Obstetrics & Gynecology:
Effective Treatment of Vaginal Atrophy With an Ultra–Low-Dose Estradiol Vaginal Tablet
Simon, James MD1; Nachtigall, Lila MD2; Gut, Robert MD, PhD3; Lang, Eva MD4; Archer, David F. MD5; Utian, Wulf MD, PhD6
From the 1Women’s Health & Research Consultants, Washington, DC; 2New York University School of Medicine, New York, New York; 3Novo Nordisk Inc., Princeton, New Jersey; 4Novo Nordisk FemCare AG, Zurich, Switzerland; 5CONRAD Clinical Research Center, Norfolk, Virginia; and 6Women’s Health and Research Consultants, Cleveland, Ohio.
For a list of principal investigators who participated in the conduct of this trial, see the Appendix online at www.greenjournal.org/cgi/content/full/112/5/1053/DC1.
Supported by Novo Nordisk A/S, Bagsvaerd, Denmark. Statistical and editorial support was provided by Novo Nordisk Inc., Princeton, NJ.
Corresponding author: James A. Simon, MD, CCD, FACOG, Women’s Health & Research Consultants, 1850 M Street, NW, Suite 450, Washington, DC 20036; e-mail: email@example.com.
Financial Disclosure Dr. Simon has served as a consultant or on the advisory boards of Allergan (Irvine, CA), Alliance for Better Bone Health (Cincinnati, OH), Ascend (Herndon, VA), Barr (Pomona, NY), Bayer (Leverkusen, Germany), BioSante (Lincolnshire, IL), Corcept Therapeutics, Inc. (Menlo Park, CA), GlaxoSmithKline (Philadelphia, PA), KV Pharmaceutical Co. (St. Louis, MO), Meditrina (Ann Arbor, MI), Merck (Whitehouse Station, NJ), Merrion (Wilmington, NC), Nanma/Tripharma/Trinity, (Glen Arm, MD), Novo Nordisk A/S (Bagsvaerd, Denmark), Novogyne (East Hanover, NJ), Pear Tree (Cambridge, MA), QuatRx Pharmaceuticals (Ann Arbor, MI), Roche (Basel, Switzerland), Sciele (Atlanta, GA), Solvay (Marietta, GA), Ther-Rx (Bridgeton, MO), Warner Chilcott (Rockaway, NJ), and Wyeth (Madison, NJ). He has received grant/research support From BioSante, Boehringer Ingelheim, (Ingelheim, Germany), FemmePharma (Wayne, PA), GlaxoSmithKline, Nanma/Tripharma/Trinity, Novartis (Basel, Switzerland), and Proctor and Gamble (Cincinnati, OH). He has also served on the speakers bureaus of Ascend, Barr, Bayer, GlaxoSmithKline, KV Pharmaceutical Co., Merck, Novartis, Novogyne, Sciele, TherRx, Warner Chilcott, and Wyeth. Dr. Gut is an employee of Novo Nordisk. Dr. Lang is an employee of Novo Nordisk FemCare AG. Dr. Archer has been a consultant to or received research support from Novo Nordisk, Solvay, Organon (Roseland, NJ), Wyeth, Bayer, and Warner Chilcott. Dr. Utian has had advisory relationships with Organon, Barr/Duramed, GlaxoSmithKline, Depomed, (Menlo Park, CA), KV Pharmaceutical Co., Bionovo (Emoryville, CA), Merck, Pfizer (New York, NY), Merrion, Wyeth, and Proctor and Gamble. Dr. Nachtigall has no potential conflicts of interest to disclose.
OBJECTIVE: To evaluate the efficacy of ultra–low-dose 10-microgram 17β-estradiol (E2) vaginal tablets for treatment of vaginal atrophy.
METHODS: Postmenopausal women (N=309) were randomly assigned to 10-microgram E2 or placebo vaginal tablets for 52 weeks in a multicenter, double-blind study. Primary efficacy endpoints included change from baseline to week 12 in vaginal cytology, vaginal pH, and most bothersome urogenital symptoms score. Grading of vaginal health was a secondary efficacy assessment. Safety assessments included endometrial biopsy, physical and gynecologic examinations, and recording adverse events.
RESULTS: At week 12, the change from baseline for 10 micrograms E2 compared with placebo demonstrated significant improvement in vaginal Maturation Index (proportion of parabasal cells: –37% compared with –9%; superficial cells: 13% compared with 4%; intermediate cells: 24% compared with 5%; P<.001 for each), Maturation Value (25.0 compared with 6.5, P<.001), grading of vaginal health (–0.91 compared with –0.51, P<.001), vaginal pH grade (–1.3 compared with –0.4, P<.001), and most bothersome symptoms score (–1.23 compared with –0.87, P=.003). For each component of vaginal Maturation Index, vaginal Maturation Value, grading of vaginal health, and vaginal pH, treatment effects were statistically different from placebo after 2 weeks of treatment. For most bothersome symptoms, treatment effect became apparent after 4 weeks and reached statistical significance at week 8 of therapy. All treatment effects were statistically significant at week 52. There were no major safety findings regarding physical, gynecologic, or laboratory assessments.
CONCLUSION: After 12 weeks of treatment, an ultra–low-dose 10-microgram E2 vaginal tablet, compared with placebo, demonstrated significant improvement for the primary endpoints: vaginal cytology and pH and most bothersome urogenital symptoms score.
CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, http://clinicaltrials.gov, NCT00108849
LEVEL OF EVIDENCE: I
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After menopause, endogenous estradiol (E2) concentrations decline dramatically from an average of 120 pg/mL (premenopausal) to approximately 18 pg/mL (postmenopausal).1 As a result, the epithelium of the vagina and other estrogen-dependent tissues gradually undergo atrophy.1 The loss of estrogen-dependent cellular maturation in the vagina (vaginal atrophy) is manifested as a thin, friable vaginal epithelium, with symptoms of dryness, soreness, irritation, and dyspareunia. Vaginal atrophy may often lead to a reduced quality of life because of issues related to general vaginal discomfort as well as pain and bleeding during sexual activity. Additionally, the vaginal pH becomes less acidic, altering the normal vaginal flora, with the vaginal and bladder epithelium becoming more susceptible to infection and inflammation.2,3
Estrogen therapy (ET) can counteract many of these changes and reduce associated complications. A low-dose estrogen vaginal tablet containing 25 micrograms 17β-E2 (Vagifem; Novo Nordisk A/S, Bagsvaerd, Denmark) was first introduced in 1988 as a hydrophilic cellulose-based matrix and has been shown to provide continuous release of E2 in an atrophic vaginal vault, with transient absorption being significantly reduced after maturation of the epithelium.4 It was initially believed that the 25-microgram E2 dose (initiation therapy once daily dosing with twice weekly maintenance dosing) would be necessary for the effective treatment of vaginal atrophy. However, there were indications from clinical trials that a lower-dose tablet containing 10 micrograms E2 may also be effective for the relief of vaginal atrophy symptoms.4,5 The objectives of the current investigation were to evaluate the efficacy and safety of a new ultra–low-dose 10-microgram E2 vaginal tablet in a placebo-controlled, 52-week, double-blind clinical trial.
MATERIALS AND METHODS
This double-blind, randomized, parallel-group, placebo- controlled, multicenter trial was conducted in 45 centers in the United States and four centers in Canada to evaluate the efficacy and safety of a 10-microgram E2 vaginal tablet compared with placebo for the treatment of symptoms of vaginal atrophy, as assessed by clinical symptoms and objective measures. The study was initiated in March 2005 and received approval by the following institutional review boards: Coast Independent Review Board, LLC, San Clemente, California; Eastern Virginia Medical School, Norfolk, Virginia; Western Institutional Review Board, Olympia, Washington; University of Kentucky Medical Institutional Review Board, Lexington, Kentucky; Institutional Review Board Services, Ontario, Canada; St. Michael’s Hospital Research Ethics Board, Ontario, Canada; and the University of Manitoba Bannatyne Campus Biomedical Research Ethics Board, Manitoba, Canada. Written informed consent was obtained from each participant before the start of study procedures. The total trial duration was 52 weeks. The randomly assigned study participants (N=309) were nonhysterectomized, postmenopausal (2 or more years since final menstrual cycle or bilateral oophorectomy) women who were 45 years of age or older, with at least three urogenital symptoms (vaginal dryness, vaginal and/or vulvar irritation/itching, vaginal soreness, dysuria, or dyspareunia and vaginal bleeding associated with sexual activity), one of which had to be moderate to severe in intensity. All participants were required to have serum E2 levels less than 20 pg/mL, follicle-stimulating hormone levels more than 40 milli–international units/mL, 5% or more superficial cells in vaginal cytology, vaginal pH more than 5.0, an endometrial thickness of less than 4.0 mm as assessed by transvaginal ultrasonography, and a normal mammogram within the 6 months before study entry.
Known or suspected history of breast carcinoma, hormone-dependent tumor, genital bleeding of unknown cause, acute thrombophlebitis or thromboembolic disorder associated with estrogen use, vaginal infection requiring treatment, allergy to the test drug or its constituents, or any serious disease or chronic condition that could interfere with study compliance were among the criteria for exclusion. The use of any investigational drug within the 30 days preceding screening, exogenous sex hormones within 3 months before study drug initiation, or current use of corticosteroids were prohibited.
Participants were randomly assigned in a 2:1 ratio in blocks of six to receive vaginal tablets containing either 10 micrograms E2 (Novo Nordisk A/S, Bagsvaerd, Denmark) or placebo (205:104 participants). A ratio of 2:1 was chosen to reduce the number of participants receiving placebo treatment. A sample size of at least 200 participants treated with 10 micrograms E2 and 100 placebo-treated participants was calculated to be needed to provide 90% power in change from baseline to week 12 to detect a between-treatment difference of 0.48 (standard deviation [SD] of ±1.1) for the relief of urogenital symptoms (based upon the most bothersome symptom score), a difference of 7.2% (SD±16.5%) in percentage of parabasal cells, 8.6% (SD±19.7%) in the percentage of superficial cells, and 0.44 (SD±1.0) for vaginal pH. The estimated sample size was based on a two-tailed t test significance level of 0.05, assuming a 15% dropout rate. All data reported at week 12 and week 52 are from the intent-to-treat analyses, with missing values for each individual imputed using the last observation carried forward approach. Analysis of covariance (ANCOVA) was used for the between-group comparison in analyzing the urogenital symptom data, with treatment as a fixed effect and corresponding baseline value as a covariate. These analyses were performed on change from baseline scores at week 2, week 4, week 8, week 12, week 12 (last observation carried forward), week 26, week 39, week 52, and week 52 (last observation carried forward). Treatment differences (10 micrograms E2 minus placebo) expressed as least-squares mean (standard error), and 95% confidence intervals (CIs), accompany P values for primary endpoints.
All vaginal tablets were identical in appearance. The medications package prepared for each participant had an allocation number using a drug assignment list generated by Novo Nordisk Inc. (Princeton, NJ). Copies of the randomization codes were kept in sealed envelopes at the site as well as by the clinical trial sponsor. A central telephone system was used for randomization.
Treatment instructions were to insert one vaginal tablet daily for 14 days, and subsequently one tablet twice per week. The participants were also instructed to insert the tablets at the same time each day.
The symptoms of vaginal atrophy assessed in this trial were vaginal dryness, vaginal and/or vulvar irritation/itching, vaginal soreness, dysuria, and dyspareunia and vaginal bleeding associated with sexual activity. The primary efficacy endpoints for this study included the mean change from baseline to week 12 (last observation carried forward) in vaginal Maturation Index and Value, vaginal pH, and the mean score of most bothersome moderate to severe symptoms as identified by the patient.
For vaginal cytology, vaginal smears were taken from the upper third of the right lateral vaginal wall and analyzed at a central laboratory (Covance Laboratory, Indianapolis, IN). These samples were used to determine the Maturation Index, which describes the proportion of parabasal, intermediate, and superficial cells. The Maturation Value was calculated according to the formula: MV=(0×% parabasal cells)+(0.5×% intermediate cells)+(1.0×% superficial cells), where MV is the Maturation Value. Maturation of the vaginal epithelium (a positive treatment effect) is evidenced by a decrease in parabasal cells and an increase in the proportion of superficial cells and is associated with an increase in Maturation Value.
At each visit, the definitions of the symptoms (vaginal dryness, vaginal and/or vulvar irritation/itching, vaginal soreness, dysuria, and dyspareunia and vaginal bleeding associated with sexual activity) and severity (none=0, mild=1, moderate=2, severe=3) of vaginal atrophy were explained to the participant. The participants were then asked to complete an independent self-administered questionnaire describing the symptoms as well as indicating the severity. At baseline, participants were also instructed to identify the one symptom that was most bothersome to them, and the mean score of the most bothersome urogenital symptom within each treatment group was calculated.
For grading of vaginal health, evaluations were made regarding vaginal secretions, vaginal epithelial integrity, vaginal epithelial surface thickness, vaginal color, and vaginal pH. Grading of vaginal health was quantified using a four-point scoring system (no atrophy=0, mild=1, moderate=2 and severe=3).
Vaginal pH was a part of vaginal health evaluation. The pH values were grouped as pH less than 5.0, pH 5–5.49, pH 5.5–6.49, pH more than 6.49 to allow categorical shifts in the pH to be more obvious. The clinical significance of the grouping was that pH less than 5.0 would be indicative of a lack of vaginal atrophy, pH 5–5.49 would indicate mild vaginal atrophy, pH 5.5–6.49 would indicate moderate vaginal atrophy, and a pH more than 6.5 would indicate severe atrophy.
The endometrial safety of the ultra–low-dose 10-microgram E2 tablet was evaluated through endometrial biopsies conducted at screening and at the end of the trial. The endometrial tissue was processed at a central laboratory by two independent pathologists. Other safety endpoints included gynecologic and physical examinations, Papanicolaou cervical smear, transvaginal ultrasonography, and adverse events (coded using the Medical Dictionary for Regulatory Activities 10.0, International Federation of Pharmaceutical Manufacturers and Associations, Geneva, Switzerland) and laboratory tests.
Participants were enrolled in this trial from March 2005 to May 2006. Of the 309 participants enrolled, a total of 205 participants received 10-microgram vaginal E2 tablets and 104 participants received placebo vaginal tablets (Fig. 1). Demographics and baseline characteristics were comparable across treatment groups (Table 1). Trial participants were predominantly white (93%), on average 57.6 years old (range 46–81 years) and 8 years since last menses, with body weight and body mass indices within normal ranges. In addition, the medical and gynecologic histories of these participants were appropriate for the patient population and were comparable between treatment groups. Of the enrolled participants, 67% (70 of 104) of the placebo-treated and 80% (164 of 205) of the 10 micrograms E2–treated group completed the study. Within the placebo-treatment group, 34 (32.7%) participants discontinued the study compared with 41 (20.0%) 10 micrograms E2–treated participants. Approximately 5% of participants discontinued the study because of adverse events (placebo, 5 (4.8%) participants; 10 micrograms E2, 11 (5.4%) participants). Another 17 (5.5%) participants discontinued due to ineffective therapy (placebo, 11 (10.6%) participants; 10 micrograms E2, 6 (2.9%) participants). Additionally, 16 (15.4%) participants in the placebo group and only 18 (8.8%) participants in the 10 micrograms E2 group discontinued because of “Other” reasons (eg, withdrawal of informed consent or lost to follow-up).
The results indicate that after only 2 weeks of daily administration of 10 micrograms E2 there was a marked increase in the proportion of vaginal superficial and intermediate cells, with a concurrent decrease in the proportion of vaginal parabasal cells as compared with placebo treatment (Figs. 2A and 2B). These observations were maintained until week 12 (twice weekly treatment after week 2), which was the study primary endpoint. The proportion of vaginal superficial cells increased by 13% compared with 4% for placebo (least-squares mean treatment difference 10, standard error [SE] 1.9, 95% CI 6.2–13.8, P<.001), and vaginal intermediate cells increased by 24% compared with 5% for placebo, (difference 19, SE 3.2, 95% CI 12.3–25.0, P<.001). Additionally, the proportion of vaginal parabasal cells decreased significantly by 37% compared with 9% for placebo, (difference –29, SE 3.0, 95% CI –34.6 to –22.8, P<.001). These changes indicate statistically significant improvement in the cellular subtypes toward more normal, premenopausal epithelium. The treatment effects were sustained and statistically significant at week 52 (last observation carried forward) (parabasal, P<.001; superficial, P<.001; intermediate, P<.001).
At baseline, mean Maturation Values were 29.4 for placebo and 30.6 for 10 micrograms E2. Maturation Values demonstrated a statistically significant treatment effect after only 2 weeks of treatment (change from baseline for placebo, 8.3; 10 micrograms E2, 31.6; P<.001), which was sustained until week 12 (last observation carried forward, primary endpoint) (change from baseline for placebo, 6.5; 10 micrograms E2, 25.0; difference 19.3, SE 1.94, 95% CI 15.5–23.2, P<.001; Fig. 2C) and furthermore until week 52 (last observation carried forward), where the mean change from baseline in Maturation Value was 5.9 for the placebo-treated participants and 24.5 for the 10 micrograms E2–treated participants (P<.001).
At baseline the mean grade for vaginal health was 1.78 and 1.70 for the placebo and 10 micrograms E2 treatment groups, respectively. After 2 weeks of daily treatment, the mean vaginal health score had decreased to 1.02 for the 10 micrograms E2 treatment group and 1.35 for the placebo treatment group (Fig. 3). This difference was statistically significant (P<.001) compared with placebo. These significant treatment benefits were also demonstrated at weeks 4, 8, 12, and 52 (P<.001 at all time points).
At baseline, 93 (91%) participants in the placebo group and 175 (86%) participants in the 10 micrograms E2 group had vaginal pH of 5.5 or more, indicating moderate or severe atrophy (Table 2). After 12 weeks of treatment, there was a clear shift in the numbers of participants toward more acidic, ie, normalized, vaginal pH values: In the placebo treatment group, only 37 (36%) participants had pH less than 5.5 compared with 145 (72%) participants in the 10 micrograms E2 treatment group.
In addition to identifying the presence and severity of their urogenital symptoms, the participants were also asked to identify the single symptom which they found to be most bothersome. The severity of symptoms was graded on a 4-point scale as follows: none=0, mild=1, moderate=2, severe=3. At baseline, most participants indicated dyspareunia (placebo, 62 [61%]; 10 micrograms E2, 107 [53%]) and vaginal dryness (placebo, 27 [27%]; 10 micrograms E2, 58 [28%]) as their most bothersome symptoms. After 12 weeks of treatment with 10 micrograms E2, there was a statistically significant decrease from baseline in the mean score of the most bothersome urogenital symptom when compared with placebo treatment (placebo, –0.87; 10 micrograms E2, –1.23; difference –0.33, SE 0.110, 95% CI –0.55 to –0.12, P=.003, last observation carried forward). Symptom relief associated with 10 micrograms E2 treatment became apparent by after 4 weeks (P=.053) and statistically significant at week 8 (placebo, –0.91; 10 micrograms E2, –1.20, P=.014) (Fig. 4).
Of the 309 participants enrolled in the study, 235 participants (76.3%) experienced in total 777 adverse events (placebo, 77 [75%] participants, 216 events; 10 micrograms E2, 158 [77%] participants, 561 events). Greater than half of the adverse events were mild to moderate in nature. The most common adverse events were headaches and vaginal discharge among placebo-treated participants, whereas vulvovaginal mycotic infection, back pain, and vulvovaginal pruritus were more frequent among participants treated with 10 micrograms E2.
Overall, there were seven participants (2.3%) with a total of nine serious adverse events. In the placebo group, there were two participants (1.9%) with three events (gastrointestinal hemorrhage and two events of stent occlusion), whereas in the 10 micrograms E2 group, five participants (2.4%) presented six events (pneumonia, infraorbital squamous cell carcinoma, endometrial adenocarcinoma stage II, grade 2, ventricular extra systoles, gallstones, and inflammation of the gallbladder). Except for the events described above, no clinically relevant findings from physical, gynecologic, or laboratory assessments were reported during the study.
Approximately 10% to 40% of postmenopausal women have symptoms associated with vaginal atrophy.6 When hormone therapy is considered solely for this indication, vaginal (not systemic) ET is generally recommended.7 The position statement from the North American Menopause Society concludes that although the choice of therapy should be guided by clinical experience and patient preference, estrogen can be administered locally to treat the symptoms of vaginal atrophy, and vaginal ET should be continued for women as long as the bothersome symptoms remain.8
In postmenopausal women, the declining levels of estrogen result in cytologic changes in the vaginal epithelial cells that are characterized by an increase in parabasal cells and a marked decrease in superficial cells. The results from this study indicate that the local administration of an ultra–low-dose 10-microgram E2 vaginal tablet induces vaginal epithelial maturation, shifting the atrophic epithelium from a predominantly parabasal cell population to a superficial cell population, which is more typical of premenopausal women. Similar to the results published by Nilsson et al,4 in this study, a significant improvement in vaginal cytology was achieved after only 14 days of local administration. Nilsson et al also used the vaginal Maturation Index as an objective and quantitative indicator of hormonal treatment effect on the vaginal cellular profile. The current study indicates that there was a statistically significant improvement in the vaginal maturation index at week 2, which was sustained until week 52 (last observation carried forward). Studies by Notelovitz et al5 and Bachmann et al9 used the vaginal Maturation Value as quantitative indicators of treatment benefit on vaginal cytology profile. Those studies demonstrated a statistically significant improvement in vaginal Maturation Value posttreatment with 10-microgram E2 vaginal tablet at weeks 2 (P<.001) and 12 (P<.001). The results from our study indicate improvements in the cellular profile not only at weeks 2 and 12 but also at week 52. This change in the proportions of the cell types and the increased thickness renders the vaginal epithelium less prone to bleeding, and potentially improves vaginal–cervical paracellular permeability, leading to increased cell secretions and lubrication during intercourse.11
The acidic pH of vaginal fluid is an important component of the nonspecific host defense against pathogens. With declining levels of estrogen, the natural flora (Lactobacilli) numbers decrease, shifting the vaginal pH toward less acidity (pH more than 5.0) and allowing colonization by fecal flora and other pathogens.10 Within 2 weeks of treatment with 10 micrograms E2, vaginal pH shifted toward more acidic, more premenopausal pH. These findings confirm the results from other randomized clinical trials that evaluated vaginal pH as a primary outcome measure. The local administration of various vaginal estrogen formulations have been found to significantly decrease the pH from pretreatment values of 6.0 to less than 5.0.11–15 Preliminary results from a study of seven participants published by Santen et al16 demonstrated that 10-microgram E2 cream significantly reduced the mean vaginal pH scores by –2.7 from baseline after 3 weeks, an effect which was sustained throughout the 12 week assessment period.
If vaginal atrophy remains untreated, there is an increased likelihood that the vaginal epithelium will be friable, with petechiae, ulcerations, and tears, and prone to bleeding with even minimal trauma (eg, speculum insertion, intercourse).17 Vaginal atrophy and the associated bothersome symptoms (eg, vaginal dryness, vulvovaginal irritation, itching, dysuria, and dyspareunia) are directly associated with the decreased levels of estrogen. Local administration of 10 micrograms E2 resulted in a significant relief from most bothersome urogenital symptoms indicated by the women enrolled in this study. These findings are similar to those of a previous study, which also used a urogenital questionnaire, which indicated that 10-microgram dose of E2 also resulted in a significant reduction in total vaginal bothersome symptom scores within 12 weeks of treatment.16
Studies have indicated that 55% of women using an estrogen-containing transdermal patch and 73% taking oral therapy or percutaneous gel reported relief for vaginal symptoms.18 Other reports state that of eight women using systemic hormone therapy, two women reported persistent vaginal dryness or dyspareunia even after 12 months of treatment.19 In contrast, relief of vaginal symptoms was obtained consistently in 80% to 95% of women using local estrogen therapy.20 A meta-analysis of 10 randomized placebo-controlled studies found that estrogen therapy, in general, relieved vaginal symptoms, but vaginal therapy was more efficacious than systemic oral therapy.20
Although some systemic absorption of E2 occurs with all vaginal ET products, systemic absorption of E2 from low-dose vaginal ET products was shown to be low in previous active-comparator studies.21,22 A Cochrane review reported no significant differences among the delivery methods with respect to hyperplasia, endometrial thickness, or the number of women with adverse events.23 In the 10 micrograms E2 treatment group there was one event of endometrial adenocarcinoma stage II, grade 2 in a participant for whom it is uncertain whether there was a preexisting endometrial cancer at baseline due to the lack of a baseline biopsy. Although a relationship to study drug cannot be completely excluded, it is unlikely that an endometrial adenocarcinoma stage II, grade 2 could have developed de novo during the relatively short clinical time frame of this study.
In conclusion, these results confirm the efficacy of an ultra–low-dose 10-microgram E2 vaginal tablet to treat and manage the symptoms of estrogen deficiency-induced vaginal atrophy. The 10-microgram E2 vaginal tablet was effective in significantly normalizing vaginal pH and vaginal cytology profiles, but even more importantly, significant symptom relief was obtained for the participants’ most bothersome urogenital symptoms shortly after initiation of therapy.
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