REPORT

from the Final Stage of Clinical and Biochemical Study of Pharmacological Characteristics of Vitex Agnus Castus Preparation Conducted at the Request of Institute of Plants and Herbal Preparations in Poznan, Poznan, Poland.

The study included 75 women from 25 to 39 years of age, divided into two groups. Group I contained 60 women of 31,9 ± 6.2 years of age with hyperprolactinemia, disturbed menstrual cycle and primary and secondary infertility, while group II - control group - contained 15 women normoprolactinemia of 24,3 ± 4,2 years of age with normal menstrual cycle. Statistical analysis included 50 women of group I, as 10 women of this group were eliminated: 5 as a result of pregnancy, 2 due to the use of other drugs, and 3 resigned due to family reason, Three women were eliminated from group II because of the use of other medications. Uterus and ovaries of the subjects were evaluated with clinical and ultrasonographic examinations, whereas anatomy of Turkish saddle and pituitary gland were followed by roentgenodiagnostics and tomography.

The work aimed at evaluation of possible influence of Vitex agnus castus extracts on the activity of dopaminergic and serotoninergic systems as well as on the hormonal profile in case of women with hyperprolactinemia. Blood for biochemical tests and determination of functional test parameters of kidneys and liver was drawn in the morning on the 9th day of the cycle. Blood for hormonal profiles was drawn on the 18th day of the cycle, before this study and after 90 days of using Vitex agnus castus preparation in the form of oral tablets at the dose of 0.007 mg/kg/24 h of iridoid compounds recalculated into aucubin. Women of both groups had their liver function evaluated based on the determination of AspAT, AlAT and bilirubin concentrations. The evaluation of the kidneys function was based on the plasmatic levels of urea, uric acid, and creatinine.

The concentrations of serotonin (5-HT), dopamine (DA), and 5-hydroxyindoleacetic acid (5-HIAA) in blood plasma, before and after 90 days of Vitex agnus castus administration, were determined by high pressure chromatography (HPLC), using electrochemical detection. The tests were conducted in the Institute of Biogenic Amines of the Polish Academy of Sciences, at Lodz, Poland.

The hormonal profiles, before and after administration of the preparation, were determined with radioimmunologic methods. The concentrations of gonadotrophins (FSH, LH), estradiol (E), progesterone (P), and prolactin (PRL), under basic conditions and after stimulation with metoclopramide, were determined with the help of the test sets manufactured by VIDAS. The concentrations of thyreotropic hormone (TSH) was determined with the Farmos sets. The concentrations of androgens in blood plasma were determined in the following way: total testosterone (Tt) - with the Spectria sets, androstendion (A) - with the Biomedica sets, and free testosterone (Tf) - with the DPC sets. Protein carriers (SHBG), dehydroepiandrosterone sulfate (DHAS) and estrogen (E) were determined with the DRG sets.

The results obtained were statistically analyzed with Student's t test for dependent tests, Hi test for dependent tests in Mc Nemar modification and with median test using Wilcoxon ranked signs, assuming p < 0,05 as a significance level. They were summarized in seven tables (Tables I VII.

It appears from Table I that condition of the reproductory system of the subjects, after 90 days of using Vitex agnus castus does not exhibit changes detectable by ultrasonography, while the regularity of menstrual cycles improved significantly in comparison to the initial values (p < 0.001).

Table II reports the arterial blood pressure and pulse values for the subjects. A significantly decrease of both parameters might suggest hypotensive effects of Vitex agnus castus .

The functional test parameters for liver (AspAT, AlAT, and bilirubin) as well as those for kidneys (urea, uric acid, and creatinine) were reported in Table III. Only bilirubin concentration significantly increased (p < 0,05) in comparison to the initial values.

The concentrations of prolactin in blood plasma under basic conditions and after stimulation with metoclopramide (MCP), along with the percentage increase in the concentrations of prolactin in blood plasma after MCP, were reported in Table IV. It appears that under normal conditions, after administration of Vitex agnus castus a significant decrease of the blood plasma prolactin (p < 0.001) concentration was observed. However, the prolactin concentration values as well as the percentage increase after stimulation with MCP do not show any differences since these results are influenced by many structural and functional factors of the hypothalamus - pituitary gland system. The concentration of thyreotropic hormone (TSH) remains at normal levels for both groups.

Table V illustrates concentrations of serotonin (5-HT), dopamine (DA), and serotonin metabolite, 5-hydroxyindoleacetic acid (5-HIAA). It appears that after 90 days of Vitex agnus castus administration, the concentration of serotonin decreased significantly (p < 0.001), while those of dopamine and 5-hydroxyindoleacetic acid increased significantly (p < 0.001).

Table VI shows gonadotrophin, estrogenes, and progesterone concentrations in women with hyperprolactinemia, before and after application of Vitex agnus castus. It appears that after 90 days of treatment with Vitex agnus castus , concentrations of luteotrophic hormone (p < 0,01), estradiol ( < 0,001), and progesterone (p < 0,02) increased significantly, while those of follicle stimulating hormone and estrogen show no difference in comparison to the initial values.

The concentrations of androgens and protein carriers as well as indices of free testosterone and protein carriers are shown in Table VII. It appears that the concentrations of total and free testosterone and dehydroepiandrosterone sulfate as well as indices of free testosterone and protein carriers, decreased significantly (p < 0,001), while the concentration of protein carriers increased (p < 0,001). Also, androstendion concentration decreased, however, it was not a significant decrease.

Clinical evaluation showed that tolerance of Vitex agnus castus preparation was good, except for 3 cases of women who reported nausea and headaches during the first week of the study. Vitex agnus castus, also shows hypotensive effects in women with tendency to hypertension. Pathological galactorrhea decreased significantly during the 90 days of using the preparation in 10 women, which constitutes 20%. In case of 40 women (80%), premenstrual tension syndrome disappeared and mastopathic lesions as well as mastodynia significantly subsided. In 15 women (30%) with hyperprolactinemia, the complaints disappeared completely during the treatment with Vitex agnus castus and have not return even after 3 months from the end of the clinical trials. The concentration of dopamine in blood plasma increased, while that of serotonin significantly decreased after 90 days of Vitex agnus castus administration. The concentration of 5-hydroxyindoleacetic acid (5-HIAA), which is a final serotonin metabolite, significantly increased. The above results might suggest that Vitex agnus castus preparation positively influences metabolism of serotonin, which is an antagonist in relation to dopaminergic system, responsible - among others - for correct synthesis and secretion of prolactin in the hypothalamus - pituitary gland system. Improvement of neurogenic and hormonal function does not correlate with ultrasound images of reproductive organs which might be explained by the relatively short period of the preparation application. Nonetheless, normalization of menstrual cycle was obtained in 72% of women with hyperprolactinemia. Androgenic changes in the form of acne on the face disappeared completely, while those on the skin of torso subsided only slightly. Androgenic changes in the form of facial acne disappeared completely, while nonfacial acne subsided only slightly. No improvement in relation to pathologic hair growth was found, which might have been caused by the short period of the use of Vitex agnus castus preparation. A decrease of prolactin concentration determined under normal conditions mainly in women with hyperserotoninemia was observed. However, there was no significant decrease of prolactin concentrations in women with cystoid ovaries syndrome. A decrease of androgens concentrations and free testosterone as well as protein carriers indices, and an increase of estradiol and proteins binding sexual hormones concentrations were observed.

1. Indications for application of Vitex agnus castus preparation:

- functional hyperprolactinemia with hyperserotoninemia,

- premenstrual tension syndrome,

- insufficiency of the second phase of menstrual cycle,

- androgenization,

- menstrual cycle-induced migraines,

- hypertension.

2. Contraindications none.

3. Side effects: nausea and headache in 6% of the subjects in the first week of use

4. Directions:

- orally, depending on serotonin concentrations, from 0.005 up to 0.015 mg/kg/24 h of iridoid compounds, recalculated into aucubin.

Signed:

Professor Stanislaw Stanosz, Head

Laboratory of Menopause and Andropause of Pomeranian Medical Academy

Szczecin, Poland

September 1997

(Note: tables omitted in this web version)