Introduction
A cervical erosion (or cervical ectropion) can occur for numerous reasons among women of childbearing age (1). It is considered a benign condition caused by pathogens or induced by increased exposure of the cervical epithelium to estrogen. Moreover, cervical erosions can be of traumatic, mechanical etiology, such as intrauterine devices or foreign bodies introduced into the vagina (2). Its prevalence ranges from 17 to 50% (3,4). The presence of ectropion is detected especially after the menarche, during pregnancy or with use of the combined oral contraceptive pill and is very rare in postmenopausal women (5).
Epithelialization of the vaginal mucus and cervix is crucial in the management of cervical erosions. Acute inflammation of the cervix as a result from direct infection or trauma translates into several symptoms, such as white to yellow vaginal discharge (predominant symptom caused by the mucus-secreting glandular epithelium), post-coital or intermenstrual bleeding, dysuria, pelvic pain, vulvovaginal irritation and dyspareunia (6). Symptomatic women should be screened for infective agents (7). Cervical ectropion has been associated with both the combined oral contraceptive pill and intrauterine contraceptive devices as highlighted by the study conducted by Wright et al (4). Concurrently, a number of studies have highlighted that the use of combined oral contraceptives is highly associated with the development of cervical ectopy, edema and erythema of the ectopic zone (7-9).
Pathogens such as streptococci, staphylococci, or enterococci can be promoters of acute inflammation of the cervix and cervical ectropion (10). Cervicitis (inflammation of the cervix) is often asymptomatic and can cause complications of the upper genital tract with ectopia and cervical infection by Chlamidia trachomatis, Neisseria gonorrhoeae, herpes simplex virus, and cytomegalovirus (11). Some factors involved in the pathogenesis of cervical ectopy involve the action of estrogen (12). Estrogens influence immune and inflammatory processes, by regulating chemokines and chemokine receptors. In a previous study by Straub, the complex processes of inflammation related to estrogen signaling toward immune cell trafficking were studied (13). The T helper 17 cells producing IL-17 are the main T cells responsible for chronic inflammation. The cervical epithelium is highly responsive to estrogen production. Mechanistically, it is considered that estrogens induce apoptosis in cervical cells and also increase gene expression of human papillomavirus-16 and -18, the two genotypes frequently associated with cervical cancer (14). Exposure to high levels of estrogen is also linked to an increased risk of breast cancer (15). Estrogen influences immune and inflammatory processes by modulating the production of pro-inflammatory cytokines, chemokines and other immune mediators. Specifically, estrogen can activate pathways that lead to the production of anti-inflammatory cytokines, such as interleukin-4 (IL-4), and chemokines, such as interferon-γ (IFN-γ) (16). Furthermore, estrogen can inhibit the production of pro-inflammatory mediators such as tumor necrosis factor (TNF) and IL-6. Estrogen can also regulate the expression of chemokine receptors on immune cells, which in turn helps regulate the migration of immune cells to sites of inflammation (17). For example, estrogen can downregulate the expression of the CCR5 receptor, which is involved in the migration of T cells to sites of inflammation. Estrogen can also upregulate the expression of the CXCR4 receptor, which is involved in the migration of macrophages and neutrophils to sites of inflammation (18).
The presence of endocervical columnar epithelium on the ectocervix favors an increased exposure to infections due to low cell-mediated immunity. In these areas, the subpopulation of T lymphocytes, namely, T helper cells, CD8 cells, and CD1 lymphocytes are reduced in number (19). Therefore, the columnar epithelium cells are more susceptible to infections such as Chlamydia trachomatis or Neisseria gonorrhoeae (20). Estrogens are capable of markedly altering the responses of host cells to microbes. In adolescence, pregnancy, during hormonal contraception, or during the years of menstruation (mostly in the ovulatory phase), the probability of developing cervical ectopy is very high, and sometimes goes undetected (5). Furthermore, cervical ectopy implies further risks of acquiring sexually-transmitted diseases (gonorrhea, chlamydia and human papilloma virus). In the study conducted by Sanchez et al a causal relationship was found between cervical erosion and bacterial vaginosis that alter the mucosal barrier and decrease defense mechanisms of the cervix and vagina (21).
An ongoing debate remains of whether ectopy requires a specific treatment. The association between squamous metaplasia and induction of squamous cell carcinoma of the cervix is well known. Moreover, the dysplastic cells are more susceptible to carcinogens (22). Notwithstanding this, according to a recent study conducted by Kleppa et al, ectopy may be a biological risk factor for chlamydia infection and for human immunodeficiency virus (HIV) in adolescents and in young women (7).
Currently, cryotherapy (cryosurgery) of the cervix is the standard treatment for symptomatic, benign cervical ectropion (23). Cryosurgery improves the cervical mucus characteristics and therefore it is recommended in patients with hostile cervical mucus and ectropion (24). Prior to and after surgery, adjuvant treatments should be promoted with the support of local, re-epithelizing treatments (25). For example, Belfiore et al reported the effectiveness of a topical treatment for cervical ectropion with 5 mg of deoxyribonucleic acid (26).
Cerviron® has a substance content that provides beneficial properties in non-infectious vulvovaginitis and cervical erosion. The ovule melts in the vaginal mucosa forming a cream that ensures dispersion of the substances contained and acst as a protective barrier with an astringent effect, favouring the reepithelization of damaged tissue and the restoration of the initial colpoecosystem without affecting the Döderlein bacilli. The main mechanism of action of the medical device is the dispersion of the substances in the vagina and the formation of a protective barrier that accelerates the natural healing process of the damaged epithelium.
Performance and safety data on Cerviron® vaginal ovules have been reported from multiple sources. Three clinical investigations on Cerviron were reported (NCT04735705, NCT04735718 and NCT05652959 available at https://clinicaltrials.gov/ct2/show/NCT04735705; https://clinicaltrials.gov/ct2/show/NCT04735718; and https://clinicaltrials.gov/ct2/show/NCT05652959, respectively) and published articles on Cerviron® include the characterization of its utility in the management of cervical uterine fibroids and on vaginal atrophy after surgical treatment and adjuvant radiation therapy for cervical cancer (27,28). However, previous safety data was limited and included only a restricted, homogenous population, including 50 participants in study NCT04735705 and only 27 participants in study NCT04735718.
Cerviron® is a medical device marketed by Perfect Care Distribution in the following countries: Albania, Latvia, Lithuania, Estonia, Kosovo, Montenegro, Romania, Kuwait, and the United Arab Emirates. With a complex composition including hexylresorcinol, collagen and bismuth subgallate, and four phytotherapeutic extracts including Calendula officinalis, Hydrastis canadensis, Thymus vulgaris extract and Curcuma longa, it is intended as adjuvant treatment for the management of cervical lesions and vulvovaginitis.
Discussion
A very important aspect that influences the management of cervical ectopy is age. Cervical ectopy is predominant in young adolescents, with a prevalence of up to 80% in sexually active adolescents (30). However, factors associated with the evolution and devolution of cervical ectopy are diverse and mechanisms have yet to be elucidated. Since ectopy is observed frequently in adolescent girls and pregnant women, it may vary in response to hormonal fluctuations observed in pregnancy and during contraception with combined oral contraceptives (30). Screening for Chlamydia trachomatis and Neisseria gonorrhoeae can prevent a range of gynecological conditions, such as urethritis, cervicitis, cervical erosions (31). Infection in the lower genital tract can result in upper genital tract complications, such as pelvic inflammatory diseases, ectopic pregnancy, chronic pelvic pain, and infertility in asymptomatic women, and transmission of infection during pregnancy and labor (32).
Cryotherapy (cryosurgery) of the cervix is an effective treatment for symptomatic cervical ectropion (33). Other surgical techniques have been applied for ablation of the squamocolumnar junction. Cauterization has been applied for this purpose since 1920, but it involves additional risks, such as burning lesions if the safeguard plate is not located correctly (34). Some specialists even consider the cervical ectropion as a normal finding that does not require treatment despite the red and inflamed appearance of the cervix. However, cervical ectropion is considered as one of the most common types of chronic cervicitis worldwide (35). Topical treatments for cervical ectropion, including cervical painting with gentian violet paint or microwave tissue coagulation, are still widely used (4). Although the debate is still ongoing, a harmonized treatment strategy would reduce complications of cervical ectropion, such as developing abnormal metaplasia and/or vaginal infection. Applying an intervention to treat cervical ectopy is recommended, especially when considering taking preventive action against cervical cancer. Ectopic cells are modified over time by squamous metaplasia and epithelialization, cervical infection with Neisseria gonorrhea or Chlamidia trachomatis, low pH values or trauma (12). Cerviron® appears to have a very potent action in rebalancing the vaginal pH. In a previous clinical investigation, NCT04735705, vaginal pH values measured over 90 days showed that Cerviron® restores altered vaginal pH. The difference in vaginal pH values between baseline vs. 90 days, at a 5% significance level was statistically significant (P<0.05).
A literature review conducted by Machado et al indicated that treatment can be used to relieve occasional symptoms associated with ectopy, but does not support routine treatment for ectopy (12).
By contrast, a study conducted by Soares et al, showed a positive association between cervical ectopy and human papillomavirus, HIV, bacterial vaginosis, cervical epithelial atypia, postcoital bleeding, and desquamative inflammatory vaginitis (36). Recognition of cervical ectopy should alert the clinician to the possibility of a genital chlamydia infection. Opportunistic screening for chlamydia in young people should be offered to reduce the prevalence of infection and its sequelae. Chlamydia trachomatis is the most common bacterial sexually transmitted disease. In women, chlamydial infection usually presents as cervicitis, which can lead to up to 30 to 50% of pelvic inflammatory disease episodes. Pelvic inflammatory disease has significant reproductive sequelae, such as tubal infertility and ectopic pregnancy (37).
The main mechanism of action of the medical device is the dispersion of the substances in the vagina and the formation of a protective barrier that accelerates the natural healing process of the damaged epithelium.
The effect of the medical device is obtained due to the presence of the bismuth subgallate and vegetable collagen. Bismuth subgallate is an insoluble solution, with a very low bio-availability which will create a physical barrier over the affected area of the vaginal mucosa and therefore will not allow oxygen and pathogens to come into contact with it (38,39). In this way, the substances create the premise that allows the damaged tissue to heal naturally. The role of exogenous collagen is to be a "sacrificial substrate" in order to reduce excess metalloproteins that delay wound healing and to regulate the healing of damaged tissue (14,40-43). As such, Cerviron® supportive therapy may be prescribed in sexually active patients for at least 1-3 months, 10-15 consecutive days, to prevent these infections.
The findings in the present study revealed that a 90-day treatment (3 treatment sessions of 30 days each) with Cerviron vaginal ovules was beneficial in providing a complete degree of cervical epithelialization and reduced the multitude of the vaginal symptoms, including bleeding, inflammation, malodor, dysuria, dyspareunia, pain and leukorrhea. This result is consistent with previous clinical studies that included the same medical device, NCT04735705 and NCT04735718(44).
In conclusion, the findings of the present study revealed that administration of Cerviron® vaginal ovules provided a complete degree of epithelization in majority of patients attending a 90-days tretatment. Moreover, subjects presenting a high grade of ulceration at the baseline visit, following treatment with Cerviron® presented a complete degree of epithelization. Cerviron® ovules are an exceptional adjuvant for acceleration of healing of cervical erosions. They favor the re-epithelialization of the damaged tissue and restoration of the initial colpo-ecosystem. Their topical application was observed to be effective in reducing unpleasant symptoms such as vaginal discharge, pelvic pain, and vaginal bleeding. In terms of adverse events, the medical device is considered safe. The only contraindication to Cerviron® ovules has been determined as hypersensitivity to the active substance or to any of the excipients within the medical device.