Vitex agnus castus and Premenstrual Syndrome

By Carolyn Coker Ross, MD, MPH

Premenstrual syndrome (PMS) is a complex disorder, affecting women in a regular pattern associated with their menstrual cycles. Contrary to popular belief, PMS has been a recognized malady for thousands of years. Hippocrates described a condition in which women might develop suicidal ideations and other symptoms prior to onset of menses. Many centuries later, in 1931, Frank (as noted in Htay et al1) described 15 women with severe symptoms that he called premenstrual tension syndrome.

PMS affects women in their 30s and 40s and can be very debilitating, with symptoms that occur during the last half of the menstrual cycle. Signs and symptoms include irritability, moodiness, anxiety, sleep disturbances, changes in eating patterns, and breast tenderness. Approximately 3-8% of women are affected with a more severe form called premenstrual dysphoric disorder (PMDD). PMS and PMDD are not synonymous.

The causes of PMS are poorly understood and a range of therapies has been tried including diet, exercise, vitamins, calcium, psychotherapy, antidepressants, diuretics, and contraceptives. Recent studies have supported the traditional use of chaste tree berry for the treatment of PMS and other female reproductive disorders including corpus luteum insufficiency, insufficient milk production, and menopausal symptoms.

Chaste tree is native to Greece and Italy and its peppery fruit has been used medicinally for more than 2,000 years. The Greek physician Dioscorides used it as a drink to lower libido. In the first century of the Christian era, the berry was scattered in the beds of soldier’s wives to attest to their faithfulness during times of war2 and by monks in the Middle Ages to suppress sexual excitability, thereby leading to its common name "monk’s pepper."3 Although there is no evidence to support this effect, in Italy chaste tree berries are strewn in front of novices as they enter the convent or monastery.4

Traditional Medical Use

Chaste tree berry has been used historically for the treatment of hangovers, flatulence, fevers, and constipation. It also has been known to bring on menstruation and to decrease uterine cramping. The American Eclectic doctors of the 19th century used it as an emmenagogue (agent that promotes menstrual flow) and a stimulant for lactation, and to treat impotence, sexual melancholia or irritability, and mild dementia.

Modern use consists primarily of treatment of conditions of the female reproductive system. Chaste tree was used traditionally as a "women’s herb" in Europe and in the Mediterranean, with the most common use being for treating insufficient lactation.2,3 An extract of chaste tree berry has been used in Germany since the 1950s for breast pain, ovarian insufficiency, and uterine bleeding.5

Botany and Chemistry

The ripe, dried fruit of the chaste tree (Vitex agnus castus L., Family: Verbenaceae; Pharmacopeial name: Agni casti fructus; syn: chaste berry, vitex, monk’s pepper) is the part most commonly used for therapeutic purposes, and often is referred to as vitex. The plant can grow to 22 feet in height and blooms in summer, with light purple flowers and palm-shaped leaves. The fruits are the size of peppercorns and have a pepperish aroma and flavor. The active constituents include the flavonoids casticin, kaempferol, quercetagetin, orientin, and (in water) isovitexin; diterpenes; alkaloids (viticin); the iridoid glycosides aucubin and agnuside; and oils containing alpha-pinene and beta-pinene.6 Chaste tree berry also is known to contain several essential fatty acids, including oleic acid, linolenic acid, palmitic acid, and stearic acid, although these are not generally considered key constituents.7

Many extracts are standardized to contain 0.6% agnuside. Recent evidence, however, suggests that part of the activity of chaste berry is found in the diterpenes and the flavonoid casticin, now thought to be a more appropriate marker for effectiveness of vitex preparations. The diterpenes are highly lipophilic and may easily pass the blood-brain barrier, therefore explaining its effect on locomotor unrest and behavioral instability. Tests on a commercially available vitex preparation, Mastodynon, showed that the extract contains estrogenic activity with selectivity for the estrogen beta-subtype receptor re-sponsible for regulation of fat tissue, but exerts no effects on the uterus and has little effect on bone.6 (The estrogen alpha-subtype receptor controls endometrial proliferation, osteoporosis prevention, and cardiovascular protection.)

Laboratory Studies

In animal models, vitex has been shown to act as a dopamine agonist (binding to the dopamine D2 receptor), inhibiting prolactin secretion from the anterior pituitary. Additional pharmacologic action may be mediated through opioid receptors, beta-endorphins, or neuroactive flavonoids.8,9 These effects are very selective and the release of follicle-stimulating hormone and leutinizing hormone are not affected,10 although in one study, vitex use (20 mg of Strotan) for three months did elevate 1-beta estradiol in the luteal phase.11 Vitex is also postulated to be indirectly progesterogenic.12

In one animal study, female guinea pigs given low doses of chaste tree fruit by mouth showed a decrease in estrogenic activity and a promotion of progesterone effects. At higher doses, there was inhibition of all gonadotrophic hormones and growth hormone, suggesting that vitex may completely inhibit anterior pituitary function at high doses.13

In a laboratory study to determine the effect of phytoestrogens and herbs on human breast cancer cells, vitex was shown to inhibit growth of the T-47D breast cancer cell line, suggesting a potential role as a chemopreventive.14 Likewise, Ohyama et al demonstrated the cytotoxic activity of vitex mediated through apoptosis on breast, gastric signet ring, small cell lung, and colon cancer cell lines.15

Human Clinical Studies

Elevated prolactin levels appear to be the basis for many disorders of the female menstrual cycle, including premenstrual syndrome and premenstrual mastalgia. Many PMS patients show latent hyperprolactinemia associated with corpus luteum insufficiency. It is postulated that the benefit of vitex is related to its dopaminergic activity that results in lowering prolactin levels.

An open, placebo-controlled trial in men, using chaste tree extract (120-480 mg per day for 14 days or placebo) demonstrated well the dose-dependent effects of vitex: At lower doses, vitex increases prolactin production (linked to increases in milk production in lactating females), but at higher doses, prolactin production was decreased.16

In one pilot study (controlled clinical trial), there was significant benefit for women with all types of PMS except PMS-C (symptoms include headache, sweet cravings, palpitations, and dizziness).3

One double-blind, placebo-controlled trial used vitex (600 mg three times a day) or a soya-based placebo for three months in patients with PMS.17 Vitex was more effective than placebo only in decreasing jitters and restlessness; there also was a tendency toward improvement of the fluid retention-type symptoms, particularly mast-algia (not statistically significant). This trial could be criticized for the use of the soya-based placebo, which may have possessed pharmacological activity.

A multicenter, randomized, double-blind comparative trial examined vitex and vitamin B6 (pyridoxine) in 175 women with PMS over three cycles.18 The patients were given either vitex (3.5-4.2 mg of a 9.5-11.5:1 extract, Agnolyt) daily or 200 mg of pyridoxine on days 16-35 with placebo given on days 1-15. There was a decrease in symptoms in both treatment groups, but treatment with vitex was superior to pyridoxine overall. For characteristic PMS symptoms (breast tenderness, edema, abdominal tension, headaches, constipation, and depression), vitex showed statistically significant benefit over pyridoxine. Thirty-six percent of the vitex group reported being free of complaints vs. 21% in the pyridoxine group. There were nine patient reports of adverse effects—five from the vitex group. These side effects included gastrointestinal upset (equal in both treatment groups), skin rash, and transient headache (in the vitex group only). Lack of inclusion of a placebo group is a notable weakness of this study.

Berger et al used vitex extract Ze440 (20 mg) in 50 patients with PMS using the Moos’ menstrual distress questionnaire, a visual analog self-assessment scale, and a global impression scale as measuring instruments.19 Treatment resulted in reduction of PMS-related symptoms, and a slight reduction in the number of symptomatic days, without serious adverse effect.

Another study reported in the British Medical Journal also used the Ze440 extract in a randomized, double-blind, placebo-controlled study of 178 women with PMS over three menstrual cycles.9 There was improvement in the main endpoint (self-assessment of irritability, mood changes, anger, headache, and breast fullness) with 52% of women responding to active treatment vs. a 24% response rate to placebo. Bloating was not improved with treatment. Seven women reported mild adverse events (four active, three placebo), none of which resulted in discontinuation of treatment.

A multicenter open study tested the efficacy of vitex in 1,634 women with PMS over three menstrual cycles with 93% of patients reporting improvements in symptoms of depression, anxiety, craving, and edema.20 Overall, 81% of patients reported their status post-treatment as very much or much better, with 94% reporting good or very good tolerance of the preparation. There were no serious adverse drug reactions.

Adverse Effects

Occasional itching and hives have been reported. In one large study in Germany, 17 of 1,542 women discontinued treatment due to adverse effects. Minor side effects include gastrointestinal reactions, headaches, and menstrual flow increase. Safety profiles have not been determined for children or teens. Vitex should not be used by pregnant women because of its uterine stimulant properties and effects on the pituitary. When taken in low doses by lactating mothers, vitex has not been associated with chemical alteration of the breast milk.5

Dosage and Administration

A wide range of doses is used by herbalists. Clinical trials on PMS have used 3.5-4.5 mg/d of the dried extract, and up to 600 mg three times a day of dried fruit. The German Commission E recommends 30-40 mg of crushed fruit in aqueous-alcoholic extracts in dry or liquid form per day. The dose of Agnolyt is 4 mg daily. In the United States, an equivalent product is Femaprin.

In English-speaking countries, tinctures are most commonly used: 1-5 mL of a 1:5 tincture; 1-4 mL of a 1:2 extract, or one or two 500 mg chaste tree tablets daily. Higher doses can be used in the short term for more severe symptoms, but prolonged use of high doses should be avoided. It is recommended that vitex be taken as a single dose of tincture in the morning before breakfast throughout the menstrual cycle for more optimal hormone regulation.3 Tablet preparations usually are taken in divided doses.

Herb-Drug Interactions

The drug interactions listed below are theoretical.

• Dopamine-receptor antagonist drugs (antipsychotics, Reglan): Vitex may interfere with the action of these drugs due to its dopaminergic actions.

• Dopamine agonists, as might be used in the setting of Parkinson’s disease (parlodel, pergolide, others): Vitex may potentiate the action of these drugs.

• Hormones (oral contraceptives, hormone replacement therapy): Some herbalists believe that vitex could interfere with the efficacy of oral contraceptives and hormone replacement therapy.

Regulatory Status

The German Commission E authored a positive review on vitex and approved it for use for menstrual problems, PMS, and breast pain (mastodynia). Vitex does not have GRAS status (Generally Recognized As Safe), but is available as a dietary supplement in the United States.

Conclusion

Vitex appears to decrease many symptoms of PMS, especially edema, mood alterations, and mastalgia. Vitex may not be as effective for bloating or for symptoms of sweet craving, palpitations, and dizziness. In patients with accompanying menstrual abnormalities, such as secondary amenorrhea, oligomenorrhea (scant menstruation), and menorrhagia (excessive and prolonged menstruation), vitex may normalize bleeding patterns. Vitex is a safe and potentially effective alternative to prescription therapies.

Recommendation

The currently recommended vitex products are those standardized to 6% agnuside. Patients should be advised to use vitex for a minimum of three months to establish its efficacy. Vitex has been used safely in studies lasting from three months up to 1.5 years.

It is important for patients to be encouraged to keep a symptom diary before and after starting vitex to be able to track the effects of treatment. If a patient’s symptoms are so severe that she is unable to function well, she may fall into the category of PMDD, which is considered a psychiatric disorder and should be treated as such.

Because vitex has some hormonal effects, women with hormone-sensitive conditions such as breast, uterine, and ovarian cancer, uterine fibroids, and endome-triosis should avoid vitex preparations. Women undergoing in vitro fertilization also should avoid vitex due to possible hormonal overstimulation.6  

Dr. Coker Ross is a Fellow in the Program in Integrative Medicine, University of Arizona in Tucson.

References

1. Htay TT, et al. Premenstrual Dysphoric Disorder. Available at: www.emedicine.com.

2. Blumenthal M, et al. Herbal Medicine: Expanded Commission E Monographs. Newton, MA: Integrative Medicine Communications; 2000.

3. Mills S, Bone K. Principles and Practice of Phytotherapy. London: Churchill Livingstone; 2000.

4. Mabey R, ed. The New Age Herbalist. New York, NY: Simon and Schuster; 1988.

5. The Review of Natural Products. Facts and Comparisons. St. Louis, MO: Wolters Kluwer Co.; 1998.

6. Wuttke W, et al. Chaste tree (Vitex agnus-castus)—pharmacology and clinical indications. Phytomedicine 2003;10:348-357.

7. Natural Medicines Comprehensive Database. Available at www.naturaldatabase.com.

8. Meier B, et al. Pharmacological activities of Vitex agnus-castus extracts in vitro. Phytomedicine 2000; 7:373-381.

9. Schellenberg R. Treatment for the premenstrual syndrome with agnus castus fruit extract: Prospective, randomised, placebo-controlled study. BMJ 2001; 322:134-137.

10. Jarry H, et al. In vitro prolactin but not LH and FSH release 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.

11. Milewicz A, et al. Vitex agnus castus extract in the treatment of luteal phase defects due to latent hyperprolactinemia. Results of a randomized placebo-controlled double-blind study. Arzneimittelforschung 1993;43:752-756.

12. Liu J, et al. Evaluation of estrogenic activity of plant extracts for the potential treatment of menopausal symptoms. J Agric Food Chem 2001;49:2472-2479.

13. Haller J. The effect of plant extracts on the hormonal interrelations between hypophysis and ovary. An endocrinological study with animal experiments. Z Geburtsh Gynakol 1961:156:274-302.

14. Dixon-Shanies D, Shaikh N. Growth inhibition of human breast cancer cells by herbs and phytoestrogens. Oncol Rep 1999;6:1383-1387.

15. Ohyama K, et al. Cytotoxicity and apoptotic inducibility of Vitex agnus-castus fruit extract in cultured human normal and cancer cells and effect on growth. Biol Pharm Bull 2003;26:10-18.

16. Merz PG, et al. The effects of a special Agnus castus extract (BP1095E1) on prolactin secretion in healthy male subjects. Exp Clin Endocrinol Diabetes 1996; 104:447-453.

17. 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.

18. Lauritzen CH, et al. Treatment of premenstrual tension syndrome with vitex agnus castus controlled, double-blind study versus pyridoxine. Phytomedicine 1997;4:183-189.

19. Berger D, et al. Efficacy of Vitex agnus-castus L. extract Ze440 in patients with pre-menstrual syndrome (PMS). Arch Gynecol Obstet 2000;264:150-153.

20. Loch EG, et al. Treatment of premenstrual syndrome with a phytopharmaceutical formulation containing Vitex agnus castus. J Women’s Health Gend Based Med 2000;9:315-320.