Realities and prospects of hormonal therapy for recurrent urinary tract infections in patients with genitourinary menopausal syndrome

The problem of the growing elderly population, called the “silver tsunami”, is becoming increasingly important for modern society, including healthcare. Increasing women’s life expectancy makes it a national priority to consider improving women’s quality of life and active healthy longevity. GSM (Genitourinary Menopausal Syndrome), which is primarily a consequence of estrogen deficiency in periand postmenopausal patients and is characterized by changes in the genitourinary organs, is underdiagnosed.

The most common complaints are vaginal dryness, irritation, and dyspareunia. One of the components of GSM is urinary tract infections (UTIs), which tend to recur. Approximately 53% of women aged about 55 years report a relapse within one year. Recurrent UTIs negatively affect the quality of life of patients and are the reason for prescribing repeated courses of antibacterial therapy, which is accompanied by a change in the drug resistance of microorganisms. The pathogenesis of UTIs is associated with ascending infection by uropathogenic microorganisms, most often Escherichia coli, against the background of estrogendeficient changes in the epithelium and impaired microbiocenosis of the urogenital zone. Inadequacy of the urothelium and the lack of lactobacilli capable of direct and indirect inhibition of the growth of pathogenic microorganisms lead to colonization of the urinary tract with uropathogens and recurrence of UTIs. Consequently, the use of a vaginal combination of estriol and lactobacilli in the form of long-term intermittent maintenance treatment in order to maintain effectiveness and prevent relapses becomes pathogenetically justified. This combination contains a minimal effective dose of estriol (0.03 mg) with negligible systemic absorption and has a low level of adverse events, which ensures safety and high patient adherence to therapy. However, further clinical studies of the combination of estriol with lactobacilli in postmenopausal patients with recurrent urinary tract infections are needed to improve the efficacy of therapy.

1. Fermini B, Bell DC. On the perspective of an aging population and its potential impact on drug attrition and pre-clinical cardiovascular safety assessment. J Pharmacol Toxicol Methods. 2022;117:107184. https://doi.org/10.1016/j.vascn.2022.107184.

2. Окладников СМ (ред.). Женщины и мужчины России: статистический сборник (2022). М.; 2022. 208 с. Режим доступа: https://rosstat.gov.ru/storage/mediabank/Wom-Man%202022.pdf.

3. Адамян ЛВ, Андреева ЕН, Аполихина ИА, Артымук НВ, Ашрафян ЛА, Балан ВЕ и др. Менопауза и климактерическое состояние у женщины: клинические рекомендации. М.; 2024. Режим доступа: http://disuria.ru/_ld/11/1199_kr21N95MZ.pdf.

4. Portman DJ, Gass ML; Vulvovaginal Atrophy Terminology Consensus Conference Panel. Genitourinary syndrome of menopause: new terminology for vulvovaginal atrophy from the International Society for the Study of Women’s Sexual Health and the North American Menopause Society. Menopause. 2014;21(10):1063–1068. https://doi.org/10.1016/j.maturitas.2014.07.013.

5. Brady PH, Gin GT, Rosenblum E, Wilkinson LD. Female Pelvic Conditions: Genitourinary Syndrome of Menopause. FP Essent. 2022;515:32–42. Available at: https://pubmed.ncbi.nlm.nih.gov/35420405.

6. Rudd AB, Davis A. A Call to Change the Narrative on Genitourinary Syndrome of Menopause. Nurs Womens Health. 2020;24(6):399–403. https://doi.org/10.1016/j.nwh.2020.09.007.

7. Yarmolinskaya MI, Koloshkina AV. Algorithm for diagnosis and treatment of genitourinary menopausal syndrome. Akusherstvo i Ginekologiya. 2024;(9):22–36. (In Russ.) https://doi.org/10.18565/aig.2024.181.

8. Wasnik VB, Acharya N, Mohammad S. Genitourinary Syndrome of Menopause: A Narrative Review Focusing on Its Effects on the Sexual Health and Quality of Life of Women. Cureus. 2023;15(11):e48143. https://doi.org/10.7759/cureus.48143.

9. Panay N, Ang SB, Cheshire R, Goldstein SR, Maki P, Nappi RE; International Menopause Society Board. Menopause and MHT in 2024: addressing the key controversies – an International Menopause Society White Paper. Climacteric. 2024;27(5):441–457. https://doi.org/10.1080/13697137.2024.2394950.

10. Chee WT, Maciej PC. Urinary tract infections in adults. Singapore Med J. 2016;57(9):485–490. https://doi.org/10.11622/smedj.2016153.

11. Papp SB, Zimmern PE. Recurrent Urinary tract infections and type 2 diabetes mellitus: a systematic review predominantly in women. Front Urol. 2023;3:1275334. https://doi.org/10.3389/fruro.2023.1275334.

12. Muiños Fernández N, Martínez Salamanca JI, Pardo González de Quevedo JI, Diz Morales MP, Palomo Alameda L, Duce Tello S et al. Efficacy and safety of an ultra-low-dose 0.005% estriol vaginal gel in the prevention of urinary tract infections in postmenopausal women with genitourinary syndrome of menopause: A randomized double-blind placebo-controlled trial. Maturitas. 2024;190:108128. https://doi.org/10.1016/j.maturitas.2024.108128.

13. De Nisco NJ, Neugent M, Mull J, Chen L, Kuprasertkul A, de Souza Santos M et al. Direct Detection of Tissue-Resident Bacteria and Chronic Inflammation in the Bladder Wall of Postmenopausal Women with Recurrent Urinary Tract Infection. J Mol Biol. 2019;431(21):4368–4379. https://doi.org/10.1016/j.jmb.2019.04.008.

14. Перепанова ТС, Синякова ЛА, Локшин КЛ. Цистит у женщин: клинические рекомендации. М.; 2021. Режим доступа: http://disuria.ru/_ld/10/1014_kr21N30mz.pdf.

15. Shikh EV, Zhukova OV. The role of non-antibacterial agents in the prevention of recurrent urinary tract infections. Lechaschi Vrach. 2024;(1):27–36. (In Russ.) https://doi.org/10.51793/OS.2024.27.1.004.

16. Sihra N, Goodman A, Zakri R, Sahai A, Malde S et al. Nonantibiotic prevention and management of recurrent urinary tract infection. Nat Rev Urol. 2018;15(12):750–776. https://doi.org/10.1038/s41585-018-0106-x.

17. Ammitzbøll N, Bau BPJ, Bundgaard-Nielsen C, Villadsen AB, Jensen AM, Leutscher PDC et al. Preand postmenopausal women have different core urinary microbiota. Sci Rep. 2021;11(1):2212. https://doi.org/10.1038/s41598-021-81790-8.

18. Hugenholtz F, van der Veer C, Terpstra ML, Borgdorff H, van Houdt R, Bruisten S et al. Urine and vaginal microbiota compositions of postmenopausal and premenopausal women differ regardless of recurrent urinary tract infection and renal transplant status. Sci Rep. 2022;(12):2698. https://doi.org/10.1038/s41598-022-06646-1.

19. Dominoni M, Scatigno AL, La Verde M, Bogliolo S, Melito C, Gritti A et al. Microbiota Ecosystem in Recurrent Cystitis and the Immunological Microenvironment of Urothelium. Healthcare. 2023;11(4):525. https://doi.org/10.3390/healthcare11040525.

20. Amabebe E, Anumba DOC. The Vaginal Microenvironment: The Physiologic Role of Lactobacilli. Front Med. 2018;5:181. https://doi.org/10.3389/fmed.2018.00181.

21. Stabile G, Topouzova GA, De Seta F. The role of microbiota in the management of genitourinary syndrome of menopause. Climacteric. 2023;26(4):353–360. https://doi.org/10.1080/13697137.2023.2223923.

22. Park MG, Cho S, Oh MM. Menopausal Changes in the Microbiome – A Review Focused on the Genitourinary Microbiome. Diagnostics. 2023;13:1193. https://doi.org/10.3390/diagnostics13061193.

23. Lüthje P, Brauner H, Ramos NL, Ovregaard A, Gläser R, Hirschberg AL et al. Estrogen supports urothelial defense mechanisms. Sci Transl Med. 2013;5(190):190ra80. https://doi.org/10.1126/scitranslmed.3005574.

24. Naji A, Siskin D, Woodworth MH, Lee JR, Kraft CS, Mehta N. The Role of the Gut, Urine, and Vaginal Microbiomes in the Pathogenesis of Urinary Tract Infection in Women and Consideration of Microbiome Therapeutics. Open Forum Infect Dis. 2024;11(9):ofae471. https://doi.org/10.1093/ofid/ofae471.

25. Caretto M, Giannini A, Russo E, Simoncini T. Preventing urinary tract infections after menopause without antibiotics. Maturitas. 2017;99:43–46. https://doi.org/10.1016/j.maturitas.2017.02.004.

26. Neugent ML, Kumar A, Hulyalkar NV, Lutz KC, Nguyen VH, Fuentes JL et al. Recurrent urinary tract infection and estrogen shape the taxonomic ecology and function of the postmenopausal urogenital microbiome. Cell Rep Med. 2022;3(10):100753. https://doi.org/10.1016/j.xcrm.2022.100753.

27. Baber RJ, Panay N, Fenton A. IMS Recommendations on women’s midlife health and menopause hormone therapy. Climacteric. 2016;19(2):109–150. https://doi.org/10.3109/13697137.2015.1129166.

28. Donders GGG, Donders FHWV. New developments in the management of vulvovaginal atrophy: a comprehensive overview. Expert Opin Pharmacother. 2023;24(5):599–616. https://doi.org/10.1080/14656566.2023.2194017.

29. Kolokythas A, Betschart C, Wunder D, Janka H, Stute P. Impact of vaginal estriol on serum hormone levels: a systematic review. Climacteric. 2024;27(2):137–153. https://doi.org/10.1080/13697137.2023.2287624.

30. Palacios S. Sequential treatment in vulvovaginal atrophy. Climacteric. 2023;26(4):292–295. https://doi.org/10.1080/13697137.2023.2197588.

31. Nappi RE, Tiranini L, Martini E, Bosoni D, Cassani C, Cucinella L. Different local estrogen therapies for a tailored approach to GSM. Climacteric. 2023;26(4):361–366. https://doi.org/10.1080/13697137.2023.2218998.

32. Christmas MM, Iyer S, Daisy C, Maristany S, Letko J, Hickey M. Menopause hormone therapy and urinary symptoms: a systematic review. Menopause. 2023;30(6):672–685. https://doi.org/10.1097/GME.0000000000002187.

33. Raz R, Stamm WE. A controlled trial of intravaginal estriol in postmenopausal women with recurrent urinary tract infections. N Engl J Med. 1993;329(11):753–756. https://doi.org/10.1056/NEJM199309093291102.

34. Dessole S, Rubattu G, Ambrosini G, Gallo O, Capobianco G, Cherchi PL et al. Efficacy of low-dose intravaginal estriol on urogenital aging in postmeno pausal women. Menopause. 2004;11(1):49–56. https://doi.org/10.1097/01.GME.0000077620.13164.62.

35. Cardozo L, Benness C, Abbott D. Low dose oestrogen prophylaxis for recurrent urinary tract infections in elderly women. Br J Obstet Gynaecol. 1998;105(4):403–407. https://doi.org/10.1111/j.1471-0528.1998.tb10124.x.

36. Kirkengen AL, Andersen P, Gjersøe E, Johannessen GR, Johnsen N, Bodd E et al. Oestriol in the prophylactic treatment of recurrent urinary tract infections in postmenopausal women. Scand J Prim Health Care. 1992;10(2):139–142. https://doi.org/10.3109/02813439209014051.

37. Agrawal P, Singh SM, Able C, Dumas K, Kohn J, Kohn TP, Clifton M. Safety of Vaginal Estrogen Therapy for Genitourinary Syndrome of Menopause in Women With a History of Breast Cancer. Obstet Gynecol. 2023;142(3):660–668. https://doi.org/10.1097/AOG.0000000000005294.

38. McVicker L, Labeit AM, Coupland CAC, Hicks B, Hughes C, McMenamin Ú et al. Vaginal Estrogen Therapy Use and Survival in Females With Breast Cancer. JAMA Oncol. 2024;10(1):103–108. https://doi.org/10.1001/jamaoncol.2023.4508.

39. Donders G, Bellen G, Neven P, Grob P, Prasauskas V, Buchholz S, Ortmann O. Effect of ultra-low-dose estriol and lactobacilli vaginal tablets (Gynoflor®) on inflammatory and infectious markers of the vaginal ecosystem in postmenopausal women with breast cancer on aromatase inhibitors. Eur J Clin Microbiol Infect Dis. 2015;34(10):2023–2028. https://doi.org/10.1007/s10096-015-2447-1.

40. Адамян ЛВ, Андреева ЕН, Аполихина ИА, Артымук НВ, Ашрафян ЛА, Балан ВЕ и др. Менопауза и климактерическое состояние у женщины: клинические рекомендации. М.; 2021. Режим доступа: http://disuria.ru/_ld/11/1199_kr21N95MZ.pdf.

41. Trémollieres FA, Chabbert-Buffet N, Plu-Bureau G, Rousset-Jablonski C, Lecerf JM, Duclos M et al. Management of postmenopausal women: Collège National des Gynécologues et Obstétriciens Français (CNGOF) and Groupe d’Etude sur la Ménopause et le Vieillissement (GEMVi) Clinical Practice Guidelines. Maturitas. 2022;163:62–81. https://doi.org/10.1016/j.maturitas.2022.05.008.

42. Mueck AO, Ruan X, Prasauskas V, Grob P, Ortmann O. Treatment of vaginal atrophy with estriol and lactobacilli combination: a clinical review. Climacteric. 2018;21(2):140–147. https://doi.org/10.1080/13697137.2017.1421923.

43. Ruan X, Mueck AO. Hormonal treatment of vulvar vaginal atrophy (VVA): Are there options to reduce or avoid systemic adverse effects and risks? Clin Res Trials. 2018;4(6):1–9. Available at: https://www.oatext.com/pdf/CRT-4-239.pdf.

44. Wu LY, Yang TH, Ou YC, Lin H. The role of probiotics in women’s health: An update narrative review. Taiwan J Obstet Gynecol. 2024;63(1):29–36. https://doi.org/10.1016/j.tjog.2023.09.018.

45. Capobianco G, Wenger JM, Meloni GB, Dessole M, Cherchi PL, Dessole S. Triple therapy with Lactobacilli acidophili, estriol plus pelvic floor rehabilitation for symptoms of urogenital aging in postmenopausal women. Arch Gynecol Obstet. 2014;289(3):601–608. https://doi.org/10.1007/s00404-013-3030-6.

46. Clinical Conference Genitourinary menopausal syndrome – interdisciplinary problem. Gynecology. 2018;20(5):9–14. (In Russ.) https://doi.org/10.26442/2079-5696_2018.5.9-14.

47. Orazov МR. Combination Local Therapy of Genitourinary Menopausal Syndrome Symptoms. W J Gynecol Women’s Health. 2020;3(5). https://doi.org/10.33552/WJGWH.2020.03.000575.