According to the current findings, vulnerability for personality disorders was programmed by developmental factors prenatally and during the first 11 years of life. Parental separation played an especially relevant role if it occurred in the first five years. On a neurobiological level, in accordance with the DOHaD hypothesis and the life cycle model of stress, parental separation (Tyrka et al., 2008; Pesonen et al., 2010), other forms of early life stress such as childhood maltreatment (Dannlowski et al., 2012; McCrory et al., 2011; Teicher et al., 2012), and alterations in pre- (Kajantie et al., 2003; R. Reynolds et al., 2005) and postnatal (Fernald, Grantham-McGregor, Manandhar, & Costello, 2003) growth have been shown to be associated with altered structure and functioning of the HPA axis, hippocampus, amygdala, and prefrontal cortex; the brain areas implicated in the stress system, suggesting that one pathway, through which early developmental adversity may exert its long-term effects, is via leading to permanent changes in the individuals` vulnerability to stress, and thereby predisposing to later psychopathology. The functioning of the stress system may possibly be particularly affected by adversities in early life, since developmental plasticity of the brain areas regulating this system is at its highest then (Lupien et al., 2009; Uematsu et al., 2012). This may help in explaining the evident predictive role played by early life developmental factors for well-being in adult life.
Furthermore, the effects of prenatal developmental adversities such as maternal psychosocial stress on birth size may be mediated by developmental programming by maternal glucocorticoids. Direct associations of maternal cortisol levels during pregnancy with head circumference at birth (Li et al., 2012) and with infant cortisol levels (O'Connor, Bergman, Sarkar, & Glover, 2012) have been shown. Also particular prenatal exposures such as overexposure to maternal glucocorticoids as a consequence of glycyrrhizin in diet (Räikkönen et al., 2010) or to maternal psychosocial stress during pregnancy (Entringer et al., 2009) have been shown to alter offspring HPA axis function.
As stated, neurobiological changes in the functioning of the brain areas implicated in the stress system (Brunner et al., 2010; Carrasco et al., 2012; Carvalho Fernando et al., 2012; Herpertz et al., 2001; Nunes et al., 2009; Ruocco et al., 2012; Soloff et al., 2008;
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Wolf et al., 2012: D. Zimmerman & Choi-Kain, 2009) are also evident among patients with personality disorders, and may thus underlie the associations found in the current studies. Hence, early life adversities, parental separation and the adversities reflected in both pre- and postnatal growth may lead to long-term changes in the functioning of the stress system, in particular in the glucocorticoid functioning of the HPA axis, and thereby set forth an increased risk of personality disorders in adulthood.
Also altered functioning of growth hormone-insulin like growth factor -axis (D’Ercole, Ye, Calikoglu, & Gutierrez- Ospina, 1996; Geary, Pringle, Rodeck, Kingdom, & Hindmarsh, 2003; Gerra et al., 2003; Hochberg & Albertsson-Wikland, 2008; Juul, 2001; Veldhuis et al., 2005) and of sex steroids (Aluja & García, 2007; Geary et al., 2003; Goel & Bale, 2009; Hines, 2008; Juul, 2001; Lombardo et al., 2012) may be possible underlying neurobiological factors essential for explaining our findings, especially those on early life growth and personality disorders. Both growth and sex hormones play an important role in explaining individual (Hochberg & Albertsson- Wikland, 2008; Juul, 2001; Veldhuis et al., 2005) and sex (Geary et al., 2003; Juul, 2001) differences in growth, and in brain development in early life (D’Ercole et al., 1996; Goel & Bale, 2009; Hines, 2008; Lombardo et al., 2012). Their functioning is also markedly associated with the functioning of the stress system (Charmandari et al., 2005; Goel & Bale, 2009, Goel, Plyler, Daniels, & Bale, 2011). Both sex steroids and growth hormones have also been shown to play a possible predictive role in the etiology of antisocial personality disorder (Aluja & García, 2007; Gerra et al., 2003). Consequently, altered functioning of these hormones may have contributed to our findings of early life growth predicting severe personality disorders, and to explaining the sex-specificity of the majority of our findings.
The effects of early life adversity on personality disorders, both of parental separation in particular and of the adversities reflected in growth may be epigenetic in nature; changes in gene expression as a consequence of early life adversity. Prenatal adversities may affect growth for example via their effects on HSD11B2 gene expression in the placenta encoding the 11 HSD-2 enzyme (e.g. Jensen Peña et al., 2011), possibly via leaving the fetus more vulnerable to maternal glucocorticoids. Specific epigenetic changes have also been associated with early life growth (Marsit et al., 2012; Menon et al., 2012; Michels et al., 2012; Wyrwoll et al., 2011), and are
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evident as a consequence of prenatal malnutrition (Heeijmans et al., 2008) that also may predispose to personality disorders (Hoek et al., 1996; Neugebauer et al., 1999), and have been shown to emerge as a consequence of parental separation in childhood (Tyrka et al., 2012). Epigenetic changes are also found among patients with personality disorder (Dammann et al., 2011), and have been shown to mediate the effects of early life stress on personality dysfunction (Beach et al., 2011). Thus, epigenetic changes as a consequence of early life adversity leading to an increased vulnerability for personality disorders offer one plausible molecular genetic mechanism for all the associations found in the current study between early life developmental factors and personality disorders.