Success Chemistry

Improve who you are | Become unforgettable

Chaste Tree

GlossarySuccess Chemistry Staff

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



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

(0.001–0.004%), 6,7-diacetoxy-13-hydroxylabda-8,14-

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.



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

1.0 mL.

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).



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.


Premenstrual Syndrome

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

periods (32).

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

cyclic mastalgia.


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

capsules daily.


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

data (47).


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

term (49).


Endocrine-Dependent Dermatoses

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).



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

on PMS.



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.



1. WHOPublications. Fructus Agnus castii.WHOMonographs

on Selected Medicinal Plants. Geneva, Switzerland: WHO

Publications, 2009; 4:9–29.

2. Chaste Tree Fruit. American Herbal Pharmacopoeia and

Therapeutic Compendium. Santa Cruz, CA: American

Herbal Pharmacopoeia, 2001.

3. Christie S,Walker AF. Vitex agnus-castus L.: (1)Areview of its

traditional and modern therapeutic use: (2) Current use from

a survey of practitioners. Eur J Herbal Med 1997; 3:29–45.

4. Winterhoff H, Munster C, Gorkow C. Die Hemmung der

Laktation bei Ratten als indirekter Beweis f ¨ ur die Senkung

von Prolaktin durch Agnus castus. Z Phytother 1991; 12:175–


5. Winterhoff H. Vitex agnus castus (chaste tree) pharmacological

and clinical data. Phytomedicines of Europe: Chemistry

and Biological Activity.Washington, D.C.: American Chemical

Society, 1998:299–308. The National Osteoporosis Foundation.

Physician’s Guide to Prevention and Treatment of

Osteoporosis, 1994:1–43.

6. Amann W. Acne vulgaris and Agnus castus (Agnolyt R

). Z

Allgemeine 1975; 51:1645–1648.

7. Bleier W. Phytotherapy in irregular menstrual cycles or

bleeding periods and other gynecological disorders of endocrine

origin. Zentralbl Gynakol 1959; 81:701–709.

8. Giss G, Rothenberg. Phytotherapeutische Behandlung der

Akne. Z Haut Geschlechtskr 1968; 43:645–647.

9. Merz PG, Gorkow C, Schroedter A, et al. The effects of a special

Agnus castus extract (BP1095E1) on prolactin secretion

in healthy male subjects. Exp Clin Endocrinol Diabetes 1996;


10. Milewicz A, Gejdel E, Sworen H, et al. Vitex agnuscastus

Extrakt zur Behandlung von Regeltempoanomalien

infolge latenter Hyper-prolaktin¨amie: Ergebnisse einer

randomisierte Plazebo-kontrollierten Doppelblindstudie.

Arzneimittelforschung 1993; 43:752–756.

11. Dittmar FW, Bohnert KJ, Peeters M, et al. Pr¨menstruelles

Syndrom: Behandlung mit einem Phytopharmaka. TW

Gyn¨akol 1992; 5:60–68.

12. Coeugniet E, Elek E, K¨ uhnast R. Das pr¨amenstruelle Syndrom(

PMS) und seine Behandlung.A¨ rztezNaturheilverfahr

1986; 27:619–622.

13. Wuttke, Gorkow C, Jarry H. Dopaminergic compounds in

Vitex agnus castus. Phytopharmaka in Forschung und klinischer

Anwendung; Darmstadt, Germany: Steinkopff 1995;


14. Loch EG, Bohnert KJ, Peeters M. Die Behandlung von Blutungsst

¨orangen mit Vitex-agnus-castus-Tinktur. Frauenarzt

1991; 32:867–870.

15. Loch EG, Kaiser E. Diagnostik und Therapie dyshormonaler

Blutungen in der Praxis. Gynakol Prax 1990; 14:489–


16. Halaska M, Beles P, Gorkow C, et al. Treatment of cyclical

mastalgia with a solution containing an extract of Vitex agnus castus:

Recent results of a placebo-controlled double-blind

study. Breast 1999; 8:175–181.

17. Kress D, Thanner E. Behandlung der Mastopathie:m¨oglichst

Risiko Arm. Med Klin 1981; 76:566–567.

18. Kubista E, M¨ uller G, Spona J. Behandlung der Mastopathie

mit zyklischer Mastodynie: klinische Ergebnisse und Hormonprofile.

Gyn¨akol Rundsch 1986; 26:65–79.

19. Amann W. Amenorrhoe-günstige Wirkung von Agnus castus

(Agnolyt R

) auf Amenorrhoe. Z Allgemeinmed 1982;


20. McGuffin M, Hobbs C, Upton R, et al. Botanical Safety Handbook.

Boca Raton: CRC Press, 1997:231.

21. British Herbal Pharmacopoeia, 4th edn. Exeter, UK: British

Herbal Medicine Association, 1996.

22. European Pharmacopoeia, 4th edn. Strasbourg, France: Directorate

for the Quality of Medicines of the Council of Europe

(EDQM), 2001.

23. Abel G, Goez C, Wolf H. Vitex. Hagers Handbuch der pharmazeutischen

Praxis. vol 6 (P-Z). Berlin: Springer, 1994:1183–


24. Meier B, Hoberg E. Agni-casti fructus. New findings on quality

and effectiveness. Z Phytother 1999; 20(3):140–158.

25. Hoberg E, Meier B, Stitcher O. Quantitative high performance

liquid chromatography analysis of casticin in the fruits of

Vitex agnus-castus. Pharmaceut Biol 2001; 39:57–61.

26. Hoberg E, Orjala J, Meier B, et al. Diterpenoids from the

fruits of Vitex agnus-castus. Phytochemistry 1999; 52:1555–


27. Lauritzen C, Reuter HD, Repges R, et al. Treatment of

premenstrual tension syndrome with Vitex agnus-castus:

Controlled double-blind study versus pyridoxine. Phytomedicine

1997; 4:183–189.

28. Cahill DJ, Fox R, Wardle PG, et al. Multiple follicular development

associated with herbal medicine. Hum Reprod 1994;


29. Loch EG, Selle H, Bobbitz N. Treatment of premenstrual syndrome

with a phytopharmaceutical formulation containing

Chaste Tree 135

Vitex agnus-castus. J Womens Health Gend Based Med 2000;


30. Gerhard I, Patek A, Monga B, et al. Mastodynon bei weiblicher

Sterilit ¨ ot: randomisierte placebokontrollierte klinische

Doppelblindstudie. Forsch Komplementmed 1998; 20:272–


31. Chuong CJ, Coulam CB. Current views and the beta endorphin

hypothesis. The Premenstrual Syndrome. New

York: Churchill Livingstone, 1988:75–95.

32. Berger D, Schaffner W, Schrader E, et al. Efficacy of Vitex

agnus castus L. extract Ze 440 in patients with premenstrual

syndrome (PMS). Arch Gynecol Obstet 2000; 264:150–153.

33. Feldman HU, Albrecht M, Lamertz M, et al. Therapie bei

gelbk¨orperschw¨ache bzw. pr¨amenstruellem Syndrom mit

Vitex-agnus-castus-Tinktur. Gyne 1990; 11:421–425.

34. Liebl A. Behandlung des pr¨menstruellen Syndroms:

Agnus-castus-haltiges Kombinationsarzneimittel im Test.

TW Gyn¨akol 1992; 5:147–154.

35. Meyl C. Therapie des premenstrual Syndroms. Vergleich

einer kombinierten Behandlung von Mastodynon und Vitamin

E mit derVitamin E-Monotherapie. Therapeutikon 1991;


36. Peters-Welte C, Albrecht M. Regeltempostörungen und PMS:

Vitex agnus-castus in einer Anwendungsbeobachtung. TW

Gyn¨akol 1994; 7:49–50.

37. Schellenberg R, Kunze G, Pfaff ER, et al. Pre-menstrual syndrome

treatment with Agnus castus extract: A randomised,

placebo-controlled study. Br Med J 2001; 322:134–137.

38. Turner S, Mills S. A double-blind clinical trial on a herbal

remedy for premenstrual syndrome: A case study. Complement

Ther Med 1993; 1:73–77.

39. He Z, Chen R, Zhou YF, et al. Treatment for premenstrual

syndrome with Vitex agnus-castus: A prospective randomized,

multicenter placebo controlled study in China. Maturitas

2009; 63:99–103.

40. Fikentscher H. A¨ tiologie, Diagnose und Therapie der

Mastopathie und Mastodynie. Erfahrungen bei der Behandlung

mit Mastodynon R

. Med Klin 1977; 72:1327–1330.

41. Fournier D, Grumbrecht C. Behandlung der Mastopathie,

Mastodynie und des premenstrual Syndrome. Vergleich

medikament¨oser Behandlung zu unbehandelten Kontrollen.

Therapiewoche 1987; 37(5):430–434.

42. Gregl A. Klinik und Therapie der Mastodynie. Med Welt

1985; 36:242–246.

43. Krapfl E. Prospektiv randomisierte klinische Therapiestudie

zum Wirksamkeitsvergleich von Orgametril R

, einem

19 Nor-Testosterone-Derivat, versus Mastodynon R

, einem

Agnus castus-haltigen alkoholischen Pflanzenextrakt, bei

schmerzhafter Mastopathie [dissertation]. University of Heidelberg,

Germany; 1988.

44. Opitz G, Liebl A. Zur konservativen Behandlung der

Mastopathie mit Mastodynon. Ther Ggw 1980; 119(7):804–


45. Schwalbe E. Ein Beitrag zur Behandlung der Mastodynie. Z

Allgemeine 1979; 55(22):1239–1242.

46. Wuttke W, Solitt G, Gorkow C, et al. Behandlung zyklusabh

¨angiger Brustschmerzen mit einem Agnus-castus-haltigen

Arzneimittel. Ergebnisse einer randomisierten plazebokontrollierten

Doppelblindstudie. Geburtshilfe Frauenheilkd

1997; 57(10):569–574.

47. Propping D, Katzorke T. Behandlung der Gelbk¨orperschw

¨ache in der Praxis. Therapiewoche 1987; 38:2992–3001.

48. Mergner R. Zyklusst¨orungen: Therapie mit einem Vitex

agnus-castus haltigen Kombinationsarzneimittel. Kassenarzt

1992; 7:51–60.

49. Van Die MD, Burger HG, Bone K, et al. Hypericum perforatum

with Vitex agnus-castus in menopausal symptoms:

A randomized, controlled trial. Menopause 2009; 16:156–


50. Webster DE, Lu J, Chen CN, et al. Activation of the m-opiate

receptor by Vitex agnus-castus methanol extracts: Implication

for its use in PMS. J Ethnopharmacol 2006; 106:216–


51. Liu J, Burdette J,XuHY, et al. Evaluation of estrogenic activity

of plant extracts for the potential treatment of menopausal

symptoms. J Agric Food Chem 2001; 49:2472–2479.

52. Liu J, Burdette JE, Sun Y, et al. Isolation of linoleic acid as an

estrogenic compound from the fruits of Vitex agnus-castus L.

Phytomedicine 2004; 11:18–23.

53. Wuttke W, Jarry H, Christoffel V, et al. Chaste tree (Vitex

agnus castus)-pharmacological and clinical indications. Phytomedicine

2003; 10:348–357.

54. Meier B, Berger D, Hoberg E, et al. Pharmacological activities

of Vitex agnus-castus extracts in vitro. Phytomedicine 2000;


55. Jarry H, Leonhardt S, Gorkow C, et al. In vitro prolactin but

notLHandFSHrelease is inhibited by compounds in extracts

of Agnus castus: Direct evidence for a dopaminergic principle

by the dopamine receptor assay. Exp Clin Endocrinol

1994; 102:448–454.

56. Berger D. Vitex agnus-castus: Safety and efficacy in the treatment

of the premenstrual syndrome, principles and mechanisms

of action of a newly developed extract [Thesis].

Basel, Switzerland: University of Basel, 1998.Available from:

College of Philosophy and Natural Sciences, University of


57. Eagon CL, Elm MS, Teepe AG, et al. Medicinal botanicals:

Estrogenicity in rat uterus and liver. Proc Am Assoc Cancer

Res 1997; 38:193.

58. Christoffel V. Prolactin inhibiting dopaminergic activity

of diterpenes from Vitex agnus-castus. Phytopharmaka V,

Forschung und klinische Anwendung. Darmstadt, Germany:

Steinkopff, 1999.

59. Dugoua JJ, Seely D, Perri D, et al. Safety and efficacy of

chastetree (Vitex agnus-castus) during pregnancy and lactation.

Can J Clin Pharmacol 2008; 15:74–79.