To the Editor.

We would like to respond to a recent Personal Perspective piece by Ms. Lukas and Dr. Simon regarding the Menopause Strategies: Finding Lasting Answers for Symptoms and Health (MsFLASH) vaginal health trial. The commentary reiterates several misconceptions about the trial, misconceptions rooted in what we believe is an outdated and physician-centered view of treatment for postmenopausal vaginal discomfort. We agree with Ms. Lukas regarding the following points: 1) Vaginal estrogen is highly effective in treating the physical attributes of vulvovaginal atrophy (VVA). It decreases vaginal pH, improves the vaginal maturation index (VMI), and improves physical examination findings; and 2) It is likely that including more women in the MsFLASH vaginal health trial would have demonstrated statistical significance in the difference between placebo and vaginal estrogen in improving the most bothersome vaginal symptom (MBS). But this is where the commonalities in our views end. First and foremost, our patients want us to treat the bothersome symptoms of genitourinary syndrome of menopause (GSM), not just VVA. We know that not all women with VVA have GSM and not all women with GSM have VVA. Secondly, our study was powered to detect a difference of half a standard deviation (a difference that is accepted as likely to be clinically relevant) between treatment arms in the change from baseline to week 12 of MBS severity (approximately 0.5 point on a 0-3 scale; mean baseline score 2.5). Statistical significance of a smaller yet not clinically meaningful difference in GSM was not our goal. Our research question was, ‘‘Does vaginal estrogen provide meaningful clinical benefit beyond the effect of treatment with a noninflammatory placebo gel for improving symptoms of GSM? ’’. Our primary outcome was MBS severity, similar to prior studies. MBS is not a composite outcome, rather it is the single symptom that the patient herself chooses as the most bothersome, which allowed us to enroll women with the broad spectrum of symptoms that make up GSM – all of which negatively impact quality of life. Secondary outcomes were change in Female Sexual Function Index (FSFI) and change in frequency of sexual activity. We hypothesized a priori that estrogen would provide a meaningful clinical benefit in MBS severity above placebo. Of the 302 women in our trial, 81% reported moderate to severe dyspareunia and 82% reported moderate to severe vaginal dryness at baseline, although they may not have selected these symptoms as their MBS (chosen as MBS by 60% and 21% of women, respectively). The MsFLASH vaginal health trial was unique in its study design, a design that passed the muster of a highly competitive National Institutes of Health study section review. The trial compared vaginal estrogen tablet 10 mcg (nightly for 2 weeks and then 2 x per week)þ vaginal placebo gel to vaginal placebo tabletþ vaginal placebo gel. We found no statistically significant difference in MBS severity at 12 weeks between the active and placebo arms, suggesting that the estrogen tablet in doses that are FDA approved did not add clinically meaningful benefit beyond the placebo gel. Nor was there benefit with the addition of vaginal estrogen to the placebo gel on FSFI or frequency of sexual encounters. However, to be very clear, on average all three groups in the trial saw an improvement in both MBS severity and FSFI. Vaginal estradiol (E2) helped (70% of women experienced at least 50% reduction in symptom severity) – it just didn’t help significantly more than our placebo (65% of women experienced at least 50% reduction in severity). We did see greater changes in pH, VMI, and microbiota in the E2 arm relative to placebo, but these did not correlate with symptom improvement: over half of women across all groups with no improvement in VMI or pH had reduction in symptom severity of at least 50%. As we have stated previously: ‘‘To us, this suggests that estrogen repletion is sufficient to improve genitourinary symptoms after menopause in many women, but is not always necessary for symptom improvement. We hope that the results of our study encourage patients and physicians to appreciate the complexity of this highly burdensome problem and to discuss all options for symptom management, choosing the one that best meets the patient’s medical and financial needs. ’’ Finally, we would encourage our colleagues to focus more on the patient experience than provider-evaluated markers of ‘‘atrophy. ’’ Both measurements are subjective, despite many providers viewing markers of atrophy as objective measurements, and thus the patient-reported outcomes should have primacy. While vaginal estrogen is a very helpful tool for many women, in the REVIVE survey cited by Ms. Lukas, a quarter of women reported insufficient symptom relief from vaginal prescription treatments. Other studies demonstrate limited patient enthusiasm for vaginal estrogen: one woman said, ‘‘I have a prescription for Premarin vaginal cream that makes it less bad, but not good’’. Even the women who had found vaginal hormones effective had lingering concerns. They reported that these treatments were messy, expensive, or they had concerns about potential side effects, including cancer. Comments like this suggest we do not have a complete understanding of GSM, its impact, or how best to treat it. In another secondary analysis of trial data (one not discussed by Ms. Lukas and Dr. Simon), Diem et al found a small but statistically significant increase in MenopauseSpecific Quality of Life in women randomized to the E2 arm relative to the placebo arm. In the primary analysis, we