CLINICAL TESTING OF TRIBESTAN

Kumanov F., E. Bozadjieva, M. Platonova, V. Ankov,
Institute of Endocrinology, Gerontology, Geriatrics and HMMI

Director: E. Bozadjieva

INTRODUCTION

The present day pharmaceutical of choice for the treatment of male hypogonadism is testosterone with the exception of the cases with reduced gonadotrophic secretion when attaining fertility is the aim. Then a combination of human chronic gonadotropin (hCG) and human menopausal gonadotropin (hMG) is used. Good results with clomid have recently been reported. The action of the substitutive therapy is but temporary, sometimes inefficient and often it aggravates the hypofunction of hypothalamic-hypophyseal-gonadal axis. Those disadvantages have a to great extent been eliminated in the new Bulgarian product Tribestan. The initial substance is of plant origin. It is obtained from the above-the-ground part of the plant Tribulus terrestris and contains steroid saponins of furostanol type with predominating quantity of protodioscine. It has experimentally been proved that Tribestan stimulates spermatogenesis and increases the number of Sertoli's cells. The diameter of seminiferous tubules is not widened under its effect, neither quantitative changes in the interstitial cells of testis have in vitro and in vitro been observed. The product is supposed to have androgenetic-like factors, which exert an effect upon the germinal epithelium. The product has been proved to enhance the libido.

The objective of the study was the clinical trial of the product Tribestan on patients with primary and secondary hypogonadism, to throw light upon its mechanism of action, to specify the time and dose it occurs and to evaluate its tolerance.

MATERIAL AND METHODS

Tribestan was administered in a dose of 2 tablets, three times daily after meals to 20 selected males with primary and secondary hypogonadism, aged from 14 to 43 years. The duration of the treatment was determined by the severity of the disease. The possible ejaculation served as a criterion. The patients with lasting aspermia were treated for two months and the rest - one month. Immediately before and after the course with Tribestan, detailed anamnestic data about their sexual behavior were collected according to a special form. Clinically the effect of the product was evaluated by the growth of hair. Those who could discharge ejaculate spermograms were made prior to and post treatment as well as one month after its discontinuation. Immediately prior to the beginning and after the discontinuation of the therapeutic course, blood was withdrawn in the morning between 7:30 and 8:30 before meal to determine the serum levels of gonadotrophic hormones, progesterone, testosterone and estradiol. The fluctuations of serum cholesterol were followed up under the same conditions. The levels of the hormones were radioimmunoassayed by a trade reagent kits of the French-Italian-Belgian Association CEA-IRE-Sorin. The results from those studies were processed by variation analysis.

All patients were asked about adverse effects (allergy, dyseptic complaints, insomnia, tremor, paresthesia, etc.), Hemoglobin, erythrocyte count, leukocytes with differential count, platelets, total protein, liver function tests, urea and urine were tested prior to and post treatment.
Placebo was given to 6 of Tribestan-treated patients according to the method of simple blind test, four out of them had the syndrome of Klinefelter.

No one of the patients studied had used hormonal drugs during the study and at least one month after it.

RESULTS

The following groups were formed on the base of the clinical data, the results from the study of sex chromatin and caryo-gram: 9 with Klinefelter's syndrome, two with the syndrome of Noonan, two with varicocele and with azoospermia, one with idiopathic oligoasthenozoospermia, two with bilateral cryptorchidism, one with Kallmann's syndrome, one with secondary hypogonadism, one with pubertas tarda and one with pigmental degeneration of retine and with liver steatosis.
Klinefelter's syndrome is one of the most frequent forms of hypogonadism. It is due to chromosomopathy with increased number of X-chromosomes (7). The grave effecting of germinal epithelium leads to azoospermia, more rarely to aspermia. The gonadotrophic hormones, FSH in particular, are increased. The endocrine function of testis is affected to a light extend (4). We treated 9 patients with that disease. The sexual desire was improved in three, erections occurred in one, two had more frequent coiutuses, masturbation resp. Azoo- and aspermias persisted.

The fluctuations in the level of hormones and of cholesterol were not statistically significant under Tribestan effect. Only LH was increased after the treatment:

From x=19.99 to x=22.0. The rest of the hormones and cholesterol were decreased: FSH from x=48.19 to x=42.98, progesterone from x=2.85 to x=1.9, testosterone from x=8.02 to x=5.0, estradiol from x=0.061 to x=0.057 and cholesterol from x=203.67 to x=193.67. Closest to the statistical significance were the changes in the serum level of progesterone and testosterone. Those results were juxtaposed to the changes obtained in the level of hormones after the intake of placebo in four of the patients with Klinefelter's syndrome. No statistically significant difference was established. Most likely that was due to the small number of patients, administered placebo.

The following group Tribestan-treated covered the other 11 patients.

Noonan's syndrome is a very rare disease and is characterized by various dysplastic signs and with normal karyotype (7). The majority of the affected males were with damaged gonadal function. We had the chance to follow-up two patients with that syndrome and established a high insufficiency of the sexual glands. Tribestan treatment improved the libido and erection in both of them. Self-confidence was also improved in one of them and in the other pubis was covered with fine fluffy hair. Aspermia persisted in both of them. No changes occurred in the patients with varicocele and sterility. The concept idiopathic oligoasthenozoospermia implies inferior sperm due to causes undistinguished by the modern methods and means of investigation. A normal hormonal status has always been established (4). One patient with that malady was treated. The volume of ejaculum was increased, the increased viscosity was normalized, spermatozoa motility accelerated but their number was not changed under the effect of the therapy. The pathological forms decreased with 10%. Table 1 illustrates that the improvement of spermogram of that patient was accompanied by elevated serum level of LH and testosterone and decrease of estradiol. Because of the results, hopes were raised and the patient underwent a second one-month course, after which the basic indices of spermogram were normalized. A deterioration however in the qualities of the sperm was diagnosed one month after the discontinuation of the treatment.
Tribestan was given to two patients with bilateral cryptorchidism. That malformation was rather late corrected in one of them but in the other - 14 years old P.I.M. reported an improvement of libido and more frequent masturbation. Interesting results were obtained in the other patient from that group - 37 years old N.Z.O. With initial data about intact sexual activity, he reported a prolongation of erection time, spontaneous nocturnal erections and more frequent coituses during and after the treatment. Immediately after the course with Tribestan, his spermogram showed a deterioration - the initial high oligoasthenozoospermia was transformed into azoospermia. One month later, all indices (without spermatozoa velocity) were sharply improved versus the initial data prior to treatment. Kallmann's syndrome is a genetic malady, characterized by the combination of anosmia and hyposmia with incapability of hypothalamus to synthesize gonadotropin release hormone (LHRN)(7). The sense of fear and tearfulness disappeared in that patient under Tribestan effect and hair growth of the body intensified but azoospermia persisted.

The patient with secondary hypogonadism reported enhanced libido and frequent masturbation after the treatment. Pubis and axillary hair growth was slightly improved in him. Motility rate of spermatozoa was increased. The percentage of pathological forms grew.
The patient with pubertas tarda showed no signs of improvement,
That patient was initially supposed to have prolactinoma but later that diagnosis was rejected and the new diagnosis was pigmental degeneration of retina and liver steatosis. The product manifested a pronounced positive effect on his sexual behavior, as well as on the number of spermatozoa and their motility rate.

Reduction of FSH was observed in that combined group of 11 patients after the treatment, namely from x=16.57 to x=16.31, of LH from x=11.35 to x=9.81, of testosterone from x=11.32 to x=8.25 and of cholesterol from x=216.55 to x=165.0. Progesterone and estradiol were increased from x=2.70 to x=3.81 and from x=0.094 to x=0.116 respectively. Statistically significant was only the reduction of cholesterol - t=2.55 (p=0.02). The past history, the clinic and routine laboratory studies established no adverse effects of Tribestan.

DISCUSSION

The number of the patients is too small to allow precise conclusions about the most pronounced Tribestan effect in the groups. The treatment was not long enough so as to compare the product with the already known agents for treatment of male hypogonadism. Prominent researchers in that field reported lately that under the combined hCG (hMG therapy, positive effects as hair growth, improved libido and prolonged erections occurred between 8 and 12 weeks after the initiation of the treatment (3). The same symptoms of improvement were observed earlier under the effect of the Bulgarian product - before week 8. That juxtaposition inspired reasonable hopes.
The treatment with the so far known agents established that the stronger the spermatogenesis is affected - the poorer the chances for successful treatment (2). Tribetsan results showed no deviations from that rule.

Testosterone reduction established by us, although statistically insignificant, corresponds to the experimental data according to which Tribestan has no effect on the interstitial cells of the testes.

Improved libido and more frequent and longer erections were observed in some of the patents on the background of reduced serum level of testosterone. Particularly indicative in that aspect were the cases of D.I.Zh. and N.Z.O. Not long ago, Vogt et al. (IO) based on their observations on 15 males with various forms of hypogonadism arrived at the conclusions that sexual behavior of males depended directly on testosterone and that the limit of its serum level, under which disorder in sexual activity occurred was inevitable, was between 2.0 and 4.5 ng/ml. Our studies did not support that fact. As could be seen from Figure I, there was no essential difference between the concentrations of serum testosterone of the patients who had no complaints in that respect, testosterone serum level was between 0.75 and 5.9 ng/ml, 2.60 and 20.44 nmol/l resp. , and in the rest of the patients who had no sexual disturbances - from under 0.20 to 6.3 ng/ml, under 0.69 - 21.8 nmol/l resp. The problem of the connection between androgens and sexual behavior in males leads to heated debates. There has been a conviction since antiquity that castration leads to reduced libido and potency (3). Lately, it has been claimed that it is completely dependent on sexual steroids in lower mammals, to a lesser degree in primates and that this dependence in the lowest in humans (4). According to some other authors, testosterone has no aphrodisiac action (6). Some are in the opinion that sexual behavior depends more on dehydrotestosterone (DHT)(9). A view is also supported that the effect of androgens in that aspect is mediated centrally by serotonin and by dopamine (5). The psychological and hormonal effects are combined but the mechanism of action is still unknown (4).

Our observations provided grounds to assume that Tribestan acts centrally. Support of that assumption we find also in the LH elevation in the patients with Klinefelter's syndrome. Tribestan via its metabolization in the body into androgen-like products or via stimulation of the psychological transformation of testosterone in DHT, in androstendiol or in estrogens, exerts an effect on hypothalamus and very likely on even higher cerebral structures. Its peripheral action cannot be excluded which suggested by the improved hair growth. In that respect the increase of DHT is significant. The reduction of cholesterol established suggests that the product interferes in its metabolism as well.

CONCLUSIONS

1. The dose administered exerts an initial action, which is best manifested in the lighter cases. What impresses is that a longer treatment is needed (at least three months).
2. The discontinuation of the treatment should not be abrupt. A maintenance dose is necessary to be established.
3. Tribestan has no adverse effects.
4. The effect of the product on DHT should be followed up and its action of cholesterol metabolism should more profoundly be studied.

REFERENCES:

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