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What is uterine myoma and its symptoms
Uterine myoma – benign tumor formed
from muscular and connective tissues, which is one of the most common
tumors found in women's reproductive organs.
Depending on the prevailing type of tissues- parenchyma
or interstitial, this tumor was used to be called differently: myoma,
fibroma, fibromyoma. However, since the myoma nodules are developed
mainly from muscle cells, the most correct terminology is considered
to be myoma (leiomyoma).
Uterine myoma is the most common pelvic tumor and
they are diagnosed in upto15 to 20% of women in pubertal period [1].
Although myoma (uterine fibroids) is generally considered
to be a slowly growing tumor, in 20-40% of women at the age of 35
and more have uterine fibroids of significant sizes with severe clinical
symptoms [2]. Moreover, myoma can be relapsed in 7-28% of patients
after surgical treatments and in certain cases it may even turn into
malignant tumor.
The researchers have remarked that women who gave
birth to at least two children have 2 times less risk of developing
myoma than the childless women. Though, the scientists are not sure
at this point whether the child delivery actually protects them from
myoma, or if the myoma itself is the causative factor of infertility
in those childless women.
For the growth of thus formed tumors, they need to
be further supported by negative factors: abortions, long term use
of inadequate contraceptive pills, chronic, sub acute and acute inflammations
of uterus or its appendices, stresses, ultra-violet irradiation, cystic
formation of ovary etc. For example, the women who had 10 abortions
by the age of 30 have double the risk to develop uterine myoma at
40 years of age.
The growth of uterine myoma is featured as a benign,
hormone sensitive diffuse or nodulous hyperplasia of myometrium and
characterized by having multiple factors of pathogenesis, systemic
changes, though the exact etiology of myoma is not known yet.
Uterine myoma is developed on the background of hyper
estrogens, progesterone deficits and hyper gonadotropins. The majority
of the researchers consider, that the growth of myoma depends on concentration
of cytosolic receptors to the sexual hormones, and their interactions
with the endogen or exogen hormones. In accordance to clinical observations,
it can be admitted that both growth and regression of myoma
are estrogen-dependant; the tumor size gets increased during pregnancy
and is regressed after menopause [3]. The only moment that
needs to clear is to find out whether it is the decrease in receptor
numbers or estrogen, progesterone and androgen hormone quantities
which lead to regression in myoma size (regarding androgen –
there is an hypothesis that myoma is sensitive to androgen).
The chromosomal anomaly (12q13-15) is quite common
in myomatous cells [4]. In fact, in 30-40% cases, the predisposition
to uterine myoma is passed down from mothers to daughters on hereditary
line. A form of myoma so called 'family type' is present where uterine
myoma are seen in all the family line – in grandmother, mother,
aunts and sisters.
Uterine myomas are often identified during routine
gynecological examinations. In such examinations, the gynecologists
may only assert the fact – presence of uterine myoma. In other
cases the primary symptoms of myoma may appear as: hypo gastric pains,
low backaches, bleedings, impairments of close up organs –example,
tachyuresis (frequent urination).
We need special examinations to determine the number
of nodules, sizes and their exact localizations. Mostly ultrasound
examinations are enough for this, but in certain cases CT scans, MRI
could be necessary.
Myoma may be located in the external, middle or inner
layers of uterus (subserous, interstitial and submucous). Nodules
can be located in the isthmus (5%) or in the uterine body (95%) [5].
The most 'unpleasant' ones are those, which are located in the inner
layer.
Such types of myoma deform the uterus cavity, and
thus cause severe bleedings during menses resulting into low hemoglobin
levels (this is why during iron deficit anemia in women, they should
have gynecological examinations).
The conventional treatment
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The uterine myoma by itself is not an indication
for operative method of treatment. Mainly it depends upon the patients'
overall health condition, severities of the clinical symptoms and
the sizes of the tumor.
The major indications for the operative methods
of treatment are severe pains, fast growth rate of the nodules,
arising suspicions about the malignancy of myoma, inflammatory changes
in the tumor nodules and dysfunction of closely lying organs (urinary
bladder, intestines etc.), infertility (when all other reasons are
already excluded). If an experienced gynecologist recommends you
an operative method of treatments, you should go for it as early
as possible.
It is necessary to watch the dynamic changes
of myoma (ultrasound examination with vaginal probe), which in most
cases gives sufficient information, and neither operations nor other
therapies are required. If a woman has periodic pains, discomforts
in the pelvic regions, any NSAIDs may help to relieve
the symptoms. In case of having considerable clinical symptoms gestagen
therapy (Norcolut, dufaston, premalut, medoxyprogesterone acetate);
or using gonadotropin-releasing-hormone (Gn-RH) agonists
(joladex). Tranexamic acid in tablets can be used
during menorrhagia to decrease the heavy bleedings. Contraceptive
pills can also be used for it.
The application of danazole, having androgenic
properties, decreases the myoma sizes but on the other hand causes
adverse effects: harsh voice, hirsutism etc. More effective ones
are the hormones, which develops pseudomenapause, such as buserelin
(nasal spray) and gozerelin (one injection per
month). It is important to take into account, that the hormonal
therapy brings only a temporary relief of the patients' condition,
at the same time it causes many adverse effects. For example, long
term hypoestrogenemia leads to high risk of osteoporosis [1, 6],
where as after the withdrawn of hormones the growth of myoma speeds
up (in 20% relapses occur with in 12 months, while in 50% in 5 years
[4]. The application of hormone therapy just to shrink the
nodule sizes is unjustified.
There is one more target of the hormone therapy
– to decrease the blood loss volume and time of operative
manipulations during myomectomy or hysterectomy.
The organ bearing laparoscopic myomectomy
is done in the patients of age up to 40 years, having clear indications
for surgical treatments. Particularly, it is expedient to resect
out the macroscopic nodule of middle sizes (with diameter 2-5 cm),
before they grow into too big sizes. While deciding to go for conservative
myomectomy, it is also important to consider the morphological types
of the tumors. For example, in proliferative types of myoma we can
resect out several nodules, but many new nodules continue to grow
further. This indicates that there are a high percentage of relapses
(15-37%) after such conservative myomectomy. Moreover, the operations
have common surgical risks including severe complications.
By now one more noninvasive method of treatment
– transcatheter embolization of myomatosis nodules
– as been elaborated, in which the nudules are cut off from
blood supply and they regress out quickly with out affecting the
uterus body as a whole. This method is still under clinical investigations
and thus is not yet in wide use [7]. Various results of embolization
in relation to the infertility rate and relapses of nodules are
being analyzed.
After 40 years or in post menopause period, if
there are clear indications for surgical treatments the patients
should go for resection of the myomatous uterus (uterectomy),
since even if the myomatous nodules do not grow much during the
first 2 years of menopause, there is a high risk of changing them
further into malignant tumors (adenocarcinoma, sarcoma).
Immunotherapy using vaccine RESAN
The progression of myomatous nodules or their growth
can be controlled by checking the production of myogenic elements
around the nodules, at the same time stimulating the apoptosis
of myocites in the central regions of nodules. Regarding this,
there are no conventional treatment options, which possess these
clinical properties. It is the immune correcting therapy, which
have these necessary clinical effects. The establishment of immune
reactivity, immune correcting therapy, needs special approach
to stimulate the immune system. A very new approach – an
immunotherapy using tumor vaccine RESAN, which triggers specific
T-cell immune response against uterine myoma has been elaborated
[9, 10].
The components of immune system discern the particular
surface antigens situated on the cell membranes. A very important
role plays the proportion of cellular surface adhesion molecules
– mainly E-cadherine [11, 12, 13, 14] and the tumor associated
antigens CA125, CA19-9, CA15-3. Though, the mitotic activities
of the uterine myoma are very low, the myomatous cells express
oncoproteins of proliferation (Ki–67) and the oncoproteins
which suppress apoptosis (bcl–2, bax).
In these respects, we recommend the application
of tumor
antigen imitators, included in the structure of a vaccine RESAN,
with the purpose of correcting immune system for the treatment
of fibromyomatous patients [10].
Patient's eligibility to RESAN immune
therapy:
- Young ages (reproductive, pre menopause)
- Relatively small sizes of the myomatosis nodules (up to 10-12
weeks)
- Intermuscular localization of myomatosis nodules
- Relatively slow rate of myoma growth
- Absence of uterine cavity deformations (i.e. central growth
and submucous localization)
To certain extent, we can draw analogy of indication
for RESAN therapy to organ conserving surgical treatments at complete
safety of vaccine application.
Next we represent a short reviewed protocol of
our clinical assessment of patients suffering from different genital
pathologies, who were treated with antitumor vaccine RESAN (immunotherapy).
We observed 35 women, among which 12 were suffering
from genital endometriosis – adenomyosis, posterior isthmus
form of endometriosis, external genital endometriosis; 13 –
uterine myoma; 10 – combined form, endometriosis with uterine
myoma; 2 – ovary cysts [8]. In all the patients we observe
dishormonal hyperplasia of breast. In history, the patients were
treated with different methods including hormonal therapy, immunomodulators,
antioxidant therapy. Nevertheless, there were little clinical improvements
from the applied therapy, i.e. some temporary (2-3 months) improvements
in clinical symptoms (pain relief and some betterment in overall
health conditions). As there were lack of necessary clinical effects
from the previously applied therapy, we administered a course of
immunotherapy using xenogenic vaccine which imitated the endometriosis
and uterine myoma related antigens [10]. The vaccine was administered
intracutaneously in one shot to all the patients.
The patients were examined before and after the
vaccine treatments. The intensity of pains were measured in a "9
units” marking systems of Mac Laverty.
Pain in pelvic region, not associated
with sexual intercourse or menses (3 units – severe, sharp,
almost constant in which the patients were compelled to take analgesics;
2 units – moderate, tolerable, appreciable discomforts during
the whole period of menses; 1 – mild, occasional discomforts
or during pre menses period);
Algodysmenorrhea (3 units – severe,
compels the patients to remain in bed for one or more days; 2 units
– moderate, compels the patients to remain in bed for several
hours in a day, occasionally loose working capacity, 1 unit –
mild, with certain loss of working capacity);
Dyspareunia – pain during sexual
intercourse (3 units –severe pains, have to avoid sexual intercourses;
2 units – moderate, have to interrupt sexual intercourse,
1 unit – tolerable pains);
Dysmenorrhea (3 units – blood smears
seen 4-7 days pre menses; 2 units – blood smears seen 1-3
days pre menses; 1 unit – occasional appearance of blood smears
pre menses);
Intensity of menses (3 units – copious
menses, 2 units – moderate, 1 unit – scant menses).
Bimanual examinations, ultrasound examinations
of pelvis and breast, mammography were conducted in all the vaccinated
patients. The serum tumor markers (CEA, CA-125, CA19-9, CA-15-3),
antigens of hepatitis B virus (HBV), antibody titers to Chlamydia
trachomatis, Toxoplasma gondii, Mycobacterium tuberculosis and hepatitis
C virus (HCV) were measured through immunoenzime analysis method
before the vaccination and during the follow-ups in one month later
[applied lab instruments and lab supplies- photometer STAT FAX 303
PLUS, auto-dosator BIOHIT and reagents from HOFFMANN-LA-ROCHE, HUMAN,
BCM DIAGNOSTICS LLC, LABODIA-XEMA, VECTOR-BEST applying GLP system].
Before the treatments, the pain symptom was in
average 9 units in 27 patients, who were suffering from genital
endometriosis and in combined form (endometriosis with uterine myoma).
In 8 of the myoma patients the pain syndrome were not above 5 units.
Dysmenorrhea was evaluated as 3 units in all patients with genital
endometriosis and combined form of uterine myoma and endometriosis,
where as in patients with uterine myoma alone (13 patients) –
1 unit.
Heterogenic consistencies of endometriosis, areas
of high tenderness on uterine walls and increase in uterine body
volume were observed during bimanual examinations and ultrasound
examinations of pelvis. In the uterine isthmus, moderate swellings
and pronounced pain symptoms were noted. During ultrasound examinations,
in 12 patients with endometriosis genitalia were found adenomyosis
of III-IV stages. In the patients with combined forms (endometriosis
and myoma uterine), together with heterogenic mosaic structures,
some interstitial, subserous and submucous nodes (in 5 cases) of
22-23 mm diameter were found. The uterine sizes were enlarged upto
9-12 week sizes in all cases.
The ultrasound examinations of breast in all the
patients, diffuse (23 patients) and fibrocystic (12 patients) changes
were located. The ultrasound results were correlated with that of
mammography.
The tumor markers were elevated with in benign
tumor limits, in all patients before the treatments. The average
value of CA-125 in the group as a whole was 44.7±1.34 U/mL,
CA-19-9 28.9 ±1.5 U/mL, CA-15-3 53.2 ±4.3 U/mL, CEA
1.29 ±0.38 ng/mL.
According to different infections found in the
patients, they were classified into: Hepatitis B and C carrier –
27 (out of 35), Chlamydia trachomatis – 18, Toxoplasma gondii
– 12, Mycobacterium tuberculosis – 6. It is important
to note that the clinical states of the patients, antibody titers
to the given infections indicated the chronic persistent states
with out any signs of exacerbation of the infection. The presence
of these infections influenced somehow in the overall health conditions
of the patients in the post vaccination period.
During 7-10 days after vaccination, 30 patients admitted weakness,
while patients with chlamydia trachomatis noted joint pains. Mild
nausea, malaise were felt by patients with hepatitis carriers.
Carriers of tuberculosis and Toxoplasma gondii infections practically
showed no clinical signs of exacerbation, except in 2 cases where
we observed mild activation of chronic bronchitis within 1-1.5 months
after the vaccination. Then, their health conditions were normalized,
and no other adverse effects were recorded during next 3-4 weeks
of observation. In the beginning, there was a tendency of growth
in serum antibody titers to the given infections, while during next
1.5-2 months the titers returned to initial levels.
After one month, all the patients were followed
up again. During bimanual examinations of the patients suffering
from endomeriosis, the uterus sizes were shrank considerably and
endometrium tissues became more homogenous with small areas of tenderness.
In the cases of uterine myoma with nodules of different sizes, we
observed considerable shrinkage in nodules and uterine body sizes.
Where as in cases of endometriosis genitalia, the positive results
were even more pronounced. During ultrasound examinations of genitalia,
we observed a marked reduction in genital endometrioma and uterine
sizes in patients suffering from endometriosis, where as in patients
suffering from endometriosis in combination with uterine myoma,
we noticed a decrease in interstitial, subserous and submucous node
sizes (down by 16-26 mm). In all cases, the uterine body sizes were
shrank to 5-11 week sizes (Fig.1).
Fig. 1. Sizes of uterus
In 7 patients were observed normalization of uterine
body sizes, while in ultrasound examination there were a complete
disappearance of myoma nodules. Similarly, in 2 patients we observed
a complete disappearance of ovary cysts of sizes from 14.5 cm3
to 26.4 cm3 after the vaccination.
In ultrasound examinations of breast of patients
with diffusing mastopathy (fibrocystic breast disease), already
through one month after the vaccination no pathological changes
in the breast tissues were admitted. In case of fibrocystic form
of masthopathy the lesions of cystic formations were decreased in
1.5-3 mm sizes. The ultrasound results were correlated with that
of mammography.
The pain symptom in 22 patients suffering from
endometriosis genitalia as well as in combined forms (endometriosis
and uterine myoma) was relieved from 9 down to 5-7 units (Fig.
2).
Fig. 2. The intensity of pain
symptom
One month after the vaccination, the severity
of dysmenorrhea was reduced to 1 unit in the patients with endometriosis
as well as in those with combined forms (endometriosis and uterine
myoma), where as in the patients (13) with uterine myoma the dysmenorrhea
was corrected to 0 units (Fig. 3).
Fig. 3. Dysmenorrhea
We did not observe any clinical declines in direct
correspond to vaccination in the patients. Patients rather admitted
a decrease in edema, pain releases in the areas of estrogen-dependant
organs, betterment in general health conditions and overall lifestyle.
 Fig.
4. Changes in tumor marker levels
The changes in the tumor marker levels varied
depending on the types of tumor markers (Fig. 4).
The CA19-9 level after the vaccination, in average, went up by 23%
(P<0.05) from the initial value during the first month, but after
two months it became 15% less than the initial value. The CA-125
level, in average, dropped steadily down to 25% (P<0.05) from
the initial value. The CA15-3 level fell down to 38% (P<0.05)
from the initial value, already in the first month after the vaccination.
The average value of CA-15-3 in 2 months after the vaccination was
31.0 U/mL (P<0,1%). In overall, these changes in tumor marker
levels showed positive results of immunotherapy.
After evaluating closely the results of above clinical assessment,
we came to conclusion that the application of vaccine RESAN considerably
improved the general health condition and overall parameters of
objective examinations in all the vaccinated patients who were under
our observation.
We recommend the patients to examine for chlamidian infections,
tuberculosis as well as for HBV and HCV carriers before the vaccination.
In case of spotting high titers of antibodies against these infections,
it is necessary to carry out a 'sanitarying treatment' of patients
(using antibiotics, interferons, interleukines) before vaccination.
The immunotherapy of endometriosis and
its combined form with uterine myoma by xenogenic vaccine RESAN
results into regression or complete destruction of endometriomas,
myomatous nudules and cystic formations of ovary.
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