Vitex

Overview
Chasteberry, or Vitex, is mostly used in the treatment of PMS, but a list of the applications for which there is some clinical evidence includes: hyperprolactinemia, corpus luteum insufficiency, infertility associated with corpus luteum insufficiency, mastodynia, premenstrual tension syndrome (PTMS), perimenopausal symptoms, uterine myomas, endometriosis (adjunctive therapy), Parkinson's disease, stimulation of milk-production, reduction of an over-production in milk in lactation, and acne (McKenna et al., 2001).

The chemistry of Vitex (V. agnus-castus) has not yet become fully understood, nor has the relationship of its chemical constituents to therapeutic use. Standardized extracts of Vitex have had extensive clinical investigation. Standardization is normally to 0.5% agnusides of a 20:1 fruit extract. The fruit, leaves, and seeds of the Vitex plant have had documented traditional medicinal use, but modern-day extracts focus only on the fruits. Known chemical compounds in the fruits are: essential oils (0.15-1.0% ) made up of 73 identified compounds including, 4-terpinol, -pinene, -phellandrene, sabinene, -caryophyllene, E--farnesene, caryophylline oxide, alloaromadenedrene, and spathulenol; and flavonoids including, orientin, iso-orientin, xyloside, vitexin, and isovitexin (McKenna et al., 2001).

Vitex exhibits a dopaminergic activity that inhibits prolactin activity. It is this activity that is mostly attributed to its therapeutic applications (McKenna et al., 2001). A few of the most notable preclinical studies are summarized:
•Estrogenic activity has been reported by the equivalent of one-third the human dose administered to overiectomized female rats (Eagon et al., 1997).
•Various parts of the Vitex plant (mostly the leaves and fruits) have exhibited anti-microbial or growth-inhibitory activity against Pseudomonas aeruginosa, Escherichia coli, Bacillus subtilis, Staphylococcus aureus, Aspergillus parasiticus, Candida krusei, C. albicans, Penicillium viridactum, Streptococcus faecalis, Trichophyton mentagrophytes, Microsporaum gypseum, M. canis, Shigella sonei, Epidermophyton floccosum; and common insect pests (Snow, 1996; Pepeljnjak et al., 1996; and Kustrak et al., 1997).
•A dopamine-agonist action is exhibited by Vitex which then causes an anti-prolactin effect at the hypothalamus-pituitary axis; however, investigations have found Vitex not to increase the actual secretion of dopamine (McKenna et al., 2001; Wuttke et al., 1995).
•A concentration dependent lowering of prolactin secretion in isolated rat pituitary cells in vitro was found using Agnolyt (Wuttke, 1992).

Comments
Vitex is only second in popularity to black cohosh for women’s health. Although Vitex is generally thought of as a key phytotherapeutic for PMS, it also has good clinical support for menopausal symptoms, among other female complaints.

Scientific Support
Clinical investigation of Vitex has been ongoing since the 1930's, with the early work being done on its reputation as a galactogogue by Madus with their product, Agnolyt (McKenna et al., 2001).

Hormonal Balancing
Corpus luteum insufficiency (CLI) is a condition in which serum progesterone levels are low 3 weeks after the onset of menstruation (less than 10-12 ng/mL). Symptoms can be long menstrual periods, anovulatory periods (with resultant infertility), PMS and mastopathy. The underlying cause is thought to be hyperprolactinemia (McKenna et al., 2001). Clinical work has been performed with Vitex on various menstrual symptoms, including premenstrual syndrome (PMS), premenstrual tension syndrome (PTMS) and CLI. Due to the similarity between syndromes and symptoms, the participants groups may represent a mixture of these diagnoses.

The tolerance and effect of high doses of Vitex extract was studied in 20 healthy males subjects aged 20-32. Men were selected for this study, even though their prolactin levels are lower, because they have less hormonal variation than women. The extracts were described as mostly water- and alcohol-free “thick” extracts prepared from the ripe, dried fruits of V. agnus-castus (special extract BP1095E1). Analysis of the results found the lowest dose to decrease the 24-hour serum prolactin level by over 15%, and 21% in the middle- and highest- dose extracts. Both dopamine antagonistic and agonistic actions were suspected, with the antagonistic actions taking place with the lower dosage of Vitex. The extract was judged to be well tolerated since no significant effects were noted, and only temporary or idiosyncratic effects were found (Merz et al., 1996).

A study of 52 women with latent hyperprolactinemia found therapy with Vitex (20 mg/day) produced lower prolactin levels as well as a normalization of other hormone levels associated with the menstrual cycle. Vitex also was found to significantly reduce PMS symptoms in those women who had presented with them in the beginning of the study. No side effects were found in the study, and two of the 17 women in the Vitex group became pregnant (Milewicz et al., 1993).

In another study involving 13 women with hyperprolactinemia and cyclic disorders, a Vitex product called Mastodynon® was tested. After the three months of the study, prolactin levels were measured and found to have been reduced, and some within normal prolactin ranges. The menstrual cycle of the women on Vitex therapy was also found to be normalized (Roeder, 1994).

The use of Vitex (Agnolyt®, 40 drops/day, for 3 months) was tested in an open non-controlled study of 20 infertile women with no prolactin imbalance. Prolactin, thyroid and androgen hormones were within normal ranges in the women chosen for this study, but all had low levels of progesterone on day 20 of the menstrual cycle. At the end of the study, progesterone levels rose to normal ranges in 7 of the women, and in 4 cases their progesterone levels rose above normal. In addition, basal body temperatures rose, and the women were found to have a longer, more normal hyperthermic phase in their cycles. Two of the women became pregnant, and no side effects were noted (Propping and Katzork, 1987).

In one double blind, placebo-controlled study of 52 women with CLI and abnormal menstrual cycles, Vitex extract was administered for 3 cycles (Strotan®, 20 mg/day). In the treatment group, the luteal phase had changed from an average of 5.5 days to 10.5 days, and the follicle-phase was reduced from 23.8 days to 18.5 days. In addition, prolactin levels were normalized (previously high), and there were significant increases in both progesterone and estrogen levels compared to placebo. An added benefit from the study was that three women who had been previously unable to conceive became pregnant (Bubenzer, 1983).

A number of large drug monitoring studies reported the use of Vitex (in the form of Agnolyt® drops) (McKenna et al., 2001):

•The results of a questionnaire were reported on the use of Vitex (various preparations) by 153 members of the National Institute of Medical Herbalists from England and Ireland. Treatments were reported for PMS (94.1%), perimenopausal complaints (86.3%), female infertility (89.5%), and female acne (79.7%), and male acne (10.5%). 98.6% of respondents believed Vitex to be “very effective” or “effective” for hormonal imbalance syndromes. Mean length of treatment for PMS=4.8 months and for menopausal complaints=7.1 months. The most common preparation used was tinctures (86.4%), followed by fluid extracts (28.1%) and powdered herb preparations (9.2%). Very few practitioners used standardized powdered extracts (Christie and Walker, 1997-98).
•A multicenter study recorded the use of Agnolyt® in 1,592 cases for menstrual disorders and PMS (usually with corpus luteum insufficiency). Mean treatment was 43 drops for 5 months. A good or satisfactory response was reported in 90% of cases. There were 145 patients that stated the wish to become pregnant, and 56 of those did. 2.4% of cases reported side effects (Propping et al., 1991).
•Two drug monitoring studies were reported using Agnolyt® drops. A total of 3,162 women were followed, most with some kind of menstrual problem. Diagnoses included PMS (1,016 women), corpus luteum insufficiency (734 women), uterine myomas (320 women) and menopausal symptoms (167 women). Mean treatment was 153 days using 42 drops of Agnolyt® daily. The effectiveness of treatment was judged to be 90%, with 1% experiencing side effects (Loch et al., 1991).
•The use of Agnolyt® was recorded in 1,571 women for menstrual problems associated with corpus luteum insufficiency or ovarian dysfunction. Average treatment was 40 drops daily on an empty stomach, and lasted for 135 days. A response rate of almost 90% was recorded with adverse effects seen in only 1.9% of women (Feldmann et al., 1990).
•In a drug monitoring report by Attleman et al. (1972) on the use of Vitex (Agnolyt®) in general and consulting practices of the authors in Germany. Over 2,000 cases were analyzed which used Vitex for PMS, polymenorrhea, hypermenorrhea (due to uterine fibroids), headaches (from birth control pill use), mastopathia, amenorrhea (primary and secondary), uterine bleeding (juvenile), menopausal bleeding, and sterility. Most treatments for menopause used 40 drops daily, after meals. Side effects were reported as rare.

PMS
An extract of Vitex (Ze 440; one daily of a 20 mg native extract for 8 menstrual cycles) was administered to 50 patients with PMS in a prospective multicenter study. Results of the treatment were monitored using the validated Moos’ menstrual distress questionnaire (MMDQ), a visual analogue scale (VAS; self-assessment) and a global impression scale. PMS symptoms were found to be reduced by treatment by a significant score reduction on the MMDQ of 42.5%. The global efficacy results were moderate to excellent (in 38 patients), and the number of days of the PMS symptoms were reduced slightly from 7.5 to 6 days. There were no differences found between patients on oral contraceptives compared to the others, and no significant side effects were found (Berger et al., 2000).

A new solid extract preparation of Vitex was tested for 3 menstrual cycles in women in a large multicenter study. 1,634 patients were administered a questionnaire to follow common PMS symptoms, and 93% reported a decrease or cessation of PMS symptoms. 85% of physicians reported the treatment efficacy as good or very good, while 81% of patients assessed treatment as very much or much better. No serious side effects were reported (Loch et al., 2000).

A double blind, placebo-controlled, randomized trial of Vitex in 600 (including placebo groups) women with PMS was reported. Participants were judged using the Menstrual Distress Questionnaire. A significant improvement was found in the “feel jittery or restless” symptom, but otherwise the authors concluded the efficacy of Vitex to be no better than placebo (soy based). The authors also admitted that the design of the study could have unfairly biased the outcome of differences between the treatment and control groups (Turner and Mills, 1997).

A study reported for premenstrual tension syndrome (PTMS) was conducted in a multicenter, randomized, double-center manner involving 105 women. Efficacy was rated at 77.1% for Vitex and 60.6% for pyridoxine (by the Clinical Global Impression scale). Although the results were not statisitically valid, the authors supported the overall beneficial results of Agnolyt® (Lauritzen et al., 1997).

Another study examined the efficacy of Agnolyt® capsules (a new preparation at the time) in PTMS. The study was randomized and double blind, using 175 mg daily against pyridoxine (vitamin B6, 200 mg/day) in 175 women. Treatment lasted for 3 cycles, and was ranked using the PTMS-scale. In the treatment group, the PTMS-points fell from 15.2 to 5.1 points after treatment, and from 11.9 to 5.1 points in the pyridoxine group (reflecting a significant improvement in symptoms). Patient evaluations were 36.1% for Vitex versus 21.3% for the pyridoxine; and for physician evaluations 24% reported Vitex as excellent versus 12.1% for the pyridoxine (Reuter et al., 1995).

In a drug monitoring study involving 1,542 women, Vitex was used to treat various disorders, including PMS, corpus luteum insufficiency, uterine fibroids, and menopausal symptoms. Agnolyt® was used 20-120 drops for an average of 42 drops daily over a period of 7 days to 16 years. Symptom improvement began after an approximate mean of 25 days, and dissatisfaction rate was only approximately 4.5% for both assessors and patients (Dittmar et al., 1992).

Acne
The Madus company is the maker of Agnolyt® one of the most popular Vitex preparations in Europe. In their information booklet (1994) they describe several clinical studies. One use for which clinical studies were recorded was for the treatment of acne. In one of these, Agnolyt® was used to treat 118 patients for 12-24 months. This treatment group was compared to a group of 43 patients who received “conventional” treatment. The Vitex group was found at the end of the study to have healed more quickly and had fewer recurrences than those on conventional therapy. Men and women are both described as candidates for acne treatment by Vitex in the Madus booklet (McKenna et al., 2001).

Lactation
Vitex has been historically used for bringing on lactation in women who are having trouble producing milk. The exact mechanisms of the hormones involved in lactation are complex and not fully understood; and similarly, the use of Vitex for lactation has been a controversial topic due to our lack of complete understanding of its actions. Breastfeeding women with high prolactin levels and suppressed ovulatory function often show symptoms associated with disordered follicular development and corpus luteum insufficiency. Over half of all women with menstrual problems (62%) also have abnormally high levels of prolactin. The opposite is also true: women that are hyperprolactinemic almost always have menstrual disorders (Böhnert, 1997).

Breast Pain
Halaska et al. (1998) administered Vitex extract to patients with mastodynia in a double-blind, placebo-controlled study. Two parallel groups of 50 patients were treated for 3 menstrual cycles (60 drops daily of Vitex extract or placebo). The intensity of breast pain was found to diminish faster in the Vitex treatment groups versus placebo, and the tolerability of treatment was found to be satisfactory.

In a randomized, double-blind, placebo-controlled, multicenter study the use of Vitex (Mastodynon® N) was tested in women with cyclical mastalgia. 120 women (ages 23-40) who had presented with breast pain for 3 or more cycles (for 3 or more days of the cycle) participated in the study. A parallel group design and double-dummy technique was used in the study, using a tablet and liquid extract form of Vitex, and corresponding placebos. Prolactin levels were measured during the study, and the participants were scored using a linear analogue scale (VAS). Both the tablet form (3.7 ng/mL, p=0.015) and the liquid form (4.35 ng/mL, p=0.039) of Vitex produced significant decreases in prolactin levels in subjects. The liquid Vitex preparation was found to produce changes more quickly than the tablet, and neither of the preparations produced changes in FSH, LH or progesterone. Symptoms of headache, abdominal pains, psychological symptoms, and a tendency to edemas were decreased in the treatment groups compared to placebo, and the number of pain-free days increased by 15% in the treatment groups compared to 8% in the placebo. Estradiol levels were found to increase in the treatment groups (25.7 pg/mL for the tablet, and 28.5 pg/nL for the liquid) compared to placebo (10.8 ng/mL). In addition to this study, small studies have reported good results for the use of Vitex in mastalgia treatment (Kubista et al., 1983; and Wuttke et al., 1995).

Safety / Dosage
Most studies of black cohosh have used brand names such as Agnolyt (liquids or capsules), Strotan or Mastodyne. Dosage recommendations for the various preparations are as follows (McKenna et al., 2001):
•Agnolyt liquid (58% alcohol, 100 g of solution containing 9 g berry tincture (1:5))- 40 drops daily after meals for several months.
•Agnolyt capsule (175 mg dried berries, 1:5 alcoholic extract)- once daily with liquid for several months.
•Standardized powdered extract (175 mg of a 20:1 fruit extract, standardized to 0.5% agnusides)- one capsule per day; this is a common preparation in the U.S. and is similar to the Agnolyt capsule formulation.
•Strotan capsules (20 mg of alcoholic extract; 50-70% v/v)- one time daily.
•Mastodyne (ethanol-water extract containing 55.4% ethanol by volume)- 60 drops daily.
Serious side effects have not been cited for Vitex, but skin rashes and itching have been reported. Although no contraindications are sited in the German Commission E monographs, others have stated concerns of using Vitex along with oral contraceptives. Due to the recently discovered dopamine agonist activity of Vitex, there may be a concern with people taking Vitex that are also on dopamine antagonists (McKenna et al., 2001).

A review of the literature cites various opinions on the use of Vitex with pregnancy (especially in the initial phase), but overall it is usually contraindicated. Possible reports of negative reactions to Vitex in women undergoing in vitro fertilization have been cited. Vitex use during lactation has likewise been of mixed opinion (McKenna et al., 2001).

References
1.Attelman H, Bends K, Hellenkemper H; et al. Agnolyt® in the treatment of gynecological complaints. Zeitschrift für Praklinishche Geriatrie. 1972; 2:239 (translation).
2.Berger D, Schaffner W, Schrader E, Meier B, Brattstrom A. Efficacy of Vitex agnus castus L. extract Ze 440 in patients with pre-menstrual syndrome (PMS). Arch Gynecol Obstet. 2000 Nov;264(3):150-3.
3.Böhnert KJ. Clinical study on chaste tree for menstrual disorders. Quarterly Review of Natural Medicine (Spring) 1997; 19-21.
4.Christie S, Walker, AF. Vitex agnus-castus L.: (1) a review of its traditional and modern therapeutic use; (2) current use from a survey of practitioners. The European Journal of Herbal Medicine 1997-98; 3: 29-45.
5.Dittmar FW, Bohnert KJ, Peeters M. et al. Premenstrual syndrome treatment with a phytopharmaceutical. Therapiewoche Gynäkologie 1992; 5:60-68 (translation).
6.Eagon CL, Elm MS, Teepe AG, Eagon PK. Medicinal botanicals: estrogenicity in rat uterus and liver. Proceedings of the American Association for Cancer Research 1997; 38: 293 (abstract 1967).
7.Feldman HU, Albrechet M, Lamertz M. et al. The treatment of corpus luteum insufficiency and premenstrual syndrome. Experience in a multicenter study under clinical practice conditions. Gyne 1990; 12:422-425 (translation).
8.Halaska M, Raus K, Beles P, Martan A, Paithner KG. Treatment of cyclical mastodynia using an extract of Vitex agnus castus: results of a double-blind comparison with a placebo. Ceska Gynekol. 1998 Oct;63(5):388-92.
9.Krustrak D, Kuftinec J., Blazevic D. The composition of the essential oil of Vitex agnus-castus. Planta Medica1992; 58 (Suppl. 1): A681.
10.Kubista E, Muller G, Spona J. Conservative therapy of mastopathy. Zentralbl Gynakol. 1983;105(18):1153-62.
11.Lauritzen CH, 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.
12.Loch EG, Bohnert KJ, Peeters M. et al. The treatment of menstrual disorders with Vitex agnus-castus tincture. Der Fraunarzt 1991; 32:867-870 (translation).
13.Loch EG, Selle H, Boblitz N. Treatment of premenstrual syndrome with a phytopharmaceutical formulation containing Vitex agnus castus. J Womens Health Gend Based Med. 2000 Apr;9(3):315-20.
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15.Madaus Co. (1994). Agnolyt® - The Natural Way for Hormone Imbalance. Package insert and research summary (translation).
16.Merz PG, Gorkow C, Schrodter A, Rietbrock S, Sieder C, Loew D, Dericks-Tan JS, Taubert HD.The effects of a special Agnus castus extract (BP1095E1) on prolactin secretion in healthy male subjects. Exp Clin Endocrinol Diabetes. 1996;104(6):447-53.
17.Milewicz A, Gejdel E, Sworen H, Sienkiewicz K, Jedrzejak J, Teucher T, Schmitz H. 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 Jul;43(7):752-6.
18.Pepeljnjak S, Antolic A. Kustrak D. Antibacterial and antifungal activities of the Vitex agnus-castus L. extracts. Acta Pharmaceutica (Zagreb) 1996; 46: 201-206.
19.Propping, D and T. Katzorke. 1987. Treatment of corpus luteum insufficiency. Zeitschrift für Allgemeinmedizin 63:932-933 (English translation).
20.Propping D., Bohnert KJ, Peeters M. et al. Vitex agnus-castus treatment of gynecological syndromes. Therapeutikon 1991; 5:581-585 (translation).
21.Reuter HD, Bohnert KJ, Schmidt U. The therapy of the premenstrual syndrome with Vitex agnus castus: controlled double-blind study with pyridoxine. Zeitschrift für Phytotherapie 1995; 7 (Abstracts volume): 7 (abstract, translation).
22.Roeder DA. Therapy of cyclic disorders with Vitex agnus-castus. Zeitschrift fürPhytotherapie1994; 15:155-159 (English summary).
23.Snow JM. Vitex agnus-castus L. (Verbenaceae). Protocol Journal of Botanical Medicine (Spring) 1996; 20-23.
24.Turner S, Mills S. A double-blind clinical trial on a herbal remedy for premenstural syndrome: a case study. Complementary Therapies in Medicine1993; 1:73-77.
25.Wuttke, W. Zellbiologische untersuchungen mimt Agnolyt® –praparationen (NH 246, NH 247). Personlich Keit Mittleilung 1992; 8.7 (cited in Madaus Co., 1994).
26.Wuttke W, Gorkow C, Jarry H. Dopaminergic compounds in Vitex agnus-castus, in: Loew, D. and N. Rietbrock (eds.), Phytopharmaka un Forschung und Klinischer Anwendung. 1995; Darmstatd, Germany: Steinkopff Verlag, pp. 81-91.
27.Wuttke W, Splitt G, Gorkow C. et al. Treatment of cyclical mastalgia with Agnus castus: results of a randomized, placebo-controlled, double-blind study. Geburtshilfe und Frauenheilkunde 1997; 57:569-574 (translation).

EDITOR'S NOTE: This monograph can be found in The Health Professional's Guide to Dietary Supplements (Lippincott, Williams & Wilkins) by Shawn M. Talbott, PhD and Kerry Hughes, MS.