Background
Vulvovaginal symptoms, which include dryness, irritation, and pain with intercourse, are common among postmenopausal women and are associated with impaired sexual functioning and quality of life. Previous assessment of treatment strategies for these symptoms has been limited by a lack of sensitive patient-centered outcome measures that assess symptom impact on functional and quality-of-life domains.
Objective
We aimed to (1) examine change in the impact of postmenopausal vulvovaginal symptoms on multiple aspects of well-being and functioning in relation to vaginal estradiol and moisturizer treatment and (2) guide meaningful interpretation of scores on a structured-item questionnaire measure of condition-specific impact.
Study Design
Data were drawn from postmenopausal women who were enrolled in the Menopause Strategies: Finding Lasting Answers for Symptoms and Health Vaginal Health Trial (a 12-week, double-blind, placebo-controlled randomized trial of treatment for vulvovaginal symptoms) who were assigned to vaginal 10-μg estradiol tablet plus placebo gel (n=98), vaginal moisturizer plus placebo tablet (n=97), or dual placebo (n=94). At baseline and 12-week follow up, participants completed the Day-to-Day Impact of Vaginal Aging questionnaire to assess the impact of vaginal symptoms on 4 domains (activities of daily living, emotional well-being, sexual functioning, and body image), each on a 0-4 point scale. Day-to-Day Impact of Vaginal Aging sensitivity to change was assessed by the examination of the associations between change in Day-to-Day Impact of Vaginal Aging domain scores and vulvovaginal symptom severity from baseline to 12 weeks with analysis of covariance. Within-woman and between-group minimal clinically important improvement was assessed with the use of an anchor-based approach that relates change in Day-to-Day Impact of Vaginal Aging domain scores with self-reported benefit from treatment.
Results
Participants in all treatment arms (n=289) demonstrated reduced impact of vulvovaginal symptoms on all domains of well-being and functioning as assessed by Day-to-Day Impact of Vaginal Aging at 12-week follow up, with no significant differences in improvement between women who were assigned to either estradiol tablet or vaginal moisturizer compared with placebo. For all Day-to-Day Impact of Vaginal Aging domains, mean impact scores were reduced when participants reported symptom improvement (–0.3 to –0.8 point change in Day-to-Day Impact of Vaginal Aging scores for <2-point symptom severity change vs –0.4 to –1.6 point change in Day-to-Day Impact of Vaginal Aging scores for 2+ point symptom severity change; all P <.001). Minimal clinically important change in Day-to-Day Impact of Vaginal Aging domain scale scores, which are anchored to self-reported meaningful benefit from treatment at 12 weeks, ranged from –0.4 to –1.3 (within-woman) and –0.2 to –0.7 (between-group). Observed change and minimal clinically important difference were largest for the sexual functioning domain.
Conclusion
The impact of vulvovaginal symptoms on day-to-day activities, sexual function, emotional well-being, and body image may be improved with low-dose vaginal estradiol, moisturizer, or topical placebo. The Day-to-Day Impact of Vaginal Aging questionnaire demonstrates sensitivity to change with treatment of vulvovaginal symptoms, particularly Day-to-Day Impact of Vaginal Aging scales that focus on symptom impact on sexual functioning and body image. Minimal clinically important improvement in the impact of vulvovaginal symptoms as measured by the Day-to-Day Impact of Vaginal Aging can be defined with the use of these measures.
Bothersome vulvovaginal symptoms are common among postmenopausal women, with an estimated 40–75% reporting symptoms that included vaginal dryness, irritation, and pain with intercourse that frequently began in the late menopause transition and persisted into older age. These symptoms have been linked to impaired sexual functioning, reduced quality of life, and poorer emotional well-being, , which highlights a need to identify effective treatment options with a meaningful impact on a range of patient-centered outcomes.
Why was this study conducted?
The purpose of this study was to compare the effects of a vaginal 10-μg estradiol tablet and of a vaginal moisturizer with placebo on the day-to-day impact of postmenopausal vulvovaginal symptoms on well-being and functioning to to examine sensitivity to change to and to estimate minimal clinically important change in scores on the Day-to-Day Impact of Vaginal Aging questionnaire to as a measure of the functional and quality-of-life impact of postmenopausal vulvovaginal symptoms.
Key findings
Vaginal estradiol tablet to vaginal moisturizer to and placebo treatments resulted in similar improvements in the impact of postmenopausal vulvovaginal symptoms on well-being and functioning over 12 weeks to as measured by Day-to-Day Impact of Vaginal Aging domain scores. Self-reported improvement in vaginal symptoms and perceived benefit from treatment were accompanied by decreases in all Day-to-Day Impact of Vaginal Aging domain scale scores to particularly the scales that assess impact on sexual functioning and body image. Minimum clinically important differences that range from –0.4 to –1.3 for Day-to-Day Impact of Vaginal Aging domain scores that are associated with self-reported meaningful benefit from treatment may be used in future studies to evaluate treatment responses.
What does this add to what is known?
This research adds to our understanding of patient-centered outcomes in the treatment of bothersome postmenopausal vulvovaginal symptoms and provides meaningful metrics that may be used to guide future research and clinical efforts.
Assessment of treatment-related vulvovaginal symptom improvement traditionally has relied on limited measures that do not reflect the broad impact of these symptoms on day-to-day functioning and well-being. , The Day-to-Day Impact of Vaginal Aging questionnaire (DIVA) was developed to assess the impact of vulvovaginal symptoms on multiple functional and quality-of-life domains and included activities of daily living, emotional well-being, sexual functioning, and self-concept/body image. Although the DIVA has been used to describe symptom experience and comorbidities in observational studies, its ability to serve as a sensitive and reliable measure of treatment-related change has not been assessed.
The Menopause Strategies: Finding Lasting Answers for Symptoms and Health (MsFLASH) clinical trials network completed a randomized, 3-arm, double-blind trial of treatments commonly used for postmenopausal vulvovaginal symptoms that compared both vaginal estradiol tablets and a vaginal moisturizer with placebo. The primary results of the trial with regard to treatment effects on vulvovaginal symptoms have been reported elsewhere. In the current study, we report results related to the day-to-day impact of vulvovaginal symptoms as measured by the DIVA. We examined the sensitivity of DIVA domain scales to self-reported vulvovaginal symptom change. We also used an anchor-based approach to estimate mean changes in DIVA domain scores that corresponded to patient-reported meaningful benefit from treatment to provide a patient-centered measure of meaningful treatment-related change.
Materials and Methods
Study population
The MsFLASH Vaginal Health Trial has been previously described. Briefly, participants were enrolled in a randomized, double-blind, placebo-controlled 12-week trial that compared the treatment efficacy of 10-μg vaginal estradiol tablets and a vaginal moisturizer to matching placebos for moderate-to-severe vulvovaginal symptoms. Healthy postmenopausal women were recruited between April 2016 and April 2017. The protocol was approved by the institutional review board at each clinical site and the data coordinating center; all women provided written informed consent.
A total of 302 women enrolled. Eligible participants were aged 45-70, had their last menstrual period at least 2 years before study enrollment, and reported moderate-severe vulvovaginal itching, pain, irritation, or dryness at least weekly in the past 30 days or vulvovaginal pain with penetration in the past month. Exclusion criteria included vulvar dermatoses that was assessed by pelvic examination; current vaginal infection; use of hormonal medication in the past 2 months; use of antibiotics, vaginal moisturizer, probiotic, prebiotic, or douche in past month; and chronic premenopausal vulvovaginal symptoms.
Study procedures
Study recruitment, randomization, and intervention procedures have been described elsewhere. Women were recruited through direct mailings and Facebook ads that were targeted to women who were 50–70 years old and were within 20 miles of clinical sites. Randomization by permuted blocks of 9 and that was stratified by site was conducted in a secure web-based database and implemented via a computerized inventory system for the dispensing of identical-appearing tablets in bottles and gel in tubes. Participants, study personnel, and clinical providers were blinded to treatment assignments.
Participants were assigned randomly 1:1:1 to 10-μg vaginal estradiol tablet (Vagifem; Novo Nordisk, Plainsboro, NJ)+placebo vaginal gel; placebo vaginal tablet plus vaginal moisturizer (Replens; Church & Dwight, Ewing, NJ); or placebo vaginal tablet plus placebo vaginal gel. Participants were instructed to use the vaginal tablet (active or placebo) daily for 2 weeks and then twice weekly for 10 weeks. Participants were instructed to use the vaginal moisturizer (or placebo gel) every 3 days throughout the trial. Participants were advised to use the vaginal tablet in the morning and the vaginal gel in the evening for the first 2 weeks and then to use the products on alternate days.
Protocol adherence and adverse events were assessed by telephone contact at 1, 3, and 11 weeks after randomization. Participants completed questionnaires and underwent vaginal sample collection at 4- and 12-week in-person follow-up visits. They were also asked to bring medications to these visits; remaining pills were counted, and gel tubes were weighed to assess medication adherence.
Measurements
Impact of vaginal symptoms on well-being and functioning
Participants completed the DIVA, which is a questionnaire that previously has demonstrated good face validity, construct validity, and internal and test-retest reliability among postmenopausal women with vaginal symptoms. It includes 4 domain-specific scales to assess the impact of symptoms on (1) activities of daily living (5 items), (2) emotional well-being (4 items), (3) sexual functioning (5 items), and (4) self-concept and body image (5 items). All questions have 5-point ordered response scales (0–4); higher numbers indicate more severe impact. Domain scale scores are calculated by the averaging of the scores of individual items in each domain. In this analysis, we used scores from the short-form DIVA sexual functioning scale, which consists of 5 questions that are applicable to all women, regardless of whether they are currently sexually active.
Severity of most bothersome vulvovaginal symptom
At trial enrollment, participants identified their most bothersome symptom (MBS) as either vulvovaginal itching, pain, dryness, irritation, or pain with penetration. Severity of this symptom was rated as 0–3 (none, mild, moderate, or severe) at baseline and at 12 weeks. For this analysis, change in MBS severity was quantified in 2 ways. First, the differences between MBS severity scores at the baseline visit and week 12 were categorized as a decrease of <2 points or ≥2 points. A decrease of ≥2 points reflects improvement in symptom severity from moderate-to-severe to mild-to-none. Second, at week 12, participants retrospectively reported change in MBS severity since the baseline visit on a 7-level Likert scale. Responses were collapsed into 3 categories for analysis: “worse/no change” (very much worse, worse, slightly worse, no change), “some improvement” (slightly improved, improved) and “very much improved.”
Meaningful benefit from treatment
The week-12 questionnaire asked participants whether they had experienced meaningful benefit from study medications during trial participation (yes/no). Women who responded “yes” were considered to have met the minimum threshold for clinically meaningful benefit from treatment.
Additional measurements
Descriptive data were drawn from baseline questionnaires: demographic factors, smoking status, alcohol intake, health status, mood, and sexual function. Mood was assessed with the use of the Patient Health Questionnaire and the Generalized Anxiety Disorder questionnaires. Sexual function was assessed using the Female Sexual Function Index. Vaginal pH was assessed from vaginal samples that were collected at baseline and categorized as ≤5 vs >5.
Statistical analyses
A modified intent-to-treat analysis included all randomly assigned participants who provided baseline and 12-week DIVA assessments, regardless of treatment adherence. Characteristics of the analytic sample (total and by intervention arm) were summarized by means with standard deviations for continuous variables and frequencies with percentages for categoric variables.
Treatment effects on change in each of the 4 DIVA domains (activities of daily living, emotional well-being, sexual functioning, and self-concept and body image) from baseline to week 12 were assessed with the use of analysis of covariance models. Week-12 domain scores were modeled as a function of the intervention arm, baseline domain score, and clinical center. To evaluate intervention effects on DIVA domain scores among adherent participants, these analyses were repeated in the subset of participants who reported ≥80% adherence to their assigned intervention.
To evaluate the sensitivity of the DIVA to self-reported change in vulvovaginal symptoms, analysis of covariance models were fit to each week-12 domain score as a function of MBS severity change from baseline to 12 weeks (<2 points vs ≥2 point decrease) and self-reported improvement in MBS at week 12 (worse/no change, some improvement, or very much improved). Models were adjusted for baseline DIVA domain scores. A separate model was fit with the week-12 domain score as a function of the trend over the median self-reported MBS score within the 3 groups.
An anchor-based approach was used to estimate the within-woman minimal clinically important 12-week change (MIC) and the between-group minimal important difference (MID) , for each DIVA domain scale. For within-woman MIC, we estimated the mean and 95% DIVA domain score change in participants who reported “yes” when asked if they experienced a meaningful benefit from treatment at week 12. This estimate was selected as a threshold to reflect clinically meaningful, although not necessarily maximal, improvement. To evaluate how treatment was related to domain-specific MIC, we estimated the percentages of participants who met the MIC threshold both overall and within each intervention group. We then calculated the MID as the mean difference between change in each DIVA domain score for women who reported meaningful benefit from treatment and those who did not report meaningful benefit from treatment at 12 weeks. All analyses were conducted in SAS software for Windows (version 9.4; SAS Institute Inc, Cary, NC).
Results
Sample characteristics
The analytic sample included 289 women (mean age, 61±4 years [mean±standard deviation]) with complete study data for DIVA outcomes at baseline and 12 weeks. Data from 13 randomized participants (4 assigned to estradiol tablet, 3 to vaginal moisturizer, and 6 to placebo) were excluded because of incomplete DIVA data ( Figure 1 ). Overall, participants were largely white (89%), well-educated (67% college graduates), married (or similar; 86%), and currently sexually active (81%). The most common bothersome symptom was pain with vaginal penetration (61%), followed by vaginal dryness (21%) ( Table 1 ). On average, baseline DIVA domain scores indicated a modest impact of vulvovaginal symptoms on activities of daily living (mean, 0.5±0.6), emotional well-being (mean, 1.1±0.9), moderate-to-severe impact on sexual functioning (mean, 2.5±1.0), and self-concept/body image (mean, 2.5±1.1; range for all scores, 0–4). Treatment adherence did not vary significantly across treatment groups (estradiol tablets, 83/98 [85%] vs placebo tablets, 78/94 [83%]; P =.88; vaginal moisturizer, 72/97 [74%] vs placebo gel, 77/94 [82%]; P =.12).
| Variable | Total (n=289) | Vaginal estradiol (n=98) | Vaginal moisturizer (n=97) | Dual placebo (n=94) |
|---|---|---|---|---|
| Mean age, y±standard deviation | 61±4 | 61±4 | 61±4 | 61±4 |
| <55, n (%) | 4 (1) | 3 (3) | 0 (0) | 1 (1) |
| 55–59, n (%) | 116 (40) | 32 (33) | 42 (43) | 42 (45) |
| 60–64, n (%) | 108 (37) | 42 (43) | 39 (40) | 27 (29) |
| ≥65, n (%) | 61 (21) | 21 (21) | 16 (16) | 24 (26) |
| Race/ethnicity | ||||
| White | 257 (89) | 84 (89) | 88 (91) | 85 (90) |
| Black | 12 (4) | 7 (7) | 3 (3) | 2 (2) |
| Other/unknown | 20 (7) | 7 (7) | 6 (6) | 7 (7) |
| Body mass index, n (%) | ||||
| <25 kg/m 2 | 133 (46) | 39 (46) | 44 (45) | 50 (53) |
| 25–<30 kg/m 2 | 98 (34) | 36 (37) | 40 (41) | 22 (23) |
| ≥30 kg/m 2 | 54 (19) | 20 (20) | 13 (13) | 21 (22) |
| Education, n (%) | ||||
| High school diploma | 10 (3) | 2 (2) | 3 (3) | 5 (5) |
| School after high school | 84 (29) | 30 (31) | 26 (27) | 28 (30) |
| College graduate | 194 (67) | 65 (66) | 68 (70) | 61 (65) |
| Marital status, n (%) | ||||
| Never married | 14 (5) | 8 (8) | 2 (2) | 4 (4) |
| Divorced or widowed | 27 (9) | 9 (9) | 7 (7) | 11 (12) |
| Married or like relationship | 248 (86) | 81 (83) | 88 (91) | 79 (84) |
| Sexually active, n (%) | ||||
| Yes | 235 (81) | 78 (80) | 78 (80) | 79 (84) |
| No | 54 (19) | 20 (20) | 19 (20) | 15 (16) |
| Most bothersome symptom, n (%) | ||||
| Vulvar and/or vaginal itching | 19 (7) | 10 (10) | 3 (3) | 6 (6) |
| Vulvar and/or vaginal soreness | 13 (4) | 5 (5) | 6 (6) | 2 (2) |
| Vulvar and/or vaginal irritation | 18 (6) | 7 (7) | 4 (4) | 7 (7) |
| Vaginal dryness | 60 (21) | 20 (20) | 17 (18) | 23 (25) |
| Pain with vaginal penetration | 175 (61) | 53 (54) | 67 (69) | 55 (59) |
| Self-reported health, n (%) | ||||
| Excellent | 70 (24) | 25 (26) | 26 (27) | 19 (20) |
| Very good | 138 (48) | 40 (41) | 54 (56) | 44 (47) |
| Good | 75 (26) | 32 (32) | 14 (14) | 29 (31) |
| Fair/poor | 6 (2) | 1 (1) | 3 (3) | 2 (2) |
| Mean symptoms, n±standard deviation | ||||
| Depressive a | 3.5±3.3 | 3.4±3.5 | 3.2±2.9 | 3.7±3.4 |
| Anxiety b | 3.8±4.1 | 4.2±4.5 | 3.0±3.2 | 4.3±4.3 |
| Sexual function c | 15.5±6.4 | 15.2±6.0 | 15.1±6.6 | 16.2±6.6 |
| Vaginal pH, n (%) | ||||
| ≤5 | 38 (13) | 18 (18) | 12 (12) | 8 (9) |
| >5 | 246 (85) | 77 (79) | 84 (87) | 85 (90) |
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