## 3 Hypothalamic-Pituitary-Adrenal (HPA) Axis Functioning
### Impacts of ACEs on Individuals' HPA Axis Functioning  
Much evidence supports an association between exposure to ACEs and HPA axis dysregulation, though findings regarding the direction of the association are conflicting [23]. However, it appears that ACEs most often lead to a state of hypocortisolism in the absence of mental health conditions [23] or to blunted cortisol responses, particularly among women, when stressors are experimentally introduced [24; 25]. It is thought that this state of hypocortisolism is acquired over time as the body becomes sensitized to toxic stressors (e.g., ACEs), whereby individuals release less cortisol in response to stressors due to a higher threshold for experiencing stress [23]. For women, greater estrogen levels may play a role in observed blunted cortisol responses when an external stressor is introduced [24; 25]. Through this mechanism, ACEs may initially result in cortisol hypersecretion; however, the negative feedback mechanism of cortisol results in eventual hyposecretion through an adaptive response [23]. In a randomized controlled trial, [PERSON] et al. compared cortisol levels in children randomly assigned to remain in poor-quality institutional care, children randomized to high-quality foster care from poor-quality institutional care, and children growing up in non-institutionalized care in more typical Romanian family environments [2]. Children who were randomized to high-quality foster care at a young age approximated cortisol levels of children growing up in non-institutionalized care, as opposed to children remaining in poor-quality institutional care, who demonstrated blunted cortisol levels [2]. This study provides initial evidence supporting a causal relationship between ACEs and hypocortisolism; however, it focused mainly on neglect as the type of ACE [2]. Although hypocortisolism may serve as an adaptive means of responding to stress among those who experienced ACEs, insufficient cortisol secretion can prevent adequate responses to future stressors and result in other health sequelae (e.g., hypotension, weight loss, fatigue) [26].  
Despite meta-analytic evidence of blunted cortisol responses among those who experienced ACEs [24; 27], HPA dysregulation appears to change in direction when individuals also report a mental health condition, such that states of hypercortisolism are often observed [23]. Findings from systematic reviews consistently suggest that hypercortisolism is associated with major depressive disorder, bipolar disorder, and schizophrenia, and other mental health disorders [23]. There is also evidence that different types of ACEs predict different types of mental health conditions [28], highlighting the importance of considering the type of ACE experienced. Nevertheless, blunted cortisol responses have still been observed among individuals with a mental health condition (e.g., major depressive disorders) in response to morning and afternoon stressors [23]. These differences may arise from differences in the type and severity of ACE experienced, individual differences (e.g., genetic predispositions to certain mental health conditions), the timing of the exposure, the approach to measuring cortisol (e.g., at baseline versus introducing a stressor), and other confounders [23]. For example, it appears that abusive ACEs compared to nociceptive ACEs are often associated with mood disorders and that hypocortisolism is observed more frequently among older individuals reporting mood disorders [23]. More consistency in study design among various investigations is needed to better understand how these factors interact within an already complex system of physiological processes.