Low-dose vaginal estradiol tablets relieve symptoms of vaginal atrophy
Bachmann G, Lobo RA, Gut R, Nachtigall L, Notelovitz M. Efficacy of low-dose estradiol vaginal tablets in the treatment of atrophic vaginitis: a randomized controlled trial. Obstet Gynecol 2008;111:67-76.
Vaginal tablets with 25 μg and 10 μg estradiol both provide relief of symptoms of vaginal atrophy and improve urogenital health, found this multicenter, randomized, double-blind, parallel-group study of the two doses or placebo for 12 weeks. Both doses relieve symptoms, improve urogenital atrophy, decrease vaginal pH, and increase maturation of the vaginal and urethral epithelium, but improvements are greater with the 25-μg dose. Postmenopausal women with vaginal atrophy (N = 230,

45 y ) were randomized to receive 25 μg estradiol, 10 μg estradiol, or placebo, and were instructed to insert one tablet daily for 14 days and, subsequently, 1 tablet twice per week. The primary efficacy endpoint was change from baseline in composite score of vaginal dryness, soreness, and irritation. Additional efficacy assessment included vaginal health graded by degree of epithelial integrity and thickness, vaginal secretions, color, vaginal pH, and vagina and urethral cytology. In an open-label extension, all women received 25 μg twice weekly through 52 weeks. The goal was to evaluate the effect of long-term treatment with estradiol on the endometrium, and to determine whether efficacy will be sustained over the long term.
Treatment with 25 μg and 10 μg estradiol markedly improved vaginal symptom composite scores, with declines from approximately 1.9 at week 0 for both groups to 0.45 and 0.56, respectively, at week 12. In the placebo group, vaginal symptom scores remained at 1.1 through week 12. Vaginal health composite scores improved significantly in the treatment groups compared with the placebo group (P < 0.001). There were greater improvements in some aspects of vaginal health with the higher dose. Both doses improved vaginal pH and cell maturation values. After switching to 25 μg estradiol in the extension study, all three groups showed statistically significant reductions from baseline in vaginal symptom composite scores to week 52 (P < 0.001) and similar improvements in vaginal health composite scores. There was no significant evidence of adverse effect on the endometrium with the long-term treatment.

This well-designed study confirms the effectiveness and safety of 25 μg and 10 μg doses of estradiol tablets for intravaginal use in the treatment of vaginal atrophy. The 25-μg dose is currently approved by the Food and Drug Administration (FDA) and available (Vagifem). The enrollment for this study was from 1994 to 1996 and FDA guidelines for this type of study have subsequently changed to include baseline endometrial biopsies and to evaluate the effect on a moderate to severe "most bothersome symptom" at baseline. This study utilized baseline transvaginal ultrasound instead of endometrial biopsy and evaluated a composite score of vaginal symptoms instead of a "most bothersome symptom." Efficacy and safety are demonstrated, although the study is underpowered to identify a small increased risk that would require thousands of patients to detect. While the 25-μg dose was believed to be slightly superior, the response to the lower 10-μg dose appears nearly as effective and may represent a good alternative for many women.

The 2007 NAMS Position Statement on the role of local vaginal estrogen for the treatment of vaginal atrophy states, "The primary goals of vaginal atrophy management are to relieve symptoms and reverse atrophic anatomic changes." It has been estimated that approximately 50% of postmenopausal women experience varying degrees of vaginal discomfort. With the decline in use of systemic hormone therapy, there is a greater need for effective and convenient local therapies to ameliorate symptoms of vaginal atrophy. Fortunately, we now have a variety of local therapies available: creams containing estrogen, a ring, and tablets. As with systemic HT, finding the lowest effective dose to relieve symptoms of vaginal atrophy is desired. There are at least two more phase III trials in the United States and Europe investigating the effect and safety of the 10-μg tablet, and some results are likely to be available soon.

From the NAMS First to Know e-newsletter released March 25, 2008

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