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By Anthony Scialli, MD, and Adriane Fugh-Berman, MD
Alternative therapies abound for the treatment of fluid retention, mastalgia, and mood changes associated with premenstrual syndrome (PMS). A surprising number of trials have been performed on dietary changes, vitamins, minerals, and herbs.
Calcium. After a small randomized, double-blind, placebo- controlled crossover study in 33 women found that calcium treatment (Os-Cal®, in a dose providing 1,000 mg/d elemental calcium) for three cycles significantly reduced abdominal cramps and back pain,1 the same investigator tested calcium carbonate in a large, randomized, double-blind, placebo-controlled, multicenter trial. Calcium carbonate (two TUMS E-X® tablets bid, providing 600 mg/d elemental calcium) or placebo was administered to 497 healthy premenopausal women with moderate-to-severe PMS symptoms.2 After three menstrual cycles, compared to the placebo group, the calcium group experienced a significant improvement in negative affect (mood swings, depression, tension, anxiety, and anger); symptoms of water retention (swelling of extremities, breast tenderness, abdominal bloating, headache, and fatigue); food cravings; and pain (including lower abdominal pain, generalized aches, and low backache).
Magnesium. Magnesium appears to help cycle-related mood changes. A randomized, double-blind trial of magnesium pyrrolidone carboxylic acid (360 mg tid during the second half of the cycle for two months) in 32 women (28 completed the trial) found that magnesium significantly reduced negative affect scores as well as total scores on the Menstrual Distress Questionnaire.3
Another randomized, double-blind, placebo-controlled, cross- over study compared the effect of 200 mg/d magnesium oxide with placebo on PMS symptoms in 38 women for two menstrual cycles.4 In the first month, there were no changes in symptoms, and in the second month there were significant improvements in symptoms related to fluid retention (swelling of extremities, weight gain, breast tenderness, abdominal bloating). These doses were well tolerated.
Vitamin B6. A systematic review of 25 published trials of premenstrual syndrome and vitamin B6 (including studies of cyclical mastalgia and studies of multivitamins containing at least 50 mg of vitamin B6) identified 10 randomized, double-blind, placebo-controlled, parallel or crossover studies for which data could be acquired.5 One analysis included 10 trials and one analysis was done with nine trials (excluding one because of "statistical heterogeneity").
Methodological quality of trials was poor. Using a random effects model, the overall odds ratio in favor of vitamin B6 in the 10-trial analysis was 1.57 (95% CI 1.40-1.77). The nine-trial analysis (with a total of 934 patients) resulted in an odds ratio of 2.32 (95% CI 1.95-2.54) favoring vitamin B6. Data on depressive symptoms, extracted from five trials, found an overall odds ratio in favor of vitamin B6 of 2.12 (95% CI 1.80-2.48). Doses ranged from 50-600 mg/d; no dose-response effect was seen.
Vitamin E. Some alternative medicine practitioners and consumers believe that vitamin E "balances hormone levels" and use it for a variety of conditions, including mastalgia. There is no reasonable evidence to support this claim. A randomized, double-blind study compared 400 IU d-alpha tocopherol for three cycles in 46 women (41 completed) with various PMS symptoms.6 Although a positive result is claimed, no significant difference was seen between groups.
Adverse Effects of Dietary Supplements
High doses of calcium can cause constipation, bloating, and gas. In excess of 2,500 mg/d, calcium supplements (but not dietary calcium) can cause hypercalcemia or renal stones. In the Nurses’ Health Study, calcium supplementation was associated with increased risk of renal stones, but 67% took supplements between meals or with a low-oxalate meal.7 Because calcium binds oxalate in the gastrointestinal tract, calcium taken with a high-oxalate meal would be expected to lower the risk of stones.
Magnesium in high doses can cause diarrhea. Prolonged use of high-dose vitamin B6 can cause neurological symptoms. Sensory neuropathy has been reported in patients taking more than 2,000 mg/d vitamin B6 (usually for periods exceeding three months), but rarely has been reported with lower doses.
Some women believe that avoiding salt during the latter part of their cycles reduces bloating or mastalgia; although no studies have confirmed this, sodium restriction should decrease fluid retention. A recent crossover study of 33 women (21 completed the trial) tested the effect of a low-fat diet on water retention as well as other symptoms.8 Baseline data were gathered in the first month; then women were assigned to a low-fat vegetarian diet or their regular diet plus a placebo pill. After two months the groups were crossed over. The duration of symptoms attributable to water retention decreased significantly from baseline (2.9 days) to diet intervention (1.3 days); there was no significant difference in the placebo supplement group (2.5).
Another study also found that a low-fat diet helped symptoms of water retention. Thirty premenopausal women were randomized either to a diet containing a ratio of polyunsaturated:saturated (P/S) fatty acids of 1.0 and the other to a P/S ratio of 0.3.9 The MOOS Menstrual Distress Questionnaire was used to assess symptoms. After baseline information was collected for one menstrual cycle, both groups were fed a high-fat diet (40% fat) for four cycles, followed by a low-fat diet (20%) for four cycles. During the low-fat phase, there were significant decreases in symptoms associated with water retention during the premenstrual week and during menses.
Twenty-six women with no complaints of menstrual distress were given a disguised questionnaire on menstrual symptoms and instructed to keep diaries documenting food intake and exercise.10 During the perimenstruum (two days prior to menses and during menses), a higher carbohydrate intake was significantly associated with a higher rating of negative affect; and higher fat intake was associated with water retention. Both overeating and dieting were related to greater water retention while aerobic exercise was related to lower water retention.
A randomized, controlled trial (RCT) compared the effects of aerobic exercise (three times/week for one hour) or strength training on PMS symptoms in 23 healthy women.11 While participation in either type of exercise improved many PMS symptoms, the only significant difference between groups was in premenstrual depression, which was less in the aerobic exercise group. Compared to baseline, the aerobic exercise group improved in various measures of mood, while the strength training group improved in food cravings and feelings of bloatedness or abdominal heaviness.
Evening primrose oil (Oenothera biennis) (EPO). Oil from the seeds of evening primrose, black currant, and borage are high in gamma-linolenic acid. EPO is a popular treatment for PMS or mastalgia. However, better studies do not show a benefit of EPO.
A systematic review of seven placebo-controlled trials of EPO for PMS identified only two trials that were properly randomized and well controlled. One double-blind, crossover RCT in 27 women with PMS and 22 asymptomatic controls tested the effect of 12 capsules of evening primrose oil (Efamol®, containing 4.32 g linoleic acid and 0.54 g gamma-linolenic acid ) daily on breast swelling and discomfort (as well as happiness and feelings of well-being; depressed feelings and crying spells; irritability and short temper; headache; fatigue; sexual need and positive feelings toward sex; energetic feeling; and tension and anxiety). Each treatment was given for four cycles. Although symptoms in both groups improved over time, EPO had no beneficial effect over placebo.12 The other trial of 38 subjects with at least one symptom of fluid retention and breast discomfort and two symptoms of mood changes tested eight capsules Efamol daily; again, there was no benefit for EPO over placebo.13
St. John’s wort (Hypericum perforatum). No controlled trials were identified for St. John’s wort, a popular antidepressant herb. A recent open pilot study examined its effect on several PMS-related symptoms. Nineteen women took one 300 mg tablet containing 900 mcg/d hypericin for two complete menstrual cycles.14 There were significant improvements in mood (including anxiety, irritability, depression, and mood swings); there was also a significant decrease in tender breasts and in "swelling." The dose of St. John’s wort used in this study is one third of the usual dose for depression. St. John’s wort can cause photosensitivity and interacts with numerous drugs.
Chaste-tree berry (Vitex agnus-castus). No controlled trials were identified for chaste-tree berry, used to treat various gynecological conditions. An open study of 1,634 PMS patients in Germany tested the effect of Vitex agnus-castus (1 capsule contained 1.6-3.0 mg dried extract corresponding to 20 mg drug) on several symptoms including mastalgia.15 Compared to baseline, subjects experienced a significant decrease in pain, tenderness, and tension. While only 18.3% reported no mastalgia at baseline, at the final visit 70.4% reported no mastalgia. Bloatedness and edema also decreased significantly from 16.7% to 6.4% after treatment.
Adverse Effects of Herbs
Significant adverse effects have not been reported with EPO or Vitex. St. John’s wort has been associated with phototoxic photosensitivity and can lower levels of cyclosporine, digoxin, indinavir, tricyclic antidepressants, theophylline, and anticoagulants; additionally, it may increase the risk of breakthrough bleeding with oral contraceptives.
Almost all of the trials reviewed applied a parametric test to analyze ranks (in this case, mean scores on questionnaires). Parametric tests are appropriate for continuously varying quantities (weight, temperature, potassium concentrations), because a mean number is a biologically plausible quantity (a weight of 200 is twice as much as a weight of 100, and a potassium concentration of 4.0 is twice as much as a potassium concentration of 2.0).
However, parametric tests usually are not appropriate for analyzing ranked scores of pain, depression, or other symptoms. Ordinal data (ranks) only indicate that a higher or lower number is better or worse, and although a pain score of 8 means more pain than a score of 4, it doesn’t necessarily mean twice as much pain. And a decrease in pain score from 8 to 6 doesn’t mean that the subject had half the response of one whose pain went from 8 to 4. An appropriate test for ranked scores would be a Mann-Whitney U test or a Wilcoxon rank sum test. The use of parametric tests to analyze ranked data is rampant, and this criticism is not specific to the studies reviewed here; it applies to most studies done of conventional therapies.
Of course, the goal of any statistical testing is to reduce the likelihood of chance having produced the study result, and the choice of statistical method usually will make far less of a difference on estimation of an effect than the quality of trial implementation. Although RCTs are less subject to the biases that plague observational studies, RCTs still may suffer from improper randomization, broken blinding, and other problems that can lead to erroneous results.
A large trial supports the use of calcium for various PMS symptoms; two small trials support the use of magnesium for PMS symptoms. Clinical trials for vitamin B6 and vitamin E do not support the use of these interventions. Well-designed trials of EPO show no benefit. Limited evidence supports exercise or a low-fat diet in reducing water retention. Single open trials of St. John’s wort and Vitex claim a benefit for mastalgia and (for St. John’s wort) mood changes, but judgment on these therapies should await properly controlled and analyzed trials. Most of these trials reviewed used parametric tests to analyze ordinal data, which could affect conclusions.
Reasonable doses of most of these therapies are relatively safe; the primary exception is St. John’s wort, which has been associated with phototoxic effects and numerous drug interactions.
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