Development and Psychopathology 16 ~2004!

, 807824
Copyright 2004 Cambridge University Press
Printed in the United States of America
DOI: 10.10170S0954579404040027

Pubertal neuromaturation, stress sensitivity,

and psychopathology

ELAINE F. WALKER, ZAINAB SABUWALLA, and REBECCA HUOT

Emory University

Abstract
Normal adolescent development is often accompanied by transient emotional and behavioral problems. For most
individuals with postpubertal-onset adjustment problems, there is a resolution by early adulthood and relative
stability through the adult life span. But for a minority, adjustment problems escalate during adolescence and
portend the development of serious mental illness in adulthood. In this article, we explore adolescent behavioral
changes and neurodevelopmental processes that might contribute to stress sensitivity and vulnerability for the
emergence of the mental disorders. Of particular interest is the role that hormonal changes might play in the
expression of genetic vulnerabilities for psychopathology. Drawing on recent findings from clinical research and
behavioral neuroscience, we describe the ways in which postpubertal hormones might alter brain function and,
thereby, behavior. It is concluded that there are both activational and organization effects of hormones on the
adolescent brain, and these contribute to developmental discontinuities in behavioral adjustment. Implications for
adult psychopathology and preventive intervention are discussed.

The behavioral changes associated with ado-
lescence have been the subject of both general
public concern and scientific interest. There
are long-standing cultural assumptions that ad-
olescent behavior is often erratic and opposi-
tional. Indeed, researchers have documented
that parents tend to describe the teen years
as the most challenging, and they typically re-
port a relatively stable course beginning in
early adulthood ~Arnett, 1999!. Further, cross-
sectional and longitudinal studies of child be-
havior generally confirm the assumption that
certain adjustment problems increase after the
onset of puberty; and the debate has now
shifted to the origins of normative adolescent
behavior changes, namely, what biological and
environmental factors are involved?
Advances in neuroimaging technology have
made it possible to conduct studies of human
brain development in vivo, and the findings
have shown that neurodevelopment extends
Address correspondence and reprint requests to: Elaine F.
Walker, Department of Psychology, Emory University,
Atlanta, GA 30322; E-mail: psyefw@emory.edu.
through adolescence. Neural circuitry is reor-
ganized, and there are changes in the volume
of some brain regions, with increases in white
matter and decreases in gray matter ~Benes,
2003a, 2003b; Blumberg et al., 2003; Cham-
bers, Taylor, & Potenza, 2003; Durston,
Hulshoff, Casey, Giedd, Buitelaar, & van
Engeland, 2001; Paus, Zijdenbos, Worsley,
Collins, Blumenthal, Giedd, Rapoport, &
Evans, 1999!. These developmental pro-
cesses are presumed to subserve the enhance-
ment of higher level cognitive abilities,
including inhibitory capacities, during adoles-
cence ~Chambers et al., 2003; Tamm, Menon,
& Reiss, 2002!. There are also changes in
adult brain morphology; however, they ap-
pear to be more gradual, and may not involve
the emergence of new circuitry ~Saito, Toyama,
Uemura, Ishii, Senda, & Uchiyama, 2001!,
although more longitudinal studies of human
brain morphology are needed to clarify the
nature of postadolescent brain development.
The burgeoning field of developmental
neuroscience has stimulated renewed interest
in adolescence among clinical investigators.

807
808
In particular, researchers in the field of psy-
chopathology have begun to focus greater
attention on adolescence as a critical period
for the onset of certain psychiatric disorders
~Benes, 2003a, 2003b; Walker & Bollini,
2002!. They are seeking to understand why so
many major mental illnesses have their pro-
dromal stage in adolescence, with a full clin-
ical onset that typically occurs in the early
20s, around the transition into adulthood. To
date, relatively few cross-sectional or longitu-
dinal studies have encompassed both the ado-
lescent and early adult periods. Thus, our
knowledge of the transitional process is lim-
ited. But numerous investigations of the ado-
lescent period have been launched in the past
decade, and we can anticipate that, in the fu-
ture, the findings will shed greater light on the
adolescent0early adult trajectory. At this junc-
ture, the research has yielded some promising
leads on neurodevelopmental processes that
subserve behavioral changes in adolescence.
This article is concerned with the factors
that contribute to adolescent vulnerability for
the emergence of the mental disorders. The
chief focus is the biological level of analysis.
We address the role of hormones in altering
brain function and behavior after the onset of
puberty. Of particular interest is the role that
hormonal changes might play in the expres-
sion of psychopathology. We begin with brief
overviews of the behavioral and hormonal
changes that accompany pre- and postpuber-
tal development. Drawing on recent findings
from both behavioral and molecular neurosci-
ence, we then explore ways that hormones
might act to alter brain function and, thereby,
behavior. In particular, we consider the role
that hormones might play in creating signifi-
cant developmental discontinuities in behav-
ioral adjustment ~Cicchetti & Rogosch, 2002!.
Although the gonadal hormones have
been emphasized in discussions of hormone
behavior relations in adolescence, in this
article we highlight the adrenal hormones, es-
pecially the hypothalamicpituitaryadrenal
~ HPA! axis and release of the stress
hormone, cortisol. Recent research findings
indicate that the HPA axis may serve to stim-
ulate the onset of pubertal development and
play a role in the triggering latent liabilities
E. F. Walker, Z. Sabuwalla, and R. Huot
for psychiatric disorders ~LAllemand, Pen-
hoat, Lebrethon, Ardevol, Baehr, Oelkers, &
Saez, 1996; Mesce, 2002!. It may, in fact,
render adolescence a stress-sensitive develop-
mental period, as there is accumulating evi-
dence that the neural systems involved in the
stress response are augmented during adoles-
cence. We present new findings to support
this notion, then conclude with a discussion
of activational and organizational effects of
hormones, and how they might trigger devel-
opmental discontinuities in the phenotypic ex-
pression of genetic liabilities.
Adolescent Changes in Behavior and
Psychiatric Symptoms
During the adolescent years there are norma-
tive improvements in several domains of cog-
nitive functioning, and memory appears to
reach a plateau during the late teens ~Schneider,
2002!. Entry into high school typically marks
an expansion in social networks. There is no
doubt that some experience adolescence as a
very smooth transition to adulthood.
On average, however, after the age of 12,
both children and their parents notice an in-
creased occurrence of some problematic be-
havior ~for a review, see Arnett, 1999!. For
example, adolescence is accompanied by in-
creases in risk-taking behavior, such as sub-
stance use, as well as self-reports and parent
reports of negative mood. On average, through
the course of adolescence, youth report signif-
icant increases in feelings of awkwardness, dis-
tress, and embarrassment, and more frequent
social conflicts. Although the relative preva-
lence of these trends in nonwestern countries
has not been as well established, they have
been consistently documented in the United
States ~Arnett, 1999!.
For most individuals who experience them,
adolescent adjustment problems are transient.
Although our knowledge of the developmen-
tal course bridging adolescence and early
adulthood is sketchy, there is evidence that
adjustment problems decline in early adult-
hood, and the majority of young adults show
significant improvements in behavioral con-
trol, positive affect, and self-confidence
~McGue, Bacon, & Lykken, 1993; Roberts,
Pubertal neuromaturation, stress sensitivity, and psychopathology
Caspi, & Moffitt, 2001!. It appears that even
diagnosable personality disorders often re-
solve with the entry into adulthood. Longitu-
dinal studies of youth have shown that the
proportion who meet criteria for a personal-
ity disorder declines from adolescence to
young adulthood ~Grilo, Becker, Edell, & Mc-
Glashan, 2001!. Further, the longitudinal sta-
bility of personality dimensions increases with
age, and seems to reach an asymptote by 30
years ~McCrae et al., 2000!.
On the other hand, although the presence
of adjustment problems, or even clinical dis-
order, during adolescence does not inevitably
portend adult disorder, the risk for later psy-
chiatric disorder is significantly greater among
youth who manifest behavioral problems. As
mentioned, the modal pathway for these youth
is a rise in adjustment problems following the
onset of puberty that escalates to the level of
clinical disorder. The clinical threshold for
mood and psychotic disorders is typically not
exceeded until early adulthood, but for some,
diagnosable Axis I psychiatric disorders arise
in adolescence. Following 12 years of age,
there are significant increases in the risk for
onset of clinical depression, especially in girls
~Angold & Rutter, 1992; Cyranowski, Frank,
Young, & Shear, 2000!. Likewise, risk for psy-
chotic disorders rises ~Benes, 2003a, 2003b;
Stevens, 2002!. In fact, there is a linear in-
crease in the likelihood of psychotic symp-
toms with each year in adolescence, and this
developmental trend is especially pronounced
for males ~Galdos & van Os, 1995!.
Further, among those who succumb to schi-
zophrenia during the peak risk period in early
adulthood, research indicates that the onset of
adolescence marks the point at which their so-
cial behavior and cognitive performance be-
gins to diverge from that of individuals with
healthy adult outcomes. Preschizophrenic chil-
dren manifest an escalating rate of social ad-
justment problems through the teenage years
~Neumann, Grimes, Walker, & Baum, 1995!.
A similar developmental trend has been found
in the cognitive domain. Van Oel, Sitskoorn,
Cremer, and Kahn ~2002!, examined the aca-
demic records of monozygotic and dizygotic
twin pairs who were discordant for schizophre-
nia. They discovered that divergence in school
809
performance occurred about 7.5 years earlier
in the discordant twins than it did in control
twins. The divergence was first detectable at
12 years of age, preceding the clinical onset of
psychosis by 10 years. Taken together, these
findings suggest that the first prodromal signs
of schizophrenia manifest themselves as be-
havioral and cognitive signs around the onset
of puberty.
Several recent models of the etiology of
depression and psychosis have suggested that
the longer the duration of clinical symptoms
the worse the long-term prognosis. In the case
of depression, Post ~2002! has proposed a
sort of kindling effect, such that the expe-
rience of an episode of depression sensi-
tizes the individuals brain circuitry to
subsequent episodes. Along these same lines,
it has been suggested that there are adverse
effects of untreated psychosis on brain func-
tion ~Yung, Phillips, Yuen, Francey, McFar-
lane, Hallgren, & McGorry, 2003!. These
theories have led to a renewed emphasis on
the potential importance of adolescence as
the setting stage for adult mental health. Thus,
adolescence is viewed as a transitional gate-
way for mental health in young adulthood,
and investigators are formulating strategies
for intervention, with the goal of preventing
the onset of adult clinical disorder.
Hormones and Development
To appreciate the extent of the psychobiolog-
ical transition that takes place in adoles-
cence, it is first necessary to consider the
nature of hormones and the pervasive effects
that they are capable of exerting on the cen-
tral nervous system. In recent years, scien-
tific conceptualizations of the role of hormones
in behavior have undergone a dramatic change.
It is now known that hormone receptors exist
throughout the brain. Moreover, hormones af-
fect the way neurons function; they modulate
the response parameters of neurons to neuro-
transmitters. This has been referred to as
metamodulation, and it appears to be im-
portant in adaptive brain function ~Mesce,
2002!. The accumulating knowledge about the
pervasive effects of hormones is one factor
810
contributing to a resurgence of scientific in-
terest in puberty.
Steriod hormones
Steroid hormones are a class of chemical com-
pounds that are derived from cholesterol, and
are primarily secreted by the endocrine glands,
the adrenal, and the gonads ~testes and ova-
ries; Kawata, 1995; Keenan & Soleymani,
2001; Mesce, 2002; Reider & Coupey, 1999!.
The steroid hormones have widespread ef-
fects because they are transported through the
bloodstream and trigger activity in the cells of
various organs and serve to regulate a range of
physiological functions. The adrenal steroids
are secreted by the adrenal gland, and the sex
hormones are largely produced by the gonads.
But it is relevant to note that the adrenal also
secretes some sex hormones.
There are actually two adrenal systems
the adrenal medulla and the adrenal cortex.
The two adrenal systems are developmen-
tally and anatomically related, although the
hormonal products differ, as do the correlates
for males and females ~Fadalti, Petraglia, Lu-
isi, Bernardi, Casarosa, Ferrari, Luisi, Sag-
gese, Genazzani, & Bernasconi, 1999; Kawata,
1995!. The adrenal medulla produces neuro-
transmitters, namely, the catecholamines, epi-
nephrine, and norepinephrine. The adrenal
cortex, on the other hand, produces androgen
in both sexes. The adrenal cortex also pro-
duces mineralocorticoids and the glucocorti-
coids. Mineralocorticoids, such as aldosterone,
help maintain osmotic balance in the body.
Glucocorticoids, most notably cortisol in pri-
mates, were thus named because they serve
to elevate blood glucose concentrations. Glu-
cocorticoids influence many metabolic pro-
cesses, particularly the formation of glucose.
Further, glucocorticoids modulate blood pres-
sure, activate the antiinflammatory and immu-
nosuppressive responses, and are highly
sensitive to environmental factors.
Glucocorticoid release from the adrenals is
controlled by the HPA axis, which is influ-
enced by a range of physical and social events.
The HPA axis is particularly sensitive to stress,
and is activated in response to physical and
psychological factors that threaten homeosta-
E. F. Walker, Z. Sabuwalla, and R. Huot
sis ~Charmandari, Kino, Sauvatzogluou, &
Chrousos, 2003; Dorn & Chrousos, 1997!.
Thus, perturbations affect the organism through
actions on hypothalamic secretagogues, corti-
cotropin releasing hormone, and arginine vaso-
pressin. This, in turn, triggers the release of
adrenocorticotropin ~ACTH! from the ante-
rior pituitary. ACTH then causes the release of
glucocorticoids ~again, primarily cortisol in
humans! from the adrenal cortex and into cir-
culation. The rapid rise in cortisol levels can
be adaptive because it can increase the avail-
ability of energy substrates.
The actions of cortisol are mediated by two
types of receptors: mineralocorticoid recep-
tors ~MRs! and glucocorticoid receptors ~GRs!,
also referred to as Type I and Type II recep-
tors, respectively. These receptors are present
on many cells throughout the body, including
the brain and pituitary. The HPA axis is a self-
modulating system, in that glucocorticoids act
to suppress their own release through activa-
tion of MRs and GRs, which initiates both
fast- and slow-acting negative feedback sys-
tems that inhibit ACTH release. These feed-
back systems affect the hypothalamus and
pituitary, although other regions, such as the
frontal cortex and hippocampus, also play a
role. Thus, effects on the central nervous sys-
tem are widespread.
The hypothalamicpituitarygonadal ~HPG!
axis governs the release of sex hormones
~Buchanan, Eccles, & Becker, 1992; Reider &
Coupey, 1999!. Like adrenal hormones, the
gonadal hormones have pervasive neurophys-
iological effects. The principal male sex hor-
mone, or androgen, is testosterone. It is mainly
produced by the testes, although, as men-
tioned, it is also produced at lower levels by
the adrenal cortex. Among females, low lev-
els of androgen are produced by the ovaries.
Another important adrenal androgen is de-
hydroepiandrosterone ~DHEA!. Both of these
androgens promote the development and main-
tenance of reproductive function, and stimu-
late the production of skeletal muscles, bone,
and secondary sex characteristics in the male.
Estrogens and progestins are the two classes
of female sex hormones. Estrogens are se-
creted by the ovaries, and at lower levels by
the adrenal glands and, in males, by the testes.
Pubertal neuromaturation, stress sensitivity, and psychopathology
~The most biologically active estrogen is es-
tradiol.! Estrogens promote the development
of female sex characteristics; they also stimu-
late physical growth and maturation. The main
progestin is progesterone, a key hormone for
maintaining pregnancy. Unlike androgens, es-
trogens, and progestins are secreted cycli-
cally. As a result, their effects on the brain
wax and wane through the cycle ~Schmidt, Ni-
eman, Danaceau, Adams, & Rubinow, 1998!.
Hormones and Brain Function
Steroid hormones play such a major role in
brain function that they are sometimes re-
ferred to as neurosteroids or neuroactive ste-
roids ~StoffelWagner, 2001!. Although they
derive largely from the endocrine glands, and
are consequently detectable in blood, there are
also sites for production of steroid hormones
in various brain regions ~cortex, hypothala-
mus, pituitary, and hippocampus!. Further,
there are receptors for neurosteroids through-
out the brain, and activation of these receptors
can alter many aspects of neuronal function.
The effects of hormones on brain function
are broad, and extend across the life span, be-
ginning in the fetal period ~Kawata, 1995;
Keenan & Soleymani, 2001!. Their pervasive
effects are a consequence of their chemical
properties. Steroid hormones can cross the
bloodbrain barrier, and thus have a signifi-
cant impact on neuronal development and or-
ganization. Unlike neurotransmitters, however,
they do not communicate through synapses.
Rather, hormones diffuse in the extracellular
space. In doing so, hormones influence indi-
vidual neurons, as well as the structure and
activity of neuronal circuits.
Two general classes of hormonal effects
have been describedactivational and orga-
nizational ~Arnold & Breddlove, 1985!. Acti-
vational effects are conceptualized as transient
inductions of time-limited, functional changes
in neural circuitry. Hormones can have activa-
tional influences on sensory processes, auto-
nomic nervous system activity, and enzyme
systems ~and thus, cellular permeability to elec-
trolytes, water, or nutrients!. Changes in the
autonomic nervous system can produce alter-
ations in basal metabolic rate, blood pressure,
811
sympathetic0parasympathetic tone, heart rate,
and water and sodium retention, all of which
may influence behavior. While receptors for
gonadal and adrenal steroid hormones are
present throughout the brain, they are espe-
cially dense in regions thought to be impor-
tant for emotion and perception0interpretation
of sensory information, such as the hypothal-
amus, amygdala, septal nucleus, and hippo-
campus. Menstrual cycle variations in mood
and behavior are an example of activational
effects that are likely produced by changes in
neural circuitry that governs emotion ~Kirsch-
baum, Kudielka, Gaab, Schommer, & Hell-
hammer, 1999!.
In contrast, organizational effects are those
that result in changes in the way the brain is
organizedits structural characteristics. These
effects have been well documented during the
fetal period, when sex hormones guide sexu-
ally dimorphic brain development ~Buchanan
et al., 1992!. Until recently, it was generally
assumed that activational effects occur during
adulthood, whereas organizational effects are
restricted to the fetal neurodevelopment. But
it now appears that some organizational ef-
fects of hormones occur later in life, including
adolescence ~Arnold & Breedlove, 1985; Char-
mandari et al., 2003!. The magnitude of these
effects is suggested by accumulating longitu-
dinal studies of human adolescents, which dem-
onstrate that the brain undergoes significant
organizational changes during this period.
The Neurohormonal Course of Pubertal
Development
Given the pivotal role of steroid hormones in
the structural and functional characteristics of
the central nervous system, we now turn to the
hormonal processes involved in the transition
from childhood to sexual maturity. Research
has documented numerous changes in hor-
mone secretion during adolescence, and it is
likely that more will be discovered in the fu-
ture. A comprehensive review of peri- and post-
pubertal hormone development is beyond the
scope of this article; however, some trends will
be briefly reviewed here. These illustrate the
extent to which the neurohormonal milieu of
the brain is transformed during puberty, set-
812
ting the stage for discontinuities in behavioral
development.
Pubertal development results from a com-
bination of two maturational processes: ad-
renarche and gonadarche ~Rieder & Coupey,
1999!. Both adrenarche and gonadarche in-
volve a cascade of hormonal events that entail
changes in the secretion of steroid hormones.
Although the causal neural mechanisms in
adrenarche and gonadarche are not known,
some of the hormonal processes and their cor-
relates have been identified. It is known that,
for both adrenarche and gonadarche, body fat
~bodymass index @BMI# ! must exceed a
threshold, and adequate nutrition is essential.
There is also evidence to suggest that leptin,
an adipose tissue-derived hormone, plays a role
in both. In the following sections, some key
aspects of adrenarche and gonadarche will be
briefly described.
Adrenarche
Adrenarche is the developmental prelude to
sexual maturation ~Rieder & Coupey, 1999;
Weber, Clark, Perry, Honour, & Savage, 1997!.
It is a maturational process that begins in child-
hood, at about 68 years of age in humans. It
has its onset about the same time as the pre-
adolescent rise in BMI. Adrenarche is marked
by a physiological increase in androgen secre-
tion from the adrenal cortex, which takes place
several years before the onset of puberty. The
main hormonal product of adrenarche is the
androgen, DHEA, and its sulfate ~DHEAS!.
It has been proposed that the HPA axis may
be involved in triggering adrenarche ~Weber
et al., 1997!. In particular, it has been sug-
gested that pituitary release of ACTH and0or
adrenal release of cortisol might play a role.
Consistent with this, Weber et al. ~1997! found
that individuals with familial glucocorticoid
deficiency were more likely to manifest a lack
of adrenarche. Conversely, children who have
an early onset of adrenarche, as measured by
the early ~before age 8! appearance of Tanner
stage IIIII pubic hair, show signs of height-
ened HPA activity ~Dorn, Hitt, & Rotenstein,
1999!. When compared to age-matched con-
trols, girls with premature adrenarche show
significantly higher concentrations of corti-
E. F. Walker, Z. Sabuwalla, and R. Huot
sol, as well as estradiol, thyroid-stimulating
hormone, and adrenal androgens.
There is also a gradual increase in plasma
insulin associated with the onset of adrenarche,
and an increase in insulin-like growth factor I
~IGF-I! levels ~Guercio, Rivarola, Chaler,
Maceiras, & Belgorosky, 2003!. IGF-I is a hor-
mone that promotes neurogenesis and neuro-
maturation. It has also been proposed that IGF-I
might be a trigger to the commencement of
adrenarche, although it does not necessarily
remain elevated after the onset. In particular,
growth hormone ~GH! and IGF-I may be in-
volved in the mechanism of adrenarche dur-
ing prepuberty in girls.
In recent years it has been discovered that
adipose tissue synthesizes a hormone called
leptin that has been implicated in body weight
and fat regulation ~Faloia, Camilloni, Gi-
acchetti, & Mantero, 2000; Weise, Eisen-
hofer, & Merke, 2002!. Thus, adipose tissue
is not solely devoted to energy storage and
release, but rather is now viewed as an en-
docrine organ, as well as a potential target
for steroid hormone activity. Leptin has re-
ceived a great deal of attention as a neuro-
maturational trigger. Leptin levels increase
during childhood in both sexes, and the rise
is most pronounced in association with
adrenarche. Although the role of leptin in
adrenarche is not fully understood, there is a
positive correlation between serum leptin and
BMI in children. Another recent and poten-
tially relevant finding is that adipose tissue
produces cortisol from its inactive precursor,
cortisone.
Gonadarche and postpubertal development
Gonadarche, the onset of puberty, is marked
by activation of the HPG axis, resulting in a
very rapid escalation in testosterone in males
and estradiol in females ~Buchanan et al.,
1992; Nottelmann, Susman, Dorn, Inoff
Germain, Loriaux, Cutler, & Chrousos, 1987!.
The magnitude of the rise in gonadal hor-
mones is striking ~Mann, Johnson, Gimpel,
& Castracane, 2003; Veldhuis, 1996!. From
infancy to age 12, the level of gonadal hor-
mones is relatively stable. Then, between 12
years and early adulthood, pulsatile secretion
Pubertal neuromaturation, stress sensitivity, and psychopathology
of luteinizing hormone ~LH!, the hormone
that stimulates gonadal growth and gonadal
hormone secretion, increases more than 30-
fold in boys and 100-fold in girls ~Vedlhuis,
1996!. In girls, estradiol doubles from about
25 pg0ml in the 1012 year period, to 50
pg0ml between 13 and 15 years. Then it
skyrockets to an average of about 200 pg0ml
between 16 and 20. Beyond age 20, estradiol
levels never return to prepubertal values, al-
though there is a very gradual decline to
around 100 pg0ml during menopause and 75
pg0ml following menopause. Thus perimeno-
pausal hormone changes are much less abrupt
and of smaller magnitude than those occur-
ring during normal adolescence. In males, the
rise in testosterone is even more dramatic.
Across the normal life span, testosterone in-
creases from about 25 ng0dl prior to 12 years
of age to over 200 ng0dl from 13 to 15 years,
to 600 ng0dl between 16 and 20. Although
testosterone declines very gradually after this
peak in late adolescence, it remains well above
200 for most of the rest of the male life span.
For both sexes, compared to other life-
course developmental changes in hormone lev-
els, hormone changes during adolescence are
unparalleled with respect to both magnitude
and speed. In addition to pulsatile surges in
LH, and rapid increases in testosterone and
estradiol, there are also progressive postpuber-
tal increases in other hormones, including al-
lopregnanolone ~a steroid hormone thought to
originate in the ovaries and adrenal cortex!,
progesterone, and DHEA levels, in both boys
and girls ~Fadalti et al., 1999!. In the absence
of disease, endocrine changes are relatively
mild following the early 20s, and extending
throughout the adult life span.
Several factors have been hypothesized to
trigger gonadarche. Central among these are
two hormones implicated in adrenarche;
namely, leptin and IGF. There is some evi-
dence that a marked rise in leptin levels oc-
curs just before the onset of puberty, and then
leptin decreases to baseline levels after the
initiation of puberty ~Faloia et al., 2000!. This
suggests a role for leptin in triggering the
onset of puberty. Further evidence to support
this notion comes from experimental studies
of rodents, which indicate that exogenous lep-
813
tin administration advances the onset of pu-
bertal development.
There are data indicating that IGF also reg-
ulates pubertal onset ~Guercio et al., 2003;
LAllemand et al., 1996!. In particular, it
appears that an increase in IGF-1 may be in-
volved in the stimulation of gonadotropin-
releasing hormone activity. Conversely, it also
appears that rising sex hormones contribute to
increased GH and IGF-1 in children with nor-
mal puberty, as well as precocious puberty.
The pubertal increase in sex steroids may there-
fore induce the neuromaturational events that
activate the systems that control GH and IGF-1
secretion.
Adrenal hormones also change during pu-
berty. Developmental research has shown that
levels of the adrenomedullary hormone, epi-
nephrine, and its metabolite metanephrine, de-
crease with pubertal maturation, and are higher
in males than females ~Weise et al., 2002!.
Weise and colleagues also found that de-
creases in epinephrine were most strongly
linked with pubertal stage and leptin, whereas
metanephrine was best predicted by estradiol
and leptin. Further, epinephrine and metaneph-
rine were inversely correlated with DHEAS,
estradiol, testosterone, leptin, and insulin. In
contrast, plasma norepinephrine, which is
mainly derived from sympathetic nerve termi-
nals, increases with advancing puberty and ris-
ing testosterone levels among boys. These
findings suggest that sympathoadrenal hor-
mones may be implicated in sexual matura-
tion. In particular, the adrenal medulla might
have a significant role in linking leptin and
body weight to the timing of sexual maturation.
Puberty and the HPA axis
There is now mounting evidence of a puber-
tal increase in activity of the HPA axis. Most
cross-sectional and longitudinal studies of sal-
ivary and urinary cortisol find an increase
with age during the adolescent years. Cross-
sectional studies of normal children reveal a
gradual rise in salivary and urinary cortisol
during middle childhood, then a marked in-
crease that begins around 13 years of age and
continues through adolescence ~Kenny, Gan-
cayco, Heald, & Hung, 1966; Kenny, Preeya-
814
sombat, & Migeon, 1966; Kiess, Meidert,
Dressendorfer, Scheiver, Kessler, & Konig,
1995; Lupien, Wilkinson, Briere, Menard, Ng,
Kin, & Nair, 2002; Wingo, 2002!. Recent lon-
gitudinal studies have also revealed increases
in cortisol release during adolescence, with
the most significant augmentation occurring
at 13 years ~WajsKuto, De Beeck, Rooman,
& Caju, 1999; Walker & Bollini, 2002!. Stud-
ies that have examined pubertal stage indi-
cate that the changes are strongly linked with
sexual maturation ~Kenny et al., 1966; Kiess
et al., 1995; Tornhage, 2002!.
It is of interest, however, that studies that
measure cortisol in plasma do not always find
an increase in cortisol levels during the course
of adolescence ~Fadalti et al., 1999; Knuts-
son, Dahlgren, Marcus, Rosberg, Bronnegard,
Stierna, & AlbertssonWiklund, 1997!. For ex-
ample, a recent longitudinal investigation of
serum cortisol in 28 adolescents found no de-
velopmental change ~Knutsson et al., 1997!.
These discrepancies may be due to differ-
ences in subjects responses to blood versus
saliva sampling, or may reflect differential sub-
ject attrition based on sampling procedure. It
has been shown that research participants are
more likely to decline blood sampling, and
those with greater psychiatric symptoms show
higher attrition ~Davies, Collins, Gregory, &
Clarke, 1996; Keks, Copolov, Mackle, Stuart,
Singh, McGorry, & Coffey, 1991!. Thus, blood
sampling may alter HPA activity, and thereby
obscure the relation between cortisol levels
and other variables. Consistent with this as-
sumption, it appears that group differences in
cortisol levels, including those induced by
ACTH administration, are more readily de-
tected in salivary assays than in plasma ~Kirsch-
baum et al., 1999!. Finally, the discrepancy
between the developmental course of plasma
and salivary cortisol may be a consequence of
the fact that salivary cortisol is an index of
plasma-free cortisol, and thus may be a better
measure of neuroactive cortisol.
Cross-sectional data from a recent study of
adolescents conducted in our laboratory repli-
cates the age-related increase in salivary cor-
tisol documented in previous reports. Our
research is intended to track the developmen-
tal course of youth with personality disorders
E. F. Walker, Z. Sabuwalla, and R. Huot
to identify risk factors for conversion to Axis I
disorders. Participants range in age from 12 to
17 years. One diagnostic group ~n 5 26! com-
prises adolescents who met DSM-IV diagnos-
tic criteria for schizotypal personality disorder
~SPD!. Another group ~n 5 28! meets criteria
for one or more other Axis II personality dis-
order ~OPD!. The participants in the normal
comparison group ~n 5 26! do not meet crite-
ria for any DSM-IV disorder.
During the first assessment of this sample,
cortisol was measured in saliva. A total of five
saliva samples were taken over the course of
the assessment, and they were averaged for
the present analyses. All subjects gave their
first sample between 9:00 and 9:30 a.m. There-
after, saliva samples were collected every hour,
for a total of five samples.
The correlation of age with cortisol was
positive and significant for all groups at r 5
.30, .42, and .46 for the normal, OPD, and
SPD groups, respectively. Curve fitting tests
revealed that the relation between age and mean
cortisol had no significant nonlinear compo-
nent. Figure 1 shows the linear trend for resid-
ualized cortisol values, by age, for the three
groups of youth. ~Residualized cortisol values
were obtained with regression analysis to con-
trol for potential effects of psychotropic med-
ications.! As can be seen, the developmental
trends are similar for the two groups.
We have found the same linear trends in
cortisol for males and females. These findings
indicate that the developmental increase in cor-
tisol secretion is similar across sex and diag-
nostic group. Second-wave assessments are
now being conducted on this sample. This will
allow us to address the question of longitudi-
nal change in cortisol secretion and its rela-
tion with indicators of adjustment.
Maturational Status, Hormones,
and Behavior
Given the significant developmental changes
that are observed in both hormones and be-
havior, we now turn to the question of the
relation between them. Are hormones driving
developmental changes in adolescent adjust-
ment problems?
Pubertal neuromaturation, stress sensitivity, and psychopathology
Figure 1. The linear relationship between age and residualized cortisol levels for normal and person-
ality disordered youth.
There has been relatively little research on
the behavioral correlates of hormone levels dur-
ing adrenarche, but age at onset of adrenarche
appears to have implications for adjustment.
Dorn et al. ~1999! compared children with on-
time and premature adrenarche, and found that
children with premature adrenarche had more
self-reported psychiatric symptoms, includ-
ing depression, more parent-reported behav-
ior problems measured on the Child Behavior
Checklist, and lower full-scale IQ. By parent
report, a large proportion ~44%! met diagnos-
tic criteria for psychological disorders ~primar-
ily anxiety disorders!. As mentioned previously,
the premature adrenarche group also had sig-
nificantly higher concentrations of adrenal an-
drogens, estradiol and cortisol.
There is an empirical data base that docu-
ments an association between maturational sta-
tus and behavioral disorders in adolescence. For
example, it has been shown that in females the
risk for depression rises with each stage of pu-
bertal status ~Angold, Costello, & Worthman,
1998; Patton, Hibbert, Carlin, Shao, Rosier,
Caust, & Bowes, 1997!. Further, early onset of
815
menarche is linked with heightened behavioral
problems ~Kim & Smith, 1998!. Girls with ear-
lier menarche manifest a higher degree of anx-
iety and internalizing symptoms in later
childhood. In contrast, for boys the onset and
progression of puberty is most strongly linked
with an increase in conduct disordered and risk-
taking behavior ~Buchanan et al., 1992!.
Despite the association between pubertal
status and certain forms of maladjustment, the
findings from research directly examining the
relation between sex hormone levels and ado-
lescent behavior have been mixed. For exam-
ple, higher levels of the adrenal androgens are
associated with adjustment problems, espe-
cially in boys ~Nottelmann et al., 1987!. Also
among boys, there is evidence of an associa-
tion between testosterone levels and disrup-
tive behavior ~Buchanan et al., 1992; Susman,
Dorn, & Chrousos, 1991!. But there is no con-
sistent evidence of a link between female hor-
mones and adolescent adjustment ~Buchanan
et al., 1992; Warren & BrooksGunn, 1989!.
Based on their comprehensive review of the
literature on gonadal hormones and behavior,
816
Buchanan et al. ~1992! concluded that the in-
consistent findings may indicate that hormone
effects during adolescence are best examined
simultaneously. Thus, rather than affecting be-
havior in isolation from each other, hormones
may have interactive effects that involve both
augmentation and suppression.
Studies of the adrenal hormone, cortisol,
have yielded more consistent evidence of a re-
lation with behavior. Heightened activity of the
HPAaxis has been found in a range of adult psy-
chiatric disorders ~Muller, Holsboer, & Keck,
2002; Walker & Diforio, 1997; Wolkowitz, Epel,
& Reus, 2001!, and recent research indicates
that this may also hold for some childhood ad-
justment problems and psychiatric symptoms
~Birmaher & Heydl, 2001; Goodyer, Park, Neth-
erton, & Herbert, 2001!. Cortisol is also re-
lated to child temperament. The predominant
trends in this literature indicate that elevated lev-
els of baseline cortisol are typically associated
with shyness, fearfulness, and behavioral inhi-
bition ~Goldsmith, & Lemery, 2000; Kagan,
Reznick, & Snidman, 1988!, whereas reduced
basal concentrations of cortisol are linked with
increased aggression, hostility, and symptoms
of conduct disorder ~McBurnett, Lahey,
Rathouz, & Rolf, 2000!.
Cross-sectional studies, however, do not ad-
dress causality in the cortisolbehavior rela-
tion. Does heightened cortisol precede
decrements in adjustment, or is it a conse-
quence? The results of longitudinal studies sug-
gest that increased cortisol secretion predicts
subsequent symptom severity for a variety of
disorders in adolescence, suggesting a causal
role for HPA activity. Several reports indicate
that cortisol levels are linked with the course of
depressive symptoms. Among adolescents the
onset and persistence of depression is linked
with cortisol hypersecretion at the initial as-
sessment ~Goodyer, Herbert, Moor, & Altham,
1991; Goodyer, Herbert, Tamplin, & Altham,
2000; Goodyer, Park, & Herbert, 2001; Good-
yer, Park, Netherton, & Herbert, 2001!. Along
these same lines, Susman, Dorn, InoffGermain,
Nottelmann, and Chrousos ~1997! assessed a
community sample of preadolescents and ado-
lescents three times over a 12-month period.
Subjects who showed an increase in cortisol re-
lease over the year also manifested more ad-
E. F. Walker, Z. Sabuwalla, and R. Huot
justment problems and depression at the third
assessment. Similar findings have been reported
in studies of adolescents with anorexia ~Steiner
& Levine, 1988!, schizotypal symptoms
~Walker et al., 2001!, and mixed adjustment dis-
orders ~Granger, Weisz, McCracken, Ikeda, &
Douglas, 1996!.
Taken together, the above results suggest
that the HPA axis acts as a generalized mod-
erating system that has the potential to aug-
ment the expression of vulnerability to a variety
of disorders. Although the determinants of in-
dividual differences in the relation between
cortisol secretion and behavior dysfunction
have not been systematically studied, it is likely
that environmental and constitutional factors
determine the nature and extent of the behav-
ioral disturbance ~i.e., depression, withdrawal,
anxiety, or psychotic symptoms! that is asso-
ciated with heightened cortisol release. In fact,
such interactional processes may be critical to
hormonebehavior relationships in general.
In support of this assumption, there is evi-
dence that the association between hormones
and adolescent behavior can be moderated by
genetic and environmental factors. For exam-
ple, evidence for genetic moderation is sug-
gested by the finding that elevated cortisol is
more strongly associated with behavior prob-
lems in boys and girls with fragile X than in
their unaffected siblings ~Hessl, Glaser, Dyer
Friedman, Blasey, Hastie, Gunnar, & Reiss,
2002!. Environmental moderation is indicated
by a report that the strength of the relation
between testosterone and aggressive behavior
is greater in adolescents exposed to more con-
flictual parentchild relationships ~Booth,
Johnson, Granger, Crouter, & McHale, 2003!.
Such findings raise the more general question
of whether maturational status moderates the
relation between stress and behavior. More spe-
cifically, is adolescence a period of height-
ened sensitivity to stress?
Adolescent stress sensitivity: The behavioral
and biological levels
As with adults, research on children and ado-
lescents has shown that exposure to stressful
events is associated with increased risk for psy-
chopathology ~Chen, Matthews, & Boyce,
Pubertal neuromaturation, stress sensitivity, and psychopathology
2002; Pine, 2003!. Further, this effect may be
at least partially mediated by activity of the
HPA axis. For example, family conflict pre-
dicts cortisol levels, as well as the number of
days ill, in children and adolescents ~Flinn &
England, 1997!. Experimental studies indi-
cate that, in response to a laboratory stressor
~Trier Social Stress Test for Children!, adoles-
cents show increases in heart rate and cortisol
~BuskeKirschbaum, Jobst, Wustmans, Kir-
schbaum, Rauh, & Hellhammer, 1997!.
Many have assumed that the behavioral
changes that occur during adolescence are par-
tially a consequence of additional external
stressors impinging on the child during this
developmental transition. But is there empiri-
cal support for the notion that exposure to stress
is greater during adolescence? There is indeed
evidence that the rate of occurrence of stress-
ful events increases from childhood through
adolescence ~Gest, Reed, & Masten, 1999!.
But the increase is specific to certain classes
of events; namely those that are classified as
nonindependent. Events that are indepen-
dent of the individual ~i.e., physical illness in
the family, natural disasters, academic prob-
lems! are relatively stable from childhood
through adolescence. In contrast, negative
events that can be linked to the individuals
behavior ~e.g., conflicts with friends or family
members, interpersonal problems in work or
school! increase significantly through adoles-
cence. Further, the increase in negative, non-
independent experiences is linked with both
the childs maladjustment and parental adjust-
ment problems. Thus, the stressful events that
increase during adolescence may be a partial
consequence of the individuals behavior.
Of course, the physical changes associated
with puberty may be inherently stressful be-
cause they involve a modification in physical
appearance. As mentioned, there is evidence
that experiencing puberty earlier is a risk for
subsequent adjustment problems, particularly
in girls ~Hayward, Killen, Wilson, Hammer,
Litt, Kraemer, Haydel, Varady, & Taylor, 1997!.
Girls who mature earlier than their peers man-
ifest more problem behaviors than those who
mature at more typical ages. There is also ev-
idence of accentuation, such that girls with
preexisting behavioral problems who mature
817
early showed an exacerbation of problems,
whereas those who mature at the same time or
later than their peers do not manifest worsen-
ing of their behavioral problems ~Caspi & Mof-
fitt, 1991!. In terms of social experiences, being
either early or late in pubertal maturation might
have negative effects on the individual be-
cause they experience a deviation from nor-
mal developmental timing ~BrooksGunn,
1988; Neugarten, 1979!. Thus, early-onset pu-
berty may act as a stressor. Alternatively, early
onset of hormonal changes may trigger bio-
logical processes that render the child more
vulnerable to stress, and thereby contribute to
adjustment problems.
In addition to early onset pubertal devel-
opment acting as a stressor, it has been sug-
gested by some that the influence may be in
the opposite direction, such that negative life
events trigger an early onset of puberty. There
is evidence that factors such as nutrition, ex-
ercise ~BrooksGunn, 1988; Malina, 1983!,
and interpersonal stress ~e.g., Graber &
BrooksGunn, 1996; Graber, BrooksGunn,
& Warren, 1995! are correlated with the age
at onset of puberty. It is possible that stress-
induced activation of the HPA axis affects
the timing of puberty by altering the gonadal
hormone system. Thus, stress exposure, by
augmenting HPA activity, may hasten the rise
in glucocorticoid release that normally oc-
curs at puberty, and thus trigger premature
release of gonadal hormones.
This brings us back to the question of stress
sensitivity: are adolescents more sensitive to
stress than younger children or adults? De-
spite the strong evidence that adolescents ex-
perience greater negative affect than either
younger children or adults ~Arnett, 1999!, there
have been relatively few studies of develop-
mental changes in the biobehavioral impact of
stressful experiences. The published data that
are available, however, suggest that adoles-
cence may be linked with an increased vulner-
ability to stressful events, which is an actual
change in how stress is experienced. It has
been shown in studies of normal youth that
the strength of the relationship between nega-
tive life events and dysphoric mood increases
with age during adolescence ~Rice, Harold, &
Thapar, 2003!. An excellent study by Silberg,
818
Pickles, Rutter, Hewitt, Simonoff, Maes, Car-
bonneau, Murrelle, Foley, and Eaves ~1999!
explored the influence of genetic factors and
environmental stressors on adolescent depres-
sion in twins. They replicated the developmen-
tal increase in depression during adolescence,
especially among girls. They also observed a
significant adverse effect of negative life events
which was, again, more pronounced in the post-
pubertal girls. Thus, it appeared that the stress
behavior link grew stronger with each year
during adolescence, consistent with greater
stress sensitivity. Further, the analysis for ge-
netic effects indicated that the influence of ge-
netic factors on life events increased through
adolescence, suggesting a developmentally re-
lated increase in genetic variance for life
events. The authors conclude that latent ge-
netic liabilities are expressed after puberty, a
developmental phenomena that will be revis-
ited later in this article.
With regard to the biological substrate for
adolescent stress sensitivity, the postpubertal
increase in cortisol secretion, reviewed ear-
lier, offers one explanation: the HPA axis may
become more responsive to external events.
In conjunction with this, other neural systems
involved in the biological response to environ-
mental challenges may be subject to matura-
tional change. Animal models yield support
for this assumption. Research with rodents has
revealed that the neural systems that govern
the stress response mature during the postpu-
bertal period ~Kellogg, Awatramani, & Piekut,
1998!. For example, stress responsiveness of
cortical receptors for GABA, an inhibitory
neurotransmitter, emerges over adolescence.
Also, rodents manifest postpubertal matura-
tion in the amygdala, a structure that projects
to many other brain regions ~e.g., cortex, hip-
pocampus! that show age-related changes and
are linked with the mature stress response.
The amygdala plays a similar role in hu-
mans, regulating the affective learning that
takes place in relation to emotional and behav-
ioral responses to stressful conditions. Through
postmortem research, Benes ~2003a, 2003b! has
shown that amygdala fibers continue to de-
velop throughout childhood, well into adoles-
cence. These changes increase the ability of the
amygdala to regulate emotional and attentional
E. F. Walker, Z. Sabuwalla, and R. Huot
responses in the cingulate cortex. Because the
cingulate region is a limbic brain area impli-
cated in the pathophysiology of mental illness,
maturation of the amygdalocingulate pathway
during late adolescent years may influence the
development of psychiatric symptoms.
Other evidence of heightened biological
stress responsivity in human adolescents has
come from psychophysiological studies. One
investigation measured skin conductance re-
sponses to neutral ~loud noise! and stressful
~person screaming! sensory stimuli ~Miller &
Shields, 1980!. Both adolescents and adults ex-
hibited more pronounced responses, and more
trials to habituate, following the stressful stim-
ulus. But, compared to adults, adolescents
showed more persistent skin conductance re-
sponding, taking significantly more exposure
trials to habituate. In another study using a lab-
oratory stress paradigm, it was shown that ad-
olescents responded to stress with greater
b-adrenergic activation than did younger chil-
dren ~Allen & Matthews, 1997!. It is also of in-
terest to note that exposure to stress may enhance
sensitivity to subsequent stressors; youth who
experience a higher level of stress in their lives
manifest higher diastolic blood pressure in re-
sponse to acute laboratory stressors ~Matthews,
Gump, Block, & Allen, 1997!. Thus, consis-
tent with the findings on cortisol secretion, psy-
chophysiological research indicates that the
postpubertal period may be associated with a
more pronounced response to acute stress.
Mechanisms in Adolescent Risk for
Psychopathology: Discontinuities in
Development
We have reviewed research findings that doc-
ument postpubertal changes in mood, behav-
ior, hormone systems, stress sensitivity, and
brain structure and function. We now turn to
the question of causal mechanisms. Although
not always explicitly stated, past models of
the relation between hormones and behavior
during adolescence have tended to focus on
the activational effects of steroid hormones
~i.e., transient, receptor-mediated effects; Not-
telmann et al., 1987; Susman, Nottelmann,
Dorn, InoffGermain, & Chrousos, 1987, 1989;
Udry, Billy, Morris, Groff, & Raj, 1985; Udry
Pubertal neuromaturation, stress sensitivity, and psychopathology
& Talbert, 1988!. Thus, the role of hormones
in adolescent behavior has generally been
viewed as transitory. Such an assumption is
consistent with the evidence that ~a! most ad-
olescent adjustment problems are time-limited
perturbations and are resolved before the in-
dividual reaches early adulthood and ~b! the
maximum longitudinal stability in personality
and psychiatric disorder is reached in early
adulthood. From this perspective, postpuber-
tal hormonal surges would contribute to nor-
mative discontinuities in behavior that are a
reflection of changes in brain function.
In addition, however, recent reports of post-
pubertal maturational changes in brain struc-
ture have highlighted the potential for
organizational effects of hormones during ad-
olescence. Like activational effects, organiza-
tional effects of hormones would contribute
to developmental discontinuities in behavior.
But organizational effects of hormones, by
definition, involve more sustained changes in
brain structure. Therefore, the impact on be-
havior would persist beyond adolescence. In
this sense, organizational effects of hormones
can mark a turning point in development. Sev-
eral authors have described postpubertal mat-
urational changes in brain circuitry that are
likely to be playing a role in cognitive devel-
opment. For example, maturation of limbic
circuitry may underlie the transition from the
impulsive emotional and cognitive styles that
characterize children, to mature adult affec-
tive and cognitive functions ~Benes, 2003a,
2003b; Chambers et al., 2003!.
It is now well established that the organi-
zational effects of hormones are mediated by
genes. In recent years, our understanding of
the impact of hormones on gene expression
has increased dramatically ~for an overview,
see Kawata, 1995!. A review of this rapidly
expanding area of investigation is beyond the
scope of this article. Just a few key principals
should be noted. First, neurons have both sur-
face and intracellular ~nuclear! receptors for
hormones. Second, when activated, the intra-
cellular hormone receptors can initiate the pro-
cess of gene expression through messenger
RNA. Third, genes control both the growth
and the death ~apoptosis! of neurons and glia.
Fourth, it is known that the expression of genes
819
varies with development, and some are turned
on ~or off ! during certain maturational stages.
For example, in humans, the expression of
genes that govern the production of lipids and
lipid proteins differs in adolescence when com-
pared to adulthood ~Snieder, van Doornen, &
Boomsma, 1997!. Similarly, in rodents, there
appear to be developmental changes in the ex-
pression of genes implicated in the regulation
of the HPA axis ~Schmidt, Enthoven, van der
Mark, Levine, de Kloet, & Oitzl, 2003!. In
particular, the expression of MRs in the brain
changes over time, and these changes vary by
brain region.
In humans, maturational changes in gene
expression appear to be reflected in develop-
mental changes in heritability estimates for
behavioral characteristics that are partially ge-
netically determined. For example, it has been
documented that the heritability estimates for
cognitive performance ~Petrill, 2003!, in-
crease with age, especially in adolescence.
Such effects may be mediated by normal mat-
urational refinements in brain circuitry that re-
sult from the postpubertal expression of genes.
Along these same lines, heritability estimates
for personality characteristics appear to peak
around puberty, and there is no evidence of
new genetic contributions to individual differ-
ences in personality after age 30 ~Viken, Rose,
Kaprio, & Koskenvuo, 1994!.
It is also plausible that hormonal changes
during puberty trigger the expression of ge-
netic vulnerabilities for dysfunctional behav-
ior. Several lines of investigation lend support
to this assumption. For example, Klump,
McGue, and Iacono ~2003! found that the
intraclass correlations for eating disorder
symptoms in postpubertal 11-year-old and 17-
year-old twins were significantly higher than
in prepubertal 11-year-old twins. Genetic fac-
tors accounted for none ~0%! of the variance
in 11-year-old prepubertal twins but ex-
plained 54% of the variance in 11-year-old
and 17-year-old postpubertal twins. This in-
dicates that the genetic influence on eating
disorders is activated by puberty.
Similar developmental effects on heritabil-
ity have been demonstrated for antisocial per-
sonality disorder and depression. In a recent
twin study, researchers found that the best-
820
fitting causal model to account for antisocial
behavior was one that allowed for genetic in-
fluences on adolescents and adults that were
not measurable in childhood ~Jacobson, Pres-
cott, & Kendler, 2002!. In striking contrast,
shared environmental influences did not vary
as a function of age. The same pattern was
observed for both males and females. There
was also evidence that the sex difference in
timing of puberty was responsible for an ear-
lier presence of genetic effects among fe-
males. Further, it appears that the heritability
estimates for antisocial behavior stabilize dur-
ing adulthood ~Lyons, True, Eisen, Goldberg,
Meyer, Faraone, Eaves, & Tsuang, 1995!.
Another twin study showed that the herita-
bility of depression increases with age. As men-
tioned above, Silberg and colleagues ~1999!
used a twin paradigm and found that the rela-
tion between stress and depression increased
during adolescence. These investigators also
showed that the heritability estimate for de-
pression increased significantly in adoles-
cence, rising dramatically after puberty.
Taken together, these findings suggest that
pubertal hormones may be triggering the ex-
pression of genes that are involved in both nor-
mal and abnormal developmental processes. In
particular, some of the most serious psychiat-
ric disorders appear to have their roots in ado-
lescent neuromaturation. If this is true, then
adolescence should be viewed as a critical stage
in the etiology of mood and psychotic disor-
ders that usually have their clinical onset in late
adolescence0early adulthood. It is possible that
future research on adolescent neuromaturaton
will yield new insights about opportunities for
preventive intervention. Intervention efforts fo-
cused on adolescence may hold great potential
for preventing serious mental illness.
Conclusions
It has long been known that the adolescent pe-
riod is accompanied by a rise in gonadal hor-
mone levels that far exceeds the magnitude of
hormonal change that occurs in any other post-
natal stage. But more recently, the potential im-
plications of these changes have been brought
into clearer focus as our scientific understand-
ing of neurohormonal effects on brain function
E. F. Walker, Z. Sabuwalla, and R. Huot
has burgeoned. We have also witnessed great
strides in our understanding of adolescent neuro-
development, as researchers have documented
significant adrenal hormone and brain changes
during puberty. These changes, especially aug-
mented activity of the HPA axis, may contrib-
ute to increased stress sensitivity.
Both activational and organizational ef-
fects of hormonal changes on the central ner-
vous system have been demonstrated in various
species, and it is likely that both occur in hu-
man adolescent development. Longitudinal and
cross-sectional data on behavioral trends pro-
vide support for this assumption. Figure 2 is
intended to illustrate three potential pathways
through adolescence and into adulthood. There
are, of course, many other possibilities, but
those shown in the figure are intended to rep-
resent three prototypes. One is characterized
by relative continuity in adjustment, with in-
creasing social and cognitive competence, and
a relatively smooth transition into early adult-
hood. In this case, hormonal changes augment
functioning. A second developmental path-
way involves an increase in certain adjust-
ment problems following puberty, a decline in
problems during late adolescence, and then sta-
bilization beginning in early adulthood. In this
case, activational effects of hormones are re-
flected in transient adjustment problems fol-
lowing the onset of puberty, but organizational
hormone effects are presumably resulting in
structural brain changes that give rise to healthy
adult functioning. Finally, a modal pathway
to clinical disorder in early adulthood is
illustrated by a decline in adjustment during
adolescence that persists and worsens into
adulthood. This latter pathway is consistent
with evidence that heritability estimates for
some behavioral disorders appear to rise fol-
lowing puberty and reach adult levels by late
adolescence. Thus, postpubertal hormones may
be exerting organizational effects that impact
both normal and atypical developmental
trajectories.
At the present time, these ideas must be
considered speculative. It is obvious that re-
searchers have not yet fully elucidated the
range of hormonal processes that are associ-
ated with puberty. In particular, we do not yet
understand the causal sequence of hormonal
Pubertal neuromaturation, stress sensitivity, and psychopathology
Figure 2. The developmental pathways through adolescence and into adulthood.
events that transpire during pubertal develop-
ment. Nor do we know how this ongoing hor-
monal cascade influences gene expression and
brain structure0function. Further, very few de-
velopmental studies have charted the transi-
tional period from the onset of puberty into
early adulthood. Thus, research has not estab-
lished the growth curves for age-related
References
Allen, M. T., & Matthews, K. A. ~1997!. Hemodynamic
responses to laboratory stressors in children and ado-
lescents: The influences of age, race, and gender. Psy-
chophysiology, 34, 329339.
Angold, A., Costello, E. J., & Worthman, C. M. ~1998!.
Puberty and depression: The roles of age, pubertal
status and pubertal timing. Psychological Medicine,
28, 51 61.
Angold, A., & Rutter, M. ~1992!. Effects of age and pu-
bertal status on depression in a large clinical sample.
Development and Psychopathology, 4, 528.
Arnett, J. J. ~1999!. Adolescent storm and stress, recon-
sidered. American Psychologist, 54, 317326.
Arnold, A. P., & Breedlove, S. M. ~1985!. Organizational
and activational effects of sex steroids on brain and
behavior: A reanalysis. Hormones & Behavior, 19,
469 498.
Benes, F. M. ~2003a!. Schizophrenia, II: Amygdalar fiber
alteration as etiology? American Journal of Psychia-
try, 160, 1053.
Benes, F. M. ~2003b!. Why does psychosis develop dur-
ing adolescence and early adulthood? Current Opin-
ion in Psychiatry, 16, 317319.
Blumberg, H. P., Martin, A., Kaufman, J., Leung, H., Skud-
larski, P., Lacadie, C., Fulbright, R. K., Gore, J. C.,
821
changes in hormones, brain, and behavior dur-
ing this broader period. But ongoing longitu-
dinal studies are likely to yield valuable insights
in the near future. These data will certainly
have relevance for research on the genesis of
psychopathology, as well as for studies of pre-
ventive intervention.
Charney, D. S., Krystal, J. H., & Peterson, B. S. ~2003!.
Frontostriatal abnormalities in adolescents with bi-
polar disorder: Preliminary observations from func-
tional MRI. American Journal of Psychiatry, 160,
13451347.
Birmaher, B., & Heydl, P. ~2001!. Biological studies in
depressed children and adolescents. International Jour-
nal of Neuropsychopharmacology, 4, 149157.
Booth,A., Johnson, D. R., Granger, D.A., Crouter,A. C., &
McHale, S. ~2003!. Testosterone and child and adoles-
cent adjustment: The moderating role of parentchild
relationships. Developmental Psychology, 39, 8598.
BrooksGunn, J. ~1988!. Antecedents and consequences
of variations in girls maturational timing. Journal of
Adolescent Health Care, 9, 365373.
Buchanan, C. M., Eccles, J. S., & Becker, J. B. ~1992!.
Are adolescents the victims of raging hormones? Ev-
idence for activational effects of hormones on moods
and behavior at adolescence. Psychological Bulletin,
111, 62107.
BuskeKirschbaum, A., Jobst, S., Wustmans, A., Kirsch-
baum, C., Rauh, W., & Hellhammer, D. ~1997!. Atten-
uated free cortisol response to psychosocial stress in
children with atopic dermatitis. Psychosomatic Med-
icine, 59, 419 426.
822
Caspi, A., & Moffitt, T. E. ~1991!. Individual differences
are accentuated during periods of social change: The
sample case of girls at puberty. Journal of Personality
and Social Psychology, 61, 157168.
Chambers, R. A., Taylor, J. R., & Potenza, M. N. ~2003!.
Developmental neurocircuitry of motivation in ado-
lescence: A critical period of addiction vulnerability.
American Journal of Psychiatry, 160, 10411052.
Charmandari, E., Kino, T., Souvatzoglou, E., & Chrou-
sos, G. P. ~2003!. Pediatric stress: Hormonal media-
tors and human development. Hormone Research,
59,161179.
Chen, E., Matthews, K. A., & Boyce, W. T. ~2002!. So-
cioeconomic differences in childrens health: How and
why do these relationships change with age? Psycho-
logical Bulletin, 128, 295329.
Cicchetti, D., & Rogosch, F. A. ~2002!. A developmental
psychopathology perspective on adolescence. Jour-
nal of Consulting & Clinical Psychology, 70, 620.
Cyranowski, J. M., Frank, E., Young, E., & Shear, K.
~2000!. Adolescent onset of the gender difference in
lifetime rates of major depression. Archives of Gen-
eral Psychiatry, 57, 2127.
Davies, P. S., Collins, D. L., Gregory, J. R., & Clarke, P.
C. ~1996!. Parents and childrens reactions to taking
blood in a nutrition study. Archives of Disease in Child-
hood, 75, 309313.
Dorn, L. D., & Chrousos, G. P. ~1997!. Neurobiology of
stress: Understanding regulation of affect during fe-
male biological transitions. Seminars in Reproductive
Endocrinology, 15, 29 45.
Dorn, L. D., Hitt, S. F., & Rotenstein, D. ~1999!. Biopsy-
chological and cognitive differences in children with
premature vs. on-time adrenarche. Archives of Pedi-
atric & Adolescent Medicine, 153, 137146.
Durston, S., Hulshoff Pol, H. E., Casey, B. J., Giedd, J. N.,
Buitelaar, J. K., & van Engeland, H. ~2001!. Anatom-
ical MRI of the developing human brain: What have
we learned? Journal of the American Academy of Child
& Adolescent Psychiatry, 40, 10121020.
Fadalti, M., Petraglia, F., Luisi, S., Bernardi, F., Casarosa,
E., Ferrari, E., Luisi, M., Saggese, G., Genazzani,A. R.,
& Bernasconi, S. ~1999!. Changes of serum allopreg-
nanolone levels in the first 2 years of life and during
pubertal development. Pediatric Research, 46, 323327.
Faloia, E., Camilloni, M. A., Giacchetti, G., & Mantero,
F. ~2000!. Adipose tissue as an endocrine organ? A
review of some recent data. Eating & Weight Disor-
ders, 5, 116123.
Flinn, M. V., & England, B. G. ~1997!. Social economics
of childhood glucocorticoid stress response and health.
American Journal of Physical Anthropology, 102,
3353.
Galdos, P., & van Os, J. ~1995!. Gender, psychopathol-
ogy, and development: From puberty to early adult-
hood. Schizophrenia Research, 14, 105112.
Gest, S. D., Reed, M. J., & Masten, A. S. ~1999!. Measur-
ing developmental changes in exposure to adversity:
A life chart and rating scale approach. Development
and Psychopathology, 11, 171192.
Goldsmith, H. H., & Lemery, K. S. ~2000!. Linking tem-
peramental fearfulness and anxiety symptoms: A
behaviorgenetic perspective. Biological Psychiatry,
48, 11991209.
Goodyer, I., Herbert, J., Moor, S., & Altham, P. ~1991!.
Cortisol hypersecretion in depressed school-aged chil-
dren and adolescents. Psychiatry Research, 37,
237244.
E. F. Walker, Z. Sabuwalla, and R. Huot
Goodyer, I. M., Herbert, J., Tamplin, A., & Altham, P.
M. ~2000!. Recent life events, cortisol, dehydroepi-
androsterone and the onset of major depression in
high-risk adolescents. British Journal of Psychiatry,
177, 499504.
Goodyer, I. M., Park, R. J., & Herbert, J. ~2001!. Psycho-
social and endocrine features of chronic first-episode
major depression in 816 year olds. Biological Psy-
chiatry, 50, 351357.
Goodyer, I. M., Park, R. J., Netherton, C. M., & Her-
bert, J. ~2001!. Possible role of cortisol and dehy-
droepiandrosterone in human development and
psychopathology. British Journal of Psychiatry, 179,
243249.
Graber, J. A., & BrooksGunn, J. ~1996!. Transitions and
turning points: Navigating the passage from child-
hood through adolescence. Developmental Psychol-
ogy, 32, 768776.
Graber, J. A., BrooksGunn, J., & Warren, M. P. ~1995!.
The antecedents of menarcheal age: Heredity, family
environment, and stressful life events. Child Develop-
ment, 66, 346359.
Granger, D. A., Weisz, J. R., McCracken, J. T., Ikeda, S.
C., & Douglas, P. ~1996!. Reciprocal influences among
adrenocortical activation, psychosocial processes, and
the behavioral adjustment of clinic-referred children.
Child Development, 67, 32503262.
Grilo, C. M., Becker, D. F., Edell, W. S., & McGlashan, T.
H. ~2001!. Stability and change of DSM-III-R person-
ality disorder dimensions in adolescents followed up
2 years after psychiatric hospitalization. Comprehen-
sive Psychiatry, 42, 364368.
Guercio, G., Rivarola, M. A., Chaler, E., Maceiras, M.,
& Belgorosky, A. ~2003!. Relationship between the
growth hormone0insulin-like growth factor-I axis, in-
sulin sensitivity, and adrenal androgens in normal
prepubertal and pubertal girls. Journal of Clinical
Endocrinology & Metabolism, 88, 13891393.
Hayward, C., Killen, J. D., Wilson, D. M., Hammer, L.
D., Litt, I. F., Kraemer, H. C., Haydel, F., Varady, A.,
& Taylor, C. B. ~1997!. Psychiatric risk associated
with early puberty in adolescent girls. Journal of the
American Academy of Child & Adolescent Psychia-
try, 36, 255262.
Hessl, D., Glaser, B., DyerFriedman, J., Blasey, C., Hastie,
T., Gunnar, M., & Reiss, A. L. ~2002!. Cortisol and
behavior in fragile X syndrome. Psychoneuroendocri-
nology, 27, 855872.
Jacobson, K. C., Prescott, C. A., & Kendler, K. S. ~2002!.
Sex differences in the genetic and environmental in-
fluences on the development of antisocial behavior.
Development and Psychopathology, 14, 395 416.
Kagan, J., Reznick, J. S., & Snidman, N. ~1988!. Biolog-
ical Bases of childhood shyness. Science, 240,
167171.
Kawata, M. ~1995!. Roles of steroid hormones and their
receptors in structural organization in the nervous sys-
tem. Neuroscience Research, 24, 1 46.
Keenan, P. A., & Soleymani, R. M. ~2001!. Gonadal ste-
roids and cognition. In R. Tarter, & M. Butters ~Eds.!,
Medical neuropsychology: The impact of disease on
behavior. Critical Issues in Neuropsychology ~pp. 181
197!. New York: Plenum Press.
Keks, N. A., Copolov, D. L., Mackie, B., Stuart, G. W.,
Singh, B. S., McGorry, P. D., & Coffey, C. ~1991!.
Comparison of participants and nonparticipants in a
neuroendocrine investigation of psychosis. Acta Psy-
chiatrica Scandinavica, 83, 373376.
Pubertal neuromaturation, stress sensitivity, and psychopathology
Kellogg, C. K., Awatramani, G. B., & Piekut, D. T. ~1998!.
Adolescent development alters stressor-induced Fos im-
munoreactivity in rat brain. Neuroscience, 83, 681 689.
Kenny, F. M., Gancayco, G. P., Heald, F. P., & Hung, W.
~1966!. Cortisol production rate in adolescent males
in different stages of sexual maturation. Journal of
Clinical Endocrinology, 26, 12321236.
Kenny, F. M., Preeyasombat, C., & Migeon, C. J. ~1966!.
Cortisol production rate II: Normal infants, children
and adults. Pediatrics, 37, 34 42.
Kiess, W., Meidert, A., Dressendorfer, R. A., Scheiver,
K., Kessler, U., & Konig, A. ~1995!. Salivary cortisol
levels throughout childhood and adolescence: Rela-
tion with age, pubertal stage and weight. Pediatric
Research, 37, 502506.
Kim, K., & Smith, P. K. ~1998!. Childhood stress, behav-
ioral symptoms and motherdaughter pubertal devel-
opment. Journal of Adolescence, 21, 231240.
Kirschbaum, C., Kudielka, B. M., Gaab, J., Schommer, N.
C., & Hellhammer, D. H. ~1999!. Impact of gender,
menstrual cycle phase, and oral contraceptives on the
activity of the hypothalamuspituitaryadrenal axis.
Psychosomatic Medicine, 61, 154162.
Klump, K. L., McGue, M., & Iacono, W. G. ~2003!. Dif-
ferential heritability of eating attitudes and behaviors
in prepubertal versus pubertal twins. International
Journal of Eating Disorders, 33, 287292.
Knutsson, U., Dahlgren, J., Marcus, C., Rosberg, S., Bron-
negard, M., Stierna, P., & AlbertssonWiklund, K.
~1997!. Circadian cortisol rhythms in healthy boys
and girls: Relationship with age, growth, body com-
position and pubertal development. Journal of Clini-
cal Endocrinology & Metabolism, 82, 536540.
LAllemand, D., Penhoat, A., Lebrethon, M. C., Ardevol,
R., Baehr, V., Oelkers, W., & Saez, J. M. ~1996!. Insulin-
like growth factors enhance steroidogenic enzyme and
corticotropin receptor messenger ribonucleic acid lev-
els and corticotropin steroidogenic responsiveness in
cultured human adrenocortical cells. Journal of Clini-
cal Endocrinology & Metabolism, 81, 38923897.
Lupien, S. J., Wilkinson, C. W., Briere, S., Menard, C.,
Ng, Y., Kin, N. M., & Nair, N. P. ~2002!. The modu-
latory effects of corticosteroids on cognition: Studies
in young human populations. Psychoneuroendocrinol-
ogy, 27, 401 416.
Lyons, M. J., Ture, W. R., Eisen, S. A., Goldberg, J., Meyer,
J., Faraone, S. V., Eaves, L. J., & Tsuang, M. T. ~1995!.
Differential heritability of adult and juvenile antisocial
traits. Archives of General Psychiatry, 52, 906915.
Malina, R. M. ~1983!. Menarche in athletes: A synthesis
and hypothesis. Annals of Human Biology, 10, 124.
Mann, D. R., Johnson, A. O., Gimpel, T., & Castracane,
V. D. ~2003!. Changes in circulating leptin, leptin
receptor, and gonadal hormones from infancy until
advanced age in humans. Journal of Clinical Endo-
crinology & Metabolism, 88, 33393345.
Matthews, K. A., Gump, B. B., Block, D. R., & Allen, M.
T. ~1997!. Does background stress heighten or dampen
childrens cardiovascular responses to acute stress?
Psychosomatic Medicine, 59, 488 496.
McBurnett, K., Lahey, B. B., Rathouz, P. J., & Rolf, L.
~2000!. Low salivary cortisol and persistent aggres-
sion in boys referred for disruptive behavior. Archives
of General Psychiatry, 57, 38 43.
McCrae, R. R., Costa, P. T., Jr., Ostendorf, F., Angleitner,
A., Hrebickova, M., Avia, M. D., Sanz, J., Sanchez
Bernardos, M. L., Kusdil, M. E., Woodfield, R., Saun-
ders, P. R., & Smith, P. B. ~2000!. Nature over nurture:
823
Temperament, personality, and life span develop-
ment. Journal of Personality & Social Psychology,
78, 173186.
McGue, M., Bacon, S., & Lykken, D. T. ~1993!. Person-
ality stability and change in early adulthood: A behav-
ioral genetic analysis. Developmental Psychology, 29,
96109.
Mesce, K. A. ~2002!. Metamodulation of the biogenic
amines: Second-order modulation by steroid hor-
mones and amine cocktails. Brain, Behavior & Evo-
lution, 60, 339349.
Miller, E. M., & Shields, S. A. ~1980!. Skin conductance
response as a measure of adolescents emotional reac-
tivity. Psychological Reports, 46, 587590.
Muller, M., Holsboer, F., & Keck, M. E. ~2002!. Genetic
modification of corticosteroid receptor signalling:
Novel insights into pathophysiology and treatment
strategies of human affective disorders. Neuropep-
tides, 36, 117131.
Neugarten, B. L. ~1979!. Time, age, and the life cycle.
American Journal of Psychiatry, 136, 887894.
Neumann, C. S., Grimes, K., Walker, E. F., & Baum, K.
~1995!. Developmental pathways to schizophrenia: Be-
havioral subtypes. Journal of Abnormal Psychology,
104, 558566.
Nottelmann, E. D., Susman, E. J., Dorn, L. D., Inoff
Germain, G., Loriaux, D. L., Cutler, G. B., Jr., &
Chrousos, G. P. ~1987!. Developmental processes in
early adolescence: Relations among chronological age,
pubertal stage, height, weight, and serum levels of
gonadotropins, sex steroids, and adrenal androgens.
Journal of Adolescent Health Care, 8, 246260.
Patton, G. C., Hibbert, M. E., Carlin, J., Shao, Q., Rosier,
M., Caust, J., & Bowes, G. ~1997!. Menarche and the
onset of depression and anxiety in Victoria, Australia.
Journal of Epidemiology & Community Health, 50,
661 666.
Paus, T., Zijdenbos, A., Worsley, K., Collins, D. L., Blu-
menthal, J., Giedd, J. N., Rapoport, J. L., & Evans, A.
C. ~1999!. Structural maturation of neural pathways
in children and adolescents: In vivo study. Science,
283, 19081911.
Petrill, S. A. ~2003!. The development of intelligence:
Behavioral genetic approaches. In R. Sternberg & J.
Lautrey ~Eds.!, Models of intelligence: International
perspectives ~pp. 8189!. Washington, DC: American
Psychological Association.
Pine, D. S. ~2003!. Developmental psychobiology and re-
sponse to threats: Relevance to trauma in children and
adolescents. Biological Psychiatry, 53, 796808.
Post R. M. ~2002!. Do the epilepsies, pain syndromes,
and affective disorders share common kindling-like
mechanisms? Epilepsy Research, 50, 203219.
Rice, F., Harold, G. T., & Thapar, A. ~2003!. Negative life
events as an account of age-related differences in the
genetic aetiology of depression in childhood and ad-
olescence. Journal of Child Psychology & Psychiatry
& Allied Disciplines, 44, 977987.
Rieder, J., & Coupey, S. M. ~1999!. Update on pubertal
development. Current Opinion in Obstetrics & Gyne-
cology, 11, 457 462.
Roberts, B. W., Caspi, A., & Moffitt, T. E. ~2001!. The
kids are alright: Growth and stability in personality
development from adolescence to adulthood. Journal
of Personality & Social Psychology, 81, 670 683.
Saito, R., Toyama, H., Uemura, K., Ishii, K., Senda, M.,
& Uchiyama, A. ~2001!. Quantitative estimation of
brain atrophy and function with PET and MRI two-
824
dimensional projection images. Kaku IgakuJapanese
Journal of Nuclear Medicine, 38, 201209.
Schmidt, M., Enthoven, L., van der Mark, M., Levine, S.,
de Kloet, E. R., & Oitzl, M. S. ~2003!. The postnatal
development of the hypothalamicpituitaryadrenal
axis in the mouse. International Journal of Develop-
mental Neuroscience, 21, 125132.
Schmidt, P. J., Nieman, L. K., Danaceau, M. A, Adams, L.
F., & Rubinow, D. R. ~1998!. Differential behavioral
effects of gonadal steroids in women with and in those
without premenstrual syndrome. New England Jour-
nal of Medicine, 338, 209216.
Schneider, W. ~2002!. Memory development in child-
hood. In U. Goswami ~Ed!., Blackwell handbook of
childhood cognitive development ~pp. 236256!.
Malden, MA: Blackwell.
Silberg, J. L., Pickles, A., Rutter, M., Hewitt, J., Simonoff,
E., Maes, H., Carbonneau, R., Murrelle, L., Foley, D.,
& Eaves, L. ~1999!. The influence of genetic factors
and life stress on depression among adolescent girls.
Archives of General Psychiatry, 56, 225232.
Snieder, H., van Doornen, L. J., & Boomsma, D. I. ~1997!.
The age dependency of gene expression for plasma
lipids, lipoproteins, and apolipoproteins. American
Journal of Human Genetics, 60, 638 650.
Steiner, H., & Levine, S. ~1988!. Family environment of
adolescents and coping in the hospital. Psychoneuro-
endocrinology, 13, 333338.
Stevens, J. R. ~2002!. Schizophrenia: Reproductive hor-
mones and the brain. American Journal of Psychiatry,
159, 713719.
StoffelWagner, B. ~2001!. Neurosteroid metabolism in
the human brain. European Journal of Endocrinol-
ogy, 145, 669 679.
Susman, E. J., Dorn, L. D., & Chrousos, G. P. ~1991!.
Negative affect and hormone levels in young adoles-
cents: Concurrent and predictive perspectives. Jour-
nal of Youth and Adolescence, 20, 167190.
Susman, E. J., Dorn, L. D., InoffGermain, G., Nottel-
mann, E. D., & Chrousos, G. P. ~1997!. Cortisol
reactivity, distress behavior, and behavioral and psy-
chological problems in young adolescents: A longitu-
dinal perspective. Journal of Research on Adolescence,
7, 81105.
Susman, E. J., Nottelmann, E. D., Dorn, L. D., Inoff
Germain, G., & Chrousos, G. P. ~1989!. Physiological
and behavioral aspects of stress in adolescence. In G.
Chrousos & P. Gold ~Eds.!, Mechanisms of physical
and emotional stress ~pp. 341352!. New York: Ple-
num Press.
Susman, E. J., Nottelmann, E. D., InoffGermain, G. E.,
Dorn, L. D., & Chrousos, G. P. ~1987!. Hormonal
influences on aspects of psychological development
during adolescence. Journal of Adolescent Health Care,
8, 492504.
Tamm, L., Menon, V., & Reiss, A. L. ~2002!. Maturation
of brain function associated with response inhibition.
Journal of the American Academy of Child & Adoles-
cent Psychiatry, 41, 12311238.
Tornhage, C. J. ~2002!. Reference values for morning sal-
ivary cortisol concentrations in healthy school-aged
E. F. Walker, Z. Sabuwalla, and R. Huot
children. Journal of Pediatric Endocrinology & Me-
tabolism, 15, 197204.
Udry, J. R., Billy, J. G., Morris, N. M., Groff, T. R., & Raj,
M. H. ~1985!. Serum androgenic hormone motivate
sexual behavior in adolescent boys. Fertility & Steril-
ity, 43, 9094.
Udry, J. R., & Talbert, L. M. ~1988!. Sex hormone effects
on personality at puberty. Journal of Personality &
Social Psychology, 54, 291295.
van Oel, C. J., Sitskoorn, M. M., Cremer, M. P., & Kahn,
R. ~2002!. School performance as a premorbid marker
for schizophrenia: A twin study. Schizophrenia Bulle-
tin, 28, 401 414.
Veldhuis, J. D. ~1996!. Neuroendocrine mechanisms me-
diating awakening of the human gonadotropic axis in
puberty. Pediatric Nephrology, 10, 304317.
Viken, R. J., Rose, R. J., Kaprio, J., & Koskenvuo, M.
~1994!. A developmental genetic analysis of adult per-
sonality: Extraversion and neuroticism from 18 to 59
years of age. Journal of Personality & Social Psychol-
ogy, 66, 722730.
WajsKuto, E., De Beeck, L. O., Rooman, R. P., & Caju,
M. V. ~1999!. Hormonal changes during the first year
of oestrogen treatment in constitutionally tall girls.
European Journal of Endocrinology, 141, 579584.
Walker, E., & Bollini, A. M. ~2002!. Pubertal neurodevel-
opment and the emergence of psychotic symptoms.
Schizophrenia Research, 54, 1723.
Walker, E. F., & Diforio, D. ~1997!. Schizophrenia: A
neural diathesis-stress model. Psychological Review,
104, 667 685.
Walker, E. F., Walder, D. J., & Reynolds, F. ~2001!. De-
velopmental changes in cortisol secretion in normal
and at-risk youth. Development and Psychopathol-
ogy, 13, 721732.
Warren, M., & BrooksGunn, J. ~1989!. Mood and behav-
ior at adolescence: Evidence for hormonal factors. Jour-
nal of Clinical Endocrinology & Metabolism, 69, 7783.
Weber, A., Clark, A. J., Perry, L. A., Honour, J. W., &
Savage, M. O. ~1997!. Diminished adrenal androgen
secretion in familial glucocorticoid deficiency impli-
cates a significant role for ACTH in the induction of
adrenarche. Clinical Endocrinology, 46, 431 437.
Weise, M., Eisenhofer, G., & Merke, D. P. ~2002!. Puber-
tal and gender-related changes in the sympathoadre-
nal system in healthy children. Journal of Clinical
Endocrinology & Metabolism, 87, 50385043.
Wingo, M. K. ~2002!. The adolescent stress response to a
naturalistic driving stressor. Dissertation Abstracts In-
ternational: Section B: The Sciences & Engineering,
63, 1082 ~Transaction Periodicals Consortium, Rut-
gers University!.
Wolkowitz, O., Epel, E., & Reus, V. ~2001!. Stress
hormone-related psychopathology: Pathophysiologi-
cal and treatment implications. World Journal of Bio-
logical Psychiatry, 2, 115143.
Yung, A. R., Phillips, L. J., Yuen, H. P., Francey, S. M.,
McFarlane, C. A., Hallgren, M., & McGorry, P. D.
~2003!. Psychosis prediction: 12-month follow up of
a high-risk ~prodromal! group. Schizophrenia Re-
search, 60, 2132.
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