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In
Women, Tribestanol improves sexual activity, stimulates
ovogenesis, relieves Menopausal Syntoms, as well as
having other beneficial effects.
PHARMACOLOGICAL
STUDIES
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 a Tribestanol preparation
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
1. Schedule recommended by the manufacturer: 1 - 2
capsules, 3 times daily for 2 to 3 months.
2. Authors' schedule: 1 capsule 3 times daily to 2 capsules
three times daily from the 5th to the 14th day of menstrual
cycle for a period of 2 - 3 months.
3. After the follow up of certain parameters for assessment
of the comprehensive effect of Tribestanol individually
administered, the group was subjected to combined treatment
with Tribestanol and a hormonal drug stimulating the ovulation:
1. Tribestanol in compliance with schedule 2 + stimovul
(organon) 1 - 2 capsules daily from the 5th to the 14th
day of the cycle for total of 3 months.
2. Tribestanol in compliance with schedule 2 + clostilbegite
(Hungary) 1 - 2 capsules daily from the 5th to the 9th
day of the cycle for a total of 3 months.
Group B: Women with perimenstrual syndrome
1. Tribestanol - 2 capsules, three times daily for 20
days and reduced dose of 1 capsule daily every 4 - 5
days, reaching down to the maintenance dose of 1 capsule,
twice daily for a strictly individual period, depending
on the effect attained.
2. Tribestanol - 2 capsules, twice daily for 30 days with
subsequent reduction of the dose to 1 capsule every 4
- 5 days.
3. Tribestanol - 1 capsule, three times daily, without
a break, for a long-term period (up to 1 year).
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
capsules, 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 capsules,
the treatment was continued with Tribestanol 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 Tribestanol 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 Tribestanol 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 Tribestanol
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 Tribestanol. No
adverse effects were reported after intermittent administration
of Tribestanol.
Table 1. Comparative data on the effect of Tribestanol,
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 |
|
|
|
|
|
| Tribestanol |
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 Tribestanol
treatment in most of the female patients, mainly female
patients with post-surgical menopause.
EFFECTS OF Tribestanol 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 Tribestanol 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 capsules, 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 Tribestanol 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 capsules for attaining
a favorable effect in 50% of the treated women. In
10% of the women, that dose was higher - 190 - 220
capsules. The mean effective doses are presented in
Table 8, suggesting that the majority of the female
patients took over 100 capsules per therapeutic course.
The effect obtained is kept by maintenance dose of
2 - 3 capsules daily in 85% of the women (Table 9).
Table 7. Distribution of the female
patients according to the total
effective dose of Tribestanol
| Initial
dose (capsules/day) |
| Number
of capsules |
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 Tribestanol effective dose
| |
|
Total
Effective Dose |
Dose
(capsules/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 Tribestanol
| Maintenance dose
(capsules/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% |
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% |
The radioimmunological studies are presented in Tables
11 and 12.
Table 11. Radioimmunological studies
| Hormone |
Tribestanol 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 |
Tribestanol 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 Tribestanol 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 Tribestanol.
4.3. Side effect
in treatment with Tribestanol
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
Long-term experience with Tribestanol
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 Tribestanol 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 Tribestanol can successfully
be used for the treatment of menopausal syndrome in
women.
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