Chaste Tree

Scientific Name(s): Vitex agnus-castus L. Family: Verbenaceae

Common Name(s): Chaste tree , chasteberry , vitex , Monk's pepper , agnus castus , Indian spice , sage tree hemp , and tree wild pepper 1

Clinical Overview

Uses of Chaste Tree

Chaste tree has been used to balance progesterone and estrogen production, and to regulate menstruation in women. Although limited data are available, it also has been used for relief of breast pain, ovarian insufficiency, and uterine bleeding, and to increase breast milk production.

Chaste Tree Dosing

Daily doses of chaste tree are typically 30 to 40 mg of crushed fruit or 1.6 to 4.2 mg of dried extract. Chaste tree fruit is available in several different extracts standardized to casticin content. Agncaston is standardized to 1% casticin, while PreMens contains 0.6% casticin. Other products include Agnolyt (3.5 to 4.2 mg extract/pill), Femicur (1.6 to 3 mg extract corresponding to 20 mg/drug), Strotan , Mastodynan , and Ze 440 . Fluid extracts and tinctures are among the most common dosage forms for this product. 2 , 3 , 4

Contraindications

Do not use chaste tree to promote normal ovarian function. Patients who have an allergy or who are hypersensitive to V. agnus-castus , or are pregnant or lactating should avoid use. Products containing chaste tree (particularly liquid dosage forms) should not be used in children because many of these homeopathic preparations have a large volume of ethanol (50% to 60%, depending on the size of the bottle). See Toxicology.

Pregnancy/Lactation

Avoid use because of documented adverse effects (emmenagogue effects). 5 , 6

Chaste Tree Interactions

Chaste tree has dopamine agonist activity and, thus, may increase activity of other dopamine agonists (eg, bromocriptine, levodopa), antagonize the effect of dopamine receptor antagonists, and interact with fertility drugs. It also may reduce the efficacy of birth control.

Chaste Tree Adverse Reactions

Minor side effects include GI reactions, itching, rash, headache, fatigue, alopecia, acne, and increased menstrual flow.

Toxicology

The safety of the plant has not been determined in children.

Botany

The chaste tree is a small tree or shrub (6 to 7 m) native to river banks in southern Europe and the Mediterranean region. 7 The plant is cultivated in China. 8 It blooms in summer, developing light purple flowers and palm-shaped leaves. The dark brown to black fruits are the size of peppercorns; these fruits have a pepperish aroma and flavor and can be collected in autumn. 9 , 10

History

The dried, ripe fruit is used in traditional medicine. The plant has been recognized since antiquity and has been described in works by Hippocrates (AD 460), Dioscorides (AD 40), and Theophrastus (AD 372). 9 In Homer's epic, The Iliad , the plant was featured as a symbol of chastity, capable of warding off evil. 10 Early physicians recognized its effect on the female reproductive system, suggesting its use in controlling hemorrhages and expelling the placenta after birth. Monks have chewed it to decrease sexual desire. 9 , 10 A historical review covers chaste tree's use in ancient medicine through the present. 11

The German Commission E has approved the plant for treatment of mastodynia (breast pain) and menstrual irregularities. Chaste tree is primarily used in reproductive medicine for mastalgia, menopausal symptoms, depression, low libido, vaginal dryness, premenstrual syndrome (PMS), hyperprolactinemia, and inadequate luteal phase. 1

Chemistry

V. agnus-castus contains iridoids, flavonoids, diterpenoids, progestins, essential oils, and ketosteroids. 12 , 13

Iridoid glycosides have been isolated from the leaves and fruit of the plant and include agnuside, aucubin, eurostoside, mussaenosidic acid, 6′-O-p-hydroxybenzoylmussaenosidic acid, and agnucastoside A, B, and C. 13 , 14 , 15 , 16

Flavonoid content has been determined in chaste tree leaves (0.99% to 2.7%), flowers (1.01% to 1.47%), and fruits (0.45% to 0.97%). 17 Flavonoids include flavonol derivatives of kaempferol and quercetagetin, the major constituent being casticin. 15 An earlier report identified additional flavonols from the fruits, including 6-hydroxykaempferol-3,6,7,4′-tetramethyl ether (penduletin 4′-methyl ether), penduletin, and chrysosoplenol. 18 Other flavonoids present in the plant include orientin and isovitexin. 9 Four new flavonoids were isolated from the root bark and include the following: luteoloin 6-C-(4′-methyl-6′-O-trans-caffeoylglucoside), luteolin 6-C-6(6′O-trans-caffeoylglucoside), luteolin 6-C-(2′-O-trans-caffeoylglucoside), luteolin 7-O-(6′-p-benzoylglucoside). 19

Essential oils present in chaste tree mainly include the following: monoterpenoids, cineol, and alpha and beta pinene, along with limonene, sabinene, castine, eucalyptol, myrcene, linalool, citronellol, cymene, and camphene. Sesquiterpenoids such as caryophyllene, farnesene, cardinene, and ledol also are present. 12 , 15 , 20

Total polyphenol content for the leaves (7.36% to 20%), flowers (9% to 10.64%), and fruits (6.92% to 24%) has been determined. The highest tannin content was found in the leaves (0.68% to 3%); tannin content was similar in the flowers (0.24% to 2%) and fruits (0.24% to 1.6%). 21

The alkaloid vitricine is present in the plant. 15 Vitexlactam A, a labdane diterpene, has been isolated from the fruit of V. agnus-castus . Evidence has shown that labdane diterpenes have dopamine receptor affinity. 8 , 22 Clerodadienols are potent inhibitors of prolactin release. An overview of chaste tree is available, including chemical composition, pharmacology, and side effects. 23 , 24

Although found only in trace amounts, progesterone, hydroxyprogesterone, testosterone, and androstenedione have been isolated from the leaves and flowers of V. agnus-castus . Numerous fatty acids also have been isolated. 25

Chaste Tree Uses and Pharmacology

V. agnus-castus contains substances that competitively bind receptors, making the plant useful in disorders in which progesterone deficiency might be suspected (eg, female infertility, menopause, PMS). 1 , 26

A preparation of chaste tree (0.2% w/w) has been available in Germany since the 1950s and is used in treatment of breast pain, ovarian insufficiency (some cases resulting in pregnancy), and uterine bleeding. 15 Crude herb or alcoholic or aqueous extracts of pulverized fruit are used in commercial preparations. 27

One review article documents how V. agnus-castus was effective in treating cyclical mastalgia in a multicenter, randomized, placebo-controlled, double-blind study. Patients assessed intensity of breast pain according to a visual analog scale (VAS, 0 mm = no breast pain to 100 mm = extremely strong breast pain). Patients received the extract in tablet or solution form, and those treated with either preparation had a 35% to 40% reduction in mastalgia pain versus 25% for placebo. 25

The effects of Mastodynon (a homeopathic preparation containing V. agnus castus D1, Caulophyllum thalictroides D4, Cyclamen D4, Ignatia D6, Iris D2, and Lilium tigrinum D3 in 53% ethanol) was examined in 96 women with fertility disorders in a prospective, randomized, double-blind, placebo-controlled clinical trial. Fertility disorders were attributed to secondary amenorrhea (n = 38), luteal insufficiency (n = 31), or idiopathic causes (n = 27). Patients received either 30 drops or approximately 2 mL of the homeopathic preparation or placebo by mouth twice daily for 3 months. The primary outcome measures of pregnancy or spontaneous menstruation in women with amenorrhea, pregnancy, or improved luteal hormone concentrations were achieved in 31 of 66 patients (57% of the treatment group and 36% of the placebo group, P = 0.069). Thirty percent (n = 15) of treated patients (reasons for treatment: amenorrhea [n = 7], luteal insufficiency [n = 4], idiopathic causes [n = 4]) and 15% of the placebo group became pregnant. 28

After ingestion in women, the berries exert progesterogenic effects, balancing progesterone and estrogen production from the ovaries and regulating menstrual cycles. 9 A randomized, placebo-controlled trial used a V. agnus-castus -containing homeopathic preparation to treat infertility in 67 women, oligomenorrhea in 37 women, and amenorrhea in 30 women. All groups were treated with the preparation or placebo 3 times/day for 3 months (or 3 menstrual cycles). The researchers reported 38 of 67 women achieved spontaneous menstruation and improved progesterone concentration in the luteal phase, and experienced a shortening of the cycle, earlier ovulation, and pregnancy. 1

Chaste tree preparations inhibit basal and thyrotropin-releasing hormone (TRH)-stimulated prolactin secretion from rat pituitary cells in vitro, suggesting its possible use in the treatment of hyperprolactinemia. 29 In addition, animal studies found an increase in lactation and mammary enlargement, indicating an effect on prolactin release. 9

Agnus fruit ( V. agnus-castus L. extract Ze 440 ) was compared with placebo over 3 menstrual cycles in a prospective, randomized, placebo-controlled study of 170 women (mean, 36 years of age) with PMS. Primary variables included change from baseline to end point in women's self-assessment of irritability, mood, alternation, anger, headache, breast fullness, and other menstrual symptoms, including bloating. The authors concluded from the results of the primary ( P < 0.0001) and secondary ( P < 0.0001) variables that the extract was effective and well tolerated in relieving PMS symptoms. 2 , 30 , 31 The extract is standardized to casticin.

In a randomized, placebo-controlled trial, 170 women (mean, 36 years of age) with PMS symptoms were treated with either a 20 mg tablet of V. agnus-castus (fruit extract Ze 440 ) or placebo by mouth every day for 3 menstrual cycles. Patients were diagnosed according to DSM-III criteria. When compared with placebo, treated patients reported improvement in menstrual symptoms including irritability, mood alteration, breast fullness, and anger ( P < 0.001). 27

In a prospective, multicenter, open-label trial, V. agnus-castus extract Ze 440 was examined in 43 women (31.3 ± 7.7 years) diagnosed with PMS according to DSM-III criteria. Patients received 20 mg of Ze 440 by mouth every day for 3 menstrual cycles. Primary outcome measurements included self-assessment scores from the Moos menstrual distress questionnaire (MMDQ); secondary outcomes included self-assessment scores from the visual analog and global impression scale. Study protocol included 8 menstrual cycles: 2 at baseline, 3 during treatment, and 3 posttreatment. After treatment, patients MMDQ improved 42.5% ( P < 0.001) when compared with baseline. Symptoms returned after treatment cessation, but remained about 20% below baseline ( P < 0.001). No serious adverse reactions were reported. 32

Twenty healthy men received oral daily doses of 120, 240, and 480 mg V. agnus-castus extract (BP1095E1) versus placebo for 2 weeks. Dose-dependent effects on prolactin release were noted as compared with follicle-stimulating hormone, luteinizing hormone (LH), and testosterone serum concentrations. Prolactin secretion, stimulated by TRH, increased with the 120 mg dose and decreased with the 480 mg dose. 1

When studied in 52 women with luteal phase defects caused by latent hyperprolactinemia, a chaste tree preparation reduced prolactin release, normalized luteal phases, and eliminated deficits in luteal progesterone without side effects. Chaste tree extract contains an active principle that binds to dopamine receptor sites, inhibiting prolactin release. The prolactin-inhibiting action of the preparation was equivalent to high doses of synthetic dopamine agonists, suggesting therapeutic usefulness of the plant for treatment of premenstrual breast pain associated with prolactin hypersecretion. 33 , 34 , 35

Forty-one women (18 to 49 years of age), diagnosed with premenstrual dysphoric disorder (PMDD) according to DSM-IV criteria, were enrolled in a randomized, single-blind, rater-blind prospective trial to examine the efficacy of fluoxetine or V. agnus-castus extract in treating PMDD. Patients received fluoxetine or V. agnus-castus extract by mouth every day for 8 weeks. Primary outcome measurements included self-assessment scores from the Penn daily symptom report, Hamilton depression rating scale, and the clinical global impression-severity of illness and improvement scales. At 8 weeks, there was no difference between groups in the outcome measures. However, patients treated with fluoxetine reported decreased psychological symptoms, while patients treated with V. agnus-castus extract reported diminished physical symptoms. 36

In a 3-month, double-blind, multicenter, placebo-controlled trial, 175 women were treated for PMS. Eighty-five women received V. agnus-castus fruit extract by mouth every day or 1 placebo capsule by mouth every day. Ninety women received 1 placebo capsule by mouth twice a day on days 1 through 15 and 1 capsule of pyridoxine hydrochloride 100 mg by mouth twice a day on days 16 to 35 of their menstrual cycle. Primary outcome measurement was assessed using scores from the premenstrual tension syndrome scale (PMTS scale). Secondary outcome measurements included ratings of 6 specific PMTS scale symptoms (breast tenderness, edema, tension, headache, constipation, and depression), the Clinical Global Impression (CGI) scale, efficacy and tolerability of treatment, risk-to-benefit ratio, and investigator and patient assessment. Both treatments produced significant improvements in patient symptoms ( P < 0.05) and V. agnus-castus was as safe and effective as pyridoxine. 37

Chaste tree is reportedly effective in treating endocrine abnormalities, such as menstrual neuroses and dermatoses. It also has been used to treat acne. 15

In breast-feeding women, extracts of the plant have been used to increase milk production. 9 When analyzed chemically, the breast milk revealed no compositional changes after chaste tree use. 15

Ethanol extracts from the fruit of V. agnus-castus have cytotoxic activity against 6 human cancer cell lines, including the following: human uterine cervical canal fibroblast (HCF), ovarian cancer (MCF-7), uterine cervical carcinoma (SKG-3a), breast carcinoma (SKOV-3), gastric signet ring carcinoma (KATO-III), colon carcinoma (COLO 201), small cell lung carcinoma (Lu-134-A-H) cells. Numerous mechanisms of action may be involved in inducing apoptosis. 38

Dosage

Daily doses of chaste tree are typically 30 to 40 mg of crushed fruit or 1.6 to 4.2 mg of dried extract. Chaste tree fruit is available in several different extracts standardized to casticin content. Agncaston is standardized to 1% casticin, while PreMens contains 0.6% casticin. Other products include Agnolyt (3.5 to 4.2 mg extract/pill), Femicur (1.6 to 3 mg extract corresponding to 20 mg/drug), Strotan , Mastodynan , and Ze 440 . Fluid extracts and tinctures are among the most common dosage forms for this product. 2 , 3 , 4

Pregnancy/Lactation

Avoid use because of documented adverse effects (emmenagogue effects). 5 , 6 Chaste tree is not recommended for use during pregnancy because of its potential to inhibit secretion of prolactin.

Interactions

Because V. agnus-castus inhibits the secretion of prolactin, drug interactions may occur with dopamine agonists (eg, bromocriptine, levodopa) because V. agnus-castus produces similar effects on the pituitary, as well as dopamine-receptor antagonists because V. agnus-castus antagonizes the action of these drugs and vice-versa. Fertility drugs also are of concern because a case report documents mild ovarian hyperstimulation in the luteal phase in a woman 32 years of age undergoing in vitro fertilization. The patient was taking an herbal medicine containing V. agnus-castus . The authors concluded that a possible drug-herb interaction may have occurred and warned of similar interactions with bromocriptine, dopamine, and dopaminergic drugs. V. agnus-castus may increase the risk of a multiple pregnancy and high LH levels may increase the risk of miscarriage 1 , 31 , 39 ; V. agnus-castus may reduce the efficacy of birth control.

Adverse Reactions

Chaste tree administration has not been associated with important adverse reactions. In 1 large German market surveillance study, 17 of 1,542 women discontinued treatment because of an adverse reaction. 9 Minor side effects include GI reactions, allergic reactions (eg, itching, rash), headaches, fatigue, alopecia, acne, and increase in menstrual flow. 2 , 9 , 15 , 38

Toxicology

The safety of the plant has not been determined in children; use should be avoided because many homeopathic preparations containing V. agnus-castus have a large volume of ethanol (50% to 60%), depending on the size of the bottle.

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