Dysregulation of cardiovascular and neuroendocrine responses to stress in premenstrual dysphoric disorder
Introduction
Premenstrual dysphoric disorder (PMDD) is estimated to afflict approx. 5% of women in their reproductive years (American Psychiatric Association, 1994). PMDD is characterized by the cyclic recurrence, in the luteal phase of the menstrual cycle, of a combination of emotional and physical symptoms of sufficient severity to interfere with normal function and/or result in the deterioration of interpersonal relationships. Although it was more than 60 years ago when Frank (1931)first documented the systematic recurrence of tension, anxiety and suicidal ideation during the premenstrual phase of the cycle in 15 patients, we are little closer than Frank was to understanding the etiology of this disorder. This is, in part, because it was not until 1987 that research criteria for this disorder were established (American Psychiatric Association, 1987), the most important of which includes daily prospective symptom assessment.
The lack of consistently employed criteria for classifying women with PMDD has contributed to numerous inconsistencies in the literature and also to the controversy surrounding the severity and validity of PMDD, since it is now well documented that only 13–44% (depending on stringency of criteria) of women presenting with PMDD will actually meet strict criteria on the basis of prospective assessment (e.g. Rubinow et al., 1984, Nye et al., 1992, Girdler et al., 1993, Plouffe et al., 1993). Therefore in attempting to understand the neurobiological basis of this disorder, and to investigate its pathophysiological specificity, it is important to restrict the focus to studies that have relied on prospective diagnostic assessment.
Although the behavioral and emotional symptoms of PMDD have clear circatrigintan (menstrual) rhythms, investigations into the gonadal steroid hormones have provided little evidence that they contribute to PMDD in any direct fashion since there appear to be no abnormalities in levels or cyclical patterns of these hormones in PMDD (Rubinow et al., 1988, Reame et al., 1992, Girdler et al., 1993). Thus, investigation into other neuroendocrine candidates has continued. Consistent with the heterogeneous and syndromal nature of this disorder, evidence has emerged for dysregulation in a variety of neuroendocrine measures in PMDD, including the endogenous opioids (e.g. Giannini et al., 1990), serotonin (e.g. Steiner et al., 1995), and thyroid hormones (e.g. Roy-Byrne et al., 1987, Girdler et al., 1995). To date, however, it is unclear what role these neuroendocrine factors play in the etiology of PMDD. Paradoxically, what has been fairly consistent in the literature is that where neuroendocrine differences exist between PMDD and control women, the differences are evident in both cycle phases and not just limited to the symptomatic, luteal phase (see Rubinow and Schmidt, 1992, for review).
What has been relatively understudied in PMDD is the role of stress and stress reactivity. Indeed, a major role for stress in the pathophysiology of psychiatric disorders is well documented (e.g. Kendler et al., 1993), although the empirical evidence has yet to indicate the exact nature of the stress–illness relationship or its underlying neurobiology. Although a number of studies have confirmed that women with PMDD report more stressful life events (Girdler et al., 1993, Fontana and Palfai, 1994, Woods et al., 1994, Fontana and Badawy, 1997) and that stressors have a greater impact on the lives of PMDD women (Schmidt et al., 1990, Girdler et al., 1993, Fontana and Palfai, 1994, Fontana and Badawy, 1997), studies assessing physiological indices of stress in PMDD have been scant. The only studies of which we are aware that have assessed stress hormones in prospectively confirmed PMDD women have relied on basal levels. These studies have found greater catecholamines levels (Odink et al., 1990, Woods et al., 1997), and either no difference in basal cortisol (Rubinow et al., 1988, Bancroft et al., 1991, Redei and Freeman, 1993, Su et al., 1997, Woods et al., 1997) or decreased levels of cortisol (Rabin et al., 1990) and adrenocorticotropic hormone (ACTH) (Redei and Freeman, 1993) in PMDD relative to control subjects. In studies that have employed pharmacological challenge to investigate hypothalamic–pituitary–adrenal (HPA) axis function, results have been mixed. While Parry et al. (1991)reported that 62% of her PMDD patients showed evidence for dexamethasone non-suppression of cortisol, two other studies failed to find evidence for differences in cortisol responses to dexamethasone in either cycle phase in PMDD women relative to control subjects (Haskett et al., 1984Roy-Byrne et al., 1986). Furthermore, Rabin et al. (1990), using ovine corticotropin relasing hormone (CRH) stimulation, found that PMDD women exhibited increased ACTH responses relative to control subjects, consistent with lower endogenous CRH in PMDD, and others have reported blunted, not heightened, HPA axis response to serotonergic agents (Bancroft et al., 1991, Su et al., 1997).
There have been even fewer studies examining stress responses in PMDD women compared with control subjects (Woods et al., 1994, Woods et al., 1997). In our previous study (Girdler et al., 1993) of cardiovascular responses to a variety of stressors in PMDD and control subjects, we found evidence for blunted cardiovascular reactivity to stress in PMDD. Specifically, during all stressors, PMDD women showed significantly blunted heart rate and diastolic blood pressure responses, and tended to exhibit blunted systolic pressure and cardiac output responses relative to control subjects. Consistent with the accumulating evidence for phase-independent neuroendocrine differences in PMDD (Rubinow and Schmidt, 1992), this blunted cardiovascular reactivity was evident in both the follicular and luteal phases. Furthermore, where control subjects showed significant cycle influences on stress-induced stroke volume and total peripheral resistance measures, a finding which has been replicated in other studies of healthy women (Girdler and Light, 1994, Miller and Sita, 1994), the PMDD women showed no evidence that the menstrual cycle influenced their cardiovascular stress responses.
Thus, the purposes of this study were threefold. First, we sought to replicate our previous findings for stress dysregulation in PMDD, including blunted myocardial responses to mental stress and lack of normal circatrigintan effects on hemodynamic stress responses. Second, our aim was to extend this previous work by assessing basal and stress-induced neuroendocrine mediators of the stress response, using plasma norepinephrine (NE), epinephrine (Epi), and cortisol (C). Our third goal was to include measures of life stress, including sexual and physical abuse histories since abuse history for women is associated with a number of medical and psychiatric problems (Walker et al., 1992, Leserman et al., 1996), including menstrual distress (Golding and Taylor, 1996). A related goal was to assess neuroendocrine profiles, specifically the relationship of NE to C, which has been shown to differentiate individuals with severe stress histories from other psychiatric populations (Mason et al., 1986, Kosten et al., 1987, Mason et al., 1988). Evidence for increased life stress plus stress response dysregulation in PMDD might provide an insight into both the etiology of this disorder as well as the increased vulnerability to stress seen in PMDD women.
Section snippets
Subjects
Subjects were recruited through two separate newspaper advertisements seeking either women for a study on the menstrual cycle and stress responses (for control subjects), or seeking women with moderate to severe premenstrual emotional symptoms (for PMDD). Of the 370 women who responded to our ads for PMDD, 84 women who met initial phone screening criteria were brought in for screening and assessment of PMDD (see below), and 20 (24%) met strict DSM-IV criteria for PMDD (see below). However, two
Psychiatric histories
There were no significant differences in numbers of PMDD and control women, respectively, who had been diagnosed with psychiatric histories, including histories of major depression (five vs. two), anxiety disorders (one and one), substance abuse disorders (four vs. two), and eating disorders (one vs. zero). Despite the fact that groups did not significantly differ in MDD histories, PMDD women with vs. without histories of MDD were compared for baseline and stress-induced neuroendocrine levels.
Discussion
The results of this study replicate our previous finding (Girdler et al., 1993) for menstrual phase-independent blunting of myocardial responses (SV and CO) during stress in women with PMDD. Consistent with other reports (Odink et al., 1990, Woods et al., 1997), we also obtained evidence for greater basal noradrenergic output in PMDD women, but have extended these findings by documenting significantly greater NE levels in PMDD during mental stress, irrespective of cycle phase. In addition to
Acknowledgements
This research was supported by National Institutes of Health Grants, R01-MH51246, MHCRC-MH33127, and GCRC-RR00046 and by The Foundation of Hope for Research and Treatment of Mental Illness. The authors would also like to acknowledge Whitehall Laboratories for their generous donation of ClearPlan Easy® ovulation prediction kits. The authors are extremely grateful to Nancy Costello, Ph.D., for her helpful comments on an earlier version of this manuscript, to Dot Faulkner for manuscript
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