Chaste tree

Historical note Chaste tree has been used since ancient times for a variety of gynaecological conditions, such as aiding expulsion of the placenta after birth and promoting menstruation. Leaves of the chaste tree were worn by vestal virgins in ancient Rome as a symbol of chastity and it was used during that time to promote celibacy. The berries have been used to reduce fever and headaches, stimulate perspiration and to ‘check violent sexual desires’ in monasteries. A commercially preparation of chaste tree has been available in Germany for over 50 years and it is still commonly used for menstrual irregularities.

OTHER NAMES

Agnus castus, chasteberry, gattilier, hemp tree, keuschlammfruchte, monk’s pepper, wild pepper, vitex

BOTANICAL NAME/FAMILY

Vitex agnus-castus (family Labiatae)

PLANT PART USED

Dried ripened or fresh ripe fruits

CHEMICAL COMPONENTS

Vitex agnus-castus contains many different chemical constituents, including luteolinlike flavonoids (casticin, orientin, isovitexin), iridoid glycosides, aucubin, eurostoside, agnuside, essential fatty acids and the essential oils cineole, limonene and sabinene.

MAIN ACTIONS

A mechanism of action has not been conclusively identified, but it is thought to act on the pituitary–hypothalamic axis.

DECREASES PROLACTIN RELEASE

The most thoroughly studied mechanism for vitex is its interaction with dopamine receptors in the anterior pituitary. Several studies have indicated that vitex acts on dopamine D2 receptors and decreases prolactin levels (Berger et al 2000, Halaska et al 1998, Jarry et al 1994, Meier & Hoberg 1999, Meier et al 2000, Milewicz et al 1993, Sliutz et al 1993, Wuttke et al 2003). It is likely that this mechanism is responsible for the symptom-relieving effects seen with vitex in mastodynia and hyperprolactinaemia (Meier & Hoberg 1999, Milewicz et al 1993, Splitt et al 1997). Results from one study involving healthy males propose that this effect is dosedependent, as lower doses (120 mg) were found to increase secretion and higher doses (204–480 mg) were found to decrease secretion (Merz et al 1996). A study using the vitex extract BNO 1095 (70% ethanol, 30% H2O extract, Bionorica, Neumarkt, Germany) identified that the major dopaminergic compounds are the clerodadienols, which act as potent inhibitors of prolactin release; however, other active compounds of lesser activity were also identified (Wuttke et al 2003).

OESTROGEN-RECEPTOR BINDING

Chasteberry extract showed significant competitive binding to oestrogen-receptors alpha and beta in vitro (Liu et al 2001).

INCREASES PROGESTERONE LEVELS

A randomised controlled trial of women with hyperprolactinaemia showed that vitex extract (20 mg daily) normalises progesterone levels after 3 months’ treatment (Milewicz et al 1993). In vitro research has found that vitex stimulates progesterone receptor expression (Liu et al 2001).

OPIOID RECEPTORS

A recently published study reported that a methanol extract of vitex had affinity to the m-opiate receptor (Webster et al 2006). Of note, this receptor is the primary action site for beta-endorphin in vivo, a peptide which assists in regulating the menstrual cycle through inhibition of the hypothalamus–pituitary– adrenal axis.

CYTOTOXIC ACTIVITY

Cytotoxic activity has been reported for an ethanolic extract of the dried ripe fruit of vitex against various human cancer cell lines (Ohyama et al 2003, 2005, Weisskopf et al 2005). The extract increased intracellular oxidative stress and mitochondrial damage leading to apoptosis.

OTHER ACTIONS

Conflicting results have been obtained in studies with regard to the effect on FSH and LH levels. One clinical study found that vitex extract did not alter them, whereas another showed that it increased LH release (Lauritzen et al 1997, Milewicz et al 1993).

CLINICAL USE

Although double-blind studies have recently been conducted with chasteberry, uncontrolled trials go back to the 1940s when a product known as Agnolyt was tested. The product was developed and patented by Dr Gerhard Madaus in Germany and contained Vitex agnus-castus. Several different vitex products have been investigated to date including: Agnolyt (standardised to 3.5–4.2 mg of dried chasteberry extract), Vitex agnus-castus L. extract Ze 440 (each 20 mg tablet standardised for casticin and agnuside), Femicur (contans 1.6–3.0 mg of dried extract per capsule) and Mastodynon (53% v/v ethanol) a homeopathic preparation. Owing to difficulty in locating the German studies, secondary information sources have sometimes been used to provide a more comprehensive review.

PREMENSTRUAL SYNDROME

Chasteberry relieves some common symptoms associated with PMS, according to several clinical trials (Atmaca et al 2003, Berger et al 2000, Dittmar 1992, Lauritzen 1997, Loch et al 2000, Schellenberg 2001). According to these clinical trials, the PMS symptoms that respond best to treatment are breast tenderness, irritability, depressed mood, anger, mood changes, headache and constipation. The most studied extract investigated in PMS is Ze440 (see Clinical note below). A multicentre, randomised, controlled, double-blind study investigating the effects of Vitex (Ze 440) for PMS involved 170 women and was published in the British Medical Journal (Schellenberg 2001). Of the group, 13% were also taking OCP. Treatment with a 20 mg tablet of dry extract of chasteberry taken daily resulted in a significant improvement of PMS symptoms, particularly headache, breast fullness, irritability, anger and mood changes. Over 50% of women in the active treatment group achieved at least a 50% reduction in symptoms. Previously, a number of open studies had generally produced positive results for vitex as a symptomatic treatment in PMS. One multicentre open-label study showed that daily treatment with a 20 mg tablet of Vitex (Ze 440) over three menstrual cycles significantly reduced the Moor menstrual distress self-assessment questionnaire (MMDQ) with 46% of women experiencing a 50% reduction in the MMDQ. Treatment also reduced the duration of PMS symptoms from 7.5 days to 6 days and was as effective for women taking OCP as for those who were not (Berger et al 2000). Once treatment was stopped, PMS symptoms gradually returned to baseline within three further cycles. The largest multicentre trial was an open study of 1634 women with PMS, which found that treatment with vitex (Femicur) for three menstrual cycles decreased the number of PMS symptoms in 93% of subjects (Loch et al 2000). Symptoms completely resolved in 40% of subjects and 94% overall rated vitex treatment as well tolerated. An early study using vitex (Agnolyt) in 1542 women with PMS reported an improvement in symptoms with an average dose of 42 drops daily taken for an average of 25 days (Dittmar 1992 as reported in Ulbricht & Basch 2005). According to Ulbricht and Basch (2005), three earlier uncontrolled studies produced inconclusive results. Although vitamin B6 is a popular treatment for PMS symptoms, the results from a double-blind comparative study have found that vitex (Agnolyt) is as effective and possibly more so (Lauritzen et al 1997). The randomised, double-blind study of 175 women compared vitex, pyridoxine and placebo. In the study, 77% of women receiving vitex reported symptom alleviation compared with 61% with pyridoxine (200 mg/day), which was considered a small but significant difference. Additionally, physician assessments were more likely to rate treatment with vitex as ‘excellent’ compared with pyridoxine.
In 2003, a randomised 8 week study involving 42 women compared the effects of 20–40 mg daily of fluoxetine, a SSRI, and 20–40 mg of vitex extract and found no statistically significant difference between the groups with respect to the rate of responders (Atmaca et al 2003). More specifically, patients with premenstrual dysphoric disorder responded well to both treatments; however, fluoxetine was more effective for psychological symptoms such as depression and irritability whereas the herbal extract was more effective for diminishing physical symptoms such as breast tenderness, cramps, food cravings and swelling. Unfortunately, the authors did not report the type of vitex extract used in the study. Commission E approves the use of chasteberry for this indication.

MASTALGIA

Mastalgia is considered to relate to latent and increased basal prolactin levels; therefore, agents that reduce prolactin levels are anticipated to reduce symptoms. For this reason, vitex is a popular treatment for mastalgia. In two randomised, double-blind studies, vitex (Mastodynon) effectively reduced premenstrual mastalgia (Halaska et al 1998, Splitt et al 1997, Wuttke et al 2003). Subjects completed a visual analogue scale (VAS) and rated their breast pain from 0 (lowest breast pain) to 10 (extremely strong breast pain). Active treatment reduced the mastalgia score by 35–40%, an effect significantly stronger than that of placebo (25%). One of these studies also demonstrated that treatment with vitex reduced serum prolactin levels (Splitt et al 1997, as reported in Wuttke et al 2003). According to Halaska et al (1998), symptom relief was experienced after the first month of treatment with continued improvements experienced after the second and third months. Commission E approves the use of chasteberry for this indication.

IRREGULARITIES OF THE MENSTRUAL CYCLE

Chasteberry is used to normalise menstruation in women with shortened, lengthened or infrequent menstruation, particularly when low progesterone and luteal phase defects are suspected. A randomised controlled trial of women with luteal phase defect due to latent hyperprolactinaemia demonstrated that vitex extract (20 mg daily) effectively reduced prolactin levels and normalised luteal phase length and progesterone levels after 3 months’ treatment (Milewicz et al 1993). Commission E approves the use of chasteberry for this indication.

POOR LACTATION

Vitex has been used since ancient times as a galactagogue to promote milk production. Currently there are no double-blind studies to confirm its efficacy; favourable effect on milk production in 80% of women (Noack et al 1943). Results from a small study of males suggest that increases in prolactin may be possible with low dose vitex (120 mg daily) whereas higher doses (480 mg daily) result in decreased levels (Merz et al 1996).

FERTILITY DISORDERS

Vitex is used in practice with other herbal medicines to enhance fertility in women with progesterone deficiency or luteal phase defects. Currently no large studies have been published to evaluate the effectiveness of this approach; however, a doubleblind, randomised, placebo-controlled study of 96 women with fertility disorders (38 with secondary amenorrhea, 31 with luteal insufficiency and 27 with idiopathic infertility) used the vitex product Mastodynon with encouraging results (Gerhard et al 1988). Treatment of 30 drops was administered twice daily for 3 months and resulted in women with amenorrhea or luteal insufficiency achieving pregnancy more than twice as often as the placebo group, with 15 women conceiving during the study period (n = 7 with amenorrhoea, n = 4 with idiopathic infertility, n = 4 with luteal insufficiency). Although promising, this study has been criticised for pooling of diverse conditions, unclear reporting of results and variable significance (Ulbricht & Basch 2005).

ACNE VULGARIS

An open study of 117 subjects with different forms of acne found that after 6 weeks’ treatment with a 0.2% dried extract of Vitex agnus-castus and a topical disinfectant, 70% of cases experienced total resolution with the highest success rates reported for acne vulgaris, follicularis and excoriated acne (Amann 1975). A group that was not treated with the herb took 30–50% longer to achieve similar results. Although encouraging, it is difficult to determine the contribution of vitex treatment to these results. Until controlled studies using vitex as a stand-alone treatment are conducted, the herb’s role in this condition is still uncertain.

OTHER USES

Vitex is used to relieve menopausal symptoms, and aid the expulsion of the placenta after birth. It is also used to treat fibroids, normalise hormones following the use of OCP, and in cases of premature ovarian failure.

DOSAGE RANGE

GENERAL GUIDE

· Liquid extract (1:2): 1–2.5 mL in the morning.
· Dried fruit: 1.5–3 g in the morning.
· Dry fruit flesh (solid-dose form): 1000–1800 mg/day.
· Manufacturers have recommended vitex preparations be taken daily as a single dose upon rising, before breakfast, throughout the menstrual cycle.

ACCORDING TO CLINICAL STUDIES

· PMS
- Ze440 extract (Premular) 20 mg daily
- Femicur 40 mg daily
· Cyclic mastalgia
- Mastodynon 60 drops daily or 1 tablet daily
· Menstrual irregularities
- 20 mg daily (extract unknown)
· Infertility
- Mastodynon 30 drops twice daily

ADVERSE REACTIONS

A systematic review of the herb’s safety, published in 2005, analysed data from six electronic databases, postmarketing surveillance studies, spontaneous reporting schemes (including WHO), herbalist organisations and manufacturers (Daniele et al 2005). The review concluded that vitex is a safe herbal medicine and any adverse effects associated with its use tend to be mild and reversible. The most common adverse effects are: nausea, headache, gastrointestinal disturbances, menstrual disorders, acne, pruritis and erythematous rash. Additionally, no drug interactions have been reported.

SIGNIFICANT INTERACTIONS

Controlled studies are not available, so interactions are based on evidence of activity and are largely theoretical and speculative.

DOPAMINE ANTAGONISTS

An antagonistic interaction is theoretically possible— observe patients.

ORAL CONTRACEPTIVES

There has been speculation about the effectiveness of vitex when OCP are being taken. Several clinical studies involving women taking oral contraceptives have confirmed the herb still reduces PMS symptoms and does not affect OCP.

CONTRAINDICATIONS AND PRECAUTIONS

People with tumours sensitive to oestrogen or progesterone should avoid using this herb until safety can be established.

PREGNANCY USE

Vitex is not traditionally recommended in pregnancy. In practice, some herbalists use it during the first 8 weeks of pregnancy in cases of difficult conception.

PRACTICE POINTS/PATIENT COUNSELLING

· Several clinical trials have shown that vitex is an effective treatment for common PMS symptoms, such as mood changes and irritability, breast tenderness, headaches and constipation. According to one study, it is more effective than pyridoxine treatment and has a similar response rate to fluoxetine.
· Clinical research has also shown it to be effective in menstrual irregularities and mastalgia.
· Vitex is also used to relieve menopausal symptoms, enhance fertility in women with progesterone deficiency or luteal phase defects, and aid the expulsion of the placenta after birth, reduce fibroids and normalise hormones following the use of oral contraceptives.
· Traditionally, it is described as a galactagogue (i.e. a medicine able to increase milk production in lactation) and is used in low doses for this indication.
· A mechanism of action has not been conclusively identified, but it appears to inhibit prolactin release by selective stimulation of pituitary dopamine D2 receptors, increase progesterone levels and works via the opiate system.