Int Urogynecol J (2015) 26:15–28 DOI 10.1007/s00192-014-2464-0

REVIEW ARTICLE

Assessment of vaginal atrophy: a review M. A. Weber & J. Limpens & J. P. W. R. Roovers

Received: 31 March 2014 / Accepted: 19 June 2014 / Published online: 22 July 2014 # The International Urogynecological Association 2014

Abstract Introduction and hypothesis The aim of this study is to provide an evidence-based definition of vaginal atrophy (VA) and present an overview of subjective and objective measurements of VA applicable in clinical practice and research. Methods A systematic literature search was performed in MEDLINE and EMBASE to identify studies reporting on measurement properties of diagnostic instruments for VA. Additional searches in MEDLINE aimed to document the definitions, diagnostic criteria, and outcome measures of VA. Studies reporting on definitions, diagnosis, outcome measurements, and measurement properties of diagnostic instruments of VA were selected. Results Specific symptoms for VA that were consistently described could be identified to suggest an evidence-based definition of VA. As subjective outcome measurements, seven scoring systems to assess the signs of VA during physical examination were identified. The most bothersome symptom (MBS) approach is most useful in clinical practice and research as it focuses on the most common symptoms of VA. As objective outcome measurements, numerous ways to assess vaginal cytology and vaginal pH were identified. Conclusions At the moment, there is no consensus on the definition and assessment of VA. We propose to define VA as a common manifestation of estrogen decline associated with Electronic supplementary material The online version of this article (doi:10.1007/s00192-014-2464-0) contains supplementary material, which is available to authorized users. M. A. Weber (*) : J. P. W. R. Roovers Department of Obstetrics and Gynecology, Academic Medical Center, H4.232, P.O. Box 22660, 1100 DD Amsterdam, The Netherlands e-mail: [email protected] J. Limpens Medical Library, Academic Medical Center, Amsterdam, The Netherlands

specific symptoms of which the most common are: vaginal dryness, itching or irritation, and dyspareunia. In both clinical and research settings, subjective assessment (the MBS approach) and objective assessments of VA (measurement of vaginal maturation index and vaginal pH) should be combined. Keywords Definition . Diagnosis . Objective . Subjective . Symptoms . Vaginal atrophy

Introduction Vaginal atrophy (VA) is a condition that commonly affects postmenopausal women [1, 2]. Consensus on the most accepted definition of VA is lacking. It is estimated that up to 40 % of postmenopausal women experience symptoms of VA [1–3]. As life expectancy in many countries will further increase and exceeds 80 years, women can experience a postmenopausal state up to one third of their lives having a marked impact on, e.g., sexual functioning, everyday activities, and body image [2, 4]. The etiology of VA is mainly explained by the decline in levels of circulating estrogen associated with the natural aging process and the menopausal transition, which causes a breakdown of the collagen and elastin fibers in the vagina [1, 5–7]. The result is an overall loss of vaginal elasticity, the vagina loses its rugae, and there is a shortening and narrowing of the vagina. The epithelium of the vagina becomes thin and pale [5]. In premenopausal women, declining estrogen levels are iatrogenic, either related to cancer treatment (radiation therapy, chemotherapy), drug use (antiestrogen medications, e.g., tamoxifen), surgery (oophorectomy), or postpartum due to the loss of placental estrogen and the antagonistic action of prolactin on estrogen production during lactation [1]. Characteristics to objectify the presence of VA are either subjective (like symptoms presented by the patient or the

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clinical judgement by the practitioner) or objective (like histological or physiological tests). Concerning subjective measures to quantify VA, there is a problem related to 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 compromised and patient guidance in choosing the preferred treatment option might be inadequate. In this review we provide an overview of existing subjective and objective measurements of VA and their clinical relevance. In the discussion we will provide recommendations on the measurements that are most useful in clinical practice and research.

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Study selection A study was included if it was an original article concerning VA. Studies reporting on definitions, diagnosis, and outcome measurements were identified and subjectively selected.

Results Definition of vaginal atrophy Table 1 shows the diversity of definitions given for VA found in the reviewed articles. As shown in this table, similarity exists between the definitions of VA and atrophic vaginitis. Based on review of the literature, atrophic vaginitis should be taken into account in case signs of inflammation are present [11–13, 37]. These signs (including red labia minora, vaginal walls, urethral meatus, or a caruncle) differ from atrophic signs [15, 21] and are not described in this review. To further tease out the definition of VA we need to know which subjective and objective measurements are available to be taken into account in this definition.

Methods

Objective assessment of vaginal atrophy

Search strategy

Vaginal cytology

A medical librarian (J.L.) undertook a systematic search of MEDLINE (Ovid) from 1948 till September 2013, using free text words and subject headings (MeSH). The search consisted of four parts (see Appendix 1 for the MEDLINE search). The basis of the search was a broad search for VA. In part I VA was combined with a search filter to identify studies reporting on measurement properties of outcome measures for VA. To ensure comprehensiveness, this part of the search was also performed in EMBASE (Ovid, from 1947). This search filter was an adaptation of the filter validated for PubMed [10]. Parts II–IV aimed to document the outcome measures, diagnosis, and definitions used in VA. In part II we combined VA with an exhaustive number of interventions and a methodological filter for clinical trials and observational studies. In part III we combined the VA search with terms for diagnosis, incidence, and symptoms. In part IV VA was combined with a filter for secondary evidence (as a means to check whether all primary studies had been found in the previous searches). The search included an iterative process to refine the search strategy through adding search terms as new relevant citations were identified [i.e., by checking reference lists and citations (via Web of Science) of relevant papers]. No language restrictions were applied. All identified references were downloaded and imported into Reference Manager® software (version 12.0) to deduplicate, store, and analyze the search results.

Cytomorphologically, VA can be defined as a condition with high numbers of (para) basal and intermediate cells and very low numbers of superficial cells [38]. When estrogen levels decrease in women, squamous epithelial maturation to superficial squamous cells decreases, and with prolonged lowestrogen states, the epithelium ceases to produce superficial and intermediate squamous cells, leaving only parabasal and basal cells lining the vaginal wall. Capewell and coworkers [21], who graded VA on a smear from none to severe based on the amount of the different cell types present, attempted to correlate subjective 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 VA using vaginal cytology: Vaginal maturation index and vaginal maturation value The vaginal maturation index (VMI) represents the percentage of parabasal, intermediate, and superficial squamous cells appearing on a vaginal smear [39]. The VMI specimen consists of freely exfoliating squamous cells from the upper one third of the vaginal wall, gently scraped with a spatula [40]. The index is read from left to right, for example, a VMI of

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Table 1 Examples of definitions of VA and/or atrophic vaginitis Study

Definition of VA/atrophic vaginitis

Chollet et al. (2009) [11]; Castelo-Branco et al. (2005) [12] Brenner et al. (1988) [13]

Atrophic vaginitis is defined as inflammation of the vaginal epithelium due to atrophy secondary to decreased levels of circulating estrogen Atrophic vaginitis, with attendant inflammation, ulceration, and bleeding of the vaginal mucosa, can result from marked atrophy of the lining of the vagina The term “vaginitis” describes a spectrum of vaginal conditions that cause uncomfortable vaginal symptoms Atrophic vaginitis is used clinically to refer to several conditions: atrophic signs on physical examination, cytologically determined atrophy, and presence of vaginal symptoms Atrophic vaginitis: the result of the loss of estrogen-dependent cellular maturation Atrophic vaginitis is the main cause of vaginal discomfort among postmenopausal women and results from declining estradiol levels Atrophic vaginitis is a common and often untreated condition of urogenital aging in postmenopausal women

Nyirjesy et al. (2012) [14] Greendale et al. (1999) [15]

Bachmann et al. (2008) [16] Karaosmanoglu et al. (2011) [17] Rioux et al. (2000) [18] Lynch (2009) [19]

Stika (2010) [5]

Crothers et al. (2012) [20]

Capewell et al. (1992) [21] Yildirim et al. (2004) [22] Hummelen et al. (2011) [23]

Palacios et al. (2005) [24] Bachmann et al. (2010) [25] Bygdeman and Swahn (1996) [26]

Manonai et al. (2007) [27] Simunić et al. (2003) [28]

Rane et al. (2000) [29]

Nappi and Kokot-Kierepa (2010) [3]

Simon et al. (2008) [31]

Atrophic vaginitis is a common condition postmenopausal women experience due to estrogen deficiency that causes involution of the vaginal tissue, leading to itching, burning, dryness, irritation, and dyspareunia The term atrophic vaginitis has sometimes been restricted to the development of an inflammatory vaginal discharge associated with the overgrowth of genital pathogens after the loss of lactobacilli dominance and the associated protective acidic environment; more commonly, atrophic vaginitis is applied to a spectrum of symptoms Cytological criteria for atrophy: predominately parabasal and basal cells, with few or no superficial or intermediate squamous cells, background debris from cellular degeneration, nuclear pyknosis, cellular apoptosis, possibly histiocytes and giant cells Atrophic vaginitis is atrophy with inflammation Mucosal atrophy of the vagina reflects a fall in blood estrogen levels and is sometimes associated with vaginal symptoms and a variety of physical features VA: a deficient maturation of vaginal mucosa Vulvovaginal atrophy (VVA) is somewhat of a catchment term for several symptoms and is diagnosed by an assessment of vaginal dryness, irritation, soreness, and dyspareunia with urinary frequency, urgency, incontinence, and the presence of pale and dry vulvovaginal mucosa with petechiae, along with pH >4.6 Genital atrophy, a manifestation of estrogen withdrawal after menopause, accompanied by vaginal or urinary symptoms or both VVA is a highly prevalent, bothersome condition associated with declining estrogen levels during perimenopause and postmenopause VVA is secondary to progressive decrease in ovarian secretion of estradiol; it is clinically manifested as a syndrome consisting mainly of vaginal dryness, itching, irritation, and dyspareunia Atrophic changes in the urogenital tract are the manifestations of estrogen deprivation in postmenopausal women Urogenital aging is a complex cascade of symptoms involving the lower urinary tract, genital tract, and the pelvic floor caused by hypoestrogenism in postmenopausal women Urogenital atrophy criteria: grade 1: vaginal dryness, vaginal pallor, thin shiny mucosa; grade 2: grade 1+urethral caruncle, labial thinning, and retraction; grade 3: grade 2+labial fusion, bleeding on contact, gross contracture of the urogenital hiatus VA refers to “vaginal discomfort” and is defined as dryness, smarting pain, itching, involuntary urination, or pain in the vagina in connection with touching and/or intercourse VA: the loss of estrogen-dependent cellular maturation in the vagina

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Table 1 (continued) Study

Definition of VA/atrophic vaginitis

Chollet (2011) [32]

Introduction: VVA is a thinning of the epithelium secondary to decreased levels of circulating estrogen Abstract: VVA is defined as inflammation of the vaginal epithelium due to atrophy secondary to decreased levels of circulating estrogen VA is a frequent condition in postmenopausal women, associated with vaginal or urinary symptoms or both VA is a common manifestation of estrogen deprivation after menopause VA is defined by a thinning of the vaginal mucosa that occurs as a consequence of the decline in endogenous estrogen production that characterizes menopause; the anatomopathological basis of VA is a change in the cellular composition of the vaginal epithelium VA is a consequence of the hypoestrogenic state and resulting anatomical and physiological changes in the genitourinary tract

Le Donne et al. (2011) [33] Al-Baghdadiand Ewies (2009) [34] Cano et al. (2012) [35]

Minkin et al. (2013) [36]

0/30/70 represents 0 % parabasal cells, 30 % intermediate cells, and 70 % superficial cells. A shift to the left indicates an increase in the parabasal or intermediate cells, while a shift to the right reflects an increase in the superficial or intermediate cells. In this example, the VMI describes the proportion of parabasal, intermediate, and superficial cells. In a formula the different cell types can be multiplied by certain factors to obtain the vaginal maturation value (VMV). However, when reviewing the literature, these two terms (VMI and VMV) are frequently used inconsistently and calculated in different ways. Table 2 gives several examples of ways to calculate VMI or VMV. Consensus about the best formula is lacking

and the variety in calculations compromises comparison between studies. The measurement of VMI or VMV is an inexpensive way to evaluate hormonal influences in women. It is often used as an outcome measure to evaluate the effect of hormone therapies on VA. According to the formulas mentioned in Table 2, a lower value indicates fewer superficial cells which is indicative of absent or very low estrogen levels. In several studies, a cutoff value is used to define this low estrogen level or the presence of VA. For example, Speroff [44] defined VA, in a study of the efficacy of an estradiol vaginal ring, at baseline as a maturation index score of 52 or less. Pinkerton and

Table 2 Different formulas used to calculate VMV/VMI Formula

VMV/VMI

Study

0.2 × % parabasal cells+0.6 × % intermediate cells+1.0 × % superficial cells

VMV

Barentsen et al. (1997) [41]; Casper and Petri (1999) [42]; Henriksson et al. (1996) [43]; Cano et al. (2012) [35]

VMI

Speroff (2003) [44]; Henriksson et al. (1994) [45]; Ayton et al. (1996) [46]; Lee et al. (2011) [47]; Zeyneloglu et al. (2007) [48]; Speroff et al. (2006) [49]; Utian et al. (2005) [50]

VMV

Ekin et al. (2011) [51]; Simon et al. (2008) [31]; Bachmann et al. (2008) [16]; Pinkerton et al. (2003) [52]; Manonai et al. (2007) [27]; Meisels (1967) [53]

VMI

Raghunandan et al. (2010) [54]; Freedman et al. (2009) [55]; Manonai et al. (2006) [56]; Simon et al. (2008) [40]; Griesser et al. (2012) [57]; Simon et al. (2007) [58]

VMV

Davila et al. (2003) [59]; Karp et al. (2012) [60]

VMI

Yildirim et al. (2004) [22]; Barentsen et al. (1997) [41]; Henriksson et al. (1994) [45]; Smith et al. (1993) [61]; Ayton et al. (1996) [46]; Henriksson et al. (1996) [43]

VMI

Le Donne et al. (2011) [33]; Nilsson et al. (1995) [62]

Maturation proportion

Yumru et al. (2009) [63]

0 × % parabasal cells+0.5 × % intermediate cells+1.0 × % superficial cells

0 × % parabasal cells+0.5 × % intermediate cells+1.0 × % superficial cells divided by 2 Number or proportion of parabasal, intermediate, and superficial cells out of 100 calculated cells Percentage of parabasal, intermediate, and superficial cells out of 200 calculated cells (1.0 × % superficial cells) ± [(0.5 × % intermediate cells)+(0.5 × % parabasal cells)]

VMV vaginal maturation value, VMI vaginal maturation index

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coworkers [52], 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 less. Benjamin and Deutsch [64] described an atrophic smear as a maturation value of less than 40 %. The VMI or VMV can also be used as a qualitative indicator of estrogenic effect on the vaginal epithelium, with 0–49 reflecting little or no estrogenic effect, 50–64 a moderate estrogenic effect, and 65–100 a highly estrogen dominant environment [59, 60]. However, studies validating these values are lacking. Besides for evaluation purposes, the VMI or VMVare used as part of the inclusion criteria for participation in a study concerning VA. For this purpose, the cutoff values differ between studies as well, varying between a VMI of less than 55 in the study of Chollet and coworkers [11] to less than 40 in the study of Griesser and coworkers [57]. Another often mentioned cutoff value is the presence of less than 5 % superficial cells [8, 16, 25, 30, 51, 55, 65] or the presence of more than 75 % parabasal cells [62]. There are several factors that can influence the maturation index. Besides patient influences like cigarette smoking, a body mass index above the 90th percentile, or a diastolic blood pressure of more than 100 mmHg (all causing a shift to the right), there are also collection considerations like the influence of delayed fixing and air-drying, ectocervical, endocervical, or endometrial cell contamination, or a smear that is too thick [39]. Besides these factors, the classification of the individual cells, performed manually, is subject to intraand interobserver variations [38]. Davila and coworkers [59] assessed the correlation between symptoms and maturation value which showed that VA symptom scores (including vaginal dryness, soreness, irritation, dyspareunia, and vaginal discharge) were not correlated with maturation value. There was a moderate negative correlation between vaginal health score (consisting of assessment of vaginal secretions, epithelial integrity, surface thickness, color, and pH) and maturation value, indicating that maturation values were lower in subjects with greater degrees of atrophy. Greendale and coworkers [15] showed that findings of conization (i.e., markedly decreased elasticity), absent rugae, petechiae, and friability of the vaginal wall were statistically significantly associated with low maturation index. Karyopyknotic index The karyopyknotic index (KI) is described as measuring the relationship of superficial cells to intermediate cells [66], but also as the percentage of superficial cells found in the total population of the squamous cells examined [56, 67, 68]. The KI is considered a reliable cellular index for the determination of estrogen activity [69, 70] but is less often used than VMI or VMV. Benjamin and Deutsch [64] described an atrophic smear as a KI of less than 10 %.

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In a study of factors influencing the vaginal milieu, KI was influenced by several patient characteristics also mentioned for the VMI or VMV, like a body mass index above the 90th percentile or a diastolic blood pressure of more than 100 mmHg (both causing a higher KI value). In the same study, vaginal cytology measured as KI, vaginal pH, and the presence of lactobacilli correlated well [71]. Vaginal pH The underlying mechanism of vaginal pH changes associated with VA consists of estrogen stimulating the production of glycogen, which is broken down to glucose. In a premenopausal vagina, an estrogen-rich environment, lactobacilli convert epithelial glycogen into lactic acid, which maintains the vaginal pH between 3.5 and 4.5 [5]. With thinning of the vaginal epithelium in menopause, fewer squamous cells are sloughed into the vaginal secretions, and those that are have reduced glycogen content. As vaginal glycogen levels fall, the population of lactobacilli decreases, and the vaginal pH increases [5, 6]. Measurement of the vaginal pH is considered useful, effective, and inexpensive [72]. Studies have shown that a vaginal pH greater than 5.0 is associated with decreased serum estradiol and menopause [72, 73]. The vaginal pH can be measured in different ways. Most studies describe the use of a pH indicator strip [30, 31, 41, 43, 45, 47, 48, 51, 60–62, 67, 68, 74, 75], for example, with intervals on a 4-point scale [31, 51] or with a pH interval of 4.0–7.0 in 14 steps [57, 61] or a range of 4.0–7.5 in intervals of 0.5 [60]. Others describe it as pH paper [40, 52, 59, 76], e.g., Nitrazine paper (pH range 4.5–7.5) [15, 72] or hydrion pH paper (range 4–9) [77]. Vaginal pH is often measured as part of the vaginal health evaluation as described further ahead [16, 27, 31, 47, 54, 56, 78]. There are several locations described for measurement of the vaginal pH, e.g., the lateral vaginal wall [30, 40, 59, 79], the wall of the proximal third of the vaginal vault [41, 43], or at the introitus [48] or midvagina [60]. Testing of the vaginal pH from the lateral vaginal wall has been correlated with vaginal cytology and histology as an appropriate and objective measure for assessment of the vaginal epithelium and for monitoring the effect of estrogen treatment in VA [62]. Brizzolara and coworkers [80] concluded in their study to determine the vaginal pH level that correlates with elevated parabasal cells that a vaginal pH above 6.0 correlates with high levels of parabasal cells (20 % or more) from the midvagina. This technique has been validated [15, 80]; however, consensus on the type of pH paper or 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 (besides VMI/VMV as mentioned before) for participation in studies concerning VA. For this

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purpose, the cutoff value is often set at 5, meaning patients with a pH value of 5 or more can be included in the study [11, 25, 31, 40, 55, 57, 58, 65, 74]. This is also the cutoff value recommended by the FDA [8]. The pH values can be grouped, for example, as pH less than 5.0, pH 5–5.49, pH 5.5–6.49, and pH more than 6.49 with a clinical meaning that pH less than 5.0 could be indicative of a lack of VA, pH 5–5.49 of a mild VA, pH 5.5–6.49 of a moderate atrophy, and a pH more than 6.5 could indicate severe atrophy [31]. Again, validation of these cutoff values is not available. Vaginal pH can be elevated by bacterial vaginosis, blood, cervical mucus, semen, vaginal medications, and vaginal douches [72] and lowered by smoking [71]. Subjective assessment of vaginal atrophy Symptoms Figure 1 shows the prevalence of the different symptoms associated with VA based on the reviewed literature that reported these symptoms. For a more detailed description of the prevalence of symptoms in the studied populations at baseline, we refer to the table in the Electronic Supplementary Material (ESM). As shown in this table, studies of VA are lacking uniformity in symptom evaluation. For this reason, the FDA proposed a new 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 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 then must select a single symptom among those classified as moderate or severe as the MBS. The MBS is then followed through to the end of treatment, and the change in its severity is used to evaluate symptomatic improvement. Up till now we have found 13 published studies that have reported change in MBS [25, 30, 31, 40, 55, 57, 58, 65, 74, 76, 79, 81, 82]. Ettinger and coworkers [81] discussed that use of the MBS construct is appealing because it examines each 100

Frequency of reporting

90 80

Dryness

70

Soreness

60

Itching/irritation

50

Dyspareunia

40

Dysuria

30

Bleeding

20

Burning

10

Frequency

0

Urgency 0

20

40

60

80

symptom individually and also requires the symptoms under examination to be at least moderate in severity. It is suspected that the response in MBS may be the best reflection of treatment benefit in women who encounter bothersome symptoms. Other studies have reported the change of symptom severity for individual symptoms [17, 26–28, 41, 43–46, 48–50, 56, 61, 63, 67, 68, 75, 77, 83–85] or have employed a composite score of several symptoms, weighted for severity [16, 22, 24, 33, 35, 51, 52, 54, 59, 78]. A number of self-report instruments or questionnaires that measure menopausal symptoms and sexual well-being exist in the literature. Most of these instruments address a wide array of menopausal issues, allowing only two to four items for urogenital symptoms. McKenna and coworkers were the first to develop a urogenital atrophy-specific quality of life instrument (UGAQoL) [86]. This instrument takes into account symptoms of vaginal soreness, itching, discharge, dysuria, dyspareunia, urine loss, and urge episodes. However, as they advise themselves, the responsiveness of the instrument to changes in quality of life needs to be tested prior to its use in clinical trials and for monitoring individual cases. Lester and coworkers developed the Urogenital Atrophy Questionnaire (UAQ) to allow women to self-report urological (i.e., dysuria, incontinence, urgency), genital (i.e., vaginal dryness, itching, discharge), and sexual symptoms (i.e., dyspareunia, desire and/or interest in sexual activity, vaginal bleeding after sexual activity) [87]. The UAQ consists of 45 items that describe potential symptoms related to pain/discomfort, function, satisfaction, and urogenital quality of life from the urinary, genital, and sexual domains and was tested in women with and without breast cancer. Physical examination VA is often subjectively assessed by visually evaluating the appearance of the vaginal epithelium. Physical signs of VA most often assessed in clinical studies concerning treatment of VA include the presence of pallor, petechiae, friability, and vaginal dryness [41–46, 48–50, 58, 60, 61, 67, 68, 83, 88]. By taking into account these signs, a visual assessment of the degree of VA is made (none, moderate, or severe). Other signs associated with VA include shrinkage of vaginal length and diameter [22, 63], loss of vaginal rugae [22, 40, 52, 77], presence of fissures [28], mucosal thinning [52, 77, 84], and ulceration [52]. The way to quantify these measures is often not described and reproducibility studies regarding the assessment of these signs are lacking. Most symptoms are evaluated as part of a scoring index or instrument

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Prevalence

Fig. 1 Prevalance of symptoms and frequency of reporting at baseline

Vaginal physical examination scale Greendale and coworkers [15] were the first to validate a four-item scale for the

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assessment of VA during physical examination. The physical examination signs postulated as signifying atrophy were: presence of vaginal wall petechiae, friability of the vaginal wall (defined as any bleeding occurring during examination), conization (markedly decreased elasticity), and absence of rugae. Greendale and coworkers correlated vaginal examination appearance to biological characteristics and self-reported vaginal symptoms. Findings of conization, absent rugae, petechiae, and friability of the vaginal wall constituted the atrophic domain of the vaginal examination. These physical characteristics were statistically significantly associated with two biological indices of atrophy: low maturation index and high vaginal pH. Although symptoms of vaginal dryness or itching/irritation were common in this study, they were not correlated with physical findings or these two biomarkers of atrophy. Vaginal health index (VHI) The VHI includes scoring of vaginal moisture, vaginal fluid volume, vaginal elasticity, vaginal pH, and vaginal epithelial integrity on a scale of 1 (poorest) to 5 (best) according to the methods of Robert Wood Johnson Medical School [89]. The lower the score, the greater the atrophy [12, 27, 47, 54, 56, 75, 78]. Vaginal moisture is an assessment of the appearance and spread or consistency of the secretions which coat the vagina. Vaginal elasticity is a measure of the ability of the 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 [56]. As one can imagine, these measures can differ between practitioners. For example, overall vaginal elasticity is rated as “none, poor, fair, good, or excellent,” a relatively broad response set which could be interpreted differently by individual raters. Reproducibility studies using VHI are not available. Genital health clinical evaluation (GHCE) The GHCE is a tool used to evaluate six parameters (vaginal pH, fluid secretion, epithelial mucosa, moisture, vaginal rugosity, and mucosal color) scored on a scale 1 to 4. A higher score indicates less atrophy [65, 90]. In their studies, Raymundo and coworkers [90] and Bachmann and coworkers [65] used a maximum total score of 15 to determine the presence of VA and thus patient eligibility at study entry. Again, different interpretations by individual raters can be made, making this a subjective measurement tool. Studies assessing the intra- and interobserver agreement of the GHCE are not available. Grading of vaginal health/vaginal health score For grading of vaginal health, evaluations are made regarding vaginal secretions, vaginal epithelial integrity, vaginal epithelial surface thickness, vaginal color, and vaginal pH. Grading of

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vaginal health is then used to indicate the degree of epithelial atrophy using a 4-point scoring system (no atrophy=0, mild= 1, moderate=2, and severe=3). The composite score for vaginal health, assessed by an investigator, is defined as the mean of the individual vaginal health components [16, 31, 51, 59]. Davila and coworkers summarized the magnitude of relationships between symptoms and physical examination. In their study there was a very weak correlation between VA symptom scores (consisting of vaginal dryness, soreness, irritation, dyspareunia, and vaginal discharge) and vaginal health score. A positive relationship was found between vaginal health score and age which indicated that vaginal health scores were higher (more atrophic) in older women. A moderate negative correlation between vaginal health score and maturation value indicated that maturation values were lower in subjects with greater degrees of atrophy. Global atrophy score The global atrophy score consists of the assessment and grading of six signs: loss of rugae, pallor, petechiae, mucosal thinning, dryness, and ulceration, using a descriptive assessment table and 4-point ordinal scale. The investigator global atrophy score is calculated as the sum of the six scores [52]. Without the sign of ulceration, Parsons et al. [77] called this assessment the “vaginal atrophy score.” Reproducibility studies concerning the global or VA score are not available. Urogenital atrophy criteria Rane et al. [29] decided prospectively on criteria for urogenital atrophy in their study that were as follows: grade 1: vaginal dryness, vaginal pallor, thin shiny mucosa; grade 2: grade 1+urethral caruncle, labial thinning, and retraction; grade 3: grade 2+labial fusion, bleeding on contact, and gross contracture of the urogenital hiatus. As far as we know, no other researchers incorporated these grading criteria in a study on VA. Vaginal atrophy index The vaginal atrophy index (VAI) is a subjective evaluation of the degree of atrophy on the following genital dimensions: skin elasticity and turgor, pubic hair, labia minora and majora, introitus, vaginal mucosa, and vaginal depth. The lower the score, the greater the VA [91, 92]. The reliability of ratings of the VAI between the two gynecologists in the study of Leiblum and coworkers [92] was 0.77.

Discussion In this review we provide an overview of the clinical value of subjective and objective measurements of VA. There is no consensus on the definition of VA. The term is used to refer to several conditions including (1) presence of specific vaginal symptoms, (2) atrophic signs on physical examination, and (3) cytologically determined atrophy [15]. The lack of guidelines

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on how to assess VA may be the cause of the presence of three different ways to assess vaginal cytology, several techniques and proposed locations in the vagina 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 not expect to find such a wide range in symptoms and diagnostic measurements and so, our clinical review, shows the need for a clear definition of VA. At the end of this discussion we will recommend a definition of VA and which measurements are most often useful to objectify VA. Concerning our selection of articles, one could criticize that we did not perform a structured appraisal of the quality of the included publications. The main reason we decided to do so is that we aimed to provide a complete overview of available evidence. After thoroughly having studied the available literature, we realize that a structured appraisal would have been very challenging, as most studies do not meet the criteria of well-designed studies (i.e., not randomized, controlled, or blinded, small sample size). The decision to not differentiate between industryinitiated and investigator-initiated studies was well considered. Where industry-initiated studies appear to focus on objective parameters, clinician-initiated studies tend to focus on the subjective outcome. Studies taking into account subjective as well as objective outcomes are scarce and differ in the selected measurement tools which disenables correlating symptoms to measurements. There are studies showing no or a very weak correlation between symptoms and physical examination or maturation indices [59], while others show a strong association of vaginal symptoms with cytology [15, 21]. In the study of Capewell and coworkers several physical features associated with VA were not associated with cytological atrophy, while Davila and coworkers found a moderate correlation between physical examination and maturation values [21, 59]. Besides these conflicting results concerning the correlation between objective and subjective measurements of VA, there is a paucity of studies describing the intra- and interobserver agreement and validity of these measurements which hampers the selection of the best available reference test. We believe that different settings (i.e., clinical practice and research) have different needs regarding the diagnostic instruments to assess presence and severity of VA and we would like to make recommendations for the tools that should be selected. Recommendations In clinical practice, it is recommended that a subjective measurement tool be selected to provide a feasible and affordable treatment evaluation. In this setting we recommend the use of the MBS approach [8]. With the MBS

Int Urogynecol J (2015) 26:15–28

construct the FDA was the first to propose an instrument that assesses VA with a uniform symptom evaluation. The MBS approach is appealing because it is not as lengthy as the discussed questionnaires and it limits the focus to symptoms that are at least moderate in severity. When using the MBS approach, we recommend that the symptoms of vaginal dryness, itching/irritation, and dyspareunia 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 physical examination described before do not differ a lot regarding the signs that are considered for evaluation. As far as we know, the “vaginal physical examination scale” developed by Greendale and coworkers [15] is the first scale that was considered to be reproducible and valid in the assessment of VA. The physical examination signs signifying VA according to this approach are: presence of vaginal wall petechiae, friability of the vaginal wall (defined as any bleeding occurring during examination), conization (markedly decreased elasticity), and absence of rugae. We recommend that these subjective measurements be combined with one objective measure that is easy to perform, not expensive, and reliable, of which the only tool is measurement of vaginal pH. In studies, the pH value has been proven to correlate well with high levels of parabasal cells, and for that reason a higher pH value correlates with VA. According to Brizzolara et al. [80], a pH of more than 6.0 is considered to be abnormal and advocated as the cutoff value for VA. In research, objective measures should form the main assessment in the evaluation of VA and we therefore recommend measurement of the VMI or calculation of the VMV combined with the measurement of vaginal pH. Vaginal cytology allows easy measurement of the VMI (defined as the proportion of parabasal, intermediate, and superficial cells) [39] or calculation of the VMV [53] (when multiplying this proportion with a certain value); gaining consensus on which formula to use is advisable so reproducibility studies can be performed and values indicative for the presence of VA can be determined. Measurement of vaginal pH is easy to perform and correlates well with cytology, histology, and several physical characteristics and is for that reason easy to incorporate in the research setting. Again, objective measures should be combined with 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 [81]. 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

Int Urogynecol J (2015) 26:15–28

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 state that investigators could create an artificial population, by eliminating women with mild severity who might respond well and by eliminating asymptomatic women at baseline who may become symptomatic during the course of the study. However, Ettinger and colleagues showed in their further analysis of a clinical study of treatment for VA that using the MBS approach increased the effect size and allowed statistically significant treatment effects to be shown in relatively small groups when mild symptoms are excluded from the analyses and when analyses focus on symptoms that are most bothersome. Moreover, by restricting the evaluated number of symptoms to three, the problem of an underpowered study is limited. The comparability will improve when incorporation of the increasing use of the MBS approach would continue.

23

Conclusion In conclusion, we propose to define VA as a common manifestation of estrogen deficiency associated with specific symptoms of which the most common are: vaginal dryness, itching/ irritation, and dyspareunia. In both clinical and research settings, subjective and objective measurements of VA should be combined. In clinical practice, subjective assessment is the first priority and this is warranted by evaluating symptoms according to the MBS approach and signs according to the vaginal physical examination scale. In the research setting, we recommend an objective assessment of VA by combining vaginal cytology and measurement of pH. Future studies should assess the correlation between objective and subjective measurements. Objective measurement tools and symptom scoring systems should be validated and tested for reproducibility prior to applying them in clinical practice and future studies. Conflicts of interest None.

Appendix 1 Appendix 1 Database (s): Ovid MEDLINE (R) in-process & other non-indexed citations and Ovid MEDLINE (R) 1946 to present #

Searches

Results

1 2 3 4 5 6 7 8 9 10 11

Atrophy/or (atrophy or atrophies or atrophic or atrophied or atrophical).tw. genitalia, female/or vagina/or vulva/or vaginal diseases/or exp vaginitis/or vulvovaginitis/or vulvar diseases/or vulvitis/ ((urogenital or urovaginal or genito*) adj3 (signs or symptoms or scor*)).tw. dyspareunia/or d?spareunia.tw. Coitus/or (coitus or intercourse).tw. (vagina* adj3 (dry or dryness)).tw. urogenital system/or ((urogenital or urovaginal or genito*) adj3 (signs or symptoms or scor*)).tw. or/2-7 1 and 8 Atrophic Vaginitis/ ((atrophy or atrophies or atrophic or atrophied or atrophical) adj10 (vaginitis or vagina* or vulva* or vulvovagina* or urovaginal*)).tw. ((atrophy or atrophies or atrophic or atrophied or atrophical) adj5 (genital* or genito*)).tw. ((atrophy or atrophies or atrophic or atrophied or atrophical) adj10 urogenital*).tw. ((urogenit* or urovagina* or genito*) adj3 (signs or symptoms or scor*)).tw. and (menopau* or perimenopau* or postmenopau* or climacter* or periclimact* or postclimact* or maturit*).mp,jw,kw. ((maturation adj2 (indices or index)) or VVA or VMI).tw. and ((vagina* or vulvovagina* or atroph* or replacement therap* or hormone therap*) and (menopau* or perimenopau* or postmenopau* or climacter* or periclimact* or postclimact* or maturitas)).mp,jw,kw. (maturat* adj3 (vagina* or vulvovagina*)).tw. or/9–16 (animals/not humans/) or (rat or rats or mouse or mice or rodent*).ti. 17 not 18 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

90,512 51,625 712 3,080 20,480 723 4,943 76,846 1,060 9 779

12 13 14 15

16 17 18 19 20

135 183 238 134

181 1772 4,105,276 1,544 1,839,169

24

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Appendix 1 (continued) #

21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48

49 50 51 52

53

Searches 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 items) adj3 (discriminant* or convergent* or divergent*)) or agreement or precision or imprecision or (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. 19 and 20 [I clinimetrics] remove duplicates from 21 exp estrogens/or exp estriol/or exp Estradiol Congeners/or Estrogen Replacement Therapy/ (estrogen* or oestrogen* or estradiol* or oestradiol* or estriol* or oestriol* or estetrol* or oestetrol* or estrone* or oestrone* or dien?estrol).tw. (E1 or E2 or TTSE2 or E3 or E4 or CEE or EE or CE).tw. (Vivelle or Estrace or Aerodiol or Estraderm or Ovocyclin or hydroxyestriol or Menorest or VAGIFEM or Estring or Promestriene or Cenestin or SCE-A or Ortho-Gynest or Premarin or Synapause).tw. Estrogen Receptor Modulators/or Selective Estrogen Receptor Modulators/or Raloxifene/or Receptors, Estrogen/ai (SERM or SERMs or TSEC or SMART).tw. (raloxifene or ospemifene or lasofoxifene or CP-336156 or FC-1271a).tw. (antiestrogen* or antioestrogen*).tw. exp Testosterone Congeners/ (DHEA or DHA or DHEAs or dehydroepiandrosterone or prasterone or androstenolone or androsten or testosteron* or androgen*).tw. Administration, Intravaginal/or “Vaginal Creams, Foams, and Jellies”/or Pessaries/or Contraceptive Devices, Female/ ((vagina* or intravagina* or vulvovag*) adj4 (cream* or tablet* or jell* or gel or gels or foam* or lubricant* or douche* or moisturizer* or ring or rings or pessar* or suppositor* or caspule* or depot* or administrat* or treat* or therap*)).tw. Hyaluronic Acid/ (hyaluron* or replens).tw. exp soybeans/or exp isoflavones/ (genistein* or soy* or isoflav* or iso-flav* or Pueraria or daidzein).tw. Phytotherapy/or Plant Extracts/or Plants, Medicinal/or Herbal Medicine/or Cimicifuga/or Hypericum/or Pueraria/or Humulus/ (herb* or phytotherap* or plant extract*).tw. (Pueraria or john* wort or johnswort or hypericum* or GYNO-plus or Agnus or cohosh* or Cimicifuga or bugbane* or Racemosa or Humulus).tw. exp Vitamin D/ (Vitamin* D or vit D or Cholecalciferol* or Hydroxycholecalciferol* or Ergocalciferol* or hydroxyvitamin D or Dihydrotachysterol).tw. or/23–43 exp clinical trial/or Double-Blind Method/or (randomized or randomly or placebo or trial or groups or subgroup*).ab. or trial.ti. or ((random* or controlled) adj2 study).tw. (ad or dt).fs. exp cohort studies/or cross-sectional studies/or case–control studies/or comparative study/ (cohort* or cross-sectional or crosssectional or case–control* or prospectiv* or retrospectiv* or longitudinal* or observational or epidemiologic* or descriptive or follow-up or population-based or level of evidence or ((transverse or transversal) adj3 (study or design)) or (open adj3 label)).tw. or/45–48 19 and 44 and 49 [II intervention studies] remove duplicates from 50 “diagnostic techniques and procedures”/or diagnostic self evaluation/or “diagnostic techniques, obstetrical and gynecological”/or colposcopy/or medical history taking/or physical examination/or 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 atrophy/di or Atrophic Vaginitis/di or dyspareunia/di

Results

137 135 159,216 180,202 115,968 834 7,558 8,871 2,930 7,181 76,614 121,021 6,556 8,915 15,453 24,277 31,638 49,437 121,618 64,864 4,435 44,014 41,131 738,283 2,338,252 2,419,078 3,037,518 1,919,136

6,675,678 784 754 144,418

4,475

Int Urogynecol J (2015) 26:15–28

25

Appendix 1 (continued) #

Searches

Results

54 55 56

health surveys/or exp questionnaires/or health care surveys/or exp Interviews as Topic/ incidence/or prevalence/ (prevalence or impact or incidence).ti.

408,608 350,381 266,337

57 58 59 60 61

((defin* or prevalen* or incidence) adj4 (vagin* or vulvovaginal or vulva* or sexual* or pain or itching or atroph*)).tw,ot,kw. (cl or st).fs. ((vaginal or vulvovaginal or vulva* or karyopy?not*) adj2 (index* or indices)).tw,ot,kw. ((vagin* or vulvovagin* or vulva* or dryness or VVA) adj4 (symptom* or sign or signs)).tw,ot,kw. ((Vaginal dryness or vaginal health* or symptom* or atroph*) adj3 (rated or rating or scor* or scale* or severity or survey* or insight)).tw,ot,kw. (vagina* adj2 matur* adj2 (value or values or index* or indices or scor*)).tw,ot,kw. ((vaginal or vulvovaginal or vulva*) adj cytol*).tw,ot,kw. vagina/pa or vagina/de colposcop*.tw,ot,kw. (pH or KPI or VSS or VHI or PFSF or VMI or VMV or VIVA or GHCE).tw,kw,ot. (symptom* adj1 scor*).tw.

16,926 998,834 224 2,514 44,229

self-report*.tw,ot,kw. (((visual or point* or analog* or item* or atroph* or climacter*) adj4 scale*) or VAS).tw. or/52–69 70 and 19 [III definition, diagnosis, incidence, symptoms, measurement instruments] remove duplicates from 71 51 or 72 72 not 51 (meta-analysis.pt. or exp technology assessment, biomedical/or exp Evidence-Based Practice/or exp Databases, Bibliographic/or exp guideline/or guideline*.ti,ot. or (((hta or health technology) adj6 assessment*) or meta analy* or metaanaly* or meta?analy* or ((review* or search* or research) adj10 evidence) or ((review* or search* or research or evidence) adj10 (literature* or medical database* or systemat* or exhaustive)) or medline or pubmed or embase or cochrane or cinahl or psychinfo or psychlit or healthstar or biosis or current conten*).tw,ot,kw. or (cochrane or evidence or EBM or duodecim).jw.) not (comment or editorial or historical-article).pt. 19 and 74 [IV secondary evidence] remove duplicates from 75

84,651 72,502 2,357,852 771 743 1,020 266 524,972

62 63 64 65 66 67 68 69 70 71 72 86 87 74

75 76

References 9. 1. Bachmann GA, Nevadunsky NS (2000) Diagnosis and treatment of atrophic vaginitis. Am Fam Physician 61(10):3090–3096 2. Levine KB, Williams RE, Hartmann KE (2008) Vulvovaginal atrophy is strongly associated with female sexual dysfunction among sexually active postmenopausal women. Menopause 15(4 Pt 1): 661–666 3. Nappi RE, Kokot-Kierepa M (2010) Women’s voices in the menopause: results from an international survey on vaginal atrophy. Maturitas 67(3):233–238 4. Santoro N, Komi J (2009) Prevalence and impact of vaginal symptoms among postmenopausal women. J Sex Med 6(8):2133–2142 5. Stika CS (2010) Atrophic vaginitis. Dermatol Ther 23(5):514–522 6. Sturdee DW, Panay N, International Menopause Society Writing Group (2010) Recommendations for the management of postmenopausal vaginal atrophy. Climacteric 13(6):509–522 7. Archer DF (2010) Efficacy and tolerability of local estrogen therapy for urogenital atrophy. Menopause 17(1):194–203 8. US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Guidance for Industry (2003) Estrogen and estrogen/progestin drug

10.

11.

12.

13. 14.

81 1,164 4,114 6,622 329,080 12,992

129 118

products to treat vasomotor symptoms and vulvar and vaginal atrophy symptoms—recommendations for clinical evaluation US Department of Health an Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Guidance for Industry (2006) Patient-reported outcome measures: use in medical product development to support labeling claims Terwee CB, Jansma EP, Riphagen II, de Vet HC (2009) Development of a methodological PubMed search filter for finding studies on measurement properties of measurement instruments. Qual Life Res 18(8):1115–1123 Chollet JA, Carter G, Meyn LA, Mermelstein F, Balk JL (2009) Efficacy and safety of vaginal estriol and progesterone in postmenopausal women with atrophic vaginitis. Menopause 16(5): 978–983 Castelo-Branco C, Cancelo MJ, Villero J, Nohales F, Juliá MD (2005) Management of post-menopausal vaginal atrophy and atrophic vaginitis. Maturitas 52(Suppl 1):S46–S52 Brenner PF (1988) The menopausal syndrome. Obstet Gynecol 72(5 Suppl):6S–11S Nyirjesy P, Leigh RD, Mathew L, Lev-Sagie A, Culhane JF (2012) Chronic vulvovaginitis in women older than 50 years: analysis of a prospective database. J Low Genit Tract Dis 16(1):24–29

26 15. Greendale GA, Zibecchi L, Petersen L, Ouslander JG, Kahn B, Ganz PA (1999) Development and validation of a physical examination scale to assess vaginal atrophy and inflammation. Climacteric 2(3):197–204 16. Bachmann G, Lobo RA, Gut R, Nachtigall L, Notelovitz M (2008) Efficacy of low-dose estradiol vaginal tablets in the treatment of atrophic vaginitis: a randomized controlled trial. Obstet Gynecol 111(1):67–76 17. Karaosmanoglu O, Cogendez E, Sozen H, Asoglu MR, Akdemir Y, Eren S (2011) Hyaluronic acid in the treatment of postmenopausal women with atrophic vaginitis. Int J Gynaecol Obstet 113(2):156–157 18. Rioux JE, Devlin C, Gelfand MM, Steinberg WM, Hepburn DS (2000) 17beta-estradiol vaginal tablet versus conjugated equine estrogen vaginal cream to relieve menopausal atrophic vaginitis. Menopause 7(3):156–161 19. Lynch C (2009) Vaginal estrogen therapy for the treatment of atrophic vaginitis. J Womens Health (Larchmt) 18(10):1595–1606 20. Crothers BA, Booth CN, Darragh TM, Means MM, Souers RJ, Thomas N, Moriarty AT (2012) Atrophic vaginitis: concordance and interpretation of slides in the College of American Pathologists Cervicovaginal Interlaboratory Comparison Program in Gynecologic Cytopathology. Arch Pathol Lab Med 136(11):1332–1338 21. Capewell AE, McIntyre MA, Elton RA (1992) Post-menopausal atrophy in elderly women: is a vaginal smear necessary for diagnosis? Age Ageing 21(2):117–120 22. Yildirim B, Kaleli B, Düzcan E, Topuz O (2004) The effects of postmenopausal vitamin D treatment on vaginal atrophy. Maturitas 49(4):334–337 23. Hummelen R, Macklaim JM, Bisanz JE, Hammond JA, McMillan A, Vongsa R, Koenig D, Gloor GB, Reid G (2011) Vaginal microbiome and epithelial gene array in post-menopausal women with moderate to severe dryness. PLoS One 6(11):e26602 24. Palacios S, Castelo-Branco C, Cancelo MJ, Vázquez F (2005) Low-dose, vaginally administered estrogens may enhance local benefits of systemic therapy in the treatment of urogenital atrophy in postmenopausal women on hormone therapy. Maturitas 50(2): 98–104 25. Bachmann GA, Komi JO, Ospemifene Study Group (2010) Ospemifene effectively treats vulvovaginal atrophy in postmenopausal women: results from a pivotal phase 3 study. Menopause 17(3):480–486 26. Bygdeman M, Swahn ML (1996) Replens versus dienoestrol cream in the symptomatic treatment of vaginal atrophy in postmenopausal women. Maturitas 23(3):259–263 27. Manonai J, Chittacharoen A, Theppisai U, Theppisai H (2007) Effect of Pueraria mirifica on vaginal health. Menopause 14(5):919–924 28. Simunić V, Banović I, Ciglar S, Jeren L, Pavicić Baldani D, Sprem M (2003) Local estrogen treatment in patients with urogenital symptoms. Int J Gynaecol Obstet 82(2):187–197 29. Rane A, Hassan S, Corstiaans A (2000) Does conventional HRT protect from urogenital atrophy? A prospective study. J Obstet Gynaecol 20(3):306–307 30. Kagan R, Williams RS, Pan K, Mirkin S, Pickar JH (2010) A randomized, placebo- and active-controlled trial of bazedoxifene/ conjugated estrogens for treatment of moderate to severe vulvar/ vaginal atrophy in postmenopausal women. Menopause 17(2): 281–289 31. Simon J, Nachtigall L, Gut R, Lang E, Archer DF, Utian W (2008) Effective treatment of vaginal atrophy with an ultra-low-dose estradiol vaginal tablet. [Erratum appears in Obstet Gynecol 2008 Dec;112(6):1392]. Obstet Gynecol 112(5):1053–1060 32. Chollet JA (2011) Efficacy and safety of ultra-low-dose Vagifem (10 mcg). Patient Prefer Adherence 5:571–574 33. Le Donne M, Caruso C, Mancuso A, Costa G, Iemmo R, Pizzimenti G, Cavallari V (2011) The effect of vaginally administered genistein in comparison with hyaluronic acid on atrophic epithelium in postmenopause. Arch Gynecol Obstet 283(6):1319–1323

Int Urogynecol J (2015) 26:15–28 34. Al-Baghdadi O, Ewies AA (2009) Topical estrogen therapy in the management of postmenopausal vaginal atrophy: an up-to-date overview. Climacteric 12(2):91–105 35. Cano A, Estévez J, Usandizaga R, Gallo JL, Guinot M, Delgado JL, Castellanos E, Moral E, Nieto C, del Prado JM, Ferrer J (2012) The therapeutic effect of a new ultra low concentration estriol gel formulation (0.005 % estriol vaginal gel) on symptoms and signs of postmenopausal vaginal atrophy: results from a pivotal phase III study. Menopause 19(10):1130–1139 36. Minkin MJ, Maamari R, Reiter S (2013) Improved compliance and patient satisfaction with estradiol vaginal tablets in postmenopausal women previously treated with another local estrogen therapy. Int J Womens Health 5:133–139 37. Pandit L, Ouslander JG (1997) Postmenopausal vaginal atrophy and atrophic vaginitis. Am J Med Sci 314(4):228–231 38. van der Laak JA, Schijf CP, Kerstens HM, Heijnen-Wijnen TH, de Wilde PC, Hanselaar GJ (1999) Development and validation of a computerized cytomorphometric method to assess the maturation of vaginal epithelial cells. Cytometry 35(3):196–202 39. McEndree B (1999) Clinical application of the vaginal maturation index. Nurse Pract 24(9):48–56 40. Simon JA, Reape KZ, Wininger S, Hait H (2008) Randomized, multicenter, double-blind, placebo-controlled trial to evaluate the efficacy and safety of synthetic conjugated estrogens B for the treatment of vulvovaginal atrophy in healthy postmenopausal women. Fertil Steril 90(4):1132–1138 41. Barentsen R, van de Weijer PH, Schram JH (1997) Continuous low dose estradiol released from a vaginal ring versus estriol vaginal cream for urogenital atrophy. Eur J Obstet Gynecol Reprod Biol 71(1):73–80 42. Casper F, Petri E (1999) Local treatment of urogenital atrophy with an estradiol-releasing vaginal ring: a comparative and a placebocontrolled multicenter study. Vaginal Ring Study Group. Int Urogynecol J Pelvic Floor Dysfunct 10(3):171–176 43. Henriksson L, Stjernquist M, Boquist L, Cedergren I, Selinus I (1996) A one-year multicenter study of efficacy and safety of a continuous, low-dose, estradiol-releasing vaginal ring (Estring) in postmenopausal women with symptoms and signs of urogenital aging. Am J Obstet Gynecol 174(1 Pt 1):85–92 44. Speroff L (2003) Efficacy and tolerability of a novel estradiol vaginal ring for relief of menopausal symptoms. Obstet Gynecol 102(4): 823–834 45. Henriksson L, Stjernquist M, Boquist L, Alander U, Selinus I (1994) A comparative multicenter study of the effects of continuous low-dose estradiol released from a new vaginal ring versus estriol vaginal pessaries in postmenopausal women with symptoms and signs of urogenital atrophy. Am J Obstet Gynecol 171(3):624–632 46. Ayton RA, Darling GM, Murkies AL, Farrell EA, Weisberg E, Selinus I, Fraser ID (1996) A comparative study of safety and efficacy of continuous low dose oestradiol released from a vaginal ring compared with conjugated equine oestrogen vaginal cream in the treatment of postmenopausal urogenital atrophy. Br J Obstet Gynaecol 103(4):351–358 47. Lee YK, Chung HH, Kim JW, Park NH, Song YS, Kang SB (2011) Vaginal pH-balanced gel for the control of atrophic vaginitis among breast cancer survivors: a randomized controlled trial. Obstet Gynecol 117(4):922–927 48. Zeyneloglu HB, Oktem M, Haberal NA, Esinler I, Kuscu E (2007) The effect of raloxifene in association with vitamin D on vaginal maturation index and urogenital symptoms in postmenopausal osteoporotic women. Fertil Steril 88(2):530–532 49. Speroff L, Haney AF, Gilbert RD, Ellman H, Estradiol Acetate Investigator Group (2006) Efficacy of a new, oral estradiol acetate formulation for relief of menopause symptoms. Menopause 13(3): 442–450

Int Urogynecol J (2015) 26:15–28 50. Utian WH, Speroff L, Ellman H, Dart C (2005) Comparative controlled trial of a novel oral estrogen therapy, estradiol acetate, for relief of menopause symptoms. Menopause 12(6): 708–715 51. Ekin M, Yaşar L, Savan K, Temur M, Uhri M, Gencer I, Kivan E (2011) The comparison of hyaluronic acid vaginal tablets with estradiol vaginal tablets in the treatment of atrophic vaginitis: a randomized controlled trial. Arch Gynecol Obstet 283(3):539–543 52. Pinkerton JV, Shifren JL, La Valleur J, Rosen A, Roesinger M, Siddhanti S (2003) Influence of raloxifene on the efficacy of an estradiol-releasing ring for treating vaginal atrophy in postmenopausal women. Menopause 10(1):45–52 53. Meisels A (1967) The maturation value. Acta Cytol 11:249 54. Raghunandan C, Agrawal S, Dubey P, Choudhury M, Jain A (2010) A comparative study of the effects of local estrogen with or without local testosterone on vulvovaginal and sexual dysfunction in postmenopausal women. J Sex Med 7(3):1284–1290 55. Freedman M, Kaunitz AM, Reape KZ, Hait H, Shu H (2009) Twiceweekly synthetic conjugated estrogens vaginal cream for the treatment of vaginal atrophy. Menopause 16(4):735–741 56. Manonai J, Songchitsomboon S, Chanda K, Hong JH, Komindr S (2006) The effect of a soy-rich diet on urogenital atrophy: a randomized, cross-over trial. Maturitas 54(2):135–140 57. Griesser H, Skonietzki S, Fischer T, Fielder K, Suesskind M (2012) Low dose estriol pessaries for the treatment of vaginal atrophy: a double-blind placebo-controlled trial investigating the efficacy of pessaries containing 0.2 mg and 0.03 mg estriol. Maturitas 71(4): 360–368 58. Simon JA, Bouchard C, Waldbaum A, Utian W, Zborowski J, Snabes MC (2007) Low dose of transdermal estradiol gel for treatment of symptomatic postmenopausal women: a randomized controlled trial. Obstet Gynecol 109(3):588–596 59. Davila GW, Singh A, Karapanagiotou I, Woodhouse S, Huber K, Zimberg S, Seiler J, Kopka SL (2003) Are women with urogenital atrophy symptomatic? Am J Obstet Gynecol 188(2):382–388 60. Karp DR, Jean-Michel M, Johnston Y, Suciu G, Aguilar VC, Davila GW (2012) A randomized clinical trial of the impact of local estrogen on postoperative tissue quality after vaginal reconstructive surgery. Female Pelvic Med Reconstr Surg 18(4):211–215 61. Smith P, Heimer G, Lindskog M, Ulmsten U (1993) Oestradiolreleasing vaginal ring for treatment of postmenopausal urogenital atrophy. Maturitas 16(2):145–154 62. Nilsson K, Risberg B, Heimer G (1995) The vaginal epithelium in the postmenopause–cytology, histology and pH as methods of assessment. Maturitas 21(1):51–56 63. Yumru AE, Bozkurt M, Inci Coşkun E, Baykan G (2009) The use of local 17beta-oestradiol treatment for improving vaginal symptoms associated with post-menopausal oestrogen deficiency. J Int Med Res 37(1):198–204 64. Benjamin F, Deutsch S (1980) Immunoreactive plasma estrogens and vaginal hormone cytology in postmenopausal women. Int J Gynaecol Obstet 17(6):546–550 65. Bachmann G, Bouchard C, Hoppe D, Ranganath R, Altomare C, Vieweg A, Graepel J, Helzner E (2009) Efficacy and safety of lowdose regimens of conjugated estrogens cream administered vaginally. Menopause 16(4):719–727 66. Schaffer J, Fantl JA (1996) Urogenital effects of the menopause. Baillieres Clin Obstet Gynaecol 10(3):401–417 67. Capobianco G, Donolo E, Borghero G, Dessole F, Cherchi PL, Dessole S (2012) Effects of intravaginal estriol and pelvic floor rehabilitation on urogenital aging in postmenopausal women. Arch Gynecol Obstet 285(2):397–403 68. Dessole S, Rubattu G, Ambrosini G, Gallo O, Capobianco G, Cherchi PL, Marci R, Cosmi E (2004) Efficacy of low-dose intravaginal estriol on urogenital aging in postmenopausal women. Menopause 11(1):49–56

27 69. Mishell D (1987) Menopause: physiology and pharmacology. Yearbook, Chicago 70. Wied G, Bibbo M (1975) Evaluation of endocrinologic condition by exfoliative cytology. In: Gold JJ (ed) Textbook of gynaecologic endocrinology. Harper and Row, New York 71. Milsom I, Arvidsson L, Ekelund P, Molander U, Eriksson O (1993) Factors influencing vaginal cytology, pH and bacterial flora in elderly women. Acta Obstet Gynecol Scand 72(4):286–291 72. Caillouette J, Sharp C, Zimmerman G, Roy S (1997) Vaginal pH as a marker for bacterial pathogens and menopausal status. Am J Obstet Gynecol 176:1270–1275 73. Roy S, Caillouette J, Roy T, Faden J (2004) Vaginal pH is similar to follicle-stimulating hormone for menopause diagnosis. Am J Obstet Gynecol 190:1272–1277 74. Labrie F, Archer D, Bouchard C, Fortier M, Cusan L, Gomez JL, Girard G, Baron M, Ayotte N, Moreau M, Dubé R, Côte I, Labrie C, Lavoie L, Berger L, Gilbert L, Martel C, Balser J (2009) Intravaginal dehydroepiandrosterone (Prasterone), a physiological and highly efficient treatment of vaginal atrophy. Menopause 16(5):907–922 75. Manonai J, Theppisai U, Suthutvoravut S, Udomsubpayakul U, Chittacharoen A (2001) The effect of estradiol vaginal tablet and conjugated estrogen cream on urogenital symptoms in postmenopausal women: a comparative study. J Obstet Gynaecol Res 27(5): 255–260 76. Bachmann GA, Schaefers M, Uddin A, Utian WH (2009) Microdose transdermal estrogen therapy for relief of vulvovaginal symptoms in postmenopausal women. Menopause 16(5):877–882 77. Parsons A, Merritt D, Rosen A, Heath H III, Siddhanti S, Plouffe L Jr, Study Groups on the Effects of Raloxifene HCI With Low-Dose Premarin Vaginal Cream (2003) Effect of raloxifene on the response to conjugated estrogen vaginal cream or nonhormonal moisturizers in postmenopausal vaginal atrophy. Obstet Gynecol 101(2):346–352 78. Biglia N, Peano E, Sgandurra P, Moggio G, Panuccio E, Migliardi M, Ravarino N, Ponzone R, Sismondi P (2010) Low-dose vaginal estrogens or vaginal moisturizer in breast cancer survivors with urogenital atrophy: a preliminary study. Gynecol Endocrinol 26(6):404–412 79. Labrie F, Archer DF, Bouchard C, Fortier M, Cusan L, Gomez JL, Girard G, Baron M, Ayotte N, Moreau M, Dubé R, Côte I, Labrie C, Lavoie L, Berger L, Gilbert L, Martel C, Balser J (2011) Intravaginal dehydroepiandrosterone (prasterone), a highly efficient treatment of dyspareunia. Climacteric 14(2):282–288 80. Brizzolara S, Killeen J, Severino R (1999) Vaginal pH and parabasal cells in postmenopausal women. Obstet Gynecol 94:700–703 81. Ettinger B, Hait H, Reape KZ, Shu H (2008) Measuring symptom relief in studies of vaginal and vulvar atrophy: the most bothersome symptom approach. Menopause 15(5):885–889 82. Labrie F, Archer D, Bouchard C, Fortier M, Cusan L, Gomez JL, Girard G, Baron M, Ayotte N, Moreau M, Dubé R, Côte I, Labrie C, Lavoie L, Berger L, Martel C, Balser J (2010) High internal consistency and efficacy of intravaginal DHEA for vaginal atrophy. Gynecol Endocrinol 26(7):524–532 83. Eriksen B (1999) A randomized, open, parallel-group study on the preventive effect of an estradiol-releasing vaginal ring (Estring) on recurrent urinary tract infections in postmenopausal women. Am J Obstet Gynecol 180(5):1072–1079 84. Eriksen PS, Rasmussen H (1992) Low-dose 17 beta-estradiol vaginal tablets in the treatment of atrophic vaginitis: a double-blind placebo controlled study. Eur J Obstet Gynecol Reprod Biol 44(2):137–144 85. Swanson SG, Drosman S, Helmond FA, Stathopoulos VM (2006) Tibolone for the treatment of moderate to severe vasomotor symptoms and genital atrophy in postmenopausal women: a multicenter, randomized, double-blind, placebo-controlled study. Menopause 13(6):917–925 86. McKenna SP, Whalley D, Renck-Hooper U, Carlin S, Doward LC (1999) The development of a quality of life instrument for use with

28 post-menopausal women with urogenital atrophy in the UK and Sweden. Qual Life Res 8(5):393–398 87. Lester J, Bernhard L, Ryan-Wenger N (2012) A self-report instrument that describes urogenital atrophy symptoms in breast cancer survivors. West J Nurs Res 34(1):72–96 88. Weisberg E, Ayton R, Darling G, Farrell E, Murkies A, O’Neill S, Kirkegard Y, Fraser IS (2005) Endometrial and vaginal effects of low-dose estradiol delivered by vaginal ring or vaginal tablet. Climacteric 8(1):83–92 89. Bachmann G (1994) Vulvo-vaginal complaints. In: Lobo R (ed.) Treatment of the postmenopausal woman. Raven, New York 90. Raymundo N, Yu-cheng B, Zi-yan H, Lai CH, Leung K, Subramaniam R, Bin-rong C, Ling YS, Nasri N, Calimon N (2004) Treatment of atrophic vaginitis with topical conjugated equine estrogens in postmenopausal Asian women. Climacteric 7(3):312–318

Int Urogynecol J (2015) 26:15–28 91. Laan E, van Lunsen RH (1997) Hormones and sexuality in postmenopausal women: a psychophysiological study. J Psychosom Obstet Gynaecol 18(2):126–133 92. Leiblum S, Bachmann G, Kemmann E, Colburn D, Swartzman L (1983) Vaginal atrophy in the postmenopausal woman. The importance of sexual activity and hormones. JAMA 249(16):2195–2198 93. Nappi RE, Kokot-Kierepa M (2012) Vaginal health: insights, views & attitudes (VIVA) - results from an international survey. Climacteric 15(1):36–44 94. van Geelen JM, van de Weijer PH, Arnolds HT (2000) Urogenital symptoms and resulting discomfort in non-institutionalized Dutch women aged 50-75 years. Int Urogynecol J Pelvic Floor Dysfunct 11(1):9–14 95. Pastore LM, Carter RA, Hulka BS, Wells E (2004) Self-reported urogenital symptoms in postmenopausal women: Women’s Health Initiative. Maturitas 49(4):292–303