J Behav Med DOI 10.1007/s10865-016-9718-x
Endocrine dysregulation in women with irritable bowel syndrome according to Rome II criteria Charlotte Markert1 • Kerstin Suarez-Hitz2 • Ulrike Ehlert2 • Urs M. Nater1
Received: March 30, 2015 / Accepted: January 28, 2016 Springer Science+Business Media New York 2016
Abstract The etiology of the irritable bowel syndrome (IBS) is unexplained: biological, psychological and social factors must be considered. This study examined if differences in HPA-axis activity already exist in those who do not yet fulfill IBS criteria (i.e. ‘‘subthreshold IBS’’). We also investigated whether there were differences between those who reported clinically relevant (i.e. distressing) IBS symptoms and those who did not. Thirty-six women were subdivided into three groups (IBS group, subthreshold IBS group, control group). Results showed differences in morning cortisol levels (U = 11.58; p \ 0.05), with IBS patients showing a lower cortisol response compared to controls. Subthreshold IBS patients were comparable to controls regarding endocrine function. Diurnal cortisol levels did not differ between groups. Group comparisons between distressed subjects and non-distressed subjects regarding cortisol levels did not reach significance. The finding of endocrine abnormalities (at least in a sub-set of
& Charlotte Markert [email protected] Kerstin Suarez-Hitz [email protected] Ulrike Ehlert [email protected] Urs M. Nater [email protected] 1
Department of Psychology, Clinical Biopsychology, University of Marburg, Gutenbergstr.18, 35032 Marburg, Germany
2
Department of Psychology, Clinical Psychology and Psychotherapy, University of Zurich, Binzmu¨hlestr.14, 8050 Zurich, Switzerland
patients) is important since these might be associated with deficient pain processing in IBS. Keywords Cortisol awakening response Distress Irritable bowel syndrome Rome II criteria Rome III criteria
Introduction The irritable bowel syndrome (IBS) is one of the most common functional gastrointestinal disorders (FGID) in the general population. The Rome II criteria consist of the following: at least 12 weeks, which need not be consecutive, in the preceding 12 months of abdominal discomfort or pain that has two out of three features: it can be relieved with defecation; and/or its onset is associated with a change in frequency of stool; and/or its onset is associated with change in form (appearance) of stool (Thompson et al., 1999). Compared to the current Rome III criteria (Longstreth et al., 2006) the Rome II criteria are more restrictive (Drossman & Dumitrascu, 2006), more frequently used in clinical research (Dang et al., 2012) and there is more evidence for their validity (Whitehead & Drossman, 2010). The etiology of IBS cannot yet be explained on the basis of current knowledge, which suggests a multi-causal pathophysiology including biological, psychological, and social factors. Stress has been suggested to play a central role in the development (Bradford et al., 2012; Drossman et al., 1990; Locke et al., 2004), maintenance (Levy et al., 1997; Suarez et al., 2010) and exacerbation (Blanchard et al., 2008; Whitehead et al., 1992) of IBS symptoms. Other studies found an increased responsiveness to stress in persons with IBS, which is in turn associated with alterations in the functioning of the HPA axis (Dinan et al.,
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2006; FitzGerald et al., 2009; Kennedy et al., 2014b). The measurement of cortisol levels between awakening and about 30 min afterwards (the so-called cortisol awakening response, CAR) serves as a measure of functional integrity of the HPA axis (Clow et al., 2004). Previous studies examining the CAR in persons with IBS showed inconsistent results: one study found lower CAR values in persons with IBS compared to controls (Bohmelt et al., 2005), while others found higher CAR values in subjects with IBS (Patacchioli et al., 2001; Suarez-Hitz et al., 2012). As cortisol follows a distinct diurnal rhythm, research often also focuses on its diurnal course. The results regarding diurnal cortisol levels in persons with IBS remain ambiguous showing either no differences in cortisol levels between persons with IBS compared to healthy controls (Suarez-Hitz et al., 2012) or attenuated salivary cortisol levels (Bohmelt et al., 2005; Patacchioli et al., 2001). The studies differ in terms of sample selection, measurement methods, and use of diagnostic criteria, all of which might explain the discrepancies in the results. In addition to the dysregulations in basal HPA axis activity, persons with IBS show heightened (Chang et al., 2009), attenuated (FitzGerald et al., 2009; Suarez-Hitz et al., 2012) or sustained (Kennedy et al., 2014b) HPA axis activity to acute stressors compared to healthy controls. In the longterm these alterations may lead to underactivity of the HPA axis as a result of negative feedback inhibition (Mayer, 2000). A flattened diurnal cortisol profile is related to pain symptoms both in persons with IBS (Ehlert et al., 2005) and in healthy controls (Kuehl et al., 2010). One might query if a dysregulated HPA axis is a risk factor for the development of IBS. If alterations in HPA axis activity occur in those individuals who do not yet fulfill full criteria of IBS, but not in healthy controls, then this might be an indication that endocrine alterations may contribute to the development of IBS. In longitudinal studies, persons presenting with gastrointestinal symptoms, e.g. abdominal pain (Halder et al., 2007; Nicholl et al., 2008; Olafsdottir et al., 2012) or minor symptoms of IBS and other FGID (Agreus et al., 2001) at the first point of measurement were diagnosed with IBS at a later time point. In the current study, we included persons who did not meet the Rome II criterion of at least 12 weeks with gastrointestinal symptoms in the preceding 12 month. We termed this group ‘‘subthreshold IBS’’. Although many researchers have proposed a biopsychosocial model of IBS, the diagnostic criteria do not yet take into account psychological aspects, such as a criterion of subjective distress elicited by the symptoms. In the field of psychiatry clinical significance of a condition is only assumed when a person indicates feeling distressed by his or her symptoms. Consequently, diagnostic criteria for most psychiatric conditions encompass a so-called ‘‘distress criterion’’. In the criteria for FGID, no such infor-
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mation is included. This is interesting from both a conceptual and a clinical perspective, since a person may fulfill the diagnosis for an FGID without being at all bothered by the symptoms. The lack of a distress criterion in the diagnosis of IBS may suggest that persons who are not bothered by their symptoms are also included in epidemiological studies, which has the potential to provide skewed prevalence rates of IBS and other FGID. Given the high subjective stress levels and the above-mentioned role of biological stress systems in the manifestation of IBS, one might query whether persons with IBS who fulfill the distress criterion might differ from those without distress in biological stress measures as well. The purpose of the current study was twofold: 1.
2.
To examine whether differences in HPA axis activity already exist in subthreshold IBS. This could indicate that HPA axis abnormalities would be involved in the development of IBS. To investigate differences in HPA axis activity between persons who are distressed by their IBS symptoms and persons who are not distressed by their symptoms.
Methods Subjects Subjects were selected from a large sample of 1901 Swiss students who had participated in a previous online study (Markert et al., 2014) examining the association between psychological stress and gastrointestinal symptoms. Participants who had given their informed consent to take part in future studies were contacted via e-mail and informed about the study. All participants gave their written consent to take part in this add-on study. By this procedure, 52 subjects have been recruited for the study. 42 of the subjects were female, ten subjects were male. As there is evidence for sex differences regarding basal cortisol levels (Lederbogen et al., 2010; O’Donnell et al., 2008) and due to the increased prevalence of IBS in women (Hungin et al., 2003; Mearin et al., 2001), only women were included. 36 women were selected and subdivided into three equally sized groups, based on their data from the prior study. Twelve women fulfilled the Rome II criteria for IBS (IBS group), twelve women had a subthreshold IBS (subthreshold IBS group) and twelve women without IBS served as controls (control group). The three groups were matched for age. The subthreshold IBS group fulfilled the same symptom pattern as the IBS group, i.e. they had to report abdominal pain or discomfort with the accompanying features that are
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described in the Rome II criteria (Thompson et al., 1999) as well as symptoms that cumulatively support the diagnosis of IBS (e.g. abnormal stool passage or abdominal distension). In contrast to the group with IBS, they did not fulfill the 12 week time criterion in the Rome II criteria. The control group did not fulfill the Rome II symptom pattern. For a second analysis, we divided the group with IBS into a group which fulfilled the Rome II criteria without feeling distressed by their symptoms (non-distressed IBS group) and a group which additionally reported a high degree of feeling distressed by their symptoms (distressed IBS group). As compensation for their effort, control subjects received 80 Swiss Francs after completion of the study, whereas free stress management training was offered to the participants of the subjects with IBS or subthreshold IBS. The study was approved by a local ethics committee and was conducted in accordance with the Declaration of Helsinki. Sampling methods and biochemical analyses Saliva samples for the analysis of free morning cortisol levels were collected using Salivettes (Sarstedt, Sevelen, Switzerland) at five time points: at awakening and after 15, 30, 45, and 60 min. The diurnal course of the hormone was assessed using the same method at 8:00 A.M., 11:00 A.M., 3:00 P.M., and 8:00 P.M. The subjects collected the saliva samples in their natural home and work environment. To improve the participants’ compliance, Salivettes were stored in plastic vials equipped with Medication Event Monitoring System caps (MEMS, Aardex, Switzerland). Samples were stored at -20 C until the biochemical analyses were performed. Concentrations of salivary free cortisol were measured using a chemiluminescence immunoassay (CLIA, IBL, Hamburg, Germany). Intra- and interassay coefficients of variation were below 10 %. Assessment of psychometric data Socio-demographic data (age, education) and health-related data (BMI, smoking, consultation rates) were collected via questionnaire. IBS according to Rome II criteria (Thompson et al., 1999) was assessed using the Gastro-Questionnaire (Leibbrand et al., 2002). The ‘‘subthreshold IBS group’’ reported symptoms of IBS but did not fulfill the time criterion of at least 12 weeks within the last 12 months. For the additional analyses persons with IBS were assigned to the ‘‘distressed IBS group’’ if they fulfilled the Rome II criteria and rated their distress for at least one IBS-related symptom with values higher than/equal to 2 (intermediate distress) on a scale of 0–4. Persons with a diagnosis of IBS who were not distressed by their symptoms were assigned to the ‘‘non-distressed IBS group’’.
The Trier Inventory for the Assessment of Chronic Stress (TICS) (Schulz et al., 2004) was administered to analyze the level of perceived stress within the last 12 months. The TICS includes a ‘‘Screening Scale for Chronic Stress’’ consisting of 12 items. The Stress Reactivity Scale (SRS) (Schulz et al., 2005) was included to gather information about the individual reactivity to potentially stressful situations. It consists of 36 items with a three-level response format. A subject’s general stress reactivity score can be defined by the cumulated scores of all items. Statistical methods To compare the cortisol levels between groups, area under the curve (AUC) was calculated in accordance with Pruessner et al. (Pruessner et al., 2003). Data were tested for normal distribution and homogeneity of variance via Kolmogorov–Smirnov test and Levene’s test. Due to violation of conditions, data were analyzed by non-parametric statistics. Differences between IBS, subthreshold IBS and control subjects were verified with the Kruskal–Wallis test and the Mann–Whitney test. The Mann–Whitney test was also used to calculate differences between the distressed IBS group and the non-distressed IBS group. For all statistical analyses, SPSS Statistics 22 was used.
Results Sample characteristics One subject from the group with subthreshold IBS was excluded from analyses due to missing values in health related data. Participants also fulfilled criteria for other FGID according to the Gastro Questionnaire: eight subjects (66.67 %) in the control group, seven subjects (63.64 %) in the subthreshold group and all subjects (100 %) in the IBS group fulfilled the criteria for at least 1 FGID diagnosis. In the control group and the subthreshold IBS group the most frequent diagnosis was functional bloating. By contrast, in the group with IBS the most frequent diagnosis was functional dyspepsia. There were no significant differences between the three groups with regard to age, BMI, number of cigarettes smoked per day, or consultation rates (see Table 1 for more detailed information). Differences between the three groups regarding CAR Figure 1a shows the results for cortisol levels in the morning. Results showed significant differences in cortisol level 30 min after awakening (H(2) = 8.73, p \ 0.05).
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J Behav Med Table 1 Descriptive statistics and analysis of variance for the different IBS groups Descriptive statistics
Groups
Kruskal–Wallis test
Control group (N = 12) mean (SD)
Subthreshold IBS (N = 11) mean (SD)
IBS (N = 12) mean (SD)
H
Significance (p)
Age
23.56 (2.78)
24.10 (3.13)
26.23 (3.85)
3.66
0.16
Body Mass Index
20.88 (1.51)
21.97 (2.47)
21.13 (1.72)
1.26
0.53
Number of cigarettes smoked per day
3.75 (7.72)
0.18 (0.60)
4.00 (11.57)
1.18
0.55
Consultation rates within the last year
4.25 (8.57)
2.82 (2.64)
4.17 (4.22)
2.10
0.35
IBS irritable bowel syndrome
Post-hoc comparisons demonstrated significant differences between the IBS group and the control subjects (U = 11.58, z = 2.77, p \ 0.05, r = 0.57), with the IBS group showing lower cortisol levels 30 min after awakening. The difference between the IBS group and the subthreshold IBS group was of marginal significance (U = 9.64, z = 2.25, p = 0.07, r = 0.47), with the IBS group tending to show lower cortisol levels than the subthreshold IBS group. The other points of measurement in the morning did not differ between groups. Intergroup comparisons regarding the morning area under the curve of cortisol showed significant differences (H(2) = 8.32, p \ 0.05). Posthoc comparisons showed a reduced release of cortisol in the group of IBS compared to the control group (U = 10.42, z = 2.49, p \ 0.05, r = 0.51) and the subthreshold IBS group (U = 10.64, z = 2.49, p \ 0.05, r = 0.52). For more detailed information see Fig. 1b. Differences between groups regarding diurnal cortisol profile Figure 1c shows the results for cortisol levels during the day. Results did not show significant differences in cortisol levels during the day (all p [ 0.05). Intergroup comparisons regarding the area under the curve of cortisol levels during the day did not show significant differences, either (H(2) = 0.96, p = 0.62; see also Fig. 1d). Differences between the three groups regarding psychological parameters There were no significant differences between the three groups regarding chronic stress level, but the level of stress reactivity differed between groups (see Table 2 for more detailed information). Post-hoc comparisons revealed that the IBS group showed significantly higher levels of stress reactivity compared to the control group (U = 9.67,
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z = 2.38, p \ 0.05, r = 0.49) and the subthreshold IBS group (U = 10.08, z = 2.37, p \ 0.05, r = 0.49). Differences between the distressed IBS group and the non-distressed IBS group Differences between these two groups were all calculated by Mann–Whitney tests. The cortisol levels in the morning did not differ between the distressed IBS group and the non-distressed IBS group (all p [ 0.05). Further, the area under the curve of cortisol in the morning did not differ between the groups (U = 25.00, z = 1.12, p = 0.31). There were significant differences between the distressed IBS group and the non-distressed IBS group regarding cortisol levels during the day (U = 3.50, z = 2.33, p \ 0.05, r = 0.67), with the distressed IBS group showing lower cortisol levels at 8 pm. The mean of the non-distressed IBS group at 8 pm was 4.47 nmol/l (SD = 2.11) and the mean of the distressed IBS group was 1.73 nmol/l (SD = 1.18). Other comparisons did not reach significance (all p [ 0.05). The area under the curve for cortisol during the day did not differ between the group of distressed IBS and the group of non-distressed IBS, either (U = 20.00, z = 0.32, p = 0.82). The analyses regarding chronic stress and stress reactivity did not reveal significant differences between the two groups (both p [ 0.05).
Discussion The first aim of this study was to assess whether differences in HPA axis activity already exist in subthreshold IBS which could indicate a role of HPA axis abnormalities in the development of IBS. The group with IBS differed in morning cortisol levels in comparison to the control group and the group of subthreshold IBS. Subjects with IBS had lower cortisol levels 30 min after awakening than subjects in the control group. Moreover, the total release of cortisol in the morning
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Fig. 1 Differences between groups regarding cortisol levels. Error bars represent standard errors. a Basal cortisol levels for the three groups in the morning. b Differences between the three groups in the area under the curve of the cortisol awakening response (CAR). c Basal cortisol levels for the three groups during the day. d The area under the curve of the cortisol level during the day for the three groups
(represented by the area under the curve) was reduced in subjects with IBS in comparison with the control group and the subthreshold IBS group. Taken together, regular IBS symptoms, as reported by the IBS group, seem to go along with a lower cortisol awakening response. Subjects with subthreshold IBS did not differ from control subjects regarding morning cortisol levels. In this study, the group with subthreshold IBS fulfilled a similar number of FGID diagnoses compared to the control group. For this reason it was unlikely to detect potential differences between these two groups. No differences were found between groups regarding the diurnal rhythm of cortisol. Further, there were no significant group differences regarding chronic stress level, but the level of stress reactivity differed with the group of IBS reporting significantly higher levels of stress reactivity compared to the control group.
To date, only two studies have reported decreased cortisol awakening response levels in patients with IBS (Bohmelt et al., 2005; Kennedy et al., 2014a). No previous study has yet attempted to subdivide IBS patients into those with a fullblown diagnosis and those with subthreshold IBS, which might be a reason why other studies found inconsistent results in the cortisol awakening response between subjects with IBS and healthy controls. In general, relative hypocortisolism in subjects with an IBS diagnosis, as found in our study, may indicate a limited functionality of the HPA axis. Earlier studies found that basal (Ehlert et al., 2005) and experimentally induced hypocortisolism (Kuehl et al., 2010) is associated with higher pain ratings, suggesting a potential causal role of a dysregulated HPA axis in pain chronicity. Hypocortisolism leads to a release of pro-inflammatory cytokines, which in turn increases pain sensitivity (Heim et al., 2000). Moreover, hypocorti-
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J Behav Med Table 2 Descriptive statistics and results of the Kruskal–Wallis test for the different IBS groups regarding stress measures Descriptive statistics
Groups
Kruskal–Wallis test
Control group (N = 12) mean (SD)
Subthreshold IBS (N = 11) mean (SD)
IBS (N = 12) mean (SD)
H
Significance (p)
Screening Scale for Chronic Stress
21.67 (11.01)
20.64 (7.72)
23.58 (10.14)
1.41
0.49
Stress Reactivity Scale
59.83 (2.37)
59.64 (2.47)
68.67 (2.37)
7.57
0.02
IBS irritable bowel syndrome
solism leads to the disinhibition of prostaglandin synthesis, which may account for the development of increased pain sensitivity (Heim et al., 1998; Heim et al., 2000). To confirm these interpretations, the findings need to be replicated in studies with a larger sample size, which should also compare the Rome II criteria to the current Rome III criteria. Regarding the diurnal profile, no differences were found between the groups. This finding is in line with a previous study, which also did not detect differences between female IBS patients compared to healthy controls (Suarez-Hitz et al., 2012), although we did find attenuated diurnal cortisol levels in IBS patients in an earlier study (Bohmelt et al., 2005). In contrast to the Suarez-Hitz study, in which a sample of female IBS patients was examined during a specific phase of the menstrual cycle, Bohmelt and colleagues examined a sample of both sexes and did not consider the cycle phase of the women. Thus, the different findings might be due to differences in methodology. Furthermore, no significant differences were found in the current study regarding chronic stress, with all three groups showing normal stress levels. This finding contradicts the finding of our previous study, in which subjects with FGID presented higher levels of chronic stress compared to healthy controls (Markert et al., 2014). In the current study, we examined a relatively young and welleducated sample, which might have had good stress management skills. Future studies should investigate management strategies for chronic stress. Significant differences were found regarding stress reactivity, with the IBS group reporting higher levels compared to the control group. The subthreshold group did not differ from the control group regarding stress reactivity. Stress reactivity has often been studied using experimental designs, which have consistently found increased stress reactivity in subjects with IBS (Bach et al., 2006; Dickhaus et al., 2003; Posserud et al., 2004; Suarez-Hitz et al., 2012). The results of this study assume that higher levels of stress reactivity in subjects with IBS also occur in a more general context. The finding is in line with our previous study in which we found higher
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stress reactivity levels in participants with FGID compared to healthy controls (Markert et al., 2014). The second aim of the study was to examine differences in HPA axis activity between persons indicating that they were distressed by their IBS symptoms and persons who were not distressed by their symptoms. The current study revealed no significant differences between the distressed IBS group and the non-distressed IBS group regarding their endocrine function in the morning or psychological measures such as chronic stress and stress reactivity. To the best of our knowledge, this is the first study to examine psychological and biological differences between subjects with fullblown IBS and subjects with subthreshold IBS. So far, there has not been any research on biological differences between subjects who feel distressed by their symptoms and subjects who do not feel distressed. Despite the advantages of an unambiguous operationalization of a distress criterion and the use of a homogenous sample regarding age, sex, and education, some limitations need to be taken into account regarding the study results: to receive an IBS diagnosis according to the Rome criteria, it needs to be established that the symptoms cannot be explained by structural or biochemical abnormalities (Thompson et al., 1999). In this study, the diagnosis was based on self-report and the subjects did not undergo a medical examination. When analyzing the collected data, we found that two thirds of the subjects in our control group fulfilled the criteria for other FGID diagnoses than irritable bowel syndrome. Therefore our control group cannot be interpreted as a ‘‘healthy control group’’. Future studies in this area should also examine a healthy control group which is free of FGID diagnoses. This might be an ambitious aim, since one study found that 97.8 % of the subjects in a general population sample reported the symptom pattern of a functional gastrointestinal disorder from time to time (Leibbrand et al., 2002). Moreover, we collected data from a student sample, which is not representative of the general (Swiss) population regarding different variables such as education, socioeconomic status, or lifestyle factors. Furthermore, as a
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single diurnal profile of cortisol levels does not seem to be fully conclusive, future studies should encompass several days of assessment to diminish the influence of situational factors (Hellhammer et al., 2007). An ecological momentary assessment study of the everyday life of patients with irritable bowel syndrome would offer the opportunity to obtain valid results regarding the relationship between stress and IBS with respect to distress elicited by the symptoms.
Conclusion The results of our study indicate a potential basal endocrine dysregulation in women with IBS. The comparison between subjects who were distressed by their symptoms and non-distressed subjects did not reveal differences in our (small) sample. The finding of differences in basal endocrine functioning is important because it hints at mechanisms that may underlie pain perception in subjects with IBS. Future studies should build up on our pilot study and examine bigger samples of IBS patients, and include healthy controls devoid of any gastrointestinal symptoms. Compliance with ethical standards Conflict of interest Charlotte Markert, Kerstin Suarez-Hitz, Ulrike Ehlert and Urs M. Nater declare that they have no conflict of interest. Human and animal rights and Informed consent All procedures performed in studies involving human participants were in accordance with the ethical standards of the ethics committee of the Canton of Zurich and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Written informed consent was obtained from all individual participants included in the study.
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J Behav Med Kuehl, L. K., Michaux, G. P., Richter, S., Schachinger, H., & Anton, F. (2010). Increased basal mechanical pain sensitivity but decreased perceptual wind-up in a human model of relative hypocortisolism. Pain, 149, 539–546. Lederbogen, F., Kuhner, C., Kirschbaum, C., Meisinger, C., Lammich, J., Holle, R., … Ladwig, K. H. (2010). Salivary cortisol in a middle-aged community sample: Results from 990 men and women of the KORA-F3 Augsburg study. European Journal of Endocrinology, 163, 443–451. Leibbrand, R., Cuntz, U., & Hiller, W. (2002). Assessment of functional gastrointestinal disorders using the Gastro-Questionnaire. International Journal of Behavioral Medicine, 9, 155–172. Levy, R. L., Cain, K. C., Jarrett, M., & Heitkemper, M. M. (1997). The relationship between daily life stress and gastrointestinal symptoms in women with irritable bowel syndrome. Journal of Behavioral Medicine, 20, 177–193. Locke, G. R, 3rd, Weaver, A. L., Melton, L. J, 3rd, & Talley, N. J. (2004). Psychosocial factors are linked to functional gastrointestinal disorders: A population based nested case-control study. American Journal of Gastroenterology, 99, 350–357. Longstreth, G. F., Thompson, W. G., Chey, W. D., Houghton, L. A., Mearin, F., & Spiller, R. C. (2006). Functional bowel disorders. Gastroenterology, 130, 1480–1491. Markert, C., Suarez-Hitz, K., Ehlert, U., & Nater, U. M. (2014). Distress criterion influences prevalence rates of functional gastrointestinal disorders. BMC Gastroenterology, 14, 215. Mayer, E. A. (2000). The neurobiology of stress and gastrointestinal disease. Gut, 47, 861–869. Mearin, F., Badia, X., Balboa, A., Baro, E., Caldwell, E., Cucala, M., … Talley, N. J. (2001). Irritable bowel syndrome prevalence varies enormously depending on the employed diagnostic criteria: comparison of Rome II versus previous criteria in a general population. Scandinavian Journal of Gastroenterology, 36, 1155–1161. Nicholl, B. I., Halder, S. L., Macfarlane, G. J., Thompson, D. G., O’Brien, S., Musleh, M., & McBeth, J. (2008). Psychosocial risk markers for new onset irritable bowel syndrome-results of a large prospective population-based study. Pain, 137, 147–155. O’Donnell, K., Badrick, E., Kumari, M., & Steptoe, A. (2008). Psychological coping styles and cortisol over the day in healthy older adults. Psychoneuroendocrinology, 33, 601–611. Olafsdottir, L. B., Gudjonsson, H., Jonsdottir, H. H., Bjornsson, E., & Thjodleifsson, B. (2012). Natural history of functional gastroin-
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Endocrine dysregulation in women with irritable bowel syndrome according to Rome II criteria Charlotte Markert1 • Kerstin Suarez-Hitz2 • Ulrike Ehlert2 • Urs M. Nater1
Received: March 30, 2015 / Accepted: January 28, 2016 Springer Science+Business Media New York 2016
Abstract The etiology of the irritable bowel syndrome (IBS) is unexplained: biological, psychological and social factors must be considered. This study examined if differences in HPA-axis activity already exist in those who do not yet fulfill IBS criteria (i.e. ‘‘subthreshold IBS’’). We also investigated whether there were differences between those who reported clinically relevant (i.e. distressing) IBS symptoms and those who did not. Thirty-six women were subdivided into three groups (IBS group, subthreshold IBS group, control group). Results showed differences in morning cortisol levels (U = 11.58; p \ 0.05), with IBS patients showing a lower cortisol response compared to controls. Subthreshold IBS patients were comparable to controls regarding endocrine function. Diurnal cortisol levels did not differ between groups. Group comparisons between distressed subjects and non-distressed subjects regarding cortisol levels did not reach significance. The finding of endocrine abnormalities (at least in a sub-set of
& Charlotte Markert [email protected] Kerstin Suarez-Hitz [email protected] Ulrike Ehlert [email protected] Urs M. Nater [email protected] 1
Department of Psychology, Clinical Biopsychology, University of Marburg, Gutenbergstr.18, 35032 Marburg, Germany
2
Department of Psychology, Clinical Psychology and Psychotherapy, University of Zurich, Binzmu¨hlestr.14, 8050 Zurich, Switzerland
patients) is important since these might be associated with deficient pain processing in IBS. Keywords Cortisol awakening response Distress Irritable bowel syndrome Rome II criteria Rome III criteria
Introduction The irritable bowel syndrome (IBS) is one of the most common functional gastrointestinal disorders (FGID) in the general population. The Rome II criteria consist of the following: at least 12 weeks, which need not be consecutive, in the preceding 12 months of abdominal discomfort or pain that has two out of three features: it can be relieved with defecation; and/or its onset is associated with a change in frequency of stool; and/or its onset is associated with change in form (appearance) of stool (Thompson et al., 1999). Compared to the current Rome III criteria (Longstreth et al., 2006) the Rome II criteria are more restrictive (Drossman & Dumitrascu, 2006), more frequently used in clinical research (Dang et al., 2012) and there is more evidence for their validity (Whitehead & Drossman, 2010). The etiology of IBS cannot yet be explained on the basis of current knowledge, which suggests a multi-causal pathophysiology including biological, psychological, and social factors. Stress has been suggested to play a central role in the development (Bradford et al., 2012; Drossman et al., 1990; Locke et al., 2004), maintenance (Levy et al., 1997; Suarez et al., 2010) and exacerbation (Blanchard et al., 2008; Whitehead et al., 1992) of IBS symptoms. Other studies found an increased responsiveness to stress in persons with IBS, which is in turn associated with alterations in the functioning of the HPA axis (Dinan et al.,
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2006; FitzGerald et al., 2009; Kennedy et al., 2014b). The measurement of cortisol levels between awakening and about 30 min afterwards (the so-called cortisol awakening response, CAR) serves as a measure of functional integrity of the HPA axis (Clow et al., 2004). Previous studies examining the CAR in persons with IBS showed inconsistent results: one study found lower CAR values in persons with IBS compared to controls (Bohmelt et al., 2005), while others found higher CAR values in subjects with IBS (Patacchioli et al., 2001; Suarez-Hitz et al., 2012). As cortisol follows a distinct diurnal rhythm, research often also focuses on its diurnal course. The results regarding diurnal cortisol levels in persons with IBS remain ambiguous showing either no differences in cortisol levels between persons with IBS compared to healthy controls (Suarez-Hitz et al., 2012) or attenuated salivary cortisol levels (Bohmelt et al., 2005; Patacchioli et al., 2001). The studies differ in terms of sample selection, measurement methods, and use of diagnostic criteria, all of which might explain the discrepancies in the results. In addition to the dysregulations in basal HPA axis activity, persons with IBS show heightened (Chang et al., 2009), attenuated (FitzGerald et al., 2009; Suarez-Hitz et al., 2012) or sustained (Kennedy et al., 2014b) HPA axis activity to acute stressors compared to healthy controls. In the longterm these alterations may lead to underactivity of the HPA axis as a result of negative feedback inhibition (Mayer, 2000). A flattened diurnal cortisol profile is related to pain symptoms both in persons with IBS (Ehlert et al., 2005) and in healthy controls (Kuehl et al., 2010). One might query if a dysregulated HPA axis is a risk factor for the development of IBS. If alterations in HPA axis activity occur in those individuals who do not yet fulfill full criteria of IBS, but not in healthy controls, then this might be an indication that endocrine alterations may contribute to the development of IBS. In longitudinal studies, persons presenting with gastrointestinal symptoms, e.g. abdominal pain (Halder et al., 2007; Nicholl et al., 2008; Olafsdottir et al., 2012) or minor symptoms of IBS and other FGID (Agreus et al., 2001) at the first point of measurement were diagnosed with IBS at a later time point. In the current study, we included persons who did not meet the Rome II criterion of at least 12 weeks with gastrointestinal symptoms in the preceding 12 month. We termed this group ‘‘subthreshold IBS’’. Although many researchers have proposed a biopsychosocial model of IBS, the diagnostic criteria do not yet take into account psychological aspects, such as a criterion of subjective distress elicited by the symptoms. In the field of psychiatry clinical significance of a condition is only assumed when a person indicates feeling distressed by his or her symptoms. Consequently, diagnostic criteria for most psychiatric conditions encompass a so-called ‘‘distress criterion’’. In the criteria for FGID, no such infor-
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mation is included. This is interesting from both a conceptual and a clinical perspective, since a person may fulfill the diagnosis for an FGID without being at all bothered by the symptoms. The lack of a distress criterion in the diagnosis of IBS may suggest that persons who are not bothered by their symptoms are also included in epidemiological studies, which has the potential to provide skewed prevalence rates of IBS and other FGID. Given the high subjective stress levels and the above-mentioned role of biological stress systems in the manifestation of IBS, one might query whether persons with IBS who fulfill the distress criterion might differ from those without distress in biological stress measures as well. The purpose of the current study was twofold: 1.
2.
To examine whether differences in HPA axis activity already exist in subthreshold IBS. This could indicate that HPA axis abnormalities would be involved in the development of IBS. To investigate differences in HPA axis activity between persons who are distressed by their IBS symptoms and persons who are not distressed by their symptoms.
Methods Subjects Subjects were selected from a large sample of 1901 Swiss students who had participated in a previous online study (Markert et al., 2014) examining the association between psychological stress and gastrointestinal symptoms. Participants who had given their informed consent to take part in future studies were contacted via e-mail and informed about the study. All participants gave their written consent to take part in this add-on study. By this procedure, 52 subjects have been recruited for the study. 42 of the subjects were female, ten subjects were male. As there is evidence for sex differences regarding basal cortisol levels (Lederbogen et al., 2010; O’Donnell et al., 2008) and due to the increased prevalence of IBS in women (Hungin et al., 2003; Mearin et al., 2001), only women were included. 36 women were selected and subdivided into three equally sized groups, based on their data from the prior study. Twelve women fulfilled the Rome II criteria for IBS (IBS group), twelve women had a subthreshold IBS (subthreshold IBS group) and twelve women without IBS served as controls (control group). The three groups were matched for age. The subthreshold IBS group fulfilled the same symptom pattern as the IBS group, i.e. they had to report abdominal pain or discomfort with the accompanying features that are
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described in the Rome II criteria (Thompson et al., 1999) as well as symptoms that cumulatively support the diagnosis of IBS (e.g. abnormal stool passage or abdominal distension). In contrast to the group with IBS, they did not fulfill the 12 week time criterion in the Rome II criteria. The control group did not fulfill the Rome II symptom pattern. For a second analysis, we divided the group with IBS into a group which fulfilled the Rome II criteria without feeling distressed by their symptoms (non-distressed IBS group) and a group which additionally reported a high degree of feeling distressed by their symptoms (distressed IBS group). As compensation for their effort, control subjects received 80 Swiss Francs after completion of the study, whereas free stress management training was offered to the participants of the subjects with IBS or subthreshold IBS. The study was approved by a local ethics committee and was conducted in accordance with the Declaration of Helsinki. Sampling methods and biochemical analyses Saliva samples for the analysis of free morning cortisol levels were collected using Salivettes (Sarstedt, Sevelen, Switzerland) at five time points: at awakening and after 15, 30, 45, and 60 min. The diurnal course of the hormone was assessed using the same method at 8:00 A.M., 11:00 A.M., 3:00 P.M., and 8:00 P.M. The subjects collected the saliva samples in their natural home and work environment. To improve the participants’ compliance, Salivettes were stored in plastic vials equipped with Medication Event Monitoring System caps (MEMS, Aardex, Switzerland). Samples were stored at -20 C until the biochemical analyses were performed. Concentrations of salivary free cortisol were measured using a chemiluminescence immunoassay (CLIA, IBL, Hamburg, Germany). Intra- and interassay coefficients of variation were below 10 %. Assessment of psychometric data Socio-demographic data (age, education) and health-related data (BMI, smoking, consultation rates) were collected via questionnaire. IBS according to Rome II criteria (Thompson et al., 1999) was assessed using the Gastro-Questionnaire (Leibbrand et al., 2002). The ‘‘subthreshold IBS group’’ reported symptoms of IBS but did not fulfill the time criterion of at least 12 weeks within the last 12 months. For the additional analyses persons with IBS were assigned to the ‘‘distressed IBS group’’ if they fulfilled the Rome II criteria and rated their distress for at least one IBS-related symptom with values higher than/equal to 2 (intermediate distress) on a scale of 0–4. Persons with a diagnosis of IBS who were not distressed by their symptoms were assigned to the ‘‘non-distressed IBS group’’.
The Trier Inventory for the Assessment of Chronic Stress (TICS) (Schulz et al., 2004) was administered to analyze the level of perceived stress within the last 12 months. The TICS includes a ‘‘Screening Scale for Chronic Stress’’ consisting of 12 items. The Stress Reactivity Scale (SRS) (Schulz et al., 2005) was included to gather information about the individual reactivity to potentially stressful situations. It consists of 36 items with a three-level response format. A subject’s general stress reactivity score can be defined by the cumulated scores of all items. Statistical methods To compare the cortisol levels between groups, area under the curve (AUC) was calculated in accordance with Pruessner et al. (Pruessner et al., 2003). Data were tested for normal distribution and homogeneity of variance via Kolmogorov–Smirnov test and Levene’s test. Due to violation of conditions, data were analyzed by non-parametric statistics. Differences between IBS, subthreshold IBS and control subjects were verified with the Kruskal–Wallis test and the Mann–Whitney test. The Mann–Whitney test was also used to calculate differences between the distressed IBS group and the non-distressed IBS group. For all statistical analyses, SPSS Statistics 22 was used.
Results Sample characteristics One subject from the group with subthreshold IBS was excluded from analyses due to missing values in health related data. Participants also fulfilled criteria for other FGID according to the Gastro Questionnaire: eight subjects (66.67 %) in the control group, seven subjects (63.64 %) in the subthreshold group and all subjects (100 %) in the IBS group fulfilled the criteria for at least 1 FGID diagnosis. In the control group and the subthreshold IBS group the most frequent diagnosis was functional bloating. By contrast, in the group with IBS the most frequent diagnosis was functional dyspepsia. There were no significant differences between the three groups with regard to age, BMI, number of cigarettes smoked per day, or consultation rates (see Table 1 for more detailed information). Differences between the three groups regarding CAR Figure 1a shows the results for cortisol levels in the morning. Results showed significant differences in cortisol level 30 min after awakening (H(2) = 8.73, p \ 0.05).
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J Behav Med Table 1 Descriptive statistics and analysis of variance for the different IBS groups Descriptive statistics
Groups
Kruskal–Wallis test
Control group (N = 12) mean (SD)
Subthreshold IBS (N = 11) mean (SD)
IBS (N = 12) mean (SD)
H
Significance (p)
Age
23.56 (2.78)
24.10 (3.13)
26.23 (3.85)
3.66
0.16
Body Mass Index
20.88 (1.51)
21.97 (2.47)
21.13 (1.72)
1.26
0.53
Number of cigarettes smoked per day
3.75 (7.72)
0.18 (0.60)
4.00 (11.57)
1.18
0.55
Consultation rates within the last year
4.25 (8.57)
2.82 (2.64)
4.17 (4.22)
2.10
0.35
IBS irritable bowel syndrome
Post-hoc comparisons demonstrated significant differences between the IBS group and the control subjects (U = 11.58, z = 2.77, p \ 0.05, r = 0.57), with the IBS group showing lower cortisol levels 30 min after awakening. The difference between the IBS group and the subthreshold IBS group was of marginal significance (U = 9.64, z = 2.25, p = 0.07, r = 0.47), with the IBS group tending to show lower cortisol levels than the subthreshold IBS group. The other points of measurement in the morning did not differ between groups. Intergroup comparisons regarding the morning area under the curve of cortisol showed significant differences (H(2) = 8.32, p \ 0.05). Posthoc comparisons showed a reduced release of cortisol in the group of IBS compared to the control group (U = 10.42, z = 2.49, p \ 0.05, r = 0.51) and the subthreshold IBS group (U = 10.64, z = 2.49, p \ 0.05, r = 0.52). For more detailed information see Fig. 1b. Differences between groups regarding diurnal cortisol profile Figure 1c shows the results for cortisol levels during the day. Results did not show significant differences in cortisol levels during the day (all p [ 0.05). Intergroup comparisons regarding the area under the curve of cortisol levels during the day did not show significant differences, either (H(2) = 0.96, p = 0.62; see also Fig. 1d). Differences between the three groups regarding psychological parameters There were no significant differences between the three groups regarding chronic stress level, but the level of stress reactivity differed between groups (see Table 2 for more detailed information). Post-hoc comparisons revealed that the IBS group showed significantly higher levels of stress reactivity compared to the control group (U = 9.67,
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z = 2.38, p \ 0.05, r = 0.49) and the subthreshold IBS group (U = 10.08, z = 2.37, p \ 0.05, r = 0.49). Differences between the distressed IBS group and the non-distressed IBS group Differences between these two groups were all calculated by Mann–Whitney tests. The cortisol levels in the morning did not differ between the distressed IBS group and the non-distressed IBS group (all p [ 0.05). Further, the area under the curve of cortisol in the morning did not differ between the groups (U = 25.00, z = 1.12, p = 0.31). There were significant differences between the distressed IBS group and the non-distressed IBS group regarding cortisol levels during the day (U = 3.50, z = 2.33, p \ 0.05, r = 0.67), with the distressed IBS group showing lower cortisol levels at 8 pm. The mean of the non-distressed IBS group at 8 pm was 4.47 nmol/l (SD = 2.11) and the mean of the distressed IBS group was 1.73 nmol/l (SD = 1.18). Other comparisons did not reach significance (all p [ 0.05). The area under the curve for cortisol during the day did not differ between the group of distressed IBS and the group of non-distressed IBS, either (U = 20.00, z = 0.32, p = 0.82). The analyses regarding chronic stress and stress reactivity did not reveal significant differences between the two groups (both p [ 0.05).
Discussion The first aim of this study was to assess whether differences in HPA axis activity already exist in subthreshold IBS which could indicate a role of HPA axis abnormalities in the development of IBS. The group with IBS differed in morning cortisol levels in comparison to the control group and the group of subthreshold IBS. Subjects with IBS had lower cortisol levels 30 min after awakening than subjects in the control group. Moreover, the total release of cortisol in the morning
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Fig. 1 Differences between groups regarding cortisol levels. Error bars represent standard errors. a Basal cortisol levels for the three groups in the morning. b Differences between the three groups in the area under the curve of the cortisol awakening response (CAR). c Basal cortisol levels for the three groups during the day. d The area under the curve of the cortisol level during the day for the three groups
(represented by the area under the curve) was reduced in subjects with IBS in comparison with the control group and the subthreshold IBS group. Taken together, regular IBS symptoms, as reported by the IBS group, seem to go along with a lower cortisol awakening response. Subjects with subthreshold IBS did not differ from control subjects regarding morning cortisol levels. In this study, the group with subthreshold IBS fulfilled a similar number of FGID diagnoses compared to the control group. For this reason it was unlikely to detect potential differences between these two groups. No differences were found between groups regarding the diurnal rhythm of cortisol. Further, there were no significant group differences regarding chronic stress level, but the level of stress reactivity differed with the group of IBS reporting significantly higher levels of stress reactivity compared to the control group.
To date, only two studies have reported decreased cortisol awakening response levels in patients with IBS (Bohmelt et al., 2005; Kennedy et al., 2014a). No previous study has yet attempted to subdivide IBS patients into those with a fullblown diagnosis and those with subthreshold IBS, which might be a reason why other studies found inconsistent results in the cortisol awakening response between subjects with IBS and healthy controls. In general, relative hypocortisolism in subjects with an IBS diagnosis, as found in our study, may indicate a limited functionality of the HPA axis. Earlier studies found that basal (Ehlert et al., 2005) and experimentally induced hypocortisolism (Kuehl et al., 2010) is associated with higher pain ratings, suggesting a potential causal role of a dysregulated HPA axis in pain chronicity. Hypocortisolism leads to a release of pro-inflammatory cytokines, which in turn increases pain sensitivity (Heim et al., 2000). Moreover, hypocorti-
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J Behav Med Table 2 Descriptive statistics and results of the Kruskal–Wallis test for the different IBS groups regarding stress measures Descriptive statistics
Groups
Kruskal–Wallis test
Control group (N = 12) mean (SD)
Subthreshold IBS (N = 11) mean (SD)
IBS (N = 12) mean (SD)
H
Significance (p)
Screening Scale for Chronic Stress
21.67 (11.01)
20.64 (7.72)
23.58 (10.14)
1.41
0.49
Stress Reactivity Scale
59.83 (2.37)
59.64 (2.47)
68.67 (2.37)
7.57
0.02
IBS irritable bowel syndrome
solism leads to the disinhibition of prostaglandin synthesis, which may account for the development of increased pain sensitivity (Heim et al., 1998; Heim et al., 2000). To confirm these interpretations, the findings need to be replicated in studies with a larger sample size, which should also compare the Rome II criteria to the current Rome III criteria. Regarding the diurnal profile, no differences were found between the groups. This finding is in line with a previous study, which also did not detect differences between female IBS patients compared to healthy controls (Suarez-Hitz et al., 2012), although we did find attenuated diurnal cortisol levels in IBS patients in an earlier study (Bohmelt et al., 2005). In contrast to the Suarez-Hitz study, in which a sample of female IBS patients was examined during a specific phase of the menstrual cycle, Bohmelt and colleagues examined a sample of both sexes and did not consider the cycle phase of the women. Thus, the different findings might be due to differences in methodology. Furthermore, no significant differences were found in the current study regarding chronic stress, with all three groups showing normal stress levels. This finding contradicts the finding of our previous study, in which subjects with FGID presented higher levels of chronic stress compared to healthy controls (Markert et al., 2014). In the current study, we examined a relatively young and welleducated sample, which might have had good stress management skills. Future studies should investigate management strategies for chronic stress. Significant differences were found regarding stress reactivity, with the IBS group reporting higher levels compared to the control group. The subthreshold group did not differ from the control group regarding stress reactivity. Stress reactivity has often been studied using experimental designs, which have consistently found increased stress reactivity in subjects with IBS (Bach et al., 2006; Dickhaus et al., 2003; Posserud et al., 2004; Suarez-Hitz et al., 2012). The results of this study assume that higher levels of stress reactivity in subjects with IBS also occur in a more general context. The finding is in line with our previous study in which we found higher
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stress reactivity levels in participants with FGID compared to healthy controls (Markert et al., 2014). The second aim of the study was to examine differences in HPA axis activity between persons indicating that they were distressed by their IBS symptoms and persons who were not distressed by their symptoms. The current study revealed no significant differences between the distressed IBS group and the non-distressed IBS group regarding their endocrine function in the morning or psychological measures such as chronic stress and stress reactivity. To the best of our knowledge, this is the first study to examine psychological and biological differences between subjects with fullblown IBS and subjects with subthreshold IBS. So far, there has not been any research on biological differences between subjects who feel distressed by their symptoms and subjects who do not feel distressed. Despite the advantages of an unambiguous operationalization of a distress criterion and the use of a homogenous sample regarding age, sex, and education, some limitations need to be taken into account regarding the study results: to receive an IBS diagnosis according to the Rome criteria, it needs to be established that the symptoms cannot be explained by structural or biochemical abnormalities (Thompson et al., 1999). In this study, the diagnosis was based on self-report and the subjects did not undergo a medical examination. When analyzing the collected data, we found that two thirds of the subjects in our control group fulfilled the criteria for other FGID diagnoses than irritable bowel syndrome. Therefore our control group cannot be interpreted as a ‘‘healthy control group’’. Future studies in this area should also examine a healthy control group which is free of FGID diagnoses. This might be an ambitious aim, since one study found that 97.8 % of the subjects in a general population sample reported the symptom pattern of a functional gastrointestinal disorder from time to time (Leibbrand et al., 2002). Moreover, we collected data from a student sample, which is not representative of the general (Swiss) population regarding different variables such as education, socioeconomic status, or lifestyle factors. Furthermore, as a
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single diurnal profile of cortisol levels does not seem to be fully conclusive, future studies should encompass several days of assessment to diminish the influence of situational factors (Hellhammer et al., 2007). An ecological momentary assessment study of the everyday life of patients with irritable bowel syndrome would offer the opportunity to obtain valid results regarding the relationship between stress and IBS with respect to distress elicited by the symptoms.
Conclusion The results of our study indicate a potential basal endocrine dysregulation in women with IBS. The comparison between subjects who were distressed by their symptoms and non-distressed subjects did not reveal differences in our (small) sample. The finding of differences in basal endocrine functioning is important because it hints at mechanisms that may underlie pain perception in subjects with IBS. Future studies should build up on our pilot study and examine bigger samples of IBS patients, and include healthy controls devoid of any gastrointestinal symptoms. Compliance with ethical standards Conflict of interest Charlotte Markert, Kerstin Suarez-Hitz, Ulrike Ehlert and Urs M. Nater declare that they have no conflict of interest. Human and animal rights and Informed consent All procedures performed in studies involving human participants were in accordance with the ethical standards of the ethics committee of the Canton of Zurich and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Written informed consent was obtained from all individual participants included in the study.
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