Papers

Treatment for the premenstrual syndrome with agnus castus fruit extract: prospective, randomised, placebo controlled study

R Schellenberg, senior consultant,  for the study group.

Institute for Health Care and Science, 35625 Hüttenberg, Germany

Correspondence to: rued.schellenberg.med{at}t-online.de

	Abstract

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Objectives: To compare the efficacy and tolerability of agnus castus fruit (Vitex agnus castus L extract Ze 440) with placebo for women with the premenstrual syndrome.
Design: Randomised, double blind, placebo controlled, parallel group comparison over three menstrual cycles.
Setting: General medicine community clinics.
Participants: 178 women were screened and 170 were evaluated (active 86; placebo 84). Mean age was 36 years, mean cycle length was 28 days, mean duration of menses was 4.5 days.
Interventions: Agnus castus (dry extract tablets) one tablet daily or matching placebo, given for three consecutive cycles.
Main outcome measures: Main efficacy variable: change from baseline to end point (end of third cycle) in women's self assessment of irritability, mood alteration, anger, headache, breast fullness, and other menstrual symptoms including bloating. Secondary efficacy variables: changes in clinical global impression (severity of condition, global improvement, and risk or benefit) and responder rate (50% reduction in symptoms).
Results: Improvement in the main variable was greater in the active group compared with placebo group (P<0.001). Analysis of the secondary variables showed significant (P<0.001) superiority of active treatment in each of the three global impression items. Responder rates were 52% and 24% for active and placebo, respectively. Seven women reported mild adverse events (four active; three placebo), none of which caused discontinuation of treatment.
Conclusions: Dry extract of agnus castus fruit is an effective and well tolerated treatment for the relief of symptoms of the premenstrual syndrome.

	Introduction

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The premenstrual syndrome is a complex combination of psychological symptoms, including irritability, aggression, tension, anxiety, and depression, and somatic changes such as fluid retention, breast tenderness, headache, feeling of bloating, and weight increase.¹ Women are affected irrespective of socioeconomic status, race, or cultural background, and family clusters are well documented. ^{2 3} The causes of the premenstrual syndrome have not been clearly elucidated⁴ but have been attributed to hormonal change, neurotransmitters, prostaglandins, diet, drugs, and lifestyle, so causal treatment is difficult.³

The fruits of Vitex agnus castus (the chaste tree) contain a mixture of iridoids and flavonoids, and some compounds similar in structure to the sex hormones have been isolated from the leaves and flowers.⁵ The effects of agnus castus have been described as similar to those of the corpus luteum. ^{6 7} The mechanism of action may also be related to modulation of stress induced prolactin secretion via dopamine, without directly affecting luteinising hormone or follicle stimulating hormone.^8-15 Binding to opioid receptors,¹⁶  endorphins,¹⁷ and neuroactive flavonoids ^{18 19} may also have a role. The plant has been used traditionally to relieve the symptoms of the premenstrual syndrome, although systematic evaluation of its efficacy is relatively recent.^{2 8 20-22}

We evaluated the effects of agnus castus fruit (Ze 440) in a large, prospective, randomised, placebo controlled study over three consecutive menstrual cycles. The study and analysis were planned and conducted under strict methodology.

	Methods

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Recruitment and blinding
All women were outpatients attending six general medicine clinics from April to December 1998. All physicians were experienced in the use the instruments of assessment and underwent training before the study on the scales to enhance consistency within and between centres. In each clinic all assessments were made by the same individual.

Selection of participants
All women were aged 18 years, had the premenstrual syndrome diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, third edition, revised (DSM-III-R)²³ and gave written informed consent before entry. Exclusion criteria were participation in other trials, concomitant psychotherapy, pregnancy or breast feeding, inadequate contraception, dementia, alcohol or drug dependence, concomitant serious medical condition, hypersensitivity to agnus castus, fever, pituitary disease, and concomitant use of sex hormones except oral contraceptives for which the doses were kept unchanged.

View larger version (19K): [in this window] [in a new window]   Flow of participants through study

Statistics, assignment, and analysis
All data were processed and analysed by the department of medical information technology at the University of Giessen. Randomisation was provided centrally in blocks of four. The main efficacy variable prospectively sought in the protocol was change from baseline to end point in the combined scores of the six self assessment items (irritability, mood alteration, anger, headache, other menstrual symptoms including bloating, and breast fullness). Women rated each item using a visual analogue scale²⁵ validated for the assessment of the premenstrual syndrome, ranging from 0 (no symptoms) to 10 (unbearable), measured in millimetres on the linear scale. We chose the scale because it was validated and also because it correlates closely with other more complex tools and is a rapid and straightforward assessment of effect for use in community practice. ^{21 25 26} Secondary variables were clinical global impression items 1 (severity of condition), 2 (global improvement or deterioration), and 3 (overall treatment assessment, risk or benefit) and responder rate, defined as 50% reduction in self assessed symptoms from baseline.

	Results

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Women's characteristics and flow through study
A total of 178 women were initially screened and randomised, of whom 170 had at least one baseline and one post-baseline value recorded (intention to treat population, figure). Characteristics at entry were balanced between the two groups (table 1). Twenty three women (13%) were taking oral contraceptives (11 in the active group).

Efficacy results
Table 2 shows the results at the end of the treatment period (three cycles). Analysis of the main efficacy variable (difference from baseline to end point between the two groups in self assessed symptoms) rejected the null hypothesis of the two treatments being equal. Patients who received agnus castus had a significant improvement in combined symptoms compared with those on placebo. The self assessment scores were corroborated by the physicians' own evaluation of all three items of the clinical global impression scale. Five of the six self assessment items indicated significant superiority for agnus castus (irritability, mood alteration, anger, headache, and breast fullness), other symptoms including bloating being unaffected by treatment. The responder rate was also favourable for the treated group relative to placebo (52% v 24%, respectively). Subgroup analyses that excluded women taking oral contraceptives and included the eight women who were screened but did not have any post-baseline values (assigned mean of combined groups) did not alter the results.

Safety results
There were few adverse events (table 3). Because of the low incidence of events we could not ascertain the commonest events related to agnus castus, despite the large sample sizes of the two groups. One woman withdrew because of pregnancy (placebo group) 55 days into the trial.

	Discussion

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We have shown that agnus castus (Ze 440 extract tablets) is an effective treatment for women with the premenstrual syndrome. Treatment of this condition is a challenge for doctors, who most often treat these women in the community. ^{2 8 20-22} Although the condition tends to be mild to moderate, the effects on women can be debilitating.³ We planned the study with an open minded approach to the efficacy of agnus castus. Although other investigators used active comparators,²¹ we set out to evaluate whether or not this herbal treatment had any relevant effect on the condition. By choosing placebo rather than an active control and by informing patients of the likelihood of receiving placebo we reduced the chances of any psychological influence that an active control would have on the two groups. We reduced the clinic visits to a minimum to allow as little influence as possible from the reassurance that sometimes can be gained from frequent medical check ups. Careful screening of the women resulted in relatively few losses to follow up, which can be a problem in studies of this condition.

We chose the duration of treatment of three cycles to overcome the variability of the symptoms over time, and we set the diagnosis strictly according to established criteria. The instruments of assessment were robust and validated, and all participating physicians underwent prior training with the scales so the results were consistent across the investigating clinics (no centre effect).

Patient acceptance is crucial in the treatment of this condition. The effects of agnus castus were clear to both the women and physicians. We have no data on the progress of symptoms after cessation of treatment, but other researchers have shown that though the effects of treatment gradually decrease over time, they are still felt for as long as three cycles after treatment (Berger et al, personal communication).

Tolerability of agnus castus was good in this study. Although herbal treatments are sometimes misguidedly considered to be completely safe, we did not identify any event related to treatment that could be considered prevalent in this population. In this regard, the fact that patients were aware of the chances of receiving either a herbal or placebo tablet may have played a part in the low incidence of reported events.

Conclusions
Agnus castus is a well tolerated and effective for the treatment for the premenstrual syndrome, the effects being confirmed by physicians and patients alike. The effects are detected in most main symptoms of the syndrome. This herbal remedy ought to be considered a therapeutic option in women in whom a causal origin for this syndrome cannot be established.

	Acknowledgments

Contributors: E Schrader, Pohlheim, was the study coordinator. The investigators were R Schellenberg (Hüttenberg), G Kunze (Rottweil), E R Pfaff (Mörfelden), A Massing (Offenbach), H Wältner (Albstadt-Tailfingen), Dr M Kirschbaum (Universitäts-Frauenklinik Giessen), R H Boedecker (statistics, Giessen). J Dudeck (statistics, Giessen) was responsible for statistics and data management. RS is guarantor.

	Footnotes

Funding: Zeller AG, CH-8590, Switzerland supplied the study medication and sponsored the study through the Clinical Research Organisation Praxis Klinische Arzneimittelforschung, Polheim, Germany.

Competing interests: None declared.

	References

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(Accepted 17 November 2000)