In this study, the modifying effect of gender on the impact of early life trauma on HPA response to provocation, as measured by HPA response to CRH and the TSST, was assessed. The study allowed for examination of gender differences in HPA response in a group of individuals who had experienced a considerable amount and varied types of early life trauma, but who had no concurrent MDD or PTSD.
In this article, a novel approach to summarizing the ETI was undertaken in order to derive continuous-scale trauma domains. To our knowledge, this was a unique approach that incorporates many of the trauma items and allows trauma to be measured on a continuous scale. The derivation of a continuous measure of trauma is important, as studies have clearly shown relationships between the number of experienced childhood traumas and general mental health problems in adulthood;[10,33,39]
yet, most studies addressing the association between early life trauma and stress reactivity use a binary measure of early life trauma.[1,13,24,27]
This approach to measurement of early life adversity might be particularly important in the investigation of individuals without mood and anxiety disorders, because the impact of early life trauma on HPA axis function in these individuals may be more subtle.
The latent factors severe trauma and trauma effects, were shown to be strongly positively associated with baseline corticotropin levels in men and less so in women. Similarly, severe trauma was strongly positively associated with corticotropin response to CRH in men but not women. Finally, when considering the entire vector of response measures, severe trauma was positively associated with corticotropin response to CRH in men but not women. Trend level findings in the same direction were observed for cortisol.
Neuroendocrine response to CRH infusion has been examined in separate studies of women
with and without MDD and with and without histories of early life trauma. Using a 2 × 2 factorial design of MDD by early life trauma, Heim et al. found that women with early life trauma did not have increased cortisol in response to pharmacological challenge, but men did.[13,24,27]
The results of this study showed a similar relationship for corticotropin but not for cortisol, regardless of the presence of mood or anxiety disorders.
Neuroendocrine response to the TSST has previously been examined in studies of women and men experiencing early life trauma. In repeated measures analysis, cortisol response to the stress challenge was lower among those with self-reported history of moderate-to-severe childhood maltreatment.
Similarly, women reporting childhood physical abuse displayed a significantly blunted cortisol response to the TSST compared to controls without physical abuse.
Our findings did not confirm this for any of our trauma measures; potentially the power to detect the interaction observed with CRH was not large enough as the TSST did not produce nearly as robust a neuroendocrine response as CRH.
CRH findings imply that a blunting of HPA axis response to stress may be more substantial in the long-term consequences of severe early life trauma for women as compared to men without MDD or PTSD. Furthermore, this blunting effect of early life trauma on HPA axis response in women occurs in a dose–response fashion, with the level of neuroendocrine response decreasing with increases in the amount of early life trauma endured. To our knowledge, this is the first study to characterize a decrease in the overall corticotropin response with increasing levels of severe trauma in women. In the study by Carpenter et al.
there were subtle gender differences found in the corticotropin response to TSST, with men showing a blunting of peak response and women demonstrating a blunted corticotropin level throughout testing, as compared to a control group. Our CRH results are consistent with those observed for women; however, we note that our TSST failed to provide as robust a response as CRH stimulation.
The gender differences and dose–response relationship in neuroendocrine response to pharmacological and social stressors in relationship to severe early life trauma, but not in relation to general traumas or reported trauma effects, are of interest. The severe trauma factor loaded high on sexual, emotional, and physical traumas, which include items, such as rape, neglect, physical abuse by a primary care taker, or serious accident or injury. A number of animal studies demonstrate a gender differential in the impact of some of these early life experiences (such as neglect and physical intimidation), including stress, on brain structure and function in later life.[42–44]
In both rats and monkeys, chronic stress causes damage in the hippocampus of male rats and monkeys, but the magnitude is less in females.
In clinical and animal studies, gender differences in amygdala function during the processing of emotional memories have been demonstrated.[45,46]
Several studies have demonstrated that the corpus callosum of boys is particularly vulnerable to the effects of neglect as compared to girls.[44,47]
This is of particular interest because of emerging findings concerning significant sex differences in brain laterality, particularly in response to emotional stimuli.
Diminished corpus callosum development might exaggerate hemispheric specialization in males and exaggerate differences in response to emotional stimuli. The findings in this study contribute to the literature suggesting gender differences in the nature, timing, and extent of vulnerability to the impact of early trauma that may help explain the differential gender susceptibility to psychopathology following adverse childhood events.
Limitations of the study must be considered. First, the sample size was moderate. Second, it was not feasible to standardize the menstrual cycle phase for women at the time of testing. Previous studies have shown differences in response to CRH and TSST according to menstrual phase.[17,48]
Because this study was part of a larger study in which oral contraceptives and hormone replacement therapy were allowed, findings must be considered in light of this. Several studies have shown that exogenous horomone administration alters the HPA hormonal response to stress.[49–51]
However, only two women in this study were on oral contraceptives and one woman was on hormone replacement therapy. With only three people on exogenous steroid therapy, it was not possible to discern the effects of receiving hormone therapy. In addition, such a small group would be unlikely to affect the findings.
These findings add to the literature in several important ways. Notably, this study elaborates on previous investigations by focusing on gender-specific effects of early life trauma on stress response in a dose–response fashion in a group without concurrent mood or anxiety disorders. It is clear that early life trauma can cause lasting abnormalities in the stress responsive neural circuitry and alter the set point of the HPA axis to later stressful events. Gender and severity of trauma may be important determinants of the nature of these lasting changes, which should be carefully controlled and investigated in future studies. In this study, mean age differed significantly for men (32 years) and women (41 years). We cannot exclude the possibility that age differentially impacts HPA axis reactivity as a function of sex, which would require the inclusion of a three-way interaction, something that our study is not powered to test. However, we note that the three-way interaction, in the above described analyses, was not significant. Another important question is why general trauma and trauma effects did not reveal similar findings to severe traumas. Examples of general events include personal illness, experiencing the death of a caretaker, separation of parents, etc. Although these are traumatic events, they were very likely to be endorsed in this sample. On average, 6.4 of these were endorsed; however, this is in stark comparison to the lesser endorsement of emotional, physical, and sexual items (see ). A high prevalence of early life general traumas in this healthy population who did not develop PTSD or MDD may be an indication of their resilience and, therefore, the effects of these types of traumas on stress might be masked in this particularly resilient sample. One reason that trauma effects may not have predicted neuroendocrine response is a limitation of the scale—the instrument may not be capable of picking up wide variations in trauma effects because the range of responses was small in our sample, with most people reporting “no effect.” It is also quite possible that some participants misunderstood the directionality of the effects scale. For example, one participant reported being sexually assaulted and then reported that this had a “moderately positive” effect on them today. Such measurement error that is inherent in self-report can mask effects. Our dose–response approach to measurement of early life adversity might be particularly important in the investigation of individuals without mood and anxiety disorders, because the impact of early life trauma on HPA axis function in these individuals may be more subtle.