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The purpose of this paper is to present a new conceptual model, which emphasizes the interaction between a cognitive vulnerability for PD, anxiety sensitivity, and the effects of progesterone and its metabolite, allopregnanolone, on behavioral and physiological responses to stress during the premenstrual phase. This review paper presents preliminary evidence from both the human and animal literatures to support this new model.
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Specific topics reviewed include: psychopathology related to the menstrual cycle, anxiety sensitivity and its relationship to the menstrual cycle, PMS, and PMDD, anxiety-modulating effects of progesterone and its neuroactive metabolite, allopregnanolone, and how from the neuroendocrine literature relate to psychopathology or symptoms associated with the menstrual cycle.
Identification of sex-specific stress-susceptible systems mediating anxiety symptoms and disorders would have important implications for prevention, assessment, treatment, and research. Ovarian hormonal changes occurring in the premenstrual phase of the menstrual cycle may constitute a neuromodulatory influence that contributes to the onset and maintenance of maladaptive or clinical anxiety in women. Indeed, periods of hormonal change or flux are associated with changes in affect and an increase in the occurrence or symptoms of a myriad of mental disorders Brier et al.
The premenstrual phase has been associated with an increase in negative psychological e. Here, we propose that the interactions between premenstrual hormone fluctuations, psychological or cognitive vulnerability factors e. In this review we present a new model for understanding these interactions and provide an overview of several different literatures that support this model. Cumulatively, these topics provide preliminary evidence for the new conceptual model proposed here see Figure 1which emphasizes the association between anxiety sensitivity and the effects of progesterone and its metabolites on behavioral and physiological responses to stress during the premenstrual phase.
Although this review focuses primarily on PD, this model could be tested with other anxiety disorders given that the female-to-male sex difference exists for several anxiety disorders e. Understanding sex-specific stress-susceptible systems could lead to the development of more targeted prevention and intervention programs for women.
Figure 2 depicts the changes in sex steroid levels across the human menstrual cycle. Normal menstrual cycles range from 25—35 days.
In a day cycle, menstruation begins on Day 1 and lasts, on average, for 5 days. During the menstrual phase Days 1—5estrogen and progesterone are at their lowest. Estrogen peaks and the follicle stimulating hormone FSH levels are low at Day 6, starting off the follicular phase Days 6— During the follicular phase, estrogen declines and then rises again, progesterone levels remain low and steady, and the endometrium thickens. The ovulatory phase Days 13—15 is characterized by a peak in lutenizing hormone and the fall of estrogen. The luteal phase runs from Days 16— The late luteal or premenstrual phase Days 24—28 is characterized by a high level of progesterone, a moderate level of estrogen, and a gradual rise in FSH to begin developing a new set of follicles.
Estrogen and progesterone decline at the end of the premenstrual phase as the next menstrual phase begins Asso, ; Yen, For the purpose of this review, it is important to note the trajectory of progesterone release.
Anxiety sensitivity, the menstrual cycle, and panic disorder: a putative neuroendocrine and psychological interaction
In sum, progesterone is low throughout menses and the follicular phase, rises steadily following ovulation and throughout the luteal phase, and then declines rapidly prior to the beginning of menstruation in the next cycle. A variety of psychological and physical symptoms have been correlated with different phases of the menstrual cycle. Prospective tracking of symptoms across three consecutive menstrual cycles among healthy women who did not meet criteria for PMDD revealed that Additionally, this sample of women reported an increase in non-pathological anxiety, depressive, and obsessive-compulsive symptoms; somatization; neuroticism; and interpersonal sensitivity in the premenstrual versus the follicular phase Gonda et al.
However, some prospective studies following the same women over time have found little evidence for a consistent pattern of negative premenstrual symptom worsening as compared to other cycle phases, despite the fact that many of these women reported experiencing premenstrual syndrome in retrospective reports Hardie, ; McFarlane and Williams, This highlights the importance of using prospective symptom tracking to identify menstrual cycle-related changes.
Premenstrual syndrome PMS is defined as a cyclical pattern of symptoms that cause some degree of impairment, occur premenstrually, and decline soon after the beginning of menses Steiner, ; Freeman, Additionally, this pattern of symptoms and behavior must be confirmed by prospective daily ratings for at least two consecutive menstrual cycles.
Upon examination of each type of menstrual symptom separately, premenstrual symptoms explained most of the variance in health status Barnard et al. Degree of impairment is associated with symptom severity. Additionally, a representative population-based survey among 11, women aged 18—55 across the U. It should be noted, however, that ability to understand comorbidity between PMDD and other Axis-I disorders is limited due to the fact that many PMDD studies exclude women with concurrent Axis-I diagnoses, including some included in the Kim et al.
Studies have also found premenstrual exacerbation of symptoms in the context of other psychiatric disorders, particularly in women with Sore and tired 42 sex Colchester 42 and anxiety disorders. In a different study, however, only women with PMS exhibited a premenstrual worsening of reported anxiety symptoms, and no menstrual cycle phase late luteal vs.
Although the etiology of PMDD is still unclear, there is some evidence to suggest that psychosocial stressors such as socioeconomic status, marital status, stressful life events, and perceived stress are related to PMDD. In a prospective study of women with varying levels of premenstrual symptoms, global perceived stress, averaged across the 5 days prior to menses, predicted premenstrual symptoms Woods et al.
Additionally, premenstrual symptoms also predicted perceived stress Woods et al. Additionally, traumatic events continued to increase the risk for a PMDD diagnosis at followup, even after controlling for subthreshold PMDD and anxiety disorder diagnosis at baseline and daily hassles Perkonigg et al. Taken together, these studies provide some evidence that external stressors play a role in the etiology of PMDD. In summary, the majority of women report experiencing physical and psychological changes during the premenstrual phase associated with some degree of impairment and decreased health outcomes.
Additionally, lifetime and current comorbid depression and anxiety diagnoses as well as premenstrual exacerbation of symptoms among women with depression and anxiety are common, suggesting that the changes in the premenstrual phase have a ificant impact on the mental health of a large percentage of women. Lastly, chronic psychosocial stressors may interact with ovarian hormone changes to predict as well as exacerbate clinical levels of premenstrual symptoms.
High AS individuals hold the belief that experiencing anxiety or fear will cause severe negative consequences i. A meta-analytic review of AS and anxiety disorders demonstrated that AS level is greater among individuals with anxiety disorders i. Later versions of the ASI have identified three separate dimensions of anxiety-related symptoms, including physical, cognitive, and social concerns Taylor et al.
Collectively, these studies support AS as a unique risk factor for the development and maintenance of panic attacks. Prior studies also support the unique contribution of AS to biological challenge reactivity an external stressor induced in the laboratory.
A longitudinal study of depression, fatigue, and sleep disturbances as a symptom cluster in women with breast cancer
Consistent sex differences emerge in AS scores and panic appraisal. Sex differences also emerge in psychological responses to a CO 2 challenge. However, there were no sex differences in psychophysiological reactions to the challenge e.
To summarize, AS is an established risk factor for the development of anxiety disorders and panic attacks; and high AS is associated with increased panic-relevant responding to an external stressor e. Additionally, AS is a risk factor that is more pertinent to women than to men and plays an important role in the etiology and maintenance of anxiety and panic.
A small literature has examined the interaction between the menstrual cycle and an external stressor on anxiety response among normal individuals, individuals at risk for anxiety e. Women high and low on AS listened to descriptions of neutral and anxiety-provoking scenarios during either the premenstrual or intermenstrual phase of their cycles while psychophysiological data were recorded. High AS women measured in their premenstrual phase displayed greater skin conductance response frequency and magnitude in response to the anxiety scenes in comparison to high AS women assessed in the intermenstrual phase and low AS women assessed Sore and tired 42 sex Colchester 42 either cycle phase, above and beyond the effects of baseline state anxiety and panic history Sigmon et al.
Although these suggest preliminary support for an interaction between AS and menstrual cycle phase on psychophysiological responding to anxiety-provoking stimuli, this study is limited by its cross-sectional de. In a similar study, using a longitudinal de, women with PD exhibited greater skin conductance response magnitude while listening to anxiety-provoking scenes in comparison to controls when measured in the premenstrual phase, but not when the same women were assessed in the intermenstrual phase Sigmon et al. In both Sigmon studies described above Sigmon et al.
These suggest that autonomic reactivity to anxiety-provoking stimuli may be exacerbated premenstrually whereas general autonomic arousal may not fluctuate across the menstrual cycle. In a small study of PD patients vs. It is possible that the rapid decrease in progesterone in the premenstrual phase may prolong the sensitive period into the menstrual phase, or that the anxiolytic effects of progesterone and its metabolites following their increase in the luteal phase may serve as a protective factor. Although the exact link between these two disorders is unknown, ovarian hormonal changes e.
Thus, preliminary research suggests that healthy individuals, individuals at risk for clinical anxiety i. Additionally, women with premenstrual symptoms or PMDD experience panic attacks more frequently in response to an external stressor as compared to women without premenstrual symptoms.
Ovarian hormones and their metabolites have been shown to influence GABA A receptor expression and, subsequently, anxiety behavior. The GABA A receptor is essentially a group of five protein subunits a pentomere ed together to form a neuronal membrane ion channel that, when activated, opens to allow the negatively charged ion chloride Cl- to enter the neuron and decrease the chance that an axon potential will occur.
GABA receptors constitute the major inhibitory influence in the central nervous system. Thus, changing from one of these isoforms to another can have a major effect on inhibitory tone. As such, this metabolite has the potential to change the dynamics of the major inhibitory neurotransmitter in the brain and, thus, to profoundly affect anxiety and other emotional behaviors. Because THP binds to and increases the activity of the GABA A receptor and, therefore, enhances inhibition in brain regions, including limbic areas involved in emotional control, exposure to THP in the short term tends to have an anxiolytic effect in animal models e.
However, rapid withdrawal of THP induces particular subunit changes within the GABA A receptor, which consequently make the receptor Sore and tired 42 sex Colchester 42 sensitive to THP as well as anxiolytic drugs like benzodiazapines, leading to reduced limbic inhibition and consequently increased anxiety-like behavior Follesa et al.
Given that THP is a rapidly formed metabolite of progesterone, the amount circulating is contingent on the amount of circulating progesterone. Therefore, THP peaks during the luteal phase and rapidly declines at the end of the luteal phase and at the beginning of menstruation. This may underlie the onset of premenstrual symptoms as well as anxiety responses to stressful situations during this time. Proestrous female rats display more anxiolytic i.
Some research has suggested that the anxiolytic effect of THP becomes anxiogenic only when the THP withdrawal is paired with an aversive stimulus Smith et al. Female mice undergoing THP withdrawal demonstrated increased anxiety e.
Alternatively, female mice undergoing THP withdrawal, who did not receive a shock preceding the maze test, did not demonstrate any ificant differences on open arm time compared with vehicle-administered control mice Smith et al. Specifically, acute administration of THP in rat models decreases anxiety behavior, whereas withdrawal of THP increases anxiety behavior. Recent research suggests that the anxiolytic effect of THP becomes anxiogenic only when THP withdrawal is paired with an aversive stimulus, which provides support for the model proposed in this review.
Evidence on the relationship between progesterone levels and premenstrual symptoms has been Sore and tired 42 sex Colchester 42. Even though progesterone changes, particularly in the premenstrual phase, are hypothesized to underlie premenstrual symptoms, many studies examining hormone levels and daily symptom reports across the menstrual cycle found no relationship between progesterone level and premenstrual symptoms Backstrom et al. These negative findings may result from methodological issues related to timing. For example, some studies have observed a relationship between progesterone levels and symptom scores time lagged 4—7 days throughout the menstrual cycle Halbreich et al.
Another prospective longitudinal study of women with PMS demonstrated that progesterone levels were ificantly lower in both the follicular and luteal phases as compared to controls and that THP was lower in the luteal phase for women with PMS vs. Specifically, symptoms of irritability and depression rise as THP levels rise following ovulation among women with PMDD with the greatest symptom severity occurring 5 days prior to the onset of menses Backstrom et al.