CLINICAL STUDY OF TRIBESTAN IN FEMALES WITH ENDOCRINE STERILITY

P. TABAKOVA, M. DIMITROV, K. OGNYANOV, N. POPVASSILEV
FIRST OBSTETRIC-GYNECOLOGICAL HOSPITAL "T. KIRKOVA", SOFIA
HEAD PHYSICIAN DR. M. DIMITROV

Infertility both in males and females has shown a definite tendency to become more frequent and the successful struggle against it plays a positive role in the reproduction of the population. The battery of drugs for the treatment of sterility in females and males is rather restricted and very often, with quite modest and unsatisfactory results. That is why, the search for new drugs with similar biological activity and their clinical trial are among the fundamental problems of both pharmaceutical industry and of the clinics for preventing female and male sterility.

The present study reported the results from the clinical administration of the non-hormonal product TRIBESTAN, manufactured by Pharmachim, in women with endocrine sterility.

MATERIALS AND METHODS
PRODUCTS ON TRIAL.

Tribestan (Pharmachim), filmts of 250 mg contains natural product obtained from the above-the-ground part of the plant Tribulus terrestris L., with predominant content of steroid saponins of furostanol type with prevailing quantity of protodioscine.

SCHEDULE OF ADMINISTRATION.

1. Recommended schedule by the manufacturer (identical with that for the treatment of males) - 1-2 tablets, three times daily, for a total of 2-3 months.
2. Our schedule: 3 x 1 up to 3 x 2 tablets daily, from 5th to 14th or from 1st up to 12th day from the beginning of the menstrual cycle, a total of 2-3 months.
3. After the follow up of certain parameters for evaluating of the integral effect of Tribestan alone, we began a combined therapy - Tribestan plus hormonal drugs for inducing of ovulation:

a) Tribestan according to schedule 2 + Stimovul (Organon) - 1-2 tablets, from 5th up to 14th day of cycle; b) Tribestan - schedule 2 + Clomifen citrate (various trade drugs) - 1-2 tablets from 5th up to 9th day of the cycle, a total of 3 months.

Clinical groups.

The present study covered a total of 51 females with diagnosis "Primary and secondary endocrine sterility," treated at the First Obstetric-Gynecological Hospital "T-Kirkova" within the period 1983-1984. Fifteen out of them were treated according to schedule I and the other 36 - according to schedule 2, and after the three-month observation period, a combined therapy according to schedule 3 was administered to 20 out of them.

Other control groups with hormonal sterility and treated as follows were selected for comparison: with Stimovul (Holland) - 62 women; with Clostilbegit (Hungary) - 21 and Fertodur (Germany) - 29, so that the total number of females in that study reached 163.

Observation parameters.

The final result from the treatment was classified in three forms: a) normalization of ovulation with a following pregnancy; b) normalization of ovulation without pregnancy and c) no effect. The adverse effects that occurred were also recorded - subjective and objective ones. The classification of the results was possible on the base of the periodic follow-up of numerous subjective and objective clinical and some paraclinical parameters - changes in the general condition, libido sexualis, menstruation and its duration, basal temperature, hormonal vaginal cytosmears, pregnadiol and 17-KS and 17-OH-KS in urine, histological specimen from endometrium, dynamic changes in ovaries ultrasonographically followed up, radioimmune control of some of gonadotrophic and steroid production, hysterosalpinographies, laparoscopies for specification of the status of the uterine tubes and their elimination (as far as possible) as the reason for sterility.

RESULTS AND DISCUSSION

Fifteen patients were treated according to schedule I. Substantial positive changes in the parameters evaluating the presence of ovulation were observed in none of them. Furthermore, some undesirable effects were reported as prolongation of menstrual cycle with 10-12 days, intensified and prolonged bleeding, exceptionally strong libido sexualis and general excitation and insomnia associated with it, and in abrupt discontinuation of the drug at the end of the third month or even with only reduction of the dose - sharp decrease of libido sexualis and a general lassitude was reported in 50%. That necessitated the use of schedule 2 in the rest of 36 patients, the data being illustrated in the following figures and tablets.

The distribution of the females, Tribestan-treated is given in Figure 1. It can be seen that the predominating number (75%) were in the age group of 20-30 years and only two females were over 36 years. With primary hormonal sterility were 19 females and with secondary - 17, i.e. almost equal number. The comparison by age groups, however, showed (Figure 2) that primary sterility predominated in the younger age and over 30 years - the secondary. The distribution of the patients by the character of the preceding treatment is illustrated in Figure 3. What impresses is that about 36% were not previously treated; the number of those with preceding hormonal treatment or surgical correction of ovaries is almost identical (20-30%) and the group with combined surgical-hormonal treatment is the smallest.

The precise evaluation of the clinical effect of a new product requires the inclusion of placebo group. Because of technical problems that group was substituted for another three control groups, covering a sufficient number of patients, treated with Stimovul, Clostilbegit and Fertodur because of hormonal sterility - Table I. Regardless of the possible differences in the mechanism of action, it was important for us to evaluate the effect of the drugs compared according to the classification, indicated in "Materials and Methods". As evident from Table I, our values of unsuccessful treatment with Tribestan were lower (33.3%) as compared with Clostilbegit (52.4%) or Fertodur (76%). No doubt, best were the results attained by Stimovul - normalization of ovulation with a following pregnancy - in 39%; normalized ovulation without pregnancy - 35.5% and no effect - in 26%. On the background of that picture with an excellent inductor of ovulation, Tribestan had more modest effect, which is easy to explain with consideration given to its more general effect as non-hormonal product. Out of a total of 36 patients treated with Tribestan, 24 women were with normalized ovulation (67.7%) but only in two of them - pregnancy followed; 11 were with normalized ovulation, regular and rhythmic menstrual cycle but without pregnancy so far; and 11 were with partially corrected second phase of the cycle.

In 20 patients, after the three-month period of observation (fixed in plan-program of the study), inductor of ovulation (clomifen citrate in 12 and Stimovul - in 8 females) were included concomitantly with Tribestan. Regardless of the small number of case observed, the preliminary results from that group showed that the effect of the combined treatment was better that that of their individual administration. Most likely, the reason was the complex effect - hormonal stimulation of the ovulation was combined with the enhanced libido and improved general psycho-emotional status of the sterile couple, particularly when bearing in mind that we had recommended and Tribestan treated husband as well.

Adverse effects during the intermittent administration of Tribestan were not observed and those during the treatment according to schedule I are indicated in the respective place (see page 3).

Apart from the planned range of the present study, we administered the product to another 12 women in pre- and early climacteric period according to schedule I, from 30 to 60 days of the total duration of the treatment. The subjective complaints were favorably affected, namely: hot flashes (reduced in intensity, duration and number), general anxiety and excitability, improved libido sexualis; tension in mammary glands abated.

CONCLUSION

The non-hormonal Bulgarian product Tribestan has its place in the treatment of hormonal sterility in the women with preserved cyclic recurrence of the menstrual cycle and not grave deviations in the ovulatory mechanism.

Tribestan enhances libido sexualis and the females, improves the psycho-emotional status.

In case of hormonal sterility, Tribestan has a better manifested effect with intermittent administration in a dose of 3-6 tablets daily, from 5th to 14th or from 1st to 12th day after the beginning of the menstrual cycle.

The necessity of individual approach to Tribestan treatment has its grounds, depending on the duration of menstrual cycle, degree of disorder of ovulatory mechanism, and very likely of the various degree of metabolic competence of the patients.
The combined administration of hormonal stimulants of ovulation and Tribestan is particularly useful for the effective treatment of hormonal sterility in females.

Figure 2. Age distribution of the patients treated with Tribestan

Figure 3. Distribution of patients treated with Tribestan depending on the preceding hormonal, surgical or combined treatment.