4. CLINICAL STUDIES IN FEMALES WITH ENDOCRINE INFERTILITY OR POSTMENOPAUSAL SYNDROME

A team from the T. Kirkova Obstetric-Gynecological Hospital in Sofia, Bulgaria, headed by P. Tabakova, studied the therapeutic effect of Tribestan on the endocrine function in females. The first clinical experiments were performed on patients with dysovular syndrome and infertility, and later broadened on patients with pre- and perimenopausal syndrome. The females with postcastration menopause were included in a separate group.

Administration schedules:

Clinical patient group.

4.1. Parameters observed and evaluated

Clinical patient group A:

The final treatment result is classified in three types:

Normalization of ovulation with a subsequent pregnancy; normalization of ovulation without pregnancy; no effect. The following indices were evaluated: subjective changes in terms of the general conditions and libido; onset and duration of menstruation; basal temperature; changes in the hormonal vaginal cyto-smears; level of pregnadiol, 17-KS and 17-OH-KC in the urine; histological changes in the endometrium. Echographic and folliculometry were performed; radioimmunological control of gonadotrophic and sex steroids; hysterosalpingography and laparoscopy for evaluation of the fallopian tubes and the effect of the product on them.

Clinical patient group B:

The treatment results were classified in conformity with the clinical picture: abatement of menopausal complaints; reduction of these complaints; no effect. The following parameters and symptoms were recorded: neuro-vegetative and neuro-psychic complaints; intensity and frequency of hot flashes, depression and hyperexcitability, apathy, etc.; changes in the cardiovascular system - changes in pulse and extrasystoles, etc.; urinary disorders, pruritus of the outer genitalia, hormonal cyto-smears; blood count and blood sugar profile. Ultrasound diagnostics and radioimmunological control of gonadotrophic and steroid control were performed. The changes in the libido were evaluated.

4.2. Results and discussion

Group A:

Fifteen patients were treated in compliance with Schedule 1. No significant changes in the parameters characterizing the existence of ovulation were recorded in any of them. Furthermore, some undesired side effects were observed, such as longer menstrual cycle, excessive libido, general excitation and insomnia associated with it, and drastic decrease of libido and general weakness in the cases of abrupt withdrawal of the drug at the end of the 3rd month or reduction of the dose by only 50%. This necessitated the use of schedule 2 in the other 36 patients. The data are illustrated further in the paper in figures and tables. The distribution of the patients according to age is presented in Fig. 1. The predominating part of them are in the 20 - 30 age group and only two were over the age of 36. Nineteen of the patients had primary hormonal infertility and 18 - secondary; i.e. both groups covered and almost identical number of patients (Fig. 2). The distribution of the patients as regards their previous treatment is presented in Fig. 3. It is evident that 36% of them have not been treated prior to the study, almost equal is the percentage of the patients with previous hormonal treatment or surgical correction of ovaries - 20 - 30%, and the group of women subjected to combined hormonal-surgical therapy is least. Table 1 presents the lower incidence (33.3%) of the cases with unsatisfactory Tribestan treatment, compared with clostilbegite (52.4%) or fertodur (76%). No doubt, best results were obtained with stimovul, which normalized ovulation with a subsequent pregnancy in 39%; normalized ovulation with no subsequent pregnancy - 35.5% and without effect - in 26%. On the basis of these results, it is clear that Tribestan possesses a considerably more moderate effect: 24 of all 36 treated female patients turned out to be with normal ovulation, but pregnancy was diagnosed in only 2 of them and no effect was recorded in 12 females. Twenty women were simultaneously treated with Tribestan and ovulation stimulant. The effect of the combined treatment was better that that of the individual administration of the drugs. The effect was probably complex: the hormonal stimulation of ovulation was combined with the enhanced libido and improved general and psychosomatic status of the childless couple, especially if our recommendation was followed and the wife also received Tribestan. No adverse effects were reported after intermittent administration of Tribestan.

Group B:

The distribution of the female patients into groups according to age is presented in Table 1. Only 4 of them are younger than 40 years and 2 are above 60 years. The main part (80%) of the treated women is aged between 40 and 55. Natural menopause was registered in 26 patients and the other 24 (48%) were with postoperative castration climacterium (Table 2). The duration of menopausal syndrome is presented in Table 3. It can be seen that the menopause occurred one year prior to the start of the Tribestan treatment in most of the female patients, mainly female patients with post-surgical menopause.

EFFECTS OF TRIBESTAN IN MENOPAUSE

Some of the basic symptoms predominated in the clinical picture of menopause in the group studied, presented in Tables 4 and 5.

The neurovegetative symptoms were rather common in the treated women. Hot flashes were recorded in 100% of them, perspiration - in 78%, insomnia - in 82%, groundless hyperexcitation - in 44%. The sense of heaviness in the cardiac region predominated among the cardiovascular changes - 60%, but changes in the arterial pressure and ECG were observed in 16 women (22%). The libido remained unchanged in 2 women (compared to the preceding condition). Strong initial decrease to complete loss of desire for sexual contacts were reported in 56% of all female patients. It should be stressed that the intake of placebo tablets, prior to the treatment, by 46 out of a total of 50 women led to no favorable effect on any of the complaints (Table 6).

Complete or almost complete effect on all or on the majority of the symptoms was observed in 49 out of 50 female patients, according to symptoms selected in the classification (98%). Only in one woman Tribestan had no favorable effect on the menopausal syndrome and she was transferred to another treatment. Table 7 shows that the treatment course required the intake of less that 110 to 180 tablets for attaining a favorable effect in 50% of the treated women. In 10% of the women, that dose was higher - 190 - 220 tablets. The mean effective doses are presented in Table 8, suggesting that the majority of the female patients took over 100 tablets per therapeutic course. The effect obtained is kept by maintenance dose of 2 - 3 tablets daily in 85% of the women (Table 9).

High level of estrogens was recorded only in 14% during the dynamic cytological follow up of the vaginal cyto-smears, whereas it was low or very low in 44% (Table 10).

The radioimmunological studies are presented in Tables 11 and 12.

The variation analysis reveals that the mean values and the confidence interval are within the norm for adults. The comparison of these data prior to and after treatment shows that the gonadotrophic hormones tend to a reduction compared to the initial values, whereas no such tendency was observed in the ovarial hormones, on the contrary, even an insignificant increase was observed, in E2 in particular. These data could be responsible for the favorable effect on the menopausal complaints, as well as on the considerable enhancement of the libido in 2/3 of the female patients treated. In this case the effect of Tribestan is identical, but in some cases it is better than that of ambosex, a drug containing estrogens and testosterone, at the same time its adverse effects - virilization and tendency to body weight gain - were avoided with Tribestan.

4.3. Side effect in treatment with Tribestan

No faints spells, vomiting, allergic reactions, intolerance, etc. have been observed. The product is well tolerated. It should be pointed out that after the attaining of the desired effect, the abrupt reduction of the effective dose to the maintenance dose leads to a sudden and complete triggering of almost the whole range of symptoms of the menopausal syndrome. This is why, the transition from the effective to the maintenance dose should be very gradual and within a longer time period.

CONCLUSION

Our long-term experience with Tribestan administration in the treatment of mainly female infertility, but also quite often in males, gives us the confidence to recommend it in the cases of disordered formation of gametes, disturbed or absent libido, and other disorders leading to non-ovular menstrual cycle, dyskinetic changes of the fallopian tubes and qualitative changes in male sperm.

The combination of Tribestan with appropriate hormonal drugs leads to the potentiation of its positive effect. The opinion of the research team, based on the experience during the last several years with more than 150 females with natural and postoperative menopause, is that Tribestan can successfully be used for the treatment of menopausal syndrome in women.