Ultra-low-dose estriol and lactobacilli in the local treatment of postmenopausal vaginal atrophy

Abstract

Objective The aim of this study was to demonstrate the efficacy of an ultra-low-dose vaginal estriol 0.03 mg in combination with viable Lactobacillus acidophilus KS400 (Gynoflor® vaginal tablets) in the short-term therapy and to investigate the long-term maintenance dose in the treatment of vaginal atrophy.Methods This was a double-blind, randomized, placebo-controlled study (Controlled phase – initial therapy) followed by an open-label follow-up (Open phase – test medication initial and maintenance therapy). Included were postmenopausal women with vaginal atrophy symptoms and Vaginal Maturation Index (VMI) of ≤ 40%. The method of treatment was initial therapy with test medication (or placebo in first phase), one vaginal tablet daily for 12 days, followed by maintenance therapy, one tablet on two consecutive days weekly for 12 weeks.Results A total of 87 women completed the study. The Controlled phase results for a change in VMI demonstrated superiority of the 0.03 mg estriol–lactobacilli combination to placebo (p < 0.001). In the test group, the positive change in VMI was 35.2%, compared to 9.9% in the placebo group. In the Open phase after the initial therapy, the VMI was increased to 55.4% and, during maintenance therapy, it stayed at a comparable level (52.8–49.4%). The maturation of epithelium was followed by improvement of clinical symptoms and normalization of the vaginal ecosystem.Conclusions The ultra-low-dose, vaginal 0.03 mg estriol–lactobacilli combination (Gynoflor®) was superior to placebo with respect to changes in VMI after the 12-day initial therapy, and the maintenance therapy of two tablets weekly was sufficient to prevent the relapse of vaginal atrophy.

Treatment of vaginal atrophy with estriol and lactobacilli combination: a clinical review

“…Interestingly, maximum E3 levels were inversely correlated with VMI values, demonstrating that the maturing epithelium rapidly precludes further E3 absorption after initial therapy 53 . Additional flora parameters have also demonstrated positive dynamics in a consistent manner 61,76 . The lactobacillary grade permanently improved from onset through to the end of initial therapy, and even during maintenance therapy 53,61 .…”

“…In a pivotal study, Jaisamrarn and colleagues 61 demonstrated the superiority of 0.03 mg-E3/L combination over placebo, with a significantly higher increase in VMI. During initial treatment, VMI increased considerably from the start of treatment to the first follow-up (after 2 weeks of initial therapy) and remained within the normal estrogenization range (> 50%) during 2 months of maintenance therapy 53,61 . Interestingly, maximum E3 levels were inversely correlated with VMI values, demonstrating that the maturing epithelium rapidly precludes further E3 absorption after initial therapy 53 .…”

“…The authors recommended this combination therapy as first-line treatment for urogenital aging in postmenopausal women 59 . Overall, the clinical efficacy of 0.03 mg-E3/L combination in the treatment of vaginal atrophy has been demonstrated in various clinical studies (Table 1) 16, 53,59,61,72,73,[75][76][77] . More than 600 women have been evaluated.…”

“…Both initial (daily vaginal application for 2 weeks) and maintenance (two or three vaginal tablets weekly) therapeutic regimens have been studied and proved to be effective in treating and preventing the relapse of vaginal atrophy 53,59,61,75,76 . Relevant improvements in signs and symptoms such as vaginal dryness, soreness and dyspareunia, in affected women have been demonstrated compared to placebo 61 and comparators 59 . In a pivotal study, Jaisamrarn and colleagues 61 demonstrated the superiority of 0.03 mg-E3/L combination over placebo, with a significantly higher increase in VMI.…”

“…A meta-analysis of all published studies concluded that once-daily treatment with intravaginal E3 (0.5 mg) is safe and has no increased risk of endometrial proliferation or hyperplasia 56 . Ultra-low-dose vaginal estriol (0.03 mg E3) has a beneficial efficacy-safety profile 1,34,49,47,[57][58][59][60][61][62] : (1) it displays similar efficacy to that of conventional dose (0.5 mg) preparations; (2) it does not increase systemic E2 and/or E1 levels, while its influence on systemic E3 levels depends on the dose and maturation status of the epithelium; (3) it shows no relevant influence on systemic levels of sex hormones; (4) it does not cause endometrial proliferation after 6 months of use and, accordingly, there is no need to use opposing progestogen; and finally, (5) no systemic adverse events are expected due to negligible absorption. Hence, as mentioned, topical administration of low-dose E3 is generally preferred 35 .…”