Original articleHyperresponsiveness of hypothalamic-pituitary-adrenal axis to combined dexamethasone/corticotropin-releasing hormone challenge in female borderline personality disorder subjects with a history of sustained childhood abuse
Introduction
Recent studies suggest that childhood abuse is an important factor in the pathogenesis of borderline personality disorder (BPD; Herman et al 1989, Ogata et al 1990, Salzman et al 1993. There is also evidence, however, that early trauma may increase vulnerability to the occurrence of a major depressive disorder (MDD) or posttraumatic stress disorder (PTSD) in later life Gladstone et al 1999, Heim and Nemeroff 1999, Stein et al 1997. Moreover, MDD and PTSD are often diagnosed in patients with BPD (Zanarini et al 1998). In fact, 20 to 40% of borderline patients meet the DSM-IV criteria for PTSD in response to childhood abuse or later traumatic experiences (Gunderson and Sabo 1993).
Patients suffering from MDD or PTSD often display major disturbances in the regulation of the hypothalamic-pituitary-adrenal (HPA) axis. For PTSD, several studies have demonstrated a much more potent suppression of the HPA axis by the synthetic glucocorticoid dexamethasone compared with healthy control subjects. This observation suggests enhanced glucocorticoid feedback inhibition in PTSD. This enhanced glucocorticoid feedback is probably due to hypersensitivity on the part of the pituitary or brain glucocorticoid receptors (GRs). As a consequence of such heightened feedback, the circulating cortisol levels are low, and the patients display hypocortisolism Yehuda (1998):, Yehuda et al 1990, Yehuda et al 1993. In contrast, glucocorticoid feedback inhibition has been found to be attenuated in a large population of depressed patients. These individuals display hypercortisolism and resistance to the suppression of the HPA axis by exogenous dexamethasone Carroll 1982, Carroll et al 1981a, Evans and Nemeroff 1985; however, MDD and PTSD appear to share an enhanced central corticotropin-releasing hormone (CRH) drive toward HPA axis activation Baker et al 1999, Bremner et al 1997, Gold et al 1986, Heim et al 2001, Holsboer et al 1987a, Kaufman et al 1998, Smith et al 1989, von Bardeleben et al 1988.
Recent animal research data suggest that adverse circumstances during early development may permanently affect the HPA axis and cognitive functioning (Oitzl et al 2000). The long-term effects of deprivation of rat infants from maternal care include an enhanced CRH or arginine vasopressin (AVP) drive from the hypothalamus, an enhanced glucocorticoid response to stress, and altered expression of mineralo- and glucocorticoid receptors in the brain Coplan et al 1996, Francis et al 1999, Hatalski et al 1998, Plotsky and Meaney 1993, Sutanto et al 1995, Workel et al. The enhanced drive by corticotropin (ACTH) secretagogs is important, because AVP synergizes and thus potentiates CRH action on to release ACTH from pituitary corticotrophs De Goeij et al 1992, Lim (2000):. These preclinical HPA axis studies have prompted the examination of the specific influences mediated by the effects of early abuse on adult HPA axis function in a clinical population. Research with traumatized children and most recently with adult female victims of childhood sexual abuse has also demonstrated persistent changes in the HPA axis characterized by an enhanced central drive De Bellis et al 1994, Heim et al 2000a, Heim et al 2001, Kaufman et al 1997.
Several studies have been conducted to evaluate HPA axis function in borderline patients using the dexamethasone suppression test. The results of these studies have been inconclusive, however, because the potential effects of a concurrent MDD or PTSD (or both) have not been taken into account Baxter et al 1984, Carroll et al 1981b; Kontaxakis et al Kontaxakis et al 1987, Steiner et al 1984, Sternbach et al 1983. In one study, MDD patients with a comorbid BPD displayed less suppression of cortisol after dexamethasone than MDD patients without a comorbid BPD. This finding indeed suggests that borderline pathology enhances the feedback inhibition of the HPA axis during depression. Unfortunately, the presence of potential comorbid PTSD was not taken into account in this study (Soloff et al 1982; for review, see Lahmeyer et al 1989).
Taken together, these findings raise the question of whether alterations in HPA activity in BPD patients are associated with borderline personality disorder, comorbid MDD or PTSD (or both), or the occurrence of sustained childhood abuse.
In our study, we tested the hypothesis that severely abused borderline patients can be distinguished both from borderline patients without histories of severe abuse and from healthy control subjects by a hyperresponsive HPA axis using a combined dexamethasone/corticotropin-releasing hormone challenge (DEX/CRH) test. The test evaluates HPA activity in terms of central CRH/AVP drive and glucocorticoid feedback at the level of the pituitary gland, which is the target organ for both dexamethasone and CRH De Kloet 1997, Heuser et al 1994, Holsboer 1989, Hundt et al 2001, Modell et al 1997, von Bardeleben and Holsboer 1989, Zobel et al 2001. Differences in the DEX/CRH test among borderline patients are hypothesized to be associated with sustained childhood abuse, and a comorbid PTSD or MDD can be expected to mitigate or enhance these effects, respectively.
Section snippets
Subjects
Physically healthy women (aged 18–50 years) with a possible diagnosis of BPD were recruited from psychiatric outpatient clinics, community mental health centers, and by advertising in newspapers and on the Internet. Given this heterogeneous sampling frame, a rigorous diagnostic procedure was applied to select a homogeneous study population with a (moderately) severe DSM-IV borderline personality disorder. To be included in the study, all of the patients had to obtain a score of 110 or higher on
Sample characteristics
No significant differences were detected between the chronically abused BPD patients, non- or mildly abused BPD patients, and control subjects with respect to body mass index, contraceptive pill and nicotine usage, or living situation; however, the abused BPD patients were significantly older and had significantly fewer years of education than the healthy control subjects, whereas the nonabused BPD subjects did not differ significantly from the other groups. Significantly more of the control
Discussion
The results of our study show significantly higher plasma ACTH and cortisol concentrations after a DEX/CRH challenge for borderline patients with a history of sustained childhood abuse compared with a group of non- or mildly abused borderline patients. This heightened ACTH and cortisol response is associated with childhood abuse and appeared to be independent of BPD pathology and independent of a comorbid PTSD or MDD. Nevertheless, a comorbid PTSD was found to attenuate the ACTH response to
Acknowledgements
This study was supported by grants from De Geestgronden Institute of Mental Health Care, the Stichting tot Steun van Vereniging Bennekom, the National Fund for Mental Health Grant No. 4820, and Ferring B.V. Hoofddorp, The Netherlands. The authors thank Wouter van Ewijk, chief executive officer of De Geestgronden Institute of Mental Health Care, for providing the grant and facilities that made this study possible; Emiel Gans, Wijtske Kielstra, Rietta Oberink, Elise Ruys, and Jan van Zaane for
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