Herbal Research Review
Vitex agnus castus Clinical Monograph
by Donald J. Brown, ND
from Quarterly Review of Natural Medicine, Summer 1994
c/o NPRC, Inc.
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Vitex agnus castus, also known as chaste tree, is a shrub with finger-shaped leaves and
slender violet flowers. Vitex agnus castus grows in creek beds and on river banks in
valleys and lower foothills in the Mediterranean and Central Asia. The plant blooms in
high summer and, after pollination, develops dark-brown to black fruit the size of a
peppercorn. The fruit possess a pepper-like aroma and flavor. The ripe, dried fruit of
Vitex agnus castus is the part of the plant used in medicinal preparations today.
The genus name Vitex is derived from the Latin "vitilium" which means plaiting. The flexible, but tough and hard branches were used for construction of wattle fences. Plinius, 1st Century A.D., has the earliest reference to the plant as Vitex. The species name Agnus castus originates from the Latin "castitas" (chastity) and the equating of the Greek "agnos" with the Latin "agnus" (lamb).
Vitex agnus castus belonged to the official medicinal plants of antiquity and is mentioned in the works of Hippocrates, Dioscorides, and Theophrast. The first specific medicinal indications can be found in the writings of Hippocrates, 4th Century B.C. He recommends the plant for injuries, inflammation, and swelling of the spleen, and the leaves in wine for hemorrhages and the "passing of afterbirth." In the "Corpus Hippocratum" he states:
"If blood flows from the womb, let the woman drink dark red wine in which the leaves of the chaste tree have been steeped. A draft of chaste leaves in wine also serves to expel a chorion held fast in the womb." Dioscorides attributed to the fruit a hot and astringent activity and recommended it for wild animal bites, swelling of the spleen, and for dropsy. Decoctions of the fruit and plant were used as sitz baths for diseases of the uterus.
The English name for Vitex agnus castus, "chaste tree," is derived from the belief that the plant would suppress libido in women taking it. In Greek cities, festivals in the honor of Demeter included a vow of chastity by the local women. The Catholic church in Europe developed a variation on this theme by placing the blossoms of the plant at the clothing of novice monks to supposedly suppress libido. It is interesting to note that another common name for Vitex agnus castus, "monk's pepper," derived from the fact that monks in Southern Europe commonly used the fruit as a spice in their cooking.
The majority of clinical studies with Vitex agnus castus (Vitex) have been performed with a tincture of the fruit. Most medical texts, as well as monographs in Europe, list the entire preparation as "medicinally active."1 This is an indication that the medical activity of the fruit is examined as a whole and that specific "active constituents" have not been individually isolated.
The fruit of Vitex contains essential oils, iridoid glycosides, and flavonoids.2 Essential oils include limonene, 1,8 cineole, and sabinene.3 The primary flavonoids include castican, orientin, and isovitexin. The two iridoidglycosides isolated are agnuside and aucubin (see Figure 1).4 Agnuside serves as a reference material for quality control in the manufacture of Vitex extracts.
One other report demonstrated delta-3-ketosteroids in the flowers and leaves of Vitex. The authors report (albeit in a somewhat vague manner) that this fraction of the leaves and flowers "probably" contained progesterone and 17-hydroxyprogesterone. Testosterone and epitestosterone were also presumed to be present.5 How this relates to the content of these substances in the fruit remains to be ascertained.
The Menstrual Cycle: A Brief Overview
The female menstrual cycle is controlled by a complex interplay between hormones of the hypothalamus, pituitary, and the ovaries (see Figure 2).6 The actual center of control is the hypothalamus, which produces a gonadotropin releasing hormone (GnRH) that stimulates the anterior pituitary to release the gonadotropins follicle stimulating hormone (FSH) and lutenizing hormone (LH). Pulsatile secretion of GnRH is necessary for the pituitary to respond with adequate production of LH and FSH. When there is continuous release or disturbance in pulsatile secretion, the stimulus for follicle maturation is absent, and sterility results.
FSH is the primary hormone responsible for the maturation of follicles into fertile ova and the increased production of estrogen by the ovaries. LH causes release of the ovum, conversion of the follicle into the corpus luteum, and the subsequent production of progesterone.
The timing of the release of these pituitary hormones, as well as estrogen and progesterone, during a normal menstrual cycle are illustrated in Figure 3. At midcycle, estrogen is at its peak and progesterone begins to rise. It is at this point that FSH levels decrease and LH levels surge to cause ovulation. In the ovary, the corpus luteum produces progesterone. This hormone ensures sufficient blood supply to the endometrium so that the fertilized ovum can establish itself in the uterus. If fertilization does not occur, the corpus luteum recedes, hormone production decreases, the endometrium is not sufficiently supplied with blood and menses occurs. FSH and LH levels decline until menses and the beginning of a new menstrual cycle.
A third hormone produced by the pituitary, prolactin, also plays an important role in the menstrual cycle. Prolactin is controlled by an inhibitory factor (PIF) produced by the hypothalamus (as opposed to FSH and LH which are controlled by stimulatory factors). Prolactin regulates the development of the mammary gland and milk secretion. In non-lactating women, it is critical that this hormone be in balance with FSH and LH. Increased production of prolactin can inhibit the maturation of follicles in the ovary and induce menstrual abnormalities and sterility. It is interesting to note that prolactin release is often stress-dependent. Stress reduction should always play a role in the management of menstrual abnormalities.
It should also be noted that estrogen and progesterone formed by the ovary have a self-regulating effect on the hormones produced by the pituitary and hypothalamus via a feedback mechanism. Androgens, like testosterone, also play a part in this feedback mechanism. Disorders of other endocrine glands, such as the thyroid, adrenals, or pancreas, may also interfere with the normal functioning of this feedback mechanism.
Corpus Luteum Insufficiency
Corpus luteum insufficiency (also referred to as deficiency) is a manifestation of suboptimal ovarian function. In laboratory terms, corpus luteum insufficiency is usually defined as an abnormally low progesterone level three weeks after the onset of menstruation (serum progesterone below 10-12 ng/ml). This state is normal during puberty and at menopause. However, it is usually considered abnormal when occurring in women between the ages of 20 to 40 years.7
Corpus luteum insufficiency points to abnormal formation of ovarian follicles, an abnormality that may be so pronounced that no secondary or tertiary follicles are produced with a resulting lack of ovulation (anovulation). Corpus luteum insufficiency also leads to a relative deficiency of progesterone. Insufficient levels of progesterone may also result in the formation of ovarian cysts.
Corpus luteum insufficiency may result in a myriad of different menstrual abnormalities. Table 1 lists the most common clinical conditions in 1592 women diagnosed with corpus luteum insufficiency. Foremost are hypermenorrhea (heavy periods), polymenorrhea (abnormally frequent periods), and persistent anovulatory bleeding. It is interesting to note that secondary amenorrhea (lack of a period) may sometimes be observed in women with corpus luteum insufficiency.
Disturbances of other hormones may also be associated with corpus luteum insufficiency. One study found hyperprolactinemia in 70% of cases.9 Also noted are an exaggerated response to the thyroid releasing hormone (TRH) test which is associated with manifest or latent hypothyroidism.
How Does Vitex Work?
According to Dr. Rudolf Fritz Weiss, Vitex acts on the diencephalohypophyseal system ­p in other words, the hypothalamus and pituitary.
Vitex increases LH production and mildly inhibits the release of FSH (see Figure 4). The result is a shift in the ratio of estrogen to progesterone, in favor of proges-terone. This is, in fact, a corpus luteum like hormone effect.10 The ability of Vitex to raise or modulate progesterone levels in the body is therefore an indirect effect and not a direct hormonal action.11 This is in contrast to other phytomedicines, like Black cohosh, frequently used in gynecology because of their direct binding of estrogen receptors ("phyto-estrogens").12
Vitex also modulates the secretion of prolactin from the pituitary gland. Early animal studies indicated an increase in lactation and enlargement of the mammary gland following administration of Vitex.13 It is interesting to note that Vitex has been historically used as a lactagogue (substance to increase milk production) in lactating women with poor breast milk production. As we will note below, clinical studies have confirmed this effect.
Current research with Vitex has indicated usefulness in hyperprolactinemia. In studies with rats, Vitex was shown to inhibit prolactin release by the pituitary gland ­p particularly under stress. The mechanism of action appears to involve the ability of Vitex to directly bind dopamine receptors and subsequently inhibit prolactin release in the pituitary.14,15 Slight hyperprolactinemia is commonly associated with corpus luteum insufficiency.16
Use of Vitex in Women's Healthcare
The causes of menstrual disorders are multifaceted and can vary greatly in their manifestation. Frequently, therapeutic interventions must be used on a trial and error basis over the duration of a number of menstrual cycles to determine their efficacy. Nutritional interventions like vitamin B6, magnesium, and vitamin E, as well as phytomedicines like Black cohosh, Dong quai, and Evening Primrose oil, have all shown greater efficacy when used over time periods of several months. This reflects the gradual balancing effect that many of these interventions have on the female hormonal system. Vitex certainly fits this mold.
The majority of clinical studies completed with Vitex have been non-controlled studies with large populations of female patients in European gynecology practices. Vitex, which has a Commission E Monograph in Germany, is frequently used in these practices as an initial intervention in a number of menstrual disorders including premenstrual syndrome, hypermenorrhea, polymenorrhea, anovulatory cycles, secondary amenorrhea, infertility, and hyperprolactinemia. As we will note, many of these cases can be linked to corpus luteum insufficiency. Vitex is also used in cases of poor lactation, uterine fibroids, and climacteric.
Premenstrual syndrome (PMS) is one of the most frequent complaints noted in gynecology practices. According to some estimates, 30 to 40% of menstruating women are affected by PMS.17 Table 2 lists the different categories for PMS and the symptoms associated with them.
Two monitoring surveys of gynecology practices in Germany examined the effect of Vitex on 1542 women with a diagnosis of PMS.18 The mean age of the patients was 34.7 with a range of 13 to 62 years. Additional diagnoses noted with these patients included corpus luteum insufficiency (n = 1016) and uterine fibroids (n = 170). Patients were placed on a proprietary Vitex liquid extract known as "Agnolyt" and instructed to take 40 drops daily. The average duration of treatment was 166 days.
The efficacy of treatment was assessed by both patients and their physicians. These assessments are depicted in Figures 5 and 6. In over 90% of the cases, symptoms were completely relieved with a report of side effects in only 2% of the patients (side effects are listed in Table 3). Only 17 of the 1542 women studied had to stop treatment due to side effects. Improvement in symptoms began after an average treatment duration of 25.3 days. 562 patients continued taking Agnolyt after completion of the monitoring period.
Another study with 36 patients with a diagnosis of PMS used 40 drops of Vitex liquid extract ("Agnolyt") daily over 3 cycles. A reduction was noted in physical symptoms (headaches, pressure and tenderness in the breasts, bloating, and fatigue), psychological changes (increased appetite, craving for sweets, nervousness/restlessness, anxiety, irritability, lack of concentration, depression, mood swings, and aggressiveness). Additionally, the interval of the luteal phase was normalized from an average of 5.4 days to 11.4 days and a diphasic cycle was established.19
Abnormal Menstrual Cycles
The first major clinical study on Vitex was published in 1954. Fifty-seven women suffering from a variety of menstrual disorders were given Vitex on a daily basis. Fifty patients developed a cycle in phase with menses while seven women did not respond. Of the fifty women, six women with secondary amenorrhea demonstrated one or more cyclic menstruations. Of nine patients with oligomenorrhea (scant or infrequent menstrual flow), six experienced a shortening of the menstrual interval and an increase in bleeding
Most striking was a dramatic improvement in menstrual regularity among 40 patients with cystic hyperplasia (excessive proliferation of cells) of the endometrium (the mucous membrane lining the inner surface of the uterus). This condition is associated with a relative deficiency of progesterone and characterized by dysfunctional uterine bleeding. No side effects were observed with Vitex treatment.20
An observational study with 126 women with menstrual disorders utilized 15 drops of Vitex liquid extract three times daily over several cycles. In 33 women suffering from polymenorrhea, the duration between periods lengthened from an average of 20.1 days to 26.3 days. In 58 patients with menorrhagia (excessive bleeding at the time of the period in amount or number of days), a statistically significant shortening of menses was achieved. Fourteen patients became pregnant during the study; among them were 3 women with primary infertility over 2, 3, and 8 years respectively, as well as 2 patients with secondary infertility over 4 and 15 years.21
Twenty patients with secondary amenorrhea were admitted to a 6 month study using Vitex liquid extract at 40 drops daily. Laboratory monitoring of progesterone, FSH, LH, and pap smears were performed at pre-study, 3 months, and 6 months. At the end of the 6 month study, data was available on 15 patients. The onset of cycles with menstruation was observed with Vitex treatment in 10 out of the 15 patients. The hormone values showed increased values for progesterone and LH, while FSH values either did not change or decreased slightly.22
Propping and colleagues carried out two non-blind uncontrolled trials to study the effect of Vitex on corpus luteum function in a total of 48 infertile women of reproductive age between 23 and 39 years. The inclusion criteria were normal prolactin levels (below 20 ng/ml), normal results in the prolactin and thyroid stimulating hormone (TSH) stimulation tests and an abnormally low serum progesterone below 12.0 ng/ml on the 20th day of the cycle. Treatment consisted of Vitex liquid extract, 40 drops daily, without any other medication for 3 months.
Forty-five women completed the studies (3 were excluded because of concurrent hormone use). The outcome of therapy was assessed by the normalization of the midluteal progesterone level and by correction (lengthening) of any preexisting shortening of the phases of the cycle. Treatment was deemed successful in 39 out of the 45 patients. Seven women became pregnant; in 25 patients, serum progesterone was restored to normal (> 12 ng/ml) and in 7 cases there was a trend toward normalization of progesterone levels.23,24
As mentioned previously, Vitex has shown a modulating effect on prolactin. A double-blind, placebo-controlled study examined the effect of a proprietary Vitex preparation ("Strotan") on 52 women with luteal phase defects due to latent hyperprolactinemia. The daily dose of the Vitex extract was 20 mg and the study lasted for three months. Hormonal analysis was performed at days 5-8 and day 20 of the menstrual cycle before and after three months of therapy. 37 cases were available for analysis (20 placebo and 17 Vitex) after 3 months of therapy. Prolactin release was significantly reduced in the Vitex group. Shortened luteal phases were normalized and deficits in progesterone production were normalized. No side effects were noted and two women in the Vitex group became pregnant.25
As mentioned previously, Vitex has been used historically to increase milk production in lactating women ­p another example of its modulating effect on prolactin levels. Only one controlled study exists examining the effect of Vitex in lactating women. Mohr found that lactating women with poor milk production treated with Vitex liquid extract were able to effectively increase production. Vitex often took several weeks to show results but was then used effectively over several months. This study and clinical use in Europe indicates the safety of Vitex for breast-fed infants.26
Anecdotal clinical reports have indicated a potential use for Vitex in the management of climacteric (hot flushes) in the early stages of menopause.27 Other clinical observations include:
· Uterine fibroids which are embedded into the muscle or are subserous may have their growth arrested by use of Vitex. Submucosal fibroids, however, are not likely to respond.
· Mild cases of endometriosis for which progesterone therapy are indicated may respond to Vitex.
How to Use Vitex
Since the early 1950's, the standard Vitex extract used for clinical research and treatment in Europe has been an alcohol-based tincture of the fruits of the plant known as "Agnolyt." 100 ml of the solution is standardized to contain 9 grams of the fruit. The recommended dosage is 40 drops with some liquid in the morning over several months without interruption. It is recommended that treatment with this extract be continued over several weeks after relief of symptoms is determined. The recent development of a solid extract equivalent of the tincture has allowed use by alcohol-sensitive women. The capsules which are 175 mg by weight, have a one-a-day recommendation also.
It is important to note that Vitex is not a fast-acting medication. In cases of anovulatory cycles and infertility, treatment duration may be as long as 5-7 months before conception occurs. For secondary amenorrhea of more than two years duration, Vitex should be administered for at least 1.5 years. In other conditions mentioned, however, first indications of efficacy with Vitex are usually seen within one or two cycles. Extensive or complete freedom of symptoms usually occurs after 4 to 6 months of treatment.
Is Vitex Safe?
Human and animal studies have determined Vitex to be safe for most women of menstruating age. Vitex should not be used during pregnancy but is safe for use during lactation. Safety has not been determined in children. There are no known interactions with other drugs.
Side effects noted in one large population study are listed in Table 3. Side effects noted in other clinical observations have included itching and an occasional rash. Again, these side effects are rare and have been noted in only 1-2 % of the patients monitored on Vitex. Some women also report that menstrual flow increases during Vitex treatment. This is often an indication of therapeutic efficacy.
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2. Agni cast fructus (chaste tree fruits). Commission E Monograph, December 2, 1992.
3. Kustrak, Kuftinec J & Blazevic N: The composition of the essential oil of Vitex agnus castus. Planta Medica 58 (Suppl l): A 681, 1992.
4. Gomaa CS: Flavonoids and iridoids from Vitex agnus castus. Planta Medica 33: 277, 1978.
5. Saden-Krehula M, Kustrak D & Blazevic N: Delta-3-ketosteroids in flowers and leaves of Vitex agnus castus. Planta Medica 56: 547, 1990.
6. Principles and Practice of Clinical Gynecology (Kase NG & Weingold, eds). John Wiley & Sons, New York, 1983.
7. Propping D, Katzorke T & Beliken L: Diagnosis and therapy of corpus luteum deficiency in general practice. Therapiewoche 38: 2992-3001, 1988.
8. Propping D, Bohnert KJ, et al: Vitex agnus-castus: Treatment of gynecological syndromes. Therapeutikon 5 (11): 581-5, 1991.
9. Muhlenstedt D, Wutke W & Schneider HPG: Short luteal phase and prolactin. Fertil Steril 373-4, 1977.
10. Weiss RF: Herbal Medicine. Ab Arcanum, Sweden, 1988.
11. Amann W: Removing an ostipation using Agnolyt. Ther Gegenew 104 (9): 1263-5, 1965.
12. Reichert RG: Phyto-estrogens. Quart Rev Nat Med Spring 1994, pp. 27-33.
13. Amann W: Op. cit., 1965.
14. Sliutz G, Speiser P, et al: Agnus castus extracts inhibit prolactin secretion of rat pituitary cells. Horm Metab Res 25: 253-5,1993.
15. Jarry H, Leonhardt S & Wuttke W: Agnus Castus As Dopaminergous Effective Principle In Mastodynon N. Zeitschrift Phytother 12: 77-82, 1991.
16. Schneider HPG, Goeser R & Cirkel U: Prolactin and the inadequate corpus luteum. In: Lisuride and Other Dopamine Agonists. Raven Press, New York, 1983. pp. 113-120.
17. Lurie SR: The premenstrual syndrome. Obstet Gynecol 45 (4): 220-8, 1990.
18. Dittmar FW, Bohnert KJ, et al: Premenstrual syndrome: Treatment with a phytopharmaceutical. TW Gynakol 5(1): 60-68,1992.
19. Coeugniet E, Elek E & Kuhnast R: Premenstrual Syndrome (PMS) And Its Treatment. Arztezeitchr Naturheilverf 27 (9): 619-22, 1986.
20. Probst V & Roth OA: On A Plant Extract With A Hormone-like Effect. Dtsch Med Wschr 79 (35): 1271-4, 1954.
21. Bleier W: Phytotherapy in irregular menstrual cycles or bleeding periods and other gynecological disorders of endocrine origin. Zentralblatt Gynakol 81 (18): 701-9, 1959.
22. Losh EG & Kayser E: Diagnosis and Treatment of Dyshormonal Menstrual Periods In The General Practice. Gynakol Praxis 14 (3): 489-95, 1990.
23. Propping D & Katzorke T: Treatment of corpus luteum insufficiency. Zeits Allgemeinmedizin 63: 932-3, 1987.
24. Propping D, et al: Op. cit., 1988.
25. Milewicz A, Gejdel E, et al: Vitex agnus castus extract in the treatment of luteal phase defects due to hyperprolactinemia: Results of a randomized placebo-controlled double-blind study. Arzneim-Forsch Drug Res 43: 752-6, 1993.
26. Mohr H: Clinical investigations of means to increase lactation. Dtsch Med Wschr 79 (41): 1513-6, 1954.
27. Du Mee C: Vitex agnus castus . Aust J Med Herbalism 5 (3): 63-5, 1993.