessed multiple
times to allow examination of change in these variables and to
formally test brain development as a mediator of the association
between adrenarche and mental health (i.e., an indirect association
of adrenarche and mental health via brain development). Further-
more, this research should test conditional indirect effects whereby
biological sex may moderate this indirect association of adrenarche
and mental health, either in the association between adrenarche
and brain development, or between brain development and men-
tal health. Also, psychosocial stress should be tested as a moderator
in the association between brain development and mental health.
5. Conclusions
This review highlights the small but growing number of research
studies that show an emerging pattern whereby timing of adrenar-
che is associated with increased risk for mental health problems. It
also highlights the few studies that have begun to examine brain
development as a potential mechanism of this association. Future
longitudinal research that formally tests mediation models, con-
siders biological sex and psychosocial stress as moderators, and
assesses early life stress may provide evidence to support adrenar-
che as a sensitive period for neurobiological development. This
research will have important clinical implications and may iden-
tify novel risk and protective factors for mental health problems
across adolescence.
Conflicts of interest and source of funding
Sarah Whittle was supported by a National Health and Medial
Council (NHMRC) Career Development Fellowship (ID: 1007716).
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