Efficacy and safety of ultra-low dose vaginal estriol in the therapy of genitourinary syndrome of menopause: a phase III multicenter randomized controlled trial
Background: Topical hormonal therapy with estriol is the treatment standard for women with genitourinary syndrome of menopause. The appropriate dosages of estriol to treat its symptoms and to minimize a risk to the patient continue to be debated.Dikke G.B., Gurskaya T.Yu., Prokofievа S.V., Stolnikova I.I., Andreeva A.S., Repina N.B., Yagovkina N.V., Teplykh S.V., Fedorova E.P.
Objective: To compare the efficacy and safety of vaginal agents containing estriol 50 µg/g (gel) and 500 µg/0.5 g (cream) in the treatment of postmenopausal atrophic vaginitis.
Materials and methods: Design: this was an active controlled Phase III multicenter, open-label, prospective, randomized comparative parallel group clinical trial. It was conducted in 8 Russian research centers in 2016 to 2018. The trial included 120 postmenopausal patients with a history of vulvovaginal atrophy (VVA) lasting for at least one year, who were randomized to 2 groups; 1) 60 patients received vaginal estriol gel 50 µg and 2) 60 received vaginal estriol cream 500 µg according to the regimens (the patients used the agents on their own at night every day once daily for 3 weeks; then maintenance therapy was performed, by reducing the dose twice a week for 9 weeks). The total therapy duration was 12 weeks. The main outcome criterion was an increase in the vaginal epithelium maturation value (VEMV). The relief or disappearance rate of VVA symptoms and clinical signs, vaginal pH value, and safety were also calculated.
Results. The increase in VEMV relative to the baseline was 21.4 (SD 21.1) and 18.9 (SD 21.6) points in Groups 1 and 2, respectively; Δ=2.47 (95% CI: -4.07; 9.01 points; p=0.27), which did not exceed the upper CI limit of 10% and suggested that there was no difference in VEMV between both drugs after 12 weeks of therapy. There was relief or disappearance of VVA symptoms and a vaginal pH decrease that was comparable between the groups. The drugs compared were well tolerated, there were a total of 15 adverse events (AEs): 5 (33.3%) AEs in Group I and 10 (66.7%) in Group 2, no serious AEs were registered. The established AEs were consistent with the known safety information; the number of reported cases was comparable in both groups.
Conclusion: The efficacy of ultra-low dose (50µg/day) vaginal estriol gel in improving the symptoms and clinical signs of VVA is similar to that of standard dose vaginal cream (500 µg/day). The safety of both agents is comparable.
Keywords
menopause
genitourinary syndrome of menopause
vulvovaginal atrophy
non-hormonal agents
estriol
ultra-low doses
safety
adverse events
vaginal gel
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Received 19.12.2022
Accepted 23.12.2022
About the Authors
Galina B. Dikke, Dr. Med. Sci., Associate Professor, Professor at the Department of Obstetrics and Gynecology with the Course of Reproductive Medicine, F.I. Inozemtsev Academy of Medical Education, +7(812)334-76-50, galadikke@yandex.ru, https://orcid.org/0000-0001-9524-8962, 190013, Russia, St. Petersburg, Moskovsky Ave., 22M.Tatyana Yu. Gurskaya, Dr. Med. Sci., Chief Physician, Company «Nasledniki», +7(495)730-17-00, gurskayatu@mail.ru, 119192, Russia, Moscow, Michurinsky Ave., 7.
Svetlana V. Prokofieva, obstetrician-gynecologist of the highest category, MedEstetikTsentr Laboratory LLC, +7(812)700-88-01, s.v.prokofieva@mail.ru,
192177, Russia, St. Petersburg, Karavaevskaya str., 26, building 1A.
Irina I. Stolnikova, PhD, doctor of the highest category, Tver State Medical Academy, Ministry of Health of Russia, +7(4822)32-17-79, stolnikovaii@gmail.com,
170100, Russia, Tver, Sovetskaya str., 4.
Alla S. Andreeva, Deputy Chief Physician for Organizational and Methodological Work, Clinical Pharmacologist, Uromed LLC, +7(4812)61-13-01, alla.s.andreeva@mail.ru, 214031, Russia, Smolensk, Marshal Sokolovsky str., 18/1.
Natalya B. Repina, PhD, obstetrician-gynecologist of the highest category, Ryazan State Medical University, Ministry of Health of Russia, +7(491)235-09-91,
nrepina62@gmail.com, 390026, Russia, Ryazan, Vysokovoltnaya str., 9.
Nadezhda V. Yagovkina, PhD, Associate Professor at the Department of Obstetrics and Gynecology, Kirov State Medical Academy, Ministry of Health of Russia,
+7(8332)52-36-39, nad0511ya@rambler.ru, 610014, Russia, Kirov, Shchorsa str., 64.
Svetlana V. Teplykh, General Director, obstetrician-gynecologist, Professor’s Clinic LLC, +7(342)206-25-74, profklinika@mail.ru, 614070, Russia, Perm, Druzhby str., 15A.
Elena P. Fedorova, PhD, obstetrician-gynecologist of the highest category, Clinic «Lipetsk-Med», +7(4742)25-81-79, lena_petrovna48@mail.ru,
398006, Russia, Lipetsk, Communisticheskaya str., 24.
Corresponding author: Galina B. Dikke, galadikke@yandex.ru
Authors’ contributions: Dikke G.B. – analysis of the results of statistical processing of clinical material and their interpretation, writing and correction of the first version of the article and its editing after peer review, approval of the final version of the article before its submission for publication; Gurskaya T.Yu., Prokofievа S.V., Stolnikova I.I., Andreeva A.S., Repina N.B.,
Yagovkina N.V., Teplykh S.V., Fedorova E.P. – collection of clinical data and formation of an electronic database of the findings, approval of the final version of the article before its submission for publication.
Conflicts of interest: The authors declare that there are no conflicts of interest and guarantee that the article is the authors’ original work.
Funding: “ITF” LLC, Russia. The company’s employees have not been involved in developing and conducting the trial, in collecting, analyzing, and interpreting the data; and in preparing, reviewing, or approving the manuscript.
Registration: The trial has been registered at the Ministry of Health of the Russian Federation (Protocol RCT-BLS-01/12).
Ethical Approval: The investigation protocol has been approved by the Ethics Council, Ministry of Health of the Russian Federation (an extract from Protocol No. 133 dated September 20, 2016).
Patient Consent for Publication: All the patients have signed a written informed voluntary consent form to their participation in the trial and to the publication of their data.
Authors’ Data Sharing Statement: The data supporting the findings of this study are available on request from the corresponding author after approval from the principal investigator.
For citation: Dikke G.B., Gurskaya T.Yu., Prokofievа S.V., Stolnikova I.I.,
Andreeva A.S., Repina N.B., Yagovkina N.V., Teplykh S.V., Fedorova E.P.
Efficacy and safety of ultra-low dose vaginal estriol in the therapy of genitourinary syndrome
of menopause: a phase III multicenter randomized controlled trial.
Akusherstvo i Ginekologiya/Obstetrics and Gynecology. 2022; 12: 146-156 (in Russian)
http://dx.doi.org/10.18565/aig.2022.303
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