<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03238053</url>
  </required_header>
  <id_info>
    <org_study_id>Laser treatment</org_study_id>
    <nct_id>NCT03238053</nct_id>
  </id_info>
  <brief_title>Laser Treatment of Genito-urinary Syndrome in Women</brief_title>
  <official_title>Laser Treatment of Genito-urinary Syndrome in Women With Breast and Endometrial Cancer and Menopausal Women</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Herning Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Herning Hospital</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Women with genitourinary syndrome of menopause, overactive bladder, with breast or&#xD;
      endometrial cancer are randomized to either laser treatment og sham treatment for 3 months.&#xD;
      The randomization is stratified for estrogen treatment. The effect is evaluated by&#xD;
      questionnaire, histology and microbiology swaps&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Genitourinary syndrome of menopause (GSM) is characterized by symptoms such as vaginal&#xD;
      dryness, dyspareunia, irritation, urinary incontinence, overactive bladder , and urinary&#xD;
      tract infections. GSM replaces the previous term vulvovaginal atrophy as agreed upon by a&#xD;
      joint terminology conference sponsored by the North American Menopause Society and the&#xD;
      International Society for the Study of Women's Sexual Health. GSM is a new terminology more&#xD;
      accurate than the terms of VVA/atrophic vaginitis, because it describes the clinical signs&#xD;
      and symptoms of the vulva, vagina and lower urinary system. In contrast, VVA/atrophic&#xD;
      vaginitis describes the appearance of the vulvovaginal structures only. The GSM has a&#xD;
      prevalence of more or less 50%, depending on country of origin, with a negative impact on&#xD;
      sexuality, quality of life and well-being.&#xD;
&#xD;
      The aging process is genetically determined and environmentally modulated. Estrogen&#xD;
      deficiency occurring after menopause causes a series of modifications in many different areas&#xD;
      of the female body, including the pelvic floor. Menopause can, therefore, lead to functional&#xD;
      genital or urinary symptoms impacting women's quality of life. It is debatable to which&#xD;
      extent modifications and symptoms occurring after menopause are related to estrogen&#xD;
      deficiency or to the aging process per se. Vulvovaginal atrophy (VVA) involves histological,&#xD;
      morphological, microbiological, and clinical changes. These include alteration in collagens,&#xD;
      decreased quantity of elastic fibers, reduced vascularization, thinning and flattening of the&#xD;
      vaginal epithelium, and production of glycogen, an essential factor for the growth of vaginal&#xD;
      lactobacilli. As a consequence, the vaginal canal becomes shorter and narrower, and the&#xD;
      vaginal epithelium becomes paler and more likely to develop petechiae. Further, a decrease in&#xD;
      Lactobacillus species and a rise of vaginal pH values over 4.5 are observed, resulting in the&#xD;
      loss of the local vaginal defense mechanisms against bacterial pathogens, which may&#xD;
      predispose to local inflammation and/or infections.&#xD;
&#xD;
      Women with VVA commonly complain of vaginal dryness, burning, irritation or itching, and&#xD;
      dyspareunia. Local estrogens represent the first-line therapy for VVA. However, women's&#xD;
      compliance with and preference for this treatment are poor; alternatives and palliative&#xD;
      solutions, such as moisturizing or lubricant local creams or gels, are commonly proposed. In&#xD;
      recent years, fractional CO 2 laser has become a popular, efficient, precise, and safe&#xD;
      system, particularly for dermatologists and plastic surgeons. CO 2 laser has many&#xD;
      applications, including treatment of skin lesions (ie, seborrheic keratosis, syringomas, and&#xD;
      xanthelasmas around the eye), warts, and toenail diseases, as well as anti-aging function.&#xD;
&#xD;
      Various therapeutic strategies, hormonal or not, oral or local, have been proposed for the&#xD;
      improvement of the vaginal microecosystem of postmenopausal women (e.g. estrogens,&#xD;
      probiotics, combination of vaginal estrogens with live Lactobacillus). Hormonal therapy (oral&#xD;
      or local) has been associated with a healthier vaginal microecosystem by repopulating the&#xD;
      Lactobacillus species to a premenopausal status and by reducing the pH of vaginal fluid.&#xD;
&#xD;
      In women treated for estrogen dependent cancer i.e. endometrial and breast cancer women and&#xD;
      practioners are reluctant to use estrogens and favor non-hormonal treatment modalities. The&#xD;
      effect of these on the histological, microbiological and clinical symptoms is poorly&#xD;
      understood and lack randomized trials to evaluate effect. Several proof of concept and&#xD;
      feasibility studies have shown clinical effects of laser as potential treatment but little is&#xD;
      known if it can stand alone or if supplementation with estrogens may benefit the clinical&#xD;
      symptoms and vulvovaginal environment further. Thus, the ideal management for the achievement&#xD;
      of the optimal benefit - risk balance is still under investigation. The choice of treatment&#xD;
      is often guided by clinical experience and patient preference.&#xD;
&#xD;
      In postmenopausal women, the disturbance of Lactobacillary flora was correlated with the&#xD;
      presence of Gardnerella vaginalis, Trichomonas vaginalis, enterococci, group B streptococci,&#xD;
      and Escherichia coli. Available data indicate that pre-existing vaginal colonization with&#xD;
      pathogenic enterobacteria is essential for the appearance and recurrence of urinary tract&#xD;
      infections (UTIs). Indeed, postmenopausal women are prone to UTIs with an incidence of about&#xD;
      8% per year and a 4% likelihood of recurrence, while symptomatic bacteriuria was estimated in&#xD;
      up to 15% of women. The general population of lactobacilli, as assessed in the routine&#xD;
      practice, provides indirect information regarding the estrogenic status. To our knowledge&#xD;
      there is currently no evidence regarding the potential impact that the intravaginal laser&#xD;
      therapy may have on the vaginal microenvironment in women with symptoms of GSM.&#xD;
&#xD;
      Laser treatment improves significantly the VVA symptoms, sexual function and quality of life&#xD;
      of postmenopausal women, as well as the vaginal health index. Other studies found restored&#xD;
      thickness of the squamous stratified epithelium of the vaginal mucosa with a significant&#xD;
      storage of glycogen in the epithelial cells and remodelling the vaginal connective tissue&#xD;
      with the production of new collagen and ground substance molecules.&#xD;
&#xD;
      Breast cancer is the most common cancer in women in Denmark, annually ca. 4600 women are&#xD;
      diagnosed with the disease, of whom 30% are under the age of 55. Most patients undergo breast&#xD;
      conserving surgery followed by adjuvant therapy. Adjuvant therapy varies according to stage&#xD;
      of disease, but radiotherapy is often added, as well as chemotherapy. If the cancer is&#xD;
      hormonally responsive, long term antihormonal treatment is also given, such as the selective&#xD;
      estrogen receptor modulator (SERM) tamoxifen for pre-menopausal women, that works as a&#xD;
      inhibitor of estrogen in breast tissue, but as an estrogen in other tissues such as the&#xD;
      endometrium. Post-menopausal women with hormone responsive breast cancer are treated with&#xD;
      aromatase inhibitors for five years. Most side effects associated with tamoxifen (TAM) and&#xD;
      aromatase inhibitors (AIs) are related to estrogen deprivation, and the symptoms are similar&#xD;
      to those experienced during natural menopause. It has been reported that up to 50-75% of&#xD;
      breast cancer survivors experience one or more genitourinary symptoms and puts the sexual&#xD;
      life of women under stress. Postmenopausal women may have many common age-related symptoms&#xD;
      but also have the above mentioned iatrogenic factors entering their lives to aggravate the&#xD;
      symptom complex.&#xD;
&#xD;
      The aim of the current study was to assess the effect of laser laser therapy with and without&#xD;
      local estrogens. The study groups consist of 1) postmenopausal women and 2 ) women treated&#xD;
      for breast cancer. The laser treatment was given randomized to these women. The effects were&#xD;
      evaluated in the histopathology of the vagina, the vaginal microenvironment, and health&#xD;
      related questionnaires.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Not yet recruiting</overall_status>
  <start_date type="Anticipated">October 1, 2022</start_date>
  <completion_date type="Anticipated">December 31, 2026</completion_date>
  <primary_completion_date type="Anticipated">December 31, 2025</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>Four Groups of women randomized for thre months to either laser og sham treatment</intervention_model_description>
    <primary_purpose>Supportive Care</primary_purpose>
    <masking>Single (Participant)</masking>
    <masking_description>Laser probe perform similar noise and movement without providing rays</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Visual analogue score on vaginal symptoms</measure>
    <time_frame>three months</time_frame>
    <description>10-cm VAS to measure the overall satisfaction with vaginal symptoms, where the left extreme of the scale indicated ' the worst level of satisfaction ' and the right indicated ' the best level of satisfaction</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>histopathology</measure>
    <time_frame>three months</time_frame>
    <description>Qualitative analysis of the microscopic and ultrastructural aspects of the collagenic and elastic components of the matrix is performed. A specific image analysis with computerized morphometry is performed to demonstrate the specific action of CO2 laser and possibly to correlate the modifications of the ultrastructural pattern with specific molecular modifications. We also consider the fine cytological aspects of connective tissue proper cells, particularly fibroblasts, under the conditions of the specific laser stimulation.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>microbiology</measure>
    <time_frame>three months</time_frame>
    <description>a sterile swab is inserted into the vaginal canal and a sample obtained from the posterior fornix of the vagina. Vaginal samples are placed in a transport gel (Stuart). pH indicator strips (MColorpHastTM, Merck, Germany) are applied against the lateral vaginal wall using sterile forceps, followed by a vaginal lavage for wet mount. Smears from vaginal samples are placed on a glass slide, observed under microscope for Trichomonas vaginalis and Candida species and stained afterwards according to standard Gram stain procedure. Cultures for aerobic and anaerobic bacteria species are performed, using MacConkey agar, blood agar, Sabouraud dextrose agar, chocolate agar as culture media, focusing on bacteria with potential clinical impact (e.g. aerobic vaginitis39, UTIs, vaginal candidiasis).</description>
  </secondary_outcome>
  <number_of_arms>8</number_of_arms>
  <enrollment type="Anticipated">160</enrollment>
  <condition>Laser-Induced Scar</condition>
  <condition>Breast Cancer</condition>
  <condition>Endometrial Cancer</condition>
  <condition>Menopause</condition>
  <condition>Vaginal Atrophy</condition>
  <condition>Bladder, Overactive</condition>
  <arm_group>
    <arm_group_label>Menopausal Laser</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>20 women with vaginal laser treatment</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Menopausal sham</arm_group_label>
    <arm_group_type>Sham Comparator</arm_group_type>
    <description>20 women with probe, no active laser ray</description>
  </arm_group>
  <arm_group>
    <arm_group_label>breast cancer laser</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>20 women with breast cancer with vaginal laser treatment</description>
  </arm_group>
  <arm_group>
    <arm_group_label>breast cancer sham</arm_group_label>
    <arm_group_type>Sham Comparator</arm_group_type>
    <description>20 women with breast cancer with vaginal probe, no active laser rays</description>
  </arm_group>
  <arm_group>
    <arm_group_label>endometrial cancer laser</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>20 women with endometrial cancer with vaginal laser treatment</description>
  </arm_group>
  <arm_group>
    <arm_group_label>endometrial cancer sham</arm_group_label>
    <arm_group_type>Sham Comparator</arm_group_type>
    <description>20 women with endometrial cancer with vaginal probe, no active laser rays</description>
  </arm_group>
  <arm_group>
    <arm_group_label>overactive bladder laser</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>20 women with overactive bladder with vaginal laser treatment</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Overactive bladder sham</arm_group_label>
    <arm_group_type>Sham Comparator</arm_group_type>
    <description>20 women with overactive bladder with vaginal probe, no active laser rays</description>
  </arm_group>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Vaginal laser treatment</intervention_name>
    <description>Fractional CO 2 laser system (SmartXide 2 V 2 LR,DEKA, Florence, Italy), using the following setting: dot power 30 watt, dwell time 1000 μ s, dot spacing 1000 μ m and the smart stack parameter from 1 to 3. The laser beam is provided using a vaginal probe, which is gently inserted up to the top of the vaginal canal and subsequently withdrawn and rotated in order to provide a complete treatment of the vaginal wall. At the level of the vaginal introitus, the dot power is decreased to 20 watt 27 . A treatment cycle includes three laser applications (every 4 weeks). The procedure is performed in the outpatient clinic and does not require any specific preparation (e.g. analgesia/anesthesia).</description>
    <arm_group_label>Menopausal Laser</arm_group_label>
    <arm_group_label>breast cancer laser</arm_group_label>
    <arm_group_label>endometrial cancer laser</arm_group_label>
    <arm_group_label>overactive bladder laser</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>sham</intervention_name>
    <description>Fractional CO 2 laser system (SmartXide 2 V 2 LR,DEKA, Florence, Italy), using the following setting: dot power 30 watt, dwell time 1000 μ s, dot spacing 1000 μ m and the smart stack parameter from 1 to 3. The laser beam is provided using a vaginal probe, which is gently inserted up to the top of the vaginal canal and subsequently withdrawn and rotated in order to provide a complete treatment of the vaginal wall. At the level of the vaginal introitus, the dot power is decreased to 20 watt 27 . A treatment cycle includes three laser applications (every 4 weeks). The procedure is performed in the outpatient clinic and does not require any specific preparation (e.g. analgesia/anesthesia).</description>
    <arm_group_label>Menopausal sham</arm_group_label>
    <arm_group_label>Overactive bladder sham</arm_group_label>
    <arm_group_label>breast cancer sham</arm_group_label>
    <arm_group_label>endometrial cancer sham</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>laser system</intervention_name>
    <description>FractionalCO 2 laser system (SmartXide 2 V 2 LR,DEKA, Florence, Italy), using the following setting: dot power 30 watt, dwell time 1000 μ s, dot spacing 1000 μ m and the smart stack parameter from 1 to 3. The laser beam is provided using a vaginal probe, which is gently inserted up to the top of the vaginal canal and subsequently withdrawn and rotated in order to provide a complete treatment of the vaginal wall. At the level of the vaginal introitus, the dot power is decreased to 20 watt 27 . A treatment cycle includes three laser applications (every 4 weeks). The procedure is performed in the outpatient clinic and does not require any specific preparation (e.g. analgesia/anesthesia).</description>
    <arm_group_label>Menopausal Laser</arm_group_label>
    <arm_group_label>breast cancer laser</arm_group_label>
    <arm_group_label>endometrial cancer laser</arm_group_label>
    <arm_group_label>overactive bladder laser</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  menopause i.e. age more than 50 years and absence of menstruation for twelve months&#xD;
&#xD;
          -  breast cancer&#xD;
&#xD;
          -  endometrial cancer&#xD;
&#xD;
          -  symptoms of vaginal dryness&#xD;
&#xD;
          -  dyspareunia rated as moderate or severe most bothersome symptoms&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  use of vaginal moisturizers, lubricants or any other local preparation within the&#xD;
             thirty days prior to inclusion&#xD;
&#xD;
          -  acute or recurrent urinary tract infections&#xD;
&#xD;
          -  active genital infections i.e. herpes genitalis, candida&#xD;
&#xD;
          -  previous reconstructive pelvic surgery&#xD;
&#xD;
          -  pelvis organ prolapse stage 2&#xD;
&#xD;
          -  any serious disease or chronic condition that could interfere with study compliance&#xD;
             except from breast and endometrial cancer&#xD;
&#xD;
          -  psychiatric disorders precluding informed consent&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>N/A</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Sine Jakobsen, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Randers Regional Hospital</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Finn F Lauszus</last_name>
    <role>Study Chair</role>
    <affiliation>Herning Hopsital</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Finn F Lauszus, MD, PhD</last_name>
    <phone>+45 79972192</phone>
    <email>finn.lauszus@rsyd.dk</email>
  </overall_contact>
  <location>
    <facility>
      <name>Gynecology Dept. Herning Hospital</name>
      <address>
        <city>Herning</city>
        <zip>7400</zip>
        <country>Denmark</country>
      </address>
    </facility>
    <contact>
      <last_name>Finn F Lauszus, MD, PhD</last_name>
      <phone>+4579972192</phone>
      <email>finln.lauszus@rsyd.dk</email>
    </contact>
    <investigator>
      <last_name>Sine Jakobsen, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>Denmark</country>
  </location_countries>
  <reference>
    <citation>Salvatore S, Nappi RE, Parma M, Chionna R, Lagona F, Zerbinati N, Ferrero S, Origoni M, Candiani M, Leone Roberti Maggiore U. Sexual function after fractional microablative CO(2) laser in women with vulvovaginal atrophy. Climacteric. 2015 Apr;18(2):219-25. doi: 10.3109/13697137.2014.975197. Epub 2014 Dec 16.</citation>
    <PMID>25333211</PMID>
  </reference>
  <reference>
    <citation>Salvatore S, Leone Roberti Maggiore U, Athanasiou S, Origoni M, Candiani M, Calligaro A, Zerbinati N. Histological study on the effects of microablative fractional CO2 laser on atrophic vaginal tissue: an ex vivo study. Menopause. 2015 Aug;22(8):845-9. doi: 10.1097/GME.0000000000000401.</citation>
    <PMID>25608269</PMID>
  </reference>
  <reference>
    <citation>Athanasiou S, Pitsouni E, Antonopoulou S, Zacharakis D, Salvatore S, Falagas ME, Grigoriadis T. The effect of microablative fractional CO2 laser on vaginal flora of postmenopausal women. Climacteric. 2016 Oct;19(5):512-8. doi: 10.1080/13697137.2016.1212006. Epub 2016 Aug 24.</citation>
    <PMID>27558459</PMID>
  </reference>
  <verification_date>March 2022</verification_date>
  <study_first_submitted>August 1, 2017</study_first_submitted>
  <study_first_submitted_qc>August 2, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 3, 2017</study_first_posted>
  <last_update_submitted>March 15, 2022</last_update_submitted>
  <last_update_submitted_qc>March 15, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">March 16, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Herning Hospital</investigator_affiliation>
    <investigator_full_name>Finn Lauszus</investigator_full_name>
    <investigator_title>Senior Consultant, Research Specialist</investigator_title>
  </responsible_party>
  <keyword>laser treatment, randomized trial, menopause, vaginitis, urge</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Endometrial Neoplasms</mesh_term>
    <mesh_term>Urinary Bladder, Overactive</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03238053
org study id: Laser treatment
nct id: NCT03238053
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Women with genitourinary syndrome of menopause, overactive bladder, with breast or
      endometrial cancer are randomized to either laser treatment og sham treatment for 3 months.
      The randomization is stratified for estrogen treatment. The effect is evaluated by
      questionnaire, histology and microbiology swaps
Genitourinary syndrome of menopause (GSM) is characterized by symptoms such as vaginal
      dryness, dyspareunia, irritation, urinary incontinence, overactive bladder , and urinary
      tract infections. GSM replaces the previous term vulvovaginal atrophy as agreed upon by a
      joint terminology conference sponsored by the North American Menopause Society and the
      International Society for the Study of Women's Sexual Health. GSM is a new terminology more
      accurate than the terms of VVA/atrophic vaginitis, because it describes the clinical signs
      and symptoms of the vulva, vagina and lower urinary system. In contrast, VVA/atrophic
      vaginitis describes the appearance of the vulvovaginal structures only. The GSM has a
      prevalence of more or less 50%, depending on country of origin, with a negative impact on
      sexuality, quality of life and well-being.

      The aging process is genetically determined and environmentally modulated. Estrogen
      deficiency occurring after menopause causes a series of modifications in many different areas
      of the female body, including the pelvic floor. Menopause can, therefore, lead to functional
      genital or urinary symptoms impacting women's quality of life. It is debatable to which
      extent modifications and symptoms occurring after menopause are related to estrogen
      deficiency or to the aging process per se. Vulvovaginal atrophy (VVA) involves histological,
      morphological, microbiological, and clinical changes. These include alteration in collagens,
      decreased quantity of elastic fibers, reduced vascularization, thinning and flattening of the
      vaginal epithelium, and production of glycogen, an essential factor for the growth of vaginal
      lactobacilli. As a consequence, the vaginal canal becomes shorter and narrower, and the
      vaginal epithelium becomes paler and more likely to develop petechiae. Further, a decrease in
      Lactobacillus species and a rise of vaginal pH values over 4.5 are observed, resulting in the
      loss of the local vaginal defense mechanisms against bacterial pathogens, which may
      predispose to local inflammation and/or infections.

      Women with VVA commonly complain of vaginal dryness, burning, irritation or itching, and
      dyspareunia. Local estrogens represent the first-line therapy for VVA. However, women's
      compliance with and preference for this treatment are poor; alternatives and palliative
      solutions, such as moisturizing or lubricant local creams or gels, are commonly proposed. In
      recent years, fractional CO 2 laser has become a popular, efficient, precise, and safe
      system, particularly for dermatologists and plastic surgeons. CO 2 laser has many
      applications, including treatment of skin lesions (ie, seborrheic keratosis, syringomas, and
      xanthelasmas around the eye), warts, and toenail diseases, as well as anti-aging function.

      Various therapeutic strategies, hormonal or not, oral or local, have been proposed for the
      improvement of the vaginal microecosystem of postmenopausal women (e.g. estrogens,
      probiotics, combination of vaginal estrogens with live Lactobacillus). Hormonal therapy (oral
      or local) has been associated with a healthier vaginal microecosystem by repopulating the
      Lactobacillus species to a premenopausal status and by reducing the pH of vaginal fluid.

      In women treated for estrogen dependent cancer i.e. endometrial and breast cancer women and
      practioners are reluctant to use estrogens and favor non-hormonal treatment modalities. The
      effect of these on the histological, microbiological and clinical symptoms is poorly
      understood and lack randomized trials to evaluate effect. Several proof of concept and
      feasibility studies have shown clinical effects of laser as potential treatment but little is
      known if it can stand alone or if supplementation with estrogens may benefit the clinical
      symptoms and vulvovaginal environment further. Thus, the ideal management for the achievement
      of the optimal benefit - risk balance is still under investigation. The choice of treatment
      is often guided by clinical experience and patient preference.

      In postmenopausal women, the disturbance of Lactobacillary flora was correlated with the
      presence of Gardnerella vaginalis, Trichomonas vaginalis, enterococci, group B streptococci,
      and Escherichia coli. Available data indicate that pre-existing vaginal colonization with
      pathogenic enterobacteria is essential for the appearance and recurrence of urinary tract
      infections (UTIs). Indeed, postmenopausal women are prone to UTIs with an incidence of about
      8% per year and a 4% likelihood of recurrence, while symptomatic bacteriuria was estimated in
      up to 15% of women. The general population of lactobacilli, as assessed in the routine
      practice, provides indirect information regarding the estrogenic status. To our knowledge
      there is currently no evidence regarding the potential impact that the intravaginal laser
      therapy may have on the vaginal microenvironment in women with symptoms of GSM.

      Laser treatment improves significantly the VVA symptoms, sexual function and quality of life
      of postmenopausal women, as well as the vaginal health index. Other studies found restored
      thickness of the squamous stratified epithelium of the vaginal mucosa with a significant
      storage of glycogen in the epithelial cells and remodelling the vaginal connective tissue
      with the production of new collagen and ground substance molecules.

      Breast cancer is the most common cancer in women in Denmark, annually ca. 4600 women are
      diagnosed with the disease, of whom 30% are under the age of 55. Most patients undergo breast
      conserving surgery followed by adjuvant therapy. Adjuvant therapy varies according to stage
      of disease, but radiotherapy is often added, as well as chemotherapy. If the cancer is
      hormonally responsive, long term antihormonal treatment is also given, such as the selective
      estrogen receptor modulator (SERM) tamoxifen for pre-menopausal women, that works as a
      inhibitor of estrogen in breast tissue, but as an estrogen in other tissues such as the
      endometrium. Post-menopausal women with hormone responsive breast cancer are treated with
      aromatase inhibitors for five years. Most side effects associated with tamoxifen (TAM) and
      aromatase inhibitors (AIs) are related to estrogen deprivation, and the symptoms are similar
      to those experienced during natural menopause. It has been reported that up to 50-75% of
      breast cancer survivors experience one or more genitourinary symptoms and puts the sexual
      life of women under stress. Postmenopausal women may have many common age-related symptoms
      but also have the above mentioned iatrogenic factors entering their lives to aggravate the
      symptom complex.

      The aim of the current study was to assess the effect of laser laser therapy with and without
      local estrogens. The study groups consist of 1) postmenopausal women and 2 ) women treated
      for breast cancer. The laser treatment was given randomized to these women. The effects were
      evaluated in the histopathology of the vagina, the vaginal microenvironment, and health
      related questionnaires.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Four Groups of women randomized for thre months to either laser og sham treatment
primary purpose: Supportive Care
masking: Single (Participant)
masking description: Laser probe perform similar noise and movement without providing rays
measure: Visual analogue score on vaginal symptoms
time frame: three months
description: 10-cm VAS to measure the overall satisfaction with vaginal symptoms, where the left extreme of the scale indicated ' the worst level of satisfaction ' and the right indicated ' the best level of satisfaction
measure: histopathology
time frame: three months
description: Qualitative analysis of the microscopic and ultrastructural aspects of the collagenic and elastic components of the matrix is performed. A specific image analysis with computerized morphometry is performed to demonstrate the specific action of CO2 laser and possibly to correlate the modifications of the ultrastructural pattern with specific molecular modifications. We also consider the fine cytological aspects of connective tissue proper cells, particularly fibroblasts, under the conditions of the specific laser stimulation.
measure: microbiology
time frame: three months
description: a sterile swab is inserted into the vaginal canal and a sample obtained from the posterior fornix of the vagina. Vaginal samples are placed in a transport gel (Stuart). pH indicator strips (MColorpHastTM, Merck, Germany) are applied against the lateral vaginal wall using sterile forceps, followed by a vaginal lavage for wet mount. Smears from vaginal samples are placed on a glass slide, observed under microscope for Trichomonas vaginalis and Candida species and stained afterwards according to standard Gram stain procedure. Cultures for aerobic and anaerobic bacteria species are performed, using MacConkey agar, blood agar, Sabouraud dextrose agar, chocolate agar as culture media, focusing on bacteria with potential clinical impact (e.g. aerobic vaginitis39, UTIs, vaginal candidiasis).
arm group label: Menopausal Laser
arm group type: Active Comparator
description: 20 women with vaginal laser treatment
arm group label: Menopausal sham
arm group type: Sham Comparator
description: 20 women with probe, no active laser ray
arm group label: breast cancer laser
arm group type: Active Comparator
description: 20 women with breast cancer with vaginal laser treatment
arm group label: breast cancer sham
arm group type: Sham Comparator
description: 20 women with breast cancer with vaginal probe, no active laser rays
arm group label: endometrial cancer laser
arm group type: Active Comparator
description: 20 women with endometrial cancer with vaginal laser treatment
arm group label: endometrial cancer sham
arm group type: Sham Comparator
description: 20 women with endometrial cancer with vaginal probe, no active laser rays
arm group label: overactive bladder laser
arm group type: Active Comparator
description: 20 women with overactive bladder with vaginal laser treatment
arm group label: Overactive bladder sham
arm group type: Sham Comparator
description: 20 women with overactive bladder with vaginal probe, no active laser rays
intervention type: Procedure
intervention name: Vaginal laser treatment
description: Fractional CO 2 laser system (SmartXide 2 V 2 LR,DEKA, Florence, Italy), using the following setting: dot power 30 watt, dwell time 1000 μ s, dot spacing 1000 μ m and the smart stack parameter from 1 to 3. The laser beam is provided using a vaginal probe, which is gently inserted up to the top of the vaginal canal and subsequently withdrawn and rotated in order to provide a complete treatment of the vaginal wall. At the level of the vaginal introitus, the dot power is decreased to 20 watt 27 . A treatment cycle includes three laser applications (every 4 weeks). The procedure is performed in the outpatient clinic and does not require any specific preparation (e.g. analgesia/anesthesia).
arm group label: Menopausal Laser
arm group label: breast cancer laser
arm group label: endometrial cancer laser
arm group label: overactive bladder laser
intervention type: Device
intervention name: sham
description: Fractional CO 2 laser system (SmartXide 2 V 2 LR,DEKA, Florence, Italy), using the following setting: dot power 30 watt, dwell time 1000 μ s, dot spacing 1000 μ m and the smart stack parameter from 1 to 3. The laser beam is provided using a vaginal probe, which is gently inserted up to the top of the vaginal canal and subsequently withdrawn and rotated in order to provide a complete treatment of the vaginal wall. At the level of the vaginal introitus, the dot power is decreased to 20 watt 27 . A treatment cycle includes three laser applications (every 4 weeks). The procedure is performed in the outpatient clinic and does not require any specific preparation (e.g. analgesia/anesthesia).
arm group label: Menopausal sham
arm group label: Overactive bladder sham
arm group label: breast cancer sham
arm group label: endometrial cancer sham
intervention type: Device
intervention name: laser system
description: FractionalCO 2 laser system (SmartXide 2 V 2 LR,DEKA, Florence, Italy), using the following setting: dot power 30 watt, dwell time 1000 μ s, dot spacing 1000 μ m and the smart stack parameter from 1 to 3. The laser beam is provided using a vaginal probe, which is gently inserted up to the top of the vaginal canal and subsequently withdrawn and rotated in order to provide a complete treatment of the vaginal wall. At the level of the vaginal introitus, the dot power is decreased to 20 watt 27 . A treatment cycle includes three laser applications (every 4 weeks). The procedure is performed in the outpatient clinic and does not require any specific preparation (e.g. analgesia/anesthesia).
arm group label: Menopausal Laser
arm group label: breast cancer laser
arm group label: endometrial cancer laser
arm group label: overactive bladder laser
criteria: 
gender: Female
minimum age: N/A
maximum age: N/A
healthy volunteers: No
last name: Sine Jakobsen, MD, PhD
role: Principal Investigator
affiliation: Randers Regional Hospital
last name: Finn F Lauszus
role: Study Chair
affiliation: Herning Hopsital
last name: Finn F Lauszus, MD, PhD
phone: +45 79972192
email: finn.lauszus@rsyd.dk
facility: 
contact: 
investigator: 
country: Denmark
citation: Salvatore S, Nappi RE, Parma M, Chionna R, Lagona F, Zerbinati N, Ferrero S, Origoni M, Candiani M, Leone Roberti Maggiore U. Sexual function after fractional microablative CO(2) laser in women with vulvovaginal atrophy. Climacteric. 2015 Apr;18(2):219-25. doi: 10.3109/13697137.2014.975197. Epub 2014 Dec 16.
PMID: 25333211
citation: Salvatore S, Leone Roberti Maggiore U, Athanasiou S, Origoni M, Candiani M, Calligaro A, Zerbinati N. Histological study on the effects of microablative fractional CO2 laser on atrophic vaginal tissue: an ex vivo study. Menopause. 2015 Aug;22(8):845-9. doi: 10.1097/GME.0000000000000401.
PMID: 25608269
citation: Athanasiou S, Pitsouni E, Antonopoulou S, Zacharakis D, Salvatore S, Falagas ME, Grigoriadis T. The effect of microablative fractional CO2 laser on vaginal flora of postmenopausal women. Climacteric. 2016 Oct;19(5):512-8. doi: 10.1080/13697137.2016.1212006. Epub 2016 Aug 24.
PMID: 27558459
responsible party type: Principal Investigator
investigator affiliation: Herning Hospital
investigator full name: Finn Lauszus
investigator title: Senior Consultant, Research Specialist
mesh term: Endometrial Neoplasms
mesh term: Urinary Bladder, Overactive
sharing ipd: No