Chaste Tree vitex agnus castus L. (Verbenaceae), commonly referred to
as chaste tree or chasteberry, is a small shrubby tree, approximately
1 to 6 m in height and native to the Mediterranean
region and Asia.
The tree is also widely cultivated
in warm temperate regions of the world. The name
“chasteberry” may be derived from the traditional belief
that the plant promoted chastity (3). The fruits of V. agnus
castus (VAC) were used in ancient Greece and Rome, as
well as by the monks of the Middle Ages, to suppress
sexual desire (4,5). In the past, extracts of VAC have been
used for the treatment of gynecological disorders, such
as endometrial hyperplasia, hypermenorrhea, and secondary
amenorrhea, as well as endocrine-dependent dermatoses
(dermatitis dysmenorrhea symmetrica, acne vulgaris,
eczema, and acne rosacea) (6–8).
Today, extracts of the dried ripe fruits of VACare regulated
in the United States as dietary supplements under
the 1994 Dietary Supplement Health and Education Act.
They are widely used as a botanical dietary supplement
for the management of gynecological disorders including
corpus luteum insufficiency (9,10), premenstrual syndrome
(PMS) (11–13), menstrual problems (14,15), cyclic
mastalgia (16–18), as well as to treat hormonally induced
acne (19). In addition, VAC has been traditionally used
to treat fibroid cysts and infertility, stop miscarriages
caused by progesterone insufficiency (20), and treat indigestion
CHEMISTRY AND PREPARATION OF PRODUCTS
Commercial products ofVACare prepared from the dried,
ripe fruit, containing not less than 0.4% (v/w) of volatile
oil and at least an 8% water-soluble extractive (1,21). To
date, although the active constituents of VAC remain unknown,
the European Pharmacopoeia recommends a minimum
content of 0.08% casticin in the dried plant material
(22). Two compounds are currently used as marker compounds
for quality control: the iridoid glycoside agnuside
and the flavonol casticin (23). Most VAC preparations used
in European medicine are non standardized fluidextracts,
tinctures, and/or native dry extracts. The “native” or “total”
extract is an approximate 10:1 (w/w) drug-to-extract
ratio containing 0.6% to 1.0% casticin (2).
The ripe, dried VAC fruit yields 0.4% to 0.7% (v/w)
essential oil, depending on distillation time and comminution
size. The oil is mainly composed of bornyl
acetate, 1,8-cineole, limonene, – and -pinene, –
caryophyllene, and -terpinyl acetate (24). Flavonoids,
iridoids, and diterpenes represent major groups of secondary
constituents that are also found in the fruit
(2). Casticin (up to 0.2%) is considered to be the
major flavonoid, with chrysoplenetin, chrysosplenol
D, cynaroside, 5-hydroxy-3,4,6,7-tetramethoxyflavone, 6-
hydroxy kaempferol, isorhamnetin, luteolin, and luteolin
6-C-glycoside derivatives being other compounds of
this class (24–26). Major iridoids found include agnuside
(p-hydroxybenzoyl aucubin, 0.0014%) and aucubin
(0.0013%). Diterpene constituents include vitexilactone
diene, rotunda furan, vitex landines A–D, and vitex lactam
A (24,25). The structures of the above-mentioned components
are presented in Figure 1.
PRODUCTS AND DOSAGE
There is a wide range of VAC extracts and products available
to consumers. The following examples are a general
list of products used in clinical trials and listed in reference
texts. This list is not complete and is not intended as
a recommendation of one product over another. The dose
as listed is intended for adults, and the products are not
recommended for children.
Dry native ethanolic extracts, 8.3–12.5: 1 (w/w), approximately
1.0% casticin: one tablet, containing 2.6 to 4.2mg
native extract. The tablets should be swallowed whole
with some liquid each morning.
Dry native extract, 9.58–11.5:1 (w/w): one tablet containing
3.5 to 4.2 mg native extract each morning with
some liquid (27).
Dry native extract, 6.0–12.0:1 (w/w), approximately
0.6% casticin: PMS: one tablet containing 20 mg native
extract daily with water upon waking or just before
bedtime, before meals.
Compounds from Vitex agnus castus fruits.
Fluid extract: 1:1 (g/mL), 70% alcohol (v/v): 0.5 to
Fluid extract: 1:2 (g/mL): 1.2 to 4.0 mL.
Tinctures, alcohol 58 vol% (100 g of aqueous-alcoholic
solution contains 9 g of 1:5 tincture): 40 drops, one time
daily with some liquid each morning.
Tinctures, ethanol 19% (v/v) (100 g of aqueous-alcoholic
solution contains 0.192–0.288 g extractive corresponding
to 2.4 g dried fruit): 40 drops, once daily.
Hydroalcoholic extracts (50–70%; v/v): corresponding
to 30 to 40 mg dried fruit (2,28).
Chaste Tree CLINICAL STUDIES
Extracts from VAC fruits are primarily used for the symptomatic
management of corpus luteum insufficiency, hyperprolactinemia
(9,10), PMS (11–13,24,27,29), and cyclic
mastalgia (16–18). A few clinical studies have also indicated
that VAC may also be a potential treatment for infertility
due to hyperprolactinemia and luteal-phase defect
(30), insufficient lactation, as well as to prevent miscarriages
due to progesterone insufficiency (20).
Since the 1950s, over 35 human or clinical studies
have assessed the safety and efficacy of various VAC extracts
and tinctures (53–70% ethanol) for the treatment
of acne, corpus luteum insufficiency, cyclic breast pain,
hyperprolactinemia, menopausal symptoms, increasing
lactation, PMS, uterine bleeding disorders, and miscellaneous
menstrual irregularities. Most of these investigations
are open, uncontrolled studies assessing the effects
of VAC for the management of menstrual cycle irregularities
or PMS. The results from randomized, controlled
clinical trials are also published.
PMS refers to the regular occurrence of affective symptoms,
such as depressive moods, irritability, anxiety, confusion,
and social withdrawal, as well as somatic symptoms
including breast tenderness or heaviness and breast
pain (mastalgia), abdominal bloating, cravings, fatigue,
and headache (31). The syndrome affects approximately
30% to 40% of menstruating women and is one of the
most frequent complaints noted in gynecology practice
(27). Approximately 13 clinical trials have assessed the
safety and efficacy of VAC extracts for the symptomatic
treatment of PMS (11,12,14,27,29,32–39). Of these investigations,
only three were randomized, controlled trials and
two were double blinded (27,36–39).
The most recent clinical trial assessing the safety
and efficacy of VAC for the management of PMS was a
prospective, randomized, multicenter placebo-controlled
trial in Chinese women (39). After the screening and
preparation phase lasting three cycles, eligible patients
were randomly assigned into treatment or placebo groups
and were treated with a VAC extract daily or placebo for
up to three cycles. Efficacy was assessed using the Chinese
version of the PMS-diary (PMSD) and Premenstrual
Tension Syndrome (PMTS) scale. Two hundred and seventeen
women were eligible to enter the treatment phase
and were randomly assigned into the treatment group
(n = 108) or the placebo group (n = 109), of these 208 provided
the efficacy data (treatment: n = 104, placebo: n =
104) and 202 completed the treatment phase (treatment:
n = 101, placebo: n = 101). The mean total PMSD scores
decreased from 29.23 at baseline (0 cycle) to 6.41 at the
termination (3rd cycle) for the treatment group and from
28.14 at baseline (0 cycle) to 12.64 at the termination (3rd
cycle) for the placebo group. The total PMSD score of the
3rd cycle was significantly lower than the baseline in both
groups (P < 0.0001). The difference in the mean scores
from the baseline to the 3rd cycle in the treatment group
(22.71 °æ 10.33) was significantly lower than the difference
in the placebo group (15.50 °æ 12.94; P < 0.0001). Results of
PMTS were similar in that the total scores for PMTS were
significantly lower between the two groups (P < 0.01) and
within each group (P < 0.01). The score was decreased
from 26.17 °æ 4.79 to 9.92 °æ 9.01 for the treatment group
and from 27.10 °æ 4.76 to 14.59 °æ 10.69 for the placebo
group. A placebo effect of 50% was found in the present
study. No serious adverse events were reported in either
group. The study concluded that VAC was well tolerated
and was efficacious for the treatment of severe PMS in
Chinese women (39).
In a randomized, placebo-controlled study published
by Schellenberg et al., women with PMS symptoms
were randomized for treatment to either a VAC extract
(n=86; one tablet daily) or a placebo (n=84) for three consecutive
menstrual cycles (37).APMS diagnosis was made
according to the Diagnostic and Statistical Manual for Mental
Disorders (DSM-III). The main efficacy variable measured
was the change from baseline to the endpoint (end of
cycle 3) in the patient’s self-assessment (PSA) of six PMS
symptoms (irritability, mood alteration, anger, headache,
breast fullness, and other indications including bloating).
The secondary efficacy variable measured was a change in
the Clinical Global Impressions (CGI) score for the severity
of condition, global improvement, and risk/benefit ratio.
Mean improvement in PSA was significantly greater
in the treatment group compared with placebo group
(P < 0.001). CGI scores for each of the three factors also
revealed significant superiority of the treatment relative
to placebo (P < 0.001). The observed response rate (> 50%
reduction in symptoms) was 52% and 24% for the treatment
and placebo groups, respectively. Adverse events
reported included treatment (n = 4): acne, multiple abscesses,
intermenstrual bleeding, urticaria; placebo (n=3):
acne, early menstrual period, and gastric upset (37).
A randomized, double-blind, placebo-controlled
trial involving 217 women with self-diagnosed PMS assessed
the efficacy of the fruit in treating the syndrome.
The self-diagnosis was made according to a modified version
of the Menstrual Distress Questionnaire (MDQ), a rating
scale covering most of the important PMS symptoms
(38). Subjects were treated with either a powder of VAC
(300 mg tablets; two tablets three times daily; n = 105) or a
soy-based placebo (n = 112) for a period of three months,
after which they all completed the modified MDQ again.
Other than a statistically significant difference in effect
between the VAC powder and the soy-based placebo for
the symptom of “feeling jittery and restless” (P = 0.05), no
other significant results were reported (38). Unfortunately,
soy was a poor choice for a placebo in this study, as it is
not considered to be biologically inert.
A multicenter, randomized, double-blind, controlled
clinical trial compared the activity of a dried
Chaste Tree 131
ethanol extract of VAC fruit with that of pyridoxine (vitamin
B6) treatment of women with PMS (27). The intentto-
treat population included 127 women: 61 subjects were
given one capsule of extract plus one placebo capsule daily
for three cycles, whereas 66 were given one capsule of
placebo twice daily on days 1–15 of their cycle, followed
by one capsule (100 mg) of pyridoxine twice daily on days
16–35. Therapeutic response was assessed by using the
PMTS scale, the CGI scale, and by recording six characteristic
symptoms of PMS (breast tenderness, edema, inner
tension, headache, constipation, and depression). Therapeutic
efficacy was assessed by both patients and physicians,
at the end of the trial. Initial mean PMTS scores
were higher in the chaste tree group (15.2) compared with
the pyridoxine group (11.9). By the end of therapy, the
mean absolute change in PMTS score in each group was
5.1, representing a reduction of 10.1 and 6.8 for the chaste
tree and pyridoxine groups, respectively (P < 0.038, both
groups, 95% CI: −6.4261 to −0.1670). Therefore, no difference
could be found between the two treatment groups.
The CGI scale showed that 77.1% (chasteberry) and 60.6%
(pyridoxine) of patients showed improvement. Adverse
events were rare but included gastrointestinal complaints,
skin reactions, and transient headache (27).
Six postmarketing studies assessed the safety and
efficacy of various extracts of the fruit in 8391 female patients
with menstrual abnormalities or PMS symptoms
(11,14,29,33,34,36). Three open (uncontrolled) studies also
assessed efficacy (12,32,35). The dose used ranged from 40
to 42 drops or one capsule daily, for 1 day to 9 years, and
the outcomes measured included the physician’s assessment
and PSA. Elimination of symptoms was observed in
29% to 42% of patients, improvement in 51% to 59%, and
no change in 1% to 10%. Adverse events were reported in
1% to 5% of patients but were generally not stated to be serious.
The difficulty with these studies includes the lack of
a control group, besides most of them not distinguishing
between PMS and other menstrual disorders (12,32,35).
An open (uncontrolled) clinical trial involving 50
women (43 completed) with late-luteal phase dysphoric
disorder (DSM-III) assessed the effect of an ethanol fruit
extract on the management of PMS (32). Thirteen of the
subjects were concurrently taking oral contraceptives. After
two months of baseline observation, one tablet of the
extract was administered daily for three cycles, followed
by a posttreatment phase that lasted three cycles. Treatment
effectiveness was evaluated using both theMDQand
the visual analogue scale (VAS). The MDQ was filled out
by patients at the end of the first cycle and during cycles 3
and 6. The VAS was completed twice per cycle, once in the
late-luteal phase when symptoms peaked and the other after
menstruation during the follicular phase. By the end
of the third cycle, the MDQ scores were reduced by 42.5%
(P < 0.001), with a 50% reduction in the score in 20/43 patients.
By the end of the posttreatment period, the scores
remained approximately 20% below baseline (P < 0.001).
The main symptoms that improved following treatment
were breast tenderness, behavioral changes, negative feelings,
and edema. The average late-luteal phase VAS score
was reduced by 47.2% during the three-month treatment
phase (P < 0.01) and remained at 21.7% below baseline
(P < 0.001) during the posttreatment phase. By contrast,
the follicular phase score did not significantly change. The
number of days with PMS symptoms was reduced from
7.5 to 6 days (P < 0.001), and the concomitant use of oral
contraceptives had no significant effect on any of the parameters
investigated. Twenty patients (47%) reported 37
adverse events during the treatment and posttreatment
An open (uncontrolled) study involving 36 women
with PMS assessed the effect of a 58% ethanol extract of
the fruit for the management of PMS symptoms (12). The
subjects were treated with 40 drops of the extract daily
over three cycles and the outcomes measured were a reduction
in physical symptoms such as headache, swollen
breasts, breast tenderness, bloating, fatigue, and psychological
changes such as increased appetite, sugar craving,
nervousness and restlessness, anxiety, irritability, lack of
concentration, depression, crying spells, mood changes,
and aggressiveness. The duration of the luteal phase was
also determined. After three months of treatment, 69% of
women had a reduction in physical symptoms, where 80%
showed a decrease in psychological symptoms (P < 0.05).
The duration of the luteal phase lengthened from 5.4 to
11.4 days (12).
Breast pain (mastalgia) is a common complaint and is usually
classified as cyclical (associated with the menstrual
cycle) or noncyclical (not related to the menstrual cycle).
Mild premenstrual breast discomfort, lasting for one to
four days prior to menstruation that resolves upon initiation,
is considered cyclic mastalgia and is a symptom
of PMS. In addition to the experiments reported above, a
number of open studies (40–45) and four randomizedcontrolled
clinical trials (16,17,39,46) have assessed the
safety and efficacy of VAC extracts for the treatment of
A randomized, double-blind, placebo-controlled
clinical trial involving 104 women with cyclic breast pain
(for at least three cycles) assessed the efficacy of a VAC
tincture (10 g tincture containing 2 g of crude drug in 53%
ethanol VAC) for treatment of the pain (46). The patients
were treated with placebo, VAC tincture (30 drops twice
daily), or VAC tablets (one tablet twice daily) for three
cycles. The subjects assessed the intensity of breast pain
once per cycle using a VAS and recorded the presence of
menstrual bleeding and the intensity of pain in a diary.
Prolactin levels were measured during the premenstrual
week of cycles 1 and 3. At the end of the third treatment
cycle, a significant reduction in breast pain was observed
in the treated patients as compared with placebo (VAC
solution, P = 0.006; VAC tablets, P = 0.007). A significant
decrease in prolactin levels (P = 0.039) was also noted in
the treatment groups as compared with placebo (46).
A second randomized, placebo-controlled, doubleblind
study with a similar design compared VAC solution
(30 drops twice daily for three cycles) with placebo in the
treatment of 100 women (50 per group) who had breast
pain at least five days prior to menses in the last cycle
before the study (16). The treatment phase lasted three
menstrual cycles (2 °ø 30 drops/day = 1.8 mL of VAC
or placebo). Mastalgia for at least five days of the cycle
before the treatment was the strict inclusion condition.
For assessment of the efficacy, VAS was used. Altogether
132 Mahady et al.
97 patients were included in the statistical analysis (VAC:
n = 48, placebo: n = 49). Intensity of breast pain diminished
quicker in the VAC group. This study design and
duration were similar to that of Wuttke et al. (46). The
results of this experiment showed a decrease in the VAS
scores in both the treatment and the placebo groups. However,
as compared with the placebo, the treatment group
had significantly lower VAS values at the end of each
cycle (P = 0.018, 0.006, and 0.064 for cycles 1, 2, and 3,
In a randomized, placebo-controlled trial, the effects
of VAC solution and placebo (double-blind) were compared
with that of gestagen (Lynestrenol R ) in 160 women
with mastalgia (18). A complete remission or improvement
of symptoms was reported in 82.1%, 74.5%, and
36.8% of the patients in the Lynestrenol, VAC, and placebo
groups, respectively. The difference in effect between treatment
groups and placebo was significant (P < 0.01), but
no significant discrepancy was found between the two
treatment groups (18).
Open studies have been used to assess the effectiveness
ofVACsolution for the treatment of over 1700women
with mastalgia (40–45). All these investigations assessed
the efficacy of one VAC solution, at a dose of 45 to 75 drops
per day for 1 to 6 cycles. Two of these studies compared
VAC treatment with Lynestrenol (5 mg daily on days 12–
24 of each cycle). Elimination of symptoms was observed
in 46% to 81.5% of the treated women, improvement in
12% to 39.6%, and no effect in 6.5% to 29%. Collective
reported adverse events from these studies included circulatory
disturbances, acne, and weight gain (40–45).
Menstrual Cycle Irregularity and Infertility
Since 1954, at least 17 investigations have assessed the
efficacy of VAC extracts for the treatment of menstrual
cycle disorders including amenorrhea, oligomenorrhea,
polymenorrhea, corpus luteum insufficiency, and infertility
(2). Two double-blind placebo-controlled clinical trials
and several observational studies have investigated
the effect of various fruit extracts on corpus luteal–phase
dysfunction and infertility (10,30,47). The products tested
were ethanol extracts (53–70% ethanol), and the dose
administered was 20 drops twice daily, 15 drops three
times daily, 30 drops twice daily, or one to two tablets or
In the first randomized, double-blind, placebo controlled
trial, the efficacy of a dried VAC fruit extract
was assessed in infertile women (10). The objective of this
study was to determine whether elevated pituitary prolactin
levels could be reduced by treatment with VAC, and
whether the deficits observed in the luteal-phase length
and luteal-phase progesterone synthesis could be normalized.
Blood was obtained for hormone analysis on days 5,
8, and 20 of the menstrual cycle, both before and after three
months of VAC therapy. Latent hyperprolactinemia was
analyzed by monitoring prolactin release 15 and 30 minutes
after intravenous administration of 200 g of thyroid
hormone. Thirty-seven cases (placebo: n = 20, treatment:
n = 17) were included in the statistical analysis. After
three months of treatment, prolactin release was reduced,
a significant increase in the length of the luteal phase (10.5
days; P < 0.05) was observed and deficits in luteal progesterone
synthesis were decreased. These changes only
occurred in the treatment group and were not observed
in the placebo group. All other hormonal parameters did
not change with the exception of 17-estradiol, which was
observed to increase during the luteal phase in the treatment
group. The overall length of the menstrual cycles
did not change, suggesting that there was a corresponding
shortening of the follicular phase. Two women in the
extract group became pregnant by the end of the study.
No adverse events were reported (10).
In a second randomized, double-blind, placebo controlled
trial, the efficacy of a VAC fruit extract was
assessed in 96 infertile women (30). The outcome criteria
measured included pregnancy or menstrual bleeding in
women with secondary amenorrhea or improved luteal
hormone concentrations. The subjects were administered
30 drops of the extract twice daily for three months. Sixtysix
patients completed the study, and overall positive outcomes
were observed in 47% of women, with 61% in the
treatment group and 38% in the placebo group, although
the results did not reach statistical significance (P=0.069).
In women with amenorrhea or luteal-phase dysfunction,
pregnancy resulted twice as often in the treatment group
(15%) versus the placebo group (7%); however, no statistical
analysis was reported (30).
In open (uncontrolled) trials involving 48 (45 completed)
infertile women (due to luteal-phase dysfunction),
the efficacy of a VAC fruit extract for the normalization
of progesterone concentrations was determined
(47). Inclusion criteria were normal prolactin levels (below
20 ng/mL), normal results in prolactin and thyroid stimulating
stimulation (TSH) tests, and an abnormally low
serum progesterone level below 12 ng/mL on the 20th
day of the cycle. Treatment consisted of a fruit extract,
40 drops daily, without any other medication for three
months. Forty-five patients completed the studies (three
were excluded because of concurrent hormone use). The
outcome of therapy was assessed by the normalization
of the mid-luteal progesterone concentration and correction
(lengthening) of any preexisting shortening of the
phases of the cycle. Treatment was successful in 39 out
of the 45 women. Seven subjects became pregnant. In
25 patients, serum progesterone was restored to normal
(> 12 ng/mL), and in seven cases, there was a trend
toward normalization of progesterone levels. However,
no statistical analysis was performed on the resultant
Two larger postmarketing trials, involving 479
women, assessed the safety and efficacy of a VAC fruit
extract for the treatment of oligomenorrhea or polymenorrhea
(48). The subjects were treated with 30 drops of
the extract twice daily and the outcome measured was
the bleeding-free interval. A lengthening of the bleeding free
interval was observed for 35 days in 187/287 women
receiving treatment for oligomenorrhea and 26 days in
139/192 patients being treated for polymenorrhea (48).
The efficacy of a combination product containing Hypercum
perforatum (St. John’s wort) and VAC (300 mg and
500 mg, respectively) for the management of menopausal
Chaste Tree 133
symptoms was investigated in a double-blind, randomized,
placebo-controlled, parallel study (49). The trial was
performed over 16-week period and involved 100 eligible
late-perimenopausal or postmenopausal women experiencing
hot flushes and other menopausal symptoms. The
herbal combination therapy or placebo tablets were administered
twice daily. The primary endpoint was a reduction
in hot flush episodes. Secondary endpoints included
Greene Climacteric Scale scores, Hamilton Depression Inventory
scores, and Utian Quality of Life Scale scores. Of
the 100 women that started the trial, 93 women completed
the study. Data analysis on an intent-to-treat basis found
no significant differences between the two groups for any
of the endpoints. Analyses performed at interim data time
points revealed no significant differences at week 4, 8, or
12 for daily weighted flushes or scores on the Greene Climacteric
Scale scores or Hamilton Depression Inventory
scores. No significant change was found for either group
on quality of life. The herbal combination was well tolerated
with no significant adverse events noted in the short
Two uncontrolled clinical studies and one observational
report have assessed the effects of a VAC fruit extract on
acne caused by a hormone imbalance (6–8). In one open
study, 118 cases of acne were treated with a VAC extract
(20 drops twice daily for 4–6 weeks, and then 15 drops
twice daily for 1–2 years) and compared with conventional
acne treatments (8). Patients treated with the fruit extract
reported a more rapid healing rate after six weeks and
after three months of therapy, whereas 70% of subjects
taking the VAC extract stated complete healing.
In general, VAC products and extracts appear to be very
well tolerated and there have been few accounts of adverse
reactions (ARs). A review of 30 human studies, involving
11,506 subjects, reported a total of 246 adverse events,
thus representing an AR rate of approximately 2% (2).
The major ARs included acne, cycle changes, dizziness,
gastrointestinal distress, increased menstrual flow, nausea,
skin reactions, urticaria, and weight gain (2). Minor
side effects include fatigue, hair loss, increased intraocular
pressure, palpitations, polyurea, sweating, and vaginitis
(2,46). One case of multiple follicular development was
reported in a female patient after self-medication with a
VAC-containing product for infertility (50).
Although the potential estrogenic effects of VAC extracts
are weak (51,52), its use during pregnancy or in
women with estrogen-dependent breast cancer should not
be recommended. In addition, patients with a feeling of
tension and swelling of the breasts or other menstrual disturbances
should consult a healthcare provider for medical
diagnosis (28). Although there are no drug interactions
reported, the potential dopaminergic effects of VAC
extracts may reduce the efficacy of dopamine-receptor antagonists
(23,53). Furthermore, because of possible hormonal
effects, VAC may interfere with the effectiveness of
oral contraceptives and hormone therapy (2).
MECHANISM OF ACTION
Several potential mechanisms of action have been proposed
to explain the activity of VAC extracts, including
inhibition of prolactin secretion (50–51) and dopaminergic
(53,54) and estrogenic effects (51,55–57). Extracts have
been shown to act as a dopamine agonist in vitro and in
vivo. The binding of an ethanol VAC extract and various
fractions of the extract to the dopamine D2 and other
receptors were evaluated by both radioligand binding
studies and by superfusion experiments (54). The extract
bound to the dopamine D2 and opioid ( and subtype)
receptors with a median inhibitory concentration ranges
between 20 and 70 g/mL. Binding was not observed
for the histamine H1, benzodiazepine and OFQ receptors,
or the serotonin transporter. Two diterpenes, isolated
from a hexane fraction of the extract, rotundifuran and
6,7-diacetoxy-13-hydroxy-labda-8,14-diene (Fig. 2), exhibited
inhibitory actions on dopamine D2 receptor binding
with a median inhibitory concentration of 45 and
79 g/mL, respectively (26,54). While lipophilic fractions
of the extract bound to the – and -opioid receptors,
binding to delta opioid receptors was inhibited primarily
by an aqueous fraction of the extract. In superfusion experiments,
the aqueous fraction of a methanol extract
inhibited the release of acetylcholine in a concentrationdependent
manner. In addition, theD2 receptor antagonist
spiperone antagonized the effect of the extract suggesting
a dopaminergic action mediated byD2 receptor activation.
A labdane diterpene, -acetoxy-13-hydroxylabdadiene
(Fig. 2), isolated from a fruit extract, was found to displace
125I-sulpiride from recombinant human D2 receptor binding
sites in a dose-dependent manner (58). This group
also demonstrated that rotundifuran, at a concentration
of 100 M, significantly (P < 0.05) inhibited the secretion
of prolactin from cultured rat pituitary cells.
Several groups have demonstrated that extracts bind
to the estrogen receptor and have weak estrogenic effects,
suggesting that chasteberry may also affect the
estrogen/progesterone balance (51,56–58).Amethanol extract
of the fruit bound to both ER and ER induced the
expression of estrogen-dependent genes, progesterone receptor
(PR), and presenelin-2 (pS2) in Ishikawa cells (51).
Significant binding affinity for both ER and ER was
observed, with a median inhibitory concentration of 46.3
and 64.0 g/mL, respectively. However, the binding affinity
of the extract for ER and ER was not significantly
different (51). Based on bioassay-guided isolation, the “estrogenic”
component from the fruit extract was identified
as linoleic acid (LA), which also bound to ER and ER
(52). Similar to the extract, LA also induced the expression
of the PR mRNA in Ishikawa cells, at a concentration of
1 g/mL, indicating that binding produced a biological
estrogenic effect in vitro. In addition, low concentrations
of the extract or LA (10 g/mL) upregulate the expression
of ER mRNA in the ER plus hormone-dependent
T47D:A18 cell line, a further indication of estrogenic activity
(52). Recently, it has been suggested that methanol
extracts of VAC may also activate the -opiate receptor,
thereby exerting its effects on endogenous opiate peptides
such as -endorphin (50). This peptide assists in regulating
the menstrual cycle through the inhibition of the
hypothalamus–pituitary–adrenal axis through a complex
feedback loop involving estrogen and progesterone (50).
Levels of -endorphin decrease along with estrogen in the
late-luteal phase of the menstrual cycle, which correlated
with the development of PMS symptoms (50). Thus, since
VAC activates the -opiate receptor, it may increase the
levels of -endorphin, thereby having beneficial effects
A recent review of the safety of VAC administration during
pregnancy and lactation used database searches of
published literature and case reports (59). The review concluded
that in pregnancy, there is little evidence supporting
the use of VAC during pregnancy based on theoretical
and expert opinion and in vitro studies that chaste
tree may have estrogenic and progesteronic activity, uterine
stimulant activity, emmenagogue activity, and prevent
miscarriages. In lactation, the data are conflicted as to
whether chaste tree increases or decreases lactation. Thus,
recommendations of VAC use during pregnancy and lactation
are currently unsubstantiated and require further
investigations for both safety and efficacy.
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