- Psychiatry Research

Psychiatry Research 197 (2012) 181–198
Contents lists available at SciVerse ScienceDirect
Psychiatry Research
journal homepage: www.elsevier.com/locate/psychres
Review article
A review on the relationship between testosterone and the interpersonal/affective
facet of psychopathy
Baris O. Yildirim a,⁎, Jan J.L. Derksen b, 1
a
b
Department of Clinical Psychology, De Kluyskamp 1002, 6545 JD Nijmegen, The Netherlands
Department of Clinical Psychology, Room: A.07.04B, Radboud University Nijmegen, Montessorilaan 3, 6525 HR Nijmegen, The Netherlands
a r t i c l e
i n f o
Article history:
Received 2 December 2010
Received in revised form 20 May 2011
Accepted 26 August 2011
Keywords:
Gender differences
Testosterone
Affective empathy
Fear-reactivity
Instrumental aggression
a b s t r a c t
Testosterone (T) has received increasing interest in the recent years as a probable biological determinant in
the etiology of male-biased clinical conditions such as psychopathy (i.e. psychopathy is more prevalent in
men and leads to an earlier onset and more severe expression of antisocial and aggressive behavior in men
compared to women). In this review, the authors evaluated the potential relationship between T and different constructs closely related to the core characteristics of psychopathy (affective empathy, fear-reactivity,
and instrumental aggression). After a thorough examination of the literature, it is concluded that high T exposure in utero and high circulating T levels throughout important life phases (most notably adolescence) or
in response to social challenges (e.g. social stress, competition) could be an important etiological risk factor in
the emergence of psychopathic behavior. Nevertheless, studies consistently indicate that high T is not related
to a significantly reduced fear-reactivity and is only indirectly associated with the increased levels of instrumental aggression observed in psychopathic individuals. Therefore, psychopathy is likely to arise from an interaction between high T levels and other biological and socio-psychological risk factors, such as a
constitutionally based dampened fear-reactivity, insecure/disordered attachment processes in childhood,
and social discrimination/rejection in adolescence and/or adulthood.
© 2012 Elsevier Ireland Ltd. All rights reserved.
Contents
1.
2.
3.
4.
5.
6.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Testosterone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Behavioral constructs underlying the interpersonal/affective factor of psychopathy . . . . . . . . . . . . .
Aggression subtypes associated with the interpersonal/affective factor of psychopathy
. . . . . . . . . . .
Testosterone and empathy
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.1.
Gender differences in affective empathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.2.
Fetal T and empathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.2.1.
Relationship between amniotic T and empathy related constructs in infancy and childhood
.
5.2.2.
Congenital Adrenal Hyperplasia (CAH) and measures of affective empathy and social sensitivity
5.3.
Correlation between salivary T and empathy related constructs . . . . . . . . . . . . . . . . . . .
5.4.
Causality between T administration and empathy
. . . . . . . . . . . . . . . . . . . . . . . . .
5.5.
Influence of T on the neurobiology of empathy . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.5.1.
Direct mechanisms; T and amygdalar reactivity to interpersonal cues of distress . . . . . . .
5.5.2.
Direct mechanisms; T and orbitofrontal reactivity to socio-emotional stimuli . . . . . .
5.5.3.
Indirect mechanisms: influence of T on oxytocinergic functioning . . . . . . . . . . . . . .
Testosterone and fear-reactivity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.1.
Gender differences in fear-reactivity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.2.
Fetal T/postnatal salivary T and fear-reactivity in infancy . . . . . . . . . . . . . . . . . . . . . .
6.3.
T administration and fear-reactivity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.3.1.
T administration and fear in humans . . . . . . . . . . . . . . . . . . . . . . . . . . .
⁎ Corresponding author. Tel.: + 31 646118681.
E-mail addresses: [email protected] (B.O. Yildirim), [email protected] (J.J.L. Derksen).
1
Tel.: + 31 24 36 12666.
0165-1781/$ – see front matter © 2012 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.psychres.2011.08.016
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B.O. Yildirim, J.J.L. Derksen / Psychiatry Research 197 (2012) 181–198
6.3.2.
Influence of castration and T administration on fear-potentiated startle in animal research . . . . .
6.3.3.
Influence of T administration on behavioral measures of fear in animals . . . . . . . . . . . . . .
6.4.
Influence of T on the neurobiology of fear . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.4.1.
T and neurochemical functioning in fronto-limbic structures . . . . . . . . . . . . . . . . . . .
7.
Role of T in instrumental aggression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.1.
Gender differences in instrumental/proactive aggression
. . . . . . . . . . . . . . . . . . . . . . . . .
7.2.
Salivary T and instrumental (unprovoked) aggression . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.2.1.
Studies on salivary T and instrumental aggression in children and adolescents . . . . . . . . . . .
7.2.2.
Studies on salivary T and instrumental aggression in adults . . . . . . . . . . . . . . . . . . . .
7.2.3.
Studies on salivary T and laboratory tasks of instrumental aggression . . . . . . . . . . . . . . .
7.3.
Bio-socio-psychological influences on the expression of instrumental aggression . . . . . . . . . . . . . .
7.3.1.
Biological influences; reward reactivity, motivational drive, and need for interpersonal control . . .
7.3.2.
Socio-psychological influences; insensitive attachment experiences and social discrimination/rejection
7.3.3.
Endocrinological mediators; HPA-axis reactivity . . . . . . . . . . . . . . . . . . . . . . . . .
8.
Discussion and mediating factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.1.
Neuroendocrinological mediating factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.2.
Socio-psychological mediating factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
9.
Theoretical model . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
10.
Critical evaluation and future perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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1. Introduction
2. Testosterone
Psychopathy is a disorder of emotional and behavioral functioning which affects more men than women (Hare, 1993; Blair, 2006),
and leads to a more severe and an earlier expression of antisocial
behavior in men as compared to women (Verona and Vitale,
2006). Because of these well-known gender differences in the prevalence rate and severity of psychopathy, many researchers have
shown increasing interest in the potential role of masculine gonadal
hormones such as testosterone (abbreviated as T) in psychopathic
behavior (Stålenheim et al., 1998; Van Honk and Schutter, 2006).
Research has indicated that T administration is causally related to
some of the emotion processing deficits observed in psychopathy,
such as reduced emotional interference during decision making
(Van Honk et al., 2005), and decreased automatic facial mimicry
of emotive facial expressions (Hermans et al., 2006b). In light of
these findings, Van Honk and Schutter (2006) have suggested in
their “Triple-Balance-Model of Emotion” that heightened T is an
important biological determinant in the etiology of the emotional
processing deficits of psychopathy. However, research done with
groups of psychopathic individuals only found significant correlations between T and the antisocial/impulsive behavior observed in
psychopathy, and not with the unique emotion processing deficits
(interpersonal/affective traits) (Stålenheim et al., 1998; Loney et
al., 2006). Remarkably, there has been no attempt to review the
scientific literature in order to examine in depth the relationship between T and core characteristics of psychopathy, clarify contrasting
findings, and set up empirically grounded hypotheses to be tested in
future empirical research. The goal of this article is to review and critically evaluate the scientific literature on the relationship between T
and different behavioral constructs which are strongly and uniquely related to psychopathy in order to determine if heightened T may be a relevant biological determinant in the etiology of the core characteristics
of psychopathy. The search for literature included the following databases; PubMed, Elsevier Sciencedirect, OvidSP, JSTOR, Sage, and
Wiley Interscience. The following primary keywords were used:
(fetal-) testosterone, (fetal-) androgens, anabolic androgenic steroid
(AAS), and gender differences. These primary keywords were coupled
to the following secondary keywords: empathy, emotion recognition,
oxytocin, fear, threat processing, amygdala reactivity, prefrontal cortex,
instrumental/proactive aggression, dopamine, and serotonin (e.g.
fetal + testosterone+ empathy). Before going into this discussion, we
will first start off with an introduction into the key points about T and
psychopathy.
T is a masculine gonadal hormone (men are naturally exposed to
higher levels of fetal and circulating T than women) that has strong
influences on the maturation and reactivity of various cortical as well
as subcortical neural circuitry associated with socio-emotional and sexual functioning, and consequently, T is found to mediate gender-specific
behaviors (Phoenix et al., 1959; Schulz et al., 2009). Levels of circulating
T prominently increase during adolescence, and during competitive, socially stressful or sexually arousing situations, thereby mediating the
behavioral response to these events (Sayegh et al., 1990; Buchanan et
al., 1992; Archer, 2006; Roelofs et al., 2010). However, there is high
inter-individual heterogeneity in the typical behavioral response to a
surge of T, which is most evident in gender-specific behavioral reactions
to T administration (e.g. compare results of: Zak et al., 2009; Zak, 2011,
with the findings of: Zethraeus et al., 2009; Eisenegger et al., 2010). This
heterogeneity can be explained with the hypothesis that the behavioral
response to T is strongly dependent on the specific ways fetal levels of T
have influenced the maturation of neurobiological circuitry involved in
the behavioral response to the corresponding event (e.g. Van Honk et
al., 2011). This phenomenon, called the organizational-activational hypothesis of gonadal steroids, refers to the consistent findings in animals
that gender-specific behavioral responses in adulthood to increases in T
(activation of specific behavior) can significantly be established (organized) by levels of fetal T exposure; so that higher levels of fetal T exposure lead to increased masculine behavioral responses (e.g. dominant)
to T administration in adulthood (Phoenix et al., 1959).
Although some researchers have questioned whether permanent influences occur only prenatally, arguing that there appear to be several
sensitive periods throughout life when T might have permanent effects
on neurobiology (Arnold and Breedlove, 1985; Schulz et al., 2009;
Lürzel et al., 2010), maturation of most brain structures is predominantly prenatal (Stahl, 2008). For that reason, the strongest and most
permanent effects of gonadal hormones on neurodevelopment and
neurobiological (dys-)functioning are likely to be seen prenatally. Consequently, organizing effects of in particular fetal T are likely to play an
important role in the etiology of psychopathic traits, since these traits
are already present before adolescence (Viding et al., 2005), and are
suggested to arise partly out of temperamental dispositions (Glenn et
al., 2007). Subsequently, activating effects of circulating T during adolescence and adulthood may then exacerbate the defiant behavior, leading to the observed increases in the severity and frequency of the
antisocial behaviors of psychopathic individuals during this period
(Hare, 1993; Harpur and Hare, 1994).
B.O. Yildirim, J.J.L. Derksen / Psychiatry Research 197 (2012) 181–198
Therefore, to uncover whether T plays a potential role in the etiology of the core characteristics of psychopathy, we will review both
studies examining fetal T exposure as well as studies investigating
circulating T levels on the behavioral constructs associated with psychopathy. However, we will begin each section with an introduction
on the gender differences found in the corresponding construct
since it is logical to assume that if T has any effect on the construct
discussed, then this should be at least reflected by observed gender
differences, and, the stronger the effect of gender is, the more likely
that T is involved in its expression.
3. Behavioral constructs underlying the interpersonal/affective
factor of psychopathy
In 1980 Robert D. Hare developed the Psychopathy Checklist (PCL)
which consisted of 22 items (later shortened to 20 items in the
revised edition; PCL-R) that were based on the vivid descriptions of
Hervey Cleckley's famous work entitled “The Mask of Sanity” in
which he portrayed psychopathic individuals as irresponsible,
untrustworthy, reckless, boastful, and emotionally shallow human
beings (Cleckley, 1941; Hare, 2003). The PCL-R has been used in
different settings and populations to determine psychopathic
tendencies, and studies with the PCL-R have consistently revealed a
dominant two-factor structure that characterizes the different traits
associated with psychopathy (Harpur et al., 1988, 1989; Hare,
2003). The interpersonal/affective factor of psychopathy (in children
referred to as callous/unemotional traits) reflects the remorseless,
calculating, callous, and unscrupulous use of others and thus summarizes the core characteristics of psychopathy as proposed by Cleckley.
The lifestyle/antisocial factor is strongly related to an antisocial and
impulsive lifestyle and is more consistent with the definition of Antisocial Personality Disorder from the DSM-IV (Verona et al., 2001;
Hare, 2003). In this review, we will focus exclusively on the relationship between T and the core characteristics of psychopathy as proposed by Cleckley, which are represented by the items of the
interpersonal/affective factor.
It has been suggested and supported with experimental research
that the interpersonal/affective traits of psychopathy are strongly
related to emotional processing deficits, which correlate with attenuated amygdalar reactivity to threatening or emotionally aversive cues
(Blair, 2006). Research in psychopathic individuals regarding these
emotional processing deficits can be divided into findings associated
with low fear-reactivity, operationalized as dampened amygdalar
and autonomic responsivity to cues of threat and during fearconditioning (Patrick et al., 1993, 1994; Kiehl et al., 2001; Vanman
et al., 2003; Benning et al., 2005b; Fowles and Dindo, 2006; Holi et
al., 2006; Hansen et al., 2007; Iria et al., 2008), and lack of affective
empathy, operationalized as diminished recognition of, and also
dampened amygdalar responsivity to, fearful and sad facial and
vocal expressions (Blair et al., 1997; Sprengelmeyer et al., 1999;
Stevens et al., 2001; Blair et al., 2001, 2002, 2003; Dolan and
Fullham, 2006). Therefore, low fear-reactivity and dampened affective empathy are suggested to be the primary endophenotypes predisposing to the observable behavioral items of the interpersonal/
affective factor of psychopathy (Hare, 1993; Blair, 2006; Fowles and
Dindo, 2006). This finding has been replicated in children, with low
empathy and low fear in younger children being directly related to
the development of callous/unemotional traits later in childhood
and adolescence (Glenn et al., 2007; Pardini et al., 2007; Frick and
White, 2008).
In addition, heightened impulsivity is also strongly related to
psychopathy in general and the antisocial/lifestyle factor in particular
but is only weakly associated with the interpersonal/affective factor
(e.g. Colledge and Blair, 2001; Benning et al., 2003; Skeem et al.,
2003; Benning et al., 2005a). Moreover, Poythress and Hall
(2011) recently reviewed the vast literature on the relationship
183
between psychopathy and impulsivity; they conclude that the two
clinical conditions are not consistently related and therefore argue
the validity of regarding impulsivity as a cardinal trait of the psychopathic disorder. For this reason we have chosen not to include impulsivity in this review.
4. Aggression subtypes associated with the interpersonal/affective
factor of psychopathy
Low fear-reactivity and dampened affective empathy can heighten
the risk for both reactive and instrumental aggression, as the distress
of the victim and the emotional consequences in the long-term are
less of a restraint (Blair, 2006; Porter and Woodworth, 2006; Glenn
and Raine, 2009). Children and adolescents high in callous/unemotional
traits are more likely to show both instrumental and reactive aggression
as rated by self-report questionnaires (Fanti et al., 2009), and measured
in controlled laboratory settings (Muñoz et al., 2008). Therefore, if an
individual with dampened affective empathy and fear-reactivity
develops aggressive behaviors, he/she will most likely express a
mixture of reactive and instrumental forms of aggression, which may
be difficult to separate (Merk et al., 2005; Blair, 2006).
However, although psychopathy in general is related to both
instrumental and reactive aggression, the extra contribution of the
interpersonal/affective factor, and the differentiation with other antisocial individuals, is related to the instrumentality of the violence
(Hare, 1993; Hart and Dempster, 1997; Woodworth and Porter,
2002; Reidy et al., 2007). Reactive aggression is observed in many
other psychiatric conditions and personality disorders, whereas instrumental aggression is unique to psychopathy, and in particular to the interpersonal/affective factor (Woodworth and Porter, 2002; Blair, 2006).
Moreover, many non-violent but destructive actions of the psychopath
involve predation and planning, and are instrumental in nature (Hare,
1993; Stafford and Cornell, 2003; Porter and Woodworth, 2006).
These findings are replicated in children and adolescents, indicating
that only callous/unemotional traits are associated with instrumental
aggression (Frick et al., 2003; Marsee and Frick, 2007).
After review of the literature Merk et al. (2005) conclude that the
distinction between reactive and instrumental (also called proactive)
aggression is useful in doing research because “despite considerable
overlap between the two subtypes of aggression, reactive and
proactive aggression appear to constitute two separate forms of aggression with different precursors, correlates, outcomes, and indicated interventions” (abstract). Since the interpersonal/affective factor is
uniquely related to instrumental aggression, we suggest that discussing the influence of T on instrumental aggression would have
more contributory value to the understanding of how T might
contribute to etiology of interpersonal/affective traits, rather than
aggression in general. In addition, in the last two decades many
comprehensive reviews have already been conducted to examine
the potential relationship between T and reactive aggression, and
these articles have introduced excellent theoretical models to be
tested in empirical research (see Archer 1991; Book et al., 2001;
Archer, 2006; Carré et al., 2011).
5. Testosterone and empathy
The empathy construct can be divided into two components,
namely affective and cognitive empathy. Cognitive empathy is the
ability to put yourself in another's shoes and understand his behaviors and feelings (also referred to as “theory-of-mind”), which can
be done purely rationally and is totally intact in psychopathy (Dolan
and Fullam, 2004). In contrast, affective empathy is the automatic
emotional resonation with (i.e. autonomic reactivity to) other people's distress, which is strongly dampened in psychopathy (Hare,
1993; Blair, 2006).
184
B.O. Yildirim, J.J.L. Derksen / Psychiatry Research 197 (2012) 181–198
5.1. Gender differences in affective empathy
The hypothesis that T levels might be related to empathy arises from
the finding that men tend to be both less affectively and less cognitively
empathetic than women (e.g. Baron-Cohen, 2002; Goldenfeld et al.,
2005; Hurlemann et al., 2010). This difference is present at infancy
and by early preschool; girls exhibit greater empathy and prosociality,
social skills, remorse after transgressions, and a better understanding
of others' intentions and feelings (Zahn-Waxler et al., 2008). This difference is thought to have arisen from evolutionary pressures; while men
had to learn to ‘systemize’; namely to analyze, investigate, understand,
and build systems in order to capture prey or gather food, women were
more dependent on ‘empathizing’; to respond appropriately to social
interactions in order to maintain group cohesion (Baron−Cohen,
2002). These essential sex differences have been suggested to arise
mainly from the effect of gonadal hormones on the developing fetus
(Knickmeyer and Baron-Cohen, 2006), but this is likely a highly reductionist view on sex-differences (Jordan-Young, 2010).
Another interesting finding relevant in this context is that the affective empathetic response in men strongly depends on the individual being perceived, and whether this person is likeable or unlikable.
For example, Singer et al. (2006) investigated whether perceived
fairness of others modulates subsequent empathy-related neural
responses when observing fair or unfair players of an economic
game, receiving painful electric shocks. They reported that men
showed empathy-related activation in pain-related brain structures
(fronto-insular and anterior cingulate cortices) only toward fair
players, whereas women showed increased empathy-related responses
towards both the fair and unfair players, indicating that affective empathy in men is probably more strongly modulated by situational factors
and less by an ingrained part of personality.
5.2. Fetal T and empathy
5.2.1. Relationship between amniotic T and empathy related constructs
in infancy and childhood
Only three studies have examined the relationship between fetal T
and social sensitivity/empathy and all have used amniotic fluid to
determine fetal T exposure (Lutchmaya et al., 2002; Chapman et al.,
2006; Knickmeyer et al., 2006). Lutchmaya et al. (2002) have found
that higher amniotic T is negatively related (Spearman ρ = −0.3) to
eye-contact in 12-month-old infants (n = 70), which is associated
with dampened affective empathy and psychopathic development
in adolescence and adulthood (Dadds et al., 2010). Furthermore,
amniotic T is negatively related to the child version of the Empathy
Quotient (EQ) in boys between 6 and 9 years of age (n = 100, r =
−0.35, P b 0.01) (Chapman et al., 2006). The EQ in children is a measure of both cognitive (perspective-taking, r = 0.485) as well as affective empathy (empathetic concern r = 0.423/emotional reactivity to
others r = 0.583) (Lawrence et al., 2004). These results in infants
and children indicate that high levels of fetal T may have a small to
moderate negative relationship (r = between 0.3 and 0.4) on social
sensitivity in infancy and dampened empathy in childhood.
However, these studies are insufficient to reach firmly grounded
hypotheses specifying whether fetal T influences the various subtypes
of empathy differently, since only affective empathy and not cognitive empathy is related to psychopathy (Dolan and Fullam, 2004),
and given the finding that fetal T has also been related to measures
of cognitive empathy in 4-year-olds (Knickmeyer et al., 2006). Future
studies may answer this question if various measures of social sensitivity and empathy are administered to better differentiate between
the specific effects of fetal T on the different subtypes of empathy.
Additionally, although fetal T measured through amniocentesis may
be the best way available to study actual fetal T exposure (Van de
Beek et al., 2004), it still has different shortcomings (see
Knickmeyer et al., 2006).
5.2.2. Congenital Adrenal Hyperplasia (CAH) and measures of affective
empathy and social sensitivity
The genetic disorder, Congenital Adrenal Hyperplasia (CAH),
which causes exposure to abnormally high levels of fetal androgens,
can also inform on the relationship between fetal T and behavior in
childhood. In accord with the results of studies on fetal T and empathetic development, CAH is associated with less tender-mindedness
(d = −1.16), less caring disposition (d = −1.3), and higher physical
aggression (d = 0.51) in CAH women (n = 40) compared to healthy
controls (n = 29) from different socio-economic backgrounds and between 12 and 45 years of age (Mathews et al., 2009). Furthermore,
females with CAH (n = 22) in comparison to healthy females
(n = 22) scored higher on the Detachment scale of the Karolinska
Scales of Personality, indicating a significantly higher level of callousness and lower affective empathy in social relationship with strong
effect sizes (d = 1.58, rYl = 0.62, P b 0.001) (Helleday et al., 1993). In
contrast, males afflicted with CAH between the ages of 12 and
40 (n = 29), showed the opposite, being more tender-minded
(d = 0.52), less dominant (d = −0.84) and displaying reduced physical aggression (d = −0.72) compared to healthy controls (n = 30)
(Mathews et al., 2009). This finding is in accord with other studies
who report decreased rough-and-tumble play in boys (d = −1.21),
and increased aggression in girls (d = 0.6) with CAH (n = 38), compared to healthy controls (n = 33) (Hines and Kaufman, 1994).
These seemingly paradoxical gender-differences in fetal T exposure on measures of social sensitivity and empathy can be explained
by both endocrinological as well as psychological processes. For example, uncontrolled adrenal androgen secretion in men with CAH
can result in increased neural feedback and inhibition of testicular T
production (via the aromatization of T into estrogens) which may
lead to secondary hypogonadotrophic hypogonadism, whereas females do not produce testicular T and thus cannot counterbalance
the high levels of fetal androgen exposure (Brown-Grant et al.,
1975; Mathews et al., 2009). A second hypothesis put forward by
Mathews et al. (2009), and one more focused on psychological development, is that boys with CAH are not born with observable genital
abnormalities as girls are, and are therefore less likely to be diagnosed
and treated at an early age, which might increase incidences of hospitalization for salt-losing crises. Accordingly, most of the boys in the
Mathews study had the more severe salt-losing form of CAH. Moreover, in the Hines and Kaufman (1994) study, boys were significantly
longer and more often hospitalized in the first 2 years of life compared with girls, and these measures were inversely correlated with
aggressiveness and rough-and-tumble play (number of hospitalizations: r = −0.66, duration hospitalizations: r = − 0.75).
These findings indicate that reduced masculine type behavior and
increased empathetic concern in boys with CAH (rough-and-tumble
play, dominance, and aggressiveness), may result from the effect
the illness has had on personality development rather than being an
effect of high fetal T exposure. We can thus question whether CAH
in males is a valid method of investigating the effects of high fetal T
on socio-emotional development since this effect is strongly modulated by both biological and psychological factors more specific to males.
5.3. Correlation between salivary T and empathy related constructs
A correlative study with 306 university students indicated an inverse relationship in both sexes between prosocial behavior/personality
and levels of T measured through saliva (Harris et al., 1996). T was related to lower scores on the prosocial factor (emotional empathy scale, altruism, and nurturance) (men; r = −0.44, women; r = −0.29), and
higher scores on the antisocial factor (aggression and hostility) (men;
r = 0.36, women; r = 0.41), across different points of time (09:30/
10:30 am). After modeling of the observed associations, a causal effect
model seemed to fit the data better than a correlational effect
model, indicating a moderate causal effect of T on prosocial
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personality characteristics (r = − 0.39) (Harris et al., 1996). Finally,
in 109 undergraduate females, T measured in saliva showed a small
negative relationship with kindness (r = − 0.21), having a caring attitude (r = − 0.21), and being helpful (r = − 0.24) on self-report
questionnaires (Baucom et al., 1985).
These above results indicate a small to moderate effect of salivary T,
measured through enzyme immunoassay techniques (EIA), on emotional empathy. However, it has been supported in meta-analytic studies that when salivary T is measured using EIA, the known testosteronebehavior correlation is underestimated by 22.91% for boys and 57.65%
for girls (Granger et al., 2004), indicating that examining empathy
scores with salivary T measured through the EIA might be an underestimation of this relationship, especially in females. Future correlative
studies into the T-behavior relationship may improve on internal validity by using blood draws to determine circulating T levels.
In contrast to these findings, a third study with children of 5-years,
emotional empathy (affectivity in affiliative relationships) in girls
(n = 69) but not boys (n = 60) was found to be positively related to
salivary samples of T (r = 0.453 and β = 1.8). An interaction effect
with IQ was observed, with the association being significant only in
girls with low IQ (IQ ∗ affectivity, r = 0.549 and β = −1.38)
(Azurmendi et al., 2006), indicating that low IQ might actually be a
protective factor in the development of psychopathic traits. The
observed differences in findings between the Azurmendi study
conducted with children (age 5) and the Baucom and Harris studies
with undergraduates, may be related to the age of the participants
studied. Since personality is not yet established at the age of 5 and
activating effects have not yet fully occurred, relationships between
T and prosocial behavior are likely to be more labile and show less
stability over time compared to studies with undergraduates.
5.4. Causality between T administration and empathy
The first study examining the causal relationship between T and
empathy is the study conducted by Hermans et al. (2006b). T administration in women from 19 to 31 years of age (n = 20), was found to
reduce facial mimicry when seeing dynamic facial expressions of
happy and angry faces (Hermans et al., 2006b). The tendency to
mimic others' emotional expressions is a strong predictor of affective
empathy (Sonnby-Borgstrom, 2002), and is significantly lower in
adolescent boys who are prone to develop psychopathy in adulthood
(De Wied et al., 2006). A strong interaction effect was found for
degree of facial mimicry and independent condition (T and placebo),
with lower mimicry in participants given T compared to placebo
(happy faces; d = −0.96, angry faces; d = −0.92). In reaction to
these findings Hermans et al. (2006b) argue that “in sum the nature
of the relationship between T and human behavior likely lies in its
propensity to amplify power motives and dominance, whilst attenuating empathy” (p. 860).
Another task designed to examine altruism and prosocial behavior
in human social interactions is the ultimatum game. In this game the
participant receives a certain amount of money for his participation in
the study and is told that he may donate some of his money to another participant, who he is told, has received no money whatsoever for
his enrollment. The amount of money offered to the unpaid participant is taken as a measure for fairness, generosity, and has strongly
been connected to affective empathy (Barraza and Zak, 2009). The results of T administration on generosity in the ultimatum game are inconsistent. In the first and second study by Zak et al. (2009; Zak,
2011), T administration (10 g Androgel® = 100 mg T) to undergraduate men (n = 25), leading to a 60% increase in total T and 97% increase
in free T, was found to reduce their generosity by 27% in the ultimatum game. This decrease in generosity remained significant after controlling for altruism (Zak, 2011), and was mainly related to the
influence of T administration on higher total T levels rather than
higher free T levels (β = − 0.44 and − 0.05 respectively) (Zak et al.,
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2009; Zak, 2011). In contrast, other studies examining the effect of
long-term T administration (4 weeks) on ultimatum game behavior
in a group of 203 healthy women between ages 50 and 65, reported
no significant effects on bargaining behavior (generosity or altruism)
(Zethraeus et al., 2009). Moreover, another study in 121 women with
a mean age of 25, reported an increase in generosity (F = 4.92,
P = 0.031, effect size; Cohen f 2 = 0.24) on the ultimatum game after
administration of T (0.5 mg T = 10 fold increase of total T levels in
women; Tuiten et al., 2000) (Eisenegger et al., 2010), indicating an
unexpected increase in prosociality and fairness in social interactions.
These results indicate that T administration has a moderate negative
effect on generosity in men and a small positive effect on generosity
in women (Eisenegger et al., 2010; Zak et al., 2009; Zak, 2011).
Remarkably, the studies that report an absence or positive relationship between T and bargaining behavior are conducted only
with women (Zethraeus et al., 2009; Eisenegger et al., 2010), while
studies that report a negative relationship are conducted only with
men (Burnham, 2007; Zak et al., 2009; Zak, 2011). Men react differently to the activating effects of T administration because of prenatal
and adolescent masculinization of underlying neural circuitry. It has
been discussed that fetal T and long-term increases in circulating T
during adolescence, which are both higher in men, masculinizes underlying brain circuitry leading to differential behavioral responses
to acute increases in circulating T throughout the lifespan. Since
women differ significantly from men regarding fetal T exposure,
women might react differently to a surge of T, increasing their concern for maintaining social connections (in women status may be
defined by their social connectivity), while men might react to T administration by an increase in dominance and reactive aggression to
maintain social status (in men status may be defined by leadership
and dominance). Unfortunately, all empirical studies investigating
the influence of T administration on empathy and related constructs
use unisex designs (e.g. Hermans et al., 2006b; Burnham, 2007; Zak
et al., 2009; Zethraeus et al., 2009; Eisenegger et al., 2010; Zak,
2011), making it impossible to infer whether T administration
under the exact same conditions and leading to the same percentage
of T increase in both men and women may cause different patterns of
empathetic responding between the sexes. Interestingly, Van Honk et
al. (2011) found that the cognitive empathetic response in females is
strongly modulated by T exposure in utero, explaining more than 50%
of the variance in the effect of T administration on cognitive empathy
in females (Van Honk et al., 2011). This modulation of fetal T exposure may also account for affective empathy explaining why the
above studies find divergent results in T administration on empathetic responding between males and females.
5.5. Influence of T on the neurobiology of empathy
According to Blair (2006) one of the key limbic structures regulating the strength of affective empathy, is the amygdala, which shows
diminished activation to distress cues (sad and fearful facial and
vocal expressions) in psychopathy. Therefore, it has been suggested
that proper amygdala activation in response to distress cues (distressed facial expressions) may be an important prerequisite for
affective empathy development (see for review Blair, 2006). The
amygdala signals this affective information to the orbital frontal cortex, which is mainly involved in its appraisal. Thus, functionality of
orbital frontal structures during social interactions is paramount for
healthy emotional appreciation of social cues (Damasio et al., 1990;
Grattan et al., 1994; Eslinger, 1998).
5.5.1. Direct mechanisms; T and amygdalar reactivity to interpersonal
cues of distress
Different studies have investigated the relationship between T and
amygdalar responsivity to emotional facial expressions and consistently report that T is both causally and associatively related to
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heightened responsivity of the amygdala to fearful or angry faces
(Hermans et al., 2008; Derntl et al., 2009; Van Wingen et al., 2009;
Manuck et al., 2010). The first study conducted by Hermans et al.
(2008), observed that after sublingual T administration in women,
amygdalar reactivity to both angry and happy facial expressions was
significantly stronger than in women receiving placebo. Secondly,
Van Wingen et al. (2009) observed a significant increase in left amygdalar reactivity to negatively emotional facial expressions (left amygdala: r = 0.41) after a nasal dose of T in middle-aged women.
Furthermore, higher levels of salivary T are associated bilaterally
with heightened amygdala reactivity to emotional facial expressions
(left; r = 0.32, P b 0.05, right; r = 0.40, P b 0.02) (Manuck et al., 2010).
In agreement, Derntl et al. (2009) also observed a strong negative relationship between T levels in blood samples and reaction time to fearful
faces (r = −0.598), and a moderate positive relationship between T
levels and amygdalar reactivity to fearful faces (r = 0.453). Interestingly, female adolescents with CAH show higher amygdalar reactivity to
emotional facial expressions (anger, fear), indicating a sensitizing organizing effect of fetal T on amygdalar reactivity (Ernst et al., 2007).
These results indicate that high T does not decrease amygdalar reactivity to emotional facial expressions as is the case in psychopathy and is
therefore probably unrelated to emotion recognition capacities. Accordingly, research found that T administration significantly reduced conscious recognition of facial expressions of anger, but not fear or disgust
(Van Honk and Schutter, 2007), which runs counter to the disturbance
observed in psychopathy, namely significantly worse recognition of
fear, sadness, and disgust but not anger (see for review Blair, 2006).
5.5.2. Direct mechanisms; T and orbitofrontal reactivity to socioemotional stimuli
Although T does not decrease limbic reactivity to, and conscious
recognition of, others' distress cues, it might influence the emotional
appraisal of others' distress, which is largely dependent on prefrontal
functionality, of in particular the ventromedial prefrontal cortex,
in response to affective signals emanating from limbic structures
(Damasio et al., 1990; Grattan et al., 1994; Eslinger, 1998).
Stimulation of the limbic system evokes delta/theta activity
(4–8 Hz) (slow wave), whereas the cortical mantle of many primates
oscillate in the 8–12 Hz (alpha) and 13–30 Hz (beta) frequencies (fast
wave) (Gray, 1982; Knayzev and Slobodskaya, 2003). When EEG recordings are observed, the delta/theta frequencies (slow wave) and
the alpha frequency (fast wave) are negatively correlated, indicating
that higher limbic reactivity is associated with reduced cortical processing and reactivity to affective signals (Robinson, 1999; Schutter et al.,
2006). Accordingly, administration of T, down-regulates fronto-limbic
interactions of information-flow, indicated by an increase in slow
wave frequencies (increased limbic reactivity) (Lindberg et al., 2003;
Schutter and Van Honk, 2004), and a decoupling of EEG slow and fastwaves (decreased prefrontal reactivity to limbic signals), likely leading
to a diminished ability to cognitively analyze or regulate affective signals stemming from limbic structures (Schutter and Van Honk, 2004;
Van Honk et al., 2005; Van Wingen et al., 2010).
An example illustrating the diminished fronto-limbic information
flow is the finding that T impairs conscious recognition of the affective facial emotion of anger (Van Honk and Schutter, 2007), while it
increases limbic and autonomic reactivity when confronted with an
angry face (Van Honk et al., 2001, 2005). Furthermore, the Van
Wingen study reported that T enhanced amygdalar reactivity but
dampened orbitofrontal reactivity to fearful facial expressions (Van
Wingen et al., 2009), which may be explained by the negative influence of T on fronto-limbic coupling (Van Wingen et al., 2010). In addition, Mehta and Beer (2009) have shown that higher T is associated
(r = − 0.55, P b 0.05) with lower activation of the orbital frontal cortex during social decision making when confronted with rejection
(ultimatum game) and higher levels of reactive aggression in both
males and females. This increase in reactive aggression during
rejection was directly related to high T levels and decreased orbital
frontal cortex activity, indicating a hypersensitivity to threat (rejection), likely representing the increase in amygdalar reactivity, and
hyporesponsivity of the orbital frontal cortex when responding to social interactions (reduced social sensitivity) in high T individuals.
These results might indicate that T diminishes the cognitive appraisal
and control of strong affective signals, and impairs a healthy appreciation of the significance of certain socio-emotional consequences
(Van Honk et al., 2010), including hurting another human being
through overt or covert aggression.
5.5.3. Indirect mechanisms: influence of T on oxytocinergic functioning
The hypothesis that T might influence empathetic and prosocial
behavior is supported by research into the neuropeptide oxytocin
(OT). OT is present in all mammalian species and promotes calmness,
social sensitivity, trust, and empathy. It is the main hormonal system
of peace and connection and serves to increase emotional bonding
between individuals (Üvnas-Moberg, 2003). Different studies have
shown strong positive effects of OT administration on both emotional
and cognitive empathy (Zak et al., 2007; Barraza and Zak, 2009;
Hurlemann et al., 2010; Zak, 2011). For example, Hurlemann et al.
(2010) found that OT administration enhanced self-reported emotional empathy when watching pictures of individuals in distress
(d = 1.12, P b 0.0001). Gender differences were also found in emotional empathy, with men scoring lower than women. However, after OT
administration, this effect disappeared indicating that the lower level
of emotional empathy in men may relate to lower oxytocinergic functioning (Hurlemann et al., 2010).
In accord with this finding, steroids such as estrogens and androgens
have a great influence on neuropeptide production, release, sensitivity
and gene-expression (Rhodes et al., 1981; Crowley et al., 1995; Grazzini
et al., 1998). There is also evidence that gender specific levels of steroids,
such as testosterone and estrogen, alter the sensitivity and innervation of
OT and its receptors (De Vries et al., 1986; Johnson et al., 1991; Johnson,
1992). Oxytocinergic mechanisms are amplified by female sex-specific
hormones such as estrogen (up-regulation of receptor sensitivity)
(Rhodes et al., 1981; Johnson et al., 1991; Johnson, 1992; Grazzini et al.,
1998), and are dampened by T (down-regulation of receptor sensitivity)
(Johnson et al., 1991; Francis et al., 2002).
In sum, OT might mediate the negative relationship between T and
empathy, such that individuals exposed to higher levels of fetal T and
with higher circulating T levels later in life, might exhibit decreased
oxytocinergic sensitivity and thus lower social sensitivity/affective
empathy towards others (Zak et al., 2009). Accordingly, OT levels increase significantly after human touch or a trusting sign with women
being more sensitive to this effect than men, who are less likely to
alter their original behavior because of a trusting sign or a gentle
touch from another individual (Morhenn et al., 2008).
6. Testosterone and fear-reactivity
It has been recognized that fear and anxiety are related to different
kinds of threats and differing in their neurobiological substrates
(Grillon, 2008b). Anxiety is thought to be more chronic, consciously
controllable, less acute, and is related to potential threats in the future
(what might happen), and is mainly regulated by the bed nucleus of
the stria terminalis (BNST). In contrast, fear is the acute, uncontrollable, and unconscious reaction to an imminent threat, faced within the
here and now (e.g. being attacked), and is regulated by the amygdala
(Grillon, 2008a).
6.1. Gender differences in fear-reactivity
Gender differences regarding fear related symptoms are weak, nonconsistent, and dependent on the operationalization of fear (Grillon,
2008a; McLean and Anderson, 2009). For example, men show similar
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levels of physiological arousal (skin conductance reactivity) in response
to threatening stimuli (Katkin and Hoffman, 1976), and similar increases in heart rate during social stress challenges (Kelly et al., 2008).
Moreover, experimental studies on fear-conditioning have also found
no gender differences (Fredrikson et al., 1976). Nevertheless, a large
meta-analysis of studies on temperament found a significant but weak
negative effect of male gender on fear-reactivity in children aged between 3 months and 13 years (d = −0.12, P b 0.05 within a total sample
size of n = 4858) (Else-Quest et al., 2006).
6.2. Fetal T/postnatal salivary T and fear-reactivity in infancy
Research into the relationship between fetal T and fear-reactivity in
human infants has been inconsistent. In a recent study by Bergman et al.
(2010) fetal T measured through amniotic fluid (n = 107) was found to
be positively correlated with fear-reactivity in boy infants (r(53) = 0.34,
P = 0.01) while showing no association in girl infants of 17-months-old.
In contrast, it has also been found that higher levels of T in umbilical
cord blood (n = 163) are related to lower fear-reactivity in 6 to18month-old boys (β = −0.29, P b 0.05), but not girls (Jacklin et al.,
1983). These divergent findings may be explained by the fact that although both studies used the same measures for determining fearreactivity (behavioral reaction to novel toys), they used different measures of fetal T levels (amniotic vs. umbilical cord blood). Van de Beek
et al. (2004) have demonstrated that amniotic fluid assessment of
fetal T is a better predictor of actual exposure than umbilical cord
blood assessments, indicating that the fetal T measurement method
used in the Bergman study might be a more valid indicator of actual
fetal T exposure than the method used in the Jacklin study. Additionally,
Marcus et al. (1985) found no association between T measured in umbilical cord blood and several mood ratings, including fear and anxiety,
from a parental diary. Finally, Alexander and Saenz (2011) have investigated the role of salivary T in temperamental characteristics of 76
male and female infants (3–4 months old). In both sexes salivary T did
not show a significant association with fear-reactivity as measured by
the Infant Behavior Questionnaire-Revised.
Regarding fear reactivity in children who later become psychopaths, a study by Glenn et al. (2007) found that adults of 28 years of
age who displayed a higher number of psychopathic traits, were
rated as less fearful, less inhibited toward novelty, and more sociable
in a laboratory setting at age 3 by trained raters. In addition, contemporary researchers suggest that psychopathic traits, such as low
empathy and fearlessness, arise from constitutionally based lower
levels of limbic reactivity, in particular amygdalar reactivity (Blair,
2006). In accord with this, the amygdala achieves a high degree of
maturity by the eighth month of gestation, indicating that emotional
responsiveness is mostly modulated by genetic and prenatal factors
(Ulfig et al., 2003). Furthermore, different twin studies have indicated
that the callous/unemotional traits, which are suggested to arise from
these limbic abnormalities, show moderate to strong genetic influences (Viding et al., 2005; Larsson et al., 2006).
In light of these findings, we hypothesize that the fearlessness associated with psychopathy and which is present in early childhood is
unlikely to be related to fetal T exposure, although more research is
needed to infer valid hypotheses.
6.3. T administration and fear-reactivity
6.3.1. T administration and fear in humans
Hermans et al. (2006a) found that a single sublingual administration of 0.5 mg of T reduces fear-potentiated startle in female human
subjects compared to placebo (drug ∗ threat effect d = 1.18). Furthermore, Van Honk et al. (2005) found that a single administration of T
reduced unconscious fear indicated by abolishment of an attentional
bias toward fearful facial expressions (before T; Z(1,13) = 2.13,
P b 0.03 and after T; Z(1,13) = −0.10, ns). In addition, the study
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reported that T did not affect consciously experienced anxiety as measured by different questionnaires. The authors argue that T might be
able to reduce physiological fear-reactivity and decrease attention towards threatening stimuli in human subjects, while it has no influence
on the conscious experience of worry or anxiety. However, in the Hermans study, startle reactivity was significantly and strongly enhanced
during threat (possibility of receiving shocks) in both the T (d = 3.06,
P b 0.001) and placebo condition (d = 3.64, P b 0.001). Thus, although T
did dampen the potentiation of startle as compared to placebo, it did
not eliminate the effect of threat on startle reactivity. In contrast, the
low fear-reactivity hypothesis of psychopathy refers to an absence of
a significant effect of threat on startle reactivity (e.g. Patrick et al.,
1993; Benning et al., 2005b). Regarding the results of different studies,
it is unlikely that these alterations of threat responsivity in psychopathic individuals are due to high T levels.
6.3.2. Influence of castration and T administration on fear-potentiated
startle in animal research
In contrast to human research, most animal research has indicated
that T does not change physiological parameters of fear-reactivity
(fear-potentiated startle, heart rate reactivity) but does have an influence on the coping-style when confronted with a threat (less avoidant and more confronting).
In rodent research, different studies report that decreasing T
increases freezing time and fear-induced analgesia to olfactory signs
of nearby foxes (King et al., 2005). However, castration of male rats,
which results in significantly lower T levels, did not seem to have an
effect on eye blink conditioning, contextual fear-conditioning and
fear potentiated startle (Anagnostaras et al., 1998; Dalla and Shors,
2009). T replacement therapy in castrated male rats also did not influence fear-potentiated startle (Toufexis et al., 2005). Moreover, it has
been shown that male rats, exhibiting higher levels of T than females,
outperform female rats in classical fear-conditioning paradigms (Dalla
and Shors, 2009). However, the effect of T on fear-reactivity in rodents
and the difference with higher order animals must be interpreted with
caution, since rodents are prey animals and higher order animals such
as primates and heifers can also attack intruders in order to survive.
Therefore, increase in approach behaviors in rodents would clearly
not be adaptive to their survival, whereas in primates and humans,
both approach (eliminating) and avoidance (escaping) of threat may
have adaptive value. Therefore, rodent research regarding the influence
of T on fear has only limited validity when it is generalized to humans
and one must keep these limitations in mind.
Nevertheless, these results in rodents, indicating a null or positive
effect of T on fear-potentiated startle, are replicated in heifers and primates (Bouissy and Bouissou, 1994; Morris et al., 2009). For example,
the effect of prepubertal castration on the subsequent conditioning of
fear-potentiated startle was measured in rhesus macaques (Morris et
al., 2009). There were no significant differences between groups of
prepubertal castrated adolescent rhesus macaques and intact macaques in fear-potentiated startle, both before and after puberty, indicating that the absence of a T surge during puberty in the castrated
macaques did not affect their fear-reactivity.
6.3.3. Influence of T administration on behavioral measures of fear
in animals
Bouissy and Bouissou (1994) concluded after a thorough investigation with heifers that T influences the way a threat in the environment
is handled but it has no effects on fear-conditioning or physiological
responses to frightening situations. Their research was conducted with
two groups of heifers (T treated and control) which were subjected to
various fear-eliciting tests while their behavioral and physiological responses were measured. They showed that although long-term T treatment did not alter physiological responses to threat (heart rate) or the
degree of fear-conditioning, it did change the behavioral responses to
threat. T treated heifers were less careful and more confronting when
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entering an unknown area and examining a novel object (Bouissy and
Bouissou, 1994).
Furthermore, Archer (1976b) examined the effect of T on fearbehaviors in male chicks. He observed that T did not affect the intensity of fear-responses; both T-treated and control chicks showed similar levels of freezing, defecating, and burrowing when startled.
Nevertheless, T-treated chicks were less careful and approached,
attacked, picked, and touched the bell which startled them (the
source of threat) more often than controls, indicating a more confronting and aggressive reaction to the source of threat. In reaction
to these findings, Archer asserted that “testosterone indeed influences the tendency to emit fear responses, but the influence is on
the form of the fear responses rather than on the overall tendency
to show fear behavior” (p. 563). Other studies conducted by Archer
(1973a,b,c, 1976a) had already indicated that T reduces fear-related
behaviors such as avoidance, distress calls, and behavioral inhibition
to a novel environment, but did not alter emotional responsivity to
fear-eliciting situations.
These above results in heifers and chicks are replicated in rodent
research, which also reports that T administration has an anxiolytic
effect on male house mice (as indicated by increased open-arm time
on an elevated plus maze) (Aikey et al., 2002). In contrast, other studies
found that mice treated with testosterone propionate (T treatment)
display enhanced contextual fear responses but did not change cued
fear responses or freezing (Agis-Balboa et al., 2009).
In sum, the literature on the influence of T on fear-reactivity is mostly consistent and reports less behavioral expressions of fear in T treated
animals but no significant effects on physiological measures of fear such
as fear-potentiated startle and heart rate reactivity to stressors.
6.4. Influence of T on the neurobiology of fear
Regarding fear, the amygdala has been proven to be the core
structure regulating fear-reactivity and -behaviors (Grillon, 2008b).
In the adult human brain, the amygdala is significantly larger in men,
even after controlling for whole brain volume, and this difference is
thought to be shaped primarily by gonadal steroids (Goldstein et al.,
2001). Furthermore, as discussed above in the context of empathy, T increases amygdalar reactivity to fearful and angry faces, and higher
levels of salivary T are associated with higher general amygdala responsivity (Hermans et al., 2008; Derntl et al., 2009; van Wingen et al., 2009;
Manuck et al., 2010). Furthermore, adolescent girls with CAH, which is
associated with significantly higher exposure to fetal T, show heightened reactivity of the amygdala to negative facial emotions (fear,
anger, disgust), supporting the hypothesis that sex-differences in
amygdala-reactivity might be shaped due to differing exposure to various sex steroids in utero (Ernst et al., 2007). In addition, individuals
with high basal T levels also are more likely than others to self-report increased levels of tension (Wirth and Schultheiss, 2007), which is also
associated with heightened amygdala activation (Veit et al., 2002).
In contrast to these findings, one study reported a negative association between total T and regional cerebral blood flow (rCBF) in the
amygdala of elderly men with a mean age of 57.2 ± 11.7, indicating
lower activity (Moffat and Resnick, 2007). However, T levels in elderly men are significantly lower than in adolescents or middle-aged
adults. Therefore, this study likely does not cover the entire range of
possible T levels and it is for this reason that both internal and external
validity is compromised if one is to answer the question of how T levels
relate to amygdalar reactivity in the general population.
6.4.1. T and neurochemical functioning in fronto-limbic structures
Increased amygdalar reactivity to threat is strongly associated
with reduced serotonergic neurotransmission (Lee and Coccaro,
2001). Accordingly, T has been shown to inhibit serotonergic processes and reduce serotonergic turnover in frontal and limbic structures
in rodents (Van de Kar et al., 1978; Martinez-Conde et al., 1985;
Sundblad and Eriksson, 1997; Sumner and Fink, 1998). For example,
in rodents, amygdalar reactivity to threat related stimuli is positively
associated with the binding potential and receptor mRNA of 5HT-2A
receptors in frontal and cingulate structures (Meltzer et al., 1998;
Sumner and Fink, 1998; Fisher et al., 2009).
In human research, gender differences have been consistently
found in serotonin uptake, especially in the frontal cortex, with men
generally displaying lower serotonin levels (Maes et al., 1989; Biver
et al., 1996; Soloff et al., 2003). Nevertheless, different studies have
not been able to replicate the animal research findings of a direct association between T and serotonin. For example, studies in humans
have reported that circulating T levels did not explain any of the
interindividual variance in S-citalopram challenge test (Kuepper et
al., 2010), or prolactin responses to a d-fenfluramine challenge test
(Dolan et al., 2001). Furthermore, Fink et al. (2009) failed to report
a significant association between T level and 5HT-1A receptor binding
lateralization in both men and women. However, given that serotonin
functioning varies with a host of different variables, these challenge
tests might not be sensitive enough to pick up minor differences in
serotonergic functioning, which might explain the divergence
between rodent and human neurobiological research (Kuepper et
al., 2010). Correlational studies in aggressive and violent individuals
report contrasting results, some finding no significant association between brain serotonin as indicated by CSF 5-HIAA concentration with
CSF free T (Virkkunen and Linnoila, 1993), and others that find a significant negative relationship (Giotakos et al., 2004).
Reduced serotonergic functionality due to chronically heightened T
might explain in part higher limbic reactivity to threat as well as diminished orbital frontal reactivity. This in turn increases threat-reactivity and
threat-responding, suggesting increased rather than decreased fearreactivity in high T individuals. An explanation might be that T increases
psychological dominance (Mazur and Booth, 1998), and thus increases
reactivity to threat originating from other members in the hierarchy in
order to maintain a dominant position (Van Honk et al., 1999, 2001;
Van Honk and Schutter, 2007). In accord with this, T also augments vasopressinergic activity in limbic areas (Rasri et al., 2008), which is associated with increased power-motivation (dominance) and intermale
aggression (Compaan et al., 1991; Sewards and Sewards, 2003).
In sum, T increases approach behaviors when confronted with
threat which can imply low fear-reactivity. However, most studies report no association or influence of T on physiological fear-related measures, such as fear-potentiated startle, autonomic responsivity or threat
reactivity (e.g. Archer, 1991; Bouissy and Bouissou, 1994). In addition,
neurobiological data also suggest a sensitizing effect of T on amygdalar
reactivity, which is more consistent with a heightened threat reactivity
rather than dampened, such as observed in psychopathy. Therefore, instead of influencing fear-reactivity directly, T likely changes the way an
environmental threat is handled after detection, increasing the probability for reacting with approach behaviors (e.g. dominant/aggressive
response) instead of avoidance behaviors. One possibility is that high
levels of amygdalar reactivity may lead to either anger and aggression
or fear and avoidance, strongly depending on other mediating neurobiological factors such as vasopressinergic reactivity.
7. Role of T in instrumental aggression
Aggression is often divided into two forms; reactive and instrumental (Merk et al., 2005). Reactive aggression is described as “hotheaded” and operationalized as an aggressive reaction to frustration
or provocation. In contrast, instrumental aggression is often described
as “cold-blooded” and is operationalized as a goal-driven aggressive
action (i.e. in order to obtain materials, increase status, and satisfy
needs) (Merk et al., 2005). Different terms are used to indicate
forms of instrumental aggression in different populations; in children
and adolescents it is often referred to as proactive aggression and in
animals it is named predatory aggression.
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7.1. Gender differences in instrumental/proactive aggression
Winstok (2009) studied a large group (n = 660) of male and female adolescents with respect to their aggressive patterns and associated control needs, and found that instrumental aggression is closely
tied to the need to control others (β = 0.51) (Winstok, 2009). Since it
has been asserted that T is associated with a heightened drive for interpersonal control (dominance) (Mazur and Booth, 1998), it would
be expected to see a higher prevalence of instrumental aggression
in men as opposed to women, especially in interpersonal interactions.
Accordingly, one study in a large group of female (n = 800) and male
(n = 587) participants with a mean age of 33, reported that men were
significantly more instrumentally aggressive in their interactions
with other people (d = 0.23, P b 0.001) (Murray-Close et al., 2010).
Furthermore, in a study with 1062 school aged children (ages between 10 and 13 years), boys were rated by peers, but not teachers, to
be significantly more proactively aggressive (d = 0.46, r = 0.23,
P b 0.001) on measures of aggressive dominance (Salmivalli and
Nieminen, 2002). Instead of using overt measures for proactive aggression (i.e. uses physical aggression to force and control others),
the researchers used more “sex-neutral” measures, such as expressions of aggressive dominance (humiliating, embarrassing, bullying,
and verbally forcing others). Since they reported that these behaviors
were only observed to be higher in boys when rated by peers but not
when rated by teachers, these proactively aggressive boys likely controlled their behavior in the presence of authority, indicating that the
proactive aggression in boys may be more instrumental in nature
than the proactive aggression displayed by girls and therefore controlled in the presence of a potential punishing agent (more goaldriven than affect-driven). Moreover, in another large sample of 5606
healthy children between the ages of 11 and 15, proactive aggression
was more prevalent in boys compared to girls at all ages (main effect;
d =0.17), and increased in boys with age (d =2.68, P b 0.0001 with Bonferonni P b 0.05) but not in girls (d =0.13, P b 0.05 with Bonferonni
P =0.06) (Fung et al., 2009). These results indicate that proactive aggression is not only more prevalent among boys but also shows significant age-related increases in boys as opposed to girls, which might be
related to the increase in T during adolescence in boys but not in girls
(see for example Ramos et al., 1998).
However, another study with 323 children from both a residential
treatment center and a pediatric psychopharmacology clinic, reported
no gender differences between boys and girls with respect to proactive
aggression (Connor et al., 2003). The main difference between the studies that report significant relationships between male gender and proactive aggression in childhood (Salmivalli and Nieminen, 2002; Fung
et al., 2009) and the one that does not (Connor et al., 2003), might be
related to the populations studied. The Connor study used mainly
boys but also girls (255 males vs. 68 females) who were referred to a
clinic because of disturbing behavioral problems, which is in contrast
to the Fung and Salmivalli studies that used healthy children and adolescents. It can be argued that females who are referred to a clinic because of behavioral problems may not represent the typical feminine
personality profile of the larger population and may differ with respect
to gonadal hormone levels from healthy girls.
In light of the above findings, we can conclude that a significant small
to moderate effect (d between 0.17 and 0.46) of gender on proactive/
instrumental aggressive tendencies likely does exist in the normal population, with males scoring higher, especially in interpersonal contexts.
7.2. Salivary T and instrumental (unprovoked) aggression
7.2.1. Studies on salivary T and instrumental aggression in children and
adolescents
First off, T levels in childhood or adolescence do not consistently
correlate with direct measures of aggression, in most studies being
measures of reactive aggression (see for review Ramírez, 2003).
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Unfortunately, very few studies have examined the relationship between T and instrumental aggression during childhood or adolescence. Van Bokhoven et al. (2006) found that at age 16, salivary T
levels were significantly higher (d = 0.72, P b 0.01) in a group of highly instrumental aggressive adolescents (mean T; 53.4 ± 22.6 pg/ml)
(n = 41) vs. a control group of low instrumental aggressive adolescents (mean T; 38.3 ± 19.0 pg/ml) (n = 50). Remarkably these results
of increased T in highly instrumental aggressive adolescents was
found only at age 16, and not at age 13 or 21 (age - testosterone interaction effect). These results indicate that T might be related to proactive aggression in adolescents, especially around the 16th year of life,
which is in the midst of puberty and when the activating influence of
T on behavior is at its highest peak.
However, other studies with adolescents (n = 58) found that higher
T levels showed a small to moderate relationship with increased readiness to respond to provocation; physical aggression (r = 0.36), verbal
aggression (r = 0.38), lack of frustration tolerance (r = 0.28), but had
no effect on unprovoked aggression (Olweus et al., 1980, 1988). It is argued that T levels in childhood and adolescence may be related to
aggression in response to provocation but not with unprovoked aggression (Olweus et al., 1988; Ramírez, 2003).
From the above review it becomes clear that the relationship between T and instrumental and unprovoked aggression in childhood
and adolescence remains to be empirically established and preliminary
results are inconsistent, thereby precluding construction of powerful
hypotheses.
7.2.2. Studies on salivary T and instrumental aggression in adults
In addition to these findings in children and adolescents, some
studies show that instrumentally aggressive behaviors are increased
in adult men with higher T levels (e.g. Dabbs et al., 1995, 2001;
Andreu et al., 2006). Andreu et al. (2006) found that salivary T in 34
male university students were related to both reactive (F = 4.10,
P b 0.05) and instrumental aggression (F = 3.83, P b 0.05). Another
study by Dabbs et al. (2001) found that among a group of severely violent murderers (n = 230), those high in T more often knew their victims and planned their crimes ahead of time, indicating a higher
inclination towards callous, premeditated, and instrumental forms of
aggression.
Additionally, in a study of 692 inmates, it was found that higher
levels of T are associated with specific crimes involving a high level
of combined instrumental and reactive violence, such as rape (3.6
times more prevalent in the high vs. low T group), child molestation
(2.6 times more prevalent), homicide (2.1 times more prevalent),
and robbery (1.5 times more prevalent). In contrast, lower levels of
T were more predictive of less violent and more covert criminal acts
such as burglary, theft, and drug-dealing/possession (Dabbs et al.,
1995). Remarkably, criminals high in interpersonal/affective traits
also commit more serious types of instrumentally aggressive offenses,
such as homicide and sexual assault, at a far higher rate than nonpsychopathic criminals, who are more likely to commit less serious
offenses such as theft and burglary (Williamson et al., 1987; Serin,
1991).
Other forms of highly instrumentally aggressive acts are sexually
motivated assaults such as rape and child molestation. Different studies
have confirmed significantly higher T levels in rapists and child molesters than in healthy controls or other criminals (Rada et al., 1976;
Dabbs et al., 1995; Giotakos et al., 2004). Moreover, in a small subset of
child-molesters (n =22), T correlated with callousness of the crime
(r =0.42) (Dabbs et al., 2001), indicating a significant relationship with
the instrumentality of the crime.
7.2.3. Studies on salivary T and laboratory tasks of instrumental
aggression
One method of assessing both reactive as well as instrumental aggression in the laboratory context is with a revised version of the
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Point Subtraction Aggression Paradigm (PSAP) (Carré et al., 2010). In
this task participants are instructed to keep as many points as possible (which will be traded for money at the end). During the task participants are provoked by a fictitious partner who steals points from
them, and are given the opportunity to steal back points. However,
the points which are stolen back are not added to the total score of
the participant, making the behavior a purely aggressive act. In a
modified version by Carré et al. (2010), a new condition is added in
which participants are not provoked but do receive a reward
(point) for aggressive acts thereby differentiating between pure
forms of instrumentally (not provoked/reward) and reactively (provoked/no-reward) motivated aggression. The results indicated that
the group who were provoked but did not receive a reward, enjoyed
the task the most and demonstrated a significant increase in salivary
T (increase of 14.58%, d = 0.76, P b 0.05) which was directly related to
the level of reactive aggression (r = 0.34, P b 0.05). Importantly, these
effects were not observed in men who received a reward for aggression but were not provoked (i.e. instrumental aggression) (Carré et
al., 2010). These results indicate that T levels may be more strongly
related to reactive forms of aggression than instrumental forms of aggression and that the pleasure derived from these reactive forms of
aggression is directly related to the increase in T and not so much
on receiving a monetary reward.
A second study which is relevant in this context, measured the degree to which individuals with varying levels of T would respond to a
moral dilemma involving an instrumental act of aggression (Carney
and Mason, 2010). In the task participants (n = 117) were asked
whether they would kill a human being by pushing him in front of a
trolley to save five others who are about to get hit by the trolley. Individuals high in T were more willing to make the utilitarian decision
of killing a human being if it would lead to the greater good (r = 0.18,
P b 0.05). Importantly, mean T levels were lowest in the participants
who were unwilling to choose an aggressive option to solve the
moral dilemma. The authors conclude that high T individuals “are
able – and perhaps likely – to approach decision making in a manner
that is divorced from negative affect and disproportionally focused on
outcome” (pp. 670), which is a strong foundation for the emergence
of instrumental aggression (Blair, 2006; Glenn and Raine, 2009),
and is strongly associated with psychopathy (Glenn et al., 2010).
The above laboratory studies indicate that T may be related to instrumentally aggressive decision making during hypothetical moral
dilemmas but this does not necessarily translate into “real-time” instrumental aggression (Carney and Mason, 2010; Carré et al., 2010).
It is therefore likely that T works in concert with other modulating
factors to synergistically increase the risk for actually acting out instrumentally aggressive tendencies. We will explore potential interactions below.
7.3. Bio-socio-psychological influences on the expression of instrumental
aggression
7.3.1. Biological influences; reward reactivity, motivational drive, and
need for interpersonal control
First off, T has strong effects on reward reactivity and several lines
of research suggest that this effect is due to the influence of T on the
mesolimbic dopaminergic circuitry. In humans, a single dose of T administration significantly increases mesolimbic BOLD responses during reward anticipation in women (Hermans et al., 2010), which is
indicative of increased mesolimbic dopaminergic release (Schott et al.,
2008). In humans, T is thus a modulator of mesolimbic dopaminergic
reactivity to rewards. Furthermore, long-term T treatment in rodents
down-regulates D2 receptor density in the nucleus accumbens, indicating a dopaminergic hyper-reactivity to rewards (Kindlundh et al., 2001,
2003). This behavioral hyper-reactivity to rewards may shift the focus
from punishment towards rewards and induce the pursuit of rewards
at the risk of the potential punishment or harm done to others (see
Van Honk et al., 2004 for detailed description of this process). Accordingly, Bos et al. (2012) argue that T “strengthens motivation by acting
on the neural pathways that mediate reward-seeking, which can lead
to strengthened behavioral responses depending on the individuals'
needs and motives” (pp. 11).
Secondly, it has been discussed above in the context of fear and empathy that T may decrease social-sensitivity and increase dominant and
aggressive responding to threat. After a review of the literature on steroids and peptides on socio-emotional behavior, Bos et al. (2012) accordingly conclude that T probably reduces social sensitivity and
independently increases the motivation to act aggressively and assert
dominance in reaction to threat (perceived or real). For example, a high
T level might lead to increased threat-sensitivity in reaction to angry
faces and reduce fronto-limbic information transfer, thereby reducing
prefrontal control over reactive anger, which may provide the theoretical background for the hypothetical link between T and provoked (reactive) aggression (Van Honk et al., 1999, 2001, 2010). However, these
mechanisms may also provide an explanation why instrumental aggression may also be more prevalent in high T individuals and thus
why reactive and instrumental aggression co-occur so frequently
(Bushman and Anderson, 2001). Increased dominance coupled with
reduced fronto-limbic information transfer, may respectively increase
the need to control interpersonal relations and decrease limbic control
of motivational decision-making processes, which are both strongly related to instrumental aggression (Blair, 2006; Winstok, 2009).
7.3.2. Socio-psychological influences; insensitive attachment experiences
and social discrimination/rejection
Biology can never account fully for the complex interaction of social
and psychological processes ultimately leading to expressions of instrumental aggression. Therefore, biological processes, such as increased T,
may increase motivations to act out on internal drives and external
threats but the consequences regarded as rewards or events and stimuli
regarded as threatening, are strongly shaped by childhood socioemotional experiences with primary caregivers and adolescent/adult
socio-psychological experiences with the larger social community. For
example, if social processes strongly encourage prosocial behavior and
model the child's behavior accordingly, then high T may lead to an individual with good and sympathetic leadership qualities and a drive for
competitive achievement. In contrast, destructive social influences
combined with a high motivation to act out on internal drives, can increase the likelihood that someone will act out on these experientially
shaped malicious and antisocial tendencies.
An example of moderating influence could be the early experiences with the social environment. Attachment relationships with
caregivers shape the development of prosocial and empathic behavior through experience (Weinfield et al., 2008). When the child experiences severe emotional neglect or repeated prolonged separations,
he may eventually stop bonding to other people altogether, leading to
an emotional detachment and alienation from other people (Meloy,
1992), and chronically heightened levels of anger (Kochanska, 2001).
According to Meloy (1992) this alienation effectively dampens empathetic concern and increases the likelihood that children will learn to
use others instrumentally, rather than build long lasting relationships
based on mutual respect and emotional attunement.
A second example of a moderating influence could be the larger
social environment. The capitalistic society in which we live in inherently leads to structural classism in which the lower socio-economic
classes have fewer opportunities and are less well protected against
adversity than the higher socio-economic classes, resulting in inequality in social structures and well-being. High levels of inequality
inherent in capitalistic societies bring about a competitive imperative
in order to achieve and maintain a good living standard, leading to
increased levels of frustration in the socially discriminated and disadvantaged. The resulting underlying affect, justifying reasons for retribution and instrumental aggression, may be a deep-entrenched envy
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of others because of the perception “that life has not given them
“their due”; they have been deprived of their rightful amount of
love, support, or material reward; and others have received more
than their share. Jealous of those who have received the bounty of a
good life, they are driven by an envious desire for retribution to
take what destiny has refused them” (Millon et al., 2004, pp. 158).
This process of social discrimination/rejection may be experienced
in people living in the lower socio-economic classes but also in
many other people, such as ethnic minorities who are discriminated
against, in bully victims, and people who feel that they are excluded
from a certain social club, peer-group, or community.
Relevant in this context is a study by Singer et al. (2006) indicating
that men show increased neural responses in reward-related areas
when seeing unfair players receiving shocks which are directly related to the expressed desire for revenge, whereas women showed neural responses in empathy-related brain areas towards the suffering of
both fair and unfair players. It may then be conceivable that insensitive and abusive attachment experiences, impoverished social environments, and social discrimination or rejection – leading to a
negative worldview and a competitive/resentful stance towards
others – have a strong detrimental effect on affective empathy in
high T individuals, and can subsequently increase motivational drive
towards self-aggrandizement through instrumentally aggressing
others, thereby fulfilling both revenge needs, increasing control over
others, and gaining coveted rewards (Millon et al., 2004). Accordingly, research has supported that T mainly relates to delinquency and
antisocial behavior in the lower socioeconomic classes, whereas it
shows no associations with antisocial behavior in the higher socioeconomic classes (Dabbs and Morris, 1990; Mazur, 1995; Aromaki
et al., 1999). It has been suggested T may be more strongly related
to competitive achievement motivation and social dominance in the
higher socio-economic classes (Dabbs and Morris, 1990). In addition,
longitudinal research following 411 London boys from the age of 8 up
to 48 has found that the strongest predictors of instrumental aggression, are in particular living in impoverished environments, having a
low family income, and having a convicted father (Farrington,
2003). Furthermore, attachment experiences have been found in a
number of studies to strongly mediate the relationship between
high circulating T and delinquent or antisocial behavior in adolescence (Booth et al., 2003; Updegraff et al., 2006; Fang et al., 2009).
We will elaborate on these studies below in the discussion section.
Heightened expression of instrumental aggression in high T individuals may thus be a reaction to experienced insensitivity from attachment figures in childhood and/or to social discrimination/rejection in
adolescence and/or adulthood, increasing the drive to instrumentally
aggress in order to secure resources, fulfill deep-entrenched revenge
and domination needs, and aggrandize one's self.
7.3.3. Endocrinological mediators; HPA-axis reactivity
Nonetheless, since heightened T likely does not underlie the low
fear-reactivity observed in psychopathy, fear may still affect behavior
thereby reducing the chance of instrumentally deploying these experientially shaped and T-strengthened aggressive drives and motivations. These aggressive tendencies may therefore only be discharged
under highly emotional circumstances (e.g. impulsive robbery/rape,
maybe using drugs/alcohol to calm affect) but not in a cold predatory
manner (e.g. planned robbery/instrumental murder, without much
arousal) (Terburg et al., 2009). Our hypothesis is that T may increase
the motivation to act aggressively in reaction to provocation, especially
when the individual exhibits a history of trauma/neglect/abuse and social provocation, but when coupled with reduced fear-reactivity, leading
to low levels of fear over behavior, it may also increase the likelihood that
aggressive behaviors to obtain rewards and satisfy needs are deployed
proactively and callously. The reduced fear-reactivity is probably modulated by other neurochemicals implicated in the reactivity of the stressand sympathetic circuitry, such as a dampened HPA-axis reactivity to
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stressors and threats (Van Honk and Schutter, 2006; Terburg et al.,
2009), and/or a reduced noradrenergic potentiation of limbic structures
during aversive experiences or threat (Blair, 2006; Minzenberg and
Siever, 2006).
8. Discussion and mediating factors
The above results, which indicate inconsistent and/or weak associations between T and the behavioral constructs associated with the
interpersonal/affective factor of psychopathy, are in accord with
Stålenheim et al. (1998) and Loney et al. (2006) who reported that T
levels in psychopathic individuals, both children and adults, correlate
significantly and moderately with the antisocial/lifestyle factor and
show a weak and non-significant correlation with the interpersonal/
affective factor. Other arguments are also in line with the finding that
T is more strongly related to the antisocial/lifestyle factor of psychopathy. First off, T production decreases with age in both women and
men and research shows that the antisocial lifestyle of psychopaths
also decreases with age (Dabbs, 1990; Harpur and Hare, 1994) which
is consistent with the notion that heightened T is associated with antisocial behavior (Stålenheim et al., 1998). However, the emotional shallowness (dampened fear conditioning, absence of affective empathy)
underlying the interpersonal/affective factor, is not reduced with age
(Harpur and Hare, 1994). Many psychopaths are emotionally shallow
far into senescence (Hare, 1993). Furthermore, from the discussed findings it is indicated that T may increase threat sensitivity. However, the
absence of a threat effect on physiological responses to aversive and
threatening situations is what defines psychopathy the most and separates psychopathic offenders from non-psychopathic offenders (Fowles
and Dindo, 2006).
8.1. Neuroendocrinological mediating factors
Since hormonal systems are highly interconnected, it may be important to examine multiple systems simultaneously to understand
how they might dialectically interact to predispose for certain clinical
conditions (Glenn et al., 2011). For example, the HPG- and HPA-axis
are two hormonal axes that interactively modulate the behavioral reaction to reward and threat respectively and do this by influencing autonomic reactivity to cues of reward and threat (Van Honk and Schutter,
2006; Terburg et al., 2009). A detailed description of this intricate dialectical interaction between the HPG-axis and HPA-axis and their coregulation of socio-emotional behavior is beyond the scope of this review but excellent reviews and theoretical models are present in the literature (see for example Viau, 2002; Van Honk and Schutter, 2006;
Terburg et al., 2009).
T and cortisol (abbreviated as C) bind to steroid-responsive centers in the amygdala (Wood, 1996), where they respectively facilitate
approach to rewards and withdrawal from threat in order to maintain
an appropriate balance between withdrawing in the presence of fearful stimuli (C) and approaching in the presence of rewarding stimuli
(T) (Schulkin, 2003; Glenn et al., 2011). C probably inhibits the strong
T induced motivational drives from limbic and brainstem structures,
thereby regulating approach behavior. For example, C administration is
found to increase fronto-limbic coupling, which is related to behavioral
inhibition (Van Peer et al., 2008). Accordingly, in a study of 4462 male
US military veterans, higher behavioral inhibition was associated with
higher levels of C, whereas higher T was associated with behavioral activation, indicating that the balance (ratio) between T and C may modulate
approach-withdrawal behavior (Windle, 1994). Researchers have also
suggested that T and C jointly regulate threat processing (Van Honk
and Schutter, 2006), dominance (Mehta and Josephs, 2010), and
physical aggression (Dabbs et al., 1991).
It has been asserted that high T automatically inhibits the HPA-axis
thereby dampening its output (Van Honk and Schutter, 2006). However, it is worth noting that although the HPG- and HPA-axis have
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mutually inhibiting influences (Viau, 2002), they still largely function
independently, suggesting that high T does not necessarily lead to a
dampened HPA-axis reactivity to stressors (Rubinow et al., 2005).
For example, only one study in humans experimentally studied the effect of T on CRH-stimulated C and ACTH release (Rubinow et al., 2005).
After administration of Leuprolide, which significantly reduced
T levels, participants either received T replacement or a placebo to
measure the reactivity of C to the administration of T during a hypogonadal state. They found that T administration compared to placebo significantly dampened cortisol secretion (F1,9 = 7.39, P b 0.05) but
paradoxically increased CRH-stimulated ACTH secretion (F1,9 = 5.22,
P b 0.05), indicating that the effect of T on C secretion is likely to be
exerted peripherally instead of centrally and suggesting that T does
not necessarily dampen stress-reactivity but instead decreases adrenal sensitivity to ACTH. Therefore, T and C, although interrelated,
still have independent and interactive effects on behavior.
Therefore, Terburg et al. (2009) suggest that the prediction of psychopathy is more accurate when in addition to high T, low C is also incorporated in this prediction. More specifically, the ratio of T to C
levels (T:C), with extreme high ratios (T ⋙ C) representing the cold
predatory style of psychopathy (Van Honk and Schutter, 2006;
Glenn et al., 2011). In line with these assumptions, low C has been
found to be strongly related to the core characteristics of psychopathy
(Holi et al., 2006; Cima et al., 2008), and to moderate the relationship
between heightened T and both severe conduct disorder in adolescence (Popma et al., 2007) and psychopathy in adults (Glenn et al.,
2011).
Recently, Glenn et al. (2011) have examined the T to C ratio in
psychopathy. When controlling for gender, baseline T or C levels
were not significantly associated with psychopathy scores (β = 0.11,
P = 0.22 and β = 0.06, P = 0.42 respectively). In addition, baseline T
to C level ratios (baseline T : baseline C) were also not associated
with psychopathy (β = 0.06, P b 0.46). However, baseline T to C reactivity to stressors (baseline T : C reactivity to stressor) was significantly and uniquely associated with psychopathy (β = 0.28,
P b 0.01), in particular the lifestyle/antisocial facet of psychopathy,
and this ratio was only significantly associated if baseline T was one
standard deviation above the mean (β = 0.54, P = 0.03) and not
when baseline T was one standard deviation below the mean
(β = 0.10, P = 0.67). This result indicates that it is not the relative
ratio that predicts psychopathy but fixed ratios of low C reactivity in
the presence of high T levels (one S.D. above mean).
8.2. Socio-psychological mediating factors
As has already been discussed in the instrumental aggression
section, a second example of moderating influence could be the experiences with the social environment. Regarding the interactions between T, attachment history and antisocial behavior, three different
studies have confirmed the moderating role of family cohesion, parent–child interactions and attachment on behavioral disturbances in
children with high levels of T (Booth et al., 2003; Updegraff et al.,
2006; Fang et al., 2009). In the first study, by Booth et al. (2003), a
sample 400 children of established middle- and 3 days. Saliva T in
both boys and girls did not show any relationship to problem behaviors. However, it appeared that the positive relationship with risk behavior and negative relationship with depression were conditional on
the quality of parent–child relations. As the quality of parent–child
relationships increased, the impact of T on risk behaviors was less evident. The second study conducted by Updegraff et al. (2006) examined 331 adolescents with a mean of 15 years of age. Hierarchical
regression results revealed that T levels in boys were positively associated with peer-competence and involvement on the condition that
they also had close relationships with their mothers and sisters. The
last study by Fang et al. (2009) recruited 164 boys and 180 girls between 11 and 14 years of age and found that only under conditions of
low family cohesion, T correlated positively with delinquent behavior.
Specifically, blood samples of T were positively associated with delinquent behaviors among boys from families with low cohesion, whereas
no association between T and delinquency was observed in children
who experienced a high degree of family cohesion.
Additionally, T is related to non-aggressive CD symptoms (stealing, lying, cheating, etc.) only in boys with deviant peers but to
leadership in boys with non-deviant peers, suggesting that high
T may actually be associated with socially valued characteristics in
prosocial environments (Rowe et al., 2004). These results may indicate that not only the parent–child relationship modulates the relationship between high T and antisocial behavior but a host of
other environmental influences as well, such as the peer-group.
Accordingly, other studies confirm that T is mainly related to aggressive
motivation rather than aggressive behavior (Higley et al., 1996), and
that the heightened aggressive motivation (possibly when combined
with sensitive and loving early interactions) is more often than not sublimated into positive traits, such as social dominance (Ehrenkranz et al.,
1974; Christiansen and Knussmann, 1987; Lindman et al., 1987; Booth
et al., 1989), social assertiveness (Lindman et al., 1987), and competitiveness (Booth et al., 1989). Interestingly, the interpersonal/affective
traits of psychopathy have also been related with measures of
competitive achievement orientation, high socioeconomic status, and
social dominance (Harpur et al., 1989; Hare, 1991; Ross and Rausch,
2001; Hall et al., 2004), especially in non-criminal variants of the
disorder, also termed “successful” psychopaths (Hall and Benning,
2006). For example, it has been found that over 50% senior business
managers in Britain may exhibit psychopathic tendencies, especially
the interpersonal/affective traits, and as a group have been found
to score higher on this factor than a group of forensic offenders or
psychiatric patients (Board and Fritzon, 2005). Furthermore, since noncriminal psychopathy is associated with closer social relationships
and more secure attachments (Lykken, 1995; Hicks et al., 2004),
one can argue that the fearless dominance underlying the interpersonal/
affective factor may also lead to a variety of socially adaptive aggressive
behaviors, given that individuals with these specific predispositions are
provided with prosocial, loving, secure, accepting, and resourceful social
environments.
9. Theoretical model
The different conclusions from this review are summarized in a preliminary theoretical model that visualizes the bio-socio-psychological etiology of the interpersonal/affective traits of psychopathy (see Fig. 1). This
model may be used to create new hypotheses which can be empirically
tested in future research.
The numbers within parentheses at the beginning of a sentence
stand for the numbered circles in the model. (1) High fetal T exposure,
a constitutionally based/environmentally induced high circulating T
level, and a low HPA-axis reactivity to stressors probably work in concert to decrease amygdalar reactivity towards punishments and threats,
increase dopaminergic reactivity to rewards, and dampen oxytocinergic, limbic, and orbitofrontal reactivity to empathy-inducing social stimuli. These biological predispositions amplify the behavioral reactivity to
both rewards and threats while dampening the behavioral inhibition or
avoidance of potential threatening cues, and predispose the individual
towards a fearless and dominant/aggressive response to perceived or
real social threat. (2) The first causal hypothesis asserts that most individuals with such temperamental/hormonal predispositions are likely
to develop at least some of the interpersonal/affective traits, independent of their social environment.
(3) When an individual with this characteristic temperamental/
hormonal profile is provided with a loving, socially rewarding, and
prosocial environment, and his actions and behaviors are modeled
according to prosocial and other-conscious norms and values, he
will likely be oriented towards competitive achievement motivation
B.O. Yildirim, J.J.L. Derksen / Psychiatry Research 197 (2012) 181–198
193
Fig. 1. Bio-socio-psychological model of the etiology of interpersonal/affective features of psychopathy. The arrows originating from different input variables and leading into the
numbered circles represent the input of these different moderating factors and the arrows originating from these circles signify the hypothesized outcome. Thicker lines represent stronger relationships. Since we do not yet know how the different factors are causally related and what the exact mechanisms may be that drive these interactions, these interactions are
represented by empty white circles with only a number rather than the mechanism of action, which represents our lack of knowledge about these precise interactions.
and social dominance, valuable characteristics in a capitalistic society.
Low fear- and high behavioral reactivity to rewards may also predispose towards socially accepted forms of risk and sensation-seeking.
(4) These individuals may be more likely to come from socially
advantaged families who are respected in community and have a
high social status. However, competitive achievement motivation
and social dominance may also increase the likelihood that the individual reaches a high social status in community and assumes leadership roles. Therefore, this relationship is probably bi-directional. (5)
Furthermore, development according a pathway with many protective socio-psychological factors may decrease the likelihood of severe
interpersonal/affective traits but some features may nonetheless still
be present (a thin line illustrates this small but significant relationship).
For example, instead of developing severe affective empathy deficits, individuals from this group may be lower in social-sensitivity but still
have some capacity for affective empathy (e.g. for their family members
and friends).
(6) However, when this individual is faced with insensitive and abusive early relationships and/or is socially discriminated/excluded, the
same temperamental/hormonal predispositions may result in low affective empathy, a high need for retribution, motivation towards selfaggrandizement, and reactively/instrumentally aggressive tendencies,
and therefore increase the risk for antisocial, violent, and (both reactive
and instrumental) aggressive behaviors. (7) These individuals are more
likely to come from families with lower social statuses and to experience a high level of social discrimination/rejection. Nevertheless,
heightened antisocial and aggressive behavior may also
alienate the social environment leading to social discrimination/
rejection, and criminal records may preclude a prosperous and
wealthy future perspective, further negating the possibility of ever
climbing the ranks in society. (8) The relationship between interactional circle 6 to interpersonal/affective traits is more robust than line
nr. 5, meaning that development according this pathway significantly
increases the risk for severe interpersonal/affective traits.
10. Critical evaluation and future perspectives
Some critical comments at our own review and the field of Tbehavior research are essential here. In doing research in this area
on the border of biology and psychology, the complex relationship
between these two qualitatively different processes needs more critical thinking. Biology and psychology are two fundamentally different
processes, each operating on a separate level with different mechanisms which cannot simply be reduced to one and other. Mental
events are “not the same thing as neural activity; phenomenological
experience cannot be described in terms of ion flows, synaptic connections, and so forth” (Kosslyn and Koenig, 1992, pp.432; Miller,
2010). Therefore, different validity issues automatically arise when
studying biological “underpinnings” of psychological constructs such
as affective empathy and instrumental aggression. Since there has
been no fully developed demonstration of how psychology and biology affect each other and which neural events drive rather than correlate with psychological events, validity of conclusions regarding the
biological basis of these psychological constructs is inherently compromised (Miller, 2010).
In addition to being psychological constructs in need of a psychological theory, most behaviors related to psychopathy, such as instrumental aggression, also have strong social determinants (e.g. low SES,
alienation) and social meaning (increasing wealth and status). Therefore, reducing these constructs by means of biological explanations,
such as neuroendocrinological processes and imbalances, blatantly
ignores their intricate relationship with the social environment. Biological explanations encompassing also psychological events should
account for the complex relationship with the social environment
and we don't do right to the complexity of human behavior when
we try to reduce complex psychological constructs into localized neural activity patterns or response tendencies in reaction to very specific
and isolated tasks. Therefore, many endocrinological influences on
real-life human behavior and on psychopathological conditions,
such as psychopathy, are probably weaker than we assume and are
mediated by a host of social and psychological influences.
Furthermore, the exact mechanisms driving the causal relationship and correlation between biology and psychology are largely
unknown and it is therefore paramount to exhibit intellectual modesty about the fact or direction of causality (Miller, 2010). For
instance what exact mechanism can be held responsible for the
dampening effect of T administration on empathy? Also regarding
causality, in the last decade there has arisen the ingrained belief
194
B.O. Yildirim, J.J.L. Derksen / Psychiatry Research 197 (2012) 181–198
that psychological events are driven by, and rooted in biological
events, rather than the other way around (Miller, 2010). This belief
has restricted us in our thinking and this is apparent in the vast
amount of literature describing the “biological basis of…” or “neural
substrate for…”, and only a subset of papers which discuss the
influence of psychological processes on biological events. In the case
of T, very little research has been done to determine how circulating
levels of free and total T change in response to psychological events.
Is it possible that psychological processes leading to low empathy
also affect T production? For example, it has been known that T not
only influences behavior, but that certain behaviors (aggression, sex,
submission) and social circumstances (social stress, competitive imperatives, feelings of victory or defeat) also influences circulating T
levels (Mazur and Booth, 1998; Archer, 2006). Consequently, socialstress, -isolation, and -uncertainty during pregnancy (which many
women experience in our competitive society), can induce longlasting increases in T levels and thus T exposure to the fetus
(Sayegh et al., 1990; Roelofs et al., 2010), but may also decrease
maternal sensitivity to the infant postnatally, precluding a healthy
socio-emotional development and thus empathetic concern (Shore,
2001).
Regarding circulating T levels, it must be noted that although it is
generally regarded as a “background fact” that individuals differ
constitutionally or naturally in their basal circulating T levels it has
been indicated in research that genetic factors explain approximately
40% of interindividual variation in T levels (Meilke et al., 1987). The
remaining variation is explained by environmental factors, underscoring the importance on studying socially induced long lasting
increases or decreases in T levels. Since T is strongly activated by
competition and social provocation, growing up in a competitive
and socially stressful environment, where one has to be on-guard at
all times for possible threats and counteract in an aggressive manner
to self-protect, may induce both long-lasting changes in T levels and
reactivity, synchronously increase threat reactivity, aggression, dominance, and dampen affective empathy, thereby explaining in part the
found correlation between circulating T and these psychological and
behavioral constructs.
In addition to the more general critical comments relating to the
study of biology and psychology, there are also a number of more specific comments on the study of T and behavior. Although the organizational–activational hypothesis has been supported by a great body
of research in animals, studies that examine the co-impact of both
fetal and circulating T on behavioral measures are virtually nonexistent in the human literature, probably because of the difficulty
of collecting both measures from the same person. Future studies
may profit if they determine not only one of both androgen measures
but include both circulating T (preferably measured through blood
draws) and fetal T exposure (preferably measured trough amniocentesis and followed-up at later ages) as independent measures, to
differentiate and determine which profiles (high fetal T or not?/high
circulating T or not?) may be related to the different male-biased clinical conditions such as ADHD, autism, antisocial personality, and psychopathy. These designs require comprehensive longitudinal research
designs and are therefore expensive and complex, but the payoff
could outweigh the potential costs when they provide clearer solutions
for future preventive measures.
In the same vein, research investigating the relationship between
T and psychopathy would benefit if there are continued attempts to
uncover socio-emotional and neurochemical mediating factors rather
than trying to find a direct association between circulating T and behavior. For example, T might only be related to certain behavior under
specific circumstances. We suggest that different genetic, prenatal,
psychological, and social factors mediate the relationship between T
and psychopathology, instead of T influencing psychopathology directly. In addition to T levels, one should then also pay attention to the functioning of other neurochemical and hormonal systems, which could
exacerbate the influence of T on psychopathology. It would therefore
be wise to examine the interactions between both fetal and circulating
T and various endocrinological levels (e.g. cortisol, estrogen, SHGB, progesterone) prenatal/environmental risk factors (prenatal stress, attachment insecurity/disorders, childhood abuse, low family income, absent
father, deviant peers) on subsequent development of psychopathic
traits.
In short, we have a long way to go before we may begin to fully
understand how biology and socio-psychological processes interact,
what the exact mechanisms are that explain these reciprocal relationships and how biological determinants such as T may influence or interact with these neurobiological, social, and psychological processes.
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