Therapeutic Effect of Vitex Agnus Castus in Patients with Premenstrual Syndrome

Abstract

Medical therapies have been widely used for premenstrual syndrome (PMS), but in all of them side effects are predominant. Herbal remedies rarely have side effects and people have more tendencies toward them than chemical therapies. In this study the therapeutic effect of Vitex agnus castus on women who had the PMS, in comparison with placebo, were investigated. In this randomized, placebo-controlled, double-blind study, from 134 selected patients 128 women suffered from PMS were evaluated (active 62, placebo 66). All patients answered to a self assessment questionnaire about their headache, anger, irritability, depression, breast fullness and bloating and tympani during the premenstrual period before the study. Forty drops of Vitex agnus extract or matching placebo, administrated for 6 days before menses for 6 consecutive cycles. Patients answered the self-assessment questionnaires after 6 menstrual cycles, again. Each item rated using a visual analogue scale (VAS). The mean age was 30.77 (SD=4.37) years in the active group and 30.89 (SD=4.02) years in the placebo group.Rank of variables had significantly difference in active and placebo group before and after the study (P<0.0001) also we noticed significant differences on the use of Vitex agnus in comparison with placebo (P<0.0001). Vitex agnus can be considered as an effective and well tolerated treatment for the relief of symptoms of mild and moderate PMS.

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ORIGINAL REPORT
Corresponding Author: Nosrat Neghab
Specialty of Obstetrics and Gynecology, Hamedan University of Medical Sciences, Fatemieh Hospital, Hamedan, Iran
Tel: +98 811 8277012, 916 6431720, Fax: +98 811 8283939, E-mail:nosratneghab@umsha.ac.ir
Therapeutic Effect of Vitex Agnus Castus in
Patients with Premenstrual Syndrome
Mehrangiz Zamani1, Nosrat Neghab1, and Saadat Torabian2
1 Department of Obstetrics & Gynecology, Hamedan University of Medical Sciences, Hamedan, Iran
2 Department of Community Medicine, Hamedan University of Medical Sciences, Hamedan, Iran
Received: 1 Jun. 2011; Received in revised form: 5 Sep. 2011; Accepted: 25 Oct. 2011
Abstract- Medical therapies have been widely used for premenstrual syndrome (PMS), but in all of them
side effects are predominant. Herbal remedies rarely have side effects and people have more tendencies
toward them than chemical therapies. In this study the therapeutic effect of Vitex agnus castus on women who
had the PMS, in comparison with placebo, were investigated. In this randomized, placebo-controlled, double-
blind study, from134 selected patients 128 women suffered from PMS were evaluated (active 62, placebo
66). All patients answered to a self assessment questionnaire about their headache, anger, irritability,
depression, breast fullness and bloating and tympani during the premenstrual period before the study. Forty
drops of Vitex agnus extract or matching placebo, administrated for 6 days before menses for 6 consecutive
cycles. Patients answered the self-assessment questionnaires after 6 menstrual cycles, again. Each item rated
using a visual analogue scale (VAS). The mean age was 30.77 (SD=4.37) years in the active group and 30.89
(SD=4.02) years in the placebo group. Rank of variables had significantly difference in active and placebo
group before and after the study (P<0.0001) also we noticed significant differences on the use of Vitex agnus
in comparison with placebo (P<0.0001). Vitex agnus can be considered as an effective and well tolerated
treatment for the relief of symptoms of mild and moderate PMS.
© 2012 Tehran University of Medical Sciences. All rights reserved.
Acta Medica Iranica, 2012; 50(2): 101-106.
Keyword: Vitex agnus castus; Premenstrual syndrome; Botanical supplements
Introduction
Premenstrual syndrome (PMS) is a complex
combination of psychological symptoms and somatic
changes that occurs in 1-2 weeks before menstruation
period of women (1-5). Several medical therapies and
herbal remedies have been reported to relieve PMS
symptoms (6-8).
Nearly 50% of women in fertility ages experience
PMS. Physical, psychological and behavioral disturbing
changes of PMS are intensive enough to cause
disturbance in the interpersonal relations and normal
activities (3,4,6,9). The PMS is defined as symptoms
have occurred during the last week of the luteal phase
(premenstrual phase) in most menstrual cycles for the
past year. Within a few days of the onset of the follicular
phase (menses), the symptoms begin to remit and are
absent in the week following menses. Five or more of
the following symptoms have to be present for most of
the time during the last week of the luteal phase, with at
least 1 of the first 4 symptoms: 1) depressed mood; 2)
tension or anxiety; 3) affective liability or tearfulness; 4)
irritability or anger; 5) decreased interest in usual
activities; 6) difficulty concentrating; 7) fatigue or
lethargic; 8) changes in appetite; 9) hypersomnia or
insomnia; 10) feeling overwhelmed; and 11) Physical
symptoms (breast tenderness, headaches, bloating,
muscle pain). These symptoms are not merely an
exacerbation of the symptoms of another disorder, such
as major depressive disorder, panic disorder, dysthymic
disorder or a personality disorder, but may be
superimposed on another disorder. The presence of the
symptoms must be confirmed by prospective daily
ratings during ≥2 consecutive symptomatic cycles (10).
In addition to training, consultation, diet changes,
medical interventions and supplements, there are various
botanicals which are useful in the treatment of PMS. In
spite of a broad spectrum of the effective drugs for PMS,
the attempts still continue to find a drug with the most
efficiency and the fewest side effects. In this study we

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Therapeutic effect of vitexagnuscastus in premenstrual syndrome
102 Acta Medica Iranica, Vol. 50, No. 2 (2012)
used chaste berry. Its botanical name is Vitex agnus
castus berries. Chaste berry is derived from the Greek
word Chastity, which means chaste, because it was used
to reduce sexual intentionsin ancient Greece and Rome
(11-14). The fruits of Vitex agnus 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. The mechanism of action may
also be related to modulation of stress induced prolactin
secretion via dopamine, without directly affecting LH
and FSH. Binding to opioid receptors, endorphins, and
neuroactive flavonoids may also have a role (6).
Some side effects of Vitex agnus are minor dermal
problems and some intestinal problems such as diarrhea,
headache, vertigo and palpitation, which disappear after
stopping its use (15,16). There are no reports of herb-
drug interactions involving Vitexagnus. Some herbalists
believe that Vitexagnus could interfere with birth control
pills, hormone replacement therapy, and other hormone
replacement medication (16). Additionally, it has been
hypothesized that individuals taking drugs classified as
dopamine-receptor antagonists should use caution when
taking Vitex agnus because animal studies indicate that
Vitex agnus may interfere with the dopamine receptors
(9,17).
Several studies have been done to check the Vitex
agnus effects on PMS and most of them have revealed
its significant effects on decreasing or improving PMS
symptoms (18-20).
Since PMS is one of the restrictive causes in daily
women's activities and its excitement has some effects
on several aspects of personal life, accessing and
studying a method with a few side effects and an easy
procedure can satisfy fertility program purposes (1,2,6).
In most of the studies, patients received 20-40 drops
of Vitex agnus extract (3.5-4.5 mg) 3 times a day for 3-6
months. Then its effect on PMS determined (7,18-20).
Due to its bitterness and therefore poor compliance
in daily usage, we implemented a new method for the
drug consumption.
Materials and Methods
In this randomized, placebo-controlled, double-blind,
cross-over study, all the child bearing age patients who
had referred to Fatemie Hospital Clinic (University
hospital, Hamedan, Iran) from December 2006 to
January 2007 were evaluated by DSM-IV criteria
regarding PMS. A detailed history of pregnancy,
weaning, contraception, mental diseases and drugs
consumed for major depression (which imitates PMS
signs) and other diseases were obtained. Inclusion
criteria were reproductive age women, regular menstrual
cycles lasting 25-34 days, and met DSM-IV criteria for
PMS. Exclusion criteria were pregnancy and breast
feeding, inadequate contraception, drug and alcohol
abusers, patients with pituitary problems, those who had
used sexual hormones other than oral contraceptive pills
(for which the doses were kept unchanged) and previous
Vitex agnus users concomitant psychotherapy,
concomitant serious medical condition, hypersensitivity
to Vitex agnus. PMS diagnosis is futuristic therefore
PMS criteria were based on Penn daily symptom reports
(DSR) rated by the subjects for two menstrual
cycles prior to commencing study. The aim of this
screening period for two menstrual cycles was to screen
the patients for suitability and to confirm the
diagnosis of PMS. Each item was rated by on a five-
point scale daily (0=none to 4=extreme). Scores were
calculated by summing the ratings of cycle days 5-10
for postmenstrual score (day 1 was the first day of the
menses) and the ratings of cycle days 23-28 for the
premenstrual score. DSR criteria for this 2 month
open-label screening were an increase of 30% or
over in total premenstrual DSR scores (days 23-28)
compared with the postmenstrual scores (days 5-10)
(22).146 women were screened and 128 patients were
evaluated. The patients were randomly divided by a
computer-generated schedule into control and
experiment groups.
Sample size was calculated by this formula:
F=20%=percent of probable drop of sample
Because there is possibility for decreasing patients
due to irregular consumption and withdrawal, number of
patients considered 20% more than required (Flow
Diagram)
After complete description of the study to the
subjects, written informed consent was obtained from
each patient. Ethical permission was approved by the
Local Ethics Committee of Hamedan University of
Medical Sciences. After selecting women suffering
PMS, first questionnaire and self assessment were filled
out. Women's self assessment at baseline consisted of
the combined scores of the following six symptoms
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M. Zamani, et al.
Acta Medica Iranica, Vol. 50, No. 2 (2012) 103
related to their at least previous three cycles
(headache, nervousness, restlessness, depression, breast
swelling and pain, bloating and tympani) with VAS.
VAS ranging from 0 (no symptoms) to 10 (unbearable).
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 for use in community practice (23). All
patients were sent to one specific drugstore to
receive a packet containing 3 bottles of either
Vitex agnus extract or placebo, free of charge. There was
a sign in the prescription of those who were
in the control group. Vitex agnus extract and placebo
bottles were produced with identical appearance, and
were indistinguishable from each other. The
medications were divided into two sets of glass bottles
which were labeled: Clinical A and Clinical B. An
identification number was noted in a protocol to
allow a subsequent identification after the completion of
the study and statistical analysis. The information
on the placebo and the active substance became
available to the investigators and volunteers only
after the completion of the study and after the
statistical analysis was performed. Patients
added 40 drops of Vitex agnus or placebo in one
glass of fruit juice and drank it before breakfast
from the 6th day before menstruation until menstruation,
for 6 consecutive cycles. The use of concomitant
medications was prohibited.
After 6 menstruation cycles, patients filled out the
second questionnaire and self assessment and visited.
Data were analyzed by SPSS 13 software and
Wilcoxon signed-rank test was used to determine the
effects of the treatment before and after the study in both
groups. We used the nonparametric Wilcoxon signed
rank test to compare the median of a single column of
numbers against a hypothetical median. To compare the
two groups, differences in variables before and after the
study were calculated and then Mean Ranks were
analyzed by Mann-Whitney test because both groups are
independent of each other and the responses are
continuous measurements.
Results
The mean ages and, mean duration of PMS, mean cycle
length, mean menstruation duration of Vitex agnus
group (active) and placebo are presented in Table1
which showed no statistically differences. Urban to rural
patients’ ratio in each group was approximately 2: 1 and
regarding literacy, in both groups half of patients
finished high school.
Most of the PMS VAS scores were dropped in both
groups, however it was more significant in the
Vitex agnus group (P<0.0001). Mean headache,
nervousness, restlessness, depression, breast pain and
swelling, swelling and tympani of both groups, before
and after the treatment, are shown in (Figure 1). Mean
Rank of differences of the above variables had
significantly difference, before and after the study, in
both groups and between two groups (P<0.0001) (Table
2). No adverse effect was reported.
Table 1.Characteristics of 128 women at entry into study of Vitexagnus as treatment for the
premenstrual syndrome (active treatment, n=62; placebo, n=66)
Mean ± SD P value
Age (years)
Active 30.77±4.37 NS
Placebo 30.89±4.02
Mean days of PMS
Active 5.87±2.24 NS
Placebo 5.64±1.96
Cycle length (days)
Active 28±1.2 NS
Placebo 28±1.0
Menses duration (days)
Active 4.6±1.0 NS
Placebo 4.7±0.9

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Therapeutic effect of vitexagnuscastus in premenstrual syndrome
104 Acta Medica Iranica, Vol. 50, No. 2 (2012)
Table 2.Mean Rank of basic variables in Vitexagnus group and control group
Symptoms Vitexagnus Placebo P value
Mann-Whitney test
Headache 73.54 56.01 0.004
Nervousness 78.90 50.98 0.000
Restlessness 79.98 49.96 0.000
Depression 83.72 46.96 0.000
Breast swelling & pain 86.73 42.32 0.000
Bloating and tympani 87.41 42.98 0.000
Figure 1. Mean of basic variables in Vitex agnus group and control group before and after treatment
Discussion
The comparison between measured mean ranks of
Vitex agnus and placebo group showed that there are
significant differences in all 6 variables. Several studies
confirm our results.
Loch et al. studied the effects of Vitex agnus on four
symptoms of PMS including depression, anxiety, desire
for sweets and water blockage (16). They reported 85%
decrease of signs in patients (16). Schellenberg studied
Vitex agnus effects on 6 symptoms (headache,
nervousness, mood change, restlessness, breast pain and
tympani) in women with PMS in comparison with
placebo with successful effects on reducing symptoms
(4). Berger et al., studied the effects of Vitex agnus
effects on 1542 women with PMS from 13 to 62 years.
They had prescribed to use 40 drops of Vitex agnus for 4
months, every day. In 33% of women all symptoms
disappeared and 57% of them were improved (17). Dose
of drug in our study was the same as Berger's et al., but
the care duration was longer in our study although the
number of days of using the drug was fewer.
In another study on 217 women with PMS,
prescribing 600 mg Vitex agnus 3 times a day had
significant effects on reducing mental symptoms but not
on water blockage and pain (14). It had contrasted to our
study.
In a broad study on 1592 women, including 48 hyper
menorrheal, 359 poly menorrheal, 202 secondary
amenorrheal, 186 dysmenorrheal, 145 infertility, 175
PMS, 32 irregular menstruations and 66 menorrhagial,
were cured by 40 daily drops for 6 months. 60% of them
reported that the cure result was good and in 33% of
patients all symptoms disappeared and 51% had good
0
1
2
3
4
5
6
7
Before
After

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M. Zamani, et al.
Acta Medica Iranica, Vol. 50, No. 2 (2012) 105
responses to drug (11).
There are several studies which don’t confirm our
results. Atmaca et al. compared fluoxetine with
Vitexagnus in reducing PSM signs and didn’t observe
significant differences between them, but they reported
better effects of fluoxetine in curing mental symptoms
of PMS (20). Lauritzenet al. compared Vitex agnus by
vitamin B6 which had no significant differences
between 2 groups (18).
There were two striking differences between our
study and the others: we increased duration of treatment
(6 months instead of 3), cyclic use instead of daily usage
(6 days instead of 30 days), and finally increased
Vitex agnus acceptability in spite of its bitterness. Due to
the wide acceptance of herbal medicine for management
of PMS, their side effects must be considered.
Herbal remedies rarely have side effects and people
have more tendencies toward them than chemical
therapies. Because in this study the recovery of patients
by Vitex agnus was successful, we propose it in
management of minor and moderate cases of PMS.
Another interesting result of this study was a significant
effect of placebo in management of PMS. This finding
highlights the effect of mental factors in management of
PMS although further studies are needed to investigate
this effect.
Acknowledgement
Financial supports from the Hamedan University of
Medical Science is gratefully acknowledged.
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