Many studies in recent years have shown that the occurrence of cervical cancer is related to the imbalance of vaginal microecology, which is one of the dubious problems faced by our clinical workers in obstetrics and gynecology. In this session of the Obstetricians and Gynecologists Branch of the Chinese Medical Association, Prof. Rui-Fang An gave us a detailed explanation of the relationship between vaginal microecology and cervical lesions, which was compiled by Chinese Obstetrics and Gynecology Online for your reference and study.
Vaginal flora
More than 50 microorganisms including bacteria, fungi, viruses and protozoa can be isolated from vaginal secretions. 92.5% of healthy women have detectable lactobacilli in the vagina with H2O2.
Lactobacillus is the dominant vaginal physiological bacterium that can maintain vaginal microecological balance and resist lower genital tract infections. The specific mechanisms are: first, Lactobacillus can produce acid, H2O2 and other antibacterial substances; second, perform blanket occupancy (competition for adherence to vaginal epithelial cells); third, competition for nutrients (e.g. glycogen); and fourth, stimulation of local immune responses in the vagina.
Vaginal microecology
Microecology refers to the branch of ecology that studies the interrelationship between the normal microbiota and its hosts. Female vaginal microecology is a very sensitive system that is susceptible to alteration by endogenous and exogenous factors.
The components of vaginal microecology include the unique anatomy of the female lower genital tract, local immunity, microflora, and endocrine regulation, with the microflora being the central component of vaginal microecology research.
Vaginal microecology, as a complex ecosystem, varies with the age of the host. It is in dynamic balance during menstrual cycle, pregnancy and different physical conditions, and this balance is beneficial for the health of the host. It has been found that any alteration in the ecological balance of the vaginal flora has a significant impact on the onset and progression of disease and plays a pivotal role in the course and determination of the disease.
There are many factors affecting vaginal microecology, such as normal vaginal microecology affected by external forces, surgery, childbirth, incorrect vaginal douching, unclean sex, etc., which can disrupt the microbiota structure and anatomical barrier function; low ovarian function, systemic diseases, high doses of antibiotics, anti-tumor drugs or immunosuppressant use, which can result in altered vaginal microecology, and these can cause dysbiosis, which can lead to the development of infectious diseases – inflammation of the lower genital tract.
Evaluation system of vaginal microecology
The vaginal microecology is evaluated by five morphological descriptions, including vaginal flora density, vaginal flora diversity, dominant bacteria, organismal inflammatory response, and causative bacteria, combined with six functional indicators, such as vaginal pH, hydrogen peroxide, leukocyte esterase, sialoglucosidase, β-glucuronidase, and acetylaminoglucosidase. The normal indicators of vaginal microecology (six items) are: 1) Intensity II-III; 2) Diversity II-III; 3) Dominant bacteria, Gram-positive macrophages G+b(L); 4) Inflammatory response, leukocytes 0-5/high magnification field; 5) PH ≤ 4,5; 6) H2O2 (-). At present, our hospital is using the vaginal microecological evaluation system recommended by the Chinese Medical Association Gynecological Infection Group and developed by Jiangsu Shuoshi Biotechnology Co. The system consists of a microscopy system and a functional science detection system, which is an automated test to comprehensively analyze the main influencing factors of vaginal microecological balance and directly attack the root cause of vaginal infection. While making an accurate diagnosis of the condition, it can also obtain the patient’s true health status, better guide treatment, assess prognosis, and avoid superficial cure and overtreatment.
Clinical studies on vaginal microecology
I. Vaginal microecology and HPV infection
In 2006, Tanner and Alexander suggested that the detection rate of anaerobic bacteria, especially Prevotella, was 10 times higher than the normal vaginal flora in patients with HPV infection.
1. HPV infection causes a decline in vaginal lactobacilli
A cohort study from Korea examined the correlation between vaginal microflora and HPV infection. The results showed that the percentage of vaginal lactobacilli was significantly lower in the infected group (mean 47%) compared to the HPV uninfected group (mean 77%). In particular, in heterozygous twins, a significant reduction in inert Lactobacillus vaginal microbiota was associated with HPV infection (p=0.03). In addition, HPV infection is closely associated with many vaginal microbial species, particularly Clostridium spp. and Ciliophora spp. which are considered to be microbial markers of HPV infection.
2. HPV infection and more diverse and complex vaginal flora
In 2013, a cross-sectional study from China explored the comparison regarding the diversity of vaginal flora in women in relation to HPV infection. Their results found that the diversity and composition of the flora was more complex in the HPV-positive group compared to the HPV-negative group. Moreover, the detection rates of Gardnerella vaginalis and Lactobacillus garciae were higher in the HPV-positive group than in the HPV-negative group. This leads to the conclusion that vaginal microecological imbalance may act as a synergistic factor for HPV infection and that an in-depth study of the interaction between the two may provide new insights into the development of early cervical cancer lesions.
II. Vaginal microecology and cervical precancerous lesions
1.Cervical precancerous lesions cause changes in lactobacilli
Cervical precancerous lesions often combine with bleeding, necrosis, cervical canal adhesions and obstruction, which affect the physiological defense function of the cervix and vagina, resulting in the dominance of Lactobacillus in the vagina being replaced by a large number of other flora. Lactobacillus is significantly reduced in number, and even if it is not reduced in number, its strains and microbial characteristics are fundamentally changed, causing an imbalance in the vaginal environment.
2. Lactobacillus is a progressive factor in intraepithelial neoplasia
A study related to a Brazilian expert investigated the factors influencing the progression of low-grade intraepithelial neoplasia (LSIL) and unexplained intraepithelial neoplasia, as well as related cytohistological issues. The study was conducted in patients with cytological diagnosis of (LSIL) and intraepithelial neoplasia of unknown cause. Of these, 2,184 patients had reduced lactobacilli and 214 patients progressed to HSIL!
Their study concluded that Lactobacillus is an influential factor in the progression of LSIL or CIN of unknown cause to HSIL.
3. There is a correlation between BV and CIN
A relevant systematic review and meta-analysis of studies by Belgian experts confirmed that there is a correlation between BV and CIN, highlighting the potential role of vaginal micro-ecological dysregulation between various gynecological complications.
4. Microecological dysregulation and HPV infection are risk factors for cervical precancerous lesions
Experts in Korea have also conducted studies related to cervical microecology and increased risk of CIN. The cervical microbiota with Atobacter vaginalis, Gardnerella and Lactobacillus inertus as the dominant bacteria, accompanied by a decrease in Lactobacillus curvatus, can increase the risk of CIN development. This suggests that microecological dysbiosis combined with oncogenic HPV infection may be a risk factor for cervical neoplasia.
III. Vaginal microecology and cervical cancer
1. Lactobacillus vaginalis can kill cervical cancer cells
Iranian experts have done related Iranian studies to investigate the difference between normal cells and cervical cancer cells in response to Lactobacillus vaginalis and whether it is affected by PH and lactic acid.
It is known that cervical cancer is associated with HPV infection, but most HPV infections are gradually cleared after transient or intermittent infection. Therefore, factors such as the Lactobacillus-dominant microbiota must be associated with progression to cervical invasive cancer after HPV infection. Some reports have shown that Lactobacillus has antitumor effects and that vaginal Lactobacillus may prevent cervical cancer.
The study by this Iranian expert concluded that common Lactobacillus vaginalis exerts cytotoxic effects on cervical cancer cells, while it has no effect on normal cells, and this cytotoxic effect is independent of pH and lactic acid. This study supports the use of common Lactobacillus vaginalis as a probiotic for dosing.
2. BV, CV and VVC are associated with HPV infection
Based on the above, we also conducted a related study.In June 2015, we collected 127 patients who underwent vaginal microecology + HPV testing, aged 22-65 years (mostly 26-43 years) and 6 menopausal women.
Test results: 35 cases of HPV (+) and 92 cases of HPV (-), all patients had clinical manifestations mainly with symptoms of infection in the lower genital tract. According to the analysis of HPV infection and vaginal microecological results, the most common dysbiosis remained bacterial vaginosis (BV), intermediate BV, cytosolic vaginosis (CV), and VVC. the incidence of BV when HPV positive was 17.14%, while the incidence of BV when HPV negative was 9.78%, a large difference. Similarly, the incidence of CV was 11.43% for HPV positive and 4.35% for negative, with a statistically significant difference. However, the opposite was true for VVC, which was only 5.71% in HPV-positive patients compared to 14.13% in negative ones, and this may be related to the small sample in our study, but our study is still ongoing.
Our study showed that dysbiosis accounted for 19.69% of the patients investigated; intermediate BV was more prevalent in women of childbearing age; BV, CV and VVC were associated with HPV infection. And other scholars have shown that increased vaginal PH is associated with HPV infection. However, this phenomenon was not found in our study. This should be related to the sample size and needs further observation.
3. Vaginal microecological imbalance can lead to cervical cancer
Many studies in recent years have shown that the occurrence of cervical cancer is related to vaginal microecological imbalance! The decrease of vaginal lactobacilli, as well as the proliferation of Gardnerella or mixed anaerobic bacteria, produce many harmful metabolites. In addition, other carcinogenic factors, such as HPV and human cytomegalovirus infection, combine to act on the cervix and accelerate the development of cervical cancer.
4.Lactobacillus is expected to become an important target for cervical cancer treatment
Overall, Lactobacillus, the dominant strain of female vagina, plays an anti-inflammatory and anti-tumor role. It has been proved that the decrease of Lactobacillus is closely related to the occurrence of CIN and cervical cancer, but the research on the mechanism of the impact on cervical lesions is still superficial, suggesting that we should explore the impact of Lactobacillus and its metabolites on cervical lesions from microscopic level in the future. With the continuous development and improvement of cervical lesion prevention and treatment methods, Lactobacillus will play a more important role in all aspects of its occurrence, development and regression!