Vitex agnus castus for premenstrual syndrome

Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

To determine the effectiveness of Vitex agnus castus for the treatment of PMS symptoms.

We wish to examine the following: (1) The effect of Vitex agnus castus on combined symptoms or global scores associated with PMS versus placebo. (2) The effect of Vitex agnus castus on combined symptoms or global scores associated with PMS versus another treatment (listed below). (3) The effect of Vitex agnus castus on patient satisfaction versus placebo. (4) The effect of Vitex agnus castus on patient satisfaction versus another treatment. (5) The effect of Vitex agnus castus on specific symptoms associated with PMS versus placebo. (6) The effect of Vitex agnus castus on specific symptoms associated with PMS versus another treatment. (7) The adverse effects of Vitex agnus castus.

Background

Premenstrual syndrome (PMS) is a common condition. In the United Kingdom (UK), it is estimated that up to 1.5 million women experience significant, disruptive symptoms (Wyatt 2001). PMS is defined as the cyclical recurrence of psychological, behavioural or physical symptoms during the luteal phase of the menstrual cycle. The symptoms should resolve completely by the end of menstruation and women should be free of symptoms for at least one week between menstruation and ovulation (O'Brien 1997). Over 150 symptoms have been attributed to PMS. Common symptoms include breast pain (cyclical mastalgia), headache, backache, lack of energy, clumsiness, tension, anxiety, irritability, depression, food cravings, bloating and changes to sex drive. For diagnosis, the nature of the symptoms is less important than the timing of the symptoms, particularly the resolution of the symptoms by the end of menstruation (O'Brien 1997). If the timing of symptoms in relation to menstruation is not established, PMS can be confused with other conditions such as anxiety and depression and may be misdiagnosed or mistreated (Gardner 1998). It is estimated that up to 95% of women of reproductive age suffer mild 'physiological' premenstrual symptoms. In the majority, these are tolerated and there is no interference with normal functioning (O'Brien 1998). Five to ten per cent have 'pathological' symptoms severe enough to disrupt their lives significantly in the two weeks before menstruation, justifying the term PMS (O'Brien 1993). The term premenstrual dysphoric disorder (PMDD) describes a subgroup of women using stringent diagnostic criteria, emphasising the severity and associated major disruption to life and relationships caused by PMS (DSM IV 1994). It must be confirmed prospectively by means of daily diary ratings of symptoms over at least two consecutive cycles.

Diagnosis of PMS is based on history, questionnaires, exclusion of certain specific disorders and the use of prospectively administered symptom‐rating methods(O'Brien 1998). Retrospectively recalled symptoms are unreliable and ideally should not be used to make the diagnosis (Collier 2002) In clinical practice, however, PMS is usually diagnosed by self report from the woman. Prospective record keeping is more accurate, but can lead to high dropout rates, particularly with lengthy scales (Budieri 1994). Women often diagnose and treat themselves (Strid 2002). In clinical trials, there is wide diversity in the scales used for assessing entry eligibility and treatment outcomes in PMS. A review of 350 clinical trials for PMS found that 65 different scales or questionnaires were used to classify PMS and for entry eligibility and treatment outcomes (Budieri 1994). This makes comparative evaluation of possible treatments difficult (Budieri 1994). Some scales assign a premenstrual score according to the most troublesome symptoms. Although easy to analyse statistically, such scales can lead to potentially heterogeneous populations of PMS sufferers, grouping those who have predominantly physical symptoms with those having predominantly psychological symptoms. Other scales attempt to divide participants into subgroups according to symptoms clusters to minimise heterogeneity. Within the scales the numerical scores assigned to a question may take integer values or continuous analogue scales. Numerical ranges vary from 95 to 570 in the premenstrual assessment form (PAF) to 0 to 15 in the premenstrual tension‐cator (PMT‐cator).

Despite its prevalence, the cause of PMS is not fully understood. Elimination of ovarian function by hysterectomy and bilateral oophorectomy or by medical suppression of the cycle results in complete suppression of premenstrual symptoms, implying that they are triggered by the cyclical fluctuation in endogenous oestrogen and progesterone (O'Brien 1997). The mechanism underlying an abnormal response to these hormones in some women is not clear. Many hypotheses have been proposed, including abnormal neurotransmitter (chemicals released in the brain) response to oestrogen and progesterone, deficiencies of nutrients such as pyridoxine, magnesium and carbohydrate, and hormonal imbalances such as progesterone deficiency. An abnormality of the hypothalamic‐pituitary axis has also been proposed. (Women with PMS have significantly higher levels of prolactin, especially in the second and third week of their cycles(Tesch 2003).) Numerous treatment options exist including surgical techniques, antidepressants, nonsteroidal anti‐inflammatory drugs (NSAIDs), hormonal preparations, dietary supplements, cognitive therapy and exercise. Several are effective for one or more of the symptoms of PMS. The most convincing evidence is in favour of NSAIDs, diuretics (spironolactone) and selective serotonin re‐uptake inhibitors (SSRIs) (Wyatt 2003), but not all women respond to these. Somen women suffer adverse effects and increasingly seek 'natural methods' (Wyatt 2002). Surveys of women with PMS show that complementary therapies are popular and women report finding them more helpful than orthodox medicine (Corney 1991). Many more women use self help measures than seek advice from a physician (Johnson 1988).

VITEX AGNUS CASTUS AND PMS Vitex agnus castus (medicinal species) or Vitex, agnus castus, chaste tree, chasteberry or Monk's Pepper (common names) is a shrub that originates from the Mediterranean and western Asia. The plant has been used traditionally to relieve symptoms of a number of disorders including those attributed to PMS. It is commonly used in Europe. The berries are the most popular part of the plant used and contain a wide range of potentially active constituents, including essential oils, iridoids and flavonoids (Christie 1997; Girman 2003; Tesch 2003). These are all groups of compounds which occur naturally in plants and have a range of therapeutic properties. The mechanism of action has been investigated in human, animal and in vitro studies. It has been shown to bind to dopamine receptors, acting as an agonist (in other words stimulating the receptor) in vitro(Barnes 2002). In humans it has been shown to reduce levels of follicle‐stimulating hormone and increase luteinizing hormone (LH) resulting in decreased oestrogen and increased progesterone and prolactin levels (Girman 2003). Several studies have shown reduction of prolactin concentration after treatment with Vitex agnus castus, and one study involving healthy men found that low dose Vitex agnus castus increased prolactin levels whereas higher doses decreased prolactin levels (Barnes 2002). One proposed mechanism of action is that Vitex agnus castus causes a decrease in prolactin, which leads to a reversal of LH suppression allowing full development of the corpus lutem, increasing progesterone levels and reducing symptoms of PMS(Tesch 2003).

As with all herbal remedies, a variety of Vitex agnus castus preparations are used which can differ substantially in terms of, for instance, concentration of active ingredients or bioavailability. A survey of members of the National Institute of Medical Herbalists showed that the tincture is the most popular preparation among herbalists, but fluid extracts and powdered herb preparations are also common. A standardised solid extract of Vitex agnus castus is rarely used by herbalists (Christie 1997). Treatment regimens and doses vary. Treatment by herbalists is holistic, with different diagnostic taxonomies from orthodox medicine (for example, diagnosis may involve a body system like 'underfunctioning of a patient's system of elimination' instead of a specific disease)(Vickers 1999)and treatment usually involves individualised prescription of several herbs in combination, along with dietary advice. Vitex agnus castus is available in the UK without a prescription and this type of usage is most likely considerably more prevalent than usage via herbalists' prescriptions. It is sold as a herbal supplement and therefore not licensed as a medicine. The trials in this review will examine the effect of Vitex agnus castus in isolation, as opposed to the way in which traditional herbalists would use it..

The effects of Vitex agnus castus on premenstrual syndrome is the subject of many clinical reviews, but to date no systematic review or meta‐analyses has been published.

Objectives

To determine the effectiveness of Vitex agnus castus for the treatment of PMS symptoms.

We wish to examine the following: (1) The effect of Vitex agnus castus on combined symptoms or global scores associated with PMS versus placebo. (2) The effect of Vitex agnus castus on combined symptoms or global scores associated with PMS versus another treatment (listed below). (3) The effect of Vitex agnus castus on patient satisfaction versus placebo. (4) The effect of Vitex agnus castus on patient satisfaction versus another treatment. (5) The effect of Vitex agnus castus on specific symptoms associated with PMS versus placebo. (6) The effect of Vitex agnus castus on specific symptoms associated with PMS versus another treatment. (7) The adverse effects of Vitex agnus castus.

Methods

Criteria for considering studies for this review

Types of studies

All randomised controlled trials of Vitex agnus castus versus placebo or any other treatment for PMS symptoms. We will consider any method of randomisation, but a sensitivity analysis will examine the effect of excluding 'quasi‐randomised' trials. (Quasi‐random allocation is a method of allocation that is not truly random, for example, allocation by date of birth.) Crossover trials will be excluded unless data can be extracted from the first arm. Where such data are not available, the trial will be described qualitatively in the review.

Types of participants

Inclusion criteria: Participants in the trials need to meet these criteria for the trial to be included in the review.

• Women of reproductive age.

• Women with PMS or PMDD symptoms diagnosed either by a clinician or other health professional (for example, a medical herbalist) in any setting. Diagnosis may be based on self reported symptoms or may be prospective. The former is included as it reflects what often happens in clinical practice and is therefore pragmatic.

Exclusion criteria:

• Women with pre‐existing conditions (such as asthma, depression or headache), which are exacerbated premenstrually.

• Women with cyclical mastalgia alone, as opposed to part of the syndrome of PMS.

• Women receiving other treatments for PMS in addition to Vitex agnus castus, excepting analgesia taken as needed, which is a secondary outcome.

We will not exclude trials that involve women on the contraceptive pill as a pragmatic approach. There is evidence, however, that the contraceptive pill may be an effective treatment for PMS (Wyatt 2003). We will therefore examine the possible contribution of such trials to the overall results in a sensitivity analysis. If there are no data on contraceptive pill usage, we will contact the authors.

Types of interventions

Inclusion criteria: Interventions in the trials need to meet these criteria for the trial to be included in the review.

• Any dose of Vitex agnus castus.

• Duration of intervention must be at least one month, otherwise variation in the duration of trials and the frequency of administration of treatment is acceptable. Treatment need not be taken throughout the month, luteal phase treatment only is acceptable.

Exclusion criteria:

• Combination preparations of Vitex agnus castus and other treatments.

• Homeopathic preparations of Vitex agnus castus.

We will consider any study with placebo or other recognised treatment for premenstrual syndrome from the list below as a comparator intervention. We will exclude studies comparing intervention with no treatment (for example, waiting list control). Types of comparison intervention: All recognised treatments for premenstrual syndrome, including:

• progesterone or progestogens (any route or timing);

• oestrogens;

• tibolone;

• danazol;

• gonadotrophin releasing hormone analogues;

• bromocriptine;

• oral contraception;

• diuretics;

• prostaglandin inhibitors;

• anxiolytics and antidepressants (including non‐selective and selective serotonin reuptake inhibitors);

• vitamin B6;

• evening primrose oil;

• calcium and magnesium dietary supplements;

• cognitive behavioural therapy;

• exercise;

• surgery (including hysterectomy and/or bilateral salpingo‐oophorectomy or endometrial ablation).

We will consider all doses and length of treatment or follow up.

Types of outcome measures

We will consider all measurement tools for assessment of symptoms of PMS as well as satisfaction levels for the participants.

Primary outcomes: (1) Combined PMS symptoms or global reported scores. (2) Participant satisfaction with treatment. (3) Specific symptoms or clusters of symptoms, for example, cyclical breast pain, headache, irritability, depression, bloatedness, fatigue, increased appetite, changes in libido. Where overlapping symptoms are reported in separate trials, we will make an a priori decision to combine such symptoms. (4) Side effects of treatment with Vitex agnus castus.

Secondary outcomes: (1) Cost. Where cost is reported, we will look at comparative costs. (2) Requirements for analgesia. (3) Absence from school or work.

We will exclude studies which use surrogate endpoints such as hormone levels as an outcome measure.

Search methods for identification of studies

(1) The Cochrane Menstrual Disorder and Subfertility group's specialised register of controlled trials wil be searched by the trials search co‐ordinator for relevant trials. We will search the Cochrane Central Register of Controlled Trials (CENTRAL) for relevant trials using key words as below. We will also approach the Cochrane Complementary Field for access to their database. (2) Electronic databases: MEDLINE, EMBASE, PsycINFO, CINAHL, AMED, British Nursing Index, Martindale, phytobase and BIOMED Central will be searched using the same key words. Where possible, MESH terms will also be used. Searches will not be restricted by language.

We will develop a search strategy in consultation with the trials search co‐ordinator, using key words such as:

• premenstrual syndrome or pre menstrual syndrome or pre‐menstrual syndrome;

• premenstrual tension;

• premenstrual dysphoric disorder;

• late luteal;

• (PMS or PMT or PMDD or LLPD or LLPDD);

• vitex;

• agnus castus;

• chaste tree;

• chasteberry, chaste‐berry;

• monk's pepper;

• hemp tree;

• agneau chaste (French);

• gatillier (French);

• Keuschlamm (German);

• kyskhedstrae (Dan);

• Agnus casti Deuxrua (Lat);

• brand names: agnolyt, agnufemil, castufemin, cefanorm, femicur, gynocastus, hewekliman, kytta‐femin, strotan, agnomens.

(3) We will search for all references in the included and excluded trials and review articles. (4) Forward citation searches will be performed using the Science Citation Index. (5) National Research Register. (6) Hand searching of personal collection of Professor Ernst at the Complementary Medicine Group, Peninsula Medical School. (7) Grey literature will be sought by searching Index to Theses and System for information on grey literature. (8) Manufacturers of agnus castus products will be approached to identify other published or unpublished trials. (9) The National Association for Premenstrual Syndrome (NAPS) will be contacted. (10) Internet search for relevant studies using the Google search engine.

Data collection and analysis

SELECTION Four reviewers will undertake the review. SS and JTC will assess the studies identified in the search that are written in English, KS or EE will assess those written in German. Any papers written in other languages will be translated as necessary. SS and JTC (English) and KS or EE (German) will screen the titles and, where possible, abstracts of studies that are potentially relevant to the review and will discard those that are clearly ineligible but aim to be over inclusive rather than risk losing relevant studies. SS and JTC (English) and KS or EE (German) will independently assess whether the studies meet the inclusion criteria, with disagreements to be resolved by discussion with KW. If there is insufficient information to make a decision about eligibility, we will seek further information from the authors.

QUALITY SS and JTC and KS or EE will assess the quality of the studies that are deemed eligible for the review with discrepancies to be resolved by discussion with KW. We will grade the quality of allocation concealment as adequate (A), unclear (B) or inadequate (C), following the detailed descriptions of these categories provided by the Menstrual Disorder and Subfertility Review Group. We will assess other aspects of methodological quality with respect to both internal and external validity using the standard checklist developed by the Menstrual Disorders and Subfertility Review Group:

We will consider the following aspects of internal validity:

• whether the outcomes of patients who withdrew or were excluded after allocation were described and included in an 'intention ‐to ‐treat' analysis

• whether the outcome assessors were blind to assignment status

• whether the subjects were blind to assignment status following allocation

• whether the treatment providers were blind to assignment status following allocation

• whether the treatment and control group were comparable at entry

• whether the care programmes other than the trial options were identical

• whether the number of withdrawals were less than 10% of the study population

• whether a power calculation was performed

• study design (parallel or crossover)

We will consider the following aspects of external validity:

• whether the inclusion and exclusion criteria were clearly defined

• whether the outcome measures used were clearly defined

• whether the accuracy, precision and observer variation of the outcome measures were adequate

• whether the timing of the outcome measures were accurate

• source of funding

We will present this information in a table describing the included studies. We will consider aspects of methodological quality in order to provide a context for discussing the reliability of the results and for sensitivity analysis.

DATA COLLECTION The reviewers will independently extract information using the forms designed by the review group. We will resolve discrepancies by discussion. For each included trial, we will collect information regarding the location of the study, methods of the study (as per quality assessment checklist), participants (age range, eligibility criteria, method of diagnosis), nature of the interventions and placebo, methods used to evaluate the outcomes, which outcomes are reported and data relating to the outcomes. Where possible, we will seek missing data from the authors.

ANALYSIS We will perform statistical analysis according to the statistical guidelines for reviewers in the Cochrane Menstrual Disorders and Subfertility Review Group. We plan to use the relative risk (RR) with 95% confidence intervals (CI) as the measures of effect for each dichotomous outcome. Where continuous data are presented but measured in different ways across the studies (for example, premenstrual syndrome scores), we will calculate standardised mean differences (SMD) with 95% confidence intervals. We will use the same techniques where outcomes are ordinal. If there is only one study for a particular outcome, or if the outcome is measured in the same way across studies, we will use a weighted mean difference (WMD) with 95% confidence intervals.

Where there are sufficient data, we will calculate a summary statistic for each outcome using both fixed and random effects models. We will combine outcomes only if it is sensible to do so, and we will interpret results cautiously. We will note any heterogeneity, from a statistical point of view (assessing whether observed variability in study results is greater than that expected to occur by chance) as well as considering methodological (differences in study design) and clinical (differences in participants, interventions or outcome measures) heterogeneity. Heterogeneity will be assessed statistically by examining the scatter in the data points and the overlap of the confidence intervals, as well as by performing chi squared test. Any result with a p value greater than 0.05 will be considered to be heterogeneous. Reasons for heterogeneity will be cautiously explored. We will analyse the data for the presence of skew. Where skew is identified, the data will be log transformed, then the standardised mean difference will be used. We anticipate that there may be potential subgroups, for example, groups that meet formal diagnostic criteria for PMDD, certain formulations or doses of intervention (if there are several trials using the same dose/formulation). We will perform subgroup analyses only on these groups which have been identified a priori. We will undertake sensitivity analysis to examine the stability of the results in relation to a number of factors relating to the way the study was done. The analysis will be repeated excluding studies as follows:

• studies of lowest grade of allocation quality, and then again studies rated allocation quality grade B and grade C (in other words excluding studies using quasi‐randomisation or without adequate safeguards for allocation concealment);

• studies of poor overall methodological quality. The following aspects of quality will be considered for this sensitivity analysis: inadequate blinding, no stated method of diagnosis, incomparable groups (either because they have different baseline characteristics or because they do not have identical care programmes), no intention to treat analysis and study duration of less than three cycles;

• studies including participants taking the oral contraceptive pill.

TIMELINE We intend to complete this review by end of January 2004.

What's new

Last assessed as up‐to‐date: 23 December 2004.

Date	Event	Description
2 March 2018	Amended	The authors have withdrawn from this review

History

Protocol first published: Issue 1, 2004

Date	Event	Description
17 November 2010	Amended	Contact details updated.
6 November 2008	Amended	Converted to new review format.

Contributions of authors

SSH: Conceived the review Coordinated the review Designed the review Wrote the protocol Developed search strategy

JTC Assisted with design of the review Advised on the protocol

KW Provided general advice on the review Assisted with the design of the review Advised on the protocol

EER Provided general advice on the review Advised on the protocol

JCA Provided general advice on the review Secured funding for the review Advised on the protocol

Sources of support

Internal sources

• No sources of support supplied

External sources

• South West Deanery, UK.

Declarations of interest

None known.

Notes

The authors have withdrawn from this review

Withdrawn from publication for reasons stated in the review