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Düzce Tıp Dergisi 2012; 14(1): 1-5 1
1İbrahim AYDIN
2Davut BALTACI
3Serdar TÜRKYILMAZ
3Mustafa ÖNCÜ
1Rize District Hospital,
General Surgery Clinic, Rize,
Turkey.
2Düzce University, Medical
Faculty, Department of
Family Medicine, Duzce,
Turkey
3Karadeniz Technical
University, Medical Faculty,
Department of General
Surgery, Trabzon, Turkey
Submitted/Başvuru tarihi:
14. 05. 2010
Accepted/Kabul tarihi:
15. 12. 2011
Registration/Kayıt no:
10 05 124
Corresponding Address
/Yazışma Adresi:
Davut BALTACI, MD
Duzce University, Medical
Faculty, Department of Family
Medicine,
Phone: (90) 541 7165619
(mobile)
Phone: (90) 380 5421390–
5820(work)
E-mail:
davutbaltaci@hotmail.com
ABSTRACT
Background: Mastalgia is classified as cyclic and non-cyclic. Cyclical one constitutes
approximately 60-70% of mastalgia. It is seen between 2 to 3 decades of age, and it usually
responds to treatment.
Objectives: To compare efficacy of vitex agnus castus (VAC) preparation with meloxicam and
placebo in treatment of mastalgia.
Methods: The study was designed as prospective and placebo-controlled clinical trial. Three
groups were constituted. Before grouping, prolactin level was tested for every patient. The
group1 enrolled the patients with cyclical mastalgia and high level prolactin. VAC was
administered to patients from study group1. The second group enrolled the patients with cyclical
mastalgia along with normal prolactin level, and to which meloxicam was given. Third group
was placebo group, and placebo was applied. Before treatment, VAS (Visual analogue scale)
scoring was applied to every patient. Prolactin level was tested for patients from group 1. After
3 months of study, VAS scoring was applied to every patient, but only prolactin levels were re-
evaluated in patients from group1.
Results: 95 patients were analyzed; enrolling women aged 19 to 54 years. Intensity of mastalgia
diminished in VAC group 1, 2 more than in placebo group (p<0.0001). In addition to VAS
scoring, prolactin level in group 1 after treatment was significantly reduced, comparing with
before treatment (p<0.0001). In conclusion, we found that VAC preparation was effective in the
treatment of mastalgia and hyperprolactinemia, with good tolerability.
Key Words: Mastalgia, vitex agnus castus, prolactin.
ÖZET
Giriş: Mastalji meme ağrısı olup klinik olarak siklik ve siklik olmayan şeklinde sınıflandırılır.
Siklik mastalji mastaljilerin yaklaşık %60’ını kapsar. Siklik mastaljiler en sık 20 ve 30 yaşlarda
görülür ve genellikle tedaviye iyi cevap verir.
Amaç: Vastus Agnus Castus preparasyonunun (VAC) mastalgi ve hiperprolaktinemi üzerine
olan etkinliğinin araştırılması amaçlandı.
Metot: Araştırma prospektif ve palsebo kontrollü klinik çalışma olarak yapıldı. Hastalar gruplara
ayrılmadan önce her hastadan prolaktin seviyesine bakıldı. Hastalar gruplara ayrıldıktan sonra
her hastaya tedavi öncesi VAS uygulandı. Grub 1 siklik mastaljisi ve hiperprolaktinemisi olan
hastalardan oluştu. Bu hastalara VAC (agnucaston) başlandı. Grup 2 siklik mastaljisi ve normal
prolaktin seviyesi olan ve meloksikam 15 mg/gün başlanan hastalardan oluşmuştur. Placebo
grubu mastaljisi olan ve prolaktin seviyesi normal olan hastalardan oluştu. 3 aylık tedavi sonrası
her hastaya VAS ve grup 1 için prolactin seviyesine bakıldı.
Sonuçlar: Toplam 19–54 yaş arası 95 hastanın analizi yapıldı. VAC alan grupta mastaljinin
yoğunluğu plasebo grubundan anlamlı ölçüde azaldığı gözlendi (p<0,0001). VAS skoruna
ilaveten, prolaktin seviyesinde tedavi öncesine göre anlamlı azalma tespit edildi (p <0.0001).
Sonuç olarak, VAC preperasyonunun mastalji ve hiperprolaktinemi tedavisinde iyi tolerabilite
ile birlikte etkin olduğunu bulduk.
Anahtar Kelimeler: Mastalji, vitex agnus castus, prolaktin
INTRODUCTION
Mastalgia is a painful condition originated from breast tissue, and clinically is
classified into two types as cyclical and non-cyclical one. Cyclical one can be
Comparison of Vitex Agnus Castus with Meloxicam and Placebo
in Treatment of Patients with Cyclical Mastalgia
Siklik Mastaljili Hastaların Tedavisinde Vitex Agnus Castus
Preperatının Meloksikam Ve Plasebo İle Karşılaştırılması
2011 Düzce Medical Journal
e-ISSN 1307- 671X
www.tipdergi.duzce.edu.tr
duzcetipdergisi@duzce.edu.tr
DÜZCE TIP DERGİSİ
DUZCE MEDICAL JOURNAL
ORİJİNAL MAKALE / ORIGINAL ARTICLE
Düzce Tıp Dergisi 2012; 14(1): 1-5 2
described as middle to severe level breast pain lasting
approximately 5 days, or more. Cyclical mastalgia is
commonly seen between 20 to 30 years of age, but it
can be seen after menopause. It comprises 60-70 %
of mastalgia. Approximately 90% of cyclical
mastalgia respond to treatment. It occurs mainly
during menstrual period, so it is considered to be
associated with hormonal change. Non-cyclical
mastalgia comprises 20-30 % of cases, and is more
severe and resistant to treatment, comparing with
cyclical one (1, 2).
It is one of the most common symptoms of female
patients seeking health care at both primary health
clinics and breast referral centers. Its prevalence is not
exactly known, but is estimated to be seen as 66% in
community-based screening and 50% in outpatient
clinic (3). 50% to 80% of women are estimated to
have experienced with mastalgia at some point in their
life, but in only 1% of patients is mastalgia a symptom
of breast cancer (4,5).
Today’s, we have several options to treat mastalgia as
pharmacologic and non-pharmacologic, but these are
not standardized therapies. Firstly, it should be
evaluated carefully for its reasons. History taking,
physical examination and imaging methods such as
mammography and ultrasonography should be
performed before deciding treatment. Bromocriptine,
danazol, tamoxifen, LNRH analogues, gamma
linoleic asid, testesteron, gestrinon, gabergolin,
vitamins such as B6 and E, and analgesic agents
(6,7,8,9). However, hormonal therapies such as
bromocriptine, danazol, LNRH analogues have severe
side effects. Nevertheless, efficacy of any treatment
modality is not superior to each other.
VAC has been also used in the treatment of female
conditions such as premenstrual syndrome, corpus
luteum insufficiency, menstrual disorders,
hyperprolactinemia and menopause. Agnus castus is
thought to be effective in the management of
mastalgia because of its dopaminergic effects. It could
be helpful in the management of mastalgia may be
because of its effect on latent hyperprolactinemia,
estrogen receptors or other unknown mechanisms
(10).
The aim of study presented here was to compare
efficacy of Vitex agnus castus (VAC) preparations
with meloxicam and placebo in the treatment of
patients with cyclical mastalgia.
MATERIAL and METHODS
Study Population
The study was prospective, placebo-controlled
clinical trial, enrolling consecutive female patients
presenting with mastalgia to our clinic, general
surgery out-patient clinic, Karadeniz Technical
University, School of Medicine, and Trabzon, Turkey.
On admission, the patients suffering from mastalgia
were classified into cyclical and non-cyclical form.
Among them, 108 women were enrolled into study by
taking their informed consent. The study was
approved by ethical committee of our institution.
Study Protocol
For every patient, prolactin level was measured before
grouping. Visual Analogue Scale (VAS) for scoring
breast pain was performed for every patient before
arranging into groups. Group 1 consisted of subjects
with cyclical mastalgia and hyperprolactinemia, group
2 consisted of those with cyclical mastalgia and
normal prolactin (3.4 ng/mL-24.1 ng/mL,
radioimmunoassay method), and placebo group
consisted of those with cyclical mastalgia and normal
prolactin Mammography for patients over 35 years of
age and ultrasonography for those less than 35 years
of age were performed for every subject to rule out
malign conditions. Cyclical mastalgia during at least
5 days of menstrual cycle before grouping was the
strict inclusion criteria. The patients with non-cyclical
mastalgia, history of breast cancer and family history
of breast cancer, being male, medical conditions
requiring mammary biopsy, doubtful positive signs on
imaging, prolactin level over 120 ng/mL (high
probability sign for intracranial pathology), and the
patients who rejected to participate in study were
excluded. Other exclusion criteria are Granulomatous
infiltration of the hypothalamus, severe head trauma,
primary hypothyroidism, renal failure.
Visual Analogue Scale (VAS) was used for breast pain
scoring. The patients were asked to fill VAS scale.
VAS was degreed from one to ten degree according
to severity of pain. One degree referred very light
pain, and ten referred very severe pain on VAS. Very
light pain (VAS 1) indicated painful condition on
resting state and without working. Very severe pain
(VAS 10) indicated that it awaked the patient from
sleep, and interrupted her daily activities. Score of
middle pain indicated that interrupted her daily
activities but not awaked her.
Clinical and demographic features of patients,
including, age, marital and educational state, smoking
and alcohol drinking, co-morbid diseases, medicines,
and occupation were recorded by medical notes and
semi-structured interview with them. Vitex Agnus
Castus preparation (Agnucaston 40 mg a day in a
single dose, Biomeks) was administered to patients
from group 1. Meloxicam 15 mg/day (Mobic tablet in
a single dose, Boehringer Ingelheim) was given to
patients from group 2. For group 3, placebo (a day in
a single dose) was applied. The patients from 3 groups
AYDIN et al.
Düzce Tıp Dergisi 2012; 14(1): 1-5 3
have been followed for three menstrual cycles. They
were also recruiting to re-evaluate for tolerability and
efficacy of VAC preparation at the end of 1st and 3rd
month. VAS scoring was re-applied at the end of 3rd
month. Serum Prolactin level of patients from group
1 was measured at the end of third month of treatment.
Statistical Analysis
Data were analyzed using Statistical Package for
Social Science for Windows (SPSS) version 10.0. The
results are presented as mean ± standard deviation for
scale variables, and stated as median and range for
nominal variables and percentages for proportions.
For parametric two-dependent variables, paired
Student-t was used, but Wilcoxon Signed Ranks Test
test for non-parametric ones. Analysis for non-scale
variables was done using X2-test (Ficher’s exact test).
Comparisons of VAS scoring between groups are
computed by using one-way ANOVA with post-hoc
Bonferroni test.
RESULTS
The study was employed between April 2005 and
September 2005. Initially, 108 female patients were
enrolled, but data of 60 patients (n= 30 for group 1,
n= 30 for group 2, and 35 group placebo) were
analyzed. Out of 108 patients, 13 ones left the study.
Overall, the study sample consisted of 95 subjects
aged from 19 to 54 years, averaging 36.31±8.92 yrs.
Based on results, cyclical mastalgia was commonly
observed after 30 years of age. Average age for group
1, group 2 and group 3 (placebo) was 43.47±8.71,
35.38±9.05 and 37.38±7.77 respectively. In study,
were not any patients having consumed alcohol. Only
the patients with current smoker were recorded. Most
of them have had informal education. They were
mostly married and housewife. Before treatment,
there were not significant differences for age, VAS
scoring, marital status, education level, occupation,
mammographic and ultrasonografic findings, and
smoking situation between groups (Table 1).
In group 1, two patients for hypertension and one for
asthma had been using medicine. On the other hand,
4 patients from group2 had been using medicine for
hypertension. In placebo group, two patients for
hypertension had been using medicine.
Mammography was performed for 14 (46%), 12
(%40), and 15 (50%) patients from groups,
respectively. Ultrasonography was applied to 16
(53%), 18 (%60), and 12 (40%) patients of group 1,
2, and 3, respectively. Comparing findings on USG
and mammographic examination, there were similar
results between groups (p>0.05) (table 1).
Median of VAS scoring for groups 1 before initiating
treatment was 6. After treatment with Vitex Agnus
Castus, median of VAS scoring was 1.5. It was
statistically significant (p<0.0001). Median VAS
scoring before and after in group 2 treated with
meloxicam 15 mg7day was 6 and 2, respectively. It is
also significant. For placebo group, median VAS
scoring before and after treatment was almost similar
and not significant (VAS before: 7, VAS after: 6)
(p=0,052). 30% of patients treated with responded
completely to therapy, 56% of them were affirmative,
and remaining was unresponsive (Table 2). Average
prolactin level of patients from group 1 was
38.93±19.57 ng/mL at initial (min: 25.0 ng/mL, max:
113.0 ng/mL). After treatment, it was measured as
21.90± 10.76 ng/mL (p<0.0001) (Figure 1). moreover,
we did not observed any side effects due to vitex
agnus castus administration, but one patient from
group 2 specified gastrointestinal discomfort, but not
severe.
Comparing VAS scoring of group 1 with group 2 was
not significant, but it was significant with that of
placebo after third month of treatment administration
(p<0.0001). Median VAS scoring of group 2 after
treatment was significant with placebo, but not with
group 1.
İbrahim AYDIN et al.
Table 1. Basic features of subjects according to groups.
Table 2. Comparison of VAS scoring between groups before
and after treatment.
Düzce Tıp Dergisi 2012; 14(1): 1-5 4
DISCUSSION
Cyclical mastalgia is diffuse and transient or periodic,
non-localized and usually bilateral breast pain.
Cyclical mastalgia is seen commonly between second
and third decades. Careful evaluation of patients
presenting with mastalgia lights the way for efficacy
and harmony of treatment, because most patients
spontaneously improve without treatment after they
are ensured that it would be not due to cancer (11).
44% of Mastalgia can be continued until menopausal
period. Spontaneous regression can be seen in 22% of
patients (12).
Patients with cyclical and non-cyclical mastalgia
responded to anti-prolactin therapy in different results
(12). Gatalay and et al. (13) obtained 47% and 20%
respond in cyclical and non-cyclical mastalgia
respectively after anti-prolactin treatment in their
study. In another study, they also reported that the
patients responded as 54% in cyclical and 33% in
non-cyclical mastalgia after anti-prolactin therapy
(14). In our study, 30% of patients from group 1
completely responded, and 50% of them affirmatively
(decrease in VAS scoring as 50% and more)
responded after Vitex Agnus Castus administration. It
was statistically significant, comparing with placebo
results. Generally response ratio change between 20
and 40% in literatures (15, 16). For our patients,
response was obtained higher, comparing with
previous studies.
Although mastalgia improved in a few subjects from
our placebo group, intensity of mastalgia mostly
remained during 3 three menstrual cycles, and small
number of patients specified that intensity of their
mastalgia increased. When the patients are satisfied
that their mastalgia is due to benign conditions, after
complete assessment and work-up, intensity of
mastalgia improves in most cases, remains in a few
cases.
Results of the double-blind, placebo-controlled
clinical trial which conducted by Halaska et al. (17)
were almost consistent with our results. They included
97 patients were into their study (VACS: n = 48,
placebo: n = 49). They found that Intensity of breast
pain diminished quicker with VACS group, the
tolerability was satisfactory. They stated that VACS
was useful in the treatment of cyclical breast pain in
women. In other hands, we investigated change in
prolactin level in group 1. It was significantly
different from level before treatment administration.
Van Die et al. (28) concluded in their study that, while
evidence from rigorous randomized controlled trials
is lacking for the individual herb in this context,
emerging pharmacological evidence supports a role
for Vitex Agnus Castus in the alleviation of
menopausal symptoms. Vitex Agnus Castus extract is
considered to be dopaminergic effect. Efficacy of
VAC is between 70-90% in mastalgia. In recent
clinical trial, improvements in 53-67% of symptoms
have been reported (11, 19-21).
In several studies, spontaneous improvements in
mastalgia were reported after the patients was inspired
confidence about whose breast pain was not
commonly resulted from breast cancer and it would
be benign conditions. Although mastalgia improved
in a few subjects from our placebo group, intensity of
mastalgia mostly remained during 3 three menstrual
cycles, and small number of patients specified that
intensity of their mastalgia increased. When the
patients are satisfied that their mastalgia is due to
benign conditions, after complete assessment and
work-up, intensity of mastalgia improves in most
cases, remains in a few cases. We estimated that
improvement in mastalgia of our patients was
quenched about their medical problems related
mastalgia. This result was consistent with previous
reports (22, 23).
In conclusion, patients with mastalgia should be
carefully evaluated for breast cancer. On inquiring,
mastalgia should be classified into cyclic and non-
cyclic. If necessary, blood prolactin should be
obtained. Due to effectiveness, tolerability and
usefulness of Vitex Agnus Castus might be chosen as
first-line therapy for patients as well as non-steroidal
anti-inflammatory agents due to high its efficacy and
good tolerability. It is also used to reduce prolactin
level over normal.
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Düzce Tıp Dergisi 2012; 14(1): 1-5 5
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