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From the Department of Psychiatry (E.B.-G., C.D.-S., J.S.-R.), Hospital Ramon y Cajal, Universidad de Alcalá, Madrid, Spain; and Eastern State Hospital (J.D.), Lexington, Kentucky.
Address reprint requests to: Jose de Leon, MD, Mental Health Research Center, Eastern State Hospital, 627 W. 4th St., Lexington, KY 40508. Email: jdeleon{at}pop.uky.edu.us
| ABSTRACT |
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METHODS: The original sample included 134 women who came to the emergency room of a general hospital after a suicide attempt. One hundred eight female blood donors were recruited as control subjects. The menstrual cycle was divided into follicular, midcycle, and luteal phases using two clinical methods and serum hormonal assessment. Dividing the follicular phase into menstrual and nonmenstrual phases was also considered.
RESULTS: Two of 11 previously used sampling methods produced a sample size similar to that of the hormonal assessment.
values between the two clinical and the endocrinological methods were low (0.400.50). The number of suicide attempts during the follicular phase (particularly during the menstrual phase) was significantly higher than expected.
CONCLUSIONS: Despite the inability to control for other variables and limitations, the results of this study suggest that sample selection could introduce biases and that studies relating psychiatric symptomatology and menstrual cycle phases need to use hormonal determinations. New studies are needed to verify that suicide attempts are more frequent during the follicular phase (particularly during the menstrual phase).
Key Words: menstrual cycle suicidal behavior sexual hormones hormonal assessment agreement gonadotropins
Abbreviations: FSH = follicle-stimulating hormone; LH = luteinizinghormone.
| INTRODUCTION |
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Following the organization of the excellent review of Weztel and McClure (5), the suicide studies can be classified into studies of completed suicide, attempted suicide (the scope of this article), and suicidal threats. Regardless of whether these behaviors are different phenomena (7), the methodological problems of studying them are very different.
| COMPLETED SUICIDES |
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| SUICIDE ATTEMPTS |
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Assessment of menstrual cycle phases.
Timing is a crucial factor when the objective of the research is a state marker, such as the menstrual phase (13). Unfortunately, only 8 of 20 articles reported the interval between the suicidal behavior and assessment of the menstrual cycle. Twenty years ago, Pallis and Holding (14) pointed out that in studies of the relationship between the menstrual cycle and suicidal behavior, it is fundamental to accurately estimate the phases. Most of these studies have used patient report instead of hormonal assessment to estimate menstrual cycle phases (5). Even recent studies have continued to use patient report (6, 1519). The validity of these studies rests on the assumption that women interviewed after a suicide attempt can provide accurate enough information to permit a clinical estimation of the phase of their menstrual cycle. However, many researchers interested in the menstrual cycle believe that untrained women may not provide reliable information about their menstrual cycles (20).
The agreement between the phases estimated by patient report and by hormonal assessment has never been studied in women who have attempted suicide, and this methodological problem could explain the inconsistency of the results in this area of research (6). Recently, results of a small study (not of suicidal behavior but of the relationship between psychosis and the menstrual cycle) suggested that 32 psychotic women were not significantly different in their ability to estimate their menstrual cycle phases from 26 nonpsychotic women (21).
The second problem, also related to the determination of the menstrual cycle by patient report, is the representativeness of the samples used for analysis. Most of the studies (Table 1) exclude a significant part of the sample. The ratio of patients excluded fluctuates between 60% (22) and 6% (23) (Table 1). Besides exclusions, an additional explanation for differences in studies of the menstrual cycle in suicidal patients is the bias produced by stress (15, 17).
Other common problems associated with the clinical methods are the artificial adjustment of cycle length to 28 days and not considering the fixed duration of the luteal phase (between 12 and 14 days). This could produce errors in classification because women with cycles longer than 28 days usually have a longer follicular phase, and these methods could classify this phase as the midcycle or even luteal phase. In addition, the classification used in some studies does not follow the traditional physiological phases (9). The progressive, widespread use of hormonal contraceptives reduces the possibility of studying the effect of the "natural" menstrual cycles in suicidal behavior.
| SUICIDE THREATS |
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| CONCLUSIONS FROM THE LITERATURE REVIEW |
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Authors of six studies concluded that a relationship between menstrual cycle and suicidal behavior does not exist (15, 17, 18, 22, 27, 28), and authors of three studies (31, 32, 36) believed that the menstrual cycle plays an important role in this behavior. However, most authors think that the menstrual cycle could be considered as another contributing factor in suicide (23).
Ekeberg et al. (17) and Luggin et al. (15) concluded that the menstrual cycle is affected by the stress associated with suicidal behavior; thus, the relationship between menstrual cycle and suicidal behavior may be explained by the effect of the suicidal behavior on the menstrual cycle. Following Franks hypothesis (37), some authors have speculated that the premenstrual phase is a trigger of acute psychiatric problems (36). Glass et al. (31) and Tonks et al. (32) proposed that the premenstrual phase is a period of increased vulnerability to suicidal attempts in susceptible women (eg, nonpsychotic women with a medical or gynecological history and poor sexual and marital adjustment), whereas in others the premenstrual phase has a protective effect.
Finally, some causal explanations have been proposed as the underlying phenomena responsible for the relationship between the menstrual cycle and suicide attempts. The most popular explanation is the hormonal effect. In fact, a recently published study supports the idea that the hypoestrogenic phases of the cycle are associated with suicide attempts (16). Lester (38) hypothesized that the effect of estrogen over dopamine can influence mood in women and therefore influence suicidal behavior. Other possible explanations are emotional instability linked with premenstrual syndrome (36), the fear of unexpected pregnancy after a delay of menstruation (28), and psychosocial gender factors (39, 40).
This study had three objectives. The first objective was to explore how the effects of two methodological issues (sample selection and assessment of menstrual cycle phases) may contribute to the inconsistent results found in the literature. The second objective was to assess the relationship between the different physiological phases of the menstrual cycle and suicide attempts. The third objective was to establish the role of sexual hormones in suicide attempts. The sample sizes for the different analyses varied according to the exclusion criteria.
| MATERIALS AND METHODS |
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One hundred eight female blood donors at the same hospital who did not have a history of suicidal behavior or psychiatric disorders were also recruited to serve as control subjects.
Sample Selection
The selection criteria used in 11 previous studies (Figure 1) were used to assess the menstrual cycle. Of the initial 134 female patients selected, 44 were excluded. The reasons for exclusion were menopause (29 patients), menopause and hormonal therapy (1 patient), hormonal levels outside reference values (3 patients), use of hormonal contraceptives (7 patients), and technical reasons (4 patients). Ninety premenopausal patients were included and further characterized on the basis of their hormonal assessment, which estimated their menstrual situation. Within this group of 90 patients, different criteria were used to determine the various percentages. Confidence intervals of these proportions (see Figure 1) were calculated using the computer program Power and Precision (41).
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Of the 108 control subjects, 78 remained after exclusion criteria were considered. Thirty were excluded because of menopause (21 patients), irregular cycles (1 patient), and use of oral contraceptives (8 patients).
Patients and control subjects were asked about characteristics of their menstrual cycles in the last 6 months, including regularity, use of hormonal contraceptives, maternity status, cycle length (average and range), and menstrual phase length (average and range). They were also asked to identify their last date of bleeding onset (Figure 2). This information was used to estimate the menstrual cycle phase using two clinical methods.
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The McIntosh et al. (42) method was developed in a prospective study to obtain equations to subsequently predict the most likely day of the LH surge, and hence the time of ovulation, solely from knowledge of the average length and variability of a womens cycle. This method requires application of two formulas. The formula used to calculate the first day of midcycle is 0.770 x average days of cycle length - 7.685 - 1.96 x (0.432 x range of cycle length + 0.694). The formula used to calculate the last day of midcycle is 0.770 x average days of cycle length - 7.685 + 1.96 x (0.432 x range of cycle length + 0.694). These formulas were used to determine the midcycle; the other two phases could then be calculated by exclusion. A recent review (43) described the McIntosh et al. method as a calculation method based on average cycle length and provided formulas that allow one to predict the day of ovulation with 95% confidence. This method could be used in 68 of the 134 patients. Sixty-six patients were excluded because of a lack of information needed to apply the method and/or menopause. This method could also be used in 65 of the 108 control subjects. Forty-three control subjects were excluded because they did not provide the information required for this method and/or menopause.
A blood sample was collected from each subject in both groups to assess levels of sexual hormones (estradiol, progesterone, FSH, and LH) and was analyzed at the hospital laboratory by using Immulite assays (Diagnostic Products Corporation (DPC), Los Angeles, CA), which are chemiluminescent enzyme immunoassays (44). The three physiological phases were determined using the hormonal levels recommended by the manufacturer (4548). The levels used for the follicular phase are as follows: FSH, 3.4 to 10 mIU/ml; LH, 1.6 to 8.3 mIU/ml; estradiol, 0 to 266 pg/ml; and progesterone, 0 to 1.5 ng/ml. The levels used for midcycle are as follows: FSH, 5.7 to 20 mIU/ml; LH, 15 to 62 mIU/ml; and estradiol, 118 to 355 pg/ml. The luteal phase was determined using progesterone levels >2.3 ng/ml. The final sample for hormonal analysis included 90 patients and 75 control subjects. Forty-four patients were excluded because of menopause (29 patients), menopause and hormonal therapy (1 patient), hormonal levels outside reference values (3 patients), use of oral contraceptives (7 patients), and technical reasons (4 patients). Thirty-three control subjects were excluded because of menopause (21 patients), irregular cycles (1 patient), use of hormonal contraceptives (8 patients), and hormonal levels outside reference values (3 patients).
values and 95% confidence intervals were used to measure the agreement between the two clinical methods using subject report and hormonal assessment. Weighted
values were calculated but are not described because they were very similar.
Relationship Between Menstrual Cycle Phases and Suicide Attempts
Of the 134 patients, 90 could be assessed by the hormonal method (see exclusion above), and data from these patients were used to compare the frequency of suicide attempts during the three periods of the menstrual cycle established with the hormonal method against a theoretical distribution by means of
2 test. This theoretical distribution was calculated by dividing the sample into groups based on the duration of the three physiological phases (follicular, days 111; midcycle, days 1216; and luteal, days 1728).
In addition, the menstrual cycle can be further divided into four phases by dividing the follicular phase into menstrual and nonmenstrual follicular phases. Therefore, the menstrual cycle was divided into menstrual, follicular, midcycle, and luteal phases for the 68 patients who could be classified according to the McIntosh et al. method (ie, they gave enough information to apply the formula) and the hormonal method. These 68 patients (see exclusions in Assessment of Menstrual Cycle Phases) were used to test the association between suicide attempts and menstruation. Seventeen of the 68 patients in this group were menstruating when they attempted suicide (Figure 2). The mean, mode, and median of the duration of menstruation for these patients were 4.24, 4, and 4 days, respectively, with a standard deviation of 1.45 days. Thus, the menstrual cycle in these 68 patients could be divided into a menstrual phase (days 14), follicular phase after menstruation (days 511), midcycle (days 1216), and luteal phase (days 1728). A
2 test was performed using the same procedure described above but using these new intervals to calculate the theoretical distribution.
Role of Sexual Hormones in Suicide Attempts
The hormonal levels of 90 of the 134 patients and 75 of the 108 control subjects were compared for each phase of the cycle by means of analysis of variance for two factors (patient or control subject and menstrual cycle phases). Forty-four patients were excluded because of menopause (29 patients), menopause and hormonal therapy (1 patient), hormonal levels outside reference values (3 patients), use of hormonal contraceptives (7 patients), and technical reasons (4 patients). Thirty-three control subjects were excluded because of menopause (21 patients), irregular cycles (1 patient), use of hormonal contraceptives (8 patients), and hormonal levels outside reference values (3 patients).
| RESULTS |
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It is interesting that use of the Forestié et al., Glass et al., and Tonks et al. sampling methods led to inclusion of one, two, and one menopausal patients, respectively. These patients had FSH levels >20 mIU/ml.
Assessment of Menstrual Cycle Phases
Table 2 demonstrates the agreement between the clinical methods and the hormonal assessment. The frequency of suicidal patients correctly classified was 65% (42 of 65) for the Holding and Minkoff method (22) and 59% (40 of 68) for the McIntosh et al. method (42). The frequency was 69% for both methods (50 of 72 and 45 of 65) in control subjects. The respective
values (and their 95% confidence intervals) between the two clinical methods and the endocrinological method were 0.40 (0.210.58) and 0.32 (0.140.50) for patients and 0.48 (0.310.65) and 0.48 (0.310.65) for control subjects. The
value between both clinical methods of assessment was 0.92 (0.841.00) in patients and 1.00 in control subjects. Therefore, use of one or the other clinical method did not appear to influence agreement with the hormonal assessment.
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2 = 7.42, df = 2, p = .02) than the expected value (39%). There was a 50% drop in attempts during midcycle (see Figure 3).
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2 = 8.040, df = 3, p = .045), with more suicide attempts occurring during the nonmenstruating part of the follicular phase but with an excess of suicide attempts during the menstrual phase (75% more attempts than the theoretical distribution).
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| DISCUSSION |
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Assessment of Menstrual Cycle Phases
Considering the hormonal method as the gold standard, the two clinical methods using patient report did not seem to be reliable enough to estimate menstrual cycle phases. Although the
values between the two clinical methods and the hormonal method for both patients and control subjects were highly significant (p < .001), they were both in the moderate range, which reflects that only approximately two-thirds of the samples were in agreement (50).
Thompson et al. (21) provided original data, making it possible to calculate the percentage of agreement in psychotic women (78%, 25 of 32) and female control subjects (81%, 21 of 26) as well as the respective
values and 95% confidence intervals (0.61 (0.390.82) and 0.64 (0.380.89), respectively). Using analysis of variance, Thompson et al. did not find a significant difference between agreement in the menstrual cycle phases, so they concluded that the report of psychotic women was "extremely accurate" or as accurate as the report of nonpsychotic women. Similarly, in our study, the
value for control subjects was slightly better than that for patients. In addition, the difference in agreement between control subjects and patients was not statistically significant because the 95% confidence intervals of
values for patients and control subjects overlapped. Therefore, in our sample, patients were not significantly worse than control subjects in providing accurate information about their menstrual cycles. Although our results are similar to Thompson et al.s results, our interpretation is different. There were no differences between patients and control subjects, but inaccurate classifications of menstrual cycle phase were produced in both groups by both clinical methods when menstrual cycle data provided by the women were used to calculate cycle phases. Our results support the idea that the reliability of memory of menstrual events is low in untrained women (20). A possible reason for the slightly lower reliability of patients is that 6 patients were mildly confused after self-poisoning and 25 patients (26 using the McIntoshs method) seemed to be reluctant to disclose personal information.
In conclusion, our finding of an error rate of approximately one third in the clinical estimations suggests that subject report, in both patients and untrained control subjects, may introduce significant error measurement in studies relating psychiatric symptomatology and the menstrual cycle. Subject report may be an appropriate method for gross initial estimation in pilot studies, but more rigorous and definitive studies need to use hormonal assessments to establish menstrual cycle phases. In addition, these types of methods could produce additional sampling biases. Reviewers of studies of the menstrual cycle in psychiatry should pay attention to the serious limitations of most studies because patient report was used to establish the phases. Unless patients are highly educated or are trained to provide a better estimation of their menstrual cycle, the studies may be biased. Collins (51) noted that retrospective analysis of the data suggests that the failure rates of methods could be low when used by motivated women of reproductive age.
Relationship Between Menstrual Cycle Phases and Suicide Attempts
Our results showing that suicide attempts are more frequent during the follicular phase and to a greater extent during the menstrual period are consistent with results of the latest studies (6, 16, 35). This result must be carefully interpreted because temporal relationship is not an indicator of causality (52, 53). Despite this, the menstrual cycle could be considered a state marker of suicidal behavior.
Role of Sexual Hormone in Suicide Attempts
Another interesting result is that hormonal levels in patients with suicidal behavior were not different from those of control subjects. One might speculate that the hormonal profile during the follicular phase (characterized by low gonadotrophin levels) could induce suicidal behavior in predisposed women (31, 32, 54). Along this line of thinking, impulsivity has been proposed as a predisposing factor to suicidal behavior (55). Serotoninergic function is also linked to suicidal behavior (56). Finally, impulsivity and serotoninergic function change across the menstrual cycle (5759). In addition, serotoninergic function is lower when the levels of gonadal hormones are low, so it could be hypothesized that impulsive women are more likely to attempt suicide during the cycle phase with the lowest levels of gonadal hormones (perimenstrual phase).
Other Variables
Because of the small size of the midcycle group of patients who attempted suicide, there was not enough power to control for the relationship between sociodemographic data or clinical variables, such as mood disorders, and menstrual cycle. However, an overview of frequency distribution (Table 3) indicates a more serious profile of suicidal behavior during the follicular phase than during the midcycle and luteal phases.
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With respect to premenstrual syndrome and suicidality, we did not find a significant association between menstrual cycle phase and antecedents of premenstrual syndrome in the past year (
2 = 0.81, df = 3, p = .84). The rate of premenstrual syndrome (22%) was higher than the estimated prevalence in the US population, 8% to 13% (60), but not as high as the 30.5% described in a study of the Spanish general population (61).
Limitations
One limitation of our study is the lack of a measure of the influence of stress on the menstrual cycle to determine whether it could be responsible for the link between menstrual cycle and suicidal behavior (15, 17, 27). There is evidence that stress can increase the length of the menstrual cycle (62). However, we think that the impact of stress on the menstrual cycle in our sample was small for two reasons. First, most of the patients had hormonal profiles in the normal range, and second, only 7.5% (5 of 68 patients) had longer than expected cycles. It cannot be completely ruled out that early termination of the luteal phase may have confounded the results of the study. It is not likely that this had a major confounding effect because 1) it is an infrequent phenomenon and 2) the stress associated with the suicide attempt was too short in most cases to have an immediate effect on sexual hormones levels. Early termination of the luteal phase seems to be an infrequent phenomena, at least in normal women (56% of cycles) (63), but has not been studied in women under stress. All patients were assessed within the first 24 hours after the attempt, and 78% of the attempts were impulsive (<3 hours considering suicide) (Table 3). Therefore, in 78% of subjects, the duration of stress was <27 hours. This duration is probably not long enough to induce menses or abruptly change the progesterone levels so that early termination of the luteal phase occurs. For this analysis, one of the inclusion criteria was regular menstrual cycles before the suicide attempt. Because all patients with a history of irregularities in their cycles or abnormal values were excluded, it is likely that women prone to be sensitive to stress were also excluded. However, it cannot completely be ruled out that in a small number of patients, stress may contribute to early termination of the luteal phase.
It is possible that psychotropic medications may influence the menstrual cycle in women taking them. However, this is not likely because 1) women with prior menstrual irregularities were excluded from the analysis and 2) antipsychotics, the psychotropics consistently related to changes in the menstrual cycle, were taken by 11% of the sample. The most frequently taken psychotropics, benzodiazepines (56% of patients) and antidepressants (50% of patients), are not believed to have important and consistent influences on the menstrual cycle.
Another possible limitation of this study is the validity of the use of a single hormone sample to determine menstrual cycle phase because gonadotrophins have a pulsate diurnal pattern of secretion. In this sense, during the midcycle phase, the hormonal FSH and LH levels are higher than the highest levels during the other phases (64). The rise of progesterone is a signal that ovulation has occurred and, in this sense, confirms the luteal phase (65). Moreover, some authors have defended the idea that a single serum progesterone measurement is enough to confirm ovulation (66). Grinsted et al. (67) report that the serum estradiol peak has a positive predictive value of 83% and a negative predictive value of 100% when used to predict ovulation. The use of a single serum hormonal determination has an advantage: It is well tolerated by women (68). Repeated hormonal assessment would have been better to establish menstrual cycle phases. However, we were unable to convince patients to call us after the suicide attempt to get information on the onset of menses, so it would have been highly improbable that we could have convinced them to come back for repeated hormonal assessments.
New studies with hormonal determination are needed to test the hypothetical relationship between impulsiveness, menstrual cycle, and serotoninergic function.
| ACKNOWLEDGMENTS |
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| NOTES |
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Received for publication March 9, 1998.
Revision received July 21, 1999.
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