Dysbiosis in Localized Provoked Vulvodynia (LPV)

Brief Title

Dysbiosis in Localized Provoked Vulvodynia (LPV)

Official Title

Dysbiosis in the Vaginal Microbiota May be Associated With the Development of Localized Provoked Vulvodynia (LPV)

Brief Summary

      Currently, the pathogenesis of Localized Provoked Vulvodynia (LPV) has not been elucidated.
      Few observations may point to involvement of the microbiome: the association of LPV with
      preceding chronic recurrent candidiasis, and the reports of the beneficial effect of a diet
      avoiding oxalate on Vulvodynia.

      Studies in the new field of microbiome research focus on the composition of overall
      microorganisms in our body and their impacts on our health. Changes in the composition of the
      vaginal microbiota (dysbiosis) have been linked with different health and disease states. We
      have also shown recently that women can be divided into 2 groups according to the composition
      of their vaginal microbiome.

      The proposed study will compare the vaginal microbiome of women with severe LPV, not treated
      by diet and otherwise healthy, to women without LPV (we will also compare our results to the
      NIH HMP data). Vaginal pH and date of menstrual cycle will be checked. We propose that
      dysbiosis in the vaginal microbiota may trigger the development of LPV.
    

Detailed Description

      Vulvodynia - vulvar pain. The exact etiology has not been elucidated yet, and therapy is
      often unsatisfactory. Two main types of Vulvodynia exist, with the far more common type being
      Localized provoked vulvodynia (LPV), also known as Vestibulodynia, and in the past -
      Vestibulitis. This study will concentrate on this common disorder which affects young women,
      whose quality of life deteriorate significantly by the inability to experience vaginal sex.

      The vaginal microbiome The new field of microbiome research focuses on the composition of
      overall microorganisms in the human body and their impacts on our human health. Amazingly,
      the number of microbial cells within our body is 10 times greater than the sum of all our
      human somatic and germ cells, and they carry 150 times more genetic information than our own.
      Changes in the composition of the vaginal microbiota (dysbiosis) have been linked with
      different health and disease states.

      The vagina is colonized with around 108-109 bacteria/mL vaginal fluid which is comparable to
      the small intestine. Recently, the NIH Human Microbiome Project characterized the bacterial
      communities across the human body and found that the vagina harbors low complexity bacterial
      communities. These communities had the lowest alpha diversity (within sample diversity) among
      the different body sites and low beta diversity (between sample diversity) at the genus
      level. This diversity was high at the species level due to distinct Lactobacillus spp. The
      communities were sampled at the sub sites that included the posterior fornix, mid vagina and
      the vaginal introitus. There was little distinction between the three sites hence we will
      focus on posterior fornix. The vaginal communities of healthy women, have also been
      repeatedly observed to occupy one of five states, four dominated by Lactobacillus spp. and
      one by higher overall microbial diversity. Shifts between the community structures within
      individuals (dysbiosis) are associated with disease states so it would be interesting to
      study whether women with LPV belong to a different enterotype than healthy women.

      The vaginal microbial communities have been shown to change during different stages in a
      woman's life and to influence pregnancy. As early as 1930, Cruickshank and Baird described
      changes in the vaginal bacterial communities that occurred between the 5th and 7th month of
      pregnancy.

      In 2010 a study was undertaken among Amerindian women to examine the microbial vaginal
      signature at term in relation to delivery mode (n=9). Variability in vaginal taxa was noted
      between subjects particularly for Lactobacillus species. Metagenomic analysis of the vaginal
      microbiome in a cross-sectional study of 24 healthy pregnant women and 60 non-pregnant
      controls at three vaginal sites (introitus, posterior fornix and midvagina) found the
      richness and diversity of the vaginal microbiome to be reduced in pregnancy in ways that did
      not appear to be driven by BMI, race or ethnicity . As pregnancy progressed and as proximity
      to the uterus increased, less diversity and richness were noted. Lactobacillus species were
      enriched in pregnancy, which the authors postulated may be biologically significant as lactic
      acid bacteria produce bacteriocins that may reduce the risk of ascending infections. It has
      also been proposed that the vaginal microbiota has the potential to influence the conception
      process by influencing the local production of proinflammatory cytokines which in turn impact
      the survival rate and motility of sperm cells.

      The vaginal microbiome and Vulvodynia Several microorganisms have been discussed for presumed
      role in LPV development: LPV is frequently associated with preceding chronic recurrent
      candidiasis, LPV may be produced in a mouse model by repeated vulvovaginal fungal infection,
      the difficulty in treating women with concomitant LPV and candidiasis (complicated LPV), the
      reports of the beneficial effect of treatment with combined antibiotics, aimed at eradicating
      H. pylori peptic condition (although H. pylori has not been detected in LPV tissues).

      Indirect evidence of the role of the microbiome with the development of LPV may be deduced
      from the beneficial effect (14.3 - 50%), reported by some authors, of a diet avoiding oxalate
      and rich in Calcium citrate, on LPV. As women with LPV consume more oxalate - although not
      significantly, we suspect that the variability in response rate may be due to the indirect
      effect of the diet - through changes in the microbiome, which may be affecting LPV severity.
      In addition, the adverse effect of oral contraceptive pills (OCP) in increasing LPV symptoms;
      OCP tend to change the composition of the vaginal microbiota, consequent to their effect of
      thinning and dehydrating the vaginal mucosa. These finding prompt us to further inquire the
      possible association of vaginal microbiome dysbiosis and the development of LPV.

      Objective:

      The proposed study will first compare the vaginal microbiome of women with severe LPV, not
      treated by diet and otherwise healthy, to women without LPV (we will also compare our results
      to the NIH HMP data). At the second stage we will characterize the effect of a three-month
      low oxalate diet on the vaginal microbiota of women with LPV and on the outcome compared to a
      group of patients with LPV not treated by diet. Vaginal pH and date of menstrual cycle will
      be checked. We propose that dysbiosis in the vaginal microbiota may trigger the development
      of LPV.

      Vulvodynia subtype:

        -  The research will study women with localized provoked Vulvodynia

        -  Only secondary type of LPV will be included.

        -  LPV diagnosis will be based on documenting first two Friedrich's criteria for vulva
           vestibulits syndrome: patient's complaint of entry dyspareunia, a positive Q-tip test.

        -  Only women suffering from levels II or III dyspareunia according to Marinoff : Level II
           is where the pain prevents intercourse from taking place on most occasions; and Level
           III where pain results in total apareunia.

      Methods/Protocol This will be a double blind, prospective study comparing the microbiome of
      women with severe LPV to women without LPV, and to compare the effect of consuming the low
      oxalate diet with calcium citrate supplements for one month on the microbiome of women with
      LPV.

      The local Institutional Review Board approval has been requested. Every woman participating
      in the study will sign an informed consent prior to enrollment.

      Study group

      The study group will consist of 35 women:

        -  Meeting first two Friedrich's criteria for vulva vestibulitis syndrome

        -  Diagnosed by a gynecological examination with Localized Provoked Vulvodynia

        -  Diagnosed with a Level II or III degree of the syndrome according to Marinoff Control
           group

        -  The control group will consist of 35 consecutive women who are referred to the
           departments of the co-investigators. Presentation of LPV is an exclusion criterion.

      Materials and Methods:

      Prior to enrollment, the women will be questioned about possible inclusion and exclusion
      criteria, and fill in the ISSVD Vulvodynia questionnaire.

      Women found suitable for the study will undergo a Q-tip test to confirm the diagnosis of
      Vestibulodynia. Women of the LPV group will be instructed to consume a "low oxalate diet"
      with calcium citrate supplements, as recommended by Solomons et al for the duration of at
      least one month, to assess its impact on the vaginal microbiome.

      Clinical pain scores and vulvar sensitivity by Q-tip test will be repeated after one month
      and compared to the clinical pain scores at the beginning of the study. Subjective evaluation
      will be carried out by comparing personal data from questionnaires filled in at enrollment
      and one month later.

      Clinical evaluation will be performed by an experienced vulvar expert, using the pain
      intensity scale (The 11 points (0-10) pain intensity numerical rating scale-PI-NRS), in seven
      foci throughout the vestibule (the Q-tip test) and by comparing patients' responses to
      questionnaires evaluating pain during intercourse or other activities (riding a
      bicycle/horse), before and after diet.
    

Study Phase

Phase 3

Study Type

Interventional


Primary Outcome

Change in vaginal microbiome composition of women with localized provoked vulvodynia following three months of low oxalate diet

Secondary Outcome

 Level of dyspareunia following three months of low oxalate diet in women with localized provoked vulvodynia

Condition

Vulvodynia

Intervention

Low Oxalate Diet

Study Arms / Comparison Groups

 Study A - with diet
Description:  Patients with LPV, treated by Low Oxalate Diet for three months.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Dietary Supplement

Estimated Enrollment

70

Start Date

March 2015

Completion Date

February 2017

Primary Completion Date

February 2016

Eligibility Criteria

        Inclusion Criteria:

          -  Healthy women, aged 18-50 years, meet Friedrich's first two criteria for vulvar
             Vestibulitis syndrome, suffer from levels II or III dyspareunia according to Marinoff

        Exclusion Criteria:

          -  Women suffering from generalized Vulvodynia (constant vulvar pain - unrelated to
             provocation), pregnant or lactating. Women will also be excluded from the study if
             they were have any medical condition, acute or chronic, or anticipated not being
             available for the one month follow up visit, have received antibiotics during the
             month preceding the study.
      

Gender

Female

Ages

18 Years - 50 Years

Accepts Healthy Volunteers

Accepts Healthy Volunteers

Contacts

Jacob Bornstein, MD, 972546738094, [email protected]



Administrative Informations


NCT ID

NCT02393911

Organization ID

0146-14-NHR


Responsible Party

Principal Investigator

Study Sponsor

Western Galilee Hospital-Nahariya


Study Sponsor

Jacob Bornstein, MD, Principal Investigator, Western Galilee Hospital


Verification Date

March 2015