CME

Premenstrual syndrome

Evidence-based treatment in family practice

Sue Douglas, MD, CCFP

ABSTRACT

OBJECTIVE To evaluate the strength of evidence for treatments for premenstrual syndrome (PMS) and to derive a set of practical guidelines for managing PMS in family practice.
QUALITY OF EVIDENCE An advanced MEDLINE search was conducted from January 1990 to December 2001. The Cochrane Library and personal contacts were also used. Quality of evidence in studies ranged from level I to level III, depending on the intervention.
MAIN MESSAGE Good scientific evidence shows that calcium carbonate (1200 mg/d) and selective serotonin reuptake inhibitors are effective treatments for PMS. The most commonly used therapies (including vitamin B6, evening primrose oil, and oral contraceptives) are based on inconclusive evidence. Other treatments for which there is inconclusive evidence include aerobic exercise, stress reduction, cognitive therapy, spironolactone, magnesium, nonsteroidal anti-inflammatory drugs, various hormonal regimens, and a complex carbohydrate–rich diet. Although evidence for them is inconclusive, it is reasonable to recommend healthy lifestyle changes given their overall health benefits. Progesterone and bromocriptine, which are still widely used, are ineffective.
CONCLUSION Calcium carbonate should be recommended as first-line therapy for women with mild-to-moderate PMS. Selective serotonin reuptake inhibitors can be considered as first-line therapy for women with severe affective symptoms and for women with milder symptoms who have failed to respond to other therapies. Other therapies may be tried if these measures fail to provide adequate relief.

RÉSUMÉ

OBJECTIF Évaluer la validité des preuves à la base des différents traitements du syndrome prémenstruel (SPM) et, à partir de cette analyse, formuler des directives pratiques pour le traitement de cette affection en médecine familiale.
QUALITÉ DES PREUVES Une recherche avancée a été effectuée dans Medline entre janvier 1990 et décembre 2001. On a également eu recours à la Cockrane Library et à des contacts personnels. Dans les études retenues, les preuves étaient de niveau I à III selon le type d’intervention utilisée.
PRINCIPAL MESSAGE L’efficacité du carbonate de calcium (1200 mg/d) et des inhibiteurs sélectifs du recaptage de la sérotonine dans le traitement du SPM repose sur des données scientifiques solides. Les traitements les plus fréquemment utilisés (incluant la vitamine B6, l’huile d’onagre et les contraceptifs oraux) ne sont pas fondés sur des données probantes. Les autres traitements pour lesquels les preuves ne sont pas concluantes incluent les exercices aérobies, la réduction du stress, la thérapie cognitive, la spironolactone, le magnésium, le anti-inflammatoires non stéroïdiens, divers traitements hormonaux et un régime alimentaire riche en glucides complexes. Malgré l’absence de preuves concluantes, l’adoption d’habitudes de vie plus saines peut être préconisée, vu les avantages globaux d’un tel changement. Même si la progestérone et la bromocriptine sont largement utilisées, elles ne sont pas efficaces.
CONCLUSION Le carbonate de calcium devrait être recommandé comme traitement de première ligne pour les femmes qui présentent un SPM léger à modéré. En présence de symptômes affectifs sévères ou de symptômes moins sévères ne répondant pas aux autres formes de traitement, l’utilisation d’inhibiteurs sélectifs du recaptage de la sérotonine peut être envisagée. Si ces mesures ne procurent pas un soulagement adéquat, d’autres traitements peuvent être essayés.

This article has been peer reviewed. Cet article a fait l’objet d’une évaluation externe.
Can Fam Physician 2002;48:1789-1797.

Dr Douglas is an Assistant Professor in the Department of Family Medicine at Dalhousie University in Halifax, NS.

Premenstrual syndrome (PMS) is a common cause of substantial psychological and physical distress for women during their reproductive years. Forty percent of women have symptoms that are severe enough to disrupt some aspect of their daily lives; 5% are incapacitated by their symptoms.1,2

Despite the magnitude of this problem, a lot of confusion exists in medical and lay communities alike about what is and is not effective for treatment of PMS. This in part reflects the fact that the cause of PMS is still unknown, although several theories have been proposed including hormonal imbalances, micronutrient deficiencies, and neuroendocrine dysfunction.2 A range of treatments currently available reflect this theoretical diversity.2 Consequently, it has become increasingly difficult to counsel patients on what is safe and effective for treatment of PMS.

Despite inherent challenges, family physicians are in an ideal position to diagnose and treat this common but often overlooked condition. This study aimed to apply the principles of evidence-based medicine to derive a set of recommendations for treating PMS in family practice.

Quality of evidence

Several information sources were used including an advanced MEDLINE search, Cochrane Library database, and personal contacts. The advanced MEDLINE and Cochrane Library databases were searched first to determine the strength of evidence arising from clinical trials for various therapies. The MEDLINE search was limited to English articles from January 1990 to December 2001. Premenstrual syndrome and synonymous terms identified by the thesaurus were cross-matched with the MeSH headings diet therapy, drug therapy, prevention and control, rehabilitation, and therapy. These terms were then cross-matched with the MeSH heading “review” to help identify any systematic reviews already published on the topic. Individual searches were performed on identified treatments using the specific treatments as MeSH headings. Appropriate articles were obtained and critically appraised.

Search of the Cochrane Library database obtained review protocols on the use of vitamin B, evening primrose oil, and selective serotonin reuptake inhibitors (SSRIs) for treatment of PMS. Primary authors of the reviews3-5 were contacted, and they generously provided their preliminary conclusions along with a list of supporting references.

Possible treatments were categorized as one of the following: effective, inconclusive evidence, and ineffective. Evidence for effective treatments came from good-quality randomized controlled trials (level I evidence) that showed unequivocally positive benefits of treatment. Evidence was categorized as inconclusive if studies showed positive benefits but had methodologic limitations, including small study size, few trials, lack of true control groups, and questionable clinical significance of positive findings (level II and III evidence). Finally, treatments were categorized as ineffective if good-quality studies showed no significant benefits, if studies showed that the risks and costs clearly outweighed potential advantages, or if studies had serious methodologic flaws that invalidated any positive findings.

Effective treatments

Calcium. Thys-Jacobs et al6 conducted a large multicentre trial (12 sites) involving 466 women diagnosed with moderate-to-severe PMS. Women were randomized to a calcium carbonate (1200 mg/d) or placebo group. Women recorded their symptoms daily over three cycles. Compliance with treatment was measured. Main outcome measure was a 17-parameter complex score. No significant reduction in symptoms was reported after the first cycle. By the third cycle, however, women reported a 48% reduction in their total symptom scores (P < .001) compared with baseline. In addition all four-symptom factors (negative affect, fluid retention, cravings, pain) were significantly reduced by the third cycle. Given the study’s sound methodology, large size, and size of the treatment effect, these findings provide good evidence for the effectiveness of calcium carbonate as a treatment for PMS. Calcium is also relatively inexpensive and is important in preventing osteoporosis; therefore, it is recommended as first-line treatment for PMS.

Selective serotonin reuptake inhibitors. Another significant advance in the treatment of PMS is the use of SSRIs. Premenstrual syndrome has been linked with dysfunctional serotonin metabolism, and experimental evidence suggests that hormonal fluctuations do affect central serotonin levels.7 Dimmock et al8 recently published a comprehensive systematic review on the topic including a meta-analysis involving 15 randomized controlled trials. Results of the meta-analysis strongly support the effectiveness of SSRIs in treatment of PMS. Interestingly, the study group also found no difference in effectiveness between continuous and intermittent therapy during the luteal phase. The effectiveness of SSRIs administered intermittently has been attributed to differences in receptor sites involved in affective and PMS disorders. The doses used for PMS also tend to be lower than those used for depression. Consequently the incidence of side effects tends to be lower as well.9

Use of SSRIs is not without drawbacks, however. A host of reported side effects include headache, nervousness, insomnia, drowsiness, fatigue, sexual dysfunction, and gastrointestinal complaints. The SSRIs are also relatively expensive, especially brand-name formulations. Nonetheless, given their proven efficacy, they are recommended, particularly for women with severe affective symptoms for whom other measures have been ineffective.

Inconclusive evidence

The largest number of treatments had inconclusive evidence. For this diverse group of therapies, evidence supporting effectiveness ranges from likely effective to likely ineffective. Consequently, readers are encouraged to draw their own conclusions about the role of these therapies for management of individual patients.

Diet. Dietary restrictions are often recommended to help alleviate the physical and psychological symptoms of PMS. The most common dietary recommendations are to restrict sugar and increase consumption of complex carbohydrates.10 Of these measures, only an increase in carbohydrate consumption has been studied in a randomized controlled trial. One small trial involving 24 women found that women who consumed a carbohydrate-rich beverage daily during the late luteal phase reported fewer mood changes in the hours following consumption than women who consumed an isocaloric beverage.11 While the scientific evidence is very limited, given the overall health benefits of a healthy diet rich in complex carbohydrates, it would be reasonable to include this diet as part of initial management of PMS.

Aerobic exercise. Women who have PMS are often encouraged to increase their activity level. It has been hypothesized that exercise (particularly aerobic varieties) increases endorphin levels, which in turn improves mood.10 Several descriptive studies indicate that women who exercise regularly have fewer PMS symptoms than sedentary women.12 Another study has shown that previously sedentary women as well as women who already exercise regularly who increase their activity levels report fewer PMS symptoms.13 Finally, one randomized controlled unblinded trial involving 23 women found that women randomized to an aerobic exercise group did report fewer PMS symptoms after three cycles than women who were in a nonaerobic exercise group.14 While most of the studies are not randomized or are descriptive in nature, the cumulative evidence suggests that aerobic exercise is likely to reduce PMS symptoms. Given the associated benefits of exercise, it seems reasonable to recommend an aerobic exercise program to help alleviate PMS symptoms.

Psychological approaches. Epidemiologic evidence suggests that increased stress levels aggravate PMS symptoms.15 Various trials suggest that relaxation and cognitive therapies help alleviate PMS symptoms. In one trial, women were randomized to a group instructed to practise a relaxation technique for 20 minutes a day or to 20 minutes in a “quiet time” group. The women in the relaxation response group reported fewer PMS symptoms than women in the “quiet time” group.16

In another study, women who reported “severe” PMS symptoms were randomized to groups learning cognitive-behavioural coping skills, “nonspecific behavioural” techniques, and a waiting list. Women in the cognitive-behavioural group reported significantly fewer PMS symptoms than women in the other groups immediately following treatment and at 9-month follow up.17 In another study, both cognitive-behavioural and information-focused therapy led to substantial reductions in symptoms.18 These studies involved relatively small numbers and often lacked “true” control groups; their cumulative results suggest that various psychological approaches including instruction on relaxation techniques, cognitive-behavioural strategies, and information on ways to relieve PMS symptoms.

Pyridoxine (vitamin B6). Pyridoxine, or vitamin B6, is one of the most widely used and probably the most controversial treatment for PMS. Vitamin B6 is believed to correct a deficiency in the hypothalamic-pituitary axis.10 Vitamin B6 is a cofactor in the synthesis of tryptophan and tyrosine, which are the precursors of serotonin and dopamine, respectively.19 Theoretically, low levels of vitamin B6 lead to high levels of prolactin that in turn produce the edema and psychological symptoms associated with PMS.3

There have been at least 24 trials on use of vitamin B6 for treatment of PMS.4 Recently, Wyatt et al4 performed a systematic review and meta-analysis on the topic. They included the results of nine randomized controlled trials in the meta-analysis. Overall quality of the trials was considered to be poor. In addition the trials were quite heterogeneous in terms of their inclusion and exclusion criteria as well as the outcome measures examined, which makes interpretation of the findings difficult. The results of the meta-analysis did show “some” benefit of treatment with vitamin B6 (odds ratio 2.12, confidence interval 1.8 to 2.48). Their overall conclusions, however, were that available data suggested some benefit, but there was insufficient evidence of high enough quality to confidently recommend vitamin B6 for treatment of PMS.

Vitamin B6 can also cause substantial toxicity and unpleasant side effects. Taken at doses as low as 500 mg daily, it can produce a progressive sensory ataxia and can also cause gastrointestinal side effects, particularly nausea.20

Evening primrose oil. Evening primrose oil is used extensively to alleviate PMS symptoms. Evening primrose oil contains two essential fatty acids: linoleic and -linolenic. Some experts suggest that women with PMS are deficient in -linolenic acid, which is necessary for prostaglandin formation.20 A large body of literature explores this topic; however, the poor quality and methodologic limitations of the studies have made it difficult to draw any firm conclusions about the efficacy of evening primrose oil.21 Buderi et al21 systematically reviewed clinical trials done before 1995. Only two of the seven studies were judged to be of high methodologic quality, and these failed to show any significant benefits.

Evening primrose oil is generally well tolerated, but occasionally it can produce nausea, dyspepsia, and headache. Long-term use can be associated with increased risk of inflammation, thrombosis, and immunosuppression.20 Finally, evening primrose oil is relatively expensive, and current scientific evidence does not support its general use for treatment of PMS.

Combination oral contraceptives and progestins. Combination oral contraceptives (OCPs) are also widely used to treat PMS. Despite their popularity, only one randomized controlled trial has compared an OCP (triphasic) to placebo.22 This trial involved 82 women, of whom only 45 completed the study. There was some improvement in physical symptoms but not mood changes. Several descriptive studies have also looked at the effects of OCPs on mood and PMS and have had very mixed results.23,24

It seems counterintuitive that a treatment to suppress ovulation does not also alleviate PMS symptoms. There is some evidence, however, that it is not ovulation per se that underlies PMS, but rather the brain’s response to fluctuating hormone levels in susceptible women that triggers symptoms.2 Because they are associated with changes in hormonal levels, it is not surprising that OCPs can cause similar symptoms. The progestin to estrogen ratio is also probably important in development of negative mood changes. If OCPs are used to treat PMS, a monophasic preparation should theoretically be given continuously.2

In another double-blind crossover study involving 48 women with PMS,25 subjects were given medroxyprogesterone (MPA) or norethisterone (NET) (15 mg daily for 21 days). By the end of the second treatment cycle, women in the MPA group showed significant improvement in their overall psychological scores, whereas women in the NET group showed no difference over placebo. The rate of side effects in the MPA group was significantly higher; 74% of women reported breakthrough bleeding in the MPA group compared with 22% in the NET group.

Other therapies. Other therapies used to treat PMS include magnesium, nonsteroidal anti-inflammatory drugs, spironolactone, and various hormonal regimens to suppress ovulation. Table 1 summarizes the studies and level of evidence for these additional therapies.26-35

Ineffective treatments

Progesterone and progestogens. Progesterone has been widely publicized in the lay literature as a treatment for PMS.10 Treatment with high doses of “natural” progesterone vaginally became popular in the 1970s after publication of many case reports in the lay press, none of which had any true controls.36 Since then, several randomized controlled trials have failed to show any benefit from topical or oral micronized progesterone over placebo.37-40 Similarly, a recent comprehensive systematic review and meta-analysis on the topic failed to show any evidence supporting continued use of progesterone in treatment of PMS.41 Topical progesterone is also expensive. Given the lack of efficacy and the expense, progesterone cannot be recommended as a treatment for PMS.

Bromocriptine. Another theory popular in the 1970s was that PMS was caused by increased levels of, or an increased sensitivity to, prolactin.10 Consequently, bromocriptine was often prescribed to women suffering from PMS, particularly those with substantial fluid retention and breast tenderness. An extensive review by Andersch,42 which analyzed 14 randomized controlled trials until 1982, found no improvement in general PMS symptoms compared with placebo. One exception was severe cyclic mastalgia, for which bromocriptine might be effective.42 A more recent double-blind randomized crossover trial involving 21 women did show some improvement in abdominal bloating and mastalgia, but no effect on emotional symptoms.43 Bromocriptine is also expensive and has several side effects. Consequently its use cannot be recommended for general treatment of PMS.

Recommendations

How should family physicians interpret all this information? While the strength of evidence is central in making rational management decisions, other factors must also be taken into account. These include treatment costs, potential health benefits, adverse effects, individual risk factors, comorbidity, and severity of symptoms. In arriving at a set of guidelines, I evaluated the strength of evidence in the context of these other factors (Table 2). Physicians must judge for themselves how to translate these guidelines into individual management plans for patients.

Conclusion

Optimal management of PMS requires more than scientific knowledge. It also requires a systematic approach to screening and strong patient-centred communication skills to determine patients’ ideas about their symptoms and how they affect their lives. Personal relationships with patients are also important in negotiating treatment plans that are acceptable to patients, particularly where lifestyle changes are concerned. Finally, continuity of care is essential, as it can take months before any improvement is noted.

Acknowledgment

I thank Dr John Hickey for his encouragement and comments on early drafts and the Dalhousie Family Medicine writers’ support group for their critique of the final manuscript.

Competing interests

None declared

Correspondence to: Dr S. Douglas, Department of Family Medicine, Dalhousie University, Abbie Lane Bldg, QEII Hospital, 5909 Veterans Memorial Ln, Halifax, NS B3H 2E2; telephone (902) 473-6250; fax (902) 473-8548; e-mail sue.douglas@dal.ca

References

1. O’Brien PM. Helping women with premenstrual syndrome. BMJ 1993;307:1471-5.
2. Chakmajian ZH. A critical assessment of therapy for premenstrual tension syndrome. J Reprod Med 1983;28:532-8.
3. Iasco SM, Castro AA, Atallah AN. Vitamin B6 in premenstrual syndrome (Protocol for a Cochrane review). In: The Cochrane Library. Oxford, Engl: Update Software; 1999. Issue 4.
4. Wyatt KM, Dimmock PW, Shaughn O’Brien PM. Efficacy of vitamin B-6 in the treatment of premenstrual syndrome: systematic review. BMJ 1999;318:1375-81.
5. Strid J, Jepson R, Moore V, Kleijen J, Iasco SM. Evening primrose oil or other essential fatty acids for pre-menstrual syndrome (Protocol for a Cochrane review). In: The Cochrane Library. Oxford, Engl; Update Software; 1999. Issue 4.
6. Thys-Jacobs S, Starkey P, Bernstein D, Tian J. Calcium carbonate and the premenstrual syndrome: effects on premenstrual menstrual symptoms. Premenstrual Syndrome Study Group. Am J Obstet Gynecol 1998;179(2):444-52.
7. Wyatt KM, Drimmock PW, O’Brien PMS. Selective serotonin reuptake inhibitors for premenstrual syndrome (Protocol for a Cochrane review). In: The Cochrane Library. Oxford, Engl: Update Software; 1999. Issue 4.
8. Dimmock PW, Wyatt KM, Jones PW, O’Brien PM. Efficacy of selective serotonin-reuptake inhibitors in premenstrual syndrome: a systematic review. Lancet 2000;356(Sept 30):1131-6.
9. Eriksson E. Serotonin reuptake inhibitors for the treatment of premenstrual dysphoria. Int Clin Psychopharmacol 1999;14(Suppl 2):S27–33.
10. Johnson SR. Pre-menstrual syndrome therapy. Clin Obstet Gynecol 1998;41(2):405-21.
11. Sayegh R, Schiff I, Wurtman J, Spiers P, McDermott J, Wurtman R. The effect of a carbohydrate-rich beverage on mood, appetite, and cognitive function in women with premenstrual symptoms. Obstet Gynecol 1995;86:520-8.
12. Aganoff JA, Boyle GJ. Aerobic exercise, mood states, and menstrual cycle symptoms. J Psychosom Res 1994;38:183-92.
13. Steege JF, Blumenthal JA. The effects of aerobic exercise on premenstrual symptoms in middle-aged women: a preliminary study. J Psychosom Res 1993;37:127-33.
14. Prior JC, Vigna Y, Sciarretta D, Alojado N, Schulzer M. Conditioning exercise decreases premenstrual symptoms: a prospective controlled 6-month trial. Fertil Steril 1987;47:402-8.
15. Woods NF, Most A, Longenecker GD. Major life events, daily stressors, and perimenstrual symptoms. Nurs Res 1985;33:263-7.
16. Kirby RJ. Changes in premenstrual symptoms and irrational thinking following cognitive behavioural coping skills training. J Consult Clin Psychol 1994;62:1026-32.
17. Goodale IL, Domar AD, Benson H. Alleviation of premenstrual symptoms with the relaxation response. Obstet Gynecol 1990;75:649-55.
18. Christensen AP, Oei TP. The efficacy of cognitive behaviour therapy in treating premenstrual dysphoric change. J Affect Disord 1995;33:57-63.
19. Freidrich W. Vitamin B6. In: Vitamins. New York, NY: De Gruyter; 1988. p. 543-618.
20. Jellin JM, Batz F, Hitchens K. Pharmacists letter/Prescriber’s letter; Natural Comprehensive Database. Stockton, Calif: Therapeutic Research Faculty; 1999. p. 330-1, 550-1.
21. Budeiri D, Li Wan Po A, Dornan JC. Is evening primrose oil of value in the treatment of premenstrual syndrome? Control Clin Trials 1996;17:60-8.
22. Graham CA, Sherwin BB. A prospective treatment study of premenstrual symptoms using a triphasic oral contraceptive. J Psychosom Res 1992;36:257-66.
23. Graham CA, Sherwin BB. The relationship between retrospective premenstrual symptom reporting and present oral contraceptive use. J Psychosom Res 1987;31:45-53.
24. Bancroft J, Rennie D. The impact of oral contraceptive use on perimenstrual mood, clumsiness, food cravings, and other symptoms. J Psychosom Res 1993;37:195-202.
25. West CP. Inhibition of ovulation with oral progestins—effectiveness in premenstrual syndrome. Eur J Obstet Gynecol Reprod Biol 1990;34:119-28.
26. Facchinetti F, Borella P, Sances G, Fioroni L, Nappi RG, Genazzani AR. Oral magnesium successfully relieves premenstrual mood changes. Obstet Gynecol 1991;78:177-81.
27. Walker AF, De Souza MC, Vickers MF, Abeyasekera S, Collins ML, Trinca LA. Magnesium supplementation alleviates premenstrual symptoms of fluid retention. J Womens Health 1998;7(9):1157-65.
28. London RS, Murphy L, Kitlowski KE, Reynolds MA. Efficacy of alpha-tocopherol in the treatment of premenstrual syndrome. J Reprod Med 1987;32(6):400-4.
29. O’Brien PM, Craven D, Selby C, Symonds EM. Treatment of premenstrual syndrome by spironolactone. Br J Obstet Gynaecol 1979;86:142-7.
30. Vellacott ID, Shroff NE, Pearce MY, Stratford ME, Akbar FA. A double-blind, placebo-controlled evaluation of spironolactone in the premenstrual syndrome. Curr Med Res Opin 1987;10:450-6.
31. Wood C, Jakubowicz D. The treatment of premenstrual symptoms with mefenamic acid. Br J Obstet Gynecol 1980;87:627-30.
32. Mira M, McNeil D, Fraser IS, Vizzard J, Abraham S. Mefenamic acid in the treatment of premenstrual syndrome. Obstet Gyenecol 1986;68:395-8.
33. Facchinetti F, Fioroni L, Sances G, Romano G, Nappi G, Genazanni AR. Naproxen sodium in the treatment of premenstrual symptoms. A placebo controlled study. Gynecol Obstet Invest 1989;28:205-8.
34. Watson NR, Studd JW, Savvas M, Garnett T, Baber RJ. Treatment of severe premenstrual syndrome with oestradiol patches and cyclical oral norethisterone. Lancet 1989;2:730-2.
35. Smith RN, Studd JW, Zamblera D, Holland EF. A randomised comparison over 8 months of 100 micrograms and 200 micrograms twice weekly doses of topical oestradiol in the treatment of severe premenstrual syndrome. Br J Obstet Gynecol 1995;102:475-84.
36. Dalton K. The premenstrual syndrome and progesterone therapy. 2nd ed. Chicago, Ill: Year Book Medical Publisher; 1984.
37. Freeman E, Rickels K, Soundheimer SJ, Polansky M. Ineffectiveness of progesterone suppository treatment for premenstrual syndrome. JAMA 1990;264:349-53.
38. Andersch B, Hahn L. Progesterone treatment of premenstral tension—a double blind study. J Psychosom Res 1985;29:489-93.
39. Maddock S, Hahn P, Moller F, Reid RL. A double blind placebo-controlled trial of progesterone vaginal suppositories in the treatment of premenstrual syndrome. Am J Obstet Gynecol 1986;154:573-81.
40. Sampson GA. Premenstrual syndrome: a double-blind trial of progesterone and placebo. Br J Psychiatry 1979;135:209-15.
41. Wyatt K, Dimmock P, Jones P, Obhrai M, O’Brien S. Efficacy of progesterone and progestogens in management of premenstrual syndrome: systematic review. BMJ 2001;323:776-80.
42. Andersch B. Bromocriptine and premenstrual syndrome: a survey of double-blind trials. Obstet Gynecol Surv 1983;38:643-6.
43. Meden-Vrtovec H, Vujic D. Bromocriptine in the management of premenstrual syndrome. Clin Exp Obstet Gynecol 1992;19(4):242-8.