The Hypothalamus- Pituitary-Adrenal Axis


The Hypothalamus- Pituitary-Adrenal Axis

Role in Borderline Personality Disorder


Borderline personality disorder (BPD) is an axis II mental health disorder characterized by a series of symptoms which consists of recurrent patterns of emotional instability, strained interpersonal relationships, poor self-image and compromised inhibitory/impulse control. It is thought to affect between 1.4 to 6.0% of the population. The role of disrupted function of the hypothalamus-pituitary-adrenal (HPA) axis is an area of growing interest with respect to the pathophysiology of BPD. Overall, there is conflicting data on whether patients with uncomplicated BPD show significantly different HPA axis responsiveness compared to healthy controls, however more consistent patterns seem to emerge when evaluating BPD patients with secondary psychiatric cormorbidities. BPD patients with comorbid MDD appear to have increased cortisol levels at baseline and in response to stress, perhaps due to decreased sensitivity of the negative feedback system. BPD patients with comorbid PTSD appear to have lower levels of cortisol, indicating either cortisol hyper-suppression, or adrenal hypofunction. Treatments with the aim of regulating HPA axis responsiveness may be of benefit among this patient population.

Borderline Personality Disorder

Borderline personality disorder (BPD) is an axis II mental health disorder that has been found to be over-represented in psychiatric outpatient settings (Dixon- Gordon 2013). Its prevalence in the United States is estimated at between 1.4 % and 6.0% (Dixon-Gordon 2013, Ishak 2013), and currently there are no accurate rates of prevalence for the Canadian population (CAMH 2009). BPD is a personality disorder characterized by a series of symptoms which consists of recurrent patterns of emotional instability, strained interpersonal relationships, poor self-image and compromised inhibitory/impulse control (Carvalho 2013, Dixon-Gordon 2013, Lyons-Ruth 2011, Zimmerman 2009). Self-harm and increased suicide risk are also common features of BPD (Fox 2014). Research suggests that early life stressors are a major risk factor in the development of BPD, lending to a growing interest in the role of hypothalamus-pituitary-adrenal axis (HPA) disruption in the etiology of BPD (Carvalho 2012, Carvalho 2013, Zanarini 1997, Zimmerman 2009). This article will review current evidence pertaining to the role of the HPA-axis in BPD.

Conventional treatment for BPD focuses primarily on psychological treatments, such as Dialectical Behavioural Therapy and Cognitive Behavioural Therapy, and pharmacological therapy including use of mood stabilizers, small dose atypical antispsychotics, and antidepressants, all of which have been shown to improve the quality of life in BPD patients (Fox 2014, Ishak 2013). Due to the nature of their symptoms, in fact, BPD patients may be over-dependent on the healthcare system. A study performed by Zanarini et. al outlines the overuse of treatments available to BPD patients, such as therapy, psychiatric hospitalizations, and standing medications by BPD patients, compared to other axis II controls. Researchers found that 50-60% of BPD patients had participated in selfhelp groups, had numerous psychiatric hospitalizations, and/or day or residential treatments. Approximately 30-35% had been in either group, individual, and/or couples/family therapy, or had received intensive polypharmacy treatment (Zanarini 2001). There is a need for new strategies to enhance symptom management in this area.

Due to the complex nature of BPD, research in this area is striving to uncover new mechanisms involved in BPD, in order to improve treatment strategies that could result in more effective symptom management and enhanced quality of life for BPD patients. An area of emerging interest is the role of HPA-axis function on the pathophysiology of BPD; in this paper, we will assess the current evidence in this regard.

Hypothalamus-Pituitary-Adrenal Axis

The hypothalamus-pituitary-adrenal (HPA) axis is comprised of the hypothalamus, anterior pituitary, and adrenal cortex. This system regulates and controls the body’s response to external and internal stress by activating the commonly known “fight or flight” response. In response to a “stressor”, the hypothalamus secretes corticotropinreleasing hormone (CRH), which activates the anterior pituitary to release adrenocorticotropic hormone (ACTH), which in turn stimulates the adrenal cortex to release cortisol. Once optimal cortisol levels have concentrated the blood, this in turn activates the negative feedback system to inhibit the release of CRH from the hypothalamus, shutting down further release of hormones at all levels (Jones 2011, Zimmerman 2009). Impaired negative feedback is one of the possible problems that can occur with HPA-axis disruption.

Cortisol itself has also been an important focus as a biological mediator of psychiatric illness; conditions of hypercortisolemia, (i.e. Cushing’s syndrome), and hypocortisolemia (i.e. Addison’s disease) have both been associated with mental health symptoms such as anxiety, depression, and irritability (Sonino 1998). CRH has been found to be the stress-initiating hormone in the HPA axis; in vivo studies have shown CRH administration induces anxiety-like behaviour, such as increased emotional reactivity, withdrawal, increased motor activity and decreased social interaction in mice (Dunn 1990). Therefore, chronically elevated or depressed cortisol production by the adrenal cortex is another possible source of HPA-axis dysfunction.

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HPA axis Function in BPD

A number of studies have found altered patterns in the HPA axis in BPD patients. Lieb et. al performed a study that measured salivary cortisol collected from 23 un-medicated female patients with BPD, and 24 healthy female controls, during ambulatory conditions. On days one and two, cortisol levels in response to awakening were determined in four-15 minute intervals. A low dose dexamethasone suppression test (DST, 0.5mg of dexamethasone) was administered after the last salivary sample on day two in order to assess the level of cortisol suppression on day three. Results found that patients with BPD displayed higher levels of cortisol compared to healthy controls during days one and two as well and day three. This study suggest that BPD may have increased cortisol output compared to healthy controls, perhaps through lowered sensitivity of the HPA axis negative feedback system (Lieb 2004).

Other recent studies have shown similar results. A study performed by Lyons-Ruth et. al compared salivary cortisol levels in 17 BPD females and 15 non-BPD females in response to a conflict discussion with their mothers. Results found that not only were cortisol levels higher in BPD patients anticipating the conflict discussion, BPD patients also reported higher levels of distress, post discussion compared to non-BPD patients (Lyons-Ruth 2011). Scott et. al found that women with BPD had higher baseline cortisol levels as well as higher subjective negative affect at baseline and in response to stress, compared to two control groups consisting of non-BPD patients; 1) trait-match controls (specifically on impulsivity and negative affect) and non-trait matched controls. Interestingly, this study found attenuated cortisol levels in response to stress (Scott 2013). Increased baseline cortisol levels, but attenuated cortisol levels in response to stress have been demonstrated in earlier studies. A study by Nater et. al confirmed this pattern of cortisol, but also found that ACTH and the catecholaminergic response were no different in BPD patients compared to controls (Nater 2010). This suggests that patients with BPD may have higher baseline cortisol levels, but lower cortisol response to endogenous ACTH, or stress, possibility pointing to hypofunctioning of cortisol secretion by the adrenal glands, or perhaps hypersuppression of cortisol caused by a dysfunction of the negative feedback system.

The Influence of Comorbid Psychiatric Conditions

The pattern of HPA axis function in BPD is yet to be established, with the majority of studies producing rather inconsistent results. It is possible that factors other than simply a BPD diagnosis may contribute to HPA axis regulation in BPD. BPD is strongly associated with comorbidity with other psychiatric health conditions (Zimmerman 2009, Lange 2005). The most common clinical conditions that have been found to be associated with HPA dysregulation include major depressive disorder (MDD), post-traumatic stress disorder (PTSD), and eating disorders, which occur at high rates in those with BPD (Carvalho 2012, Morris 2014, Rosenberg 2013, Wingenfeld 2013, Zimmerman 2009). In 2009, Zimmerman et. al performed a review of 18 studies published between 1950-2007. The review found that dysfunction of the HPA axis is an apparent feature in BPD based on four assessment methods used: 1) assessment of baseline cortisol levels, 2) cortisol response to the dexamethasone-suppression test (DST), 3) cortisol and ACTH response to the combined dexamethasone (DEX)- CRH test, and 4) cortisol response to psychosocial stressors. Results typically found no difference in HPA axis function in BPD patients when compared to healthy controls, with only two studies showing non-suppression of cortisol in BPD patients in the using the DST method. However, HPA axis dysfunction was more commonly linked to BPD in the presence of comorbid conditions and trauma history.

Interestingly, Zimmerman et. al. found an apparent distinction in HPA response based on the type of comorbidity present (2009). There was a paradoxical response of the HPA axis among BPD patients with either comorbid MDD or PTSD. BPD patients with comorbid MDD were found to be have impaired negative feedback inhibition of cortisol (nonsuppression) at a rate of 16-73% when administered a 1.0 mg dose of DEX. Alternately, BPD patients with comorbid PTSD showed to have elements of enhanced negative feedback (hyper-suppression) of cortisol in response to 0.5 mg dose of DEX. Patients with high level of dissociative symptoms showed increased response to psychosocial stressors, and BPD patients with a strong history of childhood abuse demonstrated increased ACTH release levels on CRH stimulation (Zimmerman 2009). A study performed by Lange et. al also showed this paradoxical response: BPD patients with PTSD showed increased suppression of cortisol when administered 0.5 mg of DEX, whereas patients with comorbid MDD and healthy controls did not demonstrate hypersuppression (Lange 2005). Another study performed by Wingenfeld et. al found that patients with BPD or BPD+PTSD had improved (autobiographical) memory when administered cortisol, whereas this memory-enhancing response to cortisol did not occur in patients with BPD+MDD (Wingenfeld 2013).

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HPA axis function in BPD + MDD

Increased cortisol secretion has been established as a hallmark feature of MDD (Carvalho 2012, Schatzberg 2013), a condition often preceded by periods of chronic, or traumatic, episodic stress (Hammen 2005, Lee 2002). A recent study by Morris et. al found that patients diagnosed with MDD showed increase cortisol levels during the depressive episode, as well as during recovery, when compared to controls, who showed habituation of cortisol levels in response to stress (Morris 2014). Non-suppression of cortisol, or hypersecretion, among in BPD patients with comorbid MDD was also a pattern identified by Zimmerman et. al in their review (2009). A more recent study by Carvalho et. al found that patients with BPD and patients with MDD showed increased basal cortisol levels as well as higher post-DEX (0.5 mg) cortisol levels compared to healthy controls. The degree of increase was positively correlated with symptom severity, level of dissociation, and past history of childhood abuse (Carvalho 2012). Interestingly, this study did not find that increased cortisol levels was a result of impaired negative feedback in response to low dose DEX administration, as hypothesized (Carvalho 2012). Instead, these findings suggest that a history of exposure to chronic stress, characteristic of MDD, may be the reason for increased cortisol levels in BPD patients.

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HPA axis function in BPD + PTSD

PTSD is a condition triggered by exposure to acutely traumatic events. Characteristics of PTSD can be explained through symptom clusters comprised of avoidance, numbing, separating, dysphoric- and anxious- arousal (Horn 2014). The review by Zimmerman et. al., along with other studies, found that patients with BPD who display comorbid PTSD demonstrated elements of HPA hyper-suppression, or enhanced negative feedback on cortisol, ultimately resulting in lower cortisol levels (Lange 2005, Zimmerman 2009). A recent study performed by Horn et. al compared the cortisol response to trauma among that adults with PTSD or healthy adult controls (2014). Not surprisingly, the adults with PTSD had significantly lower cortisol levels compared to healthy controls, consistent with findings outlined in the Zimmerman review (Horn 2014). A crossover study by Carvalho et. al. showed similarly consistent results, finding that divergent responses in HPA axis function upon comparing patients with BPD and BPD+PTSD. A total of 32 female patients with BPD and 32 healthy females were both given 10mg of hydrocortisone. They were then required to perform an adapted emotional go/no-go paradigm to assess response times to emotional face stimuli. It was found that both BPD and healthy controls displayed quicker reaction times to target stimuli when administered hydrocortisone, while BPD patients with comorbid PTSD displayed longer reaction times (Carvalho 2013).

In a recent study, Dixon-Gordon et. al investigated the relationship between BPD and emotional reactivity to a stressor in subjects with comorbid PTSD through subjective assessment and cortisol measurement (2013). Results showed that BPD patients with low level PTSD symptoms had a rapid onset of cortisol secretion in response to a stressor. However, those with more severe PTSD showed results consistent with previous findings: no change in cortisol in response to stress (Dixon-Gordon 2013). This study suggests that the reason for hyper-suppression of cortisol found in BPD patients with comorbid PTSD could be explained through emotional “numbing”, or allostatic load, a compensatory method for patients exposed to chronic stress/arousal of the HPA axis, typical to patients with PTSD (Jones 2011). Rather than a normal level of cortisol released in response to stress, the chronic stress and trauma experienced by a PTSD patient may place an excessive demand in the HPA axis, thereby creating HPA axis hypo-functioning over time (Horn 2014, Daskalakis 2013, Jones 2011). This may be a result of decreased synthesis of hormones, down-regulation of receptors in the pituitary glands, decreased cortisol (glucocorticord) sensitivity, or hyposecretion of cortisol by the adrenal glands, as a protective mechanism to subvert negative effects of prolonged exposure to cortisol to the body (Jones 2011); however exact mechanisms are still unclear and require more research. These studies nonetheless provide strong evidence that PTSD comorbidity may be the cause of cortisol hyper-suppression in patients with BPD.


Investigations of HPA axis function in patients with BPD have produced variable results. While it appears that patients with BPD may generally exhibit altered HPA axis function, with the primary feature being increased baseline cortisol levels (Carvalho 2012, Lieb 2004), there is not yet sufficient evidence to definitively support altered HPA axis function in patients with BPD upon comparison with healthy controls (Carvalho 2013, Zimmerman 2009). Reasons for such varied results in HPA axis function in uncomplicated BPD could be due to failure to account for a number of variables. HPA axis function is easily influenced by age, gender, time of menstrual cycle, personal sleep/wake cycles, and nutritional status (Borsonelo 2011, Panagiotakopoulos 2014, Woods 2013). In addition, collection of cortisol samples can influence levels, as fear of needles can increase cortisol levels, and salivary cortisol collection can be altered by the presence of food particles in the saliva (Zimmerman 2009). Altered HPA function does appear to be more obvious in BPD patients in the presence of psychiatric comorbidities, most notably MDD and PTSD, (Carvalho 2012). BPD patients with comorbid MDD appear to have increased cortisol levels at baseline and in response to stress, perhaps due to decreased sensitivity of the negative feedback system. BPD patients with comorbid PTSD appear to have lower levels of cortisol, indicating either cortisol hyper-suppression, or adrenal hypofunction. These features are not unique to these comorbidities only in combination with BPD, but also have been demonstrated among patients with uncomplicated MDD and PTSD, independent of BPD. It is possible that while HPA axis function may not play a major role in the etiology of BPD, the presence of other psychiatric conditions contribute to altered HPA axis function. Nonetheless, current research does support possible low-grade alterations of HPA axis function in patients with BPD, suggesting that treatments focused on regulation of HPA axis may be of benefit to these patients, especially when BPD is associated with comorbid conditions, such as PTSD and MDD.


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