By Felise B. Milan, MD Associate Professor of Clinical Medicine, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY
Dr. Milan reports no consultant, stockholder, speaker’s bureau, research, or other financial relationships with companies having ties to this field of study.
The large majority of women experience unpleasant premenstrual symptoms at some times during their lives. Although 75-80% of women report some emotional or physical changes during the luteal phase of their menstrual cycle,1,2 40-50% experience these symptoms as annoying and 3-8% have symptoms severe enough to produce dysfunction in some aspect of their lives.3-5 The characteristic symptoms of premenstrual syndrome (PMS) include a mix of mood (i.e., irritability, affective lability, depression, anxiety), physical (i.e., fatigue, bloating, weight gain, breast tenderness, change in appetite), and cognitive (i.e., confusion, difficulty concentrating) changes. The hallmark of PMS is that these symptoms occur within the two weeks before menses, remit within two days of menstruation, and are absent until ovulation.4 Women typically begin to experience PMS symptoms in their 20s but usually do not seek care until their 30s.4,5 Of the women who report bothersome premenstrual symptoms, 30-40% will seek help from their primary care provider.6 It is not clear whether PMS symptoms worsen with age or whether older women are more likely to seek help for the problem.4
The exact pathophysiology of PMS is not entirely clear. It is clear that for PMS to occur, a woman must ovulate in that cycle.7 There is an obvious link between the symptoms of PMS/premenstrual dysphoric disorder (PMDD) and the rise and fall of sex steroids associated with ovulation. Cyclical PMS symptoms do not occur with pregnancy and resolve after menopause.8 Although suppression of ovulation with a synthetic androgen (danazol) and gonadotropin-releasing hormone agonists seems to be an effective therapy for PMS,9-13 suppression of ovulation with oral contraceptives (OCPs) has not been shown to be as reliably effective.7,8 There is, however, some evidence that an OCP formulated with drospirenone (a progestin and spironolactone analog) may be effective in reducing PMS symptoms.8,14 One theory, espoused by Katarina Dalton, was that progesterone deficiency is the underlying cause of PMS.15 Although some early evidence also suggested that PMS could be treated effectively with micronized progesterone,16 a subsequent large randomized controlled trial was negative.17 It has been shown that progesterone levels are not altered in women with PMS.18 There is ample evidence to suggest alterations in serotonergic functioning during the luteal phase in women with PMS/PMDD. In addition, selective serotonin reuptake inhibitors that have been studied for treating PMS have produced an average response rate of approximately 60%.8
CAM for PMS
In the 1970s and 1980s, many investigators focused on supplementation with a variety of vitamins and minerals, both singly and in combination, to treat PMS. Although calcium and magnesium both have been shown to have some potential as effective therapies for PMS/PMDD, their mechanism of action remains unclear.19-21 Vitamin E has been studied in the treatment of premenstrual mastalgia with highly variable results.7,19 Vitamin B6 as a cofactor in the synthesis of neurotransmitters was studied as a treatment for depression related to OCP use.22 These data produced interest in vitamin B6 as a treatment for PMS. Vitamin B6 has been studied both alone and in combination with other vitamins and minerals.
Mechanism of Action
Pyridoxine HCL is the standard form of vitamin B6 available as a supplement and is the least expensive form to produce commercially. Pyridoxine HCl is absorbed in the upper small intestine but is not metabolically active until it is phosphorylated in the liver into pyridoxal 5’phosphate (P5P). P5P is exported from the liver bound to albumin and is the most relevant measure of vitamin B6 status.23 Vitamin B6 nutritional status has a significant and selective modulatory impact on central production of both serotonin and gamma-aminobutyric acid,24 as P5P is a cofactor in the synthesis of these neurotransmitters. It is this biochemical activity that is behind the rationale for the use of vitamin B6 in PMS/PMDD.
Several studies conducted in the United Kingdom (UK) before 1997 found that vitamin B6 was the most commonly used therapy for PMS,25 with one survey finding 68% of general practitioners prescribing it for this indication. A similar survey of primary care providers in the United States and Canada, however, found the most prescribed treatment for PMS was progesterone.26 In 1997, the UK Department of Health proposed to limit the sales of vitamin B6 because of possible neurotoxic side effects at higher doses. A UK study that measured prescribing practices for PMS from 1993 to 1998 found a sudden 50% decrease (from 22% to 11%) in prescriptions for vitamin B6 for PMS from 1997 to 1998.27
Clinical Evidence for PMS/PMDD
Many of the studies evaluating vitamin B6 as a therapy for PMS were done before there were well-outlined clinical criteria emphasizing the need to distinguish PMS from PMDD, a more severe form of the syndrome. Therefore, studies have somewhat heterogeneous inclusion criteria and outcome measures. In addition, studies on PMS, similar to those evaluating therapies for depression, have notoriously high placebo response rates. Not surprisingly, the results of these studies have been quite variable.
A 1990 review by Kleijnen of 12 controlled trials found four trials with negative results, three with positive results, and five with ambiguous results.28 All of the studies were small (n < 50) and had some important methodological problems.
A more recent review and meta-analysis identified 25 trials: nine of which were placebo-controlled and had data that could be pooled for meta-analysis.29 The methodological quality of the trials was evaluated by Jadad30 score as well as by a second quality scale developed by the authors. The overall quality of the trials was poor with only three of the trials achieving the recommended Jadad score of 3.31-33 Of the nine trials included in the meta-analysis, three31,34,35 used a high-dose multivitamin product (Optivite) which, at the recommended dose of 6-12 tabs per day, provides 300-600 mg/d vitamin B6, 12,500-25,000 IU/d vitamin A, 250-500 mg/d magnesium in addition to a long list of other vitamins and minerals in amounts in excess of the recommended daily allowance.7,19 These multivitamin studies also divided patients into four symptomatic subgroups, so their analyses were done differently than the other studies. The other six studies used vitamin B6 alone in doses of 500 mg/d36 or 50-200 mg/d.32,33,37-39 In one study subjects took the vitamin supplement during the luteal phase only,32 while subjects in the other trials received the supplement throughout the menstrual cycle. Two of the studies evaluated only mastalgia,33,35 while the others measured effects on a variety of physical, emotional, and cognitive symptoms.
The outcome measures of the nine studies were too disparate to compare directly, so the authors of this meta-analysis calculated odds ratios (OR) by dichotomizing patients into “better” or “not better” groups. After excluding one trial for failing the homogeneity test, the overall OR was 2.32 (95% confidence interval [CI] 1.95-2.54) in favor of vitamin B6 over placebo and 1.57 (95% CI 1.40-1.77) when that trial was included.29 The authors also extracted data from five trials with outcome measures looking specifically at depressive symptoms31,32,35,37,38 and calculated an OR of 1.69 (95% CI 1.80-2.48) in favor of vitamin B6. No dose-response relationship was found among the nine studies. An additional problem with the study is that four of the nine trials used doses of vitamin B6 that are higher than what is currently considered safe. One of the larger (n = 617) and better quality studies (Jadad score of 3) randomized women with PMS to receive placebo or vitamin B6 at doses of either 50 mg/d, 100 mg/d, or 200 mg/d for three cycles.32 Improvement as measured by global assessment was significantly greater in the treatment group (P < 0.02).
Another double-blind, randomized controlled trial that was not included in the review by Wyatt treated women with PMS with either 300 mg/d vitamin B6, alprazolam, propranolol, fluoxetine, or placebo.40 Although the other groups did better than placebo, the group receiving B6 did worse than those receiving placebo. A recent systematic review looking at the use of vitamin B6 as a treatment for depression concluded that while the literature reviewed did not show vitamin B6 to be valuable in the treatment of depression in general, there did seem to be a consistent indication for its use to treat depression in premenopausal women.41
The Institute of Medicine of the National Academy of Sciences has set the upper limit of vitamin B6 at 100 mg/d after reports of neuropathy with doses as low as 200 mg/d.42 Vitamin B6 can cause nausea, vomiting, abdominal pain, loss of appetite, headache, paresthesia, somnolence, increased serum AST, decreased serum folic acid levels, allergic reactions, breast tenderness and enlargement, and photosensitivity. Large doses (1-6 g/d) can be neurotoxic. Symptoms can include tingling in the hands and feet, decreased muscle coordination, and stumbling gait.43
Conclusion and Recommendations
The diagnosis of PMS/PMDD has been aided in recent years by the establishment of clinical criteria for both the milder (PMS) and more severe (PMDD) versions of the disorder. The literature shows very clearly that women who complain of PMS symptoms often are inaccurate in their assessment of the problem. It is therefore essential to screen for other psychiatric comorbidities as well as use laboratory tests to rule out other possible diagnoses. The recommended approach to the treatment of women who have a history consistent with premenstrual symptoms is to use one of the validated instruments for symptom charting. During the cycles when she is charting, a woman can try to identify and then alter lifestyle habits that may improve her symptoms. It is also a time when a trial of vitamin B6 at 100 mg/d could be tried and assessed for efficacy. After the symptom charts are reviewed, if a diagnosis of PMS is made or if the patient with PMDD does not choose to use a psychotropic medication, a trial of vitamin B6 could be considered. However, the literature on vitamin B6 is methodologically very poor and quite equivocal as to its efficacy as a therapy for PMS.
1. Campbell EM, et al. Premenstrual symptoms in general practice patients: Prevalence and treatment. J Reprod Med 1997;42:637-646.
2. Committee on Gynecologic Practice. American College of Obstetricians and Gynecologists. ACOG committee opinion. Premenstrual syndrome. Number 155—April 1995. Int J Gynaecol Obstet 1995;50:80-84.
3. Johnson SR. The epidemiology and social impact of premenstrual symptoms. Clin Obstet Gynecol 1987;30: 367-376.
4. Johnson SR. Premenstrual syndrome, premenstrual dysphoric disorder, and beyond: A clinical primer for practitioners. Obstet Gynecol 2004;104:845-859.
5. Grady-Weliky TA. Clinical practice. Premenstrual dysphoric disorder. N Engl J Med 2003:348:433-438.
6. Kraemer GR, Kraemer RR. Premenstrual syndrome: Diagnosis and treatment experiences. J Womens Health 1998;7:893-907.
7. Johnson SR. Premenstrual syndrome therapy. Clin Obstet Gynecol 1998;41:405-421.
8. Rapkin A. A review of treatment of premenstrual syndrome and premenstrual dysphoric disorder. Psychoneuroendocrinology 2003;28:39-53.
9. Sarno AP Jr, et al. Premenstrual syndrome: Beneficial effects of periodic, low-dose danazol. Obstet Gynecol 1987;70:33-36.
10. Watts JF, et al. A clinical trial using danazol for the treatment of premenstrual tension. Br J Obstet Gynaecol 1987;94:30-34.
11. Hahn PM, et al. A randomized, placebo-controlled, crossover trial of danazol for the treatment of premenstrual syndrome. Psychoneuroendocrinology 1995;20: 193-209.
12. Muse KN, et al. The premenstrual syndrome. Effects of “medical ovariectomy.” N Engl J Med 1984;311: 1345-1349.
13. Hammarback S, Backstrom T. Induced anovulation as treatment of premenstrual tension syndrome. A double-blind cross-over study with GnRH-agonist versus placebo. Acta Obstet Gynecol Scand 1988;67: 159-166.
14. Parsey KS, Pong A. An open-label, multicenter study to evaluate Yasmin, a low-dose combination oral contraceptive containing drospirenone, a new progestogen. Contraception 2000;61:105-111.
15. Dalton K. The Premenstrual Syndrome and Progesterone Therapy. 2nd ed. Chicago IL: Year Book Medical Publishers; 1984.
16. Dennerstein L, et al. Progesterone and the premenstrual syndrome: A double-blind crossover trial. Br Med J (Clin Res Ed) 1985;290:1617-1621.
17. Freeman EW, et al. A double-blind trial of oral progesterone, alprazolam, and placebo in treatment of severe premenstrual syndrome. JAMA 1995;274:51-57.
18. Rubinow DR, et al. Changes in plasma hormones across the menstrual cycle in patients with menstrually related mood disorder and in control subjects. Am J Obstet Gynecol 1988;158:5-11.
19. Bendich A. The potential for dietary supplements to reduce premenstrual syndrome (PMS) symptoms. J Am Coll Nutr 2000;19:3-12.
20. Thys-Jacobs S, et al. Calcium carbonate and the premenstrual syndrome: Effects on premenstrual and menstrual symptoms. Premenstrual Syndrome Study Group. Am J Obstet Gynecol 1998;179:444-452.
21. Facchinetti F, et al. Reduction of monocyte’s magnesium in patients affected by premenstrual syndrome. J Psychosom Obstet Gynecol 1990;11:221-229.
22. Villegas-Salas E, et al. Effect of vitamin B6 on the side effects of a low-dose combined oral contraceptive. Contraception 1997;55:245-248.
23. Leklem JE. Vitamin B-6: A status report. J Nutr 1990;120:1503-1507.
24. Vitamin B6 (pyridoxine and pyridoxal 5’-phosphate)—monograph. Altern Med Rev 2001;6:87-92.
25. Corney RH, Stanton R. A survey of 658 women who report symptoms of premenstrual syndrome. J Psychosom Res 1991;35:471-482.
26. Lyon KE, Lyon MA. The premenstrual syndrome. A survey of current treatment practices. J Reprod Med 1984;29:705-711.
27. Wyatt KM, et al. Prescribing patterns in premenstrual syndrome. BMC Women’s Health 2002;2:4. Available at: www.biomedcentral.com/1472-6874/2/4. Accessed Aug. 7, 2005.
28. Kleijnen J, et al. Vitamin B6 in the treatment of the premenstrual syndrome—a review. Br J Obstet Gynaecol 1990;97:847-852. Erratum in: Br J Obstet Gynaecol 1991;98:329-330.
29. Wyatt KM, et al. Efficacy of vitamin B6 in the treatment of premenstrual syndrome: Systematic review. BMJ 1999;318:1375-1381.
30. Jadad AR, et al. Assessing the quality of reports of randomized clinical trials; is blinding necessary? Control Clin Trials 1996;17:1-12.
31. London RS, et al. Effect of a nutritional supplement on premenstrual symptomatology in women with premenstrual syndrome: A double-blind longitudinal study. J Am Coll Nutr 1991;10:494-499.
32. Barr W. Pyridoxine supplements in the premenstrual syndrome. Practitioner 1984;228:425-427.
33. Williams MJ, et al. Controlled trial of pyridoxine in the premenstrual syndrome. J Int Med Res 1985;13: 174-179.
34. Stewart A. Clinical and biochemical effects of nutritional supplementation on the premenstrual syndrome. J Reprod Med 1987;32:435-441.
35. Chakmakjian ZH, et al. The effect of a nutritional supplement, Optivite for women, on premenstrual tension syndrome: Effect of symptomatology, using a double-blind crossover design. J Appl Nutr 1985;37:12-17.
36. Colin C. Controlled studies on the oral administration of progestagens, an antiestrogen and vitamin B6 in the treatment of mastodynias [in French]. Rev Med Brux 1982;3:605-609.
37. Smallwood J, et al. Vitamin B6 in the treatment of pre-menstrual mastalgia. Br J Clin Pract 1986;40:532-533.
38. Kendall KE, Schnurr PP. The effects of vitamin B6 supplementation on premenstrual symptoms. Obstet Gynecol 1987;70:145-149.
39. Doll H, et al. Pyridoxine (vitamin B6) and the premenstrual syndrome: A randomized crossover trial. J R Coll Gen Pract 1989;39:364-368.
40. Diegoli MS, et al. A double-blind trial of four medications to treat severe premenstrual syndrome. Int J Gynaecol Obstet 1998;62:63-67.
41. Williams AL, et al. The role for vitamin B-6 as treatment for depression: A systematic review. Fam Pract 2005 Jun 17 (epub ahead of print).
42. Parry GJ, Bredesen DE. Sensory neuropathy with low-dose pyridoxine. Neurology 1985;35:1466-1468.
43. Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington, DC: National Academy Press; 1999. Available at books.nap.edu/ books/0309065542/html/index.html. Accessed Aug. 7, 2005.
Definitions and Diagnosis of Premenstrual Syndrome
While aspects of premenstrual mood changes were described by Hippocrates, premenstrual tension syndrome was first delineated as a disorder in the 1930s and the term premenstrual syndrome (PMS) was first defined in the 1950s.1 Although many recognized that a subset of the population suffered from a particularly severe form of PMS resulting in a significant level of dysfunction, clear clinical definitions were not outlined until recently. The American College of Obstetrics and Gynecology (ACOG) established clinical guidelines for PMS in 20002 and criteria for Premenstrual Dysphoric Disorder (PMDD) was included in DSM-IV.3 Both the ACOG criteria for PMS and the DSM-IV criteria for PMDD require confirmation of the luteal nature of the problem through the use of prospective symptom charts or a daily rating instrument for a minimum of two menstrual cycles. A number of valid and reliable diagnostic instruments are available to document symptoms including the Calendar of Premenstrual Experiences,4 the Premenstrual Syndrome Diary,5 and the Daily Record of Severity of Problems.6 One expert recommends that women record daily the presence and severity of five of their most bothersome symptoms.7 The use of prospective symptom recording is important in both clinical and research settings as the literature shows that more than half of the women who present with complaints of “severe PMS” are found not to have a pure luteal phase pattern based on prospective charts.3,7
It is necessary to establish a diagnosis of either PMS or PMDD and rule out other psychiatric disorders. One study found that of 426 women recruited from primary care obstetrics and gynecology practices who reported having PMS, 22% (93) were found to have major depressive disorder and 14% (61) had panic disorder.8 Of the women in that study who charted their symptoms for a cycle, only 22% were confirmed to have PMS.8 The symptom diaries also can identify women who present with complaints of PMS but are found to have psychological symptoms present throughout their cycle that worsen between ovulation and menstruation. This phenomenon is referred to as “menstrual magnification.”7 Many women find the information gleaned from charting their symptoms helpful in identifying potential triggers or lifestyle habits that may exacerbate them. Lastly, several experts7,9 have recommended that women try certain lifestyle changes or nutritional interventions during the cycles when they are recording their symptoms.
1. Rapkin A. A review of treatment of premenstrual syndrome and premenstrual dysphoric disorder. Psychoneuroendocrinology 2003;28:39-53.
2. American College of Obstetrics and Gynecologists. Premenstrual Syndrome. ACOG Practice Bulletin No. 15. 2000; April.
3. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (DSM-IV). 4th ed. Washington, DC: American Psychiatric Association; 1994:715-718.
4. Mortola JF, et al. Diagnosis of premenstrual syndrome by a simple, prospective, and reliable instrument: The calendar of premenstrual experiences. Obstet Gynecol 1990;76:302-307.
5. Thys-Jacobs S, et al. Comparative analysis of three PMS assessment instruments—the identification of premenstrual syndrome with core symptoms. Psychopharmacol Bull 1995;31: 389-396.
6. Endicott J. Severe premenstrual dysphoria: Differential diagnosis and treatment. J Am Med Womens Assoc 1998;53:170-175.
7. Johnson SR. Premenstrual syndrome, premenstrual dysphoric disorder, and beyond: A clinical primer for practitioners. Obstet Gynecol 2004;104:845-859.
8. Yonkers KA, et al. Premenstrual disorders: Bridging research and clinical reality. Arch Women Ment Health 2003;6:287-292.
9. Grady-Weliky TA. Clinical practice. Premenstrual dysphoric disorder. N Engl J Med 2003;348:433-438.