P the Vulvovaginal Atrophy Questionnaire (vvaq): a novel Patient-Reported Outcome (pro) for Assessing Symptoms of Vulvovaginal Atrophy in Menopausal Women

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The Vulvovaginal Atrophy Questionnaire (VVAQ): A Novel  

Patient-Reported Outcome (PRO) for Assessing Symptoms of 

Vulvovaginal Atrophy in Menopausal Women

Jan Shifren


, David Portman, MD


, Michael Krychman, MD


, James Simon


, Sheryl A. 



, Rebekah Zincavage, PhD


, Ashley Magnavita, MPH


, Raymond C. Rosen, 




New England Research Institutes, Inc., Watertown, MA; 


Massachusetts General 

Hospital, Boston, MA; 


Columbus Center for Women’s Health Research, Columbus, 



Southern California Center for Sexual Health and Survivorship Medicine, Newport 

Beach, CA; 


Women’s Health Research Consultants, Washington DC, DC; 



American Menopause Society, Cleveland, OH

Objective: Symptoms of vulvovaginal atrophy (VVA), a principal component of the 

genitourinary syndrome of menopause (GSM), are commonly reported in studies of 

menopausal women; however, the lack of a validated self-report measure of symptomatic 

VVA has greatly limited our ability to quantify its prevalence and associated outcomes 

in women. Given the prevalence of VVA symptoms and potential impact on women’s 

health, quality of life and interpersonal relationships, there is an urgent clinical and 

research need for a patient-based, culturally-sensitive, validated instrument for assessing 

VVA symptoms and their impact on women’s lives. We present results from the first 

four phases of development of a novel PRO measure for assessing VVA symptoms in 

menopausal women. Design: The overall goal of this project is to develop and validate 

a new PRO measure for assessing symptomatic VVA in both research and clinical 

settings. Following established standards and guidelines, this new PRO measure has 

been developed in four discrete stages. The first phase involved an extensive literature 

review with input from an expert advisory panel to develop a working conceptual 

model. In the second phase, concept elicitation interviews were conducted in 36 post-

menopausal women with clinically confirmed, symptomatic VVA. Based on qualitative 

interview findings, a draft questionnaire was developed during the third phase. The draft 

questionnaire was then evaluated for comprehension and relevance (content validity) 

by means of cognitive debriefing interviews in focus groups of women with and 

without symptomatic VVA (N=26 with VVA, N=15 without VVA). Participants were 

recruited from three clinical sites. All interviews were performed by a trained qualitative 

interviewer and transcribed and coded for content analysis according to well-established 

coding procedures and analysis methods. Results: Based on findings from both phases 

of qualitative interviewing, the draft questionnaire was modified and a revised 

conceptual model proposed. The revised VVAQ questionnaire consists of 14 

individual items that assess vaginal and urinary health, impact on sexual function, and 

associated distress. The revised conceptual model and questionnaire includes the 

following domains: sensations, severity, perceived distress/bother, activities/function 

associated with symptomatic VVA and patient perception and experience of GSM/

VVA. The sensation domain includes questions on dryness, burning, and pain during 

daily activities and urination. Pain during sexual activity is also addressed. Severity of 

GSM/VVA symptoms is also captured. In the perceived distress/bother domain, 

patients are asked if they have experienced any relief of their symptoms. Activities/

Function domain includes items on sexuality (sexual function and spontaneity), other 

activities (clothing selection) and quality of life (relationships with partner(s)). Lastly, 

the patient perception and experience of GSM/VVA is addressed. Results from the 

cognitive debriefing phase confirmed that all of these items are comprehensible and 

relevant to women with and without symptomatic VVA. In the next phase of 

development, the draft questionnaire will be further evaluated in a quantitative 

validation study in women with and without diagnosed symptomatic VVA. 

Conclusion: In response to the urgent need for a patient-based, validated questionnaire 

of symptomatic VVA, a novel PRO measure has been developed based on qualitative 

responses of post-menopausal women with and without VVA. This new PRO measure 

was developed in close accordance with FDA’s Guidance for PRO development and 

validation, and based also on expert advice from clinicians and researchers. Further 

clinical validation is planned, along with broader use of the measure in research and 

clinical settings.

Sources of Funding: Allergan, Shionogi, Pfizer 


Efficacy of vaginal misoprostol before diagnostic hysteroscopy in 

postmenopausal women: a randomized double-blind placebo-controlled 

clinical trial

Fabiana Y. Nakano, MD, Lucia H. Costa-Paiva, Adriana O. Pedro, MD, Joao Paulo L. 

Pinto, MD, Cristina  L. Benetti-Pinto, MD, PhD, Daniela  Y. Gomes, MD, PhD. 

Gynecology, UNICAMP, Campinas, Brazil

Objective: To evaluate the efficacy and safety of prior use of misoprostol or placebo 

for postmenopausal women undergoing diagnostic hysteroscopy. Design: Randomized 

double-blind placebo-controlled clinical trial of 158 postmenopausal women who received 

either 200μg of misoprostol or placebo by vaginal route before diagnostic hysteroscopy. 

Indication for the exam, duration of the procedure, need for additional cervical dilatation, 

pain intensity, complications and adverse effects were studied. Results: Abnormal 

bleeding and endometrial thickening were the most common indications of the exam 

in both groups (p=0.4974). The duration of hysteroscopy was similar in both groups 

(p=0.43). Additional cervical dilatation was needed in 11 women in misoprostol group 

versus 9 in placebo group (p=0.6323). In both groups, there was no significant difference 

in pain intensity and complications. Adverse effects were reported by 25.3% of women 

using misoprostol and were vaginal bleeding in 11.3%, cramping in 12.6% and diarrhea 

in 2.5% while one reported both vaginal bleeding and cramping. In the placebo group, 

only 2.5% of women presented adverse effects (p=0.0001). Conclusion: Misoprostol 

does not reduce duration of the procedure, need for additional cervical dilatation, pain 

intensity and causes more adverse effects when used in postmenopausal women prior 

diagnostic hysteroscopy.

Sources of Funding: Fundação de Amparo à Pesquisa do Estado de São Paulo 

(FAPESP), Brazil.


Cortisol Response to Acute Stress in Midlife Women with Vasomotor 


Margo Nathan, MD


, Kathryn Sullivan, BA


, Aleta Wiley, MPH


, Kathleen McCormick, 



, Akanksha  Srivastava


, Hadine  Joffe, MD, MSc



Psychiatry, Brigham and 

Women’s, Boston, MA; 


Psychosocial Oncology and Palliative Care, Dana-Farber 

Cancer Institute, Boston, MA

Objective: Hot flashes and night sweats, or vasomotor symptoms (VMS), have been 

linked with altered diurnal cortisol secretion patterns in midlife women. These patterns 

are similar to those observed in individuals with insomnia. While resting-state cortisol 

levels have been investigated in women with VMS, previous studies have not examined 

if the presence of VMS also leads to perturbed cortisol release in response to acute 

stressors. Individuals with underlying chronic stress conditions (such as PTSD and 

depression) have been found to have both abnormally blunted and hyper-reactive cortisol 

release related to experimentally induced stress. Because women with significant VMS 

have more psychological distress and report more stress, we examined whether women 

with VMS also experience abnormal cortisol release patterns in response to an acute 

experimental stress paradigm compared to women without VMS. We also investigated 

if abnormal cortisol response was intensified by the presence of insomnia as these 

conditions are frequently linked. Design: 37 midlife women completed the Montreal 

Imaging Stress Task (MIST), a stress paradigm derived from the Trier Mental Challenge 

Test that includes a computerized arithmetic task combined with a social evaluative threat. 

27 (73%) women reported VMS (mean 12.9 VMS events per 24hr) during screening 

and 10 (27%) reported none or <1 VMS event per 24 hours. All subjects completed 

questionnaires assessing insomnia (ISI), depressive (PHQ-8), and anxiety symptoms 

(HAM-A). Before and after completing the task, salivary cortisol, blood pressure, heart 

rate, and acute psychological responses (frustration, stress, anxiety, pain, comfort, calm, 

confidence) on a Visual Analog Scale (VAS) were measured. Within-person change 

in each of these measures was compared between those with and without VMS using 

Student’s t-tests. To examine the impact of comorbid insomnia (defined as ISI>=14, 

threshold score for clinical insomnia), we also examined differences between subjects 

without VMS (n=10), with VMS but no insomnia (n=16), and with both VMS and 

insomnia (n=11) using the non-parametric test for trend between the 3 groups. Results: 

Women with VMS had a smaller cortisol change in response to the MIST stress task 

compared to women without VMS (mean: 0.02 μg/dl, 54% increase vs 0.07 μg/dl, 83% 

increase, p=0.039, respectively). Mean baseline cortisol did not differ between those with 

and without VMS (0.1 μg/dl vs. 0.09 μg/dl; p=0.74). Time of day, and time from wake 

had no significant effect on baseline cortisol or cortisol response. Women with VMS had 

a diminished stress response on all VAS items, particularly on domains of confidence 

(p=0.08) and calm feelings (p<0.01) compared to women without VMS. When the VMS 

group was divided according to the presence or absence of insomnia symptoms, women 

with both VMS and insomnia had the smallest cortisol elevation in response to the acute 

stressor (mean cortisol increase 0.01 vs. 0.03 vs. 0.07 μg/dl for VMS plus insomnia vs. 

VMS but no insomnia vs. no VMS/no insomnia, respectively; p=0.09). Women with 

VMS also reported higher depressive (PHQ-8, p<0.01) and anxiety symptoms (HAM-A, 

p<0.01). No group differences were observed in cardiovascular responses to the task. 

Conclusion: Results of this study show that women with VMS have a blunted acute 

response to a cognitive and social stressor task. This association was more pronounced 

when VMS were comorbid with insomnia symptoms. These findings suggest that chronic 

exposure to VMS is associated with an abnormal adrenal acute stress response, similar to 

that observed in people with other chronic stress conditions such as PTSD.

Sources of Funding: Department of Psychiatry, Brigham and Women's Hospital


Lipoperoxide levels increase and superoxide dismutase decreases, as 

oxidative stress biomarkers, with hot flashes severity after menopause

Martha A. Sanchez-Rodriguez, PhD


, Mariano  Zacarias-Flores, MD ObGyn


, Paola 

Montserrat  Martinez-Rangel


, Victor Manuel  Mendoza-Nuñez, PhD



Facultad de 

Estudios Superiores Zaragoza, Universidad Nacional Autónoma de México, Mexico, 



Hospital Gustavo Baz Prada, Instituto de Salud del Estado de México, 

Nezahualcoyotl, Mexico

Objective: To determine the relationship among different oxidative stress biomarkers 

and the hot flashes severity in postmenopausal women. Design: We carry out a cross-

sectional study with 90 postmenopausal women of Mexico City, 48-57 yr (52.2±3.5 yr). 

We measured plasma lipoperoxides (LPO) by the TBARS assay, erythrocyte superoxide 

dismutase (SOD) and glutathione peroxidase (GPx), and total plasma antioxidant status 

with Randox kits, all as oxidative stress biomarkers. The hot flashes were evaluated 

by Hot Flush Weekly Weighted Score, developed and evaluated by Sloan J et al., and 

strengthen the concepts pictorially. In this test, the amount and intensity of the hot flashes 

in 24 hours, during 1 week, were registered by each woman. For the evaluation, we 

classified 5 categories of hot flashes intensity (0= no, 1= mild, 2= moderate, 3= severe 

and 4= very severe), we added the total of hot flashes per day, and then we multiplied 

each category by the number of times that was presented to the week. After, we obtained 

the scores and it was stratified into 3 groups per the intensity of the hot flashes as: 

mild (<17), moderate (17-59) and severe ≥60). Results: A positive correlation between 

LPO and hot flashes score was observed (r=0.342, p<0.05) [Figure A] and, a negative 

correlation between SOD and the test score (r=-0.286, p<0.05) [Figure B]; other 

oxidative stress markers were not related. LPO levels increase with hot flashes severity 

(mild 0.309±0.06, moderate 0.351±0.07 and severe 0.372±0.06 μmol/L, p<0.05) and 

SOD activity diminished (mild 1.29±0.13, moderate 1.19±0.11 and severe 1.16±0.07 

U/gHb, p<0.05). Conclusion: Our findings suggest that LPO levels increase and SOD 

activity decreases with the severity of hot flashes, showing high oxidative stress in 

postmenopausal women with severe hot flashes.

Sources of Funding: This work was supported by grant DGAPA-UNAM IN306517

Figure. A. Correlation between lipoperoxides levels and hot flashes score; B. SOD 

and hot flashes score.

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