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1 This article was downloaded by: [Universitaetsspital Basel] On: 23 November 2009 Access details: Access Details: [subscription number ] Publisher Informa Healthcare Informa Ltd Registered in England and Wales Registered Number: Registered office: Mortimer House, Mortimer Street, London W1T 3JH, UK Journal of Psychosomatic Obstetrics & Gynecology Publication details, including instructions for authors and subscription information: HPA axis reactivity in chronic pelvic pain: association with depression Katja Wingenfeld a ; Dirk H. Hellhammer b ; Iris Schmidt b ; Dieter Wagner c ; Gunther Meinlschmidt d ; Christine Heim e a Department of Psychiatry, University Medical Center Hamburg-Eppendorf, Hamburg, Germany b Department of Psychiatry, Universitiy of Trier, Trier, Germany c Department of Psychiatry, Alexianer- Hospital Krefeld, Krefeld, Germany d Department of Psychiatry, University of Basel, Basel, Switzerland e Emory University, Atlanta, USA Online publication date: 17 November 2009 To cite this Article Wingenfeld, Katja, Hellhammer, Dirk H., Schmidt, Iris, Wagner, Dieter, Meinlschmidt, Gunther and Heim, Christine(2009) 'HPA axis reactivity in chronic pelvic pain: association with depression', Journal of Psychosomatic Obstetrics & Gynecology, 30: 4, To link to this Article: DOI: / URL: PLEASE SCROLL DOWN FOR ARTICLE Full terms and conditions of use: This article may be used for research, teaching and private study purposes. Any substantial or systematic reproduction, re-distribution, re-selling, loan or sub-licensing, systematic supply or distribution in any form to anyone is expressly forbidden. The publisher does not give any warranty express or implied or make any representation that the contents will be complete or accurate or up to date. The accuracy of any instructions, formulae and drug doses should be independently verified with primary sources. The publisher shall not be liable for any loss, actions, claims, proceedings, demand or costs or damages whatsoever or howsoever caused arising directly or indirectly in connection with or arising out of the use of this material.

2 Journal of Psychosomatic Obstetrics & Gynecology, December 2009; 30(4): SHORT COMMUNICATION HPA axis reactivity in chronic pelvic pain: association with depression KATJA WINGENFELD 1, DIRK H. HELLHAMMER 2, IRIS SCHMIDT 2, DIETER WAGNER 3, GUNTHER MEINLSCHMIDT 4, & CHRISTINE HEIM 5 1 Department of Psychiatry, University Medical Center Hamburg-Eppendorf, Hamburg, Germany, 2 Department of Psychiatry, Universitiy of Trier, Trier, Germany, 3 Department of Psychiatry, Alexianer-Hospital Krefeld, Krefeld, Germany, 4 Department of Psychiatry, University of Basel, Basel, Switzerland, and 5 Emory University, Atlanta, USA (Received 13 March 2009; revised 17 June 2009; accepted 24 June 2009) Abstract Objectives. Chronic pelvic pain (CPP) is a frequent gynecological complaint. The pathophysiology of CPP is not fully understood. The aim of this study was to determine whether the presence of depressive symptoms is associated with hypothalamic-pituitary-adrenal (HPA) axis dysfunction in CPP. Methods. We measured neuroendocrine responses to a standardized social stress test and to a standard adrenocorticotropin (ACTH) 1 24 stimulation test in 18 patients with CPP, stratified based on the presence of high versus low self-reported depressive symptoms, compared with 24 controls. Results. Women with CPP and low depression exhibited enhanced ACTH responses to psychosocial stress compared with women with CPP and high depression, whereas there were no differences in cortisol responses. In the ACTH 1 24 stimulation test, CPP patients with high depression demonstrated enhanced cortisol responses. Conclusion. These results suggest a relationship between self-reported depression and reactivity of the HPA axis in patients with CPP. Keywords: Chronic pelvic pain, depression, hypothalamic-pituitary-adrenal axis, ACTH, cortisol Introduction Profound alterations of the hypothalamic-pituitaryadrenal (HPA) axis have been reported for a variety of psychiatric and psychosomatic disorders. Although increased baseline cortisol levels and impaired negative feedback inhibition is a cardinal feature of major depression (MD), posttraumatic stress disorder (PTSD) is characterized by hypocortisolism and enhanced feedback sensitivity [1,2]. Interestingly, several studies reported that HPA axis function in mood or anxiety disorders, including PTSD, may be influenced by comorbidity among these disorders [3 6]. Thus, comorbidity between different disorders might be one reason for diverging results concerning HPA axis in many psychiatric and psychosomatic disorders, where heterogeneous findings have been found repeatedly [7 28]. In fibromyalgia syndrome, for example, it has been shown that reduced cortisol release is associated with depressive symptoms [29,30]. When comparing subgroups of patients with functional gastrointestinal disorders, those with high cortisol release were characterized by more depressive symptoms [7]. Until now only few investigated the role of comorbidity in influencing HPA axis function in women with chronic pelvic pain (CPP). Previously, Heim et al. [31] performed a low-dose DEX test in women with CPP without organic correlate and observed increased suppression of cortisol release. Additionally, the cortisol response after administration of exogenous corticotropin releasing factor (CRF) was reduced, whereas adrenocorticotropin (ACTH) release was normal [31]. These findings suggested enhanced feedback sensitivity together with an adrenocortical hyporesponsiveness in CPP. In a more recent study using a standardized social laboratory stressor, the Trier Social Stress Test (TSST) [32], and the ACTH 1 24 stimulation test, no differences between women with CPP and controls have been found [9]. It must be noted that in the Heim et al. [31] study the prevalence of comorbid PTSD was about 40%, whereas the extend of depressive Correspondence: Katja Wingenfeld, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. k.wingenfeld@uke.uni-hamburg.de ISSN X print/issn online Ó 2009 Informa UK Ltd. DOI: /

3 HPA axis reactivity in chronic pelvic pain 283 symptoms was in a normal range. In the latter study only two women (11%) had co-morbid PTSD but remarkably higher depression scores have been found compared with the control group [9]. The aim of this study was to conduct a reanalysis of the existing endocrine data women with CPP [9]. We stratified women with CPP based on the presence of high versus low current depressive symptoms and compare HPA axis responses to psychosocial stress and pharmacological challenge between these subgroups and healthy controls. We hypothesized that diverging results in the literature might be in part variable because of comorbidity with depression. not suffer from comorbid psychiatric disorder, whereas eight suffered from anxiety disorder (five phobia, two panic disorder, and one PTSD), two reported current dysthymia (one with PTSD). Further, seven patients reported lifetime MD disorder. Concerning SDS scores the CPP þ group (mean [SD]: 51.4 [5.7], min: 45, max: 65) differed significantly from the CPP 7 group (mean [SD]: 34.9 [6.1], min: 23, max: 41) and both patient groups had significantly higher SDS scores compared with controls (mean [SD]: 26.9 [4.9]; F 2,39 ¼ 76.14, p ). All CPP patients who reported current dysthymia or lifetime MD were in the CPP þ group. Methods Subjects and procedure For this examination, data from a recently published study [9] which included 18 women with CPP and 24 healthy control women were reanalysed. CPP patients were diagnosed by their physician based on the following criteria: (1) acyclic CPP, (2) of at least 4 month duration, and (3) without any medical explanation. Sample characteristics and procedure of the performed tests, i.e., the TSST and the ACTH 1 24 stimulations test as well as biochemical analyses are described in detail elsewhere [9]. The CPP group was divided by median-split in subgroups with high (CPP þ ) and low (CPP 7 ) extend of depressive symptoms (each group N ¼ 9) measured by the selfrating depression scale (SDS, CPP þ : SDS score 542, CPP 7 : SDS score 4 44). In the CPP þ group five women had SDS scores about 50 and more, which is an indicator of mild to moderate depression [33]. Plasma ACTH and cortisol concentrations in response to the TSST as well as cortisol release after 1 mg of ACTH 1 24 injection were compared between healthy controls and the two CPP groups. Statistical analyses Statistical analyses were performed using SPSS Version ACTH and cortisol responses were compared between groups using ANOVA with repeated measurements. All reported results were corrected by the Huynh-Feldt procedure when assumption of sphericity was violated. Level of significance was set at p Results Clinical features All patients with CPP met diagnostic criteria for current somatoform pain disorder evaluated via the German version of the Structured Clinical Interview for DSM-IV (SCID-I) [34]. Eight of the patients did Trier social stress test As recently reported, there were no major differences in ACTH and cortisol release between CPP patients and controls in response to the TSST [9]. However, when comparing CPP patients with high and low depression scores and healthy controls, we found a significantly greater ACTH response in the CPP 7 group (main effect time: F 7,245 ¼ 22.6, p ; main effect group F 1,35 ¼ 3.94, p ¼ 0.029, time by group interaction F 14,245 ¼ 4.69, p ¼ 0.009). Controls and CPP þ patients did not differ significantly (see Figure 1). With respect to cortisol release, there was neither a significant group nor a group by time interaction effect, reflecting comparable cortisol response in the TSST between the three groups. Adrenocorticotropin 1 24 stimulation test With respect to cortisol response to ACTH 1 24 stimulation, there was a significant main effect for time (F 8,288 ¼ 115.2, p ) and group by time interaction effect (F 16,288 ¼ 2.48, p ¼ 0.033). There was a trend toward a main effect for group (F 1,36 ¼ 2.59, p ¼ 0.089). Results are also presented in Figure 1 showing higher cortisol response in the CPP þ group compared with those with low-depression scores. Discussion In a recent study [9] we showed that CPP patients and healthy controls respond similarly to standardize psychosocial stress and the ACTH 1 24 stimulation test, which was inconsistent with previous studies [31]. One major characteristic of these previous studies was a high prevalence of comorbid PTSD within the CPP sample, whereas the extent of depressive symptoms was in the normal range. The study by Wingenfeld et al. [9] on the other hand studied a CPP sample with a low rate of comorbid PTSD, although these women had high depression scores. We have therefore hypothesized that inconsistent results regarding HPA axis dysregulation in

4 284 K. Wingenfeld et al. Figure 1. ACTH and plasma cortisol to a standardized social stressor and plasma cortisol to ACTH 1 24 simulation in CPP patients with high depressions scores (CPP þ ), CPP patients with low depression scores (CPP 7 ), and healthy controls. CPP might be at least in part influenced by presence or absence of depressive symptoms. Our here presented results confirm this hypothesis. We observed enhanced responsiveness to psychosocial stress in the CPP 7 group and normal to blunted ACTH response to stress in the CPP þ group. Interestingly, blunted ACTH response combined with normal cortisol release to CRF stimulation has been reported for patients with MD. This might in part because of chronic hypersecretion of hypothalamic CRF, which might result in a down-regulation of CRF receptors of the anterior pituitary and, thus, decreased pituitary responsiveness to CRH in these patients [35]. Further, we found enhanced cortisol release to ACTH in the CPP þ group. Interestingly, in patients with functional gastrointestinal disorders enhanced cortisol was also seen in those patients with depressive mood [6]. Hypercortisolism, in general, is a prominent finding in MD [36]. Of note, CPP þ patients in this study were subsyndromally depressed, which is reflected by the fact, that none had a diagnosis of current MD (but current dysthymia or lifetime MD). Accordingly, SDS scores were in the mild to moderate range. Nevertheless, CPP patients with a mild to moderate depressive symptoms seem to be different from those without depressive symptoms. In case of CPP, one may suggest at least two clinical subgroups, one perhaps characterized by more PTSD-related symptoms, as described by Heim et al. [31] with enhanced feedback sensitivity together with an adrenocortical hyporesponsiveness and another subgroup characterized by depression and decreased pituitary responsiveness and mild hypercortisolism, as described in this study. Some limitations of this study need to be taken into account. First, the sample size was very small, especially when patients were subdivided into patients with high and low depression scores. Further, subdividing the patients by median split is somehow problematic, it would have been more appropriate to investigate patients with and without a DSM diagnosis of current MD, which was not possible in this sample. Obviously, there is need to replicate these results in a larger sample, stratified by

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6 286 K. Wingenfeld et al. 30. Gur A, Cevik R, Sarac AJ, Colpan L, Em S. Hypothalamicpituitary-gonadal axis and cortisol in young women with primary fibromyalgia: the potential roles of depression, fatigue, and sleep disturbance in the occurrence of hypocortisolism. Ann Rheum Dis 2004;63: Heim C, Ehlert U, Hanker JP, Hellhammer DH. Abuse-related posttraumatic stress disorder and alterations of the hypothalamic-pituitary-adrenal axis in women with chronic pelvic pain. Psychosom Med 1998;60: Kirschbaum C, Pirke KM, Hellhammer DH. The Trier Social Stress Test a tool for investigating psychobiological stress responses in a laboratory setting. Neuropsychobiology 1993;28: Zung WW. Depression status inventory and Self-Rating Depression Scale, Weinheim: Beltz: Collegium Internationale Psychiatriae Scalarium; Wittchen HU, Zaudig M, Fydrich T. Strukturiertes Klinisches Interview für DSM-IV. Achse I: Psychische Störungen. SKID-I.: Hogrefe, Göttingen, Bern, Toronto, Seattle; Musselmann DL, DeBattista C, Nathan KI, Kilts CD, Schatzberg AF, Nemeroff CB. Biology of Mood disorders. In: Schatzberg AF, Nemeroff, CB, editor. Textbook of psychopharmacology, 2nd ed. American Psychiatry Press, Arlington, VA; Holsboer F. Stress, hypercortisolism and corticosteroid receptors in depression: implications for therapy. J Affect Disord 2001;62: Current knowledge on this subject. Until now only few studies investigated hypothalamic-pituitary-adrenal (HPA) axis function in women with chronic pelvic pain yielding in mixed results.. Some found reduced cortisol release and an enhanced HPA axis feedback sensitivity, but another study could not show any HPA axis related disturbances. As found for other disorders, comorbidity with other disorders might play an important role in this context. What this study adds. Aim of the study was to determine whether the presence of depressive symptoms in chronic pelvic pain is associated with hypothalamic-pituitary-adrenal axis dysfunction.