Development of a core outcome set for treatment studies for provoked vestibulodynia.

BACKGROUND: There is an inconsistency in treatment outcomes used in clinical trials for provoked vestibulodynia (PVD), which makes it impossible to compare the effects of different interventions. AIM: In this study, we completed the first step in creating a core outcome set (COS), defining what outcomes should be measured in clinical trials for PVD. METHODS: Identification of outcomes used in studies was done by extracting data from clinical trials in a recently published systematic review and via review of clinical trials for PVD registered on ClinicalTrials.gov. The COS process consisted of 2 rounds of Delphi surveys and a consensus meeting, during which the final COS was decided through a modified nominal group technique. OUTCOMES: Consensus on what outcomes to include in a COS for PVD. RESULTS: Forty scientific articles and 92 study protocols were reviewed for outcomes. Of those, 36 articles and 25 protocols were eligible, resulting in 402 outcomes, which were then categorized into 63 unique outcomes. Participants consisted of patients, relatives/partners of patients, health care professionals, and researchers. Out of 463 who registered for participation, 319 and 213 responded to the first and second surveys, respectively. The consensus meeting consisted of 18 members and resulted in 6 outcomes for the COS to be measured in all treatment trials regardless of intervention: insertional pain (nonsexual), insertional pain (sexual), provoked vulvar pain by pressure/contact, pain-related interference on one's life, pain interference on sexual life, and sexual function. CLINICAL IMPLICATIONS: Critical outcomes to be measured in clinical trials will allow for accurate comparison of outcomes across treatment interventions and provide solid treatment recommendations. STRENGTHS AND LIMITATIONS: The major strengths of the study are the adherence to methodological recommendations and the intentional focus on aspects of diversity of participating stakeholders (eg, status such as patients with lived experience and researchers, inclusiveness with respect to sexual identity), the latter of which will allow for broader application and relevance of the COS. Among the limitations of the study are the low rate of participants outside North America and Europe and the lower response rate (about 50%) for the second Delphi survey. CONCLUSION: In this international project, patients, health care professionals, and researchers have decided what critical outcomes are to be used in future clinical trials for PVD. Before the COS can be fully implemented, there is also a need to decide on how and preferably when the outcomes should be measured.

Guided internet-based acceptance and commitment therapy for provoked vestibulodynia: A randomized controlled trial.

BACKGROUND: Provoked vestibulodynia (PVD) causes suffering in many women's lives due to its impact on relationships, sexual functioning and functioning in other key domains. OBJECTIVE: Here, we report a randomized controlled trial conducted to examine whether Acceptance and Commitment Therapy (ACT) with a focus on values-based exposure, delivered online, benefits women with PVD. METHODS: Participants (n = 88) were randomized to either guided online ACT for 10 weeks or a wait-list control group. Outcomes were assessed at baseline, post treatment and 1 year later. Analyses were based on intention to treat using linear mixed models. RESULTS: There were significant group differences on the primary outcomes, Female Sexual Index and Female Sexual Distress Scale, in favour of online ACT with moderate effect sizes. Differences were also found on several secondary outcomes and therapeutic process measures, all in favour of ACT. No differences were found at post-treatment for depression or anxiety. At the 1-year follow-up, results were maintained and a difference between baseline and follow-up was also found for depression. CONCLUSION/SIGNIFICANCE: In summary, a relatively brief, guided, online version of ACT appears to produce benefits for women with PVD and related impacts on daily functioning. 50% to 60% of the women who participated in the treatment reliably improved in sexual functioning and distress.

The Association Between Immune-Related Conditions Across the Life-Course and Provoked Vulvodynia.

Vulvodynia, impacts up to 8% of women by age 40, and is hypothesized to manifest through an altered immune-inflammatory response. To test this hypothesis, we identified all women born in Sweden between 1973 and 1996 diagnosed with localized provoked vulvodynia (N76.3) and/or vaginismus (N94.2 or F52.5) between 2001 and 2018. We matched each case to two women from the same birth year with no vulvar pain ICD codes. As a proxy for immune dysfunction, we used Swedish Registry data to capture 1) immunodeficiencies, 2) single organ and multiorgan autoimmune conditions, 3) allergy and atopies, and 4) malignancies involving immune cells across the life course. Women with vulvodynia, vaginismus or both were more likely to experience immune deficiencies (OR 1.8, 95% CI, 1.2-2.8), single organ (OR 1.4, 95% CI, 1.2-1.6) and/or multi-organ (OR 1.6, 95% CI, 1.3-1.9) immune disorders, and allergy/atopy conditions (OR 1.7, 95% CI, 1.6-1.8) compared to controls. We observed greater risk with increasing numbers of unique immune related conditions (1 code: OR = 1.6, 95% CI, 1.5-1.7; 2 codes: OR = 2.4, 95% CI, 2.1-2.9; 3 or more codes: OR = 2.9, 1.6-5.4). These findings suggest that women with vulvodynia may have a more compromised immune system either at birth or at points across the life course than women with no vulvar pain history. PERSPECTIVE: Women with vulvodynia are substantially more likely to experience a spectrum of immune related conditions across the life course. These findings lend support to the hypothesis that chronic inflammation initiates the hyperinnervation that causes the debilitating pain in women with vulvodynia.

Interpregnancy interval and maternal and neonatal morbidity: a nationwide cohort study.

This study aimed to assess the association between interpregnancy interval (IPI)-the time from childbirth to conception of the next pregnancy-and maternal and neonatal morbidity. The World Health Organization (WHO) currently recommends an IPI of at least 24 months after a live birth to reduce adverse birth outcomes. However, assessing the relationship between IPI and perinatal outcome is complicated by confounding factors. We conducted a nationwide population-based cohort study using Swedish registry data, allowing for adjustment of maternal characteristics and health at first birth. The study population consisted of all women with a singleton, live, and vaginal first birth with a second singleton birth within five years during 1997-2017, covering 327,912 women and 655,824 neonates. IPI was grouped into six-month intervals with 24-29 months as the reference. The association between IPI and morbidity was examined using multivariate logistic regression. For women having a vaginal delivery at their first birth, intervals < 24-29 months were associated with decreased maternal morbidity and unaffected neonatal morbidity. Intervals > 24-29 months were associated with increased maternal and neonatal morbidity. Our findings question the relevance of WHO's recommendation of an IPI of at least 24 months in a high-income country.

Botulinum Toxin A for Provoked Vestibulodynia: 12 Months' Follow-up of a Randomized Controlled Trial.

BACKGROUND: Provoked vestibulodynia (PVD) is a common pain disorder afflicting primarily young women, and botulinum toxin A (BTA) has been to a limited extent tested as a treatment. AIM: Evaluate outcome 12 months after injection with BTA as a treatment for PVD. METHODS: We conducted a double-blinded, placebo-controlled trial of twice repeated injections of 50 units of BTA or placebo in the bulbocavernosus muscles, 3 months apart, in women with PVD. Treatment outcome after six months', failed to show any significant difference in pain reduction between the groups, as previously reported. Here, we report treatment outcomes 12 months after the first injections. In addition to injections, participants where instructed to perform pelvic floor exercises during month 6-12. 38 participants/group was calculated to achieve a statistical power of 80% based on an effect size of 20 VAS units (mean score range 56-76±31 SD). OUTCOMES: Primary outcome was self-reported dyspareunia or pain at tampon use, using a visual analogue scale (VAS) 0-100. Secondary outcomes were vaginal pressure measurements, psychological health, sexual function and distress. RESULTS: From the initial 88 randomized women with PVD, 75 remained at 12 months; 38 in the BTA and 37 in the placebo group. There was no significant difference in primary outcome between the groups. Vaginal pressure in the BTA group had been restored to pre-treatment levels, with no differences between the groups at 12 months. There was an increase in sexual function in the BTA group, with a Female Sexual Function Index of 22.8 (±4.8) compared to the placebo group to 19.7 (±5.0), P=.048. No differences were observed in sexual distress, stress and anxiety. There was an increase in number of women attempting intercourse in the BTA group (74%) compared with placebo (43%), P=.005. Too few patients performed the pelvic floor exercises for this intervention to be analyzed. CLINICAL IMPLICATIONS: This study highlights BTA as a safe treatment option for patients with PVD. STRENGTHS AND LIMITATIONS: The randomized, double-blinded design and repeated treatments are the major strengths of this study and it is the first study to objectively evaluate muscular effect after BTA injections. The major shortcoming is that few participants performed the pelvic floor exercises, preventing analyses. CONCLUSION: At 12 months' follow up, no significant difference in reduction of dyspareunia or pain at tampon use was observed. Women receiving BTA attempted intercourse more often and improved their sexual function compared with women receiving placebo. Haraldson P, Mühlrad H, Heddini U, et al. Botulinum Toxin A for Provoked Vestibulodynia: 12 Months' Follow-up of a Randomized Controlled Trial. J Sex Med 2022;19:1670-1679.

Experiences of internet-based treatment for vulvodynia: A qualitative study.

OBJECTIVE: The aim of this study was to describe women's experiences before, under, and after a guided internet-based intervention for vulvodynia. METHODS: The design was qualitative, based on content analysis. Participants were women who had undergone guided internet-based treatment for vulvodynia based on acceptance and commitment therapy principles (n = 13). Data were collected through in-depth interviews approximately-one month after participants completed treatment. RESULTS: The analysis revealed the women's experiences of internet-based treatment for vulvodynia. Three themes emerged: "dealing with pain alone," which was related to experiences of living with vulvodynia before internet-based treatment; "finding new ways," which described the experiences of undergoing an internet-based treatment for vulvodynia and "feeling empowered to take control," referring to the experiences of living with vulvodynia after the internet-based treatment. The women described a long search for a diagnosis, revealing a negative experience of healthcare. The internet-based treatment helped them find new ways to manage vulvodynia, but difficulties with the treatment were also experienced. After the intervention, the women reported improvements in wellbeing and having better strategies to manage pain, but also stated that the treatment was insufficient to perceive changes in vulvar pain. CONCLUSIONS: The guided internet-based treatment program for vulvodynia based on acceptance and commitment therapy principles was perceived as credible, helpful to manage vulvodynia, and could serve as a complement to regular care. Questions regarding the need for more support and optimal length of treatment need to be further evaluated.

Treatment of Provoked Vulvodynia: A Systematic Review.

BACKGROUND: Treatment recommendations for provoked vulvodynia (PVD) are based on clinical experiences and there is a need for systematically summarizing the controlled trials in this field. AIM: To provide an overview of randomized controlled trials and non-randomized studies of intervention for PVD, and to assess the certainty of the scientific evidence, in order to advance treatment guidelines. DATA SOURCES: The search was conducted in CINAHL (EBSCO), Cochrane Library, Embase (Embase.com), Ovid MEDLINE, PsycINFO (EBSCO) and Scopus. Databases were searched from January 1, 1990 to January 29, 2021. STUDY ELIGIBILITY CRITERIA: Population: Premenopausal women with PVD. INTERVENTIONS: Pharmacological, surgical, psychosocial and physiotherapy, either alone or as combined/team-based interventions. CONTROL: No treatment, waiting-list, placebo or other defined treatment. OUTCOMES: Pain during intercourse, pain upon pressure or touch of the vaginal opening, sexual function/satisfaction, quality of life, psychological distress, adverse events and complications. STUDY DESIGN: Randomized controlled trials and non-randomized studies of interventions with a control group. STUDY APPRAISAL AND SYNTHESIS METHODS: 2 reviewers independently screened citations for eligibility and assessed relevant studies for risk of bias using established tools. The results from each intervention were summarized. Studies were synthesized using a narrative approach, as meta-analyses were not considered appropriate. For each outcome, we assessed the certainty of evidence using grading of recommendations assessment, development, and evaluation (GRADE). RESULTS: Most results of the evaluated studies in this systematic review were found to have very low certainty of evidence, which means that we are unable to draw any conclusions about effects of the interventions. Multimodal physiotherapy compared with lidocaine treatment was the only intervention with some evidential support (low certainty of evidence for significant treatment effects favoring physiotherapy). It was not possible to perform meta-analyses due to a heterogeneity in interventions and comparisons. In addition, there was a heterogeneity in outcome measures, which underlines the need to establish joint core outcome sets. CLINICAL IMPLICATIONS: Our result underscores the need of stringent trials and defined core outcome sets for PVD. STRENGTH AND LIMITATIONS: Standard procedures for systematic reviews and the Population Intervention Comparison Outcome model for clinical questions were used. The strict eligibility criteria resulted in limited number of studies which might have resulted in a loss of important information. CONCLUSION: This systematic review underlines the need for more methodologically stringent trials on interventions for PVD, particularly for multimodal treatments approaches. For future research, there is a demand for joint core outcome sets. Bohm-Starke N, Ramsay KW, Lytsy P, et al. Treatment of Provoked Vulvodynia: A Systematic Review. J Sex Med 2022;19:789-808.

Delivery mode and severe maternal and neonatal morbidity among singleton term breech births: A population-based cohort study.

OBJECTIVE: The aim of this study was to examine the association between delivery mode and severe maternal and neonatal morbidity in singleton term breech births. STUDY DESIGN: This nationwide population-based cohort study includes 41 319 singleton term and post-term breech births (37 + 0-42 + 6 gestational weeks) in Sweden from 1998 to 2016. Data was retrieved from the Swedish Medical Birth Register. The primary outcomes were two separate composite outcomes, maternal and neonatal severe morbidity. Secondary outcomes were separate severe maternal and neonatal morbidity outcomes. Hospitalization and out-patient visits during childhood were also analyzed in ages 0-5 years. Logistic regression was used to estimate unadjusted and adjusted odds ratios (aOR) with 95% confidence intervals (CI) of severe maternal and neonatal morbidity in women with vaginal breech birth or intrapartum cesarean section. Women with a prelabor breech cesarean section was used as the reference group. RESULTS: No difference between vaginal delivery and prelabor cesarean section was seen regarding maternal morbidity. Intrapartum cesarean section was associated with elevated odds for maternal morbidity (aOR 1.27, 95% CI 1.10-1.47) compared with prelabor cesarean section. A similar result was observed for vaginal delivery and intrapartum cesarean section combined (aOR 1.29, 95% CI 1.11-1.50). Vaginal delivery was associated with higher odds for composite neonatal morbidity (aOR 1.85, CI 1.54-2.21) and most separate outcomes, as well as increased number of hospital nights and out-patient visits during first year of life, compared with prelabor cesarean section. CONCLUSIONS: Prelabor cesarean section in breech births improved short-term neonatal health without increasing risks for severe maternal short-term complications.

Internet-based Treatment for Vulvodynia (EMBLA) - A Randomized Controlled Study.

BACKGROUND: Internet-based ACT (Acceptance and commitment therapy) treatment may improve accessibility and reduce stigma related to seeking health care, but there are a lack of studies investigating internet-based treatment using ACT principles for women with vulvodynia. AIM: The aim of this study was to investigate the effects of an internet-based treatment of pain during intercourse for women with provoked vulvodynia compared with no intervention during the waiting period before clinical treatment. METHODS: A multicenter randomized controlled trial was conducted during 2016 to 2020, in which 99 participants were included. Participants were randomized to either a 6 week guided internet-based treatment using ACT principles or usual care. Data were collected at baseline, 6 weeks after baseline, and approximately 10 months after baseline. OUTCOMES: Pain-related (pain during intercourse, tampon test, impact of pain on sexual function) and pain behavior-related outcomes (attempts at intercourse, sexual activities besides intercourse, willingness to perform the tampon test, chronic pain acceptance questionnaire) were used as outcomes. RESULTS: Treatment was efficacious in what concerns pain during intercourse and pain acceptance. Less pain during intercourse among women in the intervention group was observed at both post-treatment (primary endpoint, P = .01, Cohen's d = 1.4, 95% CI = 0.33, 2.4), and follow-up (P = .04). Absolut mean difference between groups for pain during intercourse at post-treatment was -2.84, (95 % CI = -4.91, -0.78), and -1.58 at follow-up, (95 % CI = -3.17, 0.02), where the intervention group rated less pain than controls. No differences between groups over time were found for tampon test measures or impact of pain on sexual function. There was a significant difference between groups at all timepoints indicating fewer attempts at intercourse among participants in the intervention group. At post-treatment, women who underwent internet-based treatment reported higher pain acceptance and a rise in activity engagement compared with the control group. CLINICAL IMPLICATIONS: There is an indication that internet-based treatment could be incorporated into clinical practice as a complement to clinical treatment. STRENGTHS & LIMITATIONS: Study strengths included using several forms of recruitment and an intervention built by different professions with long experience of treating patients with vulvodynia. High dropout rate was a limitation of this study. CONCLUSION: Internet-based treatment may have an impact on pain during intercourse and positive effects on pain acceptance. However, conclusions must be drawn with caution due to the small sample size. Engström AH, Bohm-Starke N, Kullinger M, et al. Internet-based Treatment for Vulvodynia (EMBLA) - A Randomized Controlled Study. J Sex Med 2022;19:319-330.

Early Life Health in Women with Provoked Vestibulodynia and/or Vaginismus.

Background: The lifetime prevalence of prolonged vulvar pain ranges from 3% to 28% among premenopausal women. Provoked vestibulodynia (PVD), often accompanied with various degrees of vaginismus, is the predominant cause. We explored the association between birth-related events and the risk of developing PVD/vaginismus during adulthood. Materials and Methods: We identified all women born in Sweden between 1973 and 2001 and categorized those with and without a diagnosis of PVD/vaginismus between 2001 and 2016 (during ages 15-43 years). Nationwide registry data were used to estimate the association between health during infancy (preterm birth, low birth weight, small for gestational age [SGA], Appearance, Pulse, Grimace, Activity and Respiration [APGAR] scores <7, and pain exposure during infancy) and the onset of PVD/vaginismus later in life using an event probability model. Results: Of the 1,359,315 women born in Sweden during 1973-2001, 9,247 were diagnosed with PVD (n = 6,648), vaginismus (n = 3,567), or both (n = 969). Preterm delivery <37 weeks (adjusted odds ratios [aOR]: 1.15, 95% confidence interval [CI]: 1.05-1.26), low birth weight <2,500 g (aOR: 1.24, 95% CI: 1.12-1.36), extremely low birth weight <1,500 g (aOR 1.41, 95% CI: 1.10-1.82), and SGA (aOR 1.20, 95% CI: 1.08-1.34) were factors associated with developing PVD/vaginismus. APGAR scores <7 or pain exposure during birth or infancy was not associated with PVD/vaginismus. Advanced maternal age, higher educational attainment, and being born in Sweden were associated with having a female offspring diagnosed with PVD/vaginismus. Conclusions: In a population of Swedish women 15-43 years of age, adverse health at birth was associated with developing PVD/vaginismus later on in life.

Anti-biofilm activity of chlorhexidine digluconate against Candida albicans vaginal isolates.

OBJECTIVES: Recurrent vulvovaginal candidiasis (RVVC) causes significant morbidity. Candida albicans is the main pathogen associated with both sporadic and recurrent candidiasis. Due to unsatisfactory treatment effect, the impact of chlorhexidine digluconate and fluconazole alone or in combination on C. albicans and biofilm was investigated. METHODS: Vaginal C. albicans isolates from 18 patients with recurrent candidiasis and commensals from 19 asymptomatic women were isolated by culture. Crystal violet, XTT and colony forming unit assay were used to analyze the effect of chlorhexidine digluconate and fluconazole on growth of C. albicans, formation of new and already established, mature, biofilm. RESULTS: Fluconazole reduced the growth of planktonic C. albicans. However, in established biofilm, fluconazole had no effect on the candida cells and was not able to disperse and reduce the biofilm. By contrast, chlorhexidine digluconate had a direct killing effect on C. albicans grown both planktonically and in biofilm. Chlorhexidine digluconate also dispersed mature biofilm and inhibited formation of new biofilm. No major differences were observed between commensal isolates and candida causing recurrent vulvovaginitis with respect to biofilm or growth after chlorhexidine digluconate treatment. CONCLUSION: Biofilm is a problem in patients with recurrent vulvovaginal candidiasis reducing the effect of antifungal treatment. Development of new treatment strategies are urgently needed to decrease the recurrences. In already established biofilm, chlorhexidine digluconate dispersed the biofilm and was more effective in eradicating candida compared to fluconazole. Future treatment strategy may thus be a combination of chlorhexidine digluconate and fluconazole and prophylactic use of chlorhexidine digluconate to prevent biofilm formation and restrict infections.

Botulinum Toxin A as a Treatment for Provoked Vestibulodynia: A Randomized Controlled Trial.

OBJECTIVE: To evaluate pain reduction after two injections of 50 units botulinum toxin A compared with placebo for provoked vestibulodynia. METHODS: We conducted a double-blinded, placebo-controlled randomized trial of 50 units botulinum toxin A or placebo injected in the bulbocavernosus muscles twice, 3 months apart, in women with provoked vestibulodynia. Primary outcome was self-reported dyspareunia or pain at tampon use on a visual analog scale (VAS, 0-100). Secondary outcomes were pain at weekly tampon insertion (VAS score), reduction of pelvic floor hypertonicity (measured with a vaginal manometer), adverse events, and sexual function and distress. A sample size of 38 participants for each group was calculated to achieve a statistical power of 80% based on an effect size of 20 VAS units (0-100) (mean score range 56-76±31 SD). RESULTS: Between May 2016 and June 2018, 124 women with provoked vestibulodynia were assessed, and 88 were randomized to botulinum toxin A (BTA group, n=44) or placebo (placebo group, n=44). Primary outcome showed a lower but statistically nonsignificant pain rating by 7 VAS units (95% CI -15.0 to 0.4) in the BTA group compared with the placebo group. Secondary results showed a significant decrease in pain at weekly tampon insertion by 11 VAS units (95% CI -16.6 to 6.0) with botulinum toxin A injection. The vaginal manometer measured lower maximum contraction strength by 7 mm Hg (95% CI -12.7 to -2.4) and lower 10-second endurance strength by 4 mm Hg (95% CI -7.72 to -1.16) in the BTA group compared with the placebo group. No changes were observed for sexual function and distress, but there was a significant increase in women attempting vaginal intercourse in the BTA group (0.27, 95% CI 0.06-0.48). No severe adverse events were reported. CONCLUSION: Twice-repeated injections of 50 units of botulinum toxin A in women with provoked vestibulodynia did not reduce dyspareunia or pain at tampon use, but secondary outcomes suggested positive effects of the treatment. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT02773641.

Vulvodynia.

Vulvodynia is a condition that occurs in 8-10% of women of all ages and is characterized by pain at the vulva that is present during sexual and/or non-sexual situations. Diagnosis is established through careful medical history and pelvic examination, including the cotton-swab test. The onset and maintenance of vulvodynia involves a complex interplay of peripheral and central pain mechanisms, pelvic floor muscle and autonomic dysfunction, anxiety, depression and childhood maltreatment as well as cognitive-affective, behavioural and interpersonal factors. Given the absence of empirically supported treatment guidelines, a stepwise approach of pelvic floor physical therapy and cognitive behavioural therapy as well as medical management is suggested, with surgery as the last option. Vulvodynia has a negative effect on the quality of life of women and their partners, and imposes a profound personal and societal economic burden. In addition, women with vulvodynia are more likely to report other chronic pain conditions, which further alters their quality of life. Future efforts should aim to increase girls', women's and healthcare professionals' education and awareness of vulvodynia, phenotype different subgroups of women based on biopsychosocial characteristics among more diverse samples, conduct longitudinal studies and improve clinical trial designs.

Sex steroid hormone receptor expression in the vaginal wall in cervical cancer survivors after radiotherapy.

Background: Sex steroid hormones and their receptors are important in female sexual function. The aim of this study was to investigate the expression and distribution of estrogen receptor (ER)α, ERß, G-protein-coupled ER-1 (GPER), androgen receptor (AR), progesterone receptor (PR)A, PRB and connective tissue growth factor (CTGF) in the vaginal wall among women who had been treated for cervical cancer with radiotherapy. Material and methods: We included cervical cancer survivors treated with radiotherapy and premenopausal control women of the same age scheduled for benign gynecological surgery. We analyzed the expression and distribution of sex steroid hormone receptors and CTGF in biopsies from the vaginal wall, by real-time PCR and immunohistochemistry (IHC). Serum samples were analyzed for hormone levels and radiation dose at biopsy site were calculated and correlated to levels of the sex steroid hormone receptors. Results: In the cervical cancer survivors (n = 34), we found a lower expression of ERα at both mRNA and protein levels, compared to the control women (n = 37). In the survivors with high radiation dose at biopsy site, the immunostaining of ERα and AR was lower in the epithelium and the stroma, compared to survivors with minimal radiation dose. The later group showed expression of ERα comparable to the control women. The cancer survivors were sufficiently substituted with systemic estradiol with no difference in the serum estradiol levels compared to control women. Conclusions: We found that external radiation reduces the ERα and AR protein expression in the vaginal mucosa, indicating that the vaginal changes in irradiated cervical cancer survivors and the lack of response to hormonal treatment could be due to the decreases in sex steroid hormone receptor expression.

Expression of Psoriasin in Human Papillomavirus-Induced Cervical High-Grade Squamous Intraepithelial Lesions.

OBJECTIVES: Persistent infection with human papillomavirus causes cervical high-grade squamous intraepithelial lesions (HSILs). The role of antimicrobial peptides (AMPs) in premalignant and malignant transformation is not fully understood. In this study, we examined the expression of human ß-defensin 1 (HBD-1), HBD-2, HBD-3, LL37, psoriasin, and interleukin 8 (IL-8) in women with HSIL before and 6 months after surgery. MATERIALS AND METHODS: Biopsies and secretion samples from the cervical canal were collected from 19 patients with HSIL and 14 healthy controls. The mRNA expression of HBD-1, HBD-2, HBD-3, LL37, psoriasin, and IL-8 was analyzed before and 6 months after surgery excision using reverse transcriptase real time polymerase chain reaction. For protein analyses, ELISA and immunohistochemistry were used for psoriasin and ELISA for IL-8. RESULTS: The mRNA expression of psoriasin was lower in patients before treatment compared with healthy controls (p = .05). After surgery, when the infection was cleared, psoriasin increased on mRNA (p = .04) and protein (p = .03) levels compared with before treatment. Immunostaining for psoriasin after treatment was prominent and localized in the cytoplasm of the epithelial cells. After treatment, IL-8 mRNA was reduced compared with before treatment (p = .05), but not on the protein level. No changes in mRNA expression of the other AMPs analyzed were observed in pretreatment and posttreatment samples. CONCLUSIONS: In this study of AMP expression in human papillomavirus-induced HSIL, we observed lower psoriasin levels before surgery compared with after treatment, when both mRNA and protein levels were similar to healthy controls. Interleukin 8, on the other hand, was increased before treatment, indicating an inflammatory response.

Psoriasin, a novel anti-Candida albicans adhesin.

Candida albicans belongs to the normal microbial flora on epithelial surfaces of humans. However, under certain, still not fully understood conditions, it can become pathogenic and cause a spectrum of diseases, from local infections to life-threatening septicemia. We investigated a panel of antimicrobial proteins and peptides (AMPs), potentially involved in mucosal immunity against this pathogen. Out of six studied AMPs, psoriasin was most up-regulated during a mucosal infection, an acute episode of recurrent Candida vulvovaginitis, although candidacidal activity has not been demonstrated. We here show that psoriasin binds to ß-glucan, a basic component of the C. albicans cell wall, and thereby inhibits adhesion of the pathogen to surfaces and increases IL-8 production by mucosal epithelial cells. In conclusion, we show a novel mechanism of action of psoriasin. By inhibiting C. albicans adhesion and by enhancing cytokine production, psoriasin contributes to the immune response against C. albicans. KEY MESSAGES: The antimicrobial peptide psoriasin is highly up-regulated during a local mucosal infection, Candida albicans vulvovaginitis. Psoriasin binds to ß-glucan in the Candida albicans cell wall and thereby inhibits adhesion of the pathogen. Binding of psoriasin to Candida albicans induces an immune response by mucosal epithelial cells.

Radiotherapy for cervical cancer - impact on the vaginal epithelium and sexual function.

BACKGROUND: Women who have been treated for cervical cancer have persistent changes in their sexual function, which result in considerable distress. The aim of this study was to investigate the morphology of the vaginal epithelium in cervical cancer survivors treated with radiotherapy and its correlation to serum levels of sex steroid hormones and sexual function. MATERIAL AND METHODS: We included 34 patients treated for cervical cancer with radiotherapy and 37 healthy age-matched control women scheduled for benign gynecological surgery. After inspection and grading of vaginal atrophy, vaginal biopsies were taken. Epithelial structures were analyzed by measuring epithelial thickness as well as the number, height and width of the dermal papillae and the dermal papillae distance. Sex steroid hormone levels were analyzed and a questionnaire designed to assess sexual function was filled out. RESULTS: In the cervical cancer survivors treated with radiotherapy, the vaginal epithelium volume was reduced compared to control women. Longer distance between the dermal papillae (p < .001) and a shorter distance from basal layer to epithelial surface (p < .05) were measured. Mucosal atrophy was observed in 91% of the survivors. There was no difference in serum estradiol between cancer survivors and control women, implying that the cancer survivors were sufficiently substituted. The epithelial thickness correlated to serum levels of estradiol. The cervical cancer survivors reported more physical sexual symptoms. The highest relative risk (RR) was found for insufficient vaginal lubrication (RR 12.6), vaginal inelasticity (RR 6.5), reduced genital swelling when sexually aroused (RR 5.9), and for reduction of vaginal length during intercourse (RR 3.9). CONCLUSION: We found that cervical cancer treatment including radiotherapy is associated with vaginal epithelial atrophy and sexual dysfunction. To hamper the atrophic process affecting the sexual function, an early start of local estrogen after therapy might be of importance.

Radiotherapy-induced vaginal fibrosis in cervical cancer survivors.

BACKGROUND: Cervical cancer survivors treated with radiotherapy report vaginal inelasticity and decreased lubrication that may affect their sexual health, but it is unknown which normal tissue reactions mediate these symptoms. The aim of this study was to investigate the morphology of the connective tissue of the vaginal wall in cervical cancer survivors treated with radiotherapy. MATERIAL AND METHODS: We recruited 34 cervical cancer survivors treated with radiotherapy and 37 age-matched controls. Via clinical examination the degree of vaginal atrophy and pelvic fibrosis were estimated. We collected vaginal biopsies, which underwent morphometric analysis focused on elastin and collagen. Additionally, radiation dose at biopsy site were calculated and correlated to the clinical and morphological findings. RESULTS: The survivors had marked morphological vaginal changes, most prominent in the survivors that had received the highest radiation dose at the biopsy site. Mucosal atrophy was observed in 91% and pelvic fibrosis in 97%. A shorter vagina was measured; 7.0 cm versus 10.3 cm in controls (p < 0.001). The area fraction of elastin was greater in survivors; 10.0% (range 5.8-12.9), compared with controls; 3.4% (range 1.8-5.8), p < 0.001. The survivors had signs of elastosis with thick aggregated elastin fibers irregularly scattered throughout the connective tissue, while the controls had elastin fibers in a thin sub-epithelial layer. The area fraction of high density collagen in the connective tissue was larger among the survivors (p < 0.001). The collagen with the highest density (fibrosis) was more common in the group of cancer survivors that had received external radiation. CONCLUSIONS: We found drastic differences in the vaginal wall between the irradiated cervical cancer survivors and the controls, indicating that radiotherapy-induced vaginal symptoms are mediated by connective tissue fibrosis and elastosis. Our results also support that patients treated with external radiation have the highest risk of developing vaginal fibrosis with impairment of their sexual health.

Elevated nitric oxide in recurrent vulvovaginal candidiasis - association with clinical findings.

INTRODUCTION: Recurrent vulvovaginal candidiasis is defined as having three to four episodes per year and causes substantial suffering. Little is known about the mechanisms leading to relapses in otherwise healthy women. Nitric oxide is part of the nonspecific host defense and is increased during inflammation. Nitric oxide levels were measured and the expression of inducible nitric oxide synthase was analyzed in the vagina during an acute episode of recurrent vulvovaginal candidiasis and after treatment with fluconazole. MATERIAL AND METHODS: Twenty-eight women with symptoms of recurrent vulvovaginal candidiasis were enrolled together with 31 healthy controls. Nitric oxide was measured with an air-filled 25-mL silicon catheter balloon incubated in the vagina for five minutes and then analyzed by chemiluminescence technique. Vaginal biopsies were analyzed for the expression of inducible nitric oxide synthase. Symptoms and clinical findings were surveyed using a scoring system. The measurements and biopsies were repeated in patients after six weeks of fluconazole treatment. RESULTS: Nitric oxide levels were increased during acute infection (median 352 ppb) compared with controls (median 6 ppb), p < 0.0001. The levels decreased after treatment (median 18 ppb) but were still higher than in controls. Increased expression of inducible nitric oxide synthase was observed in the epithelial basal layer in patients before and after treatment compared with controls. Before treatment, there were positive correlations between nitric oxide and symptom (rs  = 0.644) and examination scores (rs  = 0.677), p < 0.001. CONCLUSIONS: Nitric oxide is significantly elevated in patients with recurrent vulvovaginal candidiasis during acute episodes of infection and decreases after antifungal treatment. The results illustrate the pronounced inflammatory response in recurrent vulvovaginal candidiasis correlating to symptoms of pain and discomfort.

Serotonin receptor gene (5HT-2A) polymorphism is associated with provoked vestibulodynia and comorbid symptoms of pain.

INTRODUCTION: Provoked vestibulodynia (PVD) is a common type of dyspareunia among young women. The patho-physiology remains largely unclear. Women with PVD have general pain hypersensitivity and often report additional pain symptoms. Signs point towards PVD being a chronic pain disorder similar to other syndromes of longstanding pain, including a common comorbidity of anxiety and depression. Polymorphism in the serotonin receptor gene, 5HT-2A, has been associated with other chronic pain disorders such as fibromyalgia but has not been investigated in PVD patients. AIM: We aimed to investigate a possible contribution of polymorphism in the 5HT-2A gene to the etiology of PVD as well as a potential influence on pain sensitivity. METHODS: In this case-control study 98 women with PVD and 103 healthy controls between 18 and 44 years and in the same menstrual cycle phase completed questionnaires and underwent quantitative sensory testing. Venous blood samples were collected for DNA isolation. MAIN OUTCOME MEASURES: Concomitant pain was reported, a bodily pain score was created and pressure pain thresholds (PPTs) on the arm, leg, and in the vestibule were measured. Intensity of coital pain was rated on a visual analog scale, range 0-100. The T102C (rs6313) and A-1438G (rs6311) single nucleotide polymorphisms (SNPs) in the 5HT-2A gene were analyzed. RESULTS: The probability of PVD was elevated in participants carrying the 1438G- and 102C-alleles of the 5HT-2A gene (OR 2.9). The G-/C- genotypes were also associated with more concomitant bodily pain in addition to the dyspareunia, but not with experimental PPTs or coital pain ratings. PVD patients reported more concomitant bodily pain and had lower PPTs compared with controls. CONCLUSION: The results indicate a contribution of alterations in the serotonergic system to the patho-genesis of PVD and gives further evidence of PVD being a general pain disorder similar to other chronic pain disorders.