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)