CLINICAL
STUDIES
1. Materials and methods
The experimental data from Tribestanol extract administration
have been clinically confirmed so far by three groups
of researchers: by the Higher Military Medical Institute
under the guidance of Prof. I. Viktorov, Corresponding
Member of the Bulgarian Academy of Sciences; by the Medical
University of Sofia; State University Hospital of Endocrinology,
Gerontology and Geriatry, under the guidance of Prof.
E. Bozadzhieva, and by the National Institute of Obstetrics
and Gynecology - under the guidance of Prof. M. Protich.
The studies were carried on 212 male individuals, aged
between 14 and 60 years. The therapeutic properties of
Tribestanol were studied in patients with partial or complete
impotence. Both the tolerance and the adverse effects
of the product were studied. The studies were carried
out by the method of simple blind experiment, using placebo.
In nozological terms, the studies covered various types
of male impotence: idiopathic oligoasthenozoospermia -
39 patients, resection of the left internal testicular
vein in varicocele, with subsequent oligoasthenozoospermia
- 50 patients; inflammatory process of the prostate with
oligo- and azoospermia - 53 patients, primary and secondary
male hypogonadism - 20 patients, impotentia coeundi -
50 patients. The product was individually administered
to all patients who had not received hormonal agents for
at least one month prior to the treatment.
The duration of the treatment depended on acuteness of
the disease - 30 - 60 days on the average (Bozadzhieva
et al., and Protich et al.) and 90 days (Victorov et
al.). the mean daily dose was 3 - 6 servings of 0.250g.
(.250g equiv. 1 capsule=1 serve) Some of the patients
were favorably affected by 3 servings daily (Protich
et al.), whereas the other research teams administered
6 (3 x 2). The andrological state was used as the basis
for the adequate evaluation of the reproductivity of
the patients by all three teams. The basic parameters
of sperm were observed, i.e. volume and pH of the ejaculate,
concentration of spermatozoa (number/1ml), percentage
of motile spermatozoa, mean rate of population motility
and percentage of pathological forms of the spermatozoa.
Detailed case history on the sexual behavior of the
patients was recorded prior to and after the therapeutic
Tribestanal extract course. The effect of the product
on hair growth was observed in some patients. One of
the teams (Bozadzhieva et al.) also observed the changes
in the serum levels of gonadotropins, progesterone,
testosterone, estradiol and cholesterol. The other team
(Victorov et al.) followed up the changes in testosterone
serum levels in the Tribestanol extract treated patients.
The hormonal levels were radioimmunologically determined
using kits and reagents provided by the French-Italian-Belgian
Association CEA-IRE-SORIN. The results from these studies
were statistically assessed by variation analysis.
2. Results
Significant changes in spermatozoon
motility were found after Tribestanol extract intake
for 60 days (with a daily dose of 3 servings) by males
with idiopathic oligoasthenozoospermia. The number of
spermatozoa with normal motility, as well as the mean
motility rate, were increased.
The percentage of the motile spermatozoa was 29, on the
average, prior to the treatment and reached up to 36.66
after the treatment (p < 0.005). The mean motility
rate of spermatozoa prior to the treatment was 1.95 mm/sec,
after the treatment - 3.63 respectively (p < 0.001).
No changes were observed in the ejaculate volume. In both
cases (before and after treatment) the ejaculate volume
was within the limits of the norm, about 4 ml on the average.
The number of spermatozoa in the treated patients was
higher by 3 ml/ml ejaculate on the average. In some cases,
normalization of the spermogram occurred during repeated
treatment with a daily dose of 6 servings. In these cases,
the improvement of the spermogram (normalization of the
increased viscosity, increased ejaculate volume, increased
concentration and accelerated motility of the spermatozoa)
was accompanied be elevation of the serum levels of the
lutenizing hormone and testosterone, and reduction of
the estradiol level.
The patients with idiopathic azoospermia after 90-day
treatment with a daily dose of 1.5g are of particular
interest. The results were significant in three of all
7 patients treated. No spermatozoa were detected prior
to the treatment. After the treatment, 3.5-million/1ml
ejaculate were recorded in one of the patients, 15 million/ml
in the second and 28 million/ml in the third. The percentage
of motile spermatozoa in the first patient was 10, and
in the other two - between 25 and 30. The motility rate
of the spermatozoa was about 5 mm/sec. In two of the patients,
30 - 40 spermatozoa per field were observed, and in the
third - about 5 spermatozoa per field after the treatment,
compared with the absence of any prior to the treatment.
One of the patients failed to be affected by the product.
The studies on the patients from that nozological group
continued with the administration of maintenance dose.
The clinical comparison of the results from the treatment
with provirone of patients with idiopathic azoospermia
and after Tribestanol extract administration revealed
a favorable effect on three of the patients (out of 6),
unsuccessfully treated with provirone for a long period
of time. The results in the patients with varicocele and
oligoasthenozoospermia as regards the motility of the
spermatozoa were identical in the reports of all research
teams, regardless of the differences in the doses and
duration of the treatment. Protich et al. found an average
of 26.88% motile spermatozoa prior to the treatment and
after 60-day course with a dose of 1 serving, three times
daily - 39% (p < 0.02) with a mean motility rate of
spermatozoa 2.06 mm/sec prior to the treatment and 4.44
mm/sec post treatment respectively. No change in the ejaculate
volume was found. The other team (Victorov at al.) observed
more pronounced changes in the ejaculate volume after
90-day treatment with a daily dose of 1.5 g (4.5 ml compared
to 1 - 2 ml prior to the treatment, i.e. an average of
1.55 ml of ejaculate volume in all patients). The number
of spermatozoa in 1 ml reached the values in 100% of the
patients treated. The mean percentage of motile spermatozoa
prior to the treatment was 2.06 and was increased to 33.09
(Tables 1,2,3).
Table 1.
Results of Tribestanol extract treatment (1 serving
3 times daily for 60 days) of 38 males with idiopathic
oligoasthenozoospermia (represented in mean values)
| Indices |
Before treatment |
After treatment |
| a. Concentration of spermatozoa, million/ml |
22.97 |
26.66 |
| b. Motility, % |
29.00 |
35.66* |
| c. Motility rate, mm/sec |
1.95 |
3.76* |
Table 2.
Results of Tribestanol extract treatment (1 serving
3 times daily for 60 days) of 16 males after varicocele
operation with existing oligoasthenozoospermia
| Indices |
Before treatment |
After treatment |
| a. Concentration of spermatozoa, million/ml |
21.31 |
26.75 |
| b. Motility, % |
11.53 |
39.06* |
| c. Motility rate, mm/sec |
2.00 |
4.44* |
Table 3.
Results of Tribestanol extract treatment (2 servings
3 times daily for 90 days) of 36 males after varicocele
operation and existing oligoasthenozoospermia
| Indices |
Before treatment |
After treatment |
| a. Concentration of spermatozoa, million/ml |
40.60 |
76.00* |
| b. Motility, % |
3.05 |
33.09* |
| c. Motility rate, mm/sec |
2.06 |
4.44* |
*The data are statistically
significant.
The results of Tribestanol extract administration to
patients with unilateral or bilateral hypothrophy of
the testes and azoospermia deserve particular attention.
The patients complained of a sense of heaviness and
distention, as well as of a slight pain in the testes
between 40th and 60th day after the start of the treatment
with a daily dose of 6 tablets. Upon examination, a
slight pain in the testes occurred upon palpation, as
well as a slight swelling, with no other evidence of
pathological changes. Improvement both as regards the
ejaculate volume and the concentration and motility
of the spermatozoa was observed towards the end of the
treatment. The testosterone
serum level was elevated from 1.75 mg/ml to 3.75 mg/ml.
The pain in the testicular region upon palpation
abated within 2 - 3 months after treatment. Tribestanol
extract administration to patients with chronic inflammatory
process of the prostate and disorders in the spermogram
led to insignificant changes in these cases when the
inflammatory process had been treated previously.
No changes were found in patients with chronic inflammation
of the prostate (not treated previously). Out of 14 patients
with reduced libido and absence of pathology in the male
genital organs, treated for 30-days (daily dose - 2 servings,
three times), 12 manifested obvious improvement of the
libido, one patient - a slight improvement (after a 60-day
treatment cycle) and no effect was observed in another
one. Out of a total of 36 patients with chronic prostatitis
and reduced libido, 15 were very favorably affected by
the end of the treatment cycle (a total dose of 90 - 100
g), 12 - favorably, and in 9 of the cases with a duration
of the inflammatory process over 5 years, no effect occurred.
The patients with hypotrophy of the testes and idiopathic
azoospermia had no complaints as regards the libido, but
in the course of the treatment aimed at improving the
spermogram an apparent libido enhancement was recorded.
Out of 9 patients treated for one of the gravest forms
of male hypogonadism (Klinefelter's syndrome, due to chromosomal
anomalies), the libido was enhanced in three of the patients,
erection was reported in two and sexual intercourse and
masturbation were reported in another two patients. Elevated
levels of lutenizing hormone after the treatment were
found in these patients. The levels of the remaining sexual
hormones and cholesterol were reduced. Two of the patients
with secondary insufficiency of sexual glands (Noonan's
syndrome) attained improvement of the libido and erections
during the treatment. The self-confidence was improved
in one of them, and in the second - hair grew in the male
genital region.
The results of the treatment of three patients with cryptorchidism
(one of them with uncorrected malformation) comprised
improvement of the libido and often masturbation. The
duration of the erection was prolonged in one patient
from that group, aged 37. The spermogram of the same patient
was significantly better compared to the initial status
one month after treatment, i.e. on day 90 ftehr the beginning.
One patient with secondary hypogonadism reported hair
growing in the axillary and genital region, parallel with
enhanced libido and frequent masturbation.
The serum testosterone levels were elevated in 20 patients
from various nozological groups, the initial and final
values being within the norm. In seven patients with
testosterone serum level below the lower limit of the
norm, the physiological levels were reached after the
treatment.
3. Tolerance and side effects
All clinicians engaged in the studies reported a very
good tolerance and no drug-related side effects. The
clinical laboratory data on Tribestanol extract treated
males showed no deviations in the blood count, ESR,
flocculation tests and urine.
4. Discussion of the results
The clinical studies of all three research teams on a
total of 212 patients (males with disorders in the sexual
function) confirmed the experimental data on a pronounced
stimulating effect of the new Bulgarian phytochemical
preparation (Tribestanol) on the sexual functions. It
restored and improved the libido in all forms of impotentia
coeundi after the administration of a mean daily dose
of 1.5 g for 30 - 40 days. This suggests that not only
the diminished libido was stimulated, but also that a
therapeutic effect on both primary and secondary male
hypogonadism was present. The assumption that the product
was a favorable effect on spermatozoa motility after 60-day
administration corresponds to the experimental data, according
to which it stimulates both the mitosis and maturation
of the germinal cells.
It is well known that at least 80 days elapse from the
time of the division of the spermatogonia till the formation
of a mature spermatozoon in males, hence the concentrations
of the spermatozoa in the semen are different within that
period. The team that used a therapeutic course of 90
days observed very good results in terms of both the motility
and the concentration of the spermatozoa in the ejaculate.
The studies of ejaculate from patients receiving the product
for 60 days proved its apparent effect on the motility
of the spermatozoa and an insignificant effect on their
concentration on the basis of identical initial spermatozoal
levels, as well as the presence of identity in the nozological
groups prior to the treatment. This confirms the fact
that the minimum therapeutic cycle should last at least
as long as one complete germinal cycle (i.e. 80 - 90 days
in males). Both idiopathic oligo- and azoospermia are
diseases with so far undistinguished etiology. The serum
levels of sex steroids are not changed in the majority
of the patients with such deviations and good therapeutic
levels of the product are observed. No data are available
from testes biopsy that can throw light as to which of
the phases of this complicated process of spermatogenesis
has been affected pathologically and hence favorably affected
by the product. Kumanov at al. advanced the hypothesis
of diminished central effect of the product, associated
with its mechanism of action, based on the elevated level
of the lutenizing hormone. On the other hand, they admitted
the existence of a peripheral effect, which could be responsible
for the effect of the product on hair growth.
The reduced level of serum cholesterol under the effect
of the product provided grounds for the same authors
to assume that it also had an effect of cholesterol
metabolism. The mechanism of action of Tribestanol has
not been elucidated so far. It can be concluded, on
the basis of the clinical studies carried out so far,
that it has a very good stimulating and therapeutic
effect in all forms of impotentia coeundi, as well as
a very good therapeutic effect in patients with oligoasthenospermia.
The product has a very good tolerance and no undesired
side effects.
REFERENCES:
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Report, 1980
2. Viktorov, I., D. Kaloyanov, Al. Lilov,
L. Zlatanova, V. Kasabov. Clinical investigation on Tribestan
in males with disorders
in the sexual function MBI, 1982 (in print)
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Years Chemical
Pharmaceutical Research Institute' Sofia, March 22-23,
1983
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in serum of healthy subjects
(Company documentation).
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Scientific-technical Report, 1981
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14. Krueger, P.M., C.D. Hodgen, K.I.
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