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Dose-dependent efficacy of the Vitex agnus castus extract Ze 440 in patients suffering from premenstrual syndrome.

ARTICLE INFO

Keywords:

Vitex agnus astus

Chasteberry

PMS

Dose-response

RCT

Ze 440

ABSTRACT

Background: Preparations of Vitex agnus castus L. (VAC) have been shown to be effective to treat irregular menstrual cycles, cyclical mastalgia and symptoms of the premenstrual syndrome (PMS). However, the dose--effect relationship for the treatment of PMS has not yet been established. This study aimed to investigate the clinical effects of three different doses of the VAC extract Ze 440 in comparison to placebo in patients suffering from PMS.

Methods: In a multicenter, double-blind, placebo-controlled, parallel-group study, 162 female patients with PMS (18-45 years) were randomized to either placebo or different doses of Ze 440 (8, 20 and 30 mg) over three menstrual cycles. PMS symptoms' severity was assessed by patients using visual analog scales (VAS) for the symptoms irritability, mood alteration, anger, headache, bloating and breast fullness. Results: Each of the treatments was well tolerated. Improvement in the total symptom score (TSS) in the 20 mg group was significantly higher than in the placebo and 8 mg treatment group. The higher dose of 30 mg, on the other hand, did not significantly decrease symptom severity compared to the 20 mg treatment, providing a rational for the usage of 20 mg. Corresponding results were observed with the single PMS symptom scores.

Conclusion: This study demonstrated that the VAC extract Ze 440 was effective in relieving symptoms of PMS, when applied in a dose of 20 mg. Therefore, for patients suffering from PMS, 20 mg Ze 440 should be the preferred daily dose.

[c] 2012 Elsevier GmbH. All rights reserved.

Introduction

The premenstrual syndrome (PMS) is a common disorder in women during their reproductive lifespan. Up to 20% of women complain of symptoms and 3-8% are impaired in their interpersonal or workplace functioning (Rapkin and Winer 2009). PMS represents a multitude of symptoms occurring in the luteal phase of the cycle, with usually the most severe symptoms during the days before menstruation (Doll 2009). Affected patients suffer from psychological changes such as irritability, mood alterations, anger/tension, anxiety and depression. Furthermore, also physical symptoms such as feeling bloated, headache, fatigue and breast pain (mastodynia) are involved (Rapkin and Winer 2009). The exact etiology of this disorder is yet unclear, though research suggests an altered regulation of neurohormones and neurotransmitters such as serotonin (Dickerson et al. 2003) and dopamine (Sliutz et al. 1993; Jarry et al. 1994). Premenopausal mastodynia may be related to latent hyperprolactinemia. Since prolactin release is under tonic control of hypothalamic dopamine, it was not surprising that the dopamine agonist bromocriptine was effective in the treatment of cyclic mastodynia. However, this treatment was accompanied with significant adverse events such as nausea and dizziness (Manse! and Dogliotti 1990). A high percentage (up to 80%) of women suffering from PMS self-medicate with OTC products including complementary and natural products, vitamins and minerals (Singh et al. 1998).

Preparations of Vitex agnus castus L. (VAC, synonym: chasteberry or monk's pepper) have been traditionally used to treat a variety of gynecological conditions. Early open studies report on the use of VAC to treat mastodynia. These observational studies showed good effectiveness using a liquid preparation of VAC (Roeder 1976; Fikentscher 1977; Gregl 1979; Opitz and Liebl 1980). Also in two randomized, controlled trials cyclical mastalgia was successfully treated with this VAC preparation (Wuttke et al. 1997; Halaska et al. 1999). Furthermore, there is scientific evidence from previous studies that VAC might be also effective to correct irregular menstrual cycles (Milewicz et al. 1993; Roeder 1994) or female sterility (Gerhard et al. 1998). The German Commission E had approved VAC for mastodynia, irregularities of the menstrual cycle and premenstrual disturbances (Kommission E 1992).

Regarding the treatment of PMS with VAC preparations, there are several randomized controlled clinical trials that proved efficacy of such an intervention. Three studies were placebo controlled (Milewicz et al. 1993; Turner and Mills 1993; Schellenberg 2001; He et al. 2009), whereas in others, pyridoxine (Lauritzen et al. 1997), and fluoxetine (Atmaca et at., 2003) were used as a control. In each of these trials, VAC showed clinical efficacy, and the observed adverse events were of mild and reversible nature (Daniele et al. 2005).

The active principle in VAC and the pharmacological mechanism responsible for the relief of PMS symptoms have not been elucidated so far. In vitro studies showed binding to [mu]-opioid receptors (Webster et al. 2006) and to [beta]-estrogen receptors (Jarry et al. 2003). Maybe more important, binding to dopamine [D.sub.2] receptors and inhibition of prolactin release from pituitary cells could be demonstrated (Jarry et al. 1994). Characteristic constituents of VAC are, beside others, iridoicl glycosides, bicyclic diterpenes, flavonoids and flavones (E/S/C/O/P2003).

Important factors that can affect the efficacy of herbal treatment are the origin of the drug, the extract generation (e.g. extraction solvent) and the amount of crude drug that is applied (which is defined by the amount of native extract and the corresponding drug-extract-ratio, DER). Regarding the dosage used in clinical studies, a considerable variation is apparent. In the early studies, where the effect of VAC on mastodynia (Dickerson et at. 2003) was investigated, liquid preparations corresponding to 30-40 mg VAC crude drug per day have been used. In the current study we applied Ze 440, a 60% (m/m) ethanolic extract prepared from the fruits of VAC, at a dosage of 20 mg native extract, corresponding to around 180 mg VAC crude drug per day. This dosage effectively relieved symptoms of PMS in a former placebo-controlled, double-blind randomized controlled trial (Schellenberg 2001). The treatment was clearly superior to placebo and was well tolerated. The good tolerability of the same dose was further demonstrated in an open study in patients with PMS (Berger et al. 2000). As 20 mg of the extract Ze 440 proved to be safe and efficacious to treat symptoms of PMS, the aim of the current study was to compare its clinical effects with a higher dose (30 mg) and a lower dose (8 mg) in patients suffering from PMS.

Materials and methods

Study design

This multicenter, double-blind, placebo-controlled, randomized, prospective trial was performed between November 2005 and December 2006. The study was carried out according to GCP and the protocol and Informed Consent form were approved by the Ethics Committees of the Medical Association of the Federal State of Hessen, Germany prior to study start. The protocol was also registered at the central EU trials database (EUDRACT #2006-007077-73). All attending physicians underwent pre-study training to use the study instruments to enhance inter- and intra-centre consistency. In each clinic, all assessments were made by the same individual.

Patients

Outpatients were screened for eligibility by performing three baseline assessments over a two-week period to establish that PMS symptoms were stable. The diagnosis of PMS was made according to the guidelines of the University of California, San Diego, the National Institute of Mental Health (Dickerson et al. 2003) and the DSM III-R.

The inclusion criteria for the study were: PMS diagnosis according to DSM III-R criteria, written informed consent, age [greater than equal to] 18 and < 45 years. In addition, patients had to fulfill the following additional criteria of the National Institute of Mental Health and the University of California (San Diego) as stated by Dickerson et al. (2003): a 30% increase in the intensity of symptoms of premenstrual syndrome from cycle days 5 to 10 as compared with the six-day interval before the onset of menses and at least one of the following affective and somatic symptoms had to be observed during the five days before menses in the previous cycle (affective symptoms: depression, angry outbursts, irritability, anxiety, confusion, social withdrawal; somatic symptoms: breast tenderness, abdominal bloating, headache, swelling of extremities). Symptoms had to be relieved from days 4 through 13 of the menstrual cycle.

The main exclusion criteria were: presence of affective disorders, anemia, eating disorders, serious chronic diseases, history of substance abuse, dementia or any severe cognitive disorder, dysmenorrhea, endometriosis, febrile disorders, participation in other trials in the previous 6 weeks, pituitary disorders, menopause, neoplasia, pregnancy or breast-feeding, severe diseases (cardiovascular, central nervous system, endocrine, renal, hepatic or respiratory), and inadequate contraception.

Study drug

The study medication consisted of active substance at three doses of VAC or placebo. All tablets were film-coated and identical in appearance, size and color. The active substance was 8 mg, 20 mg, or 30 mg Vitex agnus castus fruit extract Ze 440 (60% ethanol Om, drug-extract ratio 6-12:1, standardized to casticin). One tablet should be taken once daily un-chewed with some liquid during a meal for the entire 3-menstrual cycle period. The study medication was provided by Max Zeller Sohne AG, Romanshorn, Switzerland. Each patient received 126 tablets at Visit 1 (randomization). Treatment compliance was assessed by counting the returned unused medication and by inquiry of patient's drug intake by the investigator. Patients, who had taken at least 75% of the tablets, were regarded as compliant.

In principle, all concomitant medications were maintained at the same dose, unless they could be discontinued. Prior chronic use of oral contraceptives was allowed, the dose remaining unchanged throughout the study period. The following concomitant medication was prohibited in the study: diuretics, gonadotropin-releasing hormones, non-steroidal anti-inflammatory drugs, prostaglandins, psychotropic drugs, serotonin uptake inhibitors, gamma-linolenic acid. Exact documentation of any concomitant medication was essential with reference to time and duration of administration as well as dosage. Non-medicinal concomitant therapies such as physical or psychotherapeutic measures (e.g. acupuncture, and hypnosis) were also prohibited.

Efficacy variables

The patients assessed the intensity of each of the 6 items: (1) irritability, (2) mood alteration, (3) anger, (4) headache, (5) bloating, and (6) breast fullness on a 10cm long, black, horizontal bar without gradations (visual analogue scale, VAS). These symptoms were chosen because they can be regarded as main symptoms of PMS (Dickerson et al. 2003). In previous studies, these items were also selected as efficacy variables (Schellenberg 2001; Landen et al. 2007).

Patients rated each item using a VAS ranging from "0 mm" (no symptoms) to "100 mm" (unbearable). VAS values of each symptom were added and defined as total symptom score (TSS). In order to guarantee reproducible baseline values, the symptoms should have increased in their severity by more than 30% from the follicular to the luteal phase (National Institute of Health, Dickerson et al. 2003). The investigator admitted only those patients into the study who demonstrated this increase.

After study inclusion, assessments were performed at the beginning and the end of therapy for 3 consecutive days (3 days before the expected start of each menstruation). The change from baseline to the final visit in TSS was the primary efficacy parameter. The baseline and final values were defined as the median of the cumulative scores of the 3 days before the start of menstruation before cycle 1 and cycle 3, respectively.

Secondary efficacy parameters were changes in each of the six individual self-assessment symptoms, physicians' evaluation of symptoms' severity, patients' and physicians' assessment of tolerability, patients' wish to continue treatment beyond study, response rate and patients' compliance.

Safety assessment

At inclusion, patients underwent full medical examinations and laboratory tests (hematology, biochemistry and pregnancy test). Intermediate examinations were left to the discretion of the investigator and were intended as patient care. A visit at week 12 (end of study) was mandatory, to repeat a full medical examination and laboratory tests (hematology and biochemistry). Furthermore, the occurrence of adverse events and physicians' assessment of tolerability was evaluated. At each visit patient's co-medication was documented.

Statistics and analysis

The sample size estimation was based on previous results with 20 mg Ze 440 (Schellenberg 2001). The expected therapeutic difference of mean values of 50 mm with a standard deviation of 78 was used to calculate sample size (Machin and Campbell 1987). For a two-sided significance of 0.05 and 80% power a sample size of 40 per group was required. The randomization plan, which allocated patients to the treatment groups in blocks of 8, was generated using a validated computer program (Mathematica, Wolfram Research, Inc. Champaign, IL, USA).

The primary efficacy variable is defined as the change from baseline to endpoint in TSS (difference: endpoint-baseline). The main analysis was performed on intention-to-treat (ITT) basis that included all patients, who were randomized and received at least one administration of study drugs and a baseline value. Missing values post-baseline were treated as unchanged baseline, i.e. "last observation carried forward". Treatment responders were defined to show a decrease in TSS of [greater than equal to] 50%.

The statistical analysis was performed on a hierarchically ordered set of hypotheses. This procedure interrupts as soon as the corresponding null-hypothesis cannot be rejected. The first null hypothesis (H01) was that the placebo and the 20 mg group are equal (corresponding hypothesis H11: placebo and the 20 mg group are not equal). Followed by H02: 8 mg and 20 mg groups are equal (corresponding hypothesis H22: 8mg and 20mg group are not equal); and H03: 30 mg and 20 mg groups are equal (corresponding hypothesis H33: 30 mg and 20 mg group are not equal). All step-scales were considered equidistant; hence the pairwise treatment comparisons were performed using a stratified Mann-Whitney procedure (stratification by center). The statistical tests were performed two-sided and significance will be declared at the 5% level. All secondary variables were analyzed descriptively and conducted with exploratory intent. All computations were done with SAS software (Cary, NC, USA: version 9.1).

Results

Disposition of patients

In total, 178 patients were screened and 162 were randomized (safety population). Of these, 142 patients had baseline values recorded (ITT population), whereas the per-protocol population consisted of 140 patients (one protocol violator in both the placebo and Ze 440 group) (Fig. 1). Patients' characteristics at entry were balanced across treatment groups (Table 1), including length of cycle and menses duration. There were no statistically significant differences between treatment groups in demographic parameters. In total, 22.7% of the patients took oral contraceptives (7, 7, 11 and 4 patients in the groups of placebo, 8 mg, 20 mg, and 30 mg, respectively). The doses were maintained throughout the study period.

Table 1 Demographic characterics

Number of         Placebo 40    8 mg Ze      20 mg Ze    30 mg Ze
patients (safety                 440 42        440 41      440 39
population)

Age (years)

Mean (SD)          31.3(7.2)  29.4 (7.7)   30.5(7.7)   32.0(8.8)
Median                  29.2        26.5        27.2        34.7

Weight (kg)

Mean (SD)         67.5(13.2)   64.7(9.7)  64.4(12.6)  68.7(10.3)
Median                  64.5        62.5        62.0        68.0

Height (cm)

Mean (SD)         167.7(5.9)  167.5(5.2)  168.0(5.5)  167.9(7.0)
Median                 168.0       167.5       168.0       168.0

Age at menarche
(years)

Mean (SD)          12.8(1.0)   12.9(1.1)   13.3(1.4)   12.9(1.3)
Median                  13.0        13.0        13.0        13.0

Length of cycle
(days)

Mean (SD)          28.0(1.5)   28.1(1.3)   28.0(1.2)   28.2(1.6)
Median                  28.0        28.0        28.0        28.0

Length of menses
(days)

Mean (SD)           4.6(1.2)    4.7(1.2)   4.3 (0.9)    4.7(1.1)
Median                   4.0         5.0         4.0         5.0

SD=standard deviation


Primary efficacy variable

The primary efficacy variable was defined as change from baseline to end of study in the TSS of the six self assessment items irritability, mood alteration, anger, headache, bloating and breast fullness. Table 2 shows the analysis of the primary efficacy variable including means, standard deviations (SD), medians, interquartile and total ranges in the ITT population. The statistical evaluation in the ITT population was performed based on the hierarchically ordered hypotheses. The two-sided stratified Mann-Whitney test of placebo vs. the 20 mg group and of the 8 mg group vs. the 20 mg group revealed a p-value < 0.0001. No statistically significant difference was demonstrated between the 20 mg group and the 30 mg group.

TABLE 2
Total symptom scores (TTS) at baseline, end of study and their
Difference in the ITT Population (n=142)

Parameters         Placebo n =    8 mg Ze    20 mg Ze   30 mg Ze
                       35             440         440        440
                                   n = 36      n = 35      n =36

Baseline (mm)

Mean                     257.0        261.8      279.8     284.8
Median                   255.0        244.5      289.0     290.5
Ql:Q3                  152:342      148;380    146;388   192:388
Min; Max               63; 570       33;535    76; 541   21; 560

End of study (mm)

Mean                     224.5        247.4       68.7      94.5
Median                   216.0        246.5       39.0      65.5
Q1:Q3                  150:282      141;337      17;82   39; 126
Min; Max               48; 545      27; 551      2:337    2; 396

Differences (mm)

Mean                     -32.5        -14.4     -211.1    -190.3
Median                   -27.0        -13.0     -180.0    -199.5
Ql:Q3                  -103;88       -87;24  -303; -89     -313;
                                                             -34
Min; Max             -489; 260     -339;345  -537; -11  -548:109
P-values               <0.0001      <0.0001  Reference  0.599 vs
                      vs 20 mg       vs20mg                20 mg

Q1:Q3=25%; 75% quartiles; Min; Max = minimum; maximum values; p-values
obtained by two-sided (stratified) Mann-Whitney test with
hierarchically ordered hypotheses.


Secondary efficacy variables

As secondary efficacy variables the individual symptoms were evaluated. The change from baseline to end of treatment in individual symptoms was analyzed using the same model as for the primary endpoint. The differences of the individual symptom scores (baseline value to end of study value) were calculated. The data are summarized in Table 3. The six self assessment items indicated significant superiority for 20 mg Ze 440 vs. placebo (irritability p < 0.0001, mood alteration p= 0.0001, anger p = 0.0001, headache p = 0.0255, bloating p < 0.0001, breast fullness p = 0.002). In addition, in all these six self assessment items 20 mg Ze 440 was significantly superior to 8 mg Ze 440. The highest dose (30 mg Ze 440) demonstrated no significant difference in these items compared to the 20 mg dose. For most of the symptoms, 8 mg Ze 440 showed no significant differences to placebo. This is partly in contrast to previous studies, where the application of 4 mg of dried extract of VAC (BNO 1095) improved symptoms of PMS (He et al. 2009). However, there was a borderline effect (p = 0.066, Wilcoxon test) with regard to the symptom breast fullness, when placebo response was directly compared to the response of the 8 mg group. Breast fullness and mastodynia are symptoms of PMS that were also successfully treated by low-dose VAC preparations (Wuttke et al. 1997; Halaska et al. 1999).

TABLE 3
Summary statistics of indivdual symptom scores-differences between end
Of study baseline in the ITT population (n=142)

                       Placebo         8 mg  20 mg Ze 440   30 mg
                                     Ze 440                Ze 440
                        n = 35       n = 36        n = 35   n =36

Irritability (mm)

Mean                     -13.2          0.4         -43.3   -33.6
Median                    -5.0         -5.0         -48.0   -34.5
Q1:Q3                   -36; 7       -22;15      -64; -12    -67;
                                                               -1
P-value vs         Reference          0.240       <0.0001   0.023
placebo
P-value vs 20mg      <0.0001        <0.0001     Reference   0.205

Mood alteration (mm)

Mean                     -12.3         -0.9         -41.1   -34.3
Median                    -7.0         -3.0         -44.0   -30.0
Q1;Q3                   -31; 6      -23: 20      -65; -18  -71;-7
P-value vs           Reference        0.223        0.0001   0.012
placebo
P-value vs 20 mg        0.0001      <0.0001     Reference   0.367

Anger (mm)

Mean                      -6.9          2.3         -34.7   -30.6
Median                    -3.0         -1.5         -31.0   -19.0
Q1:Q3                   -28:15       -9; 17       -53;-10    -66:
                                                               -1
P-value vs         Reference          0.438        0.0001   0.007
placebo
P-value vs 20 mg        0.0001      <0.0001     Reference   0.560

Headache (mm)

Mean                       0.7          2.4         -20.8   -28.2
Median                     0.0          0.5          -4.0   -14.5
Ql:Q3                   -17:19       -19:15         -46:0    -63;
                                                               -1
P-value vs         Reference          0.936         0.026   O.001
placebo
P-value vs 20 mg         0.026        0.015  Reference      0.137

Bloating (mm)

Mean                       0.1         -7.9         -36.4   -30.8
Median                    -1.0         -7.5         -42.0   -28.0
Ql:Q3                   -20:13        -27;7       -65; -1    -59;
                                                               -3
P-value vs           Reference        0.222       <0.0001  0.0002
placebo
P-value vs 20 mg       <0.0001        0.004     Reference   0.552

Breast fullness (mm)

Mean                      -0.1        -11.5         -31.7   -35.4
Median                     0.0         -2.0         -27.0   -26.5
Q1:Q3                  -16: 15       -27; 5       -62; -1    -77;
                                                               -1
P-value vs         Reference          0.075        0.0002  0.0002
placebo
P-value vs 20 mg        0.0002        0.016  Reference      0.607

Q1:Q3 = 25%; 75% quartlies; P-values obtained by two-sided (startified)
Mann-Whitney test with hierarchically ordered hypotheses.


Effect of oral contraceptives on premenopausal symptoms

Within this study, 22.7% of the participants used concomitant oral contraceptives, which are known to affect premenopausal symptoms and hence may have distorted treatment effects and induced bias in the interpretation of study results. Therefore, we evaluated the statistical analysis of baseline and total symptom score of PMS symptoms as well as score difference (between baseline and end-of-study scores) using the intake of oral contraceptives as a covariate. Results show the same treatment effects as described above. There was no statistically significant effect of oral contraceptives use on any of the investigated parameters (individual and total PMS symptom scores at baseline and respective score difference, data not shown).

Symptom evaluation by the investigator

Symptom evaluation by the investigator was assessed at the beginning and the end of the treatment on a 5-point scale. The results are summarized in Table 4, which describes the 2 populations at the beginning (safety population) and at the end of therapy (ITT population). At the end of therapy no symptoms or only mild symptoms were assessed in 23% and 22% of the patients in the placebo and 8 mg Ze 440 group, respectively. In the 20 mg Ze 440 group 49% of patients had no symptoms and 31% had mild symptoms. 30 mg Ze 440 was as effective as 20 mg Ze 440 in treating subjective symptoms. The differences between 20 mg Ze 440 and 30 mg Ze 440 vs. placebo were statistically significant (p < 0.0001).

TABLE 4
Symptoms assessed by the investigator at the begining (Safety
Population, n =162) and end of therapy (ITT Population, n =142).

Number of patients     Placebo  8 mg Ze  20 mg Ze 440  30 mg Ze 440
(safety population)      n=40     440 n =     n = 41        n = 39
                                    42

Symptoms Investigator's rating at baseline

None                         -        -             -             -
Mild                         -   1 (2%)             -         1(3%)
Moderate               19(48%)  27(64%)       24(59%)       19(49%)
Severe                 17(43%)  11(26%)       15(37%)       16(41%)
Very severe              3(8%)    3(7%)         2(5%)         3(8%)
No data                  1(3%)        -             -             -
Number of patients     Placebo  8 mg Ze  20 mg Ze 440  30 mg Ze 440
(ITT population)        n = 35  440 n =        n = 35        n = 36
                                     36

Symptoms Investigator's rating at end of study

None                     1(3%)   4(11%)       17(49%)       II(31%)
Mild                   7 (20%)   4(11%)       11(31%)       13(36%)
Moderate               12(34%)  12(33%)        4(11%)        8(22%)
Severe                 14(40%)  15(42%)        3 (9%)        4(11%)
Very severe             1 (3%)   1 (3%)             -             -
P-value (pairwise            -   0.6165       <0.0001       <0.0001
comparison to
placebo)


Responder rate

The rate of responders (i.e. reduction of TSS [greater than equal to] 50%) in the placebo group and in the 8 mg Ze 440 group was 11% and 14%, respectively. The 20 mg Ze 440 group showed the highest rate of responders (81%), whereas in the 30 mg Ze 440 group the rate was 61%. The 20 mg and 30 mg group showed a statistically significant difference compared to the placebo group (p < 0.001, Fisher's exact test).

Tolerability and readiness of the patient to continue therapy

Tolerability was assessed by the investigators and by the patients at the end of treatment on a 5-point scale (0 = very good tolerability, 1 = good tolerability, 2 = moderate tolerability, 3 = poor tolerability, 4 = very poor tolerability). There was a good agreement between the tolerability rating at the end of the treatment between investigators and patients. Both ratings indicated the tolerability as very good (69% and 91%, respectively) to good (31% and 9%, respectively) with 20 mg Ze 440.

At the end of the study, patients were asked, whether they would continue with the medication. Only YES or NO responses were possible. The evaluation of the responses shows that approximately 2/3 of the patients in the 20 mg Ze 440 group would continue with the study medication. This result is comparable to that of the 30 mg Ze 440 group. In contrary, only 38% of the 8 mg Ze 440 group would continue the treatment.

Safety results

Adverse events were collected by the attending physician during each visit. No serious adverse events occurred in the study. In the placebo group, 3 adverse events occurred in 3 patients (no toleration of the study drug in the morning, malaise after the intake and severe headache). In the 8 mg group, there were 2 adverse events documented in 2 patients (mild headache in the beginning and mild interim spotting). One adverse event (mild hypertension) occurred in a patient of the 20 mg Ze 440 group. In the 30 mg group, there occurred 4 adverse events in 4 patients (headache, vaginal fungal infection with severe itching, abdominal bloating and impure skin). Results of the laboratory tests (hematology, biochemistry), vital signs, and physical findings showed no difference between the treatment groups and also no difference between baseline and end of the study.

Discussion

Despite recent publications having shown overall usefulness of VAC in alleviating PMS symptoms, the question of dose-dependency remained to be addressed in a randomized controlled trial. With this study we have shown, for the ethanolic VAC extract Ze 440, that 20 mg represents the optimum dose for the treatment of PMS. When comparing this dose with placebo, a significant reduction of symptom severity could be observed for each of the six investigated self-assessment items. The dose of 8 mg Ze 440 was borderline effective only in the item breast fullness. For the relieve of mastodynia, the use of lower VAC dosages might therefore be adequate for symptom improvement (Wuttke et al. 1997; Halaska et al. 1999). However, our results suggest that for the treatment of PMS, as a whole symptom complex, apparently higher doses of VAC are required for a significant improvement. On the other hand, the dose of 30 mg did not show superiority over the 20 mg dose. With both doses, improvements were more or less equal, providing a rational for the usage of 20 mg. This is also in agreement with the close recommendation of the Agnus castus monograph provided by the European Scientific Cooperative on Phytotherapy (E/S/C/O/P 2003) and the Committee on Herbal Medicinal Products of the European Medicine Agency (HMPC 2010).

One recent study assessed the effect of 4 mg VAC extract (corresponding to 40 mg herbal drug) in a Chinese population (He et al. 2009). Despite this low dose, a significant improvement of PMS symptoms could be observed. However, the following points have to be considered when comparing these results to the present study. (1) The authors used a different assessment tool (PMS-diary in a Chinese version), (2) the patients had more visits with contact to the investigators, (3) there are ethnical differences between the analyzed populations (most likely with differences in the perception of PMS). This is also reflected in varying placebo effects after 3 cycles of treatment, with a reduction of 55% of total PMS scores in the Chinese study, compared to 13% in our study.

Another common treatment option for PMS is the application of oral contraceptives (Huber et al. 2008). A review showed that the use of drospirenone plus ethinylestradiol may help to treat premenstrual symptoms (Lopez et al. 2009). Consequently, concomitant intake of oral contraceptives could distort study results when assessing changes in PMS symptoms. In the present study 23% of the patients used oral contraceptives. A statistical evaluation showed that there was no significant effect of these medications on any of the investigated parameters.

One of the physical symptoms of PMS represents pain of the breast (mastodynia). This discomfort has been attributed to latent hyperprolactinemia, i.e. increased release of pituitary prolactin in response to stressful situations, stimulating the mammary glands (Wuttke et at. 2003). Prolactin release is under the control by hypothalamic dopamine. Consequently, activation of dopamine D2 receptors will result in an inhibition of prolactin release and could be beneficial for the treatment of mastodynia and other PMS related symptoms. In an open study with 20 mg Ze 440, prolactin levels were not decreased after the treatment period, despite good overall efficacy (Berger et al. 2000). This further confirms that the positive effect of VAC might be mediated through a modulation of acute prolactin release in response to stress factors, rather than a general decrease of prolactin serum levels. Thus, the present study was performed without measurement of prolactin levels.

Regarding therapeutic efficacy, it might be that in patients with no response to 20 mg Ze 440, an increase of the dosage could have achieved better results. However, since fixed doses in parallel groups were applied in this study, this question cannot be answered with the current data. Otherwise, all precautions were taken to reduce data variability, which is paramount to evaluate premenstrual symptoms. Clinic visits were kept to a minimum to avoid frequent medical checkups influencing the patients' self-assessments. The length of treatment (3 menstrual cycles) was sufficient to allow all key symptoms to be documented while adequately long to minimize the placebo effect. Diary booklets were provided for the patients to record their symptoms when they actually occurred during the cycles. When recording the severity of the symptoms on the visual analogue scales during visits, judgment should reflect symptom severity during the entire preceding period, rather than just their well-being on the day of the clinic visit. Finally, validated and robust assessment instruments were chosen for the evaluation of premenstrual symptoms, as indicated in a previous review (Wyatt et al. 2002).

Conclusion

In conclusion, this prospective, randomized, double-blind, three-dose comparison, placebo-controlled study demonstrated that the VAC extract Ze 440 was effective in relieving symptoms of PMS, when applied at a dose of 20 mg once-daily. When using 8 mg, an overall effectiveness could not be demonstrated, though the symptom breast fullness showed borderline improvement. The 30 mg dosage did not add further therapeutic benefit compared to 20 mg. Therefore, for patients suffering from PMS, an initial dose 20 mg Ze 440 should be the preferred daily dose.

Conflict of interest

CZi, JD and CZa are employees of Max Zeller Soehne AG. RS and GA have received a research grant from Max Zeller Soehne AG.

Acknowledgements

We hereby acknowledge the contribution of the following coinvestigators: Dr. E. Schrader, Dr. A. Massing and Dr. R. Pfaff.

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(*) Corresponding author at: Max Zel ler Soehne AG, Seeblickstr. 4, CH-8590 Roman-shorn, Switzerland. Tel.: +41 71 466 0546: fax: +41 71 466 0707.

E-mail address: juergen.drewe@zellerag.ch (J. Drewe).

(1.) Representative for the clinical study group.

0944-7113/$--see front matter [C] 2012 Elsevier GmbH. All rights reserved. http://dx.doi.org/10.1016/j.phymed.2012.08.006

Ruediger Sche11enberg (a), (1), Christian Zimmermann (b), Jurgen Drewe (b) *, Godehard Hoexter (c), Catherine Zahner (b)

(a.) institute for Health Care and Science, Hiittenberg, Germany

(b.) Max Zeller So/me AG, Romanshorn, Switzerland

(c.) Dr. M. Koehler GmbH Pharma Biometrie Consulting, Freiburg, Germany
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Author:Schellenberg, Ruediger; Zimmermann, Christian; Drewe, Jurgen; Hoexter, Godehard; Zahner, Catherine
Publication:Phytomedicine: International Journal of Phytotherapy & Phytopharmacology
Article Type:Clinical report
Date:Nov 15, 2012
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