Topical therapy with hyaluronic acid following electrosurgical treatment of the uterine cervix.
F. Boselli, C. Vezzani, G. Chiossi
Gynaecology Cancer Prevention Clinic
University of Modena and Reggio Emilia
Colposcopy in Italy, Year XVIII — No.2 pages 25-28
Hyaluronic acid is a polysaccharide belonging to the glycosaminoglycan group (the acid mucopolysaccharides). It is the main anatomic and functional element of connective tissues, regulating the dynamic equilibrium of their constituents. It is a polymeric molecule composed of disaccharide units (N-acetylglucosamine and D-glucuronic acid) linked together by beta glycosidic bonds. The presence of carboxylic groups gives hyaluronic acid a high negative charge.
The aim of this study is to ascertain whether vaginal pessaries containing hyaluronic acid (Cicatridina® Vaginal Pessaries, Farma-Derma) are effective and safe as topical treatment given immediately following electrosurgical removal of lesions of the uterine cervix.
Between January and April 2001, 50 patients were recruited from women attending the Gynaecology Cancer Prevention Clinic at the Polyclinic in Modena. The patients were suffering from cervical intraepithelial neoplasia (CIN) of a variety of grades of severity and underwent radio-frequency electrosurgical treatment, either destructive or excisional (loop diathermy).
Following treatment, each patient inserted one vaginal pessary at night for 20 days, starting on the day of the treatment itself.
The mean age of the patients was 37.8 years, ranging from 22 to 61.
The patients underwent colposcopy 6 weeks after the treatment and were asked if they had had blood loss or subjective symptoms such as pain, burning or itching while using the pessaries. The colposcopist had to ascertain whether congestion, fibrosis, granulation, leukoplakia, endometriosis or stenosis were present in the cervix. At 6 weeks there was one case in which a small area of granulation tissue was still to be seen, and another case in which there was a report of a mild degree of fibrosis.
The final evaluation was recorded in a table with the following headings: excellent, good, fair and bad. The results were as follows: 48 (96%) excellent outcomes and 2 (4%) good outcomes. The 2 outcomes classified as good observed at 6 weeks were those due to a small area of granulation tissue and a case of mild fibrosis. There were no outcomes classified as fair or bad.
In conclusion, Cicatridina® Vaginal Pessaries, as our study shows, seem to be very effective in facilitating recovery from the damage caused by the high temperatures and surgical excision involved in electrosurgery. It is a topical drug based on the sodium salt of hyaluronic acid in doses of 5 mg per pessary, the topical use of which creates optimal conditions for the migration and proliferation of cells responsible for the healing process.
Patients suffering from cervical intraepithelial neoplasia (CIN) of varying grades of severity (CIN I, CIN II, CIN III) may undergo a destructive type of treatment (cryotherapy, coagulation diathermy, radiofrequency electrosurgery, CO2 laser treatment) or excisional treatment (cold knife cone biopsy, using CO2 laser, or loop diathermy). Following treatment there is a relatively extensive area of destruction of the cervical epithelial tissue and, in the case of conisation, a large crater. Such wounds normally heal, with re-epithelialization of the cervix in 20 to 40 days (1). Side effects may include heavy bleeding, superinfection of the wound, exuberant granulomatous tissue with a tendency to fibrosis, leukoplakia, endometriosis, stenosis of the cervical canal and cervical incompetence. Repair of cellular damage is a fundamental function of living tissues. The tissue response is comprised of a combination of different cells acting in association, for example that of the epidermis with connective tissue, or that of fibrous tissue with soft tissue. The specific reconstructive activity of mucous membranes, particularly that of the cervico-vaginal junction allows the internal structures to be protected, as well as the stability of a series of parameters, such as level of hydration and pH, to be maintained. Hyaluronic acid is a polysaccharide belonging to the group of acid mucopolysaccharide glycosaminoglycans. It is the principal functional anatomical element of connective tissue and maintains the dynamic equilibrium of its constituents. It is a polymeric molecule made up of a sequence of disaccharide units (N-acetyl glucosamine and D-glucuronic acid) joined together by a beta-glycosidic bond. It has a high negative charge due to the presence of carboxylic groups. The molecular weight depends on the degree of polymerization, that is to say on the number of disaccharide units present (2,3).
The aim of this study is to evaluate the efficacy and safety of pessaries containing hyaluronic acid (Cicatridina ® Vaginal Pessaries, Farma-Derma) used as topical treatment immediately following electrosurgery to uterine cervical lesions.
Materials and methods
During the period January to April 2001, 50 patients attending the Gynaecology Cancer Prevention Clinic at the Modena Polyclinic were recruited. The patients were suffering from cervical intraepithelial neoplasia (CIN) of varying grades of severity and underwent ablative radio-frequency electrosurgery or loop diathermy excision.
Criteria for inclusion for the patients were: informed consent; age over 18; not pregnant. HIV positive patients were excluded. Any adverse side effects had to be accurately reported.
Following treatment, every patient had a hyaluronic acid pessary inserted, every night for 20 nights, starting on the same day the procedure was carried out.
Each patient was then followed up by a gynaecologist who performed colposcopy 6 weeks after the date of the procedure. The data were recorded on special forms to allow for subsequent analysis.
Fifty patients were treated using electrosurgery: 14 with a destructive technique and 36 with excision. The 14 patients who underwent destructive treatment had a histological diagnosis of CIN grade I (CIN I) with or without signs of infection with human papilloma virus (HPV). Of the 36 patients undergoing excisional treatment, two had an initial and final diagnosis of CIN I, with squamo-columnar junction not visible; 15 had a final diagnosis of CIN II and 19 had a final diagnosis of CIN III (Table 1).
The average age of the patients was 37.8 years, with the youngest aged 22 and the oldest 61.
Follow-up assessment at 6 weeks was structured to include colposcopic examination of the uterine cervix and to record the patients’ observations regarding blood loss, and subjective symptoms such as pain, burning and itching during the time of pessary use following the electrosurgery. The colposcopist was required to note if there were any signs of cervical congestion, fibrosis, granulation, leukoplakia, endometriosis or stenosis. There were no reports of severe blood loss nor of any subjective symptoms. The 6-week check revealed one case with a small remnant of granulation tissue and one case with a clinical picture of mild fibrosis (Table 2). The final assessment was presented in a graphic with the following headings: excellent, good, fair, bad. Results were as follows: excellent in 48 cases (96.0%), good in 2 cases (4.0%), and no cases under the fair or bad headings (Table 3).
Table 1. – Patients undergoing electrosurgical treatment of the cervi
Table 2. – Follow-up check 6 weeks after treatment
|Complications||Grade of severity|
Table 3. – Overall final evaluation following treatment
Excision using loop diathermy leaves a crater in the uterine cervix of about 2 cm in diameter and a depth varying between 0.5 and 2 cm. With destructive treatment tissue damage is less and has a depth of approximately 1.5 cm.
In both cases, over and above success from the oncological point of view it is very important to achieve good healing and repair, avoiding as far as possible the formation of cervical stenosis, leukoplakia, endometriosis, fibrosis and over-exuberant and persistent granulation tissue, beyond that expected as a physiological response. It is important to avoid severe bleeding and superinfection of the wound in the cervix. The process of repair of the vaginal mucosa involves several stages, each one of which is characterized by distinctly different types of cellular activity. Immediately following an insult there is a phase which can be described as vasculoinflammatory and which represents the primary response of the organism to the lesion. Perilesionally there is an influx of numerous cells from among the leucocytes whose function it is to clean up the necrotic area, to dispose of pathogens, dead cells and decomposing fibrous tissues. The cells with this specific function are called macrophages. The cleansing of the lesion is an important and indispensable stage for the subsequent activation of another population of cells which have a specific role in the process of repair: the fibroblasts, which produce the fundamental components of connective tissue such as collagen fibres and hyaluronic acid (2,3,4). The umbrella name given to the regenerative tissue complex is granulation tissue. The final phase of tissue repair is carried out by the epithelial cells which migrate via exudate from the healthy margins to cover over the granulation tissue. Within the basic connective tissue material, hyaluronic acid is either free or associated with other glycosaminoglycans and proteins to form macromolecular aggregates known as proteoglycans. In these macromolecules, hyaluronic acid represents the carrier, by means of bonding proteins, linking up the various glycosaminoglycans. Connective tissue hyaluronic acid is not only a structural component but takes an active part in various functions of the tissue itself. It provides the tissue with tone, trophism and elasticity which depend also on the activity of the cellular, fibrillary and vascular structures present in the exudate. The hyaluronic acid interacts with water and forms a highly dispersed molecular reticulum which is indispensable for the selective diffusion of trophic substances. The fundamental material in connective tissue is in a state of continual renewal and there is a dynamic equilibrium between synthesis of hyaluronic acid by the fibroblasts and its degradation by hyaluronidase. The importance of hyaluronic acid is attributed to its activity as a mediator of cellular migration, hastening the healing of wounds in that it influences the activity of populations of cells involved in the process of tissue repair. Hyaluronic acid influences the formation of coagulum, activity of phagocytes, motility and proliferation of fibroblasts, angiogenesis, deposition of matrix and finally re-epithelialization (2,3,4). Within the fibrin coagulum, an increase in the synthesis of hyaluronic acid can be detected, which not only has a structural role (interaction with fibrin) but also a modulatory role in the migration of inflammatory cells. By interacting with fibrin, hyaluronic acid stabilizes the coagulum, making it more porous and thus forms an ideal reticulum for the ingress of phagocytic cells. In addition, it has a stimulant effect, both in terms of chemotaxis and polymorph phagocytic activity; owing to the increased phagocytic activity of the polymorphonuclear cells and macrophages it promotes the removal of detritus from the area around the lesion, and by stimulating fibroblasts it paves the way for deposition of new matrix. It has a qualitative effect on the deposition of granulation tissue matrix and thus plays a fundamental role influencing the tensile strength of the lesion. Finally, in the process of re-epithelialization, the presence of hyaluronic acid , keeping the tissue well hydrated, provides favourable conditions for the migration of epithelial cells. The interaction of hyaluronic acid with the macromolecules of the matrix is a key determinant for the formation of an ideal local substrate for cellular migration.
As demonstrated in our study, Cicatridina® Vaginal Pessaries would appear to enhance the process of good healing following the thermoexcisional damage caused by electrosurgical treatment.
This is a preparation of the sodium salt of hyaluronic acid, 5 mg per pessary, the topical use of which creates optimal conditions for the migration and proliferation of cells central to the repair process.
Incorporation of soothing ingredients such as Centella (60 mg), Aloe Vera (60 mg) and Calendula (60 mg) is effective in improving inflammatory symptoms, burning and itching, which are often present in patients who undergo physical treatment of the cervix (5,6).
In addition, the essential oil from Melaleuca plants (2 mg) gives the product antiseptic properties as it has a predominantly germicidal action against bacteria, fungi and viruses. Its active ingredients act by damaging the wall or membrane of the micro-organism thus bringing about lysis and/or denaturing of the proteins which compose its cell but not harming healthy tissues. Melaleuca oil has no detrimental effect on the saprophytic flora and has no side effects.
1. PICCOLI, R; BOSELLI, F; SANTORO, MG: Gynaecology Outpatient Treatment EUI International Libraries Edition 19971
1 Reference No.1 is a translation from Italian. Remainder of bibliography is in English.