Tuberculosis (TB), caused predominantly by
Mycobacterium tuberculosis (
M. tuberculosis), is a major public health burden, accounting for 10.8 million incident cases and 1.25 million deaths globally in 2023, as reported by the World Health Organization (WHO)
[1]. Although most of these cases and deaths occur in developing countries, TB is making a comeback, even in the developed countries of Europe and the United States of America (USA)
[2]. TB most commonly affects the lungs; however, it can also affect bones, joints, lymph nodes, pleura, meninges, and the urogenital tract. Genital TB (GTB) is one of the most prevalent type of extrapulmonary TB and usually arises from hematogenous dissemination, lymphatic spread, or direct spread from adjacent abdominal organs
[3].
Female GTB (FGTB) commonly presents in women of reproductive age and most often impacts fallopian tubes, followed by uterine endometrium, ovaries, and the cervix
[4]. The clinical presentation of FGTB depends on the site of infection
[5]. Most patients with FGTB have no clinically significant symptoms and are often unexpectedly discovered during infertility evaluation. Infertility is seen in 40% to 80% of FGTB cases and occurs due to tubal obstruction or damage, intrauterine adhesions (IUA) causing disorders of endometrial receptivity, or ovarian damage with low ovarian reserve.
Endometrial involvement may be noted in over half of FGTB cases.
M. tuberculosis causes endometrial receptivity disorders and suppresses the sensitivity of the endometrium to ovarian hormones. This leads to a deficient secretory phase and defective glycogen secretion
[6]. The uterine cavity may be partially or totally obliterated by IUA). In TB-associated IUA, patients typically progress from oligomenorrhea or hypomenorrhea to amenorrhea and infertility. TB also causes recurrent implantation failure and miscarriages due to enhanced production of tumor necrosis factor (TNF)-α and interleukin (IL)-2
[7]. Although medical treatment may be successful in eradicating the infection, the fibrotic sequelae of the disease may prevent the occurrence of an intrauterine pregnancy.
Hysteroscopic adhesiolysis is necessary and is the main treatment for patients with IUA
[8]. However, there has been a paucity of data on the results of hysteroscopic adhesiolysis of IUA due to endometrial TB. Hence, the objective of the present study was to research the outcome of hysteroscopic adhesiolysis in women with TB-induced IUA.
1 Patients and methods
1.1 Ethics statement
This study was approved by the Ethics Committee of the Third Xiangya Hospital of Central South University (No. 23384). The procedures used in this study adhered to the tenets of the Declaration of Helsinki. Verbal consent for the study was obtained from all patients by phone.
1.2 Patients
This was a retrospective cohort study conducted in the Department of Gynecology at the Third Xiangya Hospital of Central South University from May 2014 to October 2022. Patients were identified by conducting a search of available electronic medical records.
The inclusion criteria were as follows: Women aged 20-40 years with IUA confirmed by hysteroscopy and underwent hysteroscopic adhesiolysis; endometrial TB confirmed by histopathology; and desire for fertility. The exclusion criteria included other medical conditions related to the uterus (e.g., hysteromyoma, adenomyosis, and uterine malformation); severe systemic disease or contraindications to estrogen; and amenorrhea induced by ovarian and hypothalamus-pituitary lesions.
IUA was diagnosed and scored by an experienced surgeon using hysteroscopy according to 3 factors of the classification system of the American Fertility Society (AFS), including the extent of the cavity involved, the type of adhesions, and the menstrual pattern. IUA scored 1-4 was rated as mild, 5-8 was rated as moderate, and 9-12 was rated as severe.
The following data were collected: Age; TB history (pulmonary TB or other extrapulmonary TB); obstetric history (number of previous gestations, deliveries, or miscarriages); pregnancy desire; symptoms (amenorrhea, hypomenorrhea, or infertility); diagnostic hysteroscopy (AFS score, ostia); the number of times undergoing hysteroscopic adhesiolysis; operative complications; menstrual volumes after surgery; pregnancy occurrence after IUA treatment [spontaneous pregnancy or in vitro fertilization-embryo transfer (IVF-ET)]; obstetric outcomes (live birth, miscarriage), and mode of delivery.
1.3 Hysteroscopic adhesiolysis procedure
The procedure was performed under intravenous anesthesia. Ultrasound guidance may have been used to limit the risk of perforation. Sterile saline solution was used as the uterine distension fluid, with a distension pressure of 100 to 120 mm Hg (1 mmHg=0.133 kPa)and a flow rate of 300 to 400 mL/min. A diagnostic hysteroscopy was used to evaluate the AFS scores of adhesions before performing adhesiolysis. Hysteroscopic adhesiolysis was carried out by experienced hysteroscopic surgeons using a 4.5 mm hysteroscope with an operative channel (Karl Storz, Tuttlingen, Germany) or a 5.4 mm hysteroscopy with a 5Fr working channel (Kemaisen, Hunan, China). The adhesions and scars in the uterine cavity were separated by using hysteroscopic scissors to protect the residual endometrium
[9], combined with double-action forceps that were used for the blunt spreading dissection technique if the internal cervical os, the lower segment of the uterine cavity, or the uterine cornu was completely obstructed
[10]. The hysteroscopic adhesiolysis ended when the shape of the uterine cavity was restored or if complications occurred. Afterward, either the intrauterine stent
[11] or intrauterine device was inserted into the uterine cavity to separate the walls of the uterus for prevention of its recurrence. Thereafter, hormone therapy was begun on the day of the operation, consisting of estradiol valerate at a dose of 4-6 mg/day for 21 days, oral administration, with the addition of progesterone capsules at a dose of 200 mg/day for the last 6-10 days of estrogen therapy. After the withdrawal bleeding, the hormone therapy was repeated for another cycle.
Postoperative assessment of the uterine cavity with hysteroscopy was prescribed following 2-3 menstrual cycles after hysteroscopic adhesiolysis to evaluate the efficacy of treatment. A new procedure was performed if needed.
1.4 Follow-up method
Follow-ups were conducted from the first hysteroscopic adhesiolysis to the present. The return of menstruation or menstrual volume change was evaluated after IUA treatment. Pregnancy outcomes such as pregnancy rate, live birth rate, pregnancy complications (including placental adhesion, placental implantation, placenta previa, etc.) were also followed up.
1.5 Statistical analysis
SPSS version 22.0 (IBM Corp., Armonk, NY, USA) was used for the statistical analysis. Baseline characteristics were reported as means and standard deviations for continuous data if normally distributed or as medians and range if not normally distributed. Categorical data were recorded as numbers and percentages. A value of P<0.05 was considered statistically significant.
2 Results
2.1 Patient characteristics
From May 2014 to October 2022, 39 patients were identified, 2 were lost during follow-up, and 37 were evaluated, with follow-up periods ranging from 6 months to 9 years. Their demographic and clinical characteristics are described in
Table 1. The age of the patients at the first hysteroscopic adhesiolysis was (29.3±4.8) years, and (30.0±4.6) years at the last procedure. Only 1 patient already had a child before the diagnosis of endometrial TB. Another patient had a spontaneous abortion twice before the diagnosis of endometrial TB. All patients presented with one or more of the following conditions: Hypomenorrhea, secondary amenorrhea, or infertility. Most of the patients had primary infertility, and only 2 (5.4%) patients had secondary infertility. The diagnosis of endometrial TB in all patients was confirmed by histopathological examination. There was a past history of pulmonary TB in 9 (24.3%) patients and intestinal TB in 1 (2.7%) patient. All 37 patients underwent anti-TB treatment. An intrauterine tissue biopsy was performed during the first hysteroscopic adhesiolysis, which indicated that endometrial TB had been cured. No patients received anti-TB treatment after hysteroscopic adhesiolysis.
2.2 Efficacy of hysteroscopic adhesiolysis
All the patients underwent hysteroscopic adhesiolysis. Hysteroscopic findings in the patients are shown in
Table 2. The initial median AFS score was 10 (range, 8-12), with a moderate degree of IUA in 21.6% (8/37) and a severe degree in 78.4% (29/37) of patients (
Figure 1). Neither ostia could be seen in 14 (37.8%) patients, unilateral ostia could not be seen in 10 (27.0%) patients, and both ostia could be seen in only 13 (35.2%) patients before surgery. A total of 86 operative procedures were performed in 37 patients, of whom 10, 15, 6, and 6 underwent 1, 2, 3, and >3 hysteroscopic adhesiolysis procedures, respectively. Only 1 patient had perforation during the first hysteroscopic adhesiolysis. At the last surgery, bilateral ostia were visible in 73.0% of patients, and bilateral ostia were invisible in only 6 (16.2%) patients. The uterine cavity returned to normal in 25 patients, and a shrunken cavity was observed in 12 (32.4%) at the last surgery. However, only 7 (18.9%) patients had a normal endometrium at the last surgery, and those patients had moderate adhesion at the first surgery. Three patients had no endometrium, even after multiple surgeries and estrogen and progesterone therapy. Only 12 (32.4%) patients returned to normal menstruation, and 25 (67.6%) patients continued to have hypomenorrhea.
2.3 Pregnancy and obstetric outcomes
Among the 37 patients, 29 had tried IVF-ET, and the remaining 8 women tried to conceive naturally, but were still infertile. Among the 29 patients who had tried IVF-ET, only 6 became pregnant. The pregnant patients’ characteristics and pregnancy outcomes are shown in
Table 3. Of the 6 successful pregnancies, 4 patients had moderate IUA and 2 had severe IUA before hysteroscopic adhesiolysis. After 1 or 2 surgeries, both ostia could be visualized in all 6 patients, and the endometrium in 5 patients was normal, while it was partial in 1 woman. One experienced early spontaneous miscarriage, 1 woman had an early pregnancy of 6 weeks at the last follow-up. The other 4 women experienced term delivery and underwent cesarean section. One woman had postpartum hemorrhage with a diagnosis of uterine inertia, and 1 woman was diagnosed with placental adhesion. All newborns were of normal weight and without abnormalities.
3 Discussion
Endometrial TB commonly affects women of reproductive age and is an important cause of menstrual dysfunction and infertility. In addition, women with latent TB have a significantly greater frequency of recurrent implantation failure and recurrent miscarriages
[12]. TB involves the endometrium, initially causing ulcerative lesions, followed by thinning of the endometrium, and dense endometrium, IUA (Asherman syndrome), shrunken uterine cavity, or irregular uterine cavity in later stages. The data in our study show that the most significant characteristic of endometrial TB is hypomenorrhea, followed by primary infertility, which is consistent with the common clinical manifestations of endometrial TB. Among the 37 patients, the initial median AFS score was 10, with a severe degree in 78.4% (29/37) of patients. Both ostia could be seen in only 13 patients before surgery, which suggested that TB had seriously affected the endometrium of patients and led to severe IUA.
Early diagnosis and expeditious anti-tubercular therapy (ATT) can improve menstrual cycles and endometrial thicknesses and reduce the incidence of mild adhesions in patients with early stage GTB. The reproductive potential may also be salvaged by timely ATT early in the pathogenesis of the disease. However, once the cavity is extensively fibrosed, ATT does not improve the adhesions
[13]. Hysteroscopic adhesiolysis has been accepted as the optimum surgery for restoring the size and shape of the uterine cavity, normal endometrial function, and fertility. However, there has been a paucity of data on the results of hysteroscopic adhesiolysis of IUA secondary to TB. This investigation constitutes a relatively large-scale cohort study currently available in the literature pertaining to this field.
Previous studies
[13-14] suggest that women with IUA due to GTB have a poor prognosis for the restoration of menstrual function or endometrium. Bukulmez, et al
[14] concluded that total corporal synechiae due to TB carry a poor prognosis following hysteroscopic adhesiolysis. In our study, only 10 patients underwent a single hysteroscopic adhesiolysis, while 27 patients underwent more than 2 operations, and 6 patients underwent more than 3 operations. At the time of the last operation, while 1 or both fallopian tube orifices could be seen in 31 patients, only 25 patients obtained a normal uterine cavity, and the remaining 12 patients had an overall reduction of the uterine cavity. The menstrual volume was normal in only 12 patients, while only 7 patients had normal endometrium at the last surgery, and those patients had moderate adhesion at the first surgery. It is suggested that for very serious IUA, even multiple operations are unable to restore normal menstrual function or the endometrium. However, for patients with moderate adhesions, there is still great hope that menstruation and endometrium can be restored. One point we need to be mindful of is that the nature of intrauterine synechiae associated with TB is invariably dense and cohesive. Finding the appropriate cleavage plane during hysteroscopic adhesiolysis may prove to be technically difficult with unavoidable myometrial damage. Therefore, the surgery should be performed by an experienced doctor. The use of blind instruments such as dilatation for adhesion separation is not advocated. For severe adhesions, intraoperative ultrasound or laparoscopic monitoring can be considered to reduce the risk of uterine perforation and other complications. Additionally, taking effective measures postoperatively to prevent the reformation of adhesions and promote the repair of the endometrial lining is also very important. These intraoperative and postoperative precautions are expected to improve the prognosis of patients with endometrial TB, thereby increasing the pregnancy and live birth rates.
Compared with menstruation, we paid more attention to the reproductive outcomes of patients with moderate or severe IUA. A systematic review
[15] reported that the pooled rate of pregnancy after surgical treatment of IUA was 50.7% in 53 studies, with extremes ranging from 10.5% to 100%. The pregnancy rate in women with severe adhesion was significantly lower than in women with mild adhesion
[15]. Xu, et al
[16] reported that the overall conception rate for patients after hysteroscopic adhesiolysis was 58.97%, and the live birth rate was 45.56%. In our center, we reported 55.4% of pregnancies after hysteroscopic adhesiolysis of severe IUA caused by surgical trauma, and the live birth rate was 39.6%
[17]. However, the causes of adhesions in these studies did not include endometrial TB, and almost all of them were secondary to endometrial trauma, so these values are not comparable with IUA secondary to TB. FGTB often causes irreversible damage to genital organs, and women with FGTB have a poor prognosis for fertility, even after treatment.
Although IVF-ET has been used with some success in FGTB after hysteroscopic adhesiolysis, the prognosis for fertility in women with IUA due to GTB tends to be very poor. The nature of IUA associated with TB is invariably dense and cohesive. Marcus, et al
[18] reported that, in 10 patients with tuberculous infertility who underwent 22 cycles of IVF, 6 clinical pregnancies resulted in 3 live births in 3 patients, and all had trophic endometrium. They recommended that preliminary assessment of the endometrium must be done, as the pregnancy rate is high for embryo transfer in normal endometrium and zero in atrophic endometrium. Tripathy, et al
[19] reported a post-treatment conception rate of 19%, but a live birth rate of only 7% in 97 patients, and they demonstrated that if the uterine cavity was distorted or the tubes were blocked on hysterosalpingography, not a single pregnancy occurred. No pregnancy resulted in no endometrium or caseating endometrium
[19]. Bukulmez, et al
[14] reported on 12 patients who underwent 15 attempts for hysteroscopic adhesiolysis of total corporal synechiae, and ultimately, an adequate uterine cavity was obtained in all cases. However, total intracorporal synechiae recurred in all patients
[14]. Parikh, et al
[20] reported a 16.6% pregnancy rate and a 7.2% live birth rate. The high rate of pregnancy loss in these patients likely indicates residual structural damage to the uterine cavity.
In this study, 29 patients had tried IVF-ET, but only 6 (20.7%) became pregnant. Of those, only 4 (13.8%) experienced term delivery and underwent cesarean section, while 1 woman had an early pregnancy of 6 weeks at the last follow-up. The endometrium of most pregnant patients was normal at the last operation. That is to say, patients with IUA caused by endometrial TB have a higher pregnancy rate if they have a normal uterine cavity and endometrium after hysteroscopic adhesiolysis. However, the pregnancy rate of patients with a normal uterine cavity but poor endometrium after hysteroscopic adhesiolysis is still low. How to promote endometrial repair in such patients is the focus of improving the prognosis of patients with IUA caused by endometrial TB in the future. In recent years, stem cell-based therapies
[21] or the use of bio-scaffold materials as delivery strategies for therapeutics for endometrium regeneration
[22] may both become effective methods for repairing the endometrium. Additionally, patients with moderate to severe IUA are prone to pregnancy-related complications caused by abnormal placental blood supply after IUA separation surgery. Therefore, strengthening prenatal care, dynamically observing the growth and development of the embryo, and promptly dealing with corresponding obstetric complications are particularly important.
In conclusion, endometrial TB can lead to severe IUA, resulting in hypomenorrhea, amenorrhea, or infertility. Hysteroscopic adhesiolysis may help restore the uterine cavity and improve menstruation, but it may be difficult to repair the endometrium in patients with severe IUA. If the endometrium returns to normal after hysteroscopic adhesiolysis, the fertility outcome may be better. A severely damaged endometrium carries a poor prognosis following hysteroscopic adhesiolysis.
the Wisdom Accumulation and Talent Cultivation Project of Third Xiangya Hosipital of Central South University, China(YX202112)
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