The Role of Different Medical Therapies in the Management of Adenomyosis: A Systematic Review and Meta-Analysis.

Background/Objectives: Adenomyosis is a benign condition characterized by the presence of endometrial tissue within the myometrium. Despite surgery being a valuable approach, medical options are considered as the first-line approach and have been investigated in the treatment of adenomyosis, although strong evidence in favor of these is still lacking. This study aims to gather all available data and determine the effectiveness of the aforementioned medical options in patients with associated pain and not currently seeking pregnancy, both in comparison to placebo and to one another. Methods: For this study, PubMed and EMBASE were used as data sources, searched up to January 2024. A systematic review and meta-analysis were performed in accordance to guidelines from the Cochrane Collaboration. The primary outcomes investigated were changes in dysmenorrhea, quantified by means of VAS scores, HMB in terms of number of bleeding days, and changes in uterine volume determined at ultrasound. Twelve eligible studies were selected. Results: The results highlighted that dienogest yields a reduction in dysmenorrhea that is significantly superior to that of the rest of the medical treatments investigated (p-value of <0.0002). On the other hand, GnRH agonists seem to play a more prominent role in reducing uterine volume (p-value of 0.003). While it was not possible to determine which medical treatment better decreased the number of bleeding days, it was observed that COC performed significantly worse than the other treatments studied (p-value of 0.02). Conclusions: While this meta-analysis provides valuable insights in the comparative efficacy of different treatments, the paucity of relevant studies on the topic might impact the reliability of some of the conclusions drawn.

Common Microbial Genital Infections and Their Impact on the Innate Immune Response to HPV in Cervical Cells.

The persistence of high-risk (HR) human papillomavirus (HPV) genotypes is a prerequisite of cervical cancer. It is not clear whether and how bacterial vaginosis (BV) and sexually transmitted infections (STIs) cause higher rates of persistent HPV infection. This study aimed to characterize mucosal innate immunity to HPV, comparing different conditions. Specifically, expression levels of genes coding for Toll-like receptors (TLR)7 and 9, several type III Interferon-related genes (IFNL1, 2, 3, their specific receptor subunit IFNLR1, and the IFN-stimulated gene ISG15). Chemokines CCL5 and CCL20 were measured in cervical cells positive, or not, for HPV, BV, and STIs. HPV DNA was detected in 51/120 (42.5%) enrolled women, two/third were HR-HPV genotypes. More than 50% of samples were BV- and/or STI-positive. HPV-positive women had BV, but not other STIs, more frequently than the HPV-negative. TLR9 and IFNL1 mRNAs were expressed in the LR, but much less in the HR HPV infection. Enhanced levels of TLR9, TLR7, IFNL2, and IFNLR1 were observed in HPV-positive women with BV and STI. TLR9-increased expression was associated with HPV persistence in previous studies; hence, bacterial coinfections may enhance this risk. Prospective measurements of type III IFNs and IFNLR1 are warranted to evaluate whether this response may act as a double-edged sword in infected epithelia.

HPV Vaccination after Primary Treatment of HPV-Related Disease across Different Organ Sites: A Multidisciplinary Comprehensive Review and Meta-Analysis.

OBJECTIVE: To assess evidence on the efficacy of adjuvant human papillomavirus (HPV) vaccination in patients treated for HPV-related disease across different susceptible organ sites. METHODS: A systematic review was conducted to identify studies addressing the efficacy of adjuvant HPV vaccination on reducing the risk of recurrence of HPV-related preinvasive diseases. Results were reported as mean differences or pooled odds ratios (OR) with 95% confidence intervals (95% CI). RESULTS: Sixteen studies were identified for the final analysis. Overall, 21,472 patients with cervical dysplasia were included: 4132 (19.2%) received the peri-operative HPV vaccine, while 17,340 (80.8%) underwent surgical treatment alone. The recurrences of CIN 1+ (OR 0.45, 95% CI 0.27 to 0.73; p = 0.001), CIN 2+ (OR 0.33, 95% CI 0.20 to 0.52; p < 0.0001), and CIN 3 (OR 0.28, 95% CI 0.13 to 0.59; p = 0.0009) were lower in the vaccinated than in unvaccinated group. Similarly, adjuvant vaccination reduced the risk of developing anal intraepithelial neoplasia (p = 0.005) and recurrent respiratory papillomatosis (p = 0.004). No differences in anogenital warts and vulvar intraepithelial neoplasia recurrence rate were observed comparing vaccinated and unvaccinated individuals. CONCLUSIONS: Adjuvant HPV vaccination is associated with a reduced risk of CIN recurrence, although there are limited data regarding its role in other HPV-related diseases. Further research is warranted to shed more light on the role of HPV vaccination as adjuvant therapy after primary treatment.

Selected Immunological Mediators and Cervical Microbial Signatures in Women with Chlamydia trachomatis Infection.

In the female genital ecosystem, the complex interplay between the host immune system and the resident microflora protects against urogenital pathogens, like Chlamydia trachomatis C. trachomatis is responsible for urethritis and cervicitis; however, most chlamydial infections are asymptomatic and, thus, not treated, potentially leading to severe reproductive sequelae. Here we investigated the interaction between the levels of selected immune mediators and the community state types of the cervical microbiota in C. trachomatis-infected women. Cervical samples from 42 C. trachomatis-positive women and 103 matched healthy controls were analyzed through the metagenomic analysis of the hypervariable region v4 of the 16S rRNA gene and the determination of lactoferrin, interleukin 1α (IL-1α), IL-6, alpha interferon (IFN-α), IFN-ß, and IFN-γ by ELISA. Overall, C. trachomatis infection was significantly associated with a microbiota dominated by anaerobic bacteria (P = 0.000002). In addition, a network of Gardnerella vaginalis, Prevotella amnii, Prevotella buccalis, Prevotella timonensis, Aerococcus christensenii, and Variovorax guangxiensis has been identified as a potential biomarker of C. trachomatis infection through multiple statistical approaches. Again, chlamydial infection was significantly correlated with an increased production of lactoferrin, IL-6, IL-1α, IFN-α, and IFN-ß (P < 0.05), whereas very low levels of IFN-γ were observed in C. trachomatis-infected women, levels similar to those detected in healthy women. Our findings show a distinctive signature of C. trachomatis genital infection, characterized by a specific bacterial network, constituted by anaerobes, as well as by increased levels of lactoferrin and proinflammatory cytokines (IL-1α, IL-6, IFN-α, and IFN-ß), accompanied by low levels of IFN-γ.IMPORTANCE To our knowledge, this is the first study that investigated the association of C. trachomatis with the cervical levels of lactoferrin and selected inflammatory mediators and their correlation with the different community state types characterizing the female genital ecosystem. C. trachomatis, known as the leading cause of bacterial sexually transmitted diseases, continues to be an important public health problem worldwide for its increasing incidence and the risk of developing severe reproductive sequelae, like pelvic inflammatory disease and infertility. Specifically, C. trachomatis tend to persist in the female genital tract, leading to a chronic inflammatory state characterized by increased production of immune mediators responsible for tissue damage. Therefore, our study may help to broaden the knowledge on the complex interplay between the female genital microbiota and the host immune system in response to C. trachomatis infection.

Long-term Lactobacillus rhamnosus BMX 54 application to restore a balanced vaginal ecosystem: a promising solution against HPV-infection.

BACKGROUND: Over recent years, a growing interest has developed in microbiota and in the concept of maintaining a special balance between Lactobacillus and other bacteria species in order to promote women's well-being. The aim of our study was to confirm that vaginal Lactobacilli long-lasting implementation in women with HPV-infections and concomitant bacterial vaginosis or vaginitis might be able to help in solving the viral infection, by re-establishing the original eubiosis. METHODS: A total of 117 women affected by bacterial vaginosis or vaginitis with concomitant HPV-infections were enrolled at Department of Gynecological Obstetrics and Urological Sciences, La Sapienza University, Rome, Italy between February 2015 and March 2016. Women were randomized in two groups, standard treatment (metronidazole 500 mg twice a day for 7 days or fluconazole 150 mg orally once a day for 2 consecutive days) plus short-term (3 months) vaginal Lactobacillus implementation (group 1, short probiotics treatment protocol group, n = 60) versus the same standard treatment plus long-lasting (6 months) vaginal Lactobacillus rhamnosus BMX 54 administration (group 2, treatment group, n = 57). RESULTS: After a median follow up of 14 months (range 9-30 months) the chance to solve HPV-related cytological anomalies was twice higher in probiotic long-term users (group 2) versus short probiotics implementation group (group 1) (79.4% vs 37.5%, p = 0.041). Moreover, a total HPV-clearance was shown in 11.6% of short schedule probiotics implementation patients compared to a percentage of 31.2% in vaginal Lactobacilli long term users (p = 0.044), assessed as negative HPV-DNA test documented at the end of the study period. CONCLUSIONS: The consistent percentage of clearance of PAP-smear abnormalities and HPV-clearance obtained in long-term treatment group has been interestingly high and encouraging. Obviously, larger and randomized studies are warranted to confirm these encouraging results, but we believe that eubiosis re-establishment is the key to tackle effectively even HPV-infection. TRIAL REGISTRATION: Retrospectively registered on PRS NCT03372395 (12/12/2017).

HPV/Chlamydia trachomatis co-infection: metagenomic analysis of cervical microbiota in asymptomatic women.

HPV and Chlamydia trachomatis are the most common causes of sexually transmitted diseases worldwide. Most infections are asymptomatic and left untreated lead to severe reproductive tract sequelae such as cervical cancer and infertility. Interestingly, C. trachomatis may also increase the susceptibility to HPV infection as well as contribute to viral persistence. Recently, a growing body of evidence has suggested that the composition of the cervico-vaginal microbiota plays a key role in the susceptibility and outcome of genital infections caused by several pathogens, including HPV and C. trachomatis. The aim of our study was to undertake a metagenomic analysis of sequenced 16s rRNA gene amplicons to characterize the cervical microbiota from asymptomatic women with HPV/C. trachomatis co-infection. The composition of the cervical microbiota from HPV-positive or C. trachomatis-positive women was also analysed. The main finding of our study showed that the cervical microbiota in HPV/C. trachomatis co-infected women had a higher microbial diversity than the cervical microbiota in healthy controls (p<0.05). In addition, Aerococcus christensenii was associated with C. trachomatis infection. In conclusion, the increased cervical microbial diversity observed in HPV/C. trachomatis co-infected women and the detection of potential microbiological biomarkers of C. trachomatis infection will open the way to innovative approaches that may be helpful to identify women at risk of co-infection.

Interferon lambda4 polymorphism is not associated with human papillomavirus infection outcome.

Interferon (IFN) lambdas are important specific components of the mucosal innate immune response. The IFN lambda 4 (IFNL4) dinucleotide polymorphism (ΔG/TT) determines the IFN lambdas and related Interferon-stimulated genes activation, in HCV and other chronic infections. Our group first reported that IFN Lambda response was impaired in high-risk Human Papillomavirus (HPV) cervical infections and in precancerous lesions. Accordingly, we sought to evaluate the possible role of the IFNL4 polymorphism in determining HPV infection outcome. The ΔG/TT alleles were not differently distributed in 221 women with high- or low-risk HPV infection, with HPV infection clearance or persistence, and with abnormal cytology.

Diversity of Cervical Microbiota in Asymptomatic Chlamydia trachomatis Genital Infection: A Pilot Study.

Chlamydia trachomatis genital infection continues to be an important public health problem worldwide due to its increasing incidence. C. trachomatis infection can lead to severe sequelae, such as pelvic inflammatory disease, obstructive infertility, and preterm birth. Recently, it has been suggested that the cervico-vaginal microbiota may be an important defense factor toward C. trachomatis infection as well as the development of chronic sequelae. Therefore, the investigation of microbial profiles associated to chlamydial infection is of the utmost importance. Here we present a pilot study aiming to characterize, through the metagenomic analysis of sequenced 16s rRNA gene amplicons, the cervical microbiota from reproductive age women positive to C. trachomatis infection. The main finding of our study showed a marked increase in bacterial diversity in asymptomatic C. trachomatis positive women as compared to healthy controls in terms of Shannon's diversity and Shannon's evenness (P = 0.031 and P = 0.026, respectively). More importantly, the cervical microbiota from C. trachomatis positive women and from healthy controls significantly separated into two clusters in the weighted UniFrac analysis (P = 0.0027), suggesting that differences between the two groups depended entirely on the relative abundance of bacterial taxa rather than on the types of bacterial taxa present. Furthermore, C. trachomatis positive women showed an overall decrease in Lactobacillus spp. and an increase in anaerobes. These findings are part of an ongoing larger epidemiological study that will evaluate the potential role of distinct bacterial communities of the cervical microbiota in C. trachomatis infection.

Restoring vaginal microbiota: biological control of bacterial vaginosis. A prospective case-control study using Lactobacillus rhamnosus BMX 54 as adjuvant treatment against bacterial vaginosis.

PURPOSE: Bacterial vaginosis (BV) is the most prevalent lower genital tract infection in reproductive-age women worldwide. BV is an ecological disorder of the vaginal microbiota characterized microbiologically by replacement of the lactobacilli, predominant vaginal microbiota. It is characterized by a high rate of relapse in sexual active women, and these patients show three or more relapses each year. A healthy vagina is characterized by hydrogen peroxide and acid-producing lactobacilli, which are crucial to maintain the physiological vaginal ecosystem and their depletion speeds up bacterial overgrowth with pH elevation, salidase and amine production, leading to the observed signs and symptoms of BV. The aim of this study is to evaluate the efficacy of long-term vaginal lactobacilli's implementation in restoring and maintaining vaginal microflora and pH and to collect data about prophylactic approach based on probiotics supplementation with lactobacilli. METHODS: This is a prospective case-control study, performed between January 2013 and September 2014 at Department of Gynecological Obstetrics and Urologic Sciences of "Sapienza" University of Rome. 250 non-pregnant sexually active women with diagnoses of BV were collected. Patients selected were divided in Group A (125 patients assigned to standard treatment for BV-metronidazole 500 mg orally twice a day for 7 days) and Group B (125 women undergoing the same standard antibiotic regimen followed by vaginal tablets containing Lactobacillus rhamnosus BMX 54). Patients were evaluated after 2, 6, and 9 months (T0, T2, T6, and T9) in term of recurrences rates of BV, vaginal symptoms, re-establishment of healthy vaginal flora, vaginal pH, and treatment tolerability. RESULTS: Vaginal flora was significantly replaced in Group B patients after 2 months comparing with Group A (p = 0.014). These data were confirmed at 6 and 9 months follow-up: patients that underwent prophylactic therapy with NORMOGIN(®) experienced significantly low rate of recurrences comparing with patients treated with antibiotics only (p < 0.001). During follow-up patients continuing supplementation had significant pH decrease respect to other patients (p < 0.001 at 9 months follow-up visit). CONCLUSIONS: Probiotic supplementation with vaginal Lactobacillus rhamnosus BMX54 seems to be useful in hindering bacteria growth especially after antibiotic therapy; therefore this intervention may be considered a new prophylactic treatment for preventing recurrence of BV, in particular in high-risk patients.

Vulvodynia: current opinion and treatment strategies.

Vulvodynia is a women's health problem that may affect as many as 15% of women who seek gynecological care, and yet little attention is given to this condition and it is frequently dismissed as psychosomatic. Thus, vulvodynia still remains a major health problem in Western countries, leading to significant morbidity and a reduced quality of life for many women. This condition carries large costs incurred as a result of both medical treatment and lost productivity. Vulvodynia is becoming a universal priority in the prevention, care, education, and research areas of pain and its consequences and it remains one of the poorly understood complex chronic pain syndromes, representing a multifactorial clinical syndrome of unexplained vulvar pain and sexual dysfunction.

TLR9 is expressed in human papillomavirus-positive cervical cells and is overexpressed in persistent infections.

Control of human papillomavirus (HPV) infection involves the activation of Toll-like receptors (TLRs), key components of the mucosal antiviral response. Available studies on TLR expression in HPV-positive cervical cells are limited and reported conflicting results. This study quantified TLR 2, 3, 4, 7 and 9 transcripts in low-risk (LR) and high-risk (HR) HPV-positive and HPV-negative cervical samples from 154 women attending a gynaecological clinic. Expression levels of TLR 2, 3, 4 and 7 did not differ among samples, whereas TLR9 levels were quite significantly higher in LR and marginally significant in HR HPV-positive samples, with respect to the HPV-negative samples. Interestingly, in a subgroup of women with documented previous HPV-infection, TLR9 levels were extremely higher in patients persistently positive to the same HPV genotype for more than 1 year, with respect to women who cleared HPV infection and to those re-infected with a different genotype. These findings implicate TLR9 in the response to LR and HR HPVs, including HPV 16 known to interfere with TLR9 transcription in cell lines. Elevated TLR9 levels without HPV clearance in persistently infected women could drive inflammation thereby contributing to cervical cancer risk.

Interferon lambda 1 expression in cervical cells differs between low-risk and high-risk human papillomavirus-positive women.

Persistent infection by high-risk (HR) human papillomavirus (HPV) types is a prerequisite for progression to cancer. HR-HPVs may lead to a deregulation of innate immunity by interfering with the epithelial type I interferon (IFN) response, whereas very little is known about type III IFNs, a key component of the mucosal antiviral response. This study reports a first attempt to evaluate the activation of type III IFN genes (IFN lambda 1-3), IFN lambda receptor genes (IFN-lambdaR1 and IL10R2), and IFN-induced genes (MxA, ISG15, ISG56) in HPV-positive and HPV-negative cervical cells from 154 women attending the gynecological unit of a university hospital in Rome. Despite an increased individual variability, a coordinated expression of several IFN lambda-related genes was observed. Furthermore, IFN lambda 1 and IFN-lambdaR1 genes were expressed at higher levels in cervical cells positive to low-risk (LR) HPV compared to HR-HPV and HPV-negative cells. Consistently, ISG15 expression was significantly higher in LR-HPV-infected women than in the other groups. Moreover, IFN lambda 1 expression decreased significantly with abnormal cytological results. This study is the first to show the activation of a type III IFN response in LR-HPV-positive cervical cells and suggests that the lack of this response in HR-HPV infection may be related to lesion progression.

Direct sequencing of HPV DNA detected in gynaecologic outpatients in Rome, Italy.

In order to assess the frequency of different human papillomavirus (HPV) types in Rome and the association between HPV and behavioural characteristics, we tested cervical scrapes of a population of sexually active women referring to university clinics for routine gynaecologic care. The presence of HPV DNA was revealed by polymerase chain reaction on two genome regions (L1 and E6/E7) followed by sequencing. Thirty different HPV types were identified; HPV 16 was the most prevalent (14.18%), followed by HPV 53 (9.21%), HPV 58 (7.80%), HPV 6 and 66 (both 5.67%) whereas all the other genotypes ranged below 5%. In univariate analysis the characteristics significantly associated with HPV DNA detection were the youngest age (P<0.01), the high number of lifetime partners (P<0.001) and the smoking habit (P<0.01). In multiple logistic regression analyses, the characteristics significantly associated with HPV DNA detection remained the younger age and the higher number of lifetime sexual partners. This study may be interesting in order to evaluate the circulation of HPV genotypes in Italy and to add a contribution to anti-cancer vaccine development.