GynecologyGynecologyГинекология2079-56962079-5831Consilium Medicum7608810.26442/20795696.2021.3.200905REVIEWОБЗОРReview ArticleVaginal microbiota during the menopausal transition: the role of lactobacilliМикробиота влагалища в период менопаузального перехода: роль лактобактерийhttps://orcid.org/0000-0002-7830-22903127672925-9948DobrokhotovaYulia E.ДоброхотоваЮлия Эдуардовна
Russian Federation

D. Sci. (Med.), Prof., Pirogov Russian National Research Medical University

доктор медицинских наук, профессор, заведующий кафедрой акушерства и гинекологии лечебного факультета

pr.dobrohotova@mail.ruhttps://orcid.org/0000-0002-3721-14219935-8003ShadrovaPolina A.ШадроваПолина Андреевна
Russian Federation

Graduate Student

аспирант кафедрой акушерства и гинекологии лечебного факульта

shadrovapolina@hotmail.comhttps://orcid.org/0000-0003-4510-42441102286KomagorovVladimir I.КомагоровВладимир Игоревич
Russian Federation

Graduate Student

аспирант кафедрой акушерства и гинекологии лечебного факульта

vladimirus62@gmail.comPirogov Russian National Research Medical UniversityФГАОУ ВО «Российский национальный исследовательский медицинский университет им. Н.И. Пирогова» Минздрава России130820212332142211607202116072021Copyright ©; 2021, Consilium MedicumCopyright ©; 2021, ООО "Консилиум Медикум"2021Consilium MedicumООО "Консилиум Медикум"https://creativecommons.org/licenses/by-nc-sa/4.0https://gynecology.orscience.ru/2079-5831/article/view/76088

Physiological loss of ovarian function during the menopausal transition often leads to the development of unfavorable symptoms associated with vulvovaginal atrophy, recurrent urinary tract infections and dyspareunia. Currently, the scientific community is actively discussing the risks and benefits of prescribing menopausal hormone therapy to relieve the consequences of estrogen deficiency. The study of vaginal microbiota in dynamics made it possible to take a deeper look at the development of genitourinary menopausal syndrome and associate several microorganisms with specific undesirable manifestations. The link between recurrent urinary tract infections during menopause and physiological replacement of microbiota by opportunistic flora with the development of unpleasant symptoms resolves doctors to resort to irrational courses of antibiotic therapy. The review is devoted to the generalization of information on microbiological changes in the vagina during perimenopause, the possibilities of choosing the optimal hormone therapy for the correction of symptoms, the use of new promising methods, including management by modulating the vaginal microbiota.

Физиологическое угасание функции яичников в период менопаузального перехода зачастую приводит к развитию неблагоприятных симптомов, связанных с вульвовагинальной атрофией, рецидивирующими инфекциями мочевыводящих путей и диспареунией. В настоящее время риски и польза от назначения менопаузальной гормональной терапии в купировании последствий эстрогенодефицита активно обсуждаются в научном сообществе. Исследование микробиоты влагалища в динамике позволило взглянуть глубже на процесс развития симптомов генитоуринарного менопаузального синдрома и связать отдельные микро- организмы с конкретными нежелательными проявлениями. Связь между рецидивирующими инфекциями мочевыводящих путей в период менопаузы и физиологическим замещением микробиоты на условно-патогенную флору с развитием неприятных симптомов вынуждает врачей прибегать к необоснованным курсам антибактериальной терапии. Обзор посвящен обобщению сведений о микробиологических изменениях влагалища в перименопаузе, возможностям подбора оптимальной гормональной терапии в коррекции симптомов, использованию новых перспективных методов, в том числе менеджмента путем модуляции микробиоты влагалища.

menopausemenopausal hormone therapyestrogen deficiencyvaginal microbiotalactobacilligenitourinary syndromevulvovaginal atrophyменопаузаменопаузальная гормональная терапияэстрогенодефицитмикробиота влагалищапробиотикигенитоуринарный синдромвульвовагинальная атрофияWorld population ageing 2019. Highlights. New York City (NY): United Nations, Department of Economic and Social Affairs, 2019 (ST/ESA/SER.A/430) Available at: https://www.un.org/en/development/desa/population/publications/pdf/ageing/WorldPopulationAgeing2019-Highlights.pdf. Accessed: November 2019.Portman D, Gass M. 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;21:1063-8. DOI:10.1097/GME.0000000000000329Oge T, Hassa H, Aydin Y, et al. The relationship between urogenital symptoms and climacteric complaints. Climacteric. 2013;16:646-52. DOI:10.3109/13697137.2012.756467Kim HK, Kang SY, Chung YJ, et al. The Recent Review of the Genitourinary Syndrome of Menopause. J Menopausal Med. 2015;21(2):65-71. DOI:10.6118/jmm.2015.21.2.65Lamont R, Sobel J, Akins R, et al. The vaginal microbiome: new information about genital tract flora using molecular based techniques. BJOG. 2011;118(5):533-49. DOI:10.1111/j.1471-0528.2010.02840.xSoules M, Sherman S, Parrott E, et al. Executive summary: Stages of Reproductive Aging Workshop (STRAW). Climacteric. 2001;4:267-72.Van de Wijgert JH, Borgdorff H, Verhelst R, et al. The vaginal microbiota: what have we learned after a decade of molecular characterization? Plos ONE. 2014;9(8):e105998. DOI:10.1371/journal.pone.0105998Доброхотова Ю.Э., Затикян Н.Г. Микроэкология и защитные механизмы влагалища. Акушерство, гинекология и репродукция. 2007;2:10-2 [Dobrokhotova IuE, Zatikian NG. Mikroekologiia i zashchitnye mekhanizmy vlagalishcha. Akusherstvo, ginekologiia i reproduktsiia. 2007;2:10-2 (in Russian)].Brubaker P. Linking the gut microbiome to metabolism through endocrine hormones. Endocrinology. 2018;59(8):2978-9. DOI:10.1210/en.2018-00577Saba E, Origoni M, Taccagni G, et al. Productive HIV-1 infection of human cervical tissue ex vivo is associated with the secretory phase of the menstrual cycle. Mucosal Immunol. 2013;6(6):1081-90. DOI:10.1038/mi.2013.2Berman JR, Almeida FG, Jolin J, et al. Correlation of androgen receptors, aromatase, and 5-alpha reductase in the human vagina with menopausal status. Fertil Steril. 2003;79:925-31. DOI:10.1016/s0015-0282(02)04923-3Baldassarre M, Giannone FA, Foschini MP, et al. Effects of longterm high dose testosterone administration on vaginal epithelium structure and estrogen receptor-alpha and -beta expression of young women. Int J Impot Res. 2013;25:172-7. DOI:10.1038/ijir.2013.9Nappi R, Palacios S. Impact of vulvovaginal atrophy on sexual health and quality of life at postmenopause. Climacteric. 2014;17:3-9. DOI:10.3109/13697137.2013.871696Sturdee D, Panay N. Recommendations for the management of postmenopausal vaginal atrophy. Climacteric. 2010;13:509-22. DOI:10.3109/ 13697137.2010.522875Brotman R, Shardell M, Gajer P, et al. Association between the vaginal microbiota, menopause status, and signs of vulvovaginal atrophy. Menopause. 2014;21:450-8. DOI:10.1097/GME.0b013e3182a4690bRavel J, Gajer P, Abdo Z, et al. Vaginal microbiome of reproductive-age women. Proc Natl Acad Sci USA. 2011;108 Suppl. 1(Suppl. 1):4680-7. DOI:10.1073/pnas.1002611107Donders GG, Vereecken A, Bosmans E, et al. Definition of a type of abnormal vaginal flora that is distinct from bacterial vaginosis: aerobic vaginitis. BJOG. 2002;109(1):34-43. DOI:10.1111/j.1471-0528.2002.00432.xBrotman R, Shardell M, Gajer P, et al. Association between the vaginal microbiota, menopause status, and signs of vulvovaginal atrophy. Menopause. 2014;21:450-8. DOI:10.1097/GME.0b013e3182a4690bDrew O, Sherrard J. Sexually transmitted infections in the older woman. Menopause Int. 2008;14(3):134-5. DOI:10.1258/mi.2008.008020Cauci S, Driussi S, De Santo D, et al. Prevalence of bacterial vaginosis and vaginal flora changes in peri- and postmenopausal women. J Clin Microbiol. 2002;40:2147-52. DOI:10.1128/jcm.40.6.2147-2152.2002Dennerstein GJ, Ellis DH. Oestrogen, glycogen and vaginal candidiasis. Aust N Z J Obstet Gynaecol. 2001;41(3):326-8. DOI:10.1111/j.1479-828x.2001.tb01238.xFischer G, Bradford J. Vulvovaginal candidiasis in postmenopausal women: the role of hormone replacement therapy. J Low Genit Tract Dis. 2011;15:263-7. DOI:10.1097/LGT.0b013e3182241f1aBurton JP, Reid G. Evaluation of the bacterial vaginal flora of 20 postmenopausal women by direct (Nugent score) and molecular (polymerase chain reaction and denaturing gradient gel electrophoresis) techniques. J Infect Dis. 2002;186(12):1770-80. DOI:10.1086/345761Huang AJ, Moore EE, Boyko EJ, et al. Vaginal symptoms in postmenopausal women: self-reported severity, natural history, and risk factors. Menopause. 2010;17(1):121-6. DOI:10.1097/gme.0b013e3181acb9edTaylor-Robinson D, McCaffrey M, Pitkin J, et al. Bacterial vaginosis in climacteric and menopausal women. Int J STD AIDS. 2002;13(7):449-52. DOI:10.1258/09564620260079581Hummelen R, Macklaim J, Bisanz J, et al. Vaginal microbiome and epithelial gene array in post-menopausal women with moderate to severe dryness. Plos ONE. 2011;6(11):e26602. DOI:10.1371/journal.pone.0026602Perrotta C, Aznar M, Mejia R, et al. Oestrogens for preventing recurrent urinary tract infection in postmenopausal women. Cochrane Database Syst Rev. 2008;16(2):CD005131. DOI:10.1002/14651858.CD005131.pub2Nazarko L. Recurrent urinary tract infection in older women: an evidencebased approach. Br J Community Nurs. 2013;18:407-12. DOI:10.12968/bjcn.2013.18.8.407Thomas-White KJ, Hilt EE, Fok C, et al. Incontinence medication response relates to the female urinary microbiota. Int Urogynecol J. 2016;27:723-33. DOI:10.1007/s00192-015-2847-xBaber R, Panay N, Fenton A, et al. The IMS Writing Group 2016 IMS Recommendations on women’s midlife health and menopause hormone therapy. Climacteric. 2016;19(2):109-50. DOI:10.3109/13697137.2015.1129166Moore K, Dumoulin C, Bradley C, et al. Adult conservative management. Ed. P Abrams, L Cardozo, S Khoury, A Wein. International consultation on urinary incontinence. 5th ed. Plymbridge, UK: Health Publications Ltd., 2013; p. 1101-95.Менопаузальная гормонотерапия и сохранение здоровья женщин в зрелом возрасте. Клинические рекомендации (протокол лечения). Письмо Министерства здравоохранения Российской Федерации от 2 октября 2015 г. №15-4/10/2-5804 [Menopauzal'naia gormonoterapiia i sokhranenie zdorov'ia zhenshchin v zrelom vozraste. Klinicheskie rekomendatsii (protokol lecheniia). Pis'mo Ministerstva zdravookhraneniia Rossiiskoi Federatsii ot 2 oktiabria 2015 g. №15-4/10/2-5804 (in Russian)].De Villiers TJ, Gass ML, Haines CJ, et al. Global consensus statement on menopausal hormone therapy. Climacteric. 2013;16(2):203-4. DOI:10.3109/13697137.2013.771520Larsen B, Markovetz AJ, Galask RP. Relationship of vaginal cytology to alterations of the vaginal microflora of rats during the estrous cycle. Appl Environ Microbiol. 1977;33(3):556-62. DOI:10.1128/AEM.33.3.556-562.1977Devillard E, Burton JP, Hammond JA, et al. Novel insight into the vaginal microflora in postmenopausal women under hormone replacement therapy as analyzed by PCR-denaturing gradient gel electrophoresis. Eur J Obstet Gynecol Reprod Biol. 2004;117(1):76-81. DOI:10.1016/j.ejogrb.2004.02.001Ginkel PD, Soper DE, Bump RC, Dalton HP. Vaginal flora in postmenopausal women: the effect of estrogen replacement. Infect Dis Obstet Gynecol. 1993;1(2):94-7. DOI:10.1155/S1064744993000225Heinemann C, Reid G. Vaginal microbial diversity among postmenopausal women with and without hormone replacement therapy. Can J Microbiol. 2005;51(9):777-81. DOI:10.1139/w05-070Setty P, Redekal L, Warren MP. Vaginal estrogen use and effects on quality of life and urogenital morbidity in postmenopausal women after publication of the Women's Health Initiative in New York City. Menopause. 2016;23(1):7-10. DOI:10.1097/GME.0000000000000493Galhardo CL, Soares JM Jr, Simoes RS, et al. Estrogen effects on the vaginal pH, flora and cytology in late postmenopause after a long period without hormone therapy. Clin Exp Obstet Gynecol. 2006;33(2):85-9.Goldstein I, Alexander JL. Practical aspects in the management of vaginal atrophy and sexual dysfunction in perimenopausal and postmenopausal women. J Sex Med. 2005;2 (Suppl. 3):154-65. DOI:10.1111/j.1743-6109.2005.00131.xLethaby A, Ayeleke RO, Roberts H. Local oestrogen for vaginal atrophy in postmenopausal women. Cochrane Database Syst Rev. 2016;2016(8):CD001500. DOI:10.1002/14651858.CD001500.pub3Nappi RE, Davis SR. The use of hormone therapy for the maintenance of urogynecological and sexual health post WHI. Climacteric. 2012;15:267-74. DOI:10.3109/13697137.2012.657589Caretto M, Giannini A, Russo E, Simoncini T. Preventing urinary tract infections after menopause without antibiotics. Maturitas. 2017;99:43-6. DOI:10.1016/j.maturitas.2017.02.004Russo E, Caretto M, Giannini A, et al. Management of urinary incontinence in postmenopausal women: An EMAS clinical guide. Maturitas. 2021;143:223-30. DOI:10.1016/j.maturitas.2020.09.005Cobin RH, Goodman NF; AACE Reproductive Endocrinology Scientific Committee. American association of clinical endocrinologists & American college of endocrinology position statement on menopause-2017 Update. Endocr Pract. 2017;23(7):869-80. DOI:10.4158/EP171828.PSArcher DF, Constantine GD, Simon JA, et al. TX-004HR vaginal estradiol has negligible to very low systemic absorption of estradiol. Menopause. 2017;24(5):510-6. DOI:10.1097/GME.0000000000000790Constantine GD, Bouchard C, Pickar JH, et al. Consistency of effect with a low-dose, estradiol vaginal capsule (TX-004HR): evaluating improvement in vaginal physiology and moderate-to-severe dyspareunia in subgroups of postmenopausal women. J Women’s Health. 2017;26(6):616-23. DOI:10.1089/jwh.2016.6187Yarbrough VL, Winkle S, Herbst-Kralovetz MM. Antimicrobial peptides in the female reproductive tract: a critical component of the mucosal immune barrier with physiological and clinical implications. Hum Reprod Update. 2015;21(3):353-77. DOI:10.1093/humupd/dmu065.UDonders GGG, Ruban K, Bellen G, Grinceviciene S. Pharmacotherapy for the treatment of vaginal atrophy. Expert Opin Pharmacother. 2019;20(7):821-35. DOI:10.1080/14656566.2019.1574752Griesser H, Skonietzki S, Fischer T, et al. Low dose estriol pessaries for the treatment of vaginal atrophy: a double-blind placebo-controlled trial investigating the efficacy of pessaries containing 0.2 mg and 0.03 mg estriol. Maturitas. 2012;71(4):360-8. DOI:10.1016/j.maturitas.2011.12.022Jaisamrarn U, Triratanachat S, Chaikittisilpa S, et al. Ultra-low-dose estriol and lactobacilli in the local treatment of postmenopausal vaginal atrophy. Climacteric. 2013;16(3):347-55. DOI:10.3109/13697137.2013.769097Donders G, Bellen G, Neven P, et al. 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):2023-8. DOI:10.1007/s10096-015-2447-1Buchholz S, Mogele M, Lintermans A, et al. Vaginal estriol-lactobacilli combination and quality of life in endocrine-treated breast cancer. Climacteric. 2015;18(2):252-9. DOI:10.3109/13697137.2014.991301Perrota C, Aznar M, Mejia R, et al. Oestrogens for preventing recurrent urinary tract infection in postmenopausal women. Cochrane Database Syst Rev. 2008;16(2):CD005131. DOI:10.1002/14651858.CD005131.pub2Labrie F, Belanger A, Pelletier G, et al. Science of intracrinology in postmenopausal women. Menopause. 2017;24(6):702-12. DOI:10.1097/GME.0000000000000808Labrie F, Archer DF, Koltun W, et al. Efficacy of intravaginal dehydroepiandrosterone (DHEA) on moderate to severe dyspareunia and vaginal dryness, symptoms of vulvovaginal atrophy, and of the genitourinary syndrome of menopause. Menopause. 2016;23(3):243-56. DOI:10.1097/GME.0000000000000571Brown JM, Hess KL, Brown S, et al. Intravaginal practices and risk of bacterial vaginosis and candidiasis infection among a cohort of women in the United States. Obstet Gynecol. 2013;121(4):773-80. DOI:10.1097/AOG.0b013e31828786f8Lima SM, Bernardo BF, Yamada SS, et al. Effects of Glycine max (L.) Merr. soy isoflavone vaginal gel on epithelium morphology and estrogen receptor expression in postmenopausal women: a 12-week, randomized, double-blind, placebo-controlled trial. Maturitas. 2014;78(3):205-11. DOI:10.1016/j.maturitas.2014.04.007Arunkalaivanan A, Kaur H, Onuma O. Laser therapy as a treatment modality for genitourinary syndrome of menopause: a critical appraisal of evidence. Int Urogynecol J. 2017;28(5):681-5. DOI:10.1007/s00192-017-3282-y.