Journal of Traumatic Stress February 2015, 28, 1–7
Menstrual Cycle Effects on Psychological Symptoms in Women With PTSD Yael I. Nillni,1,2 Suzanne L. Pineles,1,2 Samantha C. Patton,1 Matthew H. Rouse,2,3 Alice T. Sawyer,2,3 and Ann M. Rasmusson1,2 1
National Center for PTSD, Women’s Health Sciences Division, VA Boston Healthcare System, Boston, Massachusetts, USA 2 Department of Psychiatry, Boston University School of Medicine, Boston, Massachusetts, USA 3 VA Boston Healthcare System, Boston, Massachusetts, USA
The menstrual cycle has been implicated as a sex-specific biological process influencing psychological symptoms across a variety of disorders. Limited research exists regarding the role of the menstrual cycle in psychological symptoms among women with posttraumatic stress disorder (PTSD). The current study examined the severity of a broad range of psychological symptoms in both the early follicular (Days 2–6) and midluteal (6–10 days postlutenizing hormone surge) phases of the menstrual cycle in a sample of trauma-exposed women with and without PTSD (N = 49). In the sample overall, total psychological symptoms (d = 0.63), as well as depression (d = 0.81) and phobic anxiety (d = 0.81) symptoms, specifically, were increased in the early follicular compared to midluteal phase. The impact of menstrual cycle phase on phobic anxiety was modified by a significant PTSD × Menstrual Phase interaction (d = 0.63). Women with PTSD reported more severe phobic anxiety during the early follicular versus midluteal phase, whereas phobic anxiety did not differ across the menstrual cycle in women without PTSD. Thus, the menstrual cycle appears to impact fear-related symptoms in women with PTSD. The clinical implications of the findings and future research directions are discussed.
Compared to men, women are twice as likely to be diagnosed with posttraumatic stress disorder (PTSD) and experience a more chronic course of the disorder (Breslau et al., 1998), suggesting a sex-specific vulnerability for risk and/or maintenance of PTSD. One potential sex-specific vulnerability factor is the cyclical variability of estradiol and progesterone levels across the menstrual cycle. Hormone patterns associated with certain phases of the menstrual cycle have been associated with an increase in the occurrence or symptoms of a variety of psychological disorders and conditions (Hendrick, Altshuler, & Burt, 1996), including panic disorder (e.g., Kaspi, Otto, Pollack, Eppinger, & Rosenbaum, 1994), bipolar disorder (e.g., Rasgon, Bauer, Glenn, Elman, & Whybrow, 2003), major depressive disorder (e.g., Kornstein et al., 2005), eating disorders (e.g., Lester, Keel, & Lipson, 2003), and alcohol (e.g., Allen, 1996) or substance use (e.g., Evans, Haney, & Foltin, 2002) disorders.
Typically, although not universally, there is an exacerbation of symptoms of these disorders during the late luteal phase (Days 5 to 1 relative to the start of menses), when progesterone and estradiol are declining, and during the early follicular phase (Days 1 to 5 after the start of menses), when levels of progesterone and estradiol are both at their lowest levels (Hendrick et al., 1996). For example, women with panic disorder exhibit an increase in the frequency or intensity of panic attacks during the late luteal phase as compared to other menstrual cycle phases (Kaspi et al., 1994). The possible contribution of estradiol and progesterone to menstrual cycle phase-related differences in affect may be related to these hormones’ influence on a variety of systems, including hypothalamus–pituitary–adrenal (HPA) axis response to stressors (Kirschbaum, Kudielka, Gaab, Schommer, & Hellhammer, 1999), and function of the serotonergic (Rubinow, Schmidt, & Roca, 1998), gamma-aminobutyric acid (GABA) ergic, and noradrenergic (Rasmusson & Friedman, 2002) systems. There may also be cultural beliefs or stereotypes about symptoms during specific phases of the menstrual cycle that contribute to symptom fluctuations (Klebanov & Jemmott, 1992). The literature examining the role of menstrual cycle phase in expression of psychological symptoms among individuals with PTSD is limited. There are a few studies with relevance to PTSD, but not performed in PTSD patients specifically, that implicate the menstrual cycle and related hormones in
Support for this work was provided by a VA Career Development Award (Principal Investigator: S. L. Pineles) from the Clinical Sciences R&D Service, Department of Veterans Affairs Correspondence concerning this article should be addressed to Yael Nillni, National Center for PTSD, Women’s Health Sciences Division, Veteran’s Affairs Boston Healthcare System, 150 South Huntington Ave. (116B-3), Boston, MA 02130. E-mail: [email protected] Published 2015. This article is a US Government work and is in the public domain in the USA. View this article online at wileyonlinelibrary.com DOI: 10.1002/jts.21984
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fear-conditioning models (Milad et al., 2010) and reactivity to stressors (Nillni, Rohan, & Zvolensky, 2012). To our knowledge, Bryant and colleagues (2011) are the only investigators to date who have examined PTSD symptom expression in different phases of the menstrual cycle among trauma-exposed women. In this study, women assessed 1 to 2 weeks after trauma exposure reported more trauma-related flashbacks on the Clinician Administered PTSD Scale (CAPS; Blake et al., 1995) if they were in the midluteal phase either at the time of trauma or the time of assessment. This study, thus, may contribute to our understanding of how the menstrual cycle influences expression of at least one salient PTSD reexperiencing symptom in the acute aftermath of trauma before PTSD is formally diagnosed. Most other studies of menstrual phase effects on other psychological disorders document menstrual cycle related increases in a range of psychological symptoms during the late luteal and early follicular phases (Hendrick et al., 1996). PTSD is a heterogeneous disorder, consisting of both traumaspecific symptoms (e.g., avoidance of trauma reminders or physiological or emotional arousal when confronted with a specific trauma reminder) as well as symptoms of general distress and dysphoria (e.g., irritability, sleep disturbance, loss of interest, negative mood). Given the extant literature demonstrating exacerbation of general anxiety and depressive symptoms across the menstrual cycle, we might expect symptoms in these more general domains to fluctuate across the menstrual cycle among women with PTSD as well. Therefore, the aim of the present study was to examine the interactive effects of menstrual cycle phase (early follicular vs. midluteal) and current PTSD diagnosis on self-reported general psychological symptoms measured by the Symptom Checklist90-Revised (SCL-90-R; Derogatis, Lipman, & Covi, 1976). Based on the larger literature (Hendrick et al., 1996) examining expression of symptoms across the menstrual cycle, we were particularly interested in examining a time when estradiol and progesterone levels were declining or low to a time when estradiol and progesterone levels were rising or high. We therefore examined women in the early follicular phase (Days 2–6 after onset of menses) and midluteal phase (6– 10 days after the lutenizing hormone [LH] surge). Additionally, we aimed to improve upon the methodology of many previous menstrual cycle-focused studies by more precisely assessing and confirming menstrual phase, assessing the same women across menstrual cycle phases, and excluding women on hormone contraception. In addition, all participants in the study were free from psychotropic medications and use of alcohol or drugs of abuse for at least a month (or longer for medications with long half-lives) prior to testing as these substances affect hormone levels. In this study, we hypothesized that individuals with PTSD would report more symptoms of fear, depression, anxiety, interpersonal sensitivity, and hostility during the early follicular phase than the midluteal phase, whereas individuals without PTSD would not exhibit menstrual cycle phase differences. We did not expect the trauma control group to exhibit menstrual
cycle phase fluctuations in mood because they were screened to be medically healthy and to have no Axis I psychopathology. In addition, due to the rigorous study eligibility criteria for the PTSD participants, who had to be medically healthy and free of psychotic disorders, we did not expect to see menstrual phase effects on symptoms of somatization, obsessive compulsive disorder, paranoia, or psychosis in either study group.
Method Participants The sample included 49 women (Mage = 32.62 years, SD = 9.58) who met criteria for lifetime trauma exposure according to Criterion A of the Diagnostic and Statistical Manual of Mental Disorders (4th ed., text rev.; DSM-IV-TR; American Psychiatric Association, 2000) on the CAPS. These women were recruited from the local Veterans Affairs hospitals and the surrounding community using flyers and online advertisements. Measures included in the current study were administered as part of a larger investigation examining the effects of menstrual cycle phase on the psychophysiology and neurobiology of PTSD (Pineles et al., 2014). Plasma was available for assay of progesterone and estradiol for 75% of the 100 study visits of the 50 women who initially completed this study. One participant’s cycle phase was not confirmed by hormone assay; data from this participant were removed from analysis, resulting in a total sample size of 49. Participants were diagnosed with current PTSD based on the CAPS. For the current study, we formed two groups: a PTSD group and a trauma control group. Members of the PTSD group reported at least one reexperiencing symptom, three avoidance symptoms, and two hyperarousal symptoms, and had a total severity score (frequency plus intensity) of 40 or greater on the CAPS (MCAPS = 67.05, SD = 19.10). Because we were interested in symptom fluctuations over time, we added the additional severity criteria to ensure a sufficient level of symptoms in the PTSD group. Members of the trauma control group experienced a Criterion A traumatic event, but did not meet criteria for lifetime or current PTSD based on the criteria stated above (MCAPS_CURRENT = 11.00, SD = 10.36). Furthermore, participants in the trauma control group were excluded if they met DSM-IV-TR criteria for a current Axis I psychological disorder (with the exception of a specific or public speaking phobia) or had a lifetime history of recurrent major depression based on the Structured Clinical Interview for DSM-IV-TR Axis I Disorders (SCID-I; First, Spitzer, Gibbon, & Williams, 2007). Other exclusion criteria for all participants included these conditions: (a) infectious illness; (b) current or past organic brain disorder; (c) major neurological problems; (d) endocrine disorders; (e) schizophrenia; (f) psychotic disorder; (g) Bipolar I disorder; (h) active substance or alcohol abuse or dependence within 6 months of the study; (i) irregular menstrual cycle; (j) current participation in active trauma-focused psychotherapy; (k) use of psychotropic medications, alcohol, or illicit
Journal of Traumatic Stress DOI 10.1002/jts. Published on behalf of the International Society for Traumatic Stress Studies.
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Menstrual Cycle and PTSD
Table 1 Demographic Characteristics for Total Sample and by Group Total (n = 49) Variable
n
PTSD (n = 22) %
n
Trauma control (n = 27) %
n
%
χ2
Ethnicity 2.56 Hispanica 2 4 2 9 0 0 Non-Hispanic 47 96 20 91 27 100 Race 8.46 Caucasian 17 35 5 23 12 44 African American 20 41 9 41 12 41 Asian American 5 10 4 18 1 4 American Indian 1 2 1 5 0 0 Other 4 8 1 5 3 11 Years of education 11.33 .05).
Data Analysis Given that we did not expect to see menstrual phase effects on symptoms of somatization, obsessive compulsive disorder, paranoia, or psychosis in either study group because of eligibility criteria, we did not include these subscales in the analyses in an effort to reduce the familywise error rate. We were interested in within-person menstrual cycle-phase differences; therefore, participants were only included if they completed assessments at both cycle phases. Eight participants only completed one menstrual cycle-phase visit and were not included in the analyses. First, demographic characteristics were compared between the PTSD and trauma control groups using independent samples
Discussion The goal of the current study was to examine the influence of menstrual cycle phase on the expression of a range of psychological symptoms in a sample of trauma-exposed women with and without PTSD. Studies of other psychological disorders implicating the menstrual cycle in exacerbation of symptoms of the target disorder studied, typically demonstrate symptom worsening in the late luteal and early follicular cycle phases (Hendrick et al., 1996). Initial research among trauma-exposed women also supports a role for the menstrual cycle in the expression of flashbacks during the early weeks following
Journal of Traumatic Stress DOI 10.1002/jts. Published on behalf of the International Society for Traumatic Stress Studies.
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Menstrual Cycle and PTSD
Table 2 Main Effects and Interactions for PTSD Group × Menstrual Cycle Phase for Selected SCL 90-R Subscales Early follicular PTSD N = 22 Variable Interpersonal sensitivity Depression Anxiety Hostility Phobic anxiety Global Severity Index
Effect sizea
Midluteal
No PTSD n = 27
PTSD n = 22
No PTSD n = 27
M
SD
M
SD
M
SD
M
SD
Group
1.20 1.62 0.98 1.02 0.85 1.16
0.90 0.89 0.66 0.99 0.74 0.67
0.41 0.50 0.19 0.27 0.10 0.31
0.51 0.54 0.23 0.43 0.20 0.30
1.05 1.37 0.91 0.79 0.70 1.03
0.79 0.73 0.75 0.78 0.77 0.64
0.38 0.42 0.15 0.28 0.08 0.28
0.50 0.52 0.21 0.36 0.20 0.30
1.15*** 1.67*** 1.63*** 1.06*** 1.34*** 1.74***
Phase 0.41 0.81* 0.46 0.41 0.81** 0.63*
Group × Phase 0.23 0.41 0.00 0.41 0.63* 0.41
Note. SCL-90-R = Self-Report Checklist 90-Revised; PTSD = posttraumatic stress disorder. a Cohen’s d. *p < .05. **p < .01. ***p < .001.
trauma exposure, but the influence of particular menstrual cycle phases on a broad range of self-reported psychological symptoms among women with PTSD had yet to be examined. As would be expected, the current study found that women with PTSD were more likely to report psychological symptoms across all SCL-90 symptom clusters regardless of cycle phase as compared to a nonclinical trauma-exposed control group. Additionally, among all participants, women assessed in the early follicular phase when ratings encompassed the late luteal to early follicular cycle phases reported more symptoms of depression over the past week than when they were assessed in the midluteal phase when ratings encompassed the early to midluteal phases. These findings are in line with literature documenting increases in anxiety and depressive symptoms during the late luteal and early follicular cycle phases among clinical (Hendrick et al., 1996) and nonclinical samples (e.g., Gonda et al., 2008). This suggests that menstrual cycle impacts affect, particularly depression and anxiety, across a wide range of women. Although there was a main effect of menstrual cycle phase on phobic anxiety, this effect was qualified by a significant PTSD × Menstrual Phase interaction. Specifically, women with PTSD reported more symptoms of phobic anxiety during the early follicular phase compared to the midluteal phase, whereas phobic anxiety did not change across the menstrual phase in women without PTSD. The items on the phobic anxiety subscale include fear-related symptoms (e.g., “feeling afraid in open spaces or on the streets”) and behavioral avoidance symptoms (e.g., “having to avoid certain places or activities because they frighten you,” “feeling afraid to travel on buses, subways, or trains”). Thus, it is possible that periods of declining or low estradiol and progesterone are periods in which women with PTSD are particularly susceptible to fear-related symptoms and associated avoidance, symptoms that may or may not be PTSD specific. For example, women with PTSD may be more likely
to avoid trauma-related triggers during the late luteal and early follicular cycle phases. The findings of the current study align with previous studies describing menstrual cycle-related patterns in the expression of symptoms of other psychological disorders. Previous literature has documented late luteal and/or early follicular exacerbation of symptoms in a variety of mood and anxiety disorders (Hendrick et al., 1996; Hsiao, Liu, & Hsiao, 2004). These findings are partially consistent with those of Bryant and colleagues (2011) who found that women who experienced a trauma in the midluteal phase reported more flashbacks (i.e., a fear-related PTSD symptom) when assessed an average of 7.19 ± 10.4 (SD) days later, meaning that most were likely assessed during the late luteal phase or early follicular phase—a finding consistent with the current study. They also found, however, increases in flashbacks for women assessed in the midluteal phase, who had experienced a trauma 7.2 ± 10.4 (SD) days prior. These divergent results may be due, at least in part, to several methodological differences between the study by Bryant et al. (2011) and the current study. In contrast to Bryant et al. (2011), the current study (a) included participants with chronic PTSD and more remote trauma, (b) compared symptoms across menstrual phases within individual participants, and (c) focused on a range of psychological symptoms not unique to PTSD. It is possible that specific menstrual cycle phases may differentially influence the effects of acute trauma versus chronic PTSD. For example, better encoding of trauma memories may occur in the midluteal phase (Bryant et al., 2011; Soni, Curran, & Kamboj, 2013), which may influence the development of psychopathology after acute trauma. Extinction deficits and increased fear symptoms occurring during the late luteal and early follicular phases, however, may contribute to maintenance of PTSD once developed. Future work that disentangles menstrual cycle influences on PTSD risk and PTSD specific symptoms versus a range of general mood and anxiety symptoms in both the
Journal of Traumatic Stress DOI 10.1002/jts. Published on behalf of the International Society for Traumatic Stress Studies.
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acute and long term phases following trauma exposure is thus warranted. Although this study provides important information regarding the influence of particular menstrual cycle phases on psychological symptom reports, it does not elucidate the underlying mechanisms responsible for this effect. In fact, the literature examining correlations between estradiol or progesterone and anxiety or depressive symptoms has been mixed (Hsiao et al., 2004). This suggests that future examinations of the relationship between hormone levels and such symptoms may require inclusion of moderating variables (e.g., diagnostic group), examination of dynamic hormonal changes, and/or examination of neuroactive metabolites of these hormones. Specifically, changes in levels of estradiol and progesterone have been shown to modulate many of the neurobiological systems (e.g., noradrenergic, serotonergic, GABAergic, hypothalamus–pituitary–adrenal axis) implicated in PTSD (Rasmusson & Friedman, 2002). For example, declining levels of progesterone during the late luteal phase are thought to influence anxiety via a decline in levels of the neurosteroid, allopregnanolone, a potent GABAergic metabolite of progesterone (Nillni, Toufexis, & Rohan, 2011). Allopregnanolone has also been related to PTSD reexperiencing and depressive symptoms in women with PTSD (Rasmusson et al., 2006). Low estrogen levels have also been associated with deficits in extinction (i.e., the ability to learn that a previously dangerous stimulus is no longer dangerous) in women with PTSD (Glover et al., 2012). High estradiol has been associated with enhanced extinction retention (i.e., the ability to retain extinction learning at a later assessment) in women without psychopathology (Milad et al., 2010; Zeidan et al., 2011). In contrast, recent work from our group suggests that women with PTSD may exhibit a different pattern of menstrual phase effects on extinction retention (Pineles et al., 2013). Thus, examination of dynamic changes in hormones and their associated neurosteroid metabolites will be an important next step toward understanding the impact of menstrual cycle phase on symptom expression in women with PTSD. It is important to note several study limitations. First and foremost, this study did not include a PTSD symptom measure anchored to the specific menstrual phases of interest. In addition, the “past 7 day” time frame queried in the SCL-90 caused women to report their experiences during the late luteal to early follicular phases, as well as during the early to midluteal phases. Combining distinct menstrual cycle phases into one phase for assessment may have obscured more precise menstrual cycle-phase effects. Thus, future research should examine PTSD specific symptoms across multiple, more precisely circumscribed menstrual cycle phases to further elucidate the unique impact of the menstrual cycle and related hormones or hormone metabolites on expression of symptoms. The PTSD group reported more symptoms than the trauma control group across all subscales of the SCL-90-R. Therefore, it is possible that the individuals in the PTSD group had a negative reporting bias. Finally, it is important to note that the six scales of the
SCL-90-R included in this study are highly correlated (rs range from .71 to .93). Despite these limitations, the current study is the first study we are aware of that documents late luteal/early follicular menstrual phase exacerbations of depressive and fear-related symptoms in women previously exposed to trauma. Given that women tend to have a more chronic course of PTSD than men (Breslau et al., 1998), elucidating potential mechanisms involved in the maintenance of PTSD for women may have important implications—both for prevention and for treatment. Further work to establish the precise means by which late luteal/early follicular menstrual status exacerbates fear and anxiety in this population is therefore warranted, so that targeted therapies can be developed. There are likely multiple factors contributing to fluctuations of symptoms across the menstrual cycle. Consistent with biopsychosocial models, psychological (e.g., psychological vulnerability), biological (e.g., hormone changes), and social or cultural (e.g., cultural expectations regarding menstruation) factors likely interact to influence the cyclicity of affective symptoms during the menstrual cycle. The current study examined the interaction between psychological (i.e., PTSD diagnosis) and biological (i.e., menstrual cycle phase) vulnerabilities. Future work would benefit from incorporation of other moderating variables that may influence the impact of the menstrual cycle on affect.
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Journal of Traumatic Stress DOI 10.1002/jts. Published on behalf of the International Society for Traumatic Stress Studies.
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Menstrual Cycle Effects on Psychological Symptoms in Women With PTSD Yael I. Nillni,1,2 Suzanne L. Pineles,1,2 Samantha C. Patton,1 Matthew H. Rouse,2,3 Alice T. Sawyer,2,3 and Ann M. Rasmusson1,2 1
National Center for PTSD, Women’s Health Sciences Division, VA Boston Healthcare System, Boston, Massachusetts, USA 2 Department of Psychiatry, Boston University School of Medicine, Boston, Massachusetts, USA 3 VA Boston Healthcare System, Boston, Massachusetts, USA
The menstrual cycle has been implicated as a sex-specific biological process influencing psychological symptoms across a variety of disorders. Limited research exists regarding the role of the menstrual cycle in psychological symptoms among women with posttraumatic stress disorder (PTSD). The current study examined the severity of a broad range of psychological symptoms in both the early follicular (Days 2–6) and midluteal (6–10 days postlutenizing hormone surge) phases of the menstrual cycle in a sample of trauma-exposed women with and without PTSD (N = 49). In the sample overall, total psychological symptoms (d = 0.63), as well as depression (d = 0.81) and phobic anxiety (d = 0.81) symptoms, specifically, were increased in the early follicular compared to midluteal phase. The impact of menstrual cycle phase on phobic anxiety was modified by a significant PTSD × Menstrual Phase interaction (d = 0.63). Women with PTSD reported more severe phobic anxiety during the early follicular versus midluteal phase, whereas phobic anxiety did not differ across the menstrual cycle in women without PTSD. Thus, the menstrual cycle appears to impact fear-related symptoms in women with PTSD. The clinical implications of the findings and future research directions are discussed.
Compared to men, women are twice as likely to be diagnosed with posttraumatic stress disorder (PTSD) and experience a more chronic course of the disorder (Breslau et al., 1998), suggesting a sex-specific vulnerability for risk and/or maintenance of PTSD. One potential sex-specific vulnerability factor is the cyclical variability of estradiol and progesterone levels across the menstrual cycle. Hormone patterns associated with certain phases of the menstrual cycle have been associated with an increase in the occurrence or symptoms of a variety of psychological disorders and conditions (Hendrick, Altshuler, & Burt, 1996), including panic disorder (e.g., Kaspi, Otto, Pollack, Eppinger, & Rosenbaum, 1994), bipolar disorder (e.g., Rasgon, Bauer, Glenn, Elman, & Whybrow, 2003), major depressive disorder (e.g., Kornstein et al., 2005), eating disorders (e.g., Lester, Keel, & Lipson, 2003), and alcohol (e.g., Allen, 1996) or substance use (e.g., Evans, Haney, & Foltin, 2002) disorders.
Typically, although not universally, there is an exacerbation of symptoms of these disorders during the late luteal phase (Days 5 to 1 relative to the start of menses), when progesterone and estradiol are declining, and during the early follicular phase (Days 1 to 5 after the start of menses), when levels of progesterone and estradiol are both at their lowest levels (Hendrick et al., 1996). For example, women with panic disorder exhibit an increase in the frequency or intensity of panic attacks during the late luteal phase as compared to other menstrual cycle phases (Kaspi et al., 1994). The possible contribution of estradiol and progesterone to menstrual cycle phase-related differences in affect may be related to these hormones’ influence on a variety of systems, including hypothalamus–pituitary–adrenal (HPA) axis response to stressors (Kirschbaum, Kudielka, Gaab, Schommer, & Hellhammer, 1999), and function of the serotonergic (Rubinow, Schmidt, & Roca, 1998), gamma-aminobutyric acid (GABA) ergic, and noradrenergic (Rasmusson & Friedman, 2002) systems. There may also be cultural beliefs or stereotypes about symptoms during specific phases of the menstrual cycle that contribute to symptom fluctuations (Klebanov & Jemmott, 1992). The literature examining the role of menstrual cycle phase in expression of psychological symptoms among individuals with PTSD is limited. There are a few studies with relevance to PTSD, but not performed in PTSD patients specifically, that implicate the menstrual cycle and related hormones in
Support for this work was provided by a VA Career Development Award (Principal Investigator: S. L. Pineles) from the Clinical Sciences R&D Service, Department of Veterans Affairs Correspondence concerning this article should be addressed to Yael Nillni, National Center for PTSD, Women’s Health Sciences Division, Veteran’s Affairs Boston Healthcare System, 150 South Huntington Ave. (116B-3), Boston, MA 02130. E-mail: [email protected] Published 2015. This article is a US Government work and is in the public domain in the USA. View this article online at wileyonlinelibrary.com DOI: 10.1002/jts.21984
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fear-conditioning models (Milad et al., 2010) and reactivity to stressors (Nillni, Rohan, & Zvolensky, 2012). To our knowledge, Bryant and colleagues (2011) are the only investigators to date who have examined PTSD symptom expression in different phases of the menstrual cycle among trauma-exposed women. In this study, women assessed 1 to 2 weeks after trauma exposure reported more trauma-related flashbacks on the Clinician Administered PTSD Scale (CAPS; Blake et al., 1995) if they were in the midluteal phase either at the time of trauma or the time of assessment. This study, thus, may contribute to our understanding of how the menstrual cycle influences expression of at least one salient PTSD reexperiencing symptom in the acute aftermath of trauma before PTSD is formally diagnosed. Most other studies of menstrual phase effects on other psychological disorders document menstrual cycle related increases in a range of psychological symptoms during the late luteal and early follicular phases (Hendrick et al., 1996). PTSD is a heterogeneous disorder, consisting of both traumaspecific symptoms (e.g., avoidance of trauma reminders or physiological or emotional arousal when confronted with a specific trauma reminder) as well as symptoms of general distress and dysphoria (e.g., irritability, sleep disturbance, loss of interest, negative mood). Given the extant literature demonstrating exacerbation of general anxiety and depressive symptoms across the menstrual cycle, we might expect symptoms in these more general domains to fluctuate across the menstrual cycle among women with PTSD as well. Therefore, the aim of the present study was to examine the interactive effects of menstrual cycle phase (early follicular vs. midluteal) and current PTSD diagnosis on self-reported general psychological symptoms measured by the Symptom Checklist90-Revised (SCL-90-R; Derogatis, Lipman, & Covi, 1976). Based on the larger literature (Hendrick et al., 1996) examining expression of symptoms across the menstrual cycle, we were particularly interested in examining a time when estradiol and progesterone levels were declining or low to a time when estradiol and progesterone levels were rising or high. We therefore examined women in the early follicular phase (Days 2–6 after onset of menses) and midluteal phase (6– 10 days after the lutenizing hormone [LH] surge). Additionally, we aimed to improve upon the methodology of many previous menstrual cycle-focused studies by more precisely assessing and confirming menstrual phase, assessing the same women across menstrual cycle phases, and excluding women on hormone contraception. In addition, all participants in the study were free from psychotropic medications and use of alcohol or drugs of abuse for at least a month (or longer for medications with long half-lives) prior to testing as these substances affect hormone levels. In this study, we hypothesized that individuals with PTSD would report more symptoms of fear, depression, anxiety, interpersonal sensitivity, and hostility during the early follicular phase than the midluteal phase, whereas individuals without PTSD would not exhibit menstrual cycle phase differences. We did not expect the trauma control group to exhibit menstrual
cycle phase fluctuations in mood because they were screened to be medically healthy and to have no Axis I psychopathology. In addition, due to the rigorous study eligibility criteria for the PTSD participants, who had to be medically healthy and free of psychotic disorders, we did not expect to see menstrual phase effects on symptoms of somatization, obsessive compulsive disorder, paranoia, or psychosis in either study group.
Method Participants The sample included 49 women (Mage = 32.62 years, SD = 9.58) who met criteria for lifetime trauma exposure according to Criterion A of the Diagnostic and Statistical Manual of Mental Disorders (4th ed., text rev.; DSM-IV-TR; American Psychiatric Association, 2000) on the CAPS. These women were recruited from the local Veterans Affairs hospitals and the surrounding community using flyers and online advertisements. Measures included in the current study were administered as part of a larger investigation examining the effects of menstrual cycle phase on the psychophysiology and neurobiology of PTSD (Pineles et al., 2014). Plasma was available for assay of progesterone and estradiol for 75% of the 100 study visits of the 50 women who initially completed this study. One participant’s cycle phase was not confirmed by hormone assay; data from this participant were removed from analysis, resulting in a total sample size of 49. Participants were diagnosed with current PTSD based on the CAPS. For the current study, we formed two groups: a PTSD group and a trauma control group. Members of the PTSD group reported at least one reexperiencing symptom, three avoidance symptoms, and two hyperarousal symptoms, and had a total severity score (frequency plus intensity) of 40 or greater on the CAPS (MCAPS = 67.05, SD = 19.10). Because we were interested in symptom fluctuations over time, we added the additional severity criteria to ensure a sufficient level of symptoms in the PTSD group. Members of the trauma control group experienced a Criterion A traumatic event, but did not meet criteria for lifetime or current PTSD based on the criteria stated above (MCAPS_CURRENT = 11.00, SD = 10.36). Furthermore, participants in the trauma control group were excluded if they met DSM-IV-TR criteria for a current Axis I psychological disorder (with the exception of a specific or public speaking phobia) or had a lifetime history of recurrent major depression based on the Structured Clinical Interview for DSM-IV-TR Axis I Disorders (SCID-I; First, Spitzer, Gibbon, & Williams, 2007). Other exclusion criteria for all participants included these conditions: (a) infectious illness; (b) current or past organic brain disorder; (c) major neurological problems; (d) endocrine disorders; (e) schizophrenia; (f) psychotic disorder; (g) Bipolar I disorder; (h) active substance or alcohol abuse or dependence within 6 months of the study; (i) irregular menstrual cycle; (j) current participation in active trauma-focused psychotherapy; (k) use of psychotropic medications, alcohol, or illicit
Journal of Traumatic Stress DOI 10.1002/jts. Published on behalf of the International Society for Traumatic Stress Studies.
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Menstrual Cycle and PTSD
Table 1 Demographic Characteristics for Total Sample and by Group Total (n = 49) Variable
n
PTSD (n = 22) %
n
Trauma control (n = 27) %
n
%
χ2
Ethnicity 2.56 Hispanica 2 4 2 9 0 0 Non-Hispanic 47 96 20 91 27 100 Race 8.46 Caucasian 17 35 5 23 12 44 African American 20 41 9 41 12 41 Asian American 5 10 4 18 1 4 American Indian 1 2 1 5 0 0 Other 4 8 1 5 3 11 Years of education 11.33 .05).
Data Analysis Given that we did not expect to see menstrual phase effects on symptoms of somatization, obsessive compulsive disorder, paranoia, or psychosis in either study group because of eligibility criteria, we did not include these subscales in the analyses in an effort to reduce the familywise error rate. We were interested in within-person menstrual cycle-phase differences; therefore, participants were only included if they completed assessments at both cycle phases. Eight participants only completed one menstrual cycle-phase visit and were not included in the analyses. First, demographic characteristics were compared between the PTSD and trauma control groups using independent samples
Discussion The goal of the current study was to examine the influence of menstrual cycle phase on the expression of a range of psychological symptoms in a sample of trauma-exposed women with and without PTSD. Studies of other psychological disorders implicating the menstrual cycle in exacerbation of symptoms of the target disorder studied, typically demonstrate symptom worsening in the late luteal and early follicular cycle phases (Hendrick et al., 1996). Initial research among trauma-exposed women also supports a role for the menstrual cycle in the expression of flashbacks during the early weeks following
Journal of Traumatic Stress DOI 10.1002/jts. Published on behalf of the International Society for Traumatic Stress Studies.
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Menstrual Cycle and PTSD
Table 2 Main Effects and Interactions for PTSD Group × Menstrual Cycle Phase for Selected SCL 90-R Subscales Early follicular PTSD N = 22 Variable Interpersonal sensitivity Depression Anxiety Hostility Phobic anxiety Global Severity Index
Effect sizea
Midluteal
No PTSD n = 27
PTSD n = 22
No PTSD n = 27
M
SD
M
SD
M
SD
M
SD
Group
1.20 1.62 0.98 1.02 0.85 1.16
0.90 0.89 0.66 0.99 0.74 0.67
0.41 0.50 0.19 0.27 0.10 0.31
0.51 0.54 0.23 0.43 0.20 0.30
1.05 1.37 0.91 0.79 0.70 1.03
0.79 0.73 0.75 0.78 0.77 0.64
0.38 0.42 0.15 0.28 0.08 0.28
0.50 0.52 0.21 0.36 0.20 0.30
1.15*** 1.67*** 1.63*** 1.06*** 1.34*** 1.74***
Phase 0.41 0.81* 0.46 0.41 0.81** 0.63*
Group × Phase 0.23 0.41 0.00 0.41 0.63* 0.41
Note. SCL-90-R = Self-Report Checklist 90-Revised; PTSD = posttraumatic stress disorder. a Cohen’s d. *p < .05. **p < .01. ***p < .001.
trauma exposure, but the influence of particular menstrual cycle phases on a broad range of self-reported psychological symptoms among women with PTSD had yet to be examined. As would be expected, the current study found that women with PTSD were more likely to report psychological symptoms across all SCL-90 symptom clusters regardless of cycle phase as compared to a nonclinical trauma-exposed control group. Additionally, among all participants, women assessed in the early follicular phase when ratings encompassed the late luteal to early follicular cycle phases reported more symptoms of depression over the past week than when they were assessed in the midluteal phase when ratings encompassed the early to midluteal phases. These findings are in line with literature documenting increases in anxiety and depressive symptoms during the late luteal and early follicular cycle phases among clinical (Hendrick et al., 1996) and nonclinical samples (e.g., Gonda et al., 2008). This suggests that menstrual cycle impacts affect, particularly depression and anxiety, across a wide range of women. Although there was a main effect of menstrual cycle phase on phobic anxiety, this effect was qualified by a significant PTSD × Menstrual Phase interaction. Specifically, women with PTSD reported more symptoms of phobic anxiety during the early follicular phase compared to the midluteal phase, whereas phobic anxiety did not change across the menstrual phase in women without PTSD. The items on the phobic anxiety subscale include fear-related symptoms (e.g., “feeling afraid in open spaces or on the streets”) and behavioral avoidance symptoms (e.g., “having to avoid certain places or activities because they frighten you,” “feeling afraid to travel on buses, subways, or trains”). Thus, it is possible that periods of declining or low estradiol and progesterone are periods in which women with PTSD are particularly susceptible to fear-related symptoms and associated avoidance, symptoms that may or may not be PTSD specific. For example, women with PTSD may be more likely
to avoid trauma-related triggers during the late luteal and early follicular cycle phases. The findings of the current study align with previous studies describing menstrual cycle-related patterns in the expression of symptoms of other psychological disorders. Previous literature has documented late luteal and/or early follicular exacerbation of symptoms in a variety of mood and anxiety disorders (Hendrick et al., 1996; Hsiao, Liu, & Hsiao, 2004). These findings are partially consistent with those of Bryant and colleagues (2011) who found that women who experienced a trauma in the midluteal phase reported more flashbacks (i.e., a fear-related PTSD symptom) when assessed an average of 7.19 ± 10.4 (SD) days later, meaning that most were likely assessed during the late luteal phase or early follicular phase—a finding consistent with the current study. They also found, however, increases in flashbacks for women assessed in the midluteal phase, who had experienced a trauma 7.2 ± 10.4 (SD) days prior. These divergent results may be due, at least in part, to several methodological differences between the study by Bryant et al. (2011) and the current study. In contrast to Bryant et al. (2011), the current study (a) included participants with chronic PTSD and more remote trauma, (b) compared symptoms across menstrual phases within individual participants, and (c) focused on a range of psychological symptoms not unique to PTSD. It is possible that specific menstrual cycle phases may differentially influence the effects of acute trauma versus chronic PTSD. For example, better encoding of trauma memories may occur in the midluteal phase (Bryant et al., 2011; Soni, Curran, & Kamboj, 2013), which may influence the development of psychopathology after acute trauma. Extinction deficits and increased fear symptoms occurring during the late luteal and early follicular phases, however, may contribute to maintenance of PTSD once developed. Future work that disentangles menstrual cycle influences on PTSD risk and PTSD specific symptoms versus a range of general mood and anxiety symptoms in both the
Journal of Traumatic Stress DOI 10.1002/jts. Published on behalf of the International Society for Traumatic Stress Studies.
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acute and long term phases following trauma exposure is thus warranted. Although this study provides important information regarding the influence of particular menstrual cycle phases on psychological symptom reports, it does not elucidate the underlying mechanisms responsible for this effect. In fact, the literature examining correlations between estradiol or progesterone and anxiety or depressive symptoms has been mixed (Hsiao et al., 2004). This suggests that future examinations of the relationship between hormone levels and such symptoms may require inclusion of moderating variables (e.g., diagnostic group), examination of dynamic hormonal changes, and/or examination of neuroactive metabolites of these hormones. Specifically, changes in levels of estradiol and progesterone have been shown to modulate many of the neurobiological systems (e.g., noradrenergic, serotonergic, GABAergic, hypothalamus–pituitary–adrenal axis) implicated in PTSD (Rasmusson & Friedman, 2002). For example, declining levels of progesterone during the late luteal phase are thought to influence anxiety via a decline in levels of the neurosteroid, allopregnanolone, a potent GABAergic metabolite of progesterone (Nillni, Toufexis, & Rohan, 2011). Allopregnanolone has also been related to PTSD reexperiencing and depressive symptoms in women with PTSD (Rasmusson et al., 2006). Low estrogen levels have also been associated with deficits in extinction (i.e., the ability to learn that a previously dangerous stimulus is no longer dangerous) in women with PTSD (Glover et al., 2012). High estradiol has been associated with enhanced extinction retention (i.e., the ability to retain extinction learning at a later assessment) in women without psychopathology (Milad et al., 2010; Zeidan et al., 2011). In contrast, recent work from our group suggests that women with PTSD may exhibit a different pattern of menstrual phase effects on extinction retention (Pineles et al., 2013). Thus, examination of dynamic changes in hormones and their associated neurosteroid metabolites will be an important next step toward understanding the impact of menstrual cycle phase on symptom expression in women with PTSD. It is important to note several study limitations. First and foremost, this study did not include a PTSD symptom measure anchored to the specific menstrual phases of interest. In addition, the “past 7 day” time frame queried in the SCL-90 caused women to report their experiences during the late luteal to early follicular phases, as well as during the early to midluteal phases. Combining distinct menstrual cycle phases into one phase for assessment may have obscured more precise menstrual cycle-phase effects. Thus, future research should examine PTSD specific symptoms across multiple, more precisely circumscribed menstrual cycle phases to further elucidate the unique impact of the menstrual cycle and related hormones or hormone metabolites on expression of symptoms. The PTSD group reported more symptoms than the trauma control group across all subscales of the SCL-90-R. Therefore, it is possible that the individuals in the PTSD group had a negative reporting bias. Finally, it is important to note that the six scales of the
SCL-90-R included in this study are highly correlated (rs range from .71 to .93). Despite these limitations, the current study is the first study we are aware of that documents late luteal/early follicular menstrual phase exacerbations of depressive and fear-related symptoms in women previously exposed to trauma. Given that women tend to have a more chronic course of PTSD than men (Breslau et al., 1998), elucidating potential mechanisms involved in the maintenance of PTSD for women may have important implications—both for prevention and for treatment. Further work to establish the precise means by which late luteal/early follicular menstrual status exacerbates fear and anxiety in this population is therefore warranted, so that targeted therapies can be developed. There are likely multiple factors contributing to fluctuations of symptoms across the menstrual cycle. Consistent with biopsychosocial models, psychological (e.g., psychological vulnerability), biological (e.g., hormone changes), and social or cultural (e.g., cultural expectations regarding menstruation) factors likely interact to influence the cyclicity of affective symptoms during the menstrual cycle. The current study examined the interaction between psychological (i.e., PTSD diagnosis) and biological (i.e., menstrual cycle phase) vulnerabilities. Future work would benefit from incorporation of other moderating variables that may influence the impact of the menstrual cycle on affect.
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Journal of Traumatic Stress DOI 10.1002/jts. Published on behalf of the International Society for Traumatic Stress Studies.
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Journal of Traumatic Stress DOI 10.1002/jts. Published on behalf of the International Society for Traumatic Stress Studies.
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