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Review |
Associate Director, New Product Research, SmithKline Beecham Consumer Healthcare, Parsippany, New Jersey
Address reprint requests to: Dr. Adrianne Bendich, SmithKline Beecham Consumer Healthcare, 1500 Littleton Road, Parsippany, NJ 07054-3884.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONSCIENTIFIC EVIDENCE ON THE...CONCLUSIONREFERENCES |
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Key words: calcium, magnesium, manganese, vitamin B6, vitamin E, gamma-linolenic acid
Key teaching points:
• There is convincing evidence that calcium supplementation, at a dose of 1,000–1,200 mg/day, substantially decreases many of the symptoms associated with PMS.
• Magnesium supplements, at a dose of 200–400 mg/day, may be helpful in relieving PMS symptoms. However, the evidence of efficacy is less convincing than that for calcium, and some individuals may experience a mild laxative effect at the higher dose range.
• Trials of vitamin B6 supplementation in women with PMS have had conflicting results; the evidence of efficacy is not convincing. If vitamin B6 is used, doses should be limited to no more than 100 mg/day to avoid any risk of neuropathy.
• Carbohydrate supplements may provide some immediate relief of PMS symptoms, but the same effect can probably be achieved through simple dietary changes.
• Evening primrose oil has not been demonstrated to be consistently effective in reducing the symptoms of PMS.
• Herbal supplements for PMS are currently of unproven efficacy. Some herbs (such as chaste tree fruit and dong quai) are considered unsafe for women who may become pregnant. Others (such as St. John’s Wort and kava-kava) may interact with prescription drugs that are used in the treatment of severe PMS.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONSCIENTIFIC EVIDENCE ON THE...CONCLUSIONREFERENCES |
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A wide variety of strategies for PMS have been proposed. For women with mild symptoms, education, supportive counseling and general self-care measures such as increased exercise and adoption of a healthful diet are sometimes sufficient [3]. For those with severe symptoms, a variety of drugs may be helpful. These include fluoxetine (Prozac) or other selective serotonin reuptake inhibitors, the anxiolytic drug alprazolam (Xanax), oral contraceptives, nonsteroidal anti-inflammatory drugs, the diuretic spironolactone, and (in extreme cases) gonadotropin-releasing hormone agonists that temporarily obliterate the menstrual cycle [2,3].
For many women, however, neither lifestyle change nor the use of drugs is an entirely satisfactory approach to PMS. Some women with moderate symptoms may find lifestyle modifications insufficient to control their symptoms yet may be reluctant to consider the long-term use of prescription drugs, all of which have significant side effects. Others, with mild to moderate symptoms, may be reluctant to use medications that they perceive as "unnatural" in an effort to control symptoms associated with a natural biological function. Still others need to avoid the use of medications because they may become pregnant.
The desire for safe and effective non-drug alternatives has prompted many women to consider the use of dietary supplements for PMS. Numerous supplements have been advocated for this purpose. Many women have found these to be helpful in relieving their symptoms and have shared their experiences with others. Such anecdotal reports, however, are not sufficient to establish objectively the benefit of a dietary supplement for PMS. Rigorous scientific studies, including double-blind, placebo-controlled trials, are needed. To date, only a few supplements have received this type of intense scientific scrutiny.
This review summarizes the scientific evidence of the efficacy and safety of a variety of mineral, vitamin, herbal and other supplements that have been examined in women with PMS.
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SCIENTIFIC EVIDENCE ON THE EFFICACY AND SAFETY OF SPECIFIC SUPPLEMENTS |
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TOPABSTRACTINTRODUCTIONSCIENTIFIC EVIDENCE ON THE...CONCLUSIONREFERENCES |
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In that trial, 466 women with rigorously diagnosed PMS received 1,200 mg/day of elemental calcium (as calcium carbonate) or placebo for three menstrual cycles. By the third treatment cycle, those receiving calcium showed an overall 48% reduction in total symptom scores of 17 criteria from baseline, as compared to a 30% reduction in the placebo group. All of four symptom factor scores (negative affect, water retention, food cravings, and pain) were significantly improved by calcium supplementation. For instance, the three criteria used to describe pain—aches and pains, low back pain and abdominal cramping—were all significantly reduced [Table 1].
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There is evidence that abnormalities in calcium and vitamin D regulation may contribute to the causation of PMS and that PMS may be linked to other disorders associated with inadequate calcium intake, such as osteoporosis. In a study that compared women with established vertebral osteoporosis to controls [10], it was found that the risk of osteoporosis was higher among those with a history of PMS. Another study found evidence of reduced bone mass in women with PMS as compared to asymptomatic controls [11]. Thus, PMS may serve as a clinical marker of low calcium status, perhaps reflecting an underlying abnormality in calcium metabolism, and it may serve as an early warning sign to young women of a possible increased risk of osteoporosis. The use of calcium supplements may therefore benefit women with PMS both by reducing their current symptoms and by promoting better bone health in later life.
Manganese
Manganese levels have also been shown to vary with the menstrual or estrus cycle in humans and animals, and low manganese intakes are associated with disruption of reproduction in animals. Thus, there is good reason to suspect that manganese might play a role in PMS or other menstrual cycle-related disorders. In a metabolic ward study, healthy women were assigned to diets high and low in manganese (5.6 vs. 1.0 mg/day) for 39-day periods [6]. The lower dietary manganese intake was associated with increased mood and pain symptoms during the premenstrual phase of the cycle. It is unclear, however, whether the difference between the two conditions represents a benefit of manganese supplementation or an adverse effect of manganese depletion; the lower intake level tested in this study was about 50% of the typical manganese intake. No other studies of manganese and PMS have been reported.
Magnesium
Serum magnesium concentrations have been shown to vary cyclically in women of reproductive age [12]. The levels of magnesium in erythrocytes and leukocytes of women with PMS have been found to be lower than those of women without PMS; plasma magnesium levels, however, do not show this pattern [13–19]. Since magnesium is found predominantly within cells, intracellular magnesium concentrations may be a better biological indicator of body status than plasma values.
Since magnesium is involved in the activity of serotonin and other neurotransmitters, as well as in vascular contraction, neuromuscular function and cell membrane stability, there are many possible pathways by which it might influence PMS. Three randomized, double-blind trials have evaluated the effect of magnesium supplementation on various premenstrual symptoms. All of these studies have been small, but their results have been promising.
In a trial involving 38 subjects with relatively mild premenstrual symptoms [20], a daily supplement of 200 mg of mag-nesium reduced one out of six symptom categories. Fluid retention in the second, but not the first month of use, was significantly reduced; no significant effects on mood-related symptoms were reported. In 32 women with PMS, supplementation with 360 mg/day of magnesium (during the second half of the menstrual cycle) significantly reduced total PMS symptoms and specifically those symptoms related to mood changes. It should be noted that the experimental design resulted in the placebo group’s receiving only two months of supplementation at crossover, whereas the magnesium group received the supplement for four months [21]. In 20 patients with premenstrual migraine, prophylactic supplementation with magnesium (360 mg/day or placebo during the second half of the menstrual cycle) significantly reduced the number of days with headache [22].
In addition, it is also possible that some of the favorable results obtained in trials of combination vitamin/mineral supplements in patients with PMS may have been due to the magnesium content of the products. In particular, as noted in a recent review [3], the doses of the combination supplement "Optivite" that were used in several controlled trials would have provided at least 250 mg/day of magnesium, in addition to other vitamins and minerals. A yeast-based supplement used with some success [23] was also high in magnesium, providing 400 mg/day.
Magnesium supplementation, at the doses used in the trials described above, is usually well tolerated. One possible side effect, however, is mild osmotic diarrhea. In various studies of magnesium supplementation (not specifically focused on PMS), some individuals have experienced diarrhea at magnesium doses of 350–400 mg/day [8]. Other individuals, however, appear to be able to tolerate substantially larger doses of magnesium without experiencing gastrointestinal symptoms [8].
In light of the safety of moderate doses of magnesium and the promising preliminary evidence on the efficacy of this mineral in PMS, additional, larger randomized trials of magnesium supplementation are warranted.
Vitamin B6
During the 1970s, the successful use of vitamin B6 in the treatment of depression caused by the use of oral contraceptives prompted interest in the possible value of this vitamin in the treatment of PMS [24]. Vitamin B6 supplementation was discussed in the popular press during the late 1970s and early 1980s for potentially decreasing PMS symptoms. Since vitamin B6 is a cofactor in the synthesis of neurotransmitters, there is a reasonable basis for its role in alleviating mood-related premenstrual symptoms. However, controlled trials of this supplement have had equivocal results.
A 1990 review of 12 controlled trials [25] found three with positive results [26–28], five with ambiguous results [29–33] and four with negative results [34–37]. All of the studies had important methodological shortcomings, and all except one were small, with fewer than 50 subjects in each treatment group. A trial involving 53 women [38], which was not included in the review, also showed no significant differences [39,40]. Subsequent to the review, two additional trials have been published [41,42]. Neither found a significant PMS benefit of vitamin B6 supplementation.
The most recent review, published in 1999 [43], included unpublished data from authors of several of the 25 published trials of vitamin B6 and PMS. These authors also conclude that the studies suffer from several methodological problems and only one included sufficient subjects. The authors suggest that the pooled data indicate the potential for B6 to reduce PMS symptoms and may beneficially affect depression associated with PMS; however, the studies are of "insufficient quality to draw definitive conclusions."
Women with PMS who choose to take vitamin B6 supplements despite the lack of clear evidence of efficacy need to be aware that high doses of this vitamin can cause sensory neuropathy. Most reported cases of neuropathy associated with vitamin B6 supplementation have involved intakes of at least 500 mg/day for two years or more (or larger doses for shorter periods of time) [44]. There have been a few reported cases of neuropathy in individuals taking lower doses of vitamin B6, but the validity of those reports has been disputed [45]. The Institute of Medicine of the National Academy of Sciences has set the UL of vitamin B6 at 100 mg/day [45].
Vitamin E
A single double-blind trial evaluated the effects of vitamin E supplementation in PMS. In that trial, 41 women with PMS received 400 IU/day of vitamin E or placebo for three cycles; significant improvements in some affective and physical symptoms were observed in the vitamin E group. Unlike in most other studies, there was no effect seen in the placebo group [46]. No further trials have been reported. It would be of interest to investigate vitamin E again in a new trial with more rigorous, up-to-date methods of subject selection and symptom assessment.
If vitamin E is effective in relieving PMS, it evidently acts by some mechanism other than the correction of a deficiency. Women with PMS are not biochemically deficient in vitamin E, and their plasma vitamin E levels are not lower than those of women who do not have PMS [18,47].
Combination Supplements Containing Essential Nutrients
Several supplements containing combinations of vitamins, minerals and/or other ingredients have been advocated for use in PMS. One formulation, a multivitamin/multimineral supplement high in magnesium and vitamin B6 (Optivite) was significantly more effective than placebo in relieving premenstrual symptoms in several clinical trials [48–50]. However, the formulation of this product is not consistent with current safety recommendations. The recommended dose (6–12 tablets per day) provides 300–600 mg of vitamin B6, which is well in excess of the UL of 100 mg/day that was established in 1998 [45]. Also, 6 to 12 tablets provide 12,500–25,000 IU of vitamin A as retinol, which is above the safety limit of 8,000 IU/day for women of childbearing potential that has been established by the Centers for Disease Control and Prevention and other authorities [51].
Of the components of Optivite, the one with the greatest evidence of efficacy is magnesium. A dose of 6 to 12 tablets per day of Optivite would provide 250–500 mg/day of this mineral, which is within the range associated with beneficial effects on PMS symptoms in studies of magnesium alone.
A yeast-based, magnesium-containing combination supplement called Sillix Donna was shown to reduce premenstrual symptoms in a single double-blind study [23]. As is the case with Optivite, the most likely beneficial ingredient in Sillix Donna is magnesium; the recommended dose (2 tablets twice a day) provides 400 mg of this mineral. Unlike Optivite, Sillix Donna does not contain any components in quantities that exceed current safety limits.
Several combination herbal/vitamin products are currently being marketed. No double-blind trials of these specific formulations have been reported in the scientific literature.
Carbohydrate Supplements
Increased consumption of carbohydrates ("carbohydrate craving") is one of the characteristic features of PMS in some women. It has been hypothesized that this change in food intake may lead to an increase in the serum ratio of tryptophan to other large neutral amino acids, which may in turn lead to a serotonin-mediated improvement in mood [52].
It is sometimes recommended that women with PMS eat small, frequent meals high in carbohydrates in an effort to improve symptoms such as tension and depression [53]. In a placebo-controlled study, a single dose of a drink mix containing the sugars dextrose and maltodextrin produced an increase in self-reported recognition memory in women with PMS three hours post-dosing; no data are available on the reproducibility of this effect [52]. It is also unclear whether the use of this drink, which contains 200 calories/dose, has any advantage over simple changes in eating patterns.
Long Chain Fatty Acids
Supplements containing long-chain fatty acids such as evening primrose oil, black currant oil and borage seed oil have been suggested for reduction of PMS symptoms. Of these, only evening primrose oil has undergone formal scientific study in women with PMS.
Evening primrose oil is derived from the seeds of the native American wildflower, evening primrose (Oenothera biennis). It is a rich source of gamma-linolenic acid, a long chain fatty acid that is a precursor in the synthesis of prostaglandins. The use of evening primrose oil in the reduction of symptoms of PMS is based on the hypothesis that women with PMS have a relative deficiency of gamma-linolenic acid and that this may lead to abnormalities in prostaglandin synthesis, which may contribute to PMS symptoms [3]. A recent review [54] identified seven placebo-controlled trials of evening primrose oil in PMS, five of which were randomized. The results of these trials were inconsistent, and the two trials with the most rigorous study design [55,56] showed no advantage of evening primrose oil over placebo. Because these trials were small, however, the possibility of a modest beneficial effect cannot be excluded [54]. Evening primrose oil appears to be safe at the dosages used in these studies [56,57].
Black currant oil (made from the seeds of the European black currant, Ribes nigrum) and borage seed oil (made from the seeds of Borago officinalis) are sometimes used as alternatives to evening primrose oil. These oils are used because of their gamma-linolenic acid content, which is even greater than that of evening primrose oil [57]. As is the case with evening primrose oil, the efficacy of these oils for PMS has not been proven. Concerns have been raised about the safety of borage seed oil, since the borage plant contains potentially toxic pyrrolizidine alkaloids, and it may be possible for small amounts of these substances to contaminate the oil [57].
Herbal Products
In the U.S., herbal products with traditional medicinal uses are marketed as dietary supplements. In Europe and Asia, products containing these herbs are tested and then marketed as over-the-counter or prescription drugs. Evaluation of the safety and efficacy of some of these newer products produced in the U.S. is difficult because few of these specific products have been tested in double-blind, placebo-controlled trials.
Nevertheless, the use of herbal remedies is widespread and increasing in the U.S. [58]. Herbs that have been suggested for the reduction of PMS symptoms include black cohosh, blue cohosh, wild yam root, chaste tree fruit (also called chasteberry) and dong quai.
Black cohosh (Cimicifuga racemosa) is an herb which appears to affect estrogenic receptors [57]. In Germany (where herbal remedies can be officially approved if they are known to be safe and if there is "reasonable certainty" of benefit), black cohosh root is officially approved to be sold for the reduction of PMS [58]. Most of the scientific study of this herb, however, has focused on the treatment of menopausal symptoms rather than PMS. No controlled trials have demonstrated the efficacy of black cohosh in PMS. No serious toxicity has been reported for this herb, but experts recommend that it should not be used for more than six months because its long-term safety has not yet been demonstrated [58,59].
Blue cohosh (Caulophyllum thalictroides) is an entirely different herb from black cohosh. Unlike black cohosh, blue cohosh has significant toxicity, and experts recommend against its use for any type of medical self-treatment [57].
Wild yam root (Dioscorea villosa) contains diosgenin, a substance used in the laboratory synthesis of steroid hormones. The use of this herb in the treatment of PMS is based on the rationale that diosgenin will be converted in the body into progesterone, which may relieve premenstrual symptoms. However, the conversion of diosgenin to progesterone has been demonstrated only in vitro; it has not been shown to occur in the human body [57]. Little is known about the effects of wild yam root in women with PMS [53].
The rationale for the use of the chaste tree fruit (Vitex agnus-castus) in PMS is that this herb may inhibit the secretion of prolactin [57]. Chaste tree fruit is approved in Germany for the reduction of PMS symptoms [58]. A recent German study found chaste tree fruit extract to be at least as effective as vitamin B6 for PMS [60]; however, since no placebo control was included in this study and since the efficacy of vitamin B6 is uncertain, the results of this study are difficult to interpret. Chaste tree fruit is not safe for use during pregnancy [58] and should not be taken by women with PMS who are sexually active and who are not using a reliable form of contraception.
Dong quai (Angelica polymorpha var sinensis) is a Chinese herb advocated for a variety of gynecological ailments, including PMS. Controlled scientific studies of this herb in PMS have not been conducted [57]. Since dong quai is not considered safe for use during pregnancy [57], it should not be taken by sexually active women who are not using a reliable form of contraception.
Health care professionals should be aware that some women may use other herbal products to treat specific premenstrual symptoms. Clinicians should inquire about the use of all products including herbals, since herb/herb interactions are possible. Some herbal products may also interact adversely with drugs used in the treatment of PMS. For example, St. John’s Wort (an herb used to treat mild depression) may interact with selective serotonin reuptake inhibitors [61], and kava-kava (an herb used to relieve anxiety) may interact with alprazolam [62].
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CONCLUSION |
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TOPABSTRACTINTRODUCTIONSCIENTIFIC EVIDENCE ON THE...CONCLUSIONREFERENCES |
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A conventional multivitamin supplement can be recommended to all women with PMS (and all other women of childbearing age), even though specific benefits in the treatment of PMS have not been demonstrated. It has been recommended that all women of childbearing potential consume 400 µg/day of synthetic folate from fortified foods or supplements in order to minimize their risk of bearing a child with a neural tube birth defect [45]. The use of a multivitamin that contains 400 µg of folate (100% of the Daily Value) is the simplest and most reliable way to achieve this goal. In addition, many clinicians believe that improvement of diet and lifestyle is a useful first step in the reduction of PMS, even though rigorous evidence of efficacy is lacking; the use of a multivitamin can be one part of an overall strategy of dietary improvement.
Of the various specific supplements that have been advocated for reducing the symptoms of PMS, the evidence of efficacy is most convincing for calcium (Tables 1 and 2). The controlled trial of calcium supplementation by Thys-Jacobs et al. [7] is by far the largest and most rigorous of all the trials of dietary supplementation for PMS that have been completed to date, and its results point to a clear benefit of calcium in relieving PMS symptoms. The overall risk-benefit ratio for calcium supplementation is also favorable; calcium offers long-term benefits for bone health in addition to its immediate benefit in relieving PMS symptoms, and the recommended doses are safe even for women who may become pregnant. A recommendation for the use of a calcium supplement can and should be incorporated into the general dietary and lifestyle suggestions that are usually offered as first-line treatment for patients with PMS. It should be mentioned that the usual multivitamin contains only 10% of the calcium associated with reducing symptoms of PMS.
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Vitamin B6 has been widely advocated for PMS, but evidence of its efficacy is insufficient. Women who wish to try self-treatment with vitamin B6 should be cautioned not to exceed the accepted safety limit of 100 mg/day.
Although there is some evidence that a carbohydrate-based drink may acutely affect PMS symptoms, it is unclear whether this high-calorie drink offers any benefit that could not be achieved through simple dietary changes.
Supplements containing long chain fatty acids have been examined for the reduction of PMS. Evening primrose oil is the only such product tested for efficacy. Controlled studies of this supplement have had inconsistent results, with the most rigorous studies showing no evidence of a beneficial effect.
The use of herbals is becoming increasingly popular in the U.S. Their efficacy for PMS is uncertain because of limited data from controlled trials. There are important safety concerns with some herbals, especially for women who are considering pregnancy or may become pregnant and for those who are taking prescription drugs (especially drugs used for PMS).
Health professionals should ask women with PMS about their use of all products (prescription, OTC and dietary supplements) and counsel them about possible benefits, risks and drug interactions.
Received August 1, 1999. Accepted September 1, 1999.
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This article has been cited by other articles:
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  E. R. Bertone-Johnson, S. E. Hankinson, A. Bendich, S. R. Johnson, W. C. Willett, and J. E. Manson Calcium and Vitamin D Intake and Risk of Incident Premenstrual Syndrome Arch Intern Med, June 13, 2005; 165(11): 1246 - 1252. [Abstract] [Full Text] [PDF]
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 M. L. Neuhouser Dietary Supplement Use by American Women: Challenges in Assessing Patterns of Use, Motives and Costs J. Nutr., June 1, 2003; 133(6): 1992S - 1996. [Abstract] [Full Text] [PDF]
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