The possibilities of vaginal estrogen therapy in the prevention and treatment of recurrent urinary tract infection in postmenopausal women

DOI

https://dx.doi.org/10.18565/aig.2024.259

Belyi L.E.
Ulyanovsk State University, Ulyanovsk, Russia

It is currently known that 50–60% of women will experience at least one episode of urinary tract infection (UTI) in their lifetime, and of these, 25% will suffer from recurrent infections. Postmenopausal women are more prone to recurrent UTIs. The treatment of a symptomatic episode of the urinary tract infection (UTI) is mainly antibiotic-based, and its primary goal is to achieve urinary tract sterility. At the same time, the results of recent scientific studies have demonstrated a steady increase in the antibiotic resistance of uropathogenic microflora; therefore, it is reasonable to limit the use of antibiotics and to follow alternative therapeutic strategies.
Topical vaginal application of estrogens is a promising preventive strategy in postmenopausal women with recurrent UTI. A decrease in the level of estrogens has a negative impact on the defense mechanisms of the urinary tract against pathogenic bacteria. This is due to the fact that estrogens, in addition to their effects on the growth and differentiation of organs and tissues of the female reproductive system, influence other body systems, and the urinary tract in particular.
This review provides new scientific evidence on the role of estrogens in modulating the mechanisms of the urinary tract antimicrobial defense. The results of experimental studies proving the effect of estrogen replacement therapy on the course of UTI under conditions of hypoestrogenism and reproductive ageing are presented. The analysis of the clinical studies demonstrated effectiveness of estrogen replacement therapy in the prevention of recurrent UTIs.
Conclusion: The local use of estrogens leads to the restoration of the vaginal microbiota with an increase in the population of Lactobacillus, enhanced synthesis of antimicrobial peptides by urothelial cells, strengthening of intercellular connections between urothelial cells. Therefore, vaginal estrogen therapy can be considered as a promising treatment for the prevention of recurrent UTIs in postmenopausal women if there are no contraindications.

Conflicts of interest: The author declares lack of the possible conflicts of interest.
Funding: The study was conducted without sponsorship.
For citation: Belyi L.E. The possibilities of vaginal estrogen therapy in the prevention and treatment of recurrent urinary tract infection in postmenopausal women.
Akusherstvo i Ginekologiya/Obstetrics and Gynecology. 2025; (2): 15-22 (in Russian)
https://dx.doi.org/10.18565/aig.2024.259

urinary tract infection

vaginal estrogen therapy

postmenopausal period

cystitis

Full text (in Russian)

Dielubanza E.J., Schaeffer A.J. Urinary tract infections in women. Med. Clin. North Am. 2011; 95(1): 27-41. https://dx.doi.org/10.1016/j.mcna.2010.08.023.
Лисицына О.И. Фосфомицин в лечении острого неосложненного цистита. Взгляд акушера-гинеколога. Акушерство и гинекология. 2019; 2: 165-9. [Lisitsina O.I. Using Fosfomycin in the treatment of acute uncomplicated cystitis. An ob-gyn perspective. Obstetrics and Gynecology. 2019; (2): 165-9.
(in Russian)]. https://dx.doi.org/10.18565/aig.2019.2.165-169.
Балушкина А.А., Кан Н.Е., Тютюнник В.Л. Терапия инфекций мочевыводящих путей. Медицинский cовет. 2019; (7): 87-92. [Balushkina AA, Kan NE, Tyutyunnik VL. Therapy of urinary tract infections in gynecological practice. Medical Council. 2019; (7): 87-92. (in Russian)]. https://doi.org/10.21518/2079-701X-2019-7-87-92.
Sen A., Iyer J., Boddu S., Kaul A., Kaul R. Estrogen receptor alpha differentially modulates host immunity in the bladder and kidney in response to urinary tract infection. Am. J. Clin. Exp. Urol. 2019; 7(3): 110-22.
Зайцев А.В., Аполихина И.А., Ходырева Л.А., Берников А.Н., Куприянов Ю.А., Строганов Р.В., Арефьева О.А., Тетерина Т.А. Роль нарушения микробиоты влагалища в патогенезе рецидивирующей инфекции нижних мочевыводящих путей: современный взгляд на проблему. Акушерство и гинекология. 2021; 5: 40-6. [Zaitsev A.V., Apolikhina I.A., Khodyreva L.A., Bernikov A.N., Kupriyanov Yu.A., Stroganov R.V., Arefyeva O.A., Teterina T.A. Role of abnormal vaginal microbiota in the pathogenesis of reccurent lower urinary tract infection: a modern view of the problem. Obstetrics and Gynecology. 2021; (5): 40-6. (in Russian)]. https://dx.doi.org/10.18565/aig.2021.5.40-46.
EAU Guidelines on Urological Infections. Edn. presented at the EAU Annual Congress Paris 2024. Available at: https://uroweb.org/guidelines/urological-infections/chapter/citation-information
Белый Л.Е. Перспективы применения D-маннозы в профилактике и лечении инфекции мочевых путей у женщин. Акушерство и гинекология. 2023; 5: 21-8. [Belyi L.E. Prospects for using D mannose in the prevention and treatment of urinary tract infection in women. Obstetrics and Gynecology. 2023; (5): 21-8. (in Russian)]. https://dx.doi.org/10.18565/aig.2022.295.
Flores-Mireles A.L., Walker J.N., Caparon M., Hultgren S.J. Urinary tract infections: epidemiology, mechanisms of infection and treatment options. Nat. Rev. Microbiol. 2015; 13(5): 269-84. https://dx.doi.org/10.1038/nrmicro3432.
Ермакова Е.И. Рецидивирующие инфекции мочевыводящих путей у женщин. Акушерство и гинекология. 2020; 7: 151-8. [Ermakova E.I. Recurrent urinary tract infections in women. Obstetrics and Gynecology. 2020; (7): 151-8. (in Russian)]. https://dx.doi.org/10.18565/aig.2020.7.151-158.
Foxman B. Recurring urinary tract infection: incidence and risk factors. Am. J. Public Health. 1990; 80(3): 331-3. https://dx.doi.org/10.2105/ajph.80.3.331.
Lüthje P., Hirschberg A.L., Brauner A. Estrogenic action on innate defense mechanisms in the urinary tract. Maturitas. 2014; 77(1): 32-6. https://dx.doi.org/10.1016/j.maturitas.2013.10.018.
Ala-Jaakkola R., Laitila A., Ouwehand A.C., Lehtoranta L. Role of D-mannose in urinary tract infections - a narrative review. Nutr. J. 2022; 21(1): 18. https://dx.doi.org/10.1186/s12937-022-00769-x.
Ligon M.M., Joshi C.S., Fashemi B.E., Salazar A.M., Mysorekar I.U. Effects of aging on urinary tract epithelial homeostasis and immunity. Dev. Biol. 2023; 493: 29-39. https://dx.doi.org/10.1016/j.ydbio.2022.11.003.
Joshi C.S., Salazar A.M., Wang C., Ligon M.M., Chappidi R.R., Fashemi B.E. et al. D-Mannose reduces cellular senescence and NLRP3/GasderminD/IL-1β-driven pyroptotic uroepithelial cell shedding in the murine bladder. Dev. Cell. 2024; 59(1): 33-47.e5. https://dx.doi.org/10.1016/j.devcel.2023.11.017.
Olson P.D., Hunstad D.A. Subversion of host innate immunity by uropathogenic Escherichia coli. Pathogens. 2016; 5(1): 2. https://dx.doi.org/10.3390/pathogens5010002.
Munoz J.A., Uhlemann A.C., Barasch J. Innate Bacteriostatic mechanisms defend the urinary tract. Annu. Rev. Physiol. 2022; 84: 533-58. https://dx.doi.org/10.1146/annurev-physiol-052521-121810.
Pak J., Pu Y., Zhang Z.T., Hasty D.L., Wu X.R. Tamm-Horsfall protein binds to type 1 fimbriated Escherichia coli and prevents E. coli from binding to uroplakin Ia and Ib receptors. J. Biol. Chem. 2001; 276(13): 9924-30. https://dx.doi.org/10.1074/jbc.M008610200.
Bates J.M., Raffi H.M., Prasadan K., Mascarenhas R., Laszik Z., Maeda N. et al. Tamm-Horsfall protein knockout mice are more prone to urinary tract infection: rapid communication. Kidney Int. 2004; 65(3): 791-7. https://dx.doi.org/10.1111/j.1523-1755.2004.00452.x.
Han J.S., Kim G.H., Kim J., Jeon U.S., Joo K.W., Na K.Y. et al. Secretory-defect distal renal tubular acidosis is associated with transporter defect in H(+)-ATPase and anion exchanger-1. J. Am. Soc. Nephrol. 2002; 13(6): 1425-32. https://dx.doi.org/10.1097/01.asn.0000013882.73122.2b.
Sen A., Kaul A., Kaul R. Estrogen receptors in human bladder cells regulate innate cytokine responses to differentially modulate uropathogenic E. coli colonization. Immunobiology. 2021; 226(1): 152020. doi: 10.1016/j.imbio.2020.152020.
Kovats S. Estrogen receptors regulate innate immune cells and signaling pathways. Cell. Immunol. 2015; 294(2): 63-9. https://dx.doi.org/10.1016/j.cellimm.2015.01.018.
Маянский А.Н. Цитокины и медиаторные функции уроэпителия в воспалительных реакциях мочевыводящей системы. Цитокины и воспаление. 2003; 2(4): 3-9. [Mayansky A.N. Cytokines and mediator functions of uroepithelial cells in inflammatory reactions of urinary tract. Cytokines and Inflammation. 2003; 2(4): 3-9. (in Russian)].
Kaul A.K., Kumar D., Nagamani M., Goluszko P., Nowicki S., Nowicki B.J. Rapid cyclic changes in density and accessibility of endometrial ligands for Escherichia coli Dr fimbriae. Infect. Immun. 1996; 64(2): 611-5. https://dx.doi.org/10.1128/iai.64.2.611-615.1996.
Ганцев Ш.Х., Рустамханов Р.А., Ганцев К.Ш., Кзыргалин Ш.Р. Третичные лимфоидные структуры (лимфоидный неогенез). Иммунология. 2019; 40(2): 58-63. [Gantsev Sh.Kh., Rustamkhanov R.A., Gantsev K.Sh., Kzyrgalin Sh.R. Tertiary lymphoid structures (lymphoid neogenesis). Immunologiya. 2019; 40(2): 58-63. (in Russian)]. https://dx.doi.org/10.24411/0206-4952-2019-12008.
Ковылина М.В., Прилепская Е.А., Цыбуля О.А., Тупикина Н.В., Рева И.А., Махмудов Т.Б. Кистозный и железистый цистит, корреляция с уротелиальным раком мочевого пузыря. Онкоурология. 2015; 11(4): 51-3. [Kovylina М.V., Prilepskaya Е.А., Tsybulya О.A., Tupikina N.V., Reva I.А., Makhmudov T.B. Cystitis cystica and cystitis glandularis: its relationship to the development of urothelial bladder cancer. Cancer Urology. 2015; 11(4): 51-3. (in Russian)]. https://doi.org/10.17650/1726-9776-2015-11-4-51-53.
Ligon M.M., Liang B., Lenger S.M., Parameswaran P., Sutcliffe S., Lowder J.L. et al. Bladder mucosal cystitis cystica lesions are tertiary lymphoid tissues that correlate with recurrent urinary tract infection frequency in postmenopausal women. J. Urol. 2023; 209(5): 928-36. https://doi.org/10.1097/JU.0000000000003196.
Hamade A., Li D., Tyryshkin K., Xu M., Conseil G., Yolmo P. et al. Sex differences in the aging murine urinary bladder and influence on the tumor immune microenvironment of a carcinogen-induced model of bladder cancer. Biol. Sex. Differ. 2022; 13(1): 19. https://dx.doi.org/10.1186/s13293-022-00428-0.
Truschel S.T., Clayton D.R., Beckel J.M., Yabes J.G., Yao Y., Wolf-Johnston A. et al. Age-related endolysosome dysfunction in the rat urothelium. PLoS One. 2018; 13(6): e0198817. https://dx.doi.org/10.1371/journal.pone.0198817.
Neugent M.L., Hulyalkar N.V., Kumar A., Xing C., Zimmern P.E., Shulaev V. et al. Urinary glycosaminoglycans are associated with recurrent UTI and urobiome ecology in postmenopausal women. ACS Infect. Dis. 2023; 9(4): 1022-32. https://dx.doi.org/10.1021/acsinfecdis.3c00027.
Anand M., Wang C., French J., Isaacson-Schmid M., Wall L.L., Mysorekar I.U. Estrogen affects the glycosaminoglycan layer of the murine bladder. Female Pelvic Med. Reconstr. Surg. 2012; 18(3): 148-52. https://dx.doi.org/10.1097/SPV.0b013e31824b76bd.
de Deus J.M., Girão M.J., Sartori M.G., Baracat E.C., Rodrigues de Lima G., Nader H.B. et al. Glycosaminoglycan profile in bladder and urethra of castrated rats treated with estrogen, progestogen, and raloxifene. Am. J. Obstet. Gynecol. 2003; 189(6): 1654-9. https://dx.doi.org/10.1016/s0002-9378(03)00867-6.
Yang Z.M., Yang M.F., Yu W., Tao H.M. Molecular mechanisms of estrogen receptor β-induced apoptosis and autophagy in tumors: implication for treating osteosarcoma. J. Int. Med. Res. 2019; 47(10): 4644-55. https://dx.doi.org/10.1177/0300060519871373.
Park M.G., Cho S., Oh M.M. Menopausal changes in the microbiome-a review focused on the genitourinary microbiome. Diagnostics (Basel). 2023; 13(6): 1193. https://dx.doi.org/10.3390/diagnostics13061193.
Ammitzbøll N., Bau B.P.J., Bundgaard-Nielsen C., Villadsen A.B., Jensen A.M., Leutscher P.D.C. et al. Pre- and postmenopausal women have different core urinary microbiota. Sci. Rep. 2021; 11(1): 2212. https://dx.doi.org/10.1038/s41598-021-81790-8.
Wang C., Symington J.W., Ma E., Cao B., Mysorekar I.U. Estrogenic modulation of uropathogenic Escherichia coli infection pathogenesis in a murine menopause model. Infect. Immun. 2013; 81(3): 733-9. https://dx.doi.org/10.1128/IAI.01234-12.
Lüthje P., Brauner H., Ramos N.L., Ovregaard A., Gläser R., Hirschberg A.L. et al. Estrogen supports urothelial defense mechanisms. Sci. Transl. Med. 2013; 5(190): 190ra80. https://dx.doi.org/ 10.1126/scitranslmed.3005574.
Fashemi B.E., Wang C., Chappidi R.R., Morsy H., Mysorekar I.U. Supraphysiologic vaginal estrogen therapy in aged mice mitigates age-associated bladder inflammatory response to urinary tract infections. Urogynecology (Phila). 2023; 29(4): 430-42. https://dx.doi.org/10.1097/SPV.0000000000001276.
Sugarman B., Epps L.R. Effect of estrogens on bacterial adherence to HeLa cells. Infect. Immun. 1982; 35(2): 633-8. https://dx.doi.org/10.1128/iai.35.2.633-638.1982.
Chotirmall S.H., Smith S.G., Gunaratnam C.., Cosgrove S., Dimitrov B.D., O'Neill S.J. et al. Effect of estrogen on pseudomonas mucoidy and exacerbations in cystic fibrosis. N. Engl. J. Med. 2012; 366(21): 1978-86. https://dx.doi.org/10.1056/NEJMoa1106126.
Sobel J.D., Kaye D. Enhancement of Escherichia coli adherence to epithelial cells derived from estrogen-stimulated rats. Infect. Immun. 1986; 53(1): 53-6. https://dx.doi.org/10.1128/iai.53.1.53-56.1986.
Engelsöy U., Svensson M.A., Demirel I. Estradiol alters the virulence traits of uropathogenic Escherichia coli. Front. Microbiol. 2021; 12: 682626. https://dx.doi.org/10.3389/fmicb.2021.682626.
Chen Y.Y., Su T.H., Lau H.H. Estrogen for the prevention of recurrent urinary tract infections in postmenopausal women: a meta-analysis of randomized controlled trials. Int. Urogynecol. J. 2021; 32(1): 17-25. https://dx.doi.org/10.1007/s00192-020-04397-z.
Perrotta C., Aznar M., Mejia R., Albert X., Ng C.W. Oestrogens for preventing recurrent urinary tract infection in postmenopausal women. Cochrane Database Syst. Rev. 2008; (2): CD005131. https://dx.doi.org/10.1002/14651858.CD005131.pub2.
Xu R., Wu Y., Hu Y. Prevention and treatment of recurrent urinary system infection with estrogen cream in postmenopausal women. Zhonghua Fu Chan Ke Za Zhi. 2001; 36(9): 531-3. (in Chinese).
Raz R., Stamm W.E. A controlled trial of intravaginal estriol in postmenopausal women with recurrent urinary tract infections. N. Engl. J. Med. 1993; 329(11): 753-6. https://dx.doi.org/10.1056/NEJM199309093291102.
Anglim B., Phillips C., Shynlova O., Alarab M. The effect of local estrogen therapy on the urinary microbiome composition of postmenopausal women with and without recurrent urinary tract infections. Int. Urogynecol. J. 2022; 33(8):2107-17. https://dx.doi.org/10.1007/s00192-021-04832-9.
Meister M.R., Wang C., Lowder J.L., Mysorekar I.U. Vaginal estrogen therapy is associated with decreased inflammatory response in postmenopausal women with recurrent urinary tract infections. Female Pelvic Med. Reconstr. Surg. 2021; 27(1): e39-e44. https://dx.doi.org/10.1097/SPV.0000000000000790.
Beerepoot M.A., Geerlings S.E., van Haarst E.P., van Charante N.M., ter Riet G. Nonantibiotic prophylaxis for recurrent urinary tract infections: a systematic review and meta-analysis of randomized controlled trials. J. Urol. 2013; 190(6): 1981-9. https://dx.doi.org/10.1016/j.juro.2013.04.142.

Received 26.10.2024

Accepted 31.01.2025

Lev E. Belyi, Dr. Med. Sci., Professor of the Department of Hospital Surgery, Anesthesiology, Reanimatology, Urology, Traumatology, Orthopedics, Ulyanovsk State University, 432017, Russia, Ulyanovsk, Leo Tolstoy str., 42, +7(917)605-97-19, lbely@yandex.ru, https://orcid.org/0000-0003-0908-1321

The possibilities of vaginal estrogen therapy in the prevention and treatment of recurrent urinary tract infection in postmenopausal women

Belyi L.E.

Keywords

References

About the Authors

Similar Articles