Assessment of Vaginal Atrophy: a Review

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Effects of vaginal prolapse surgery and ageing on vaginal vascularization

Weber, M.A.

Publication date 2016 Document Version Final published version

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Citation for published version (APA): Weber, M. A. (2016). Effects of vaginal prolapse surgery and ageing on vaginal vascularization.

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UvA-DARE is a service provided by the library of the University of Amsterdam (https://dare.uva.nl) Download date:03 Oct 2021

CHAPTER 5

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Assessment of vaginal atrophy: a review

Weber MA, Limpens J, Roovers JP Int Urogynecol J. 2015 Jan;26(1):15-28

503427-L-sub01-bw-Weber

ABSTRACT INTRODUCTION Introduction and hypothesis: The aim of this study is to provide an evidence-based Vaginal atrophy (VA) is a condition that commonly affects postmenopausal women (1;2). definition of vaginal atrophy (VA) and present an overview of subjective and objective Consensus on the most accepted definition of VA is lacking. measurements of VA applicable in clinical practice and research. It is estimated that up to 40% of postmenopausal women experience symptoms of VA (1- Search Methods: A systematic literature search was performed in MEDLINE and EMBASE 3). As life expectancy in many countries will further increase and exceeds 80 years, to identify studies reporting on measurement properties of diagnostic instruments for VA. women can experience a postmenopausal state up to one third of their lives having a Additional searches in MEDLINE aimed to document the definitions, diagnostic criteria, marked impact on, e.g., sexual functioning, everyday activities, and body image (2;4). and outcome measures of VA. Studies reporting on definitions, diagnosis, outcome The aetiology of VA is mainly explained by the decline in levels of circulating estrogen measurements, and measurement properties of diagnostic instruments of VA were associated with the natural aging process and the menopausal transition, which causes a selected. breakdown of the collagen and elastin fibers in the vagina (1;5-7). The result is an overall Results: Specific symptoms for VA that were consistently described could be identified to loss of vaginal elasticity, the vagina loses its rugae, and there is a shortening and suggest an evidence-based definition of VA. As subjective outcome measurements, seven narrowing of the vagina. The epithelium of the vagina becomes thin and pale (5). scoring systems to assess the signs of VA during physical examination were identified. The In premenopausal women, declining estrogen levels are iatrogenic, either related to Most Bothersome Symptom (MBS) approach is most useful in clinical practice and cancer treatment (radiation therapy, chemotherapy), drug use (antiestrogen medications, research as it focuses on the most common symptoms of VA. As objective outcome e.g., tamoxifen), surgery (oophorectomy), or postpartum due to the loss of placental measurements, numerous ways to assess vaginal cytology and vaginal pH were identified. estrogen and the antagonistic action of prolactin on estrogen production during lactation Conclusion: At the moment, there is no consensus on the definition and assessment of (1). VA. We propose to define VA as a common manifestation of estrogen decline associated Characteristics to objectify the presence of VA are either subjective (like symptoms with specific symptoms of which the most common are: vaginal dryness, itching or presented by the patient or the clinical judgement by the practitioner) or objective (like irritation and dyspareunia. In both clinical and research settings, subjective assessment histological or physiological tests). (the MBS approach) and objective assessments of VA (measurement of vaginal Concerning subjective measures to quantify VA, there is a problem related to maturation index and vaginal pH) should be combined. definition and the variety of measurement tools. In 2003, the US Food and Drug Administration (FDA) published a draft guidance for the conduct of clinical studies for the treatment of VA (8). Three years later, the FDA published a separate, more comprehensive guidance developed and used to document symptomatic improvement among study participants, also defined as the patient-reported most bothersome symptom (MBS) approach (9). Concerning objective tests the problems are related to the reproducibility of these tests and their correlation with symptoms and severity of VA. Due to the lack of consensus on the quantification of VA, comparisons between interventions are

503427-L-sub01-bw-Weber

Assessment of vaginal atrophy

ABSTRACT INTRODUCTION Introduction and hypothesis: The aim of this study is to provide an evidence-based Vaginal atrophy (VA) is a condition that commonly affects postmenopausal women (1;2). definition of vaginal atrophy (VA) and present an overview of subjective and objective Consensus on the most accepted definition of VA is lacking. measurements of VA applicable in clinical practice and research. It is estimated that up to 40% of postmenopausal women experience symptoms of VA (1- Search Methods: A systematic literature search was performed in MEDLINE and EMBASE 3). As life expectancy in many countries will further increase and exceeds 80 years, to identify studies reporting on measurement properties of diagnostic instruments for VA. women can experience a postmenopausal state up to one third of their lives having a Additional searches in MEDLINE aimed to document the definitions, diagnostic criteria, marked impact on, e.g., sexual functioning, everyday activities, and body image (2;4). and outcome measures of VA. Studies reporting on definitions, diagnosis, outcome The aetiology of VA is mainly explained by the decline in levels of circulating estrogen measurements, and measurement properties of diagnostic instruments of VA were associated with the natural aging process and the menopausal transition, which causes a selected. breakdown of the collagen and elastin fibers in the vagina (1;5-7). The result is an overall Results: Specific symptoms for VA that were consistently described could be identified to loss of vaginal elasticity, the vagina loses its rugae, and there is a shortening and suggest an evidence-based definition of VA. As subjective outcome measurements, seven narrowing of the vagina. The epithelium of the vagina becomes thin and pale (5). scoring systems to assess the signs of VA during physical examination were identified. The In premenopausal women, declining estrogen levels are iatrogenic, either related to Most Bothersome Symptom (MBS) approach is most useful in clinical practice and cancer treatment (radiation therapy, chemotherapy), drug use (antiestrogen medications, research as it focuses on the most common symptoms of VA. As objective outcome e.g., tamoxifen), surgery (oophorectomy), or postpartum due to the loss of placental 05 measurements, numerous ways to assess vaginal cytology and vaginal pH were identified. estrogen and the antagonistic action of prolactin on estrogen production during lactation Conclusion: At the moment, there is no consensus on the definition and assessment of (1). VA. We propose to define VA as a common manifestation of estrogen decline associated Characteristics to objectify the presence of VA are either subjective (like symptoms with specific symptoms of which the most common are: vaginal dryness, itching or presented by the patient or the clinical judgement by the practitioner) or objective (like irritation and dyspareunia. In both clinical and research settings, subjective assessment histological or physiological tests). (the MBS approach) and objective assessments of VA (measurement of vaginal Concerning subjective measures to quantify VA, there is a problem related to maturation index and vaginal pH) should be combined. definition and the variety of measurement tools. In 2003, the US Food and Drug Administration (FDA) published a draft guidance for the conduct of clinical studies for the treatment of VA (8). Three years later, the FDA published a separate, more comprehensive guidance developed and used to document symptomatic improvement among study participants, also defined as the patient-reported most bothersome symptom (MBS) approach (9). Concerning objective tests the problems are related to the reproducibility of these tests and their correlation with symptoms and severity of VA. Due to the lack of consensus on the quantification of VA, comparisons between interventions are

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Chapter 5

compromised and patient guidance in choosing the preferred treatment option might be Study selection inadequate. A study was included if it was an original article concerning VA. Studies reporting on In this review we provide an overview of existing subjective and objective definitions, diagnosis, and outcome measurements were identified and subjectively measurements of VA and their clinical relevance. In the discussion we will provide selected. recommendations on the measurements that are most useful in clinical practice and research. RESULTS Definition of vaginal atrophy METHODS Table 1 shows the diversity of definitions given for VA found in the reviewed articles. As Search strategy shown in this table, similarity exists between the definitions of VA and atrophic vaginitis. A medical librarian (J.L.) undertook a systematic search of MEDLINE (Ovid) from 1948 till Based on review of the literature, atrophic vaginitis should be taken into account in case September 2013, using free text words and subject headings (MeSH). The search signs of inflammation are present (11-14). These signs (including red labia minora, vaginal consisted of four parts (see Appendix 1 for the MEDLINE search). The basis of the search walls, urethral meatus, or a caruncle) differ from atrophic signs (15;16) and are not was a broad search for VA. In part I VA was combined with a search filter to identify described in this review. studies reporting on measurement properties of outcome measures for VA. To ensure To further tease out the definition of VA we need to know which subjective and comprehensiveness, this part of the search was also performed in EMBASE (Ovid, from objective measurements are available to be taken into account in this definition. 1947). This search filter was an adaptation of the filter validated for PubMed (10). Part II-IV aimed to document the outcome measures, diagnosis, and definitions used Objective assessment of vaginal atrophy in VA. In Part II we combined VA with an exhaustive number of interventions and a Vaginal cytology methodological filter for clinical trials and observational studies. In part III we combined Cytomorphologically, VA can be defined as a condition with high numbers of (para)basal the VA search with terms for diagnosis, incidence, and symptoms. In Part IV VA was and intermediate cells and very low numbers of superficial cells (17). When estrogen combined with a filter for secondary evidence (as a means to check whether all primary levels decrease in women, squamous epithelial maturation to superficial squamous cells studies had been found in the previous searches). The search included an iterative decreases, and with prolonged low-estrogen states, the epithelium ceases to produce process to refine the search strategy through adding search terms as new relevant superficial and intermediate squamous cells, leaving only parabasal and basal cells lining citations were identified [i.e., by checking reference lists and citations (via Web of the vaginal wall. Science) of relevant papers]. No language restrictions were applied. All identified Capewell and coworkers (16), who graded VA on a smear from none to severe based references were downloaded and imported into Reference Manager® software (version on the amount of the different cell types present, attempted to correlate subjective 12.0) to deduplicate, store, and analyse the search results. assessment of atrophy with the cytological smear. Vaginal dryness was strongly associated with cytological atrophy, but no other gynecological feature (including vaginal color, presence of petechiae or purpura, introital size) was associated with cytological atrophy. There are several ways to assess vaginal atrophy using vaginal cytology:

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Assessment of vaginal atrophy

compromised and patient guidance in choosing the preferred treatment option might be Study selection inadequate. A study was included if it was an original article concerning VA. Studies reporting on In this review we provide an overview of existing subjective and objective definitions, diagnosis, and outcome measurements were identified and subjectively measurements of VA and their clinical relevance. In the discussion we will provide selected. recommendations on the measurements that are most useful in clinical practice and research. RESULTS Definition of vaginal atrophy METHODS Table 1 shows the diversity of definitions given for VA found in the reviewed articles. As Search strategy shown in this table, similarity exists between the definitions of VA and atrophic vaginitis. A medical librarian (J.L.) undertook a systematic search of MEDLINE (Ovid) from 1948 till Based on review of the literature, atrophic vaginitis should be taken into account in case September 2013, using free text words and subject headings (MeSH). The search signs of inflammation are present (11-14). These signs (including red labia minora, vaginal consisted of four parts (see Appendix 1 for the MEDLINE search). The basis of the search walls, urethral meatus, or a caruncle) differ from atrophic signs (15;16) and are not was a broad search for VA. In part I VA was combined with a search filter to identify described in this review. studies reporting on measurement properties of outcome measures for VA. To ensure To further tease out the definition of VA we need to know which subjective and comprehensiveness, this part of the search was also performed in EMBASE (Ovid, from objective measurements are available to be taken into account in this definition. 05 1947). This search filter was an adaptation of the filter validated for PubMed (10). Part II-IV aimed to document the outcome measures, diagnosis, and definitions used Objective assessment of vaginal atrophy in VA. In Part II we combined VA with an exhaustive number of interventions and a Vaginal cytology methodological filter for clinical trials and observational studies. In part III we combined Cytomorphologically, VA can be defined as a condition with high numbers of (para)basal the VA search with terms for diagnosis, incidence, and symptoms. In Part IV VA was and intermediate cells and very low numbers of superficial cells (17). When estrogen combined with a filter for secondary evidence (as a means to check whether all primary levels decrease in women, squamous epithelial maturation to superficial squamous cells studies had been found in the previous searches). The search included an iterative decreases, and with prolonged low-estrogen states, the epithelium ceases to produce process to refine the search strategy through adding search terms as new relevant superficial and intermediate squamous cells, leaving only parabasal and basal cells lining citations were identified [i.e., by checking reference lists and citations (via Web of the vaginal wall. Science) of relevant papers]. No language restrictions were applied. All identified Capewell and coworkers (16), who graded VA on a smear from none to severe based references were downloaded and imported into Reference Manager® software (version on the amount of the different cell types present, attempted to correlate subjective 12.0) to deduplicate, store, and analyse the search results. assessment of atrophy with the cytological smear. Vaginal dryness was strongly associated with cytological atrophy, but no other gynecological feature (including vaginal color, presence of petechiae or purpura, introital size) was associated with cytological atrophy. There are several ways to assess vaginal atrophy using vaginal cytology:

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Chapter 5

Vaginal maturation index and vaginal maturation value. The vaginal maturation index between studies as well, varying between a VMI of less than 55 in the study of Chollet (VMI) represents the percentage of parabasal, intermediate and superficial squamous and coworkers (13) to less than 40 in the study of Griesser and coworkers (25). Another cells appearing on a vaginal smear (18). The VMI specimen consists of freely exfoliating often mentioned cutoff value is the presence of less than 5% superficial cells (8;26-31) or squamous cells from the upper one-third of the vaginal wall, gently scraped with a spatula the presence of more than 75% parabasal cells (32). (19). The index is read from left to right, for example, a VMI of 0/30/70 represents 0% There are several factors that can influence the maturation index. Besides patient parabasal cells, 30% intermediate cells, and 70% superficial cells. A shift to the left influences like cigarette smoking, a body mass index above the 90th percentile, or a indicates an increase in the parabasal or intermediate cells, while a shift to the right diastolic blood pressure of more than 100 mmHg (all causing a shift to the right), there reflects an increase in the superficial or intermediate cells. In this example, the VMI are also collection considerations like the influence of delayed fixing and air drying, describes the proportion of parabasal, intermediate and superficial cells. In a formula the ectocervical, endocervial, or endometrial cell contamination or a smear that is too thick different cell types can be multiplied by certain factors to obtain the vaginal maturation (18). Besides these factors, the classification of the individual cells, performed manually, value (VMV). However, when reviewing the literature, these two terms (VMI and VMV) is subject to intra- and interobserver variations (17). are frequently used inconsistently and calculated in different ways. Table 2 gives several Davila and coworkers (24) assessed the correlation between symptoms and examples of ways to calculate VMI or VMV. Consensus about the best formula is lacking maturation value which showed that VA symptom scores (including vaginal dryness, and the variety in calculations compromises comparison between studies. soreness, irritation, dyspareunia, and vaginal discharge) were not correlated with The measurement of VMI or VMV is an inexpensive way to evaluate hormonal maturation value. There was a moderate negative correlation between vaginal health influences in women. It is often used as an outcome measure to evaluate the effect of score (consisting of assessment of vaginal secretions, epithelial integrity, surface hormonal therapies on VA. According to the formulas mentioned in table 2, a lower value thickness, color, and pH) and maturation value, indicating that maturation values were indicates fewer superficial cells which is indicative of absent or very low estrogen levels. lower in subjects with greater degrees of atrophy. Greendale and coworkers (15) showed In several studies, a cutoff value is used to define this low estrogen level or the presence that findings of conization (i.e., markedly decreased elasticity), absent rugae, petechiae, of VA. For example, Speroff (20) defined VA, in a study of the efficacy of an estradiol and friability of the vaginal wall were statistically significant associated with low vaginal ring, at baseline as a maturation index score of 52 or less. Pinkerton and maturation index. coworkers (21) however used a different formula in their study on the influence of raloxifene on the efficacy of an estradiol-releasing ring and set the cutoff value at 50 or Karyopyknotic Index. The karyopyknotic index (KI) is described as measuring the less. Benjamin and Deutsch (22) described an atrophic smear as a maturation value of less relationship of superficial cells to intermediate cells (33), but also as the percentage of than 40%. superficial cells found in the total population of the squamous cells examined (34-36). The The VMI or VMV can also be used as a qualitative indicator of estrogenic effect on KI is considered as a reliable cellular index for the determination of estrogen activity the vaginal epithelium, with 0-49 reflecting little or no estrogenic effect, 50-64 a (37;38) but is less often used than VMI or VMV. Benjamin and Deutsch (22) described an moderate estrogenic effect, and 65-100 a highly estrogen dominant environment (23;24). atrophic smear as a KI of less than 10%. However, studies validating these values are lacking. In a study of factors influencing the vaginal milieu, KI was influenced by several Besides evaluation purposes the VMI or VMV are used as part of the inclusion criteria patient characteristics also mentioned for the VMI or VMV, like a body mass index above for participation in a study concerning VA. For this purpose, the cutoff values differ the 90th percentile or a diastolic blood pressure of more than 100 mmHg (both causing a

503427-L-sub01-bw-Weber

Assessment of vaginal atrophy

Vaginal maturation index and vaginal maturation value. The vaginal maturation index between studies as well, varying between a VMI of less than 55 in the study of Chollet (VMI) represents the percentage of parabasal, intermediate and superficial squamous and coworkers (13) to less than 40 in the study of Griesser and coworkers (25). Another cells appearing on a vaginal smear (18). The VMI specimen consists of freely exfoliating often mentioned cutoff value is the presence of less than 5% superficial cells (8;26-31) or squamous cells from the upper one-third of the vaginal wall, gently scraped with a spatula the presence of more than 75% parabasal cells (32). (19). The index is read from left to right, for example, a VMI of 0/30/70 represents 0% There are several factors that can influence the maturation index. Besides patient parabasal cells, 30% intermediate cells, and 70% superficial cells. A shift to the left influences like cigarette smoking, a body mass index above the 90th percentile, or a indicates an increase in the parabasal or intermediate cells, while a shift to the right diastolic blood pressure of more than 100 mmHg (all causing a shift to the right), there reflects an increase in the superficial or intermediate cells. In this example, the VMI are also collection considerations like the influence of delayed fixing and air drying, describes the proportion of parabasal, intermediate and superficial cells. In a formula the ectocervical, endocervial, or endometrial cell contamination or a smear that is too thick different cell types can be multiplied by certain factors to obtain the vaginal maturation (18). Besides these factors, the classification of the individual cells, performed manually, value (VMV). However, when reviewing the literature, these two terms (VMI and VMV) is subject to intra- and interobserver variations (17). are frequently used inconsistently and calculated in different ways. Table 2 gives several Davila and coworkers (24) assessed the correlation between symptoms and examples of ways to calculate VMI or VMV. Consensus about the best formula is lacking maturation value which showed that VA symptom scores (including vaginal dryness, and the variety in calculations compromises comparison between studies. soreness, irritation, dyspareunia, and vaginal discharge) were not correlated with The measurement of VMI or VMV is an inexpensive way to evaluate hormonal maturation value. There was a moderate negative correlation between vaginal health 05 influences in women. It is often used as an outcome measure to evaluate the effect of score (consisting of assessment of vaginal secretions, epithelial integrity, surface hormonal therapies on VA. According to the formulas mentioned in table 2, a lower value thickness, color, and pH) and maturation value, indicating that maturation values were indicates fewer superficial cells which is indicative of absent or very low estrogen levels. lower in subjects with greater degrees of atrophy. Greendale and coworkers (15) showed In several studies, a cutoff value is used to define this low estrogen level or the presence that findings of conization (i.e., markedly decreased elasticity), absent rugae, petechiae, of VA. For example, Speroff (20) defined VA, in a study of the efficacy of an estradiol and friability of the vaginal wall were statistically significant associated with low vaginal ring, at baseline as a maturation index score of 52 or less. Pinkerton and maturation index. coworkers (21) however used a different formula in their study on the influence of raloxifene on the efficacy of an estradiol-releasing ring and set the cutoff value at 50 or Karyopyknotic Index. The karyopyknotic index (KI) is described as measuring the less. Benjamin and Deutsch (22) described an atrophic smear as a maturation value of less relationship of superficial cells to intermediate cells (33), but also as the percentage of than 40%. superficial cells found in the total population of the squamous cells examined (34-36). The The VMI or VMV can also be used as a qualitative indicator of estrogenic effect on KI is considered as a reliable cellular index for the determination of estrogen activity the vaginal epithelium, with 0-49 reflecting little or no estrogenic effect, 50-64 a (37;38) but is less often used than VMI or VMV. Benjamin and Deutsch (22) described an moderate estrogenic effect, and 65-100 a highly estrogen dominant environment (23;24). atrophic smear as a KI of less than 10%. However, studies validating these values are lacking. In a study of factors influencing the vaginal milieu, KI was influenced by several Besides evaluation purposes the VMI or VMV are used as part of the inclusion criteria patient characteristics also mentioned for the VMI or VMV, like a body mass index above for participation in a study concerning VA. For this purpose, the cutoff values differ the 90th percentile or a diastolic blood pressure of more than 100 mmHg (both causing a

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Chapter 5

higher KI value). In the same study, vaginal cytology measured as KI, vaginal pH and the technique has been validated (15;57); however, consensus on the type of pH paper or presence of lactobacilli correlated well (39). strip to use and the most reliable interval and location in the vagina is lacking. Besides for evaluation purposes, the pH is used as part of the inclusion criteria Vaginal pH (besides VMI/VMV as mentioned before) for participation in studies concerning VA. For The underlying mechanism of vaginal pH changes associated with VA consists of estrogen this purpose, the cutoff value is often set at 5, meaning patients with a pH value of 5 or stimulating the production of glycogen, which is broken down to glucose. In a more can be included in the study (13;19;25;27;28;30;45;48;58). This is also the cutoff premenopausal vagina, an estrogen-rich environment, lactobacilli convert epithelial value recommended by the FDA (8). glycogen into lactic acid, which maintains the vaginal pH between 3.5 and 4.5 (5). With The pH values can be grouped, for example as pH less than 5.0, pH 5-5.49, pH 5.5- thinning of the vaginal epithelium in menopause, fewer squamous cells are sloughed into 6.49 and pH more than 6.49 with a clinical meaning that pH less than 5.0 could be the vaginal secretions, and those that are have reduced glycogen content. As vaginal indicative of a lack of VA, pH 5-5.49 of a mild VA, pH 5.5-6.49 of a moderate atrophy, and glycogen levels fall, the population of lactobacilli decreases, and the vaginal pH increases a pH more than 6.5 could indicate severe atrophy (48). Again, validation of these cutoff (5;6). values is not available. Vaginal pH can be elevated by bacterial vaginosis, blood, cervical Measurement of the vaginal pH is considered useful, effective, and inexpensive (40). mucus, semen, vaginal medications, vaginal douches (40) and lowered by smoking (39). Studies have shown that a vaginal pH greater than 5.0 is associated with decreased serum estradiol and menopause (40;41). Table 1 Examples of definitions of VA and/or atrophic vaginitis The vaginal pH can be measured in different ways. Most studies describe the use of a Study Definition of VA / atrophic vaginitis pH indicator strip (23;29;31;32;34;35;42-50), for example with intervals in a 4-point scale Chollet et al. 2009 (13) Atrophic vaginitis is defined as inflammation of the vaginal epithelium due to (29;48) or with a pH interval of 4.0-7.0 in 14 steps (25;49) or a range of 4.0-7.5 in intervals Castelo-Branco et al. atrophy secondary to decreased levels of circulating estrogen of 0.5 (23). Others describe it as pH paper (19;21;24;51), e.g., Nitrazine paper (pH range 2005 (12) Brenner et al. 1988 (11) Atrophic vaginitis, with attendant inflammation, ulceration, and bleeding of the 4.5-7.5) (15;40) or hydrion pH paper (range 4-9) (52). Vaginal pH is often measured as vaginal mucosa, can result from marked atrophy of the lining of the vagina part of the vaginal health evaluation as described further ahead (26;36;46;48;53-55). Nyirjesy et al. 2012 (85) The term ‘vaginitis’ describes a spectrum of vaginal conditions that cause There are several locations described for measurement of the vaginal pH, e.g., the uncomfortable vaginal symptoms lateral vaginal wall (19;24;31;56), the wall of the proximal third of the vaginal vault Greendale et al. 1999 Atrophic vaginitis is used clinically to refer to several conditions: atrophic signs (42;44) or at the introitus (50) or midvagina (23). (15) on physical examination, cytologically determined atrophy and presence of vaginal symptoms Testing of the vaginal pH from the lateral vaginal wall has been correlated with Bachmann et al. 2008 Atrophic vaginitis: the result of the loss of estrogen-dependent cellular vaginal cytology and histology as an appropriate and objective measure for assessment of (26) maturation the vaginal epithelium and for monitoring the effect of estrogen treatment in vaginal Karaosmanoglu et al. Atrophic vaginitis is the main cause of vaginal discomfort among atrophy (32). Brizzolara and coworkers (57) concluded in their study to determine the 2011 (65) postmenopausal women, and results from declining estradiol levels vaginal pH level that correlates with elevated parabasal cells, that a vaginal pH above 6.0 Rioux et al. 2000 (86) Atrophic vaginitis is a common and often untreated condition of urogenital correlates with high levels of parabasal cells (20% or more) from the midvagina. This aging in postmenopausal women Lynch 2009 (87) Atrophic vaginitis is a common condition post-menopausal women experience

503427-L-sub01-bw-Weber

Assessment of vaginal atrophy

higher KI value). In the same study, vaginal cytology measured as KI, vaginal pH and the technique has been validated (15;57); however, consensus on the type of pH paper or presence of lactobacilli correlated well (39). strip to use and the most reliable interval and location in the vagina is lacking. Besides for evaluation purposes, the pH is used as part of the inclusion criteria Vaginal pH (besides VMI/VMV as mentioned before) for participation in studies concerning VA. For The underlying mechanism of vaginal pH changes associated with VA consists of estrogen this purpose, the cutoff value is often set at 5, meaning patients with a pH value of 5 or stimulating the production of glycogen, which is broken down to glucose. In a more can be included in the study (13;19;25;27;28;30;45;48;58). This is also the cutoff premenopausal vagina, an estrogen-rich environment, lactobacilli convert epithelial value recommended by the FDA (8). glycogen into lactic acid, which maintains the vaginal pH between 3.5 and 4.5 (5). With The pH values can be grouped, for example as pH less than 5.0, pH 5-5.49, pH 5.5- thinning of the vaginal epithelium in menopause, fewer squamous cells are sloughed into 6.49 and pH more than 6.49 with a clinical meaning that pH less than 5.0 could be the vaginal secretions, and those that are have reduced glycogen content. As vaginal indicative of a lack of VA, pH 5-5.49 of a mild VA, pH 5.5-6.49 of a moderate atrophy, and glycogen levels fall, the population of lactobacilli decreases, and the vaginal pH increases a pH more than 6.5 could indicate severe atrophy (48). Again, validation of these cutoff (5;6). values is not available. Vaginal pH can be elevated by bacterial vaginosis, blood, cervical Measurement of the vaginal pH is considered useful, effective, and inexpensive (40). mucus, semen, vaginal medications, vaginal douches (40) and lowered by smoking (39). Studies have shown that a vaginal pH greater than 5.0 is associated with decreased serum estradiol and menopause (40;41). Table 1 Examples of definitions of VA and/or atrophic vaginitis 05 The vaginal pH can be measured in different ways. Most studies describe the use of a Study Definition of VA / atrophic vaginitis pH indicator strip (23;29;31;32;34;35;42-50), for example with intervals in a 4-point scale Chollet et al. 2009 (13) Atrophic vaginitis is defined as inflammation of the vaginal epithelium due to (29;48) or with a pH interval of 4.0-7.0 in 14 steps (25;49) or a range of 4.0-7.5 in intervals Castelo-Branco et al. atrophy secondary to decreased levels of circulating estrogen of 0.5 (23). Others describe it as pH paper (19;21;24;51), e.g., Nitrazine paper (pH range 2005 (12) Brenner et al. 1988 (11) Atrophic vaginitis, with attendant inflammation, ulceration, and bleeding of the 4.5-7.5) (15;40) or hydrion pH paper (range 4-9) (52). Vaginal pH is often measured as vaginal mucosa, can result from marked atrophy of the lining of the vagina part of the vaginal health evaluation as described further ahead (26;36;46;48;53-55). Nyirjesy et al. 2012 (85) The term ‘vaginitis’ describes a spectrum of vaginal conditions that cause There are several locations described for measurement of the vaginal pH, e.g., the uncomfortable vaginal symptoms lateral vaginal wall (19;24;31;56), the wall of the proximal third of the vaginal vault Greendale et al. 1999 Atrophic vaginitis is used clinically to refer to several conditions: atrophic signs (42;44) or at the introitus (50) or midvagina (23). (15) on physical examination, cytologically determined atrophy and presence of vaginal symptoms Testing of the vaginal pH from the lateral vaginal wall has been correlated with Bachmann et al. 2008 Atrophic vaginitis: the result of the loss of estrogen-dependent cellular vaginal cytology and histology as an appropriate and objective measure for assessment of (26) maturation the vaginal epithelium and for monitoring the effect of estrogen treatment in vaginal Karaosmanoglu et al. Atrophic vaginitis is the main cause of vaginal discomfort among atrophy (32). Brizzolara and coworkers (57) concluded in their study to determine the 2011 (65) postmenopausal women, and results from declining estradiol levels vaginal pH level that correlates with elevated parabasal cells, that a vaginal pH above 6.0 Rioux et al. 2000 (86) Atrophic vaginitis is a common and often untreated condition of urogenital correlates with high levels of parabasal cells (20% or more) from the midvagina. This aging in postmenopausal women Lynch 2009 (87) Atrophic vaginitis is a common condition post-menopausal women experience

503427-L-sub01-bw-Weber

Chapter 5

due to estrogen deficiency that causes involution of the vaginal tissue, leading Nappi et al. 2010 (31) Vaginal atrophy refers to ‘vaginal discomfort’ and is defined as dryness, to itching, burning, dryness, irritation, and dyspareunia smarting pain, itching, involuntary urination or pain in the vagina in connection Stika 2010 (5) The term atrophic vaginitis has sometimes been restricted to the development with touching and/or intercourse of an inflammatory vaginal discharge associated with the overgrowth of genital Simon et al. 2008 (48) Vaginal atrophy: the loss of estrogen-dependent cellular maturation in the pathogens after the loss of lactobacilli dominance and the associated protective vagina acidic environment. More commonly, atrophic vaginitis is applied to a spectrum Chollet 2011 (90) Introduction: Vulvovaginal atrophy is a thinning of the epithelium secondary to of symptoms decreased levels of circulating estrogen Crothers et al. 2012 (88) Cytologic criteria for atrophy: predominately parabasal and basal cells, with few Abstract: Vulvovaginal atrophy is defined as inflammation of the vaginal or no superficial or intermediate squamous cells, background debris from epithelium due to atrophy secondary to decreased levels of circulating estrogen cellular degeneration, nuclear pyknosis, cellular apoptosis, possibly histiocyes Le Donne et al. 2011 (71) Vaginal atrophy is a frequent condition in postmenopausal women, associated and giant cells. with vaginal or urinary symptoms or both Atrophic vaginitis is atrophy with inflammation Al-Baghdadi et al. 2009 Vaginal atrophy is a common manifestation of estrogen deprivation after the Capewell et al. 1992 (16) Mucosal atrophy of the vagina reflects a fall in blood estrogen levels and is (91) menopause sometimes associated with vaginal symptoms and a variety of physical features Cano et al. 2012 (74) Vaginal atrophy is defined by a thinning of the vaginal mucosa that occurs as a Yildirim et al. 2004 (73) Vaginal atrophy: a deficient maturation of vaginal mucosa consequence of the decline in endogenous estrogen production that Hummelen et al. 2011 Vulvovaginal atrophy (VVA) is somewhat of a catchment term for several characterizes menopause. The anatomopathological basis of vaginal atrophy is a (89) symptoms and is diagnosed by an assessment of vaginal dryness, irritation, change in the cellular composition of the vaginal epithelium soreness and dyspareunia with urinary frequency, urgency, incontinence and Minkin et al. 2013 (92) Vaginal atrophy is a consequence of the hypoestrogenic state and resulting the presence of pale and dry vulvovaginal mucosa with petechiae, along with anatomical and physiological changes in the genitourinary tract pH >4.6 Palacios et al. 2005 (72) Genitalia atrophy, a manifestation of estrogen withdrawal after menopause,

accompanied by vaginal or urinary symptoms or both. Bachmann et al. 2010 Vulvovaginal atrophy (VVA) is a highly prevalent, bothersome condition

(28) associated with declining estrogen levels during perimenopause and postmenopause

Bygdeman et al. 1996 Vulvovaginal atrophy is secondary to progressive decrease in ovarian secretion (62) of estradiol. It is clinically manifested as a syndrome consisting mainly of vaginal dryness, itching, irritation and dyspareunia

Manonai et al. 2007 (54) Atrophic changes in the urogenital tract are the manifestations of estrogen

deprivation in postmenopausal women Simunic et al. 2003 (66) Urogenital aging (UGA) is a complex cascade of symptoms involving the lower urinary tract, genital tract and the pelvic floor caused by hypoestrogenism in postmenopausal women Rane et al. 2000 (81) Urogenital atrophy (UGA) criteria: Grade I: vaginal dryness, vaginal pallor, thin shiny mucosa; Grade II: Grade I + urethral caruncle, labial thinning and retraction; Grade III: Grade II + labial fusion, bleeding on contact, gross contracture of the urogenital hiatus

503427-L-sub01-bw-Weber

Assessment of vaginal atrophy

due to estrogen deficiency that causes involution of the vaginal tissue, leading Nappi et al. 2010 (31) Vaginal atrophy refers to ‘vaginal discomfort’ and is defined as dryness, to itching, burning, dryness, irritation, and dyspareunia smarting pain, itching, involuntary urination or pain in the vagina in connection Stika 2010 (5) The term atrophic vaginitis has sometimes been restricted to the development with touching and/or intercourse of an inflammatory vaginal discharge associated with the overgrowth of genital Simon et al. 2008 (48) Vaginal atrophy: the loss of estrogen-dependent cellular maturation in the pathogens after the loss of lactobacilli dominance and the associated protective vagina acidic environment. More commonly, atrophic vaginitis is applied to a spectrum Chollet 2011 (90) Introduction: Vulvovaginal atrophy is a thinning of the epithelium secondary to of symptoms decreased levels of circulating estrogen Crothers et al. 2012 (88) Cytologic criteria for atrophy: predominately parabasal and basal cells, with few Abstract: Vulvovaginal atrophy is defined as inflammation of the vaginal or no superficial or intermediate squamous cells, background debris from epithelium due to atrophy secondary to decreased levels of circulating estrogen cellular degeneration, nuclear pyknosis, cellular apoptosis, possibly histiocyes Le Donne et al. 2011 (71) Vaginal atrophy is a frequent condition in postmenopausal women, associated and giant cells. with vaginal or urinary symptoms or both Atrophic vaginitis is atrophy with inflammation Al-Baghdadi et al. 2009 Vaginal atrophy is a common manifestation of estrogen deprivation after the Capewell et al. 1992 (16) Mucosal atrophy of the vagina reflects a fall in blood estrogen levels and is (91) menopause sometimes associated with vaginal symptoms and a variety of physical features Cano et al. 2012 (74) Vaginal atrophy is defined by a thinning of the vaginal mucosa that occurs as a Yildirim et al. 2004 (73) Vaginal atrophy: a deficient maturation of vaginal mucosa consequence of the decline in endogenous estrogen production that Hummelen et al. 2011 Vulvovaginal atrophy (VVA) is somewhat of a catchment term for several characterizes menopause. The anatomopathological basis of vaginal atrophy is a (89) symptoms and is diagnosed by an assessment of vaginal dryness, irritation, change in the cellular composition of the vaginal epithelium soreness and dyspareunia with urinary frequency, urgency, incontinence and Minkin et al. 2013 (92) Vaginal atrophy is a consequence of the hypoestrogenic state and resulting 05 the presence of pale and dry vulvovaginal mucosa with petechiae, along with anatomical and physiological changes in the genitourinary tract pH >4.6 Palacios et al. 2005 (72) Genitalia atrophy, a manifestation of estrogen withdrawal after menopause, accompanied by vaginal or urinary symptoms or both. Bachmann et al. 2010 Vulvovaginal atrophy (VVA) is a highly prevalent, bothersome condition

(28) associated with declining estrogen levels during perimenopause and postmenopause

Manonai et al. 2007 (54) Atrophic changes in the urogenital tract are the manifestations of estrogen deprivation in postmenopausal women Simunic et al. 2003 (66) Urogenital aging (UGA) is a complex cascade of symptoms involving the lower urinary tract, genital tract and the pelvic floor caused by hypoestrogenism in postmenopausal women Rane et al. 2000 (81) Urogenital atrophy (UGA) criteria: Grade I: vaginal dryness, vaginal pallor, thin shiny mucosa; Grade II: Grade I + urethral caruncle, labial thinning and retraction; Grade III: Grade II + labial fusion, bleeding on contact, gross contracture of the urogenital hiatus

503427-L-sub01-bw-Weber Chapter 5

(55)

0) )

(44) (43) (43) (44) (50)

(26)

(42) (42) (3

(21) (71)

(54) (36)

(25

(67) (32) (77)

(70) 49) (48) (19) (58) (24)

(61) (61) (

1994 (69) (74)

(23) (29) (46) (84) (73) (20)

t al. 2011 riksson et al. 1994 Study Barentsen et al. 1997 Casper et al. 1999 Henriksson et al. 1996 Cano et al. 2012 Speroff 2003 Hen Ayton et al. 1996 Lee e Zeyneloglu et al. 2007 Speroff et al. 2006 Ekin et al. 2011 Simon et al. 2008 Bachmann et al. 2008 Pinkerton et al. 2003 Manonai et al. 2007 Meisels 1967 Raghunandan et al. 2010 Manonai et al. 2006 Simon et al. 2008 Griesser et al. 2012 Simon et al. 2007 Davila et al. 2003 Yildirim 2004 Barentsen et al. 1997 Henriksson et al. Smith et al. 1993 Ayton et al. 1996 Henriksson et al. 1996 Le Donne et al. 2011 Nilsson et al. 1995 Yumru et al. 2009 Utian et al. 2005 Freedman et al. 2007 Karp et al. 2012

VMV / VMI VMV VMI VMV VMI VMV VMI VMI Maturation proportion

00 calculated cells

cells out of 200 calculated cells

VMI: Vaginal maturation index

- Different formulas used to calculate VMV / VMI

V: Vaginal maturation value; Table 2 Formula 0.2 x % parabasal cells + 0.6 x % intermediate cells + 1.0 x % superficial cells 0 x % parabasal cells + 0.5 x % intermediate cells + 1.0 x % superficial cells 0 x % parabasal cells + 0.5 x % intermediate cells + 1.0 x % superficial cells divided by 2 Number or proportion of parabasal, intermediate and superficial cells out of 1 Percentage of parabasal, intermediate and superficial (1.0 x % superficial cells) +/ ([0.5 x % intermediate cells] + [0.5 x % parabasal cells]) VM

503427-L-sub01-bw-Weber Assessment of vaginal atrophy

)

(43) (44)

(42)

(71) (36)

(25 (32) (70) 49) (19) (58) (24)

(61) ( 1994

(23) (73) Manonai et al. 2006 Simon et al. 2008 Griesser et al. 2012 Simon et al. 2007 Davila et al. 2003 Yildirim 2004 Barentsen et al. 1997 Henriksson et al. Smith et al. 1993 Ayton et al. 1996 Henriksson et al. 1996 Le Donne et al. 2011 Nilsson et al. 1995 Yumru et al. 2009 Karp et al. 2012

VMV VMI VMI Maturation proportion

00 calculated cells

cells out of 200 calculated cells

VMI: Vaginal maturation index

- V: Vaginal maturation value;

0 x % parabasal cells + 0.5 x % intermediate cells + 1.0 x % superficial cells divided by 2 Number or proportion of parabasal, intermediate and superficial cells out of 1 Percentage of parabasal, intermediate and superficial (1.0 x % superficial cells) +/ ([0.5 x % intermediate cells] + [0.5 x % parabasal cells]) VM

503427-L-sub01-bw-Weber

Chapter 5

symptoms (20;34-36;42-44;47;49;50;52;54;61-70), or have employed a composite score of several symptoms, weighted for severity (21;24;26;29;53;55;71-74). Physical examination A number of self-report instruments or questionnaires that measure menopausal VA is often subjectively assessed by visually evaluating the appearance of the vaginal symptoms and sexual well-being exist in the literature. Most of these instruments address epithelium. Physical signs of vaginal atrophy most often assessed in clinical studies a wide array of menopausal issues, allowing only two to four items for urogenital concerning treatment of vaginal atrophy include the presence of pallor, petechiae, symptoms. McKenna and co-workers were the first to develop a urogenital atrophy friability and vaginal dryness (20;23;34;35;42-44;49;50;58;61;63;67;69;77;78). By taking specific quality of life instrument (UGAQoL) (75). This instrument takes into account into account these signs a visual assessment of the degree of vaginal atrophy is made symptoms of vaginal soreness, itching, discharge, dysuria, dyspareunia, urine loss, and (none, moderate, or severe). urge episodes. However, as they advise themselves, the responsiveness of the instrument Other signs associated with vaginal atrophy include shrinkage of vaginal length and to changes in quality of life needs to be tested prior to its use in clinical trials and for diameter (70;73), loss of vaginal rugae (19;21;52;73), presence of fissures (66), mucosal monitoring individual cases.

503427-L-sub01-bw-Weber

Assessment of vaginal atrophy

Subjective assessment of vaginal atrophy Lester and co-workers developed the Urogenital Atrophy Questionnaire (UAQ) to Symptoms allow women to self-report urologic (i.e., dysuria, incontinence, urgency), genital (i.e., Figure 1 shows the prevalence of the different symptoms associated with VA based on vaginal dryness, itching, discharge), and sexual symptoms (i.e., dyspareunia, desire and/or the reviewed literature that reported these symptoms. For a more detailed description of interest in sexual activity, vaginal bleeding after sexual activity) (76). The UAQ consists of the prevalence of symptoms in the studied populations at baseline, we refer to the table 45 items that describe potential symptoms related to pain/discomfort, function, in the Electronic Supplemental Material (ESM). As shown in this table, studies of VA are satisfaction, and urogenital quality of life from the urinary, genital, and sexual domains lacking uniformity in symptom evaluation. For this reason, the FDA proposed a new and was tested in women with and without breast cancer. symptom measure: the MBS approach (8). The MBS is derived from a selected list of symptoms (most commonly consisting of the four symptoms of vaginal dryness, vaginal Figure 1: Prevalance of symptoms and frequency of reporting at baseline itching/irritation, vaginal soreness, and dyspareunia). At baseline, participants are instructed to rate each of these symptoms as not present, mild, moderate, or severe and 100 then must select a single symptom among those classified as moderate or severe as the 90 Dryness MBS. The MBS is then followed through to the end of treatment, and the change in its 80 Soreness severity is used to evaluate symptomatic improvement. Up till now we found 13 70 60 Itching/irritation published studies that have reported change in MBS (19;25;27;28;30;31;45;48;51;56;58- 50 Dyspareunia 05 60). Ettinger and co-workers (59) discussed that use of the MBS construct is appealing 40 Dysuria Frequency of reporting of Frequency because it examines each symptom individually and also requires the symptoms under 30 Bleeding 20 examination to be at least moderate in severity. It is suspected that the response in MBS Burning 10 may be the best reflection of treatment benefit in women who encounter bothersome Frequency 0 Prevalence Urgency symptoms. Other studies have reported the change of symptom severity for individual 0 20 40 60 80 100 symptoms (20;34-36;42-44;47;49;50;52;54;61-70), or have employed a composite score of several symptoms, weighted for severity (21;24;26;29;53;55;71-74). Physical examination A number of self-report instruments or questionnaires that measure menopausal VA is often subjectively assessed by visually evaluating the appearance of the vaginal symptoms and sexual well-being exist in the literature. Most of these instruments address epithelium. Physical signs of vaginal atrophy most often assessed in clinical studies a wide array of menopausal issues, allowing only two to four items for urogenital concerning treatment of vaginal atrophy include the presence of pallor, petechiae, symptoms. McKenna and co-workers were the first to develop a urogenital atrophy friability and vaginal dryness (20;23;34;35;42-44;49;50;58;61;63;67;69;77;78). By taking specific quality of life instrument (UGAQoL) (75). This instrument takes into account into account these signs a visual assessment of the degree of vaginal atrophy is made symptoms of vaginal soreness, itching, discharge, dysuria, dyspareunia, urine loss, and (none, moderate, or severe). urge episodes. However, as they advise themselves, the responsiveness of the instrument Other signs associated with vaginal atrophy include shrinkage of vaginal length and to changes in quality of life needs to be tested prior to its use in clinical trials and for diameter (70;73), loss of vaginal rugae (19;21;52;73), presence of fissures (66), mucosal monitoring individual cases.

503427-L-sub01-bw-Weber

Chapter 5

thinning (21;52;64), and ulceration (21). The way to quantify these measures is often not Genital Health Clinical Evaluation (GHCE). The GHCE is a tool used to evaluate six described and reproducibility studies regarding the assessment of these signs are lacking. parameters (vaginal pH, fluid secretion, epithelial mucosa, moisture, vaginal rugosity, and Most symptoms are evaluated as part of a scoring index or instrument: mucosa color) scored on a scale 1 to 4. A higher score indicates less atrophy (27;80). In their studies, Raymundo and coworkers (80) and Bachmann and coworkers (27) used a Vaginal physical examination scale. Greendale and coworkers (15) were the first to maximum total score of 15 to determine the presence of VA and thus patient eligibility at validate a four-item scale for the assessment of VA during physical examination. The study entry. Again, different interpretations by individual raters can be made, making this physical examination signs postulated as signifying atrophy were: presence of vaginal wall a subjective measurement tool. Studies assessing the intra- and interobserver agreement petechiae, friability of the vaginal wall (defined as any bleeding occurring during of the GHCE are not available. examination), conization (markedly decreased elasticity), and absence of rugae. Greendale and coworkers correlated vaginal examination appearance to biological Grading of vaginal health / vaginal health score. For grading of vaginal health, evaluations characteristics and self-reported vaginal symptoms. Findings of conization, absent rugae, are made regarding vaginal secretions, vaginal epithelial integrity, vaginal epithelial petechiae, and friability of the vaginal wall constituted the atrophic domain of the vaginal surface thickness, vaginal color, and vaginal pH. Grading of vaginal health is then used to examination. These physical characteristics were statistically significantly associated with indicate the degree of epithelial atrophy using a four-point scoring system (no atrophy = two biological indices of atrophy: low maturation index and high vaginal pH. Although 0, mild = 1, moderate = 2 and severe = 3). The composite score for vaginal health, symptoms of vaginal dryness or itching/irritation were common in this study, they were assessed by an investigator, is defined as the mean of the individual vaginal health not correlated with physical findings or these two biomarkers of atrophy. components (24;26;29;48). Davila and coworkers summarized the magnitude of relationships between symptoms and physical examination. In their study there was a Vaginal Health Index (VHI). The VHI includes scoring of vaginal moisture, vaginal fluid very weak correlation between VA symptom scores (consisting of vaginal dryness, volume, vaginal elasticity, vaginal pH, and vaginal epithelial integrity on a scale of 1 soreness, irritation, dyspareunia, and vaginal discharge) and vaginal health score. A (poorest) to 5 (best) according to the methods of Robert Wood Johnson Medical School positive relationship was found between vaginal health score and age which indicated (79). The lower the score, the greater the atrophy (12;36;46;47;53-55). that vaginal health scores were higher (more atrophic) in older women. A moderate Vaginal moisture is an assessment of the appearance and spread or consistency of negative correlation between vaginal health score and maturation value indicated that the secretions which coat the vagina. Vaginal elasticity is a measure of the ability of the maturation values were lower in subjects with greater degrees of atrophy. vaginal tissue to stretch from the examiner’s finger. Vaginal epithelial integrity takes into account color, thickness, and ability of the tissue to resist breaking secondary to touch Global atrophy score. The global atrophy score consists of the assessment and grading of (36). As one can imagine, these measures can differ between practitioners. For example, six signs: loss of rugae, pallor, petechiae, mucosal thinning, dryness, and ulceration, using overall vaginal elasticity is rated as ‘none, poor, fair, good or excellent,’ a relatively broad a descriptive assessment table and four-point ordinal scale. The investigator global response set which could be interpreted differently by individual raters. Reproducibility atrophy score is calculated as the sum of the six scores (21). studies using VHI are not available. Without the sign of ulceration, Parsons et al. (52) called this assessment the ‘vaginal atrophy score’. Reproducibility studies concerning the global or vaginal atrophy score are

not available.

503427-L-sub01-bw-Weber

Assessment of vaginal atrophy

thinning (21;52;64), and ulceration (21). The way to quantify these measures is often not Genital Health Clinical Evaluation (GHCE). The GHCE is a tool used to evaluate six described and reproducibility studies regarding the assessment of these signs are lacking. parameters (vaginal pH, fluid secretion, epithelial mucosa, moisture, vaginal rugosity, and Most symptoms are evaluated as part of a scoring index or instrument: mucosa color) scored on a scale 1 to 4. A higher score indicates less atrophy (27;80). In their studies, Raymundo and coworkers (80) and Bachmann and coworkers (27) used a Vaginal physical examination scale. Greendale and coworkers (15) were the first to maximum total score of 15 to determine the presence of VA and thus patient eligibility at validate a four-item scale for the assessment of VA during physical examination. The study entry. Again, different interpretations by individual raters can be made, making this physical examination signs postulated as signifying atrophy were: presence of vaginal wall a subjective measurement tool. Studies assessing the intra- and interobserver agreement petechiae, friability of the vaginal wall (defined as any bleeding occurring during of the GHCE are not available. examination), conization (markedly decreased elasticity), and absence of rugae. Greendale and coworkers correlated vaginal examination appearance to biological Grading of vaginal health / vaginal health score. For grading of vaginal health, evaluations characteristics and self-reported vaginal symptoms. Findings of conization, absent rugae, are made regarding vaginal secretions, vaginal epithelial integrity, vaginal epithelial petechiae, and friability of the vaginal wall constituted the atrophic domain of the vaginal surface thickness, vaginal color, and vaginal pH. Grading of vaginal health is then used to examination. These physical characteristics were statistically significantly associated with indicate the degree of epithelial atrophy using a four-point scoring system (no atrophy = two biological indices of atrophy: low maturation index and high vaginal pH. Although 0, mild = 1, moderate = 2 and severe = 3). The composite score for vaginal health, symptoms of vaginal dryness or itching/irritation were common in this study, they were assessed by an investigator, is defined as the mean of the individual vaginal health 05 not correlated with physical findings or these two biomarkers of atrophy. components (24;26;29;48). Davila and coworkers summarized the magnitude of relationships between symptoms and physical examination. In their study there was a Vaginal Health Index (VHI). The VHI includes scoring of vaginal moisture, vaginal fluid very weak correlation between VA symptom scores (consisting of vaginal dryness, volume, vaginal elasticity, vaginal pH, and vaginal epithelial integrity on a scale of 1 soreness, irritation, dyspareunia, and vaginal discharge) and vaginal health score. A (poorest) to 5 (best) according to the methods of Robert Wood Johnson Medical School positive relationship was found between vaginal health score and age which indicated (79). The lower the score, the greater the atrophy (12;36;46;47;53-55). that vaginal health scores were higher (more atrophic) in older women. A moderate Vaginal moisture is an assessment of the appearance and spread or consistency of negative correlation between vaginal health score and maturation value indicated that the secretions which coat the vagina. Vaginal elasticity is a measure of the ability of the maturation values were lower in subjects with greater degrees of atrophy. vaginal tissue to stretch from the examiner’s finger. Vaginal epithelial integrity takes into account color, thickness, and ability of the tissue to resist breaking secondary to touch Global atrophy score. The global atrophy score consists of the assessment and grading of (36). As one can imagine, these measures can differ between practitioners. For example, six signs: loss of rugae, pallor, petechiae, mucosal thinning, dryness, and ulceration, using overall vaginal elasticity is rated as ‘none, poor, fair, good or excellent,’ a relatively broad a descriptive assessment table and four-point ordinal scale. The investigator global response set which could be interpreted differently by individual raters. Reproducibility atrophy score is calculated as the sum of the six scores (21). studies using VHI are not available. Without the sign of ulceration, Parsons et al. (52) called this assessment the ‘vaginal atrophy score’. Reproducibility studies concerning the global or vaginal atrophy score are

not available.

503427-L-sub01-bw-Weber

Chapter 5

Urogenital atrophy criteria. Rane et al. (81) decided prospectively on criteria for appraisal would have been very challenging, as most studies do not meet the criteria of urogenital atrophy in their study that were as follows: grade 1: vaginal dryness, vaginal well-designed studies (i.e., not randomized, controlled, or blinded, small sample size). pallor, thin shiny mucosa; grade 2: grade 1 + urethral caruncle, labial thinning, and The decision to not differentiate between industry-initiated and investigator-initiated retraction; grade 3: grade 2 + labial fusion, bleeding on contact, and gross contracture of studies was well considered. Where industry-initiated studies appear to focus on the urogenital hiatus. As far as we know, no other researchers incorporated these grading objective parameters, clinician-initiated studies tend to focus on the subjective outcome. criteria in a study on VA. Studies taking into account subjective as well as objective outcomes are scarce and differ in the selected measurement tools which disenables correlating symptoms to Vaginal atrophy index. The vaginal atrophy index (VAI) is a subjective evaluation of the measurements. There are studies showing no or a very weak correlation between degree of atrophy on the following genital dimensions: skin elasticity and turgor, pubic symptoms and physical examination or maturation indices (24), while others show a hair, labia minora and majora, introitus, vaginal mucosa, and vaginal depth. The lower the strong association of vaginal symptoms with cytology (15;16). In the study of Capewell score, the greater the VA (82;83). The reliability of ratings of the VAI between the two and co-workers several physical features associated with VA were not associated with gynecologists in the study of Leiblum and coworkers (83) was 0.77. cytological atrophy, while Davila and co-workers found a moderate correlation between physical examination and maturation values (16;24). DISCUSSION Besides these conflicting results concerning the correlation between objective and In this review we provide an overview of the clinical value of subjective and objective subjective measurements of VA, there is a paucity of studies describing the intra- and measurements of VA. There is no consensus on the definition of VA. The term is used to inter-observer agreement and validity of these measurements which hampers the refer to several conditions including [1] presence of specific vaginal symptoms, [2] selection of the best available reference test. atrophic signs on physical examination and [3] cytological determined atrophy (15). The We believe that different settings (i.e., clinical practice and research) have different lack of guidelines how to assess VA may be the cause of the presence of three different needs regarding the diagnostic instruments to assess presence and severity of VA and we ways to assess vaginal cytology, several techniques and proposed locations in the vagina would like to make recommendations for the tools that should be selected. to measure vaginal pH, a wide array of symptoms related to VA and the presence of at least seven scoring systems to assess the signs of VA during physical examination. We did Recommendations not expect to find such a wide range in symptoms and diagnostic measurements and so, In clinical practice, it is recommended to select a subjective measurement tool to provide our clinical review, shows the need for a clear definition of VA. At the end of this a feasible and affordable treatment evaluation. In this setting we recommend the use of discussion we will recommend a definition of VA and which measurements are most the MBS approach (8). With the MBS construct the FDA was the first to propose an useful to objectify VA. instrument that assesses VA with a uniform symptom evaluation. The MBS approach is Concerning our selection of articles, one could criticize that we did not perform a appealing because it is not as lengthy as the discussed questionnaires and it limits the structured appraisal of the quality of the included publications. The main reason we focus to symptoms that are at least moderate in severity. When using the MBS approach, decided to do so, is that we aimed to provide a complete overview of available evidence. we recommend that the symptoms of vaginal dryness, itching/irritation, and dyspareunia After thoroughly having studied the available literature, we realize that a structured be taken into account (also see Table 3). In the clinical practice setting, the MBS approach should be combined with a physical examination. The different scoring systems for the

100

503427-L-sub01-bw-Weber

Assessment of vaginal atrophy

Urogenital atrophy criteria. Rane et al. (81) decided prospectively on criteria for appraisal would have been very challenging, as most studies do not meet the criteria of urogenital atrophy in their study that were as follows: grade 1: vaginal dryness, vaginal well-designed studies (i.e., not randomized, controlled, or blinded, small sample size). pallor, thin shiny mucosa; grade 2: grade 1 + urethral caruncle, labial thinning, and The decision to not differentiate between industry-initiated and investigator-initiated retraction; grade 3: grade 2 + labial fusion, bleeding on contact, and gross contracture of studies was well considered. Where industry-initiated studies appear to focus on the urogenital hiatus. As far as we know, no other researchers incorporated these grading objective parameters, clinician-initiated studies tend to focus on the subjective outcome. criteria in a study on VA. Studies taking into account subjective as well as objective outcomes are scarce and differ in the selected measurement tools which disenables correlating symptoms to Vaginal atrophy index. The vaginal atrophy index (VAI) is a subjective evaluation of the measurements. There are studies showing no or a very weak correlation between degree of atrophy on the following genital dimensions: skin elasticity and turgor, pubic symptoms and physical examination or maturation indices (24), while others show a hair, labia minora and majora, introitus, vaginal mucosa, and vaginal depth. The lower the strong association of vaginal symptoms with cytology (15;16). In the study of Capewell score, the greater the VA (82;83). The reliability of ratings of the VAI between the two and co-workers several physical features associated with VA were not associated with gynecologists in the study of Leiblum and coworkers (83) was 0.77. cytological atrophy, while Davila and co-workers found a moderate correlation between physical examination and maturation values (16;24). DISCUSSION Besides these conflicting results concerning the correlation between objective and In this review we provide an overview of the clinical value of subjective and objective subjective measurements of VA, there is a paucity of studies describing the intra- and 05 measurements of VA. There is no consensus on the definition of VA. The term is used to inter-observer agreement and validity of these measurements which hampers the refer to several conditions including [1] presence of specific vaginal symptoms, [2] selection of the best available reference test. atrophic signs on physical examination and [3] cytological determined atrophy (15). The We believe that different settings (i.e., clinical practice and research) have different lack of guidelines how to assess VA may be the cause of the presence of three different needs regarding the diagnostic instruments to assess presence and severity of VA and we ways to assess vaginal cytology, several techniques and proposed locations in the vagina would like to make recommendations for the tools that should be selected. to measure vaginal pH, a wide array of symptoms related to VA and the presence of at least seven scoring systems to assess the signs of VA during physical examination. We did Recommendations not expect to find such a wide range in symptoms and diagnostic measurements and so, In clinical practice, it is recommended to select a subjective measurement tool to provide our clinical review, shows the need for a clear definition of VA. At the end of this a feasible and affordable treatment evaluation. In this setting we recommend the use of discussion we will recommend a definition of VA and which measurements are most the MBS approach (8). With the MBS construct the FDA was the first to propose an useful to objectify VA. instrument that assesses VA with a uniform symptom evaluation. The MBS approach is Concerning our selection of articles, one could criticize that we did not perform a appealing because it is not as lengthy as the discussed questionnaires and it limits the structured appraisal of the quality of the included publications. The main reason we focus to symptoms that are at least moderate in severity. When using the MBS approach, decided to do so, is that we aimed to provide a complete overview of available evidence. we recommend that the symptoms of vaginal dryness, itching/irritation, and dyspareunia After thoroughly having studied the available literature, we realize that a structured be taken into account (also see Table 3). In the clinical practice setting, the MBS approach should be combined with a physical examination. The different scoring systems for the

101

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physical examination described before do not differ a lot regarding the signs that are state that investigators could create an artificial population, by eliminating women with considered for evaluation. As far as we know, the ‘Vaginal physical examination scale’ mild severity who might respond well and by eliminating asymptomatic women at developed by Greendale and co-workers (15) is the first scale that was considered to be baseline who may become symptomatic during the course of study. However, Ettinger reproducible and valid in the assessment of VA. The physical examination signs signifying and colleagues showed in their further analysis of a clinical study of treatment for VA that vaginal atrophy according to this approach are: presence of vaginal wall petechiae, using the MBS approach increased the effect size and allowed statistically significant friability of the vaginal wall (defined as any bleeding occurring during examination), treatment effects to be shown in relative small groups when mild symptoms are excluded conization (markedly decreased elasticity), and absence of rugae. We recommend that from the analyses and when analyses focus on symptoms that are most bothersome. these subjective measurements be combined with one objective measure that is easy to Moreover, by restricting the evaluated number of symptoms to three, the problem of an perform, not expensive, and reliable, of which the only tool is measurement of vaginal underpowered study is limited. The comparability will improve when incorporation of the pH. In studies, the pH value has been proven to correlate well with high levels of increasing use of the MBS approach would continue. parabasal cells, and for that reason a higher pH value correlates with VA. According to Brizzolara et al. (57), a pH of more than 6.0 is considered to be abnormal and advocated Conclusion as cut off value for VA. In conclusion we propose to define VA as a common manifestation of estrogen deficiency In research, objective measures should form the main assessment in the evaluation associated with specific symptoms of which the most common are: vaginal dryness, of VA and we therefore recommend measurement of the VMI or calculation of the VMV itching/irritation, and dyspareunia. In both clinical and research settings, subjective and combined with the measurement of vaginal pH. Vaginal cytology allows easy objective measurements of VA should be combined. measurement of the VMI (defined as the proportion of parabasal, intermediate and In clinical practice subjective assessment is the first priority and this is warranted by superficial cells) (18) or calculation of the VMV (84) (when multiplying this proportion evaluating symptoms according to the MBS approach and signs according to the vaginal with a certain value); gaining consensus on which formula to use is advisable so physical examination scale. In the research setting, we recommend an objective reproducibility studies can be performed and values indicative for the presence of VA can assessment of VA by combining vaginal cytology and measurement of pH. Future studies be determined. Measurement of vaginal pH is easy to perform and correlates well with should assess the correlation between objective and subjective measurements. Objective cytology, histology, and several physical characteristics and is for that reason easy to measurement tools and symptom scoring systems should be validated and tested for incorporate in the research setting. Again, objective measures should be combined with reproducibility prior to applying them in clinical practice and future studies. subjective assessment implying one should include at least symptom evaluation (taking into account vaginal dryness, itching/irritation and dyspareunia) according to the MBS approach. Ettinger and coworkers discussed possible statistical limitations of this method (59). One of the most important is that it is difficult to determine in advance if a study will be adequately powered, considering that the numbers of women with each MBS symptom to be enrolled cannot be influenced. In addition, it is difficult to predict what the distribution of women needs to be with respect to each symptom, while it is unknown in advance which symptom will be rated as the MBS. Moreover, Ettinger and colleagues

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physical examination described before do not differ a lot regarding the signs that are state that investigators could create an artificial population, by eliminating women with considered for evaluation. As far as we know, the ‘Vaginal physical examination scale’ mild severity who might respond well and by eliminating asymptomatic women at developed by Greendale and co-workers (15) is the first scale that was considered to be baseline who may become symptomatic during the course of study. However, Ettinger reproducible and valid in the assessment of VA. The physical examination signs signifying and colleagues showed in their further analysis of a clinical study of treatment for VA that vaginal atrophy according to this approach are: presence of vaginal wall petechiae, using the MBS approach increased the effect size and allowed statistically significant friability of the vaginal wall (defined as any bleeding occurring during examination), treatment effects to be shown in relative small groups when mild symptoms are excluded conization (markedly decreased elasticity), and absence of rugae. We recommend that from the analyses and when analyses focus on symptoms that are most bothersome. these subjective measurements be combined with one objective measure that is easy to Moreover, by restricting the evaluated number of symptoms to three, the problem of an perform, not expensive, and reliable, of which the only tool is measurement of vaginal underpowered study is limited. The comparability will improve when incorporation of the pH. In studies, the pH value has been proven to correlate well with high levels of increasing use of the MBS approach would continue. parabasal cells, and for that reason a higher pH value correlates with VA. According to Brizzolara et al. (57), a pH of more than 6.0 is considered to be abnormal and advocated Conclusion as cut off value for VA. In conclusion we propose to define VA as a common manifestation of estrogen deficiency In research, objective measures should form the main assessment in the evaluation associated with specific symptoms of which the most common are: vaginal dryness, of VA and we therefore recommend measurement of the VMI or calculation of the VMV itching/irritation, and dyspareunia. In both clinical and research settings, subjective and 05 combined with the measurement of vaginal pH. Vaginal cytology allows easy objective measurements of VA should be combined. measurement of the VMI (defined as the proportion of parabasal, intermediate and In clinical practice subjective assessment is the first priority and this is warranted by superficial cells) (18) or calculation of the VMV (84) (when multiplying this proportion evaluating symptoms according to the MBS approach and signs according to the vaginal with a certain value); gaining consensus on which formula to use is advisable so physical examination scale. In the research setting, we recommend an objective reproducibility studies can be performed and values indicative for the presence of VA can assessment of VA by combining vaginal cytology and measurement of pH. Future studies be determined. Measurement of vaginal pH is easy to perform and correlates well with should assess the correlation between objective and subjective measurements. Objective cytology, histology, and several physical characteristics and is for that reason easy to measurement tools and symptom scoring systems should be validated and tested for incorporate in the research setting. Again, objective measures should be combined with reproducibility prior to applying them in clinical practice and future studies. subjective assessment implying one should include at least symptom evaluation (taking into account vaginal dryness, itching/irritation and dyspareunia) according to the MBS approach. Ettinger and coworkers discussed possible statistical limitations of this method (59). One of the most important is that it is difficult to determine in advance if a study will be adequately powered, considering that the numbers of women with each MBS symptom to be enrolled cannot be influenced. In addition, it is difficult to predict what the distribution of women needs to be with respect to each symptom, while it is unknown in advance which symptom will be rated as the MBS. Moreover, Ettinger and colleagues

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References 23. Karp DR, Jean-Michel M, Johnston Y, Suciu G, Aguilar VC, Davila GW. A randomized clinical 1. Bachmann GA, Nevadunsky NS. Diagnosis and treatment of atrophic vaginitis. Am Fam trial of the impact of local estrogen on postoperative tissue quality after vaginal reconstructive Physician2000 May 15;61(10):3090-6. surgery. Female pelvic med 2012 Jul;18(4):211-5. 2. Levine KB, Williams RE, Hartmann KE. Vulvovaginal atrophy is strongly associated with 24. Davila GW, Singh A, Karapanagiotou I, Woodhouse S, Huber K, Zimberg S, Seiler J, Kopka SL. female sexual Are women with urogenital atrophy symptomatic? Am J Obstet Gynecol 2003 Feb;188(2):382-8. dysfunction among sexually active postmenopausal women. Menopause 2008 Jul;15(4 Pt 1):661-6. 25. Griesser H, Skonietzki S, Fischer T, Fielder K, Suesskind M. Low dose estriol pessaries for the 3. Nappi RE, Kokot-Kierepa M. Women's voices in the menopause: results from an international treatment of vaginal atrophy: a double-blind placebo-controlled trial investigating the efficacy of survey on vaginal atrophy. Maturitas 2010 Nov;67(3):233-8. pessaries containing 0.2mg and 0.03mg estriol. Maturitas 2012 Apr;71(4):360-8. 4. Santoro N, Komi J. Prevalence and impact of vaginal symptoms among postmenopausal 26. Bachmann G, Lobo RA, Gut R, Nachtigall L, Notelovitz M. Efficacy of low-dose estradiol women. J Sex Med 2009 Aug;6(8):2133-42. vaginal tablets in the treatment of atrophic vaginitis: a randomized controlled trial. Obstet Gynecol 5. Stika CS. Atrophic vaginitis. Dermatol Ther 2010 Sep;23(5):514-22. 2008 Jan;111(1):67-76. 6. Sturdee DW, Panay N, International Menopause Society Writing Group. Recommendations 27. Bachmann G, Bouchard C, Hoppe D, Ranganath R, Altomare C, Vieweg A, Graepel J, Helzner or the management of postmenopausal vaginal atrophy. Climacteric 2010 Dec;13(6):509-22. E. Efficacy and safety of low-dose regimens of conjugated estrogens cream administered vaginally. 7. Archer DF. Efficacy and tolerability of local estrogen therapy for urogenital atrophy. [Review] Menopause 2009 Jul;16(4):719-27. [75 refs]. Menopause 2010 Jan;17(1):194-203. 28. Bachmann GA, Komi JO, Ospemifene Study Group. Ospemifene effectively treats 8. US Department of Health and Human Services.Food and Drug Administration.Center for Drug vulvovaginal atrophy in postmenopausal women: results from a pivotal phase 3 study. Menopause Evaluation and Research (CDER). Guidance for Industry. Estrogen and estrogen/progestin drug 2010 May;17(3):480-6. products to treat vasomotor symptoms and vulvar and vaginal atrophy symptoms - recommendations 29. Ekin M, Yasar L, Savan K, Temur M, Uhri M, Gencer I, Kivanc E. The comparison of hyaluronic for clinical evaluation. 2003. acid vaginal tablets with estradiol vaginal tablets in the treatment of atrophic vaginitis: a randomized 9. US Department of Health an Human Services. Food and Drug Administration. Center for Drug controlled trial. Arch Gynecol Obstet 2011 Mar;283(3):539-43. Evaluation and Research (CDER). Guidance for Industry. Patient-reported outcome measures: use in 30. Freedman M, Kaunitz AM, Reape KZ, Hait H, Shu H. Twice-weekly synthetic conjugated medical product development to support labeling claims. 2006. estrogens vaginal cream for the treatment of vaginal atrophy. Menopause 2009 Jul;16(4):735-41. 10. Terwee CB, Jansma EP, Riphagen II, de Vet HC. Development of a methodological PubMed 31. Kagan R, Williams RS, Pan K, Mirkin S, Pickar JH. A randomized, placebo- and active search filter for finding studies on measurement properties of measurement instruments. Qual Life controlled trial of bazedoxifene/conjugated estrogens for treatment of moderate to severe Res 2009 Oct;18(8):1115-23. vulvar/vaginal atrophy in postmenopausal women. Menopause 2010 Mar;17(2):281-9. 11. Brenner PF. The menopausal syndrome. Obstet Gynecol 1988 Nov;72(5 Suppl):6S-11S. 32. Nilsson K, Risberg B, Heimer G. The vaginal epithelium in the postmenopause--cytology, 12. Castelo-Branco C, Cancelo MJ, Villero J, Nohales F, Julia MD. Management of post histology and pH as methods of assessment. Maturitas 1995 Jan;21(1):51-6. menopausal vaginal atrophy and atrophic vaginitis. [Review] [32 refs]. Maturitas 2005 Nov 15;52 33. Schaffer J, Fantl JA. Urogenital effects of the menopause. [Review] [69 refs]. Baillieres Clin Suppl 1:S46-S52. Obstet Gynaecol 1996 Sep;10(3):401-17. 13. Chollet JA, Carter G, Meyn LA, Mermelstein F, Balk JL. Efficacy and safety of vaginal estriol 34. Capobianco G, Donolo E, Borghero G, Dessole F, Cherchi PL, Dessole S. Effects of intravaginal and progesterone in postmenopausal women with atrophic vaginitis. Menopause 2009 Sep;16(5):978 estriol and pelvic floor rehabilitation on urogenital aging in postmenopausal women. Arch Gynecol 83. Obstet 2012 Feb;285(2):397-403. 14. Pandit L, Ouslander JG. Postmenopausal vaginal atrophy and atrophic vaginitis. [Review] [28 35. Dessole S, Rubattu G, Ambrosini G, Gallo O, Capobianco G, Cherchi PL, Marci R, Cosmi E. refs]. Am J Med Sci 1997 Oct;314(4):228-31. Efficacy of low-dose intravaginal estriol on urogenital aging in postmenopausal women. Menopause 15. Greendale GA, Zibecchi L, Petersen L, Ouslander JG, Kahn B, Ganz PA. Development and 2004 Jan;11(1):49-56. validation of a physical examination scale to assess vaginal atrophy and inflammation. Climacteric 36. Manonai J, Songchitsomboon S, Chanda K, Hong JH, Komindr S. The effect of a soy-rich diet 1999 Sep;2(3):197-204. on urogenital atrophy: a randomized, cross-over trial. Maturitas 2006 May 20;54(2):135-40. 16. Capewell AE, McIntyre MA, Elton RA. Post-menopausal atrophy in elderly women: is a vaginal 37. Mishell D. Menopause: physiology and pharmacology. Yearbook Medical Publisher, Chicago smear necessary for diagnosis? Age Ageing 1992 Mar;21(2):117-20. 1987. 17. van der Laak JA, Schijf CP, Kerstens HM, Heijnen-Wijnen TH, de Wilde PC, Hanselaar GJ. 38. Wied G, Bibbo M. Evaluation of endocrinologic condition by exfoliative cytology. Gold JJ (ed) Development and validation of a computerized cytomorphometric method to assess the maturation Textbook of gynaecologic endocrinology. 1975. New York, Harper and Row. of vaginal epithelial cells. Cytometry 1999 Mar 1;35(3):196-202. 39. Milsom I, Arvidsson L, Ekelund P, Molander U, Eriksson O. Factors influencing vaginal 18. McEndree B. Clinical application of the vaginal maturation index. [Review] [31 refs]. Nurse cytology, pH and bacterial flora in elderly women. Acta Obstet Gynecol Scand 1993 May;72(4):286-91. Pract 1955 Jun 9;24(9):48-2. 40. Caillouette J, Sharp C, Zimmerman G, Roy S. Vaginal pH as a marker for bacterial pathogen 19. Simon JA, Reape KZ, Wininger S, Hait H. Randomized, multicenter, double-blind, placebo and menopausal status. Am J Obstet Gynecol 1997;176:1270-5. controlled trial to evaluate the efficacy and safety of synthetic conjugated estrogens B for the 41. Roy S, Caillouette J, Roy T, Faden J. Vaginal pH is similar to follicle-stimulating hormone for treatment of vulvovaginal atrophy in healthy postmenopausal women. Fertil Steril 2008 menopause diagnosis. Am J Obstet Gynecol 2004;190:1272-7. Oct;90(4):1132-8. 42. Barentsen R, van de Weijer PH, Schram JH. Continuous low dose estradiol released from a 20. Speroff L. Efficacy and tolerability of a novel estradiol vaginal ring for relief of menopausal vaginal ring versus estriol vaginal cream for urogenital atrophy. Eur J Obstet Gynecol Reprod Biol 1997 symptoms. Obstet Gynecol 2003 Oct;102(4):823-34. Jan;71(1):73-80. 21. Pinkerton JV, Shifren JL, La VJ, Rosen A, Roesinger M, Siddhanti S. Influence of raloxifene on 43. Henriksson L, Stjernquist M, Boquist L, Alander U, Selinus I. A comparative multicenter study the efficacy of an estradiol-releasing ring for treating vaginal atrophy in postmenopausal women. of the effects of continuous low-dose estradiol released from a new vaginal ring versus estriol vaginal Menopause 2003 Jan;10(1):45-52. pessaries in postmenopausal women with symptoms and signs of urogenital atrophy. Am J Obstet 22. Benjamin F, Deutsch S. Immunoreactive plasma estrogens and vaginal hormone cytology in Gynecol 1994 Sep;171(3):624-32. postmenopausal women. Int J Gynaecol Obstet 1980 May;17(6):546-50. 44. Henriksson L, Stjernquist M, Boquist L, Cedergren I, Selinus I. A one-year multicenter study of efficacy and safety of a continuous, low-dose, estradiol-releasing vaginal ring (Estring) in

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References 23. Karp DR, Jean-Michel M, Johnston Y, Suciu G, Aguilar VC, Davila GW. A randomized clinical 1. Bachmann GA, Nevadunsky NS. Diagnosis and treatment of atrophic vaginitis. Am Fam trial of the impact of local estrogen on postoperative tissue quality after vaginal reconstructive Physician2000 May 15;61(10):3090-6. surgery. Female pelvic med 2012 Jul;18(4):211-5. 2. Levine KB, Williams RE, Hartmann KE. Vulvovaginal atrophy is strongly associated with 24. Davila GW, Singh A, Karapanagiotou I, Woodhouse S, Huber K, Zimberg S, Seiler J, Kopka SL. female sexual Are women with urogenital atrophy symptomatic? Am J Obstet Gynecol 2003 Feb;188(2):382-8. dysfunction among sexually active postmenopausal women. Menopause 2008 Jul;15(4 Pt 1):661-6. 25. Griesser H, Skonietzki S, Fischer T, Fielder K, Suesskind M. Low dose estriol pessaries for the 3. Nappi RE, Kokot-Kierepa M. Women's voices in the menopause: results from an international treatment of vaginal atrophy: a double-blind placebo-controlled trial investigating the efficacy of survey on vaginal atrophy. Maturitas 2010 Nov;67(3):233-8. pessaries containing 0.2mg and 0.03mg estriol. Maturitas 2012 Apr;71(4):360-8. 4. Santoro N, Komi J. Prevalence and impact of vaginal symptoms among postmenopausal 26. Bachmann G, Lobo RA, Gut R, Nachtigall L, Notelovitz M. Efficacy of low-dose estradiol women. J Sex Med 2009 Aug;6(8):2133-42. vaginal tablets in the treatment of atrophic vaginitis: a randomized controlled trial. Obstet Gynecol 5. Stika CS. Atrophic vaginitis. Dermatol Ther 2010 Sep;23(5):514-22. 2008 Jan;111(1):67-76. 6. Sturdee DW, Panay N, International Menopause Society Writing Group. Recommendations 27. Bachmann G, Bouchard C, Hoppe D, Ranganath R, Altomare C, Vieweg A, Graepel J, Helzner or the management of postmenopausal vaginal atrophy. Climacteric 2010 Dec;13(6):509-22. E. Efficacy and safety of low-dose regimens of conjugated estrogens cream administered vaginally. 7. Archer DF. Efficacy and tolerability of local estrogen therapy for urogenital atrophy. [Review] Menopause 2009 Jul;16(4):719-27. [75 refs]. Menopause 2010 Jan;17(1):194-203. 28. Bachmann GA, Komi JO, Ospemifene Study Group. Ospemifene effectively treats 8. US Department of Health and Human Services.Food and Drug Administration.Center for Drug vulvovaginal atrophy in postmenopausal women: results from a pivotal phase 3 study. Menopause Evaluation and Research (CDER). Guidance for Industry. Estrogen and estrogen/progestin drug 2010 May;17(3):480-6. products to treat vasomotor symptoms and vulvar and vaginal atrophy symptoms - recommendations 29. Ekin M, Yasar L, Savan K, Temur M, Uhri M, Gencer I, Kivanc E. The comparison of hyaluronic for clinical evaluation. 2003. acid vaginal tablets with estradiol vaginal tablets in the treatment of atrophic vaginitis: a randomized 9. US Department of Health an Human Services. Food and Drug Administration. Center for Drug controlled trial. Arch Gynecol Obstet 2011 Mar;283(3):539-43. Evaluation and Research (CDER). Guidance for Industry. Patient-reported outcome measures: use in 30. Freedman M, Kaunitz AM, Reape KZ, Hait H, Shu H. Twice-weekly synthetic conjugated medical product development to support labeling claims. 2006. estrogens vaginal cream for the treatment of vaginal atrophy. Menopause 2009 Jul;16(4):735-41. 10. Terwee CB, Jansma EP, Riphagen II, de Vet HC. Development of a methodological PubMed 31. Kagan R, Williams RS, Pan K, Mirkin S, Pickar JH. A randomized, placebo- and active search filter for finding studies on measurement properties of measurement instruments. Qual Life controlled trial of bazedoxifene/conjugated estrogens for treatment of moderate to severe Res 2009 Oct;18(8):1115-23. vulvar/vaginal atrophy in postmenopausal women. Menopause 2010 Mar;17(2):281-9. 11. Brenner PF. The menopausal syndrome. Obstet Gynecol 1988 Nov;72(5 Suppl):6S-11S. 32. Nilsson K, Risberg B, Heimer G. The vaginal epithelium in the postmenopause--cytology, 12. Castelo-Branco C, Cancelo MJ, Villero J, Nohales F, Julia MD. Management of post histology and pH as methods of assessment. Maturitas 1995 Jan;21(1):51-6. 05 menopausal vaginal atrophy and atrophic vaginitis. [Review] [32 refs]. Maturitas 2005 Nov 15;52 33. Schaffer J, Fantl JA. Urogenital effects of the menopause. [Review] [69 refs]. Baillieres Clin Suppl 1:S46-S52. Obstet Gynaecol 1996 Sep;10(3):401-17. 13. Chollet JA, Carter G, Meyn LA, Mermelstein F, Balk JL. Efficacy and safety of vaginal estriol 34. Capobianco G, Donolo E, Borghero G, Dessole F, Cherchi PL, Dessole S. Effects of intravaginal and progesterone in postmenopausal women with atrophic vaginitis. Menopause 2009 Sep;16(5):978 estriol and pelvic floor rehabilitation on urogenital aging in postmenopausal women. Arch Gynecol 83. Obstet 2012 Feb;285(2):397-403. 14. Pandit L, Ouslander JG. Postmenopausal vaginal atrophy and atrophic vaginitis. [Review] [28 35. Dessole S, Rubattu G, Ambrosini G, Gallo O, Capobianco G, Cherchi PL, Marci R, Cosmi E. refs]. Am J Med Sci 1997 Oct;314(4):228-31. Efficacy of low-dose intravaginal estriol on urogenital aging in postmenopausal women. Menopause 15. Greendale GA, Zibecchi L, Petersen L, Ouslander JG, Kahn B, Ganz PA. Development and 2004 Jan;11(1):49-56. validation of a physical examination scale to assess vaginal atrophy and inflammation. Climacteric 36. Manonai J, Songchitsomboon S, Chanda K, Hong JH, Komindr S. The effect of a soy-rich diet 1999 Sep;2(3):197-204. on urogenital atrophy: a randomized, cross-over trial. Maturitas 2006 May 20;54(2):135-40. 16. Capewell AE, McIntyre MA, Elton RA. Post-menopausal atrophy in elderly women: is a vaginal 37. Mishell D. Menopause: physiology and pharmacology. Yearbook Medical Publisher, Chicago smear necessary for diagnosis? Age Ageing 1992 Mar;21(2):117-20. 1987. 17. van der Laak JA, Schijf CP, Kerstens HM, Heijnen-Wijnen TH, de Wilde PC, Hanselaar GJ. 38. Wied G, Bibbo M. Evaluation of endocrinologic condition by exfoliative cytology. Gold JJ (ed) Development and validation of a computerized cytomorphometric method to assess the maturation Textbook of gynaecologic endocrinology. 1975. New York, Harper and Row. of vaginal epithelial cells. Cytometry 1999 Mar 1;35(3):196-202. 39. Milsom I, Arvidsson L, Ekelund P, Molander U, Eriksson O. Factors influencing vaginal 18. McEndree B. Clinical application of the vaginal maturation index. [Review] [31 refs]. Nurse cytology, pH and bacterial flora in elderly women. Acta Obstet Gynecol Scand 1993 May;72(4):286-91. Pract 1955 Jun 9;24(9):48-2. 40. Caillouette J, Sharp C, Zimmerman G, Roy S. Vaginal pH as a marker for bacterial pathogen 19. Simon JA, Reape KZ, Wininger S, Hait H. Randomized, multicenter, double-blind, placebo and menopausal status. Am J Obstet Gynecol 1997;176:1270-5. controlled trial to evaluate the efficacy and safety of synthetic conjugated estrogens B for the 41. Roy S, Caillouette J, Roy T, Faden J. Vaginal pH is similar to follicle-stimulating hormone for treatment of vulvovaginal atrophy in healthy postmenopausal women. Fertil Steril 2008 menopause diagnosis. Am J Obstet Gynecol 2004;190:1272-7. Oct;90(4):1132-8. 42. Barentsen R, van de Weijer PH, Schram JH. Continuous low dose estradiol released from a 20. Speroff L. Efficacy and tolerability of a novel estradiol vaginal ring for relief of menopausal vaginal ring versus estriol vaginal cream for urogenital atrophy. Eur J Obstet Gynecol Reprod Biol 1997 symptoms. Obstet Gynecol 2003 Oct;102(4):823-34. Jan;71(1):73-80. 21. Pinkerton JV, Shifren JL, La VJ, Rosen A, Roesinger M, Siddhanti S. Influence of raloxifene on 43. Henriksson L, Stjernquist M, Boquist L, Alander U, Selinus I. A comparative multicenter study the efficacy of an estradiol-releasing ring for treating vaginal atrophy in postmenopausal women. of the effects of continuous low-dose estradiol released from a new vaginal ring versus estriol vaginal Menopause 2003 Jan;10(1):45-52. pessaries in postmenopausal women with symptoms and signs of urogenital atrophy. Am J Obstet 22. Benjamin F, Deutsch S. Immunoreactive plasma estrogens and vaginal hormone cytology in Gynecol 1994 Sep;171(3):624-32. postmenopausal women. Int J Gynaecol Obstet 1980 May;17(6):546-50. 44. Henriksson L, Stjernquist M, Boquist L, Cedergren I, Selinus I. A one-year multicenter study of efficacy and safety of a continuous, low-dose, estradiol-releasing vaginal ring (Estring) in

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postmenopausal women with symptoms and signs of urogenital aging. Am J Obstet Gynecol 1996 Obstet Gynecol 1999 May;180(5):1072-9. Jan;174(1 Pt 1):85-92. 64. Eriksen PS, Rasmussen H. Low-dose 17 beta-estradiol vaginal tablets in the treatment of 45. Labrie F, Archer D, Bouchard C, Fortier M, Cusan L, Gomez JL, Girard G, Baron M, Ayotte N, atrophic vaginitis: a double-blind placebo controlled study. Eur J Obstet Gynecol Reprod Biol 1992 Apr Moreau M, Dube R, Cote I, Labrie C, Lavoie L, Berger L, Gilbert L, Martel C, Balser J. Intravaginal 21;44(2):137-44. dehydroepiandrosterone (Prasterone), a physiological and highly efficient treatment of vaginal 65. Karaosmanoglu O, Cogendez E, Sozen H, Asoglu MR, Akdemir Y, Eren S. Hyaluronic acid in the atrophy. Menopause 2009 Sep;16(5):907-22. treatment of postmenopausal women with atrophic vaginitis. Int J Gynaecol Obstet 2011 46. Lee YK, Chung HH, Kim JW, Park NH, Song YS, Kang SB. Vaginal pH-balanced gel for the May;113(2):156-7. control of atrophic vaginitis among breast cancer survivors: a randomized controlled trial. Obstet 66. Simunic V, Banovic I, Ciglar S, Jeren L, Pavicic BD, Sprem M. Local estrogen treatment in Gynecol 2011 Apr;117(4):922-7. patients with urogenital symptoms. Int J Gynaecol Obstet 2003 Aug;82(2):187-97. 47. Manonai J, Theppisai U, Suthutvoravut S, Udomsubpayakul U, Chittacharoen A. The effect of 67. Speroff L, Haney AF, Gilbert RD, Ellman H, Estradiol Acetate Investigator Group. Efficacy of a estradiol vaginal tablet and conjugated estrogen cream on urogenital symptoms in postmenopausal new, oral estradiol acetate formulation for relief of menopause symptoms. Menopause 2006 women: a comparative study. J Obstet Gynaecol Res 2001 Oct;27(5):255-60. May;13(3):442-50. 48. Simon J, Nachtigall L, Gut R, Lang E, Archer DF, Utian W. Effective treatment of vaginal 68. Swanson SG, Drosman S, Helmond FA, Stathopoulos VM. Tibolone for the treatment of atrophy with an ultra-low-dose estradiol vaginal tablet.[Erratum appears in Obstet Gynecol. 2008 moderate to severe vasomotor symptoms and genital atrophy in postmenopausal women: a Dec;112(6):1392]. Obstet Gynecol 2008 Nov;112(5):1053-60. multicenter, randomized, double-blind, placebo-controlled study. Menopause 2006 Nov;13(6):917-25. 49. Smith P, Heimer G, Lindskog M, Ulmsten U. Oestradiol-releasing vaginal ring for treatment of 69. Utian WH, Speroff L, Ellman H, Dart C. Comparative controlled trial of a novel oral estrogen postmenopausal urogenital atrophy. Maturitas 1993 Mar;16(2):145-54. therapy, estradiol acetate, for relief of menopause symptoms. Menopause 2005 Nov;12(6):708-15. 50. Zeyneloglu HB, Oktem M, Haberal NA, Esinler I, Kuscu E. The effect of raloxifene in 70. Yumru AE, Bozkurt M, Inci CE, Baykan G. The use of local 17beta-oestradiol treatment for association with vitamin D on vaginal maturation index and urogenital symptoms in postmenopausal improving vaginal symptoms associated with post-menopausal oestrogen deficiency. J Int Med Res osteoporotic women. Fertil Steril 2007 Aug;88(2):530-2. 2009 Jan;37(1):198-204. 51. Bachmann GA, Schaefers M, Uddin A, Utian WH. Microdose transdermal estrogen therapy 71. Le DM, Caruso C, Mancuso A, Costa G, Iemmo R, Pizzimenti G, Cavallari V. The effect of for relief of vulvovaginal symptoms in postmenopausal women. Menopause 2009 Sep;16(5):877-82. vaginally administered genistein in comparison with hyaluronic acid on atrophic epithelium in 52. Parsons A, Merritt D, Rosen A, Heath H, III, Siddhanti S, Plouffe L, Jr., Study Groups on the postmenopause. Arch Gynecol Obstet 2011 Jun;283(6):1319-23. Effects of Raloxifene HCI With Low-Dose Premarin Vaginal Cream. Effect of raloxifene on the response 72. Palacios S, Castelo-Branco C, Cancelo MJ, Vazquez F. Low-dose, vaginally administered to conjugated estrogen vaginal cream or nonhormonal moisturizers in postmenopausal vaginal estrogens may enhance local benefits of systemic therapy in the treatment of urogenital atrophy in atrophy. Obstet Gynecol 2003 Feb;101(2):346-52. postmenopausal women on hormone therapy. Maturitas 2005 Feb 14;50(2):98-104. 53. Biglia N, Peano E, Sgandurra P, Moggio G, Panuccio E, Migliardi M, Ravarino N, Ponzone R, 73. Yildirim B, Kaleli B, Duzcan E, Topuz O. The effects of postmenopausal Vitamin D treatment Sismondi P. Low-dose vaginal estrogens or vaginal moisturizer in breast cancer survivors with on vaginal atrophy. Maturitas 2004 Dec 10;49(4):334-7. urogenital atrophy: a preliminary study. Gynecol Endocrinol 2010 Jun;26(6):404-12. 74. Cano A, Estevez J, Usandizaga R, Gallo JL, Guinot M, Delgado JL, Castellanos E, Moral E, Nieto 54. Manonai J, Chittacharoen A, Theppisai U, Theppisai H. Effect of Pueraria mirifica on vaginal C, del Prado JM, Ferrer J. The therapeutic effect of a new ultra low concentration estriol gel health. Menopause 2007 Sep;14(5):919-24. formulation (0.005% estriol vaginal gel) on symptoms and signs of postmenopausal vaginal atrophy: 55. Raghunandan C, Agrawal S, Dubey P, Choudhury M, Jain A. A comparative study of the results from a pivotal phase III study. Menopause 2012 Oct;19(10):1130-9. effects of local estrogen with or without local testosterone on vulvovaginal and sexual dysfunction in 75. McKenna SP, Whalley D, Renck-Hooper U, Carlin S, Doward LC. The development of a quality postmenopausal women. J Sex Med 2010 Mar;7(3):1284-90. of life instrument for use with post-menopausal women with urogenital atrophy in the UK and 56. Labrie F, Archer DF, Bouchard C, Fortier M, Cusan L, Gomez JL, Girard G, Baron M, Ayotte N, Sweden. Qual Life Res 1999 Aug;8(5):393-8. Moreau M, Dube R, Cote I, Labrie C, Lavoie L, Berger L, Gilbert L, Martel C, Balser J. Intravaginal 76. Lester J, Bernhard L, Ryan-Wenger N. A self-report instrument that describes urogenital dehydroepiandrosterone (prasterone), a highly efficient treatment of dyspareunia. Climacteric 2011 atrophy symptoms in breast cancer survivors. West J Nurs Res 2012 Feb;34(1):72-96. Apr;14(2):282-8. 77. Casper F, Petri E. Local treatment of urogenital atrophy with an estradiol-releasing vaginal 57. Brizzolara S, Killeen J, Severino R. Vaginal pH and parabasal cells in postmenopausal women. ring: a comparative and a placebo-controlled multicenter study. Vaginal Ring Study Group. Int Obstetrics and Gynecology 1999;94:700-3. Urogynecol J Pelvic Floor Dysfunct 1999;10(3):171-6. 58. Simon JA, Bouchard C, Waldbaum A, Utian W, Zborowski J, Snabes MC. Low dose of 78. Weisberg E, Ayton R, Darling G, Farrell E, Murkies A, O'Neill S, Kirkegard Y, Fraser IS. transdermal estradiol gel for treatment of symptomatic postmenopausal women: a randomized Endometrial and vaginal effects of low-dose estradiol delivered by vaginal ring or vaginal tablet. controlled trial. Obstet Gynecol 2007 Mar;109(3):588-96. Climacteric 2005 Mar;8(1):83-92. 59. Ettinger B, Hait H, Reape KZ, Shu H. Measuring symptom relief in studies of vaginal and 79. Bachmann G. Vulvo-vaginal complaints. Lobo R, editor; 1994. vulvar atrophy: the most bothersome symptom approach. Menopause 2008 Sep;15(5):885-9. 80. Raymundo N, Yu-cheng B, Zi-yan H, Lai CH, Leung K, Subramaniam R, Bin-rong C, Ling YS, 60. Labrie F, Archer D, Bouchard C, Fortier M, Cusan L, Gomez JL, Girard G, Baron M, Ayotte N, Nasri N, Calimon N. Treatment of atrophic vaginitis with topical conjugated equine estrogens in Moreau M, Dube R, Cote I, Labrie C, Lavoie L, Berger L, Martel C, Balser J. High internal consistency postmenopausal Asian women. Climacteric 2004 Sep;7(3):312-8. and efficacy of intravaginal DHEA for vaginal atrophy. Gynecol Endocrinol 2010 Jul;26(7):524-32. 81. Rane A, Hassan S, Corstiaans A. Does conventional HRT protect from urogenital atrophy? A 61. Ayton RA, Darling GM, Murkies AL, Farrell EA, Weisberg E, Selinus I, Fraser ID. A comparative prospective study. J Obstet Gynaecol 2000 May;20(3):306-7. study of safety and efficacy of continuous low dose oestradiol released from a vaginal ring compared 82. Laan E, van Lunsen RH. Hormones and sexuality in postmenopausal women: a with conjugated equine oestrogen vaginal cream in the treatment of postmenopausal urogenital psychophysiological study. J Psychosom Obstet Gynaecol 1997 Jun;18(2):126-33. atrophy. Br J Obstet Gynaecol 1996 Apr;103(4):351-8. 83. Leiblum S, Bachmann G, Kemmann E, Colburn D, Swartzman L. Vaginal atrophy in the 62. Bygdeman M, Swahn ML. Replens versus dienoestrol cream in the symptomatic treatment of postmenopausal woman. The importance of sexual activity and hormones. JAMA 1983 Apr vaginal atrophy in postmenopausal women. Maturitas 1996 Apr;23(3):259-63. 22;249(16):2195-8. 63. Eriksen B. A randomized, open, parallel-group study on the preventive effect of an estradiol 84. Meisels A. The maturation value. Acta Cytol 1967;11:249. releasing vaginal ring (Estring) on recurrent urinary tract infections in postmenopausal women. Am J 85. Nyirjesy P, Leigh RD, Mathew L, Lev-Sagie A, Culhane JF. Chronic vulvovaginitis in women

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postmenopausal women with symptoms and signs of urogenital aging. Am J Obstet Gynecol 1996 Obstet Gynecol 1999 May;180(5):1072-9. Jan;174(1 Pt 1):85-92. 64. Eriksen PS, Rasmussen H. Low-dose 17 beta-estradiol vaginal tablets in the treatment of 45. Labrie F, Archer D, Bouchard C, Fortier M, Cusan L, Gomez JL, Girard G, Baron M, Ayotte N, atrophic vaginitis: a double-blind placebo controlled study. Eur J Obstet Gynecol Reprod Biol 1992 Apr Moreau M, Dube R, Cote I, Labrie C, Lavoie L, Berger L, Gilbert L, Martel C, Balser J. Intravaginal 21;44(2):137-44. dehydroepiandrosterone (Prasterone), a physiological and highly efficient treatment of vaginal 65. Karaosmanoglu O, Cogendez E, Sozen H, Asoglu MR, Akdemir Y, Eren S. Hyaluronic acid in the atrophy. Menopause 2009 Sep;16(5):907-22. treatment of postmenopausal women with atrophic vaginitis. Int J Gynaecol Obstet 2011 46. Lee YK, Chung HH, Kim JW, Park NH, Song YS, Kang SB. Vaginal pH-balanced gel for the May;113(2):156-7. control of atrophic vaginitis among breast cancer survivors: a randomized controlled trial. Obstet 66. Simunic V, Banovic I, Ciglar S, Jeren L, Pavicic BD, Sprem M. Local estrogen treatment in Gynecol 2011 Apr;117(4):922-7. patients with urogenital symptoms. Int J Gynaecol Obstet 2003 Aug;82(2):187-97. 47. Manonai J, Theppisai U, Suthutvoravut S, Udomsubpayakul U, Chittacharoen A. The effect of 67. Speroff L, Haney AF, Gilbert RD, Ellman H, Estradiol Acetate Investigator Group. Efficacy of a estradiol vaginal tablet and conjugated estrogen cream on urogenital symptoms in postmenopausal new, oral estradiol acetate formulation for relief of menopause symptoms. Menopause 2006 women: a comparative study. J Obstet Gynaecol Res 2001 Oct;27(5):255-60. May;13(3):442-50. 48. Simon J, Nachtigall L, Gut R, Lang E, Archer DF, Utian W. Effective treatment of vaginal 68. Swanson SG, Drosman S, Helmond FA, Stathopoulos VM. Tibolone for the treatment of atrophy with an ultra-low-dose estradiol vaginal tablet.[Erratum appears in Obstet Gynecol. 2008 moderate to severe vasomotor symptoms and genital atrophy in postmenopausal women: a Dec;112(6):1392]. Obstet Gynecol 2008 Nov;112(5):1053-60. multicenter, randomized, double-blind, placebo-controlled study. Menopause 2006 Nov;13(6):917-25. 49. Smith P, Heimer G, Lindskog M, Ulmsten U. Oestradiol-releasing vaginal ring for treatment of 69. Utian WH, Speroff L, Ellman H, Dart C. Comparative controlled trial of a novel oral estrogen postmenopausal urogenital atrophy. Maturitas 1993 Mar;16(2):145-54. therapy, estradiol acetate, for relief of menopause symptoms. Menopause 2005 Nov;12(6):708-15. 50. Zeyneloglu HB, Oktem M, Haberal NA, Esinler I, Kuscu E. The effect of raloxifene in 70. Yumru AE, Bozkurt M, Inci CE, Baykan G. The use of local 17beta-oestradiol treatment for association with vitamin D on vaginal maturation index and urogenital symptoms in postmenopausal improving vaginal symptoms associated with post-menopausal oestrogen deficiency. J Int Med Res osteoporotic women. Fertil Steril 2007 Aug;88(2):530-2. 2009 Jan;37(1):198-204. 51. Bachmann GA, Schaefers M, Uddin A, Utian WH. Microdose transdermal estrogen therapy 71. Le DM, Caruso C, Mancuso A, Costa G, Iemmo R, Pizzimenti G, Cavallari V. The effect of for relief of vulvovaginal symptoms in postmenopausal women. Menopause 2009 Sep;16(5):877-82. vaginally administered genistein in comparison with hyaluronic acid on atrophic epithelium in 52. Parsons A, Merritt D, Rosen A, Heath H, III, Siddhanti S, Plouffe L, Jr., Study Groups on the postmenopause. Arch Gynecol Obstet 2011 Jun;283(6):1319-23. Effects of Raloxifene HCI With Low-Dose Premarin Vaginal Cream. Effect of raloxifene on the response 72. Palacios S, Castelo-Branco C, Cancelo MJ, Vazquez F. Low-dose, vaginally administered to conjugated estrogen vaginal cream or nonhormonal moisturizers in postmenopausal vaginal estrogens may enhance local benefits of systemic therapy in the treatment of urogenital atrophy in atrophy. Obstet Gynecol 2003 Feb;101(2):346-52. postmenopausal women on hormone therapy. Maturitas 2005 Feb 14;50(2):98-104. 53. Biglia N, Peano E, Sgandurra P, Moggio G, Panuccio E, Migliardi M, Ravarino N, Ponzone R, 73. Yildirim B, Kaleli B, Duzcan E, Topuz O. The effects of postmenopausal Vitamin D treatment 05 Sismondi P. Low-dose vaginal estrogens or vaginal moisturizer in breast cancer survivors with on vaginal atrophy. Maturitas 2004 Dec 10;49(4):334-7. urogenital atrophy: a preliminary study. Gynecol Endocrinol 2010 Jun;26(6):404-12. 74. Cano A, Estevez J, Usandizaga R, Gallo JL, Guinot M, Delgado JL, Castellanos E, Moral E, Nieto 54. Manonai J, Chittacharoen A, Theppisai U, Theppisai H. Effect of Pueraria mirifica on vaginal C, del Prado JM, Ferrer J. The therapeutic effect of a new ultra low concentration estriol gel health. Menopause 2007 Sep;14(5):919-24. formulation (0.005% estriol vaginal gel) on symptoms and signs of postmenopausal vaginal atrophy: 55. Raghunandan C, Agrawal S, Dubey P, Choudhury M, Jain A. A comparative study of the results from a pivotal phase III study. Menopause 2012 Oct;19(10):1130-9. effects of local estrogen with or without local testosterone on vulvovaginal and sexual dysfunction in 75. McKenna SP, Whalley D, Renck-Hooper U, Carlin S, Doward LC. The development of a quality postmenopausal women. J Sex Med 2010 Mar;7(3):1284-90. of life instrument for use with post-menopausal women with urogenital atrophy in the UK and 56. Labrie F, Archer DF, Bouchard C, Fortier M, Cusan L, Gomez JL, Girard G, Baron M, Ayotte N, Sweden. Qual Life Res 1999 Aug;8(5):393-8. Moreau M, Dube R, Cote I, Labrie C, Lavoie L, Berger L, Gilbert L, Martel C, Balser J. Intravaginal 76. Lester J, Bernhard L, Ryan-Wenger N. A self-report instrument that describes urogenital dehydroepiandrosterone (prasterone), a highly efficient treatment of dyspareunia. Climacteric 2011 atrophy symptoms in breast cancer survivors. West J Nurs Res 2012 Feb;34(1):72-96. Apr;14(2):282-8. 77. Casper F, Petri E. Local treatment of urogenital atrophy with an estradiol-releasing vaginal 57. Brizzolara S, Killeen J, Severino R. Vaginal pH and parabasal cells in postmenopausal women. ring: a comparative and a placebo-controlled multicenter study. Vaginal Ring Study Group. Int Obstetrics and Gynecology 1999;94:700-3. Urogynecol J Pelvic Floor Dysfunct 1999;10(3):171-6. 58. Simon JA, Bouchard C, Waldbaum A, Utian W, Zborowski J, Snabes MC. Low dose of 78. Weisberg E, Ayton R, Darling G, Farrell E, Murkies A, O'Neill S, Kirkegard Y, Fraser IS. transdermal estradiol gel for treatment of symptomatic postmenopausal women: a randomized Endometrial and vaginal effects of low-dose estradiol delivered by vaginal ring or vaginal tablet. controlled trial. Obstet Gynecol 2007 Mar;109(3):588-96. Climacteric 2005 Mar;8(1):83-92. 59. Ettinger B, Hait H, Reape KZ, Shu H. Measuring symptom relief in studies of vaginal and 79. Bachmann G. Vulvo-vaginal complaints. Lobo R, editor; 1994. vulvar atrophy: the most bothersome symptom approach. Menopause 2008 Sep;15(5):885-9. 80. Raymundo N, Yu-cheng B, Zi-yan H, Lai CH, Leung K, Subramaniam R, Bin-rong C, Ling YS, 60. Labrie F, Archer D, Bouchard C, Fortier M, Cusan L, Gomez JL, Girard G, Baron M, Ayotte N, Nasri N, Calimon N. Treatment of atrophic vaginitis with topical conjugated equine estrogens in Moreau M, Dube R, Cote I, Labrie C, Lavoie L, Berger L, Martel C, Balser J. High internal consistency postmenopausal Asian women. Climacteric 2004 Sep;7(3):312-8. and efficacy of intravaginal DHEA for vaginal atrophy. Gynecol Endocrinol 2010 Jul;26(7):524-32. 81. Rane A, Hassan S, Corstiaans A. Does conventional HRT protect from urogenital atrophy? A 61. Ayton RA, Darling GM, Murkies AL, Farrell EA, Weisberg E, Selinus I, Fraser ID. A comparative prospective study. J Obstet Gynaecol 2000 May;20(3):306-7. study of safety and efficacy of continuous low dose oestradiol released from a vaginal ring compared 82. Laan E, van Lunsen RH. Hormones and sexuality in postmenopausal women: a with conjugated equine oestrogen vaginal cream in the treatment of postmenopausal urogenital psychophysiological study. J Psychosom Obstet Gynaecol 1997 Jun;18(2):126-33. atrophy. Br J Obstet Gynaecol 1996 Apr;103(4):351-8. 83. Leiblum S, Bachmann G, Kemmann E, Colburn D, Swartzman L. Vaginal atrophy in the 62. Bygdeman M, Swahn ML. Replens versus dienoestrol cream in the symptomatic treatment of postmenopausal woman. The importance of sexual activity and hormones. JAMA 1983 Apr vaginal atrophy in postmenopausal women. Maturitas 1996 Apr;23(3):259-63. 22;249(16):2195-8. 63. Eriksen B. A randomized, open, parallel-group study on the preventive effect of an estradiol 84. Meisels A. The maturation value. Acta Cytol 1967;11:249. releasing vaginal ring (Estring) on recurrent urinary tract infections in postmenopausal women. Am J 85. Nyirjesy P, Leigh RD, Mathew L, Lev-Sagie A, Culhane JF. Chronic vulvovaginitis in women

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older than 50 years: analysis of a prospective database. Journal of Lower Genital Tract Disease 2012 Appendix 1 Database(s): Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations and Jan;16(1):24-9. Ovid MEDLINE(R) 1946 to Present 86. Rioux JE, Devlin C, Gelfand MM, Steinberg WM, Hepburn DS. 17beta-estradiol vaginal tablet # Searches Results versus conjugated equine estrogen vaginal cream to relieve menopausal atrophic vaginitis. Menopause 2000 May;7(3):156-61. 1 Atrophy/ or (atrophy or atrophies or atrophic or atrophied or atrophical).tw. 90512 87. Lynch C. Vaginal estrogen therapy for the treatment of atrophic vaginitis. [Review] [69 refs]. J genitalia, female/ or vagina/ or vulva/ or vaginal diseases/ or exp vaginitis/ or vulvovaginitis/ or 2 51625 Womens Health (Larchmt ) 2009 Oct;18(10):1595-606. vulvar diseases/ or vulvitis/ 88. Crothers BA, Booth CN, Darragh TM, Means MM, Souers RJ, Thomas N, Moriarty AT. Atrophic 3 ((urogenital or urovaginal or genito*) adj3 (signs or symptoms or scor*)).tw. 712 vaginitis: concordance and interpretation of slides in the College of American Pathologists 4 dyspareunia/ or d?spareunia.tw. 3080 Cervicovaginal Interlaboratory Comparison Program in Gynecologic Cytopathology. Arch Pathol Lab Med 2012 Nov;136(11):1332-8. 5 Coitus/ or (coitus or intercourse).tw. 20480 89. Hummelen R, Macklaim JM, Bisanz JE, Hammond JA, McMillan A, Vongsa R, Koenig D, Gloor 6 (vagina* adj3 (dry or dryness)).tw. 723 GB, Reid G. Vaginal microbiome and epithelial gene array in post-menopausal women with moderate 7 urogenital system/ or ((urogenital or urovaginal or genito*) adj3 (signs or symptoms or scor*)).tw. 4943 to severe dryness. PLoS ONE 2011;6(11):e26602. 8 or/2-7 76846 90. Chollet JA. Efficacy and safety of ultra-low-dose Vagifem (10 mcg). Patient Prefer Adherence 2011;5:571-4. 9 1 and 8 1060 91. Al-Baghdadi O, Ewies AA. Topical estrogen therapy in the management of postmenopausal 10 Atrophic Vaginitis/ 9 vaginal atrophy: an up-to-date overview. [Review] [87 refs]. Climacteric 2009 Apr;12(2):91-105. ((atrophy or atrophies or atrophic or atrophied or atrophical) adj10 (vaginitis or vagina* or vulva* or 11 779 92. Minkin MJ, Maamari R, Reiter S. Improved compliance and patient satisfaction with estradiol vulvovagina* or urovaginal*)).tw. vaginal tablets in postmenopausal women previously treated with another local estrogen therapy. Int 12 ((atrophy or atrophies or atrophic or atrophied or atrophical) adj5 (genital* or genito*)).tw. 135 J Women Health 2013;5:133-9. 93. Nappi RE, Kokot-Kierepa M. Vaginal Health: Insights, Views & Attitudes (VIVA) - results from 13 ((atrophy or atrophies or atrophic or atrophied or atrophical) adj10 urogenital*).tw. 183 an international survey. Climacteric 2012 Feb;15(1):36-44. ((urogenit* or urovagina* or genito*) adj3 (signs or symptoms or scor*)).tw. and (menopau* or 94. van Geelen JM, van de Weijer PH, Arnolds HT. Urogenital symptoms and resulting discomfort 14 perimenopau* or postmenopau* or climacter* or periclimact* or postclimact* or 238 in non-institutionalized Dutch women aged 50-75 years. Int Urogynecol J Pelvic Floor Dysfunct maturit*).mp,jw,kw. 2000;11(1):9-14. ((maturation adj2 (indices or index)) or VVA or VMI).tw. and ((vagina* or vulvovagina* or atroph* or 95) Pastore LM, Carter RA, Hulka BS, Wells E. Self-reported urogenital symptoms in postmenopausal 15 replacement therap* or hormone therap*) and (menopau* or perimenopau* or postmenopau* or 134 women: Women's Health Initiative. Maturitas 2004 Dec 10;49(4):292-303. climacter* or periclimact* or postclimact* or maturitas)).mp,jw,kw.

16 (maturat* adj3 (vagina* or vulvovagina*)).tw. 181 17 or/9-16 1772 18 (animals/ not humans/) or (rat or rats or mouse or mice or rodent*).ti. 4105276 19 17 not 18 1544 validation studies.pt. or observer variation/ or discriminant analysis/ or Psychometrics/ or "Reproducibility of Results"/ or factor analysis, statistical/ or evaluation studies/ or (audit or audits or psychometr* or clin?metr* or ((outcome* or clinical or observer* or utility or satisfaction or QoL or quality of life or score or scores or method or methods or physicians or gyn?ecol* or modelling or objective) adj3 assessm*) or observer variation* or reproducib* or reliab* or unreliab* or valid* or coefficient or homogeneity or homogeneous or ((internal or external) adj3 (consistency or inconsistency)) or cronbach* or (item and (correlation* or selection* or reduction*)) or ((item or 20 items) adj3 (discriminant* or convergent* or divergent*)) or agreement or precision or imprecision or 1839169 (precise adj values) or (test and retest) or accuracy test* or stability or interrater or intrarater or intertester or intratester or interobserver or intraobserver or intertechnician or intratechnician or interexaminer or intraexaminer or interassay or intraassay or interindividual or intraindividual or interparticipant or intraparticipant or ((inter or intra) adj (rater or tester or observer or technician or examiner or assay or individual or participant)) or kappa or kappa's or kappas or generaliza* or generalisa* or concordance or interscale or inter-scale or interscales or inter-scales or subscale* or sub-scale*).tw,ot,kw. 21 19 and 20 [I clinimetrics] 137 22 remove duplicates from 21 135 23 exp estrogens/ or exp estriol/ or exp Estradiol Congeners/ or Estrogen Replacement Therapy/ 159216 (estrogen* or oestrogen* or estradiol* or oestradiol* or estriol* or oestriol* or estetrol* or 24 180202 oestetrol* or estrone* or oestrone* or dien?estrol).tw. 25 (E1 or E2 or TTSE2 or E3 or E4 or CEE or EE or CE).tw. 115968

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older than 50 years: analysis of a prospective database. Journal of Lower Genital Tract Disease 2012 Appendix 1 Database(s): Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations and Jan;16(1):24-9. Ovid MEDLINE(R) 1946 to Present 86. Rioux JE, Devlin C, Gelfand MM, Steinberg WM, Hepburn DS. 17beta-estradiol vaginal tablet # Searches Results versus conjugated equine estrogen vaginal cream to relieve menopausal atrophic vaginitis. Menopause 2000 May;7(3):156-61. 1 Atrophy/ or (atrophy or atrophies or atrophic or atrophied or atrophical).tw. 90512 87. Lynch C. Vaginal estrogen therapy for the treatment of atrophic vaginitis. [Review] [69 refs]. J genitalia, female/ or vagina/ or vulva/ or vaginal diseases/ or exp vaginitis/ or vulvovaginitis/ or 2 51625 Womens Health (Larchmt ) 2009 Oct;18(10):1595-606. vulvar diseases/ or vulvitis/ 88. Crothers BA, Booth CN, Darragh TM, Means MM, Souers RJ, Thomas N, Moriarty AT. Atrophic 3 ((urogenital or urovaginal or genito*) adj3 (signs or symptoms or scor*)).tw. 712 vaginitis: concordance and interpretation of slides in the College of American Pathologists 4 dyspareunia/ or d?spareunia.tw. 3080 Cervicovaginal Interlaboratory Comparison Program in Gynecologic Cytopathology. Arch Pathol Lab Med 2012 Nov;136(11):1332-8. 5 Coitus/ or (coitus or intercourse).tw. 20480 89. Hummelen R, Macklaim JM, Bisanz JE, Hammond JA, McMillan A, Vongsa R, Koenig D, Gloor 6 (vagina* adj3 (dry or dryness)).tw. 723 GB, Reid G. Vaginal microbiome and epithelial gene array in post-menopausal women with moderate 7 urogenital system/ or ((urogenital or urovaginal or genito*) adj3 (signs or symptoms or scor*)).tw. 4943 to severe dryness. PLoS ONE 2011;6(11):e26602. 8 or/2-7 76846 90. Chollet JA. Efficacy and safety of ultra-low-dose Vagifem (10 mcg). Patient Prefer Adherence 2011;5:571-4. 9 1 and 8 1060 91. Al-Baghdadi O, Ewies AA. Topical estrogen therapy in the management of postmenopausal 10 Atrophic Vaginitis/ 9 vaginal atrophy: an up-to-date overview. [Review] [87 refs]. Climacteric 2009 Apr;12(2):91-105. ((atrophy or atrophies or atrophic or atrophied or atrophical) adj10 (vaginitis or vagina* or vulva* or 11 779 92. Minkin MJ, Maamari R, Reiter S. Improved compliance and patient satisfaction with estradiol vulvovagina* or urovaginal*)).tw. vaginal tablets in postmenopausal women previously treated with another local estrogen therapy. Int 12 ((atrophy or atrophies or atrophic or atrophied or atrophical) adj5 (genital* or genito*)).tw. 135 J Women Health 2013;5:133-9. 93. Nappi RE, Kokot-Kierepa M. Vaginal Health: Insights, Views & Attitudes (VIVA) - results from 13 ((atrophy or atrophies or atrophic or atrophied or atrophical) adj10 urogenital*).tw. 183 an international survey. Climacteric 2012 Feb;15(1):36-44. ((urogenit* or urovagina* or genito*) adj3 (signs or symptoms or scor*)).tw. and (menopau* or 94. van Geelen JM, van de Weijer PH, Arnolds HT. Urogenital symptoms and resulting discomfort 14 perimenopau* or postmenopau* or climacter* or periclimact* or postclimact* or 238 in non-institutionalized Dutch women aged 50-75 years. Int Urogynecol J Pelvic Floor Dysfunct maturit*).mp,jw,kw. 2000;11(1):9-14. ((maturation adj2 (indices or index)) or VVA or VMI).tw. and ((vagina* or vulvovagina* or atroph* or 95) Pastore LM, Carter RA, Hulka BS, Wells E. Self-reported urogenital symptoms in postmenopausal 15 replacement therap* or hormone therap*) and (menopau* or perimenopau* or postmenopau* or 134 05 women: Women's Health Initiative. Maturitas 2004 Dec 10;49(4):292-303. climacter* or periclimact* or postclimact* or maturitas)).mp,jw,kw.

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Chapter 5

(Vivelle or Estrace or Aerodiol or Estraderm or Ovocyclin or hydroxyestriol or Menorest or VAGIFEM or atroph*)).tw,ot,kw. 26 834 or Estring or Promestriene or Cenestin or SCE-A or Ortho-Gynest or Premarin or Synapause).tw. 58 (cl or st).fs. 998834 Estrogen Receptor Modulators/ or Selective Estrogen Receptor Modulators/ or Raloxifene/ or 27 7558 59 ((vaginal or vulvovaginal or vulva* or karyopy?not*) adj2 (index* or indices)).tw,ot,kw. 224 Receptors, Estrogen/ai 60 ((vagin* or vulvovagin* or vulva* or dryness or VVA) adj4 (symptom* or sign or signs)).tw,ot,kw. 2514 28 (SERM or SERMs or TSEC or SMART).tw. 8871 ((Vaginal dryness or vaginal health* or symptom* or atroph*) adj3 (rated or rating or scor* or scale* 61 44229 29 (raloxifene or ospemifene or lasofoxifene or CP-336156 or FC-1271a).tw. 2930 or severity or survey* or insight)).tw,ot,kw. 30 (antiestrogen* or antioestrogen*).tw. 7181 62 (vagina* adj2 matur* adj2 (value or values or index* or indices or scor*)).tw,ot,kw. 81 31 exp Testosterone Congeners/ 76614 63 ((vaginal or vulvovaginal or vulva*) adj cytol*).tw,ot,kw. 1164 (DHEA or DHA or DHEAs or dehydroepiandrosterone or prasterone or androstenolone or androsten 32 121021 64 vagina/pa or vagina/de 4114 or testosteron* or androgen*).tw. 65 colposcop*.tw,ot,kw. 6622 Administration, Intravaginal/ or "Vaginal Creams, Foams, and Jellies"/ or Pessaries/ or Contraceptive 33 6556 66 (pH or KPI or VSS or VHI or PFSF or VMI or VMV or VIVA or GHCE).tw,kw,ot. 329080 Devices, Female/ 67 (symptom* adj1 scor*).tw. 12992 ((vagina* or intravagina* or vulvovag*) adj4 (cream* or tablet* or jell* or gel or gels or foam* or 34 lubricant* or douche* or moisturizer* or ring or rings or pessar* or suppositor* or caspule* or 8915 68 self-report*.tw,ot,kw. 84651 depot* or administrat* or treat* or therap*)).tw. 69 (((visual or point* or analog* or item* or atroph* or climacter*) adj4 scale*) or VAS).tw. 72502 35 Hyaluronic Acid/ 15453 70 or/52-69 2357852 36 (hyaluron* or replens).tw. 24277 71 70 and 19 [III definition, diagnosis, incidence, symptoms, measurement instruments] 771 37 exp soybeans/ or exp isoflavones/ 31638 72 remove duplicates from 71 743 38 (genistein* or soy* or isoflav* or iso-flav* or Pueraria or daidzein).tw. 49437 86 51 or 72 1020 Phytotherapy/ or Plant Extracts/ or Plants, Medicinal/ or Herbal Medicine/ or Cimicifuga/ or 87 72 not 51 266 39 121618 Hypericum/ or Pueraria/ or Humulus/ (meta-analysis.pt. or exp technology assessment, biomedical/ or exp Evidence-Based Practice/ or exp 40 (herb* or phytotherap* or plant extract*).tw. 64864 Databases, Bibliographic/ or exp guideline/ or guideline*.ti,ot. or (((hta or health technology) adj6 (Pueraria or john* wort or johnswort or hypericum* or GYNO-plus or Agnus or cohosh* or Cimicifuga assessment*) or meta analy* or metaanaly* or meta?analy* or ((review* or search* or research) 41 4435 or bugbane* or Racemosa or Humulus).tw. 74 adj10 evidence) or ((review* or search* or research or evidence) adj10 (literature* or medical 524972 database* or systemat* or exhaustive)) or medline or pubmed or embase or cochrane or cinahl or 42 exp Vitamin D/ 44014 psychinfo or psychlit or healthstar or biosis or current conten*).tw,ot,kw. or (cochrane or evidence or (Vitamin* D or vit D or Cholecalciferol* or Hydroxycholecalciferol* or Ergocalciferol* or 43 41131 EBM or duodecim).jw.) not (comment or editorial or historical-article).pt. hydroxyvitamin D or Dihydrotachysterol).tw. 75 19 and 74 [IV secondary evidence] 129 44 or/23-43 738283 76 remove duplicates from 75 118 exp clinical trial/ or Double-Blind Method/ or (randomized or randomly or placebo or trial or groups 45 2338252 or subgroup*).ab. or trial.ti. or ((random* or controlled) adj2 study).tw.

level of evidence or ((transverse or transversal) adj3 (study or design)) or (open adj3 label)).tw. 49 or/45-48 6675678 50 19 and 44 and 49 [II intervention studies] 784

51 remove duplicates from 50 754 "diagnostic techniques and procedures"/ or diagnostic self evaluation/ or "diagnostic techniques, obstetrical and gynecological"/ or colposcopy/ or medical history taking/ or physical examination/ or 52 144418 gynecological examination/ or neurologic examination/ or self-examination/ or symptom assessment/ or Pain Measurement/ or self-assessment/ vaginal diseases/di or exp vaginitis/di or vulvovaginitis/di or vulvar diseases/di or vulvitis/di or 53 4475 atrophy/di or Atrophic Vaginitis/di or dyspareunia/di 54 health surveys/ or exp questionnaires/ or health care surveys/ or exp Interviews as Topic/ 408608 55 incidence/ or prevalence/ 350381 56 (prevalence or impact or incidence).ti. 266337 57 ((defin* or prevalen* or incidence) adj4 (vagin* or vulvovaginal or vulva* or sexual* or pain or itching 16926

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Assessment of vaginal atrophy

(Vivelle or Estrace or Aerodiol or Estraderm or Ovocyclin or hydroxyestriol or Menorest or VAGIFEM or atroph*)).tw,ot,kw. 26 834 or Estring or Promestriene or Cenestin or SCE-A or Ortho-Gynest or Premarin or Synapause).tw. 58 (cl or st).fs. 998834 Estrogen Receptor Modulators/ or Selective Estrogen Receptor Modulators/ or Raloxifene/ or 27 7558 59 ((vaginal or vulvovaginal or vulva* or karyopy?not*) adj2 (index* or indices)).tw,ot,kw. 224 Receptors, Estrogen/ai 60 ((vagin* or vulvovagin* or vulva* or dryness or VVA) adj4 (symptom* or sign or signs)).tw,ot,kw. 2514 28 (SERM or SERMs or TSEC or SMART).tw. 8871 ((Vaginal dryness or vaginal health* or symptom* or atroph*) adj3 (rated or rating or scor* or scale* 61 44229 29 (raloxifene or ospemifene or lasofoxifene or CP-336156 or FC-1271a).tw. 2930 or severity or survey* or insight)).tw,ot,kw. 30 (antiestrogen* or antioestrogen*).tw. 7181 62 (vagina* adj2 matur* adj2 (value or values or index* or indices or scor*)).tw,ot,kw. 81 31 exp Testosterone Congeners/ 76614 63 ((vaginal or vulvovaginal or vulva*) adj cytol*).tw,ot,kw. 1164 (DHEA or DHA or DHEAs or dehydroepiandrosterone or prasterone or androstenolone or androsten 32 121021 64 vagina/pa or vagina/de 4114 or testosteron* or androgen*).tw. 65 colposcop*.tw,ot,kw. 6622 Administration, Intravaginal/ or "Vaginal Creams, Foams, and Jellies"/ or Pessaries/ or Contraceptive 33 6556 66 (pH or KPI or VSS or VHI or PFSF or VMI or VMV or VIVA or GHCE).tw,kw,ot. 329080 Devices, Female/ 67 (symptom* adj1 scor*).tw. 12992 ((vagina* or intravagina* or vulvovag*) adj4 (cream* or tablet* or jell* or gel or gels or foam* or 34 lubricant* or douche* or moisturizer* or ring or rings or pessar* or suppositor* or caspule* or 8915 68 self-report*.tw,ot,kw. 84651 depot* or administrat* or treat* or therap*)).tw. 69 (((visual or point* or analog* or item* or atroph* or climacter*) adj4 scale*) or VAS).tw. 72502 35 Hyaluronic Acid/ 15453 70 or/52-69 2357852 36 (hyaluron* or replens).tw. 24277 71 70 and 19 [III definition, diagnosis, incidence, symptoms, measurement instruments] 771 37 exp soybeans/ or exp isoflavones/ 31638 72 remove duplicates from 71 743 38 (genistein* or soy* or isoflav* or iso-flav* or Pueraria or daidzein).tw. 49437 86 51 or 72 1020 Phytotherapy/ or Plant Extracts/ or Plants, Medicinal/ or Herbal Medicine/ or Cimicifuga/ or 87 72 not 51 266 39 121618 Hypericum/ or Pueraria/ or Humulus/ (meta-analysis.pt. or exp technology assessment, biomedical/ or exp Evidence-Based Practice/ or exp 40 (herb* or phytotherap* or plant extract*).tw. 64864 Databases, Bibliographic/ or exp guideline/ or guideline*.ti,ot. or (((hta or health technology) adj6 (Pueraria or john* wort or johnswort or hypericum* or GYNO-plus or Agnus or cohosh* or Cimicifuga assessment*) or meta analy* or metaanaly* or meta?analy* or ((review* or search* or research) 41 4435 05 or bugbane* or Racemosa or Humulus).tw. 74 adj10 evidence) or ((review* or search* or research or evidence) adj10 (literature* or medical 524972 database* or systemat* or exhaustive)) or medline or pubmed or embase or cochrane or cinahl or 42 exp Vitamin D/ 44014 psychinfo or psychlit or healthstar or biosis or current conten*).tw,ot,kw. or (cochrane or evidence or (Vitamin* D or vit D or Cholecalciferol* or Hydroxycholecalciferol* or Ergocalciferol* or 43 41131 EBM or duodecim).jw.) not (comment or editorial or historical-article).pt. hydroxyvitamin D or Dihydrotachysterol).tw. 75 19 and 74 [IV secondary evidence] 129 44 or/23-43 738283 76 remove duplicates from 75 118 exp clinical trial/ or Double-Blind Method/ or (randomized or randomly or placebo or trial or groups 45 2338252 or subgroup*).ab. or trial.ti. or ((random* or controlled) adj2 study).tw.

46 (ad or dt).fs. 2419078 47 exp cohort studies/ or cross-sectional studies/ or case-control studies/ or comparative study/ 3037518 (cohort* or cross-sectional or crosssectional or case-control* or prospectiv* or retrospectiv* or 48 longitudinal* or observational or epidemiologic* or descriptive or follow-up or population-based or 1919136 level of evidence or ((transverse or transversal) adj3 (study or design)) or (open adj3 label)).tw. 49 or/45-48 6675678 50 19 and 44 and 49 [II intervention studies] 784

111

503427-L-sub01-bw-Weber Chapter 5 Urgency

Frequency

Vaginal burning 9 (6.5) 5 (7.1) 10 (7.3) 5 (7.5)

Vaginal bleeding 0 (0.0) 0 (0.0) 1 (0.4) 0 (0.0)

Dysuria 0 (0.0) 0 (0.0) 0 (0.0)

Dyspareunia 12 (57.2) 9 (42.8) 120 (55.3) 125 (58.7) 45 (42.9) 7 (16.3) 7 (16.7) 9 (25.0) 88 (63.8) 33 (47.1) 83 (60.6) 86 (31.3) 107 (52.2) 62 (59.6) 13 (61.9) 7 (33.3) 40 (40.4) 37 (55.2)

Vaginal irritation / Itching 13 (61.9) 7 (33.3) 13 (61.9) 29 (13.3) 24 (11.3) 17 (16.2) 1 (2.3) 2 (4.8) 6 (16.7) 7 (5.1) 11 (15.7) 12 (8.8) 45 (16.4) 7 (33.3) 14 (14.1) 9 (13.4)

Vaginal soreness 10 (47.6) 10 (47.6) 12 (57.3) 8 (38.9) 11 (4.0)

Vaginal dryness 9 (42.8) 12 (57.2) 13 (61.9) 8 (38.1) 68 (31.3) 64 (30.1) 43 (41.0) 45 (45.5) 35 (81.4) 33 (78.6) 21 (58.3) 34 (24.6) 21 (30.0) 32 (23.4) 16 (23.9) 132 (48.0) 58 (28.3) 27 (26.0)

Prevalence of symptoms associated with VA at baseline

)

Moderate Severe Moderate Severe Group I: 25 microgr estradiol II: 5 mg hyaluronic acid BZA20/CE0.45mg (n=217) BZA20/CE0.625mg (n=213 BZA20 mg (n=105) Placebo (n=99) E2/LNG (n=43) E2 (n=42) Placebo (n=36) CE cream 21/7 (n=143) Placebo 21/7 (n=72) CE cream 2x/wk (n=140) Placebo 2x/wk (n=68) E2 10 microgr (n=205) Placebo (n=104)

N 42 634 121 423 275 309

(29)

Electronic Supplementary Material (ESM) Study Ekin et al. 2011 Kagan et al. 2010 (31) Bachmann et al. 2009 (51) Bachmann et al. 2009 (27) Freedman et al. 2009 (30) Simon et al. 2008

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Assessment of vaginal atrophy 102 (45.9) 70 (53.4) 31 (49.2)

54 (48.6) 53 (48.6) 60 (57.1)

56 (25.2) 20 (15.3) 13 (20.6) 11 (8.8) 11 (8.9)

38 (86.3) 37 (84.1) 19 (17.1) 24 (22.0) 25 (23.8) 156 (70.3) 19 (63.3) 68 (51.9) 37 (58.7) 35 (28.0) 40 (32.5) 7 (18.4) 3 (7.9) 75 (72.8) 3 (7.9) 4 (10.5)

(10.8) 4 35 (31.5) 29 (26.6) 32 (30.5) 108 (48.6) 14 (46.7) (irritation) 18 (60.0) 55 (42.0) 30 (47.6) 19 (15.2) 15 (12.2) 5 (13.5) 3 (8.1) 5 (13.5) (itching)

4 (3.2) 3 (2.4)

44 (100) 44 (100) 58 (52.3) 70 (64.2) 60 (57.1) 214 (96.4) 28 (93.3) 131 (100) 63 (100) 56 (44.8) 54 (43.9) 103 (100)

intravaginal (n=44)

severe severe moderate moderate B (n=125) - VR 50 microgr (n=111) VR 100microgr(n=109) - -

- - - - Estriol Control (n=44) E2 E2 Placebo (n=105) Hyaluronic acid Estring (n=131) Premarin (n=63) SCE Placebo (n=123) Dienoestrol Replens I: Estriol ovules + pelvic floor

94 88 333 222 30 1 248 39 206

(20) (49)

(48) Dessole et al. 2004 (35) Speroff 2003 Smith et al 1993 Karaosma noglu et al. 2011 (65) Ayton et al. 1996 (61) Simon et al. 2008 (19) Bygdeman et al. 1996 (62) Capobianc

113

503427-L-sub01-bw-Weber

Chapter 5 49 (75.3) 30 (71) 35 (65)

27 (24.1)**** 14 (26.4) 79.2%

410 (52.3)** 48 (42.1) 18 (34) 9 (25.7) 4 (11.4) 14% 83.3% 361 (49.2)**

6 (4.8) 10 (8.1)

12 (18.5) 20 (48) 8 (15)

4.5)

65 (63.1) 49 (26.0)*** 110 (58.1)*** 361 (46.1) 298 (40.6) 23 (35.4) 101 (90.2)**** 48 (90.6) 7 (20.0) 12 (34.3) 55 (44.0) 67 (5 23 (55) 18 (33) 42% 43% 19% 87.5%

(52.3)

57 (26.4) 13 (6.0) 410 361 (49.2) 20 (31.1) 55 (48.2) 29 (54.7) 9 (25.7) 4 (11.4) 47 (37.6) 49 (39.8) 28 (67) 12 (22) 26% 33% 18%

45 (39.5) 44 (35.8) 28 (67) 17 (31) 27% 29% 10%

103 (100) 118 (54.6) 48 (22.2) 560 (71.5) 504 (68.7) 44 (67.6) 114 (100) 53 (100) 9 (25.7) 16 (45.7) 114 (91.2) 110 (89.4) 83% 36% 12% 100%

tablet

inal B (n=125) - rehabilitation (n=103) II: Estriol ovules (n=103) Moderate Severe Vaginal ERT (n=783) Placebo (n=734) Estring Placebo ring Control Estriol vaginal gel (n=114) Placebo gel (n=53) Moderate Severe SCE Placebo (n=123) UK (n=42) Sweden (n=54) Moderate Severe E2 vag

216 1517 65 167 35 248 96 1548* 1761* 53*

(34) (75)

(70) (59) (93) (94)

o et al. 2012 Labrie et al. 2009 (56) Simunic et al. 2003 (66) Karp et al. (23) Cano et al. (74) Yumru et al. Ettinger et al. McKenna et al. Nappi et al. Van Geelen et al. Manonai

114

503427-L-sub01-bw-Weber Assessment of vaginal atrophy

51% 38.3% 47.2% 59% 53% 49%

83.3% 52.8% 50.0% 56.9% 70.0%

79.2% 46.3%* 38.6%* 13.3%

46% 1%

79.2% 76% 84.2% 68.4% 86% 88% 42.5% 45.8% 46% 17.2% 56.9% 45.0% 10% 05

52.8% 47.2% 56% 64% 46.3% 38.6% 13% 6.9%

100% 98% 58.3% 55.6% 100% 100% 70.0% 65.1% 39% 60.8% 70.6% 80.0% 24%

(n=51) .03 mg

rich diet - VR (n=101) - Conjugated estrogen cream Estring Soy Control diet E2 Pessary (n=45) Vagifem (n=75) Placebo (n=79) Ospemifene 30mg Ospemifene 60mg Placebo Pessary estriol 0.2mg Pessary estriol 0 Placebo Pueraria mirifica Placebo (n=20) Tibolone 1.25 mg Tibolone 2.5 mg Placebo

136* 36* 146* 164* 826* 436* 71* 396*

(44) (43)

et al. 2001 (47) Henriksso n et al. 1996 Manonai et al. 2006 (36) Henriksso n et al. 1994 Eriksen et al. 1992 (64) Bachmann et al. 2010 (28) Griesser et al. 2012 (25) Manonai et al. 2007 (54) Swanson et al. 2006 (68)

115

503427-L-sub01-bw-Weber Chapter 5

13% 20%

16% 29% ; ERT, estrogen replacement therapy replacement estrogen ERT, ;

8% 15% 5.2%

Synthetic Conjugated Estrogens B Estrogens Conjugated Synthetic B, 71% 78% -

11% (itching) 40% 29% 56% 18.6% (irritation) (itching) (irritation) vaginal ring; SCE ring; vaginal -

21% 42% VR, estradiol -

79% 85% 27.0%

ning 57 yrs (n=41) - ≥ 58 yrs (n=38) 35

combined with bur with combined

79* 98,705*

(92) (95)

** Itching reported reported Itching ** Minkin et al. Pastore et al. alone percentage or (%) patients of number are Numbers E2 estradiol; E2, estrogens; conjugated CE, bazedoxifene; BZA, reported symptomnot per patients of number Exact * baseline at activity sexual no womenreported 28 *** women2 in missing symptomwas this on Information ****

116

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