Genitourinary syndrome of menopause (GSM) describes anatomical changes and bothersome symptoms associated with menopausal estrogen deficiency involving the labia, vagina, urethra, and bladder.1 Genital symptoms of dryness and burning, urinary symptoms of urgency and dysuria, and sexual symptoms of pain and dryness are common. Symptoms must be bothersome and not accounted for by another diagnosis.2 Vulvovaginal atrophy (VVA) is a component of GSM.
Bothersome vaginal dryness, dyspareunia, urinary symptoms, and related sexual and quality-of-life sequelae are common problems for women during and after the menopause transition. These genitourinary symptoms, including vaginal dryness, itching, irritation, and pain, significantly affect the lives of menopausal women, impacting their daily activities, emotional well-being, sexual function, and interpersonal relationships.3-7
Despite effective and safe treatment options for GSM, many women remain untreated.8 Women often are not aware that their symptoms are part of a medical condition for which treatment is available, typically believing it is a part of aging one must accept.6 Many women do not discuss their bothersome urogenital symptoms with a clinician due to the sensitive nature of GSM, safety concerns about treatments, and embarrassment.9 Clinicians may not discuss GSM with their patients due to insufficient information about available therapeutic options, time constraints during patient visits, and limited knowledge of the syndrome and its impact on women's lives. The misperception that GSM affects only sexually active women also contributes to many women with GSM not receiving a thorough evaluation.
Although VVA symptoms are commonly reported in community-based studies of menopausal women, the lack of a validated measure of symptomatic VVA or GSM has limited our ability to accurately quantify its prevalence, predictive factors, and associated outcomes. Using ad hoc or nonvalidated survey questions, past studies have reported vulvovaginal symptoms in 27% to 85% of menopausal women.3,4,10-16 Despite the broad sampling and diverse populations included in these studies, the absence of a validated measurement tool limits our understanding of the true prevalence of this disorder.
To provide a validated measure for assessing symptomatic VVA or GSM, a new patient-reported outcome measure (PROM) is under development in collaboration with The North American Menopause Society (NAMS) and the Massachusetts General Hospital Midlife Women's Health Center, with funding support from several life science companies. Significant advances in research and improved patient care are anticipated from availability of a brief, patient-friendly, validated PROM for evaluating GSM in menopausal women. Self-administered questionnaires and brief symptom scales for other common problems affecting women, including vasomotor symptoms,17 insomnia, overactive bladder,18 and sexual dysfunction,19 have greatly impacted the way research studies are performed and clinical problems addressed in midlife women.
The Vulvovaginal Atrophy Questionnaire (VVAQ) is being developed for use both in clinical and epidemiological research, and patient care settings, with the goal of advancing knowledge about GSM and improving the care of menopausal women. A validated measure for assessing GSM and response to treatment interventions, freely available in the public domain, will provide a critical research tool for epidemiologic studies and efficacy assessment in clinical trials of new therapies. A validated PROM will provide clinicians from multiple specialties and researchers from a wide range of fields with a practical and efficient means for assessing GSM in midlife women.
As recommended by US Food and Drug Administration (FDA) Guidance for PRO measures, the initial development of the VVAQ incorporated existing knowledge, expert input, and, most importantly, the perspectives and experiences of menopausal women.20-22 Qualitative research methods enabled us to extract the most common and relevant themes from women's narratives regarding their experience of GSM, and these data have been used to construct the questionnaire. Although the VVAQ will be freely available after final validation, the goal of this report is to describe menopausal women's experience of GSM in their own words to better understand the syndrome and its impact on women's lives.
This novel PROM was developed in five discrete phases from multiple sources of information in accordance with the designated standards for PROM development20: a conceptual model was constructed based on literature review and clinical input from experts; semistructured qualitative interviews elicited the subjective experiences of women with symptomatic VVA; an initial questionnaire was drafted with items based on the conceptual model and qualitative findings; the draft items were tested for content validity by means of cognitive debriefing focus groups; and finally, a revised draft was developed based on these findings (Fig. 1; stages of PROM development).
Based on systematic review of the relevant literature and input from clinical experts, we developed an initial conceptual model of four domains contributing to the subjective experience of GSM (Fig. 2; initial conceptual model). Based on this conceptual model, we then created a semistructured interview guide with open-ended questions to allow unanticipated topics to emerge. Interviewers were senior qualitative research scientists. All interviews began by asking women to describe their experiences with GSM. Probing techniques were used when necessary to prompt additional discussion and/or clarify respondents’ comments. Throughout the interviews, new topics were introduced by women when asked to elaborate on their experience.
Discussion topics for the qualitative interviews included the women's experience in four general areas. Symptoms and sensations included dryness, pain, itching, burning, and odor. Quality of life included daily activity, travel, clothing selection, and relationships with family and friends. Sexuality and intimate relationships included sexual function, sexual desire, pain with sexual activity, satisfaction, orgasm, and relationship with partner. Well-being included body image, self-esteem, mood/temperament, and sense of femininity. Interviewers conducted 36 concept elicitation interviews that ranged in length from 45 to 120 minutes. Sample sizes were determined to ensure saturation of relevant concepts given anticipated variation in subjective experiences of symptoms associated with GSM. The sample size was dictated by anticipated variability in subjective experiences, and also the need to ensure adequate sample size for concept saturation.23 Because the final sample size for concept elicitation studies is determined based on an assessment of whether the analysis has reached saturation, the expected sample sizes are an estimate. We employed a conservative sample size estimate to mitigate potential adverse effects of heterogeneity in participant characteristics and other factors. Typically, in concept elicitation interviews, 92% of concepts emerge by the 15th interview and 99% by the 25th interview.24 Our sample is slightly larger to ensure we achieved saturation across all concepts. Sample was considered complete at the point that no new concepts were emerging.
Interviewers focused on identifying the verbal expressions and unique terminology women used to describe their experiences, including the conditions under which symptoms occurred, their impact on everyday life, and the degree of associated bother. Based on results of the concept elicitation interviews, a draft PROM was constructed to reflect the most prevalent descriptions and language respondents used to describe their experiences.
During the cognitive debriefing phase, interviewers used open-ended questions to evaluate whether the draft items reflected women's experiences, elicited suggestions for other items that might better represent their experiences, and assessed comprehension of items, instructions, and response options. There were 9 focus groups, which consisted of women with GSM confirmed by physical examination and laboratory assessment (five groups, 26 women) or asymptomatic women (four groups, 15 women). Cognitive debriefing focus groups ranged in length from 45 to 120 minutes. Items were drafted for inclusion in a revised PROM based on findings in the concept elicitation interviews and cognitive debriefing focus groups.
All interviews and focus groups were audio-recorded and transcribed verbatim. Transcripts were imported into ATLAS.ti qualitative analysis software to facilitate data management and analysis.25-31 Analysts used consensus-based coding. During the coding process, analysts systematically recorded emerging themes, domains, and connections between categories and met regularly to review findings. Inter-rater reliability was determined by comparing the way each independent analyst applied codes to the data. After each analyst independently coded the transcripts, a comparison of all codes applied by each analyst indicated that average inter-rater reliability was 94%.
The study was conducted at three clinical sites to allow racial, ethnic, and geographic diversity. Participants were recruited through clinical practices and advertising by radio, mail, and internet. The study was approved by the New England Research Institutes Institutional Review Board, and informed consent was obtained from all participants. Women with GSM confirmed by physical examination and laboratory assessment were studied in the concept elicitation interviews. Women with and without GSM were included in cognitive debriefing to ensure comprehension of the PROM in women both with and without bothersome urogenital symptoms. Inclusion and exclusion criteria were similar for both studies.
Study participants were age 45 years or older and postmenopausal. In keeping with current diagnostic criteria for GSM,1 participants with GSM were required to have a combination of bothersome urogenital symptoms and characteristic findings on pelvic examination. Women with GSM reported one or more bothersome symptoms in the past 4 weeks, including vaginal dryness, soreness, irritation, or pain with sexual activity. To be certain that symptoms and signs were due to GSM and not another condition, an elevated vaginal PH and a vaginal maturation index (VMI) consistent with atrophy were required for inclusion. Exclusion criteria included bothersome vaginal symptoms before menopause, prior vulvovaginal surgery, or a history of vulvodynia, lichen sclerosus, or chronic vaginitis. Women currently using estrogen products or any other prescription or compounded product specifically for the treatment of vaginal dryness were excluded. Participants without GSM reported no symptoms consistent with genitourinary atrophy in the past 6 months. The definition of GSM requires that menopausal women have both pelvic examination findings consistent with genitourinary atrophy and bothersome symptoms. If a woman has genitourinary atrophic changes on examination, but no bothersome symptoms, then she would not meet criteria for the syndrome of GSM. Therefore, we were comfortable classifying women who reported no genitourinary symptoms as not having GSM without a pelvic examination. Use of prescription or over-the-counter products specifically for the treatment of vaginal dryness, including estrogen therapy, was allowed in these women.
To assist in characterizing the study population, three gynecologists (one at each study site), all of whom had extensive experience and expertise in the care of menopausal women, were asked to rate the severity of vulvovaginal atrophic physical examination findings as mild, moderate, or severe. Study participants also were asked to rate the overall severity of their vulvovaginal symptoms as mild, moderate, or severe. Both clinician and participant assessments of severity are subjective, and there is no validated measure available for either outcome.
Study participants were recruited to achieve a diverse sample, including varied geographic regions, older and younger ages, sexually active and inactive, a range of symptom severity, and black, white, and Hispanic racial/ethnic backgrounds.
Seventy-five women were enrolled in the study overall, including 36 women participating in the concept elicitation interviews and 41 women participating in the cognitive debriefing study. Two women participated in both parts of the study.
Concept elicitation interviews were completed with 36 women, all of whom had a confirmed diagnosis of GSM. Demographic and clinical characteristics are summarized in Table 1. Participants spanned a variety of age groups, and 25% were non-white.
Participants reported a range of symptoms and described associated impacts on more than 15 quality-of-life domains (Fig. 3; prevalence of symptoms). Eighty six per cent of women reported that their symptoms impacted their sexual functioning and 83% indicated negative effects on their overall quality of life.
Pain associated with sexual activity was the most commonly reported symptom overall (n = 33, 92%) and was very frequently associated with a high degree of bother. Many women described it as “excruciating pain,” often associated with vaginal dryness. The majority of participants reported vaginal dryness (n = 31, 86%), which also often was accompanied by a high degree of bother. Analysis of the data revealed that there was nuance to the original concept vaginal dryness, and that participants described vaginal dryness in two distinct contexts: sexual activity and activities of daily living. Vaginal dryness associated with sexual activity, in particular, was very bothersome. Other commonly reported symptoms reported by at least a third of participants included vaginal irritation (n = 18, 50%), discomfort with wiping after urination (n = 13, 36%), and vaginal itching (n = 12, 33%).
Overall, results supported the domains of the original conceptual model, but also led to substantive changes in concepts and terminology to more closely reflect respondents’ experiences. These changes are shown in the revised conceptual model (Fig. 4; revised conceptual model).
Nineteen concepts across four domains were retained for item generation, and a draft instrument comprised of 35 items was developed. Items addressing nonsexual symptoms were designed to be applicable to all respondents, whereas a subset of items focused on sexual function was designed only for sexually active women (with or without a partner). Women's own words best illustrate item domains and concepts (see representative quotations in Table 2).
In the cognitive debriefing study, there were nine focus groups, including five groups of women with confirmed GSM (26 women) and four groups of asymptomatic women (15 women). Participants spanned a variety of age groups and 46% were non-white (Table 3).
The majority of participants reported a positive overall impression of the questionnaire and indicated that the questions were meaningful and relevant to their experiences and were easy to understand. Among the 26 women with confirmed GSM, 6/26 (23.1%) noted redundancy in parts of the questionnaire, 7/26 (26.9%) reported minor ambiguities in specific items in the nonsexual compared with sexual portion of the questionnaire, and almost one-third (30.8%) felt the 4-week time frame was too short to capture their personal experiences, although all understood the 4-week frame of reference. Among the 15 women without GSM who completed the cognitive debriefing, 2/15 (13.3%) found the questions on lubricant use to be confusing and 1/15 (6.7%) did not understand the bother question. No respondents expressed any problem with the length of time it took to fill out the survey or the survey itself. Women with and without GSM reported the questionnaire to be comprehensive, thorough, and relevant. All women with GSM (100%) felt the questionnaire captured important aspects of their personal experience.
This report describes women's experience of menopausal urogenital symptoms as ascertained during the development of a novel patient-reported outcome measure to assess GSM. It is hoped that the VVAQ will be able to identify women who would benefit from treatment in clinical care settings, differentiate between women with and without the condition in epidemiologic studies, and assess response to treatment interventions in clinical trials.
By strictly following guidance for the development of PRO measures, the VVAQ incorporates existing knowledge, expert input, and, most importantly, the experiences and perspectives of women affected by this condition. Using qualitative research methods, we identified the most common and relevant themes from women's narratives to capture their experience of GSM.
During focus groups and cognitive debriefing sessions, women described a range of genitourinary symptoms and associated impacts on more than 15 quality-of-life domains. The majority of women reported that their symptoms adversely affected their sexual functioning and overall quality of life.
Sexually inactive women comprised 15% to 28% of participants, as GSM negatively impacts aspects of menopausal women's lives, irrespective of sexual activity. There is a common misperception that GSM does not need to be assessed or treated in sexually inactive women. It is clear from their own words that GSM affects many aspects of menopausal women's lives beyond sexual function, with descriptions of pain when walking, urinating, wearing tight clothes, cleaning the house, and even sitting in the car. In addition, GSM may be the reason for sexual inactivity.
Clinicians who specialize in the care of menopausal women often hear personal statements from patients similar to the ones included in this report illustrating GSM domains and concepts. It is hoped that the distress inherent in these women's words will inspire all clinicians to take the time to ask their midlife patients about bothersome genitourinary symptoms and review available treatment options.32
The majority of currently available questionnaires that assess genitourinary symptoms of menopausal women focus principally on VVA, whereas the VVAQ was designed to assess urinary symptoms associated with estrogen deficiency also (excluding incontinence). In addition, most questionnaires were not developed as PROMs and, therefore, did not use women's own words as the basis of the survey. The principal self-report efficacy assessment advised by US FDA is limited to change from baseline in the severity of the most bothersome symptom from a list including vaginal dryness, vaginal and/or vulvar irritation/itching, dysuria, and vaginal pain or bleeding associated with sexual activity.33
The Vulvovaginal Symptoms Questionnaire (VSQ) is a 21-item self-report survey of predominantly vulvar symptoms, including an assessment of emotions, life impact, and sexual impact. This questionnaire is based on modifications to Skindex-16—a validated questionnaire for measuring the impact of skin disease.34
PROMIS is a collection of PRO measures on a variety of topics. Questions relevant to GSM are limited to sexual function and satisfaction.35 There is an assessment of physical discomfort, including pain, of the vagina, clitoris, or labia with sexual activity and an additional question about vaginal lubrication during sexual activity.
The Day-to-Day Impact of Vaginal Aging (DIVA) questionnaire is a 23-item self-report measure that assesses the impact of vaginal symptoms of dryness, soreness, irritation, or itching on daily activities, emotions, sexual activity, and self-image.36 DIVA is a very useful questionnaire, developed as a PROM in an ethnically diverse group of menopausal women. Unlike the VVAQ, DIVA is not designed to assess whether or not bothersome symptoms are present, but rather focuses on symptom impact. In addition, pelvic examinations and laboratory measures were not performed in the DIVA study to ensure that symptoms were not due to an alternative etiology.
Strengths of this report include the systematic assessment of women with GSM, strictly following guidance for PRO development. Women's own words and experiences formed the basis of the resulting draft questionnaire. Interviewers and analysts were highly trained in the field of qualitative research. Although even greater racial and ethnic diversity would be preferred, 25% to 37% of study participants were black.
A limitation of the study is that initial PRO development required all participants to speak English. After final statistical validation in English, a goal of the project will be to translate and validate the VVAQ in additional languages with cognitive debriefing studies to ensure comprehension and cultural sensitivity.
This study describes women's experiences of GSM as elicited through focus groups and cognitive debriefing sessions during development of a novel PROM. The long-term goal of this survey development program is to provide a freely available, validated PROM with broad applicability to menopausal women with GSM. The current 16-item draft PROM represents 12 concepts from four domains. The VVAQ and a scoring algorithm will be finalized based on results of the last phase of psychometric testing. It is hoped that the VVAQ will provide an effective research tool for studying the development of genitourinary estrogen-deficiency symptoms during the menopause transition and the prevalence and predictors of this disorder in large populations of midlife women. It also is designed to serve as an efficacy outcome measure in clinical trials of new therapies, providing a much richer assessment of treatment response than the current endpoint determined by the US FDA, change in most bothersome symptom. A brief, culturally appropriate and validated measure also may help clinicians identify affected women and assess severity of symptoms and response to treatment as part of evidence-based care of aging women.
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