The Effects of St. John's Wort on Premenstrual Syndrome in Single Women: A Randomized Double-Blind, Placebo-Controlled Study

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1 Original Article pissn / eissn Clinical Psychopharmacology and Neuroscience 2010;8(1):30-37 Copyrightc 2010, Korean College of Neuropsychopharmacology The Effects of St. John's Wort on Premenstrual Syndrome in Single Women: A Randomized Double-Blind, Placebo-Controlled Study Jung-Gum Ryoo 1, Sae-Il Chun 1, Young-Jin Lee 2, Ho-Suk Suh 3 1 Graduate School of Complementary Alternative Medicine, 2 Department of Family Medicine, School of Medicine, 3 Department of Psychiatry, School of Medicine, CHA University, Seoul, Korea Objective: St. John's wort (SJW) is known to be effective in treating depression and mood disorders. This study was designed to verify the effect of SJW for mood symptoms of premenstrual syndrome in single women. Methods: A total of 30 single women who suffered from premenstrual symptoms were recruited for this study and followed up for three menstrual cycles. The study used double-blind randomized controlled clinical trials. Subjects were recruited from among healthy single women with no history of medication. We included women who scored above 10 on the Beck Depression Inventory (BDI) or above 217 on the Premenstrual Assessment Form (PAF). We excluded women with endocrine disease, genitourinary, obstetric or gynecologic disease, any previous psychiatric disease, or who were taking medication. The 30 subjects were divided randomly into two groups. The experimental group (n = 16) were treated with 600 mg/day of hypericin, an extract of SJW. The control group (n = 14) were given a placebo that looked similar to the SJW extract. From the first to the third menstrual cycle, all subjects wrote a daily diary to record any PMS symptoms. From the second to the third menstrual cycle, all subjects took two pills daily and continued to take the pills for about two months. We investigated BDI, PAF, and self-assessment of unpleasant feelings using a visual analogue scale (VAS) at baseline and again at the end of the third menstrual cycle. Each variant was further analyzed via nonparametric testing, and changes in values from before to after the study were assessed using the Mann-Whitney U-test. Results: Compared to the placebo group, the SJW group exhibited no significant differences in VAS, total PAF, or BDI. However, the groups differed significantly (p<0.05) on three PAF subtype scores: emotional lability, hostility/anger, and impulsivity. Conclusion: The results suggest that SJW affects emotional lability, hostility or anger, and impulsivity related to premenstrual syndrome in single women. KEY WORDS: Premenstrual syndrome (PMS); Saint John's wort; Premenstrual assessment form (PAF); Beck depression inventory scale (BDI); Visual analogue scale (VAS); Daily diary for PMS. INTRODUCTION Females begin to menstruate in adolescence, and menstrual cycles occur on average every days until the time of menopause. Women therefore experience their menses every month for approximately 35 years; these menses are often preceded by emotional and physical changes due to changes in hormone levels. Premenstrual syndrome (PMS) is characterized by depression and changes in emotional state, appetite, sleep patterns, and Received: July 31, 2009 / Revised: September 24, 2009 Accepted: November 3, 2009 Address for correspondence: Ho-Suk Suh, MD Department of Psychiatry, Gangnam CHA Hospital, School of Medicine, CHA University, Yeoksam 1-dong, Gangnam-gu, Seoul , Korea Tel: , Fax: freud@chol.com several physical symptoms. Up to 75% of women experience premenstrual symptoms during their fertile years, 20-50% have PMS, and 3-8% have severe PMS or Premenstrual Dysphoric Disorder (PMDD). 1) A previous study of 500 women in Korea evaluated premenstrual symptoms and reported that 59.3% experienced uncomfortable physical symptoms, 45.7% experienced social dysfunction, 31.7% experienced major depressive symptoms, 19.8% experienced impulsive symptoms, and 17.7% experienced water retention. 2) In addition, 82.6% of female university students in Korea report dysmenorrhea, most frequently during the first and second days of menstruation. 3) Women in their 20s are most likely to experience premenstrual symptoms, and women in this age group are also most likely to report physical symptoms such as pain and fatigue. 4) The most prominent symptoms of PMS are negative emotions and consistent irritability, 30

2 The Effects of St. John's Wort on Premenstrual Syndrome 31 but patients who report fewer PMS symptoms are most likely to exhibit physical symptoms. 5) Antidepressants such as selective serotonin reuptake inhibitors (SSRIs), anxiolytics, and anovulants such as estrogen/progestin, GnRH agonist, and danazol are prescribed for severe symptoms, but use of these medications is limited due to potential problems related to taking medications and concerns about side effects. 6) St. John's wort (SJW) has been used for a long time in Europe to treat depression. It is a kind of herb, and it has traditionally been used in herbal teas to treat insomnia and stress. The effectiveness of SJW in treating mild depression has been demonstrated 7-9) and it is now sold as a popular over-the-counter medicine in the United States and Europe to treat depression. SJW contains hypericin, hyperforin, and bioflavonoid; some of those are known to effectively treat mood disorders. Several studies have shown that SJW has a treatment efficacy similar to SSRIs or imipramine in treating mild to moderate depression, 10-12) but the anti-depressive mechanisms of SJW are still unclear. Many women cope with PMS symptoms by resting or taking painkillers. 13) Changes in moods are a major symptom of PMS, and use of herbal medicines such as SJW may be very helpful to treat mild to moderate depression. Many studies have assessed how SJW affects depression, but few have elucidated how it affects the depressive symptoms of PMS and mood disorders. Therefore, this study investigated how SJW affects PMS symptoms. METHODS Study Populations The study was conducted between Aug. 1, 2008 and Oct. 31, Our participants included nurses at K. hospital and students at the S. women s university, both in Seoul, Korea. Applicants filled out a basic questionnaire, and participants were screened using evaluation forms and interviews. Due to the circadian rhythm of hormones, we excluded three nurses who worked night shifts; nurses working in outpatient departments were included as subjects. We collected data about menstruation using evaluation forms and then investigated whether subjects had any other diseases or were currently taking medicines. We enrolled participants who met our inclusion criteria; subjects were unmarried, in their 20s or 30s, had no underlying disease or problems related to the genitourinary organs, and had no history of using medicines. In addition, subjects scored above 10 on the Beck Depression Inventory (BDI) or over 217 on the Premenstrual Assessment Form (PAF). We excluded participants who had psychiatric or medication histories, who were currently taking medicines, who had been treated for or diagnosed with any obstetric or gynecological problems, or who were experiencing or being treated for endocrine illnesses. Women currently taking oral contraceptives were also excluded. A total of 109 participants applied for the first survey. Of these, 42 were excluded because they did not meet the inclusion criteria; another 16 withdrew part way through the process due to personal reasons or because they were taking Chinese medicines. A total of 51 women therefore participated in the research and carried out the required tasks. However, 21 of these participants ended contact with us or refused to carry out all the tasks. The reasons for this are unclear, it but may be related to the fact that the subjects were young and healthy and found it unnerving to take medicine regularly and write a daily diary. We tried to contact the missing participants to no avail. Of the 21 women who dropped out of the study, three were taking Chinese medicine during the study period, two requested our consent to their withdrawal, and the remainder left without notice. Therefore, we were only able to conduct our per-protocol analysis for a final total of 30 women. We obtained informed written consent from all subjects, and the study protocol was approved by the Korea University Hospital Institutional review board. Study Design The 51 participants who were enrolled based on surveys and interviews were subjected to randomized double-blind placebo-controlled clinical trials. We divided the participants randomly into two groups, experimental (n=25) and placebo (n=26), using a table of random numbers. However, because only 30 participants completed the study, the final numbers were 16 in the experimental group and 14 in the placebo group. From the first to the third menstrual cycle during the study, participants were required to keep menstruation diaries. From the second to the third menstrual cycle, subjects in the experimental groups took 600 mg/day of hypericin, which is an extract from SJW; the control group took a placebo that looked similar to the SJW extract. All subjects were required to take the medication for about two months and to maintain their diaries. Before their fourth menstrual cycle began, they were asked to fill out the final questionnaire, which contained BDI, VAS, and PAF (Fig. 1). We checked with all participants to ensure

3 32 J.G. Ryoo, et al. Fig. 1. Study design. that none was allergic to the medication. The placebo pill was made of lactose and cellulose and looked similar to the SJW extract. 14) The SJW extract pills used in the experiment were 300 mg; each pill contained 0.3% hypericin and 3% hyperforin. To ensure compliance among these young and healthy participants, we allowed subjects to take two 300 mg tablets per day at a regular, convenient time. Based on previous studies, we selected a dosage of 600 mg per day for six weeks; this has been demonstrated to effectively treat mild depression. 7) We permitted subjects to take acetaminophen only if necessary for severe menstrual pain. Acetaminophen is known to have no interaction with hypericin and no effect on depression or mood disorders. To improve compliance, we phoned or sent texts messages by cell phone every week; subjects were required to hand in their diary at the first week of every month, and subjects were requested to relinquish any remaining pills on the final day as they handed in their questionnaires. Hypericin is an herbal medicine and appears to have adverse effects when used as an over-the-counter drug, but it may cause allergy, nausea, and dyspepsia in some individuals. We told respondents that if they experienced a mild reaction, they could choose to continue medication, but if they had more severe symptoms or chose to discontinue treatment, we would end treatment immediately and pay for any medical bills required to diagnose and treat symptoms. Hypericin is known to interact with several medicines such as digoxin, warfarin, cyclosporin, tacrolimus, diltiazem, and nifedipine. Because the subjects had no underlying illnesses and were not taking any medicines, we did not consider the issue of interactions to be problematic. 15) We educated all participants about these effects and possible side effects of the medicine and emphasized that subjects should not take any other medicines during the study. If subjects began taking any other medication, including Chinese medicine or oral contraceptives, we removed them from the experiment. Side effects were evaluated during weekly phone counseling, and participants were also requested to describe any side effects on the final day in the questionnaire. Instruments Participants kept menstruation diaries about the three menstrual cycles they experienced during the study period; these contained their evaluations of symptoms. We observed whether their symptoms changed after taking medicines and evaluated the effects of medication by comparing BDI, PAF, and VAS scores before and after medication. We also measured variation between the first and last entry and compared variation between the two groups. Beck Depression Inventory (BDI) The BDI is based on clinical depressive symptoms and is used as a tool to measure the severity of depression. It includes 21 items, and the total score is an aggregate of all items. A score of 9 or less is interpreted as normal, as mild depression, as moderate depression, and scores of 24 or more are interpreted as severe depression. 16) Participants completed the BDI twice: before the study began and after their third menstrual cycle (Fig. 1). The BDI used in this study has a reliability of Cronbach s α=.98, a split-reliability coefficient of. 91, 17) and a validity of r = ) Visual Analogue Scale (VAS) We asked subjects to rate their premenstrual symptoms according to the degree of unpleasant feeling on a scale of 0 to 10, where 0 indicated no pain and 10 indicated very painful symptoms. We compared ratings given before the study with those given after participants third menstrual cycle (Fig. 1).

4 The Effects of St. John's Wort on Premenstrual Syndrome 33 Premenstrual Assessment Form (PAF) The PAF is a commonly used scale to assess PMS symptoms. It was developed by Halbreich et al. 19) to measure changes in mood, behavior, and physical conditions during the premenstrual period. It involves unipolar summary scales to assess the severity of premenstrual symptoms: 95 items are ranked on six-point scales. Possible scores range from 95 to 570; higher scores indicate more severe symptoms. The PAF retrospectively assesses PMS symptoms during the previous three menstrual periods. It has the advantage of being able to measure changes other than those in degree or strength of symptoms. Many studies have applied the PAF to assess PMS because it includes a variety of symptoms and can highlight some aspects of symptoms and their severity by providing categories of symptoms. 20) In addition, it provides baseline scores that enable a comparison of scores before and after treatment. The PAF includes 18 symptom areas: low mood/loss of pleasure, endogenous depressive features, lability, atypical depressive features, hysteroid features, hostility/anger, social withdrawal, anxiety, increased well-being, impulsivity, organic mental features, general physical discomfort, signs of water retention, autonomic physical changes, fatigue, impaired social functioning, miscellaneous mood/behavior, and miscellaneous physical changes. Daily Diary for PMS Each participant kept a diary for three menstrual cycles, which required about 3 to 4 months. Participants began by recording their symptoms and observations during the first menstrual cycle, and continued to record these observations as they took their medication. When their fourth menstrual period began, they stopped taking the medication and recording observations in their diary (Fig. 1). The menstrual diary supplemented the PAF; it was a contemporary record in contrast to the PAF, which measures symptoms retrospectively. Participants recorded daily symptoms during the experiment. We considered the 7th day before menses to be the start of the premenstrual period, and the 7th day after menstruation to be the postmenstrual period. We considered a change to have occurred when scores during the premenstrual period differed from postmenstrual scores by more than 30%. 21) We based the menstrual diary on the diary developed by Freeman, 22) which included 17 items: 'Anxiety,' 'Irritability,' 'Depression,' 'Nervous tension,' 'Mood swings,' 'Feeling out of control,' 'Poor coordination,' 'Insomnia,' 'Confusion,' 'Headache,' 'Crying,' 'Fatigue,' 'Aches,' 'Breast tenderness,' 'Cramps,' 'Swelling,' and 'Food craving.' We added 7 more items: 'Want to eat sweets,' 'Appearance of acne,' 'No joy in daily life,' 'Constipation,' 'Dizziness or feeling faint,' 'Back pain,' and 'Feeling hopeless or useless,' for a total of 24 items. Each item was rated on a four-point scale: 0 indicated no symptoms, 1 indicated minimal or slight symptoms, 2 indicated moderate awareness of symptoms but daily routine was unaffected, 3 indicated continuous symptoms and/or symptoms interfere with daily routine, and 4 indicated severe, overwhelming symptoms and/or inability to carry out daily routine. These scores were recorded in the menstrual diary. Analysis Characteristics of participants were analyzed using means and standard deviations. Categorical variables such as education level and cycle regularity were analyzed using a chi-square test. Non-parametric statistics were used due to the small number of subjects. Differences between groups and comparisons of scores before and after treatment were examined using the Mann-Whitney U- test. Data were analyzed using SPSS We analyzed differences in BDI, PAF, and VAS scores before and after treatment and measured differences in mean values for pre-menstrual and post-menstrual weeks. In addition, we assessed differences in changes between the first and last cycles as recorded in menstrual diaries. In cases where diary data were missing, data were repeated from the previous month. Statistical significance was set at RESULTS General Characteristics of the Participants A total of 51 subjects were enrolled at the start of the study, and 30 participants completed all requirements. Of these 30 subjects, the experimental group included 16 women and the control group included 14; the groups did not differ significantly in general characteristics or BDI or VAS scores (Table 1, 2). Changes in BDI and VAS Scores VAS scores were checked before and after subjects completed treatment, and differences between scores were evaluated using non-parametric statistics. Analyses revealed no significant differences between the two

5 34 J.G. Ryoo, et al. Table 1. General characteristics of the study populations (Mean ±SD) Table 4. Premenstrual assessment form & subtype scale: comparison with before and after value between groups (Mean±SD) Characteristics Age Menarche (years) Menstruation interval (days) Menstruation duration (days) VAS* BDI PAF SJW group 25.94± ± ± ± ± ± ±63.54 Placebo group 25.57± ± ± ± ± ± ±84.27 p-value *VAS, visual analogue scale; BDI, beck depression inventory scale; p-value is 0.05; PAF, premenstrual assessment form Table 2. General characteristics of the study populations on categorical scale variables Characteristics Cycle regularity Regular Irregular Education level College High school Middle school SJW group 10 (62.50%) 6 (37.50%) 11 (68.75%) 5 (31.25%) 0 Placebo group 11 (78.57%) 3 (21.43%) 12 (85.71%) 2 (14.29%) 0 p-value* *Categorical variables were analyzed via chi-square test; p-value is 0.05 Measured scales* Total PAF Low mood/loss of pleasure Endogenous depressive features Lability Atypical depressive features Hysteroid features Hostility/Anger Social withdrawal Anxiety Increased well-being Impulsivity Organic mental features General physical discomfort Sign of water retention Autonomic physical changes Fatigue Impaired social functioning Miscellaneous mood/behavior Miscellaneous physical changes SJW group 46.75± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±4.16 Placebo group 17.29± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±3.30 p-value Table 3. VAS & BDI: comparison with before and after value between groups (Mean±SD) Measured scales* VAS BDI SJW group 0.13± ±4.71 Placebo group 0.39± ±8.54 p-value *pre-score minus post score; p-values of Mann-Whitney test; 0.05 groups in changes from before to after treatment (p=0.64). BDI scores also revealed no significant differences between the two groups in changes from before to after treatment (Table 3). Changes in PAF Scores and PAF Subtype Scores Subjects completed the PAF before and after treatment; the total scores did not differ significantly between the two groups (p =0.22). However, the SJW group improved significantly in scores for emotional lability, hostility/anger, and impulsivity items compared to the placebo group (p <0.03; p<0.04, p<0.02, respectively) (Table 4). Of the symptoms evaluated, only these three showed significant differences. *pre-score minus post score; p-values of Mann-Whitney test: 0.05; p-value of these items is below 0.05 We conducted non-parametric statistics to estimate PAF values using the difference between scores recorded before and those recorded after treatment. More severe symptoms corresponded to higher scores. Differences between the groups were greater after treatment than before treatment because the scores for the SJW group decreased, indicating that SJW medication had an effect. Fig. 2 shows that the experimental group improved more than the placebo group in scores on these three symptoms. Changes in Daily Diary for PMS Menstrual diaries were kept over three menstrual cycles, which took 3-4 months. To evaluate the diaries, we added up the scores for each item for pre- and post-menstrual weeks and calculated their means. Higher scores indicated more severe symptoms, and we analyzed scores based on differences between scores before and those after menstruation. We calculated differences in values before and after the first and last menstrual period and analyzed any changes

6 The Effects of St. John's Wort on Premenstrual Syndrome 35 Table 5. Daily diary for PMS: comparison with before and after value between groups (Mean±SD) Measured scales* SJW group Placebo group p-value Fatigue Cooperation disorder Lack mood control Hopelessness Headache Anxiety General pain Restless Mood change Edema, Floating Binging Indifference Dysmenorrhea Melancholy Breast tenderness Insomnia, hypersomnia Concentration disorder Sugar craving Acne Feel tearful Constipation Diarrhea Dizziness, Fainting Back pain 0.32± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± *pre-score minus post score; p-values of Mann-Whitney test: 0.05 DISCUSSION Fig. 2. PAF: improvement of lability, hostility/anger, impulsivity items in SJW group. over time. In cases where diary data were missing, data were repeated from the previous cycle. The menstrual diary included 24 items. Overall, we observed no significance differences between the two groups in changes (Table 5). The experimental group scored higher than the placebo group on the 'swelling, abdominal bloating, weight gain' item related to edema (p=0.02), but this finding was probably misleading because many parts of the diary dataset were missing. We measured BDI, VAS, and PAF scores before and after treatment, and had participants keep a daily diary of their menses for three cycles. Upon the beginning of their second menstrual period, the experimental group of 16 women was treated with 600 mg/day of hypericin, an extract of SJW; the control group of 14 women was treated with a placebo that looked similar to the SJW extract. Participants halted treatment upon the start of their fourth period, and we observed differences in symptom changes between the two groups. Changes during the three menstrual periods were compared between groups based on comparisons of scores for each item before and after treatment. Overall, no meaningful differences were observed between the placebo and experimental groups in terms of changes in BDI, VAS, or total PAF scores or in menstrual diaries. However, scores for PAF items related to anger and impulsivity appeared to be significantly improved in the experimental group compared to the placebo group. The three PAF items on which improvement was observed after SJW treatment were described as follows: 'Rapid mood changes (e.g., smiling, crying, anger, happi-

7 36 J.G. Ryoo, et al. ness) occur within one day'; ' becoming violent (e.g., break things on purpose, hit someone)'; 'lack of self control'; 'impulsive behavior'; 'mood swings (moods go up and down)'; 'hysterical when upset'; 'outbursts of irritability'; 'feel "at war"'; 'act spiteful'; 'intolerant/impatient'; and 'blame others'. SJW is thought to be effective for treating depression related to PMS, but the placebo and experimental groups did not differ significantly in BDI scores. The size of the sample was small, so these results may not be representative of a larger population. In addition, we assumed that SJW would reduce mood disorders associated with dysmenorrhea and improve symptoms, but we observed no effect on dysmenorrhea: VAS scores indicating dysmenorrhea and PAF subscores related to dysmenorrhea did not change significantly. The antidepressive mechanisms of SJW are still unclear. Previous studies have found that hyperforin and hypericin, components of SJW, interfere with the reuptake of serotonin and norepinephrine in the synapse. 23,24) An in vitro experiment revealed that SJW extract has a chemical affinity with adenosin and GABA A and GABA B glutamate receptors. 25) An in vivo experiment revealed that SJW extract induced downregulation of the β-adrenergic receptor in the frontal lobe with upregulation of the serotonin 5-HT 2 receptor in rats, and altered the concentration of neurotransmitters in the brain. 25) These findings suggest that SJW might change the concentration of neurotransmitters in the brain and thereby gradually alleviate the symptoms of depression. Recent neuroendocrinological studies have suggested that SJW extract may control genes that restrain the function of hypothalamic-pituitary-adrenal axis. 25) Huang and Tsai 26) conducted a case study and found that when PMDD patients were restricted from using SSRIs because of side effects, SJW was an effective alternative treatment. Other studies have found that SJW extract has effects similar to SSRIs, 10) but it is important to be aware of drug interactions. On the other hand, when patients report labile feelings and anxious or depressive symptoms, self-treatment with SJW has been recommended. SJW has been used for a long time to treat depression and anxiety in Europe. SJW is metabolized in the liver; it induces cytochrome P450 in the liver and interacts with some medicines, 27) particularly antiviral agents, anticonvulsants, tacrolimus, and cyclosporine. It may cause side effects including nausea, headache, abdominal discomfort, and constipation. More rare side effects include hypersensitive skin reaction and increasing liver enzymes. 24,28) We observed no side effects in the experimental or placebo group during the experiment, although four participants complained of nausea on the first day. Their symptoms were not severe, so they continued treatment, and their side effects disappeared the next day. Two participants in the control group and one in the experimental group complained of pimples after treatment, but it was not clear whether this was a result of the treatment of simply increased acne due to their menstrual cycle. Again, their symptoms were not severe, so they continued treatment and did not report any aggravation of their symptoms. SJW extract appears to cause few side effects and seems to have a positive effect on PMS mood symptoms. Therefore, it appears to be an appropriate choice to minimize PMS symptoms among fertile women with no underlying illnesses. Women of childbearing age tend to feel burdened by taking antidepressants to treat mood changes or mood disorders related to PMS. Herbal medicines such as SJW extract may lessen the feeling of being burdened and minimize side effects. In addition, healthy women of childbearing age who are not taking medication can take SJW extract without worrying about possible drug interactions. This study had several limitations. First, the sample size was small, so we cannot be sure of the results. Larger-scale studies will be required to verify the effects of SJW on mood changes or mood disorders related to PMS. The second limitation is that all subjects were single women. We were unable to include women in all stages of their fertile years, so the generalizability of these findings is limited; we could not assess the effects of SJW on mood disorders related to PMS at different ages. Further research will be required to evaluate the effectiveness of SJW on symptoms in women at all ages of their fertile years. The third limitation is that we did not check whether PMS symptoms could be improved by taking medicines for two weeks, considering that PMS generally occurs after the ovulatory phase. Some studies of SJW s effects on depression have indicated that treatment with 900 mg of SJW can improve depressive symptoms. 29,30) Others have reported that 300 mg of SJW extract (WS 5570) taken three times a day effectively treats the symptoms of mild and moderate depression and Fava et al. 29) reported that treatment with 900 mg extract of SJW is more effective on depressive symptoms than is 20 mg fluoxetine.

8 The Effects of St. John's Wort on Premenstrual Syndrome 37 Therefore, further studies will be required to assess whether treatment with a dosage of 900 mg of SJW extract would be more effective in treating mood disorders related to PMS than was the 600 mg dosage used in this study. Acknowledgments This article is a condensed form of the first author's masters thesis from graduate school of complementary alternative medicine, CHA university. REFERENCES 1. Steiner M. Premenstrual syndrome and premenstrual dysphoric disorder: guidelines for management. J Psychiatry Neurosci 2000;25: Lee JY, Kang BJ. Ha JC. The Analysis of the Premenstrual Symptoms in Different Age Groups. J Korean Neuropsychiatr Assoc 1986;25: Han SH, Hur MH. A study on the menstrual pain and dysmenorrhea, factors influenced to them, and self-management method for them of college students. J Korean Acad Soc Nurs Edu 1999;5: Min AK. The effects of educational program for women with premenstrual syndrome. 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