Katherine M. Newton

Efficacy of Vaginal Estradiol or Vaginal Moisturizer vs Placebo for Treating Postmenopausal Vulvovaginal Symptoms: A Randomized Clinical Trial

Importance Nearly half of postmenopausal women report bothersome vulvovaginal symptoms, but few data support the efficacy of 2 commonly recommended treatments. Objective To compare the efficacy of a low-dose vaginal estradiol tablet and a vaginal moisturizer, each vs placebo, for treatment of moderate-to-severe postmenopausal vulvovaginal symptoms. Design, Setting, and Participants This 12-week multicenter randomized clinical trial enrolled postmenopausal women with moderate to severe symptoms of vulvovaginal itching, pain, dryness, irritation, or pain with penetration. Interventions Vaginal 10-&mgr;g estradiol tablet (daily for 2 weeks, then twice weekly) plus placebo gel (3 times a week) (n = 102) vs placebo tablet plus vaginal moisturizer (n = 100) vs dual placebo (n = 100). Main Outcomes and Measures The main outcome was decrease in severity (0-3) of most bothersome symptom (MBS) between enrollment and 12 weeks. Additional measures included a composite vaginal symptom score, Female Sexual Function Index (FSFI) score (2-36), modified Female Sexual Distress Score–Revised item 1, treatment satisfaction and meaningful benefit, Vaginal Maturation Index, and vaginal pH. Results The 302 women had a mean (SD) age of 61 (4) years and were primarily white (267 [88%]), college educated (200 [66%]), and sexually active (245 [81%]). Most women (294 [97%]) provided data for the primary analysis. The most commonly reported MBS was pain with vaginal penetration (182 [60%]), followed by vulvovaginal dryness (63 [21%]). Mean baseline MBS severity was similar between treatment groups: estradiol, 2.4 (95% CI, 2.3 to 2.6); moisturizer, 2.5 (95% CI, 2.3 to 2.6); placebo, 2.5 (95% CI, 2.4 to 2.6). All treatment groups had similar mean reductions in MBS severity over 12 weeks: estradiol, −1.4 (95% CI, −1.6 to −1.2); moisturizer, −1.2 (95% CI, −1.4 to −1.0); and placebo, −1.3 (95% CI, −1.5 to −1.1). No significant differences were seen between estradiol (P = .25) or moisturizer (P = .31) compared with placebo. Mean total FSFI improvement was similar between estradiol (5.4; 95% CI, 4.0 to 6.9) and placebo (4.5; 95% CI, 2.8 to 6.1) (P = .64), and between moisturizer (3.1; 95% CI, 1.7 to 4.5) and placebo (P = .17). Conclusions and Relevance Our results suggest that neither prescribed vaginal estradiol tablet nor over-the-counter vaginal moisturizer provides additional benefit over placebo vaginal tablet and gel in reducing postmenopausal vulvovaginal symptoms. Trial Registration clinicaltrials.gov Identifier: NCT02516202

Endometrial Hyperplasia Risk in Relation to Recent Use of Oral Contraceptives and Hormone Therapy

PURPOSE We sought to examine the relationship between recent use of oral contraceptives and hormone therapy and endometrial hyperplasia (EH) risk. METHODS Cases comprised women diagnosed with complex EH (n = 289) or atypical EH (n = 173) between 1985 and 2003. One age-matched control was selected for each case; excluded were women with a prior hysterectomy or diagnosis of EH or endometrial cancer. Hormone use in the 6 months prior to the date of the cases first symptoms was ascertained using a pharmacy database and medical records. Odds ratios (OR) and 95% confidence intervals (CI) were calculated. RESULTS Three (1.1%) cases had used oral contraceptives, compared to 16 (6.0%) controls (OR = 0.2, 95% CI: 0.0-0.6). Fifty-one (16.8%) cases had taken estrogen-only hormone therapy, in contrast to two (0.7%) controls (OR = 37.6, 95% CI: 8.8-160.0). The risk of EH among estrogen plus progestin hormone users did not differ from that of non-users (OR = 0.7, 95% CI: 0.4-1.1). CONCLUSIONS This study suggests that previous findings of the association of estrogen-only hormone therapy with increased risk of EH and the lack of an association between estrogen plus progestin hormone therapy and EH risk are likely to apply to both complex EH and atypical EH. Further examination of the association between oral contraceptives and EH, with greater numbers of OC users, is warranted.

Associations between improvement in genitourinary symptoms of menopause and changes in the vaginal ecosystem

Objective: The aim of the study was to identify associations between improvement in genitourinary symptoms of menopause (GSM) and vaginal microbiota, vaginal glycogen, and serum estrogen. Methods: Thirty postmenopausal women enrolled in a hot flash treatment trial (oral estradiol vs venlafaxine vs placebo) who reported GSM and provided vaginal swabs at 0, 4, and 8 weeks were studied. Bacterial communities were characterized using deep sequencing targeting the 16S rRNA gene V3-V4 region. Participants selected a most bothersome genitourinary symptom (dryness, discharge, pain, itch/burn, or inability to have sex) and rated severity on a 10-point scale at baseline and 8 weeks. Vaginal glycogen and serum estradiol and estrone were measured at enrollment and 8 weeks. Comparisons according to improvement in most bothersome symptom (MBS) were made using &khgr;2, Wilcoxon signed-rank test, or Hotellings t test. Results: Of 30 participants, 21 (70%) had improvement in MBS over the 8-week study and 9 (30%) had no improvement or worsening of MBS. A higher proportion of women receiving estradiol or venlafaxine reported improvement in MBS (88%, 78%) compared with placebo (54%; P = 0.28). MBS improvement was associated with Lactobacillus-dominant vaginal microbiota at enrollment (57% vs 22%, P = 0.08). Vaginal glycogen, serum estradiol, and estrone significantly increased in women whose MBS improved. Conclusions: A larger proportion of women whose MBS improved had a Lactobacillus dominant microbiota at enrollment than those who had no improvement during the trial, though this difference was not statistically significant. Larger trials are needed to determine whether vaginal microbiota modify or mediate treatment responses in women with GSM.

Abstract A22: Associations between dietary intake and novel genotoxic estrogen biomarkers implicated in breast cancer risk

Background: An expansive body of evidence implicates estrogen in the development of breast cancer (BC). Recently, a novel estrogen biomarker, the genotoxoic estrogen ratio (GER), was shown to be associated with BC. In addition, an elevated GER was observed in women at high-risk of BC, and furthermore, high GER has been shown to be reversible. Because of the potential for phytochemicals to inhibit activating enzymes and induce protective enzymes within the metabolism pathway resulting in reduced GER, we sought to examine associations between dietary factors and GER. Methods: This analysis was conducted in 53 pre-menopausal, healthy women aged 40-45 years from a cross-sectional study in which participants provided first-void urine samples and 3-day food records. The estrogen metabolites, conjugates and depurinating DNA adducts comprising the GER were identified from urine samples using ultraperformance liquid chromatography/ tandem mass spectrometry. The numerator of GER contains estrogen compounds which are bound to DNA as depurinating adducts, and thus have the potential to be genotoxic; the denominator contains the unbound estrogen counterparts consisting of estrogen metabolites and conjugates. A trend test was used to assess associations between tertiles of nutrient and food intake. Results: We observed GER to be associated with dietary intake after adjustment for age, total calories, percent adiposity, and estradiol. Specifically, elevated GER was associated with low vegetable intake (p=0.01), low carbohydrate consumption (p=0.01), low botanical intake (p=0.04), and high animal protein consumption (p=0.05). In particular, elevated GER was associated with the increasing servings of eggs (p=0.01) and fish (p=0.02) per day. In addition, low GER was associated with three botanical groupings: highest category of umbelliferae consumption (which includes carrots and celery; p=0.01), middle category of cruciferae consumption (which includes broccoli and cabbages; p=0.05), and middle category of ericaceae consumption (which includes blueberries and cranberries; p=0.05). Conclusion: These data provide the first investigation of lifestyle factors in relation to this novel GER biomarker. While these data would require replication, this early report suggesting inverse associations between dietary intake of botanical foods and GER provides an intriguing link between dietary factors and a novel biomarker with implications for breast cancer risk. Citation Format: Kerryn W. Reding, Muhammed Zahid, Ercole Cavalieri, Eleanor G. Rogan, Charlotte Atkinson, Mellissa Yong, Katherine Newton, Johanna Lampe. Associations between dietary intake and novel genotoxic estrogen biomarkers implicated in breast cancer risk. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr A22.