Abstract: To overview phytotherapy of vaginitis in order to identify new approaches for new pharmacological treatments. All related literature databases were searched for herbal medicinal treatment in vaginitis. The search terms were plant, herb, herbal therapy, phytotherapy, vaginitis, vaginal, anti-candida, anti-bacterial and anti-trichomonas. All of the human, animal and in vitro studies were included. Anti-candida, anti-bacterial and anti-trichomonas effects were the key outcomes. The plants including carvacrol, 1,8-cineole, geranial, germacrene-D, limonene, linalool, menthol, terpinen-4-ol and thymol exhibited anti-candida effects. A very low concentration of geranium oil and geraniol blocked mycelial growth, but not yeast. Tea tree oil including terpinen-4-ol, α-terpinene, γ-terpinene and α-terpineol showed anti-bacterial, anti-fungal and anti-protozoal properties against trichomonas. Allium hirtifolium (persian shallot) comparable to metronidazole exhibited anti-trichomonas activity due to its components such as allicin, ajoene and other organosulfides. The plants having beneficial effects on vaginitis encompass essential oils that clear the pathway that future studies should be focused to standardize theses herbs.
INTRODUCTION
Recognized as a prevalent medical problem in women, vulvovaginitis causes substantial discomfort and frequent medical visits. It may occur secondary to infection, allergy, irritation, or systemic disease. The most rampant causes of vaginal discharge in premenopausal women are bacterial vaginosis, vulvovaginal candidiasis and trichomonas vaginitis (Nyirjesy et al., 2006).
Bacterial vaginosis: Bacterial Vaginosis (BV), the most common reason of vaginitis in childbearing-age women, happens in up to 30% of the population. It arises when there is a complex change in vaginal flora, involving reduction in the prevalence of hydrogen peroxide-producing lactobacilli and an increase in that of anaerobic micro-organisms such as Gardnerella vaginalis, Prevotella, Peptostreptococcus and Bacteroides spp. (Livengood, 2009).
Notwithstanding that about half of the patients with diagnosable BV reveal no vivid symptoms, others may have a malodorous vaginal discharge or local irritation (Srinivasan and Fredricks, 2008). A simple and useful diagnostic criteria was established, requiring the presence of three of four clinical signs for diagnosis of BV. Criteria consists of homogeneous discharge, a positive whiff-amine test, pH >4.5 and the presence of clue cells (Turovskiy et al., 2011). Seven days of oral metronidazole (400 mg twice daily) or, vaginal clindamycin (1 g at night) are the first line recommended therapies. Single dose therapy of 2 g metronidazole has been shown to be less effective and is considered in the second line. Side effects of oral metronidazole involve a metallic taste, nausea, peripheral neuropathy and candida infection (Menard, 2011). According to the comparative studies, oral tinidazole, a second generation nitroimidazole has equal efficacy to oral and intra-vaginal metronidazole, tabletes and intra-vaginal clindamycin cream. Besides, tinidazole reveals less side effects. Overall, it conspicuously has better gastrointestinal tolerability and less metallic taste which are often reported in poor conformity to metronidazole therapy (Armstrong and Wilson, 2010).
Vulvovaginal candidosis: Vulvovaginal candidosis (VVC), the second most common reason of vaginitis, is recognized in up to 40% of women with vaginal complaints in the primary care setting (Ilkit and Guzel, 2011). About 70% of women underwent the infection-caused by Candida spp. at least once through their lives. Moreover, 40-50% of women will experience a reappearance (Corsello et al., 2003). The symptoms of vulvovaginal candidiasis encompass pruritus (itching), soreness, irritation, vulvar burning change in vaginal discharge and dyspareunia. Physical investigation often unveils discharge considered as thick, adherent and “cottage cheese-like”. In contrast, the discharge can be thin and loose and even resembling to the other types of vaginitis. The vaginal pH is typically 4 to 4. 5 and different in comparison to trichomoniasis or bacterial vaginosis (where the pH is heightened). Clinical diagnosis includes microscopic examination of the vaginal secretions for the purpose of diagnosis and separation of vaginal infections. Butoconazole, clotrimazole, miconazole, econazole, fenticonazole, sertaconazole, ticonazol, terconazole are diverse effective topical azole agents accessible in a variety of formulations for VVC treatment. In general, topical azoles are notably safe and well tolerated notwithstanding that subjects may complain of a burning sense. Besides, cure rates for topical azoles range from 80 to 90% and for oral azole agents, fluconazole, itraconazole and ketoconazole have even higher cure rates. In contrast, oral azoles can cause systemic toxicity dramatically with ketoconazole (Sobel, 2007).
Tricomonas vaginitis: Trichomoniasis is known as the most dominant sexually transmitted disease (Harp and Chowdhury, 2011). Tricomonas vaginalis is the causative agent of trichomonasis accounting for about 4 to 35% of vaginitis diagnosed in symptomatic women (Anderson et al., 2004). It varies from an asymptomatic to the critical inflammatory disease. Clinical signs and symptoms encompass vaginal discharge green to brown color, foul odor, edema or erythema and colpitis macularis (Harp and Chowdhury, 2011; Sood and Kapil, 2008). Clinical features of trichomonas vaginitis are not sensitive or specific ample to allow a diagnosis of trichomonal infection based on signs and symptoms alone. Hence, precise, reliable, accessible and economical laboratory diagnostic tests enact a fundamental role in the identification of T. vaginalis (Harp and Chowdhury, 2011). Currently metronidazole and the other 5-nitroimidazoles (tinidazole, ornidazole and secnidazole) provide curative therapy of trichomoniasis and remain the basis of therapy (a single oral dose of 2 g of metronidazole or 500 mg twice a day for seven days, or a single dose of 2 g of tinidazole), but metronidazole-resistance (MzR) against T. vaginalis, allergic reactions and failure to remedy the infection with two consecutive courses are its critical problems (Lofmark et al., 2010; Harp and Chowdhury, 2011).
Herbal medicine: Since long time ago, medicinal plants have been used for the remedy of enormous infectious diseases without any scientific evidence. At present, there is more emphasis on demonstrating the scientific evidence and rationalization of the use of these preparations. Immense research is in progress to identify plants and their active compounds against vaginitis pathogens for the purpose that they may provide an effective approach for treatment of vaginitis (Vermani and Garg, 2002). In the contemporary review, the plants exhibited beneficial effects on the treatment of vaginitis including BV, VVC and trichomonas vaginitis have been discussed.
METHODS
All electronic databases were searched for studies which investigated medicinal plants and their active compounds having effects on vaginitis. The search terms were plant, herb, herbal therapy, phytotherapy, vaginitis, vaginal, anti-candida, anti-bacterial and anti-trichomonas. Besides, the reference lists of articles were reviewed for extra pertinent studies.
Study selection: All of the human, animal and in vitro studies with key outcomes of anti-candida, anti-bacterial and anti-trichomonas activities were followed. Data were extracted according to study design, medicinal plant, family name, part of use, active compound and effects (Table 1-3).
RESULTS
Vulvovaginal candidosis: Ethanol extracts of Acalypha indica L., Allium cepa var. aggregatum L., A. cepa var. cepa L., A. sativum L., A. schoenoprasum L., Azadirachta indica A. Juss, Camellia sinensis (L) O. Ktze, Capsicum annum L., Cassia alata L., C. stula L., C. occidentalis L., Coffea arabica L., Curcuma longa L., Lawsonia inermis L., Ocimum sanctum L., Piper betle L. and Psoralea corylifolia L. manifested more anti-candida activity than others and it was observed that their active principle is more soluble in a non-polar solvent (Vaijayanthimala et al., 2000). Essential oils of Aloysia triphylla, Anthemis nobilis, Cymbopogon martini, Cymbopogon winterianus, Cyperus articulatus, C. rotundus, Lippia alba, Mentha arvensis, M. piperita, M. sp., Mikania glomerata, Stachys byzantina and Solidago chilensis had anti-candida activity. Chemical analyses unfolded the presence of compounds with eminent anti-microbial activity, including 1,8-cineole, geranial, germacrene-D, limonene, linalool and menthol (Duarte et al., 2005).
| Table 1: | In vitro studies considering the plants with beneficial effects on vaginitis |
| Table 2: | Animal studies considering the plants with beneficial effects on vaginitis |
| Table 3: | Human studies considering the plants with beneficial effects on vaginitis |
Essential oils of Pelargonium roseum, Rosmarinus officinalis, Artemisia sieberi, Communis hominis, Anethum graveolens, Citrus aurantifolia, Saturella hortensis, Foeniculum vulgare, M. spicata, Z. multiflora, Arthemesia dracunculus, Eucalyptus globulus and Lavandula estoechas exhibited inhibitory effect on C. albicans and G. vaginalis, whereas Z. multiflora showed the most activity (Bayat et al., 2008). Liquiritigenin (LG) and liquiritin (LQ), of root of Glycyrrhiza uralensi deterred growth of C. albicans yeast cells on in vitro. Moreover, LG sheltered mice from disseminated candidiasis by the CD4+ (cluster of differentiation 4) Th (helper) 1 immune response (Lee et al., 2009). The flowers extract of Inula viscosa uncovered anti-fungal activity against dermatophytes and candida species. These results may be revalent to the diverse flavonoids and different flavonoid concentrations in samples (Cafarchia et al., 1999). Essential oil of Lavandula angustifolia showed both fungistatic and fungicidal activity against C. albicans strains (D'Auria et al., 2005). Melaleuca alternifolia Cheel essential oils i.e., 1,8-cineole and terpinen-4-ol had anti-candida properties. Furthermore, terpinen-4-ol could control C. albicans vaginal infections in rat (Mondello et al., 2006). Essential oils of Origanum vulgare L., Satureja montana L. and Thymus vulgaris L. which are rich in thymol and carvacrol shed in anti-fungal activity against clinical isolates of pathogenic candida species (Jirovetz et al., 2007). A very low concentration of geranium oil and geraniol impeded mycelial growth, but not yeast growth on in vitro. Hence, that vaginal application of geranium oil or its main component, geraniol, would block candida cell growing in the vagina and its local inflammation since combine with vaginal washing is estimated (Maruyama et al., 2008). The extract of Sapindus saponaria L. showed anti-candida action against all isolates of yeasts C. albicans and C. non-albicans and the saponins isolated unveiled vigorous activity against C. parapsilosis (Tsuzuki et al., 2007). TTS-12 and TTS-15 (two saponins isolated of Tribulus terrestris L.) were very efficient against numerous pathogenic candida species and Cryptococcus neoformans on in vitro. Moreover, TTS-12 divulged imperative anti-fungal action on in vitro and in vivo, weakening the virulence of C. albicans and killing fungi through destroying the cell membrane (Zhang et al., 2005). In provided ethanol extracts of the rhizomes, aboveground portion of Trillium grandiflorum composed of the saponin glycosides 1 and 3 as the active components revealed paramount anti-fungal action (Hufford et al., 1988). While Zeamatin, a natural plant-derived anti-fungal protein plenteously born in corn, was ineffective alone, it reinforced the efficacy of both nikkomycin Z, a chitin synthase inhibitor and clotrimazole when they were given in combination (Stevens et al., 2002). The essential oil of Origanum syriacum can surpass the marketable douche materials in elimination and reducing the colonization and adaptability of the C. albicans (Kassaify et al., 2008). Sc-hmp (spirostanic saponins) had as clinical effectiveness as ketoconazole, but with lower percentages of mycological obliteration (Herrera-Arellano et al., 2009). The extract of Solanum nigrescens shed in anti-candida activity as the same as nystatin in patients (Giron et al., 1988).
Bacterial vaginosis: Lactobacilli and other organisms related to BV were susceptive to trichomonas tree oil, an essential oil from the leaves and twigs of M. alternifolia, on in vitro (Hammer et al., 1999). In another study, tea tree oil including terpinen-4-ol, α-terpinene, γ-terpinene and α-terpineol showed anti-bacterial, anti-fungal and anti-protozoal properties against trichomonas (Vila and Canigueral, 2006). Therapeutic effects of Zataria multiflora vaginal cream were parallel to metronidazole vaginal gel on BV in patients (Simbar et al., 2008).
Trichomonasis vaginitis: Allium hirtifolium (persian shallot) comparable to metronidazole showed anti-trichomonas activity, which it can be because of its components like allicin, ajoene and other organosulfides (Taran et al., 2006). Berberine derived from Berberis aristata on T. vaginalis in vitro showed potency comparable to metronidazole. On the other hand, it has the advantage of being more safe and probable replacement in metronidazole-resistant cases (Soffar et al., 2001). The alcoholic extracts of Calendula officinalis and Echinacea angustifolia revealed activity against T. vaginalis on in vitro (Samochowiec et al., 1979). The extracts of Myrtus communis and Eucalyptus camaldulensis caused death of T. vaginalis (Mahdi et al., 2006). The extract of Punica granatum (in vitro) and Commiphora molmol (human study) deEl-Sherbinicreased the pathogenicity of T. vaginalis (El-Sherbini et al., 2009). Emodin of the root and rhizome of Rheum palmatum L. manifested an inhibitory effect on T. vaginalis in mice (Hwang-Huei, 1993). Anapsos (Polypodium leukotomas extract) was effective against trichomonas pathogenicity as compared to those of the untreated control group (Nogal-Ruiz et al., 2003). In a study, the cure rate was 100% for T. vaginalis, 77% for C. albicans and 68% for BV in patient treated with PPT (Praneem polyherbal tablets) (Sharma et al., 2009).
DISCUSSION
In the present paper, we studied the plants having effects on vaginitis owing to three mechanisms encompassing anti-candida, anti-bacterial and anti-trichomonas activities. These plants noticeably involve essential oils showing anti-candida, in some cases anti-bacterial and even anti-trichomonas properties. For instance, carvacrol, 1,8-cineole, geranial, germacrene-D, limonene, linalool, menthol, terpinen-4-ol, thymol had anti-candida action (Duarte et al., 2005; Mondello et al., 2006; Jirovetz et al., 2007). A very low concentration of geranium oil and geraniol obstructed mycelial growth, but not yeast growth on in vitro (Maruyama et al., 2008). Tea tree oil including terpinen-4-ol, α-terpinene, γ-terpinene and α-terpineol exhibited anti-bacterial, anti-fungal and anti-protozoal properties against trichomonas (Vila and Canigueral, 2006). A. hirtifolium (persian shallot) comparable to metronidazole showed anti-trichomonas activity, which can be on account of some anti-trichomonas components encompassing allicin, ajoene and other organosulfides (Taran et al., 2006).
Vaginitis is a commonplace medical problem in women (Nyirjesy et al., 2006). Hence, there is an essential need to find new agents having more efficacy and safety rather than current ones. To use natural remedies dates back thousands of years. It is also calculated that there are 250,000-500,000 species of plants on Earth (Borris, 1996) that it can be a great hope to discover new pharmacological agents with more efficiency and less or no undesirable side effects.
To sum up, that essential oils have anti-candida, anti-bacterial and anti-trichomonas activities can be a new approach for the future researches in addition to the screening, standardization and combination therapy of the plants being efficient in treatment of vaginitis.