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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:
| Group A: |
Women with dysovular disturbances and infertility |
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- Schedule recommended by the manufacturer: 1 - 2 tablets,
3 times daily for 2 to 3 months.
- Authors' schedule: 1 tablet 3 times daily to 2 tablets
three times daily from the 5th to the 14th day of
menstrual cycle for a period of 2 - 3 months.
- After the follow up of certain parameters for assessment
of the comprehensive effect of Tribestan individually
administered, the group was subjected to combined
treatment with Tribestan and a hormonal drug stimulating
the ovulation:
- Tribestan in compliance with schedule 2 + stimovul
(organon) 1 - 2 tablets daily from the 5th to the 14th
day of the cycle for total of 3 months.
- Tribestan in compliance with schedule 2 +
clostilbegite (Hungary) 1 - 2 tablets daily from the
5th to the 9th day of the cycle for a total of 3
months.
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| Group B: |
Women with perimenstrual syndrome |
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- Tribestan - 2 tablets, three times daily for 20 days and
reduced dose of 1 tablet daily every 4 - 5 days, reaching
down to the maintenance dose of 1 tablet, twice daily for
a strictly individual period, depending on the effect
attained.
- Tribestan - 2 tablets, twice daily for 30 days with
subsequent reduction of the dose to 1 tablet every 4 - 5
days.
- Tribestan - 1 tablet, three times daily, without a
break, for a long-term period (up to 1 year).
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Clinical patient group.
| Group A: |
Fifty-one women with diagnosed primary and
secondary endocrine infertility, treated at the T. Kirkova
Obstetric and Gynecological Hospital in Sofia within the 1983
- 1984 period. Fifteen of them were treated in compliance with
Schedule 1, the rest - in compliance with Schedule 2. After a
three-month observation period, 20 of them underwent the
combined treatment in compliance with Schedule 3. Parallel
control studies were carried out on a similar group receiving
hormonal drugs: stimovul (organon) - 62 women; clostilbegite
(Hungary) - 21 women; fertodur (Schering) - 29 women. The
total number of the patients included in the study was 163. |
| Group B: |
Fifty women with diagnosed natural or
postcastration menopausal syndrome, treated within the 1986 -
1987 period. A pilot study on 12 patients was carried out as
early as 1984. A treatment was initiated with 2 placebo
tablets, three times daily, for a period of 20 - 30 days to 46
out of 50 women (92%), immediately after the final diagnosis
and depending on the stage of the clinical picture
characterizing the menopause. After the evaluation of the
effect of the placebo tablets, the treatment was continued
with Tribestan according to the above schedules. |
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.
Table 1. Comparative data on the effect of Tribestan, Stimovul,
Clostilbegite and Fertodur on females with endogenous
infertility
Groups according
to treatment mode |
Number
of patents |
Therapeutic results
|
Normalized ovulation
with pregnancy |
Normalized ovulation
without pregnancy |
No effect |
Adverse
effects |
| Treated with |
|
|
|
|
|
| Tribestan |
36 |
2 (5.6%)
|
22 (61.1%)
|
12 (33.3%)
|
None
|
| Stimovul |
62 |
24 (38.7%)
|
22 (35.5%)
|
16 (25.8%)
|
4 (6.6%)
|
| Clostilbegite |
21 |
4 (19.0%)
|
6 (28.6%)
|
11 (52.4%)
|
8 (38.1%)
|
| Fertodur |
29 |
2 (6.9%)
|
5 (17.2%)
|
22 (75.9%)
|
3 (10.6%)
|
| Total |
148 |
32 |
55 |
61 |
15 |
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
Table 1. Distribution of female patients according to age
| Age group (years) |
Number of
patients |
Percentage |
| 30 - 35 |
1 |
2% |
| 36 - 39 |
3 |
6% |
| 40 - 44 |
8 |
16% |
| 45 - 49 |
19 |
38% |
| 50 - 54 |
13 |
26% |
| 55 - 59 |
4 |
8% |
| 60 |
2 |
4% |
| Total |
50 |
100% |
Table 2. Distribution of female patients according to the type of
their menopause
| Type of Menopause |
Number of
patients |
Percentage |
| Natural |
26 |
52% |
| Postoperative |
24 |
48% |
| Total |
50 |
100% |
Table 3. Distribution of female patients according to the
duration of menopause
| Duration of Menopause (months) |
Number of
patients |
Percentage |
| < 12 |
19 |
38% |
| 12 - 35 |
16 |
32% |
| 36 - 60 |
7 |
14% |
| > 60 |
8 |
16% |
| Total |
50 |
100% |
Some of the basic symptoms predominated in the clinical picture
of menopause in the group studied, presented in Tables 4 and 5.
Table 4. Distribution of the female patients according to the
presence of some symptoms prior to Tribestan treatment
| Symptoms |
Number of
patients |
Percentage |
| Hot flashes |
50 |
100% |
| Perspiration |
39 |
78% |
| Depression |
27 |
54% |
| Hyperexcitability |
22 |
44% |
| Insomnia |
41 |
82% |
| Anxiety |
18 |
36% |
| Sense of heaviness of the cardiac
region |
30 |
60% |
| RR - changes |
11 |
22% |
| ECG - changes |
8 |
16% |
Table 5. Distribution of the female patients according to the
type of sexual libido
| Type of sexual libido |
Number of
patients |
Percentage |
| Normal |
2 |
4.0 |
| Low |
20 |
40.0 |
| Very low |
28 |
56.0 |
| Total |
50 |
100.0 |
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).
Table 6. Distribution of the female patients to the duration of
placebo intake
| Duration of course (days) |
Number of
patients |
Percentage |
| 0 |
4 |
8% |
| 14 |
6 |
12% |
| 15 - 20 |
32 |
64% |
| 21 - 30 |
8 |
16% |
| Total |
50 |
100% |
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).
Table 7. Distribution of the female patients according to the
total effective dose of Tribestan
|
Initial dose (tablets/day)
|
| Number of
Tablets |
3 x 1 |
2 x 2 |
3 x 2 |
Total |
| No |
% |
No |
% |
No |
% |
No |
% |
| < 60 |
2 |
4% |
- |
- |
- |
- |
2 |
4% |
| 60 - 100 |
5 |
10% |
5 |
10% |
8 |
16% |
18 |
36% |
| 110 - 180 |
- |
- |
7 |
14% |
18 |
36% |
25 |
50% |
| 190 - 220 |
- |
- |
1 |
2% |
1 |
2% |
2 |
4% |
| > 220 |
- |
- |
- |
- |
3 |
6% |
3 |
6% |
| Total |
7 |
14% |
13 |
26% |
30 |
60% |
50 |
100% |
Table 8. Total Tribestan effective dose
| |
|
Total Effective Dose
|
Dose
(tablets/day) |
Number |
Mean |
Confidence limit
(mean ± 1.96 SEM) |
| 3 x 1 |
7 |
68.6 |
53.0 ÷ 84.2 |
| 2 x 2 |
13 |
115.4 |
93.7 ÷ 137.1 |
| 3 x 2 |
30 |
141.5 |
113.7 ÷ 169.3 |
Table 9. Distribution of the female patients according to the
maintenance dose of Tribestan
| Maintenance dose (tablets/day) |
Number of
patients |
Percentage |
| 2 x 1 |
27 |
55.1% |
| 3 x 1 |
14 |
28.6% |
| 2 x 2 |
8 |
16.3% |
| Total |
49* |
100.0% |
*1 patient without effect
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).
Table 10. Distribution of the female patients in conformity with
the level of progesterone/estrogen in hormonal cytological
study
| Level |
Number
of patients |
Percentage |
| High |
7 |
14% |
| Normal |
1 |
2% |
| Low |
6 |
12% |
| Very Low |
16 |
32% |
| Total |
30* |
100% |
*20 patients without cytological examination
The radioimmunological studies are presented in Tables 11 and
12.
Table 11. Radioimmunological studies
| Hormone |
Tribestan administration |
No |
Confidence limit
(mean ±1.96SEM) |
| FSH |
Prior to
After |
46
42 |
51.38 ÷ 72.34
42.30 ÷ 59.74 |
| LH |
Prior to
After |
42
43 |
32.45 ÷ 46.05
29.62 ÷ 38.38 |
| Prl |
Prior to
After |
42
37 |
265.20 ÷ 378.20
200.60 ÷ 267.60 |
Table 12. Radioimmunological studies
| Hormone |
Tribestan treatment |
No |
Confidence limit
(mean ± 1.96 SEM) |
| E2 |
Prior to
After |
42
40 |
0.10 ÷ 0.22
0.20 ÷ 0.54 |
| Prg |
Prior to
After |
32
34 |
5.00 ÷ 10.30
4.14 ÷ 7.44 |
| Tst |
Prior to
After |
41
45 |
1.15 ÷ 1.74
0.96 ÷ 1.30 |
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.
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