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Genital Tuberculosis and Infertilty

Tono Djuwantono,1 David Halim,1 Leri Septiani,1 Ahmad Faried,2


Ida Parwati3, Shela Mareta4

1
Department of Obstetric and Gynecology; 2Oncology and Stem Cell Working Group;
3
Department of Clinical Pathology, 4Limijati Maternal and Child Hospital, Faculty of
Medicine, Universitas Padjadjaran-Dr. Hasan Sadikin Hospital, Bandung 40161, Indonesia

Introduction cells. Patient was treated and discharged 1


week after surgery.
Tuberculosis (TB) is still a major
global health problems. TB is a highly
infectious disease caused by the bacillus Case 2
Mycobacterium. Commonly, it affects the A 30 years old female, P0A0 came to clinic
lungs (pulmonary TB) but in some cases, with chief complaint of irregular menstrual
there are other sites can be affected by cycle. Last menstrual period was 1 year
these bacteria (extrapulmonary TB). In ago. Patient had been married for 2.5 years
female, one of the most common site for with no pregnancy. Patient was diagnosed
extrapulmonary TB is at genital area which with secondary amenorrhoea and
called as Genital Tuberculosis. infertility. Patients was admitted to
Female genital tuberculosis (GTB) is hospital for laparoscopic procedure.
a common health problem in developing During surgery, we found both of
countries.1 It frequently causes chronic the fallopian tubes were destroyed with
pelvic inflammatory disease, menstrual
adhesions to surrounding tissues. The
abnormalities, and infertility.2 The actual
tissues were taken for further analysis in
incidence of GTB cannot be assessed
accurately because it is often silent and pathology anatomy department. Histology
only 50% of cases are diagnosed without result showed that there were necrotic
surgery.3,4,5 tissue, there were endometrial cell with
formation of tubercles and langhans giant
Case Report cells. Patients was diagnosed with
Case 1 endometrial tuberculosis. Patient was
A 30 years old female, P0A0 came discharged one day after surgery and
to clinic with chief complaint of irregular referred to internal medicine department
menstrual cycle. Patient had been married for further evaluation.
for 5 years with no pregnancy. USG
examination was done with the result of
bilateral endometriosis cysts. Patients was Case 3
admitted for laparoscopic surgery with
diagnosis of Bilateral Endometriosis Cysts. A 30 years old female, P0A0 came
During surgery, we found pus on to clinic with chief complaint of infertility
both of the fallopian tubes. Sample was after 3 years of marriage. Patient had
taken for further analysis on pathology regular menstrual cycle (30-31 days) with
anatomy department. The results showed no other complains. During ultrasound
there are tubercles with langhans giant examination, we found any irregularity in
uterine mucosal with bilateral tube permanent fulminating destruction of
obstruction. Patient was diagnosed with these organs could result making women
endometriosis cysts with bilateral tube unable to do their reproductive functions
obstruction. Patient was admitted for namely menstruation and fertility.
laparoscopic surgery.
Microbiology and Pathology
During surgery, bilateral 90-95% of Genital TB infected by
salpingectomny was done because of Mycobacterium Tuberculosis. However,
obstruction in both of the tubes with Mycobacterium bovis may be the causal
adhesion to surrounding tissues. The tissue agent if the organism acquired from
were sent to pathology anatomy gastrointestinal tract.11
department for further analysis. From the Genital tuberculosis mostly
histologic result, tubercles and langhans acquired secondary from other sites of
giant cells were found on the wall of the infection. There are three routes that TB
tubes. Patients were diagnosed as bilateral bacilli can enter to genital tract. 90% of
Genital TB incidence was preceded from
tuberculosis of the fallopian tubes.
lungs, lymph nodes or skeletal system
Discussion infection and 90% of infections involving
the fallopian tubes and both tubes become
The incidence of genital involved almost invariably.
tuberculosis are accounted for 27% (range, Infections usually begins in the
14 to 41%) in worldwide. In Indonesia, mucosa and spreads through the tubal wall
there is no specific data for the incidence to the peritoneal surfaces. It is
of genital TB has been recorded. Genital macroscopically seen similar as tubal
tuberculosis is a common problems in thickening, adhesion and fibrosis of
developing countries. Actual numbers of chronic salpingitis.12
genital TB cannot be assessed accurately
because the symptoms of the disease is
often silent.

Tuberculosis exists in two forms:


Pulmonary and extra pulmonary.
Genital tuberculosis is a form of extra
pulmonary tuberculosis that affects 12.1%
of patients with pulmonary tuberculosis
and represents 15-20% of extra pulmonary
tuberculosis. It is estimated that 5-13% of Figure 1. AAFB Staining with Ziehl-Neelsen from
Endometrial Curretings9
patient in infertility clinics have genital
Obstruction at tubes site can leads
tuberculosis. Majority are in age group of
20-40 year. GTB is mostly secondary to formation of hydrosalphinx or
infection acquired by hematogenous pyosalpingx. These obstructions can leads
spread from an extragenital source such as to failure of tubal functions that cause
pulmonary or abdominal tuberculosis. The infertility.
anatomical predilection sites of GTB mainly
fallopian tubes and the endometrium are
the actual challenging problem.3,6,7 If
infection is not recognized early,
Pathogenesis Direct Spread From a Neighboring Viscus

Genital TB is almost always secondary to Most of the literature state that


other TB infections in the body with most genital tract never became the primary
common infected sites is lungs. Other infection sites. The criteria necessary for a
sites includes bone, joint, gastrointestinal diagnosis of primary genital TB are that
and renal. If patients did not treated well the genital lesions should be the first
to eradicate the bacteria, there is chance tuberculous infection in the body and
that the bacteria will be reactivated regional lymph nodes should demonstrate
especially when the immune response of the same stage of tuberculous
the patients is decreased. Getting diseases development as do the genital organs.
or drugs that cause attenuation of T-cell
response (e.g. Hodgkins lymphoma, AIDS, Endometrial Tuberculosis
steroids, stress, or malnutrition) will also Endometrial Tuberculosis was
increase the risk of bacteria reactivation. difficult to be diagnosed. In women
The mode of spread is usually infected with Endometrial TB, it is often
hematogenous or lymphatic and asymptomatic or present with non-specific
occasionally occurs by way of direct symptoms. The appearance of the disease
contiguity with an intraabdominal or usually different in women on
peritoneal focus. In some cases, reproductive age or postmenopausal
women. Most common symptoms in
treatment usually focus on lung sites but
reproductive ages women are menstrual
other lesions may lie dormant in other
disturbance, oligo-amenorrhoea, or pelvic
sites such as genital tract and could be
pain. The menstrual cycle may be normal
reactivate later.
and undisturbed in some cases of genital
Hematogenous Spread TB. Superficial tuberculous endometritis
does not interfere with the secretory
When tubercle bacilli invade the response of the endometrium to hormonal
lung , it will enter into the bloodstream stimulation. When the menstrual cycle is
and spread through various organs in the disturbed, some theory stated that it may
body. This bacteria will remains in the resulted from active pulmonary TB that
body if not diagnosed and treated well produce amenorrhea, if it is associated
with antituberculous drugs. with fever and weight loss. But, not all of
active pulmonary TB found concomitantly
In genital tract tuberculosis, with active genital TB. Amenorrhoea from
fallopian tubes is the most common genital TB can be could be resulted from to
common sites for tubercle bacilli end organ failure secondary to
infections with the earliest lesion found in endometrial caseation. Symptoms
the mucosa. Infection of tubercle bacilli commonly occur on postmenopausal
almost always infected bilateral tubes. woman are postmenopausal bleeding,
pyometra, or leucorrhoea.7,8,9
Lymphatic Spread When extensive involvement of the
endometrium occurs, there may be
Infection of tubercle bacilli
ulcerative, granular, or fungating lesions
through lymphatic spread usually happens
present, or the endometrial cavity may be
if the primary lesions originate from
obliterated with intrauterine adhesions.
abdominal cavity. It is more less common
Sometimes, the macroscopic appearance
infection routes.
may resemble carcinoma, and TB has been Tubal occlusion, especially at the
suggested microscopically. In some cases, transition between the isthmus and
total destruction of the endometrium with ampulla, multiple occlusion causing
resulting amenorrhea secondary to end- a beaded appearance or a rigid pipe
organ failure and predisposition to stem appearance
pyometra should the internal os becomes Hydrosalphinx showing up as tubal
occluded. dilatation with thick mucosal folds
Imaging is not a gold standard for Peritubal adhesions giving the tube
diagnosing Endometrial TB but it may help a corkscrew appearance, a
to confirm the diagnosis. A thickened peritubal halo, or loculated spillage
endometrium or pyometra can be found of contrast medium
during transvaginal ultrasound. A distorted The rare finding of enterotubal
contour of uterine cavity commonly found fistulae-most common between
during hysterosalpingogram procedure. the sigmoid colon and fallopian
Endometrial biopsy is a mandatory tube.
procedure to confirm the typical non- Nowadays, laparoscopy procedure has
caseating lesion consistent with TB.9 been done to help physician to
diagnose tuberculosis of fallopian
Tuberculosis of The Fallopian Tubes tubes. It allows better visualisation of
and Infertility fallopian tubes, ovaries, and peritoneal
Infertility defined as failure of a cavity and help to restore anatomical
couple to get offspring after 1 year (<35 abnormalities found in the pelvis if it is
years old) or 6 months (>35 years old) with possible. There are several findings can
regular sexual intercourse (3-4 times a be found during laparoscopy which
week) without any contraception in are:
normal physical and psychological Tubercles on the peritoneal
condition. It can also defined as inability of surface
a couple to get pregnant to achieve live Inflamed or blue-coloured
birth.13 It is one of the most common uterus
symptoms of patients with genital TB. Salpingitis, oophoritis, or a
Together with endometrial involvement, tubo-ovarian mass
Tuberculosis of the Fallopian Tubes is the Tubal occlusion with
leading cause of infertility in genital TB. hydrosalphinx
Prevalence of genital TB in infertile Dye drippling from the fimbrial
population in developing countries is opening on chromopertubation
between 5% and 20% and is even higher Free peritoneal fluid looking
among patients with tubal factor infertility like blood
(39-41%).8 Caseation in the pouch of
There are several hysterosalpingographic Douglas
appearance from tubal involvement such Frozen pelvis
as:8 Omental adhesions
Hysteroscopy should be combined
Calcifications showing up as linear with laparoscopy to exclude/confirmed
streaks endometrial involvement. Synechiae or
Tufted tubal outline or tubal destruction of endometrium by
diverticula
tuberculosis infection should be repaired
as soon as possible using oestrogen.

Clinical Features
Symptoms appears on each patient can be
differently found based on severity sites
and stage of the disease. Some of the
patients may not develop any symptoms.
Several symptoms discovered on patients Magnification 200x
are:
Formation of a large pelvic mass
Chronic pelvic inflammatory
disease symptoms
Menstrual abnormalities, eg.
Amenorroea, menorrhagia,
hypomenorroea, polymenorhoea,
postmenopausal bleeding and
oligomenorrhoea.
Excessive vaginal discharge Magnification 400x
General symptoms of typical
tuberculosis such as weight loss,
anorexia, pyrexia.
Infertility problems which may be
primary or secondary.

Histological Examination
For histopathological studies, a
portion of the endometrial and falopian- Magnification 400x
tube tissue from the lesion was fixed in ten Figure 2. Presence of caseating granulomas
percent formalin; routine processing was surrounded by epitheloid cells,
done and the stained with haemotoxylin
lymphocytes, plasma cells and giant cells
and eosin (H&E). Presence of caseating
granulomas surrounded by epitheloid
cells, lymphocytes, plasma cells and giant
cells were diagnostic of genital
tuberculosis (TB).

Magnification 100x

Magnification 100x
centrifuged at 11200 g for 20 min. The
supernatant was discarded and the pellet
was processed to extract DNA.
(ii) Isolation of DNA - Pellets were
resuspended in 500l of TE buffer by
repeated pipetting. Then 50l of 10 mg/ml
of lysozyme was added, mixed well and
incubated for one hour at 37oC. To this,
70l of 10 percent SDS (sodium dodecyl
Magnification 200x sulphate) and 6l of 10 mg/ml of
proteinase K were mixed and incubated for
10 min at 65oC. After incubation 100l of 5
M NaCl was added and mixed thoroughly.
The samples were further incubated with
80l of CTAB/NaCl (Cetyl trimethyl
ammonium bromide in sodium chloride)
solution for 10 min at 65oC. To this
prepared sample approximately equal
volume (700-800l) of chloroform/
Magnification 400x isoamyl alcohol were added, mixed
thoroughly and centrifuged for 10 min. All
these chemicals were purchased from
sigma chemical (St. Louis MO), USA. To the
supernatant, 0.6 volume isopropanol was
added to precipitate the nucleic acids and
placed at -20oC for 60 min. The resultant
sample was spun at 16128 g for 20 min at
6oC. The resulting DNA pellet was washed
with 70 percent ethanol to remove
Magnification 400x
residual CTAB. The supernatant was
Figure 3. Presence of caseating granuloma
carefully removed and the pellet was
surrounded by epitheloid cells, dried. The prepared pellet was re-
lymphocytes, plasma cells and giant cells dissolved in 25l of TE buffer (910 mM TRIS
and 1 mM EDTA) and stored at 4oC for
future use.
Polymerase chain reaction
examination
To diagnose tuberculosis of fallopian
tubes and endometrial tuberculosis,
polymerase chain reaction procedure was
done as described below:
(i) Processing of samples - The
endometrial and falopian-tube tissue was
finely chopped using a sterile scalpel and
homogenized in TE buffer (TRIS-EDTA-
Figure 4. PolyChain Reaction (PCR)
10mM Tris. Cl. pH 8.0; 1 mM EDTA pH 8.0)
until the solution became turbid. This was
(iii) Amplification of mycobacterial DNA initial denaturation at 95oC for 5 min,
PCR was performed using Gene followed by denaturation at 94oC for 30
amplification 9700 Thermal cycler with sec, annealing at 58oC for 30 sec, extension
standard 25l working volume (Gene at 72oC for 30 sec with 25 cycles and a final
Amplification PCR System 9700-Applied extension at 72oC for 5 min. Detection of
Biosystems USA). Precautions were taken amplified products was done by agarose
to avoid false positivity. Preparation of PCR gel electrophoresis (2%) at 80 volts for 45
reagents, addition of template DNA and min. Gel was stained with ethidium
analysis of amplified products were done bromide and viewed under UV
in three different rooms to avoid carryover transilluminator (VILBER-LOURMAT,
contamination. Reagents were aliquoted France, TCP-20.M).
and each aliquot was used only once. Wax (v) Evaluation of specific diagnostics - For
beads were added to minimize nonspecific the diagnosis of genital TB there is no
amplification. DNAs from the samples absolute gold standard test available.
were amplified using the following Therefore, based on the clinical profile
primers. and laparoscopic evaluation of patients, a
IS6110 forward (5 CCT GCG AGC GTA diagnostic criteria were derived to suspect
GGC GTC GG 3) TB. A woman was said to be suspected of
IS6110 reverse (5 CTC GTC CAG CGC having genital TB if she has had findings
CGC TTC GG 3) suggestive of TB at laparoscopy with one
The IS6110 primers amplify a fragment or more of the following findings: A
with a length of 123 base pair (bp). DNA definite past history of TB, in the presence
extraction chemicals and PCR chemicals of active extra-genital TB, characteristic
were obtained from USB, Amersham features on histerosalphyngograpgy
Bioscience. (HSG), elevated erytocyte sedimen rate
(ESR), positive Mantoux test, evidence of
calcification/complex adnexal mass by
scan.
Nucleic Acid extraction

PCR amplification

Figure 5. PCR Amplification

(iv) Cycling Parameters - The reaction was


performed on ice to minimize non-
specificity. The cycling parameter used: Thermocycler
Figure 6. PCR Detection

Figure 7. PCR Result

Conclusion
We report three cases of female
with genital tuberculosis diagnosed during
laparoscopic surgery and confirmed with
pathology anatomy result. All of these
three cases were managed distinctively
according to its clinical presentation and
course. Most of the patients came with
clinical symptoms of irregular menstrual
cycle and infertility that mimicked other
disease. Our case series is a good
educational lesson that can be used by
obstetrician for better diagnosing and
handling of patients with similar problems.
12. Malhotra M. Genital tuberculosis.
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