Вопросы диагностики и тактики ведения пациенток с вульвовагинальной атрофией с позиции международных клинических рекомендаций

Вульвовагинальная атрофия (ВВА) является одним из мочеполовых симптомов, вызванных дефицитом эстрогенов, приводящим к недостаточному созреванию эпителия влагалища, к дефициту гликогена, снижению количества и элиминации лактобацилл, смещению рН влагалища в щелочную сторону и формированию почвы для присоединения вторичной инфекции влагалища и мочевыводящих путей. Наиболее характерными симптомами являются появление сухости, жжения, зуда в области гениталий и возникновение диспареунии. Диагностика основана в основном на фиксации жалоб пациентки и клинических проявлений патологии. Для лечения могут быть использованы эстрогенсодержащие препараты для местного применения в разных формах и негормональные средства. Низкодозированные вагинальные эстрогены можно использовать как в виде монотерапии, когда вульвовагинальная атрофия является единственным симптомом дефицита эстрогенов, так и добавлять к системной менопаузальной гормональной терапии (МГТ). В случае монотерапии нет необходимости в добавлении препаратов прогестерона для защиты эндометрия. Исследования последних лет показали отсутствие повышенного риска онкопатологии, сердечно-сосудистых заболеваний и венозной тромбоэмболии на фоне приема локальных форм эстрогенов. Альтернативным методом лечения считается применение вагинальных лубрикантов и увлажняющих средств у пациенток с гормонофобией или перенесших раки различной локализации. Гели с добавлением лактата у пациенток, перенесших рак молочной железы, при длительности применения 12 недель снизили вагинальный рН и увеличили индекс вагинального здоровья. Однако вагинальная терапия эстрогенами превосходит негормональные методы лечения. Данный вид терапии не приводит к снижению частоты и выраженности симптомов недержания мочи или предотвращению инфекции мочевыводящих путей.

1. Менопауза и климактерическое состояние у женщины. Клинические рекомендации. 2021. Ссылка активна на 28.08.2022. https://minzdrav.samregion.ru/wp-content/uploads/sites/28/2021/07/kr117.pdf

2. Тазина Т.В., Князева А.В., Бебнева Т.В. Современное решение проблемы вагинальной сухости. РМЖ. Мать и дитя. 2021;4(3):250-253. https://doi.org/10.32364/2618-8430-2021-4-3250-253

3. Nappi RE, Mattsson LÅ, Lachowsky M, Maamari R, Giraldi A. The CLOSER survey: impact of postmenopausal vaginal discomfort on relationships between women and their partners in Northern and Southern Europe. Maturitas. 2013;75(4):373-379. https://doi.org/10.1016/j.maturitas.2013.05.003

4. Palacios S, Nappi RE, Bruyniks N, Particco M, Panay N; EVES Study Investigators. The European Vulvovaginal Epidemiological Survey (EVES): prevalence, symptoms and impact of vulvovaginal atrophy of menopause. Climacteric. 2018;21(3):286-291. https://doi.org/10.1080/13697137.2018.1446930

5. Nappi RE, Palacios S, Bruyniks N, Particco M, Panay N; EVES Study investigators. The burden of vulvovaginal atrophy on women's daily living: implications on quality of life from a face-to-face real-life survey. Menopause. 2019;26(5):485-491. https://doi.org/10.1097/GME.0000000000001260

6. Krychman M, Graham S, Bernick B, Mirkin S, Kingsberg SA. The Women's EMPOWER Survey: Women's Knowledge and Awareness of Treatment Options for Vulvar and Vaginal Atrophy Remains Inadequate. J Sex Med. 2017;14(3):425-433. https://doi.org/10.1016/j.jsxm.2017.01.011

7. Shufelt CL, Torbati T, Dutra E. Hypothalamic Amenorrhea and the Long-Term Health Consequences. Semin Reprod Med. 2017;35(3):256-262. https://doi.org/10.1055/s-0037-1603581

8. Аполохина И.А., Горбунова Е.А. Клинико-морфологические аспекты вульвовагинальной атрофии. Медицинский совет. 2014;9:110-117.

9. Bleibel B, Nguyen H. Vaginal Atrophy. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021. Available at: https://www.ncbi.nlm.nih.gov/books/NBK559297/. Accessed: June 27, 2022.

10. Nucci M, Parra-Herrna C, editors. Gynecologic Pathology. 2nd ed. Elsevier Hardcover; 2020.

11. Cagnacci A, Venier M, Xholli A, Paglietti C, Caruso S; ANGEL Study. Female sexuality and vaginal health across the menopausal age. Menopause. 2020;27(1):14-19. https://doi.org/10.1097/GME.0000000000001427

12. Hirschberg AL, Bitzer J, Cano A, Ceausu I, Chedraui P, Durmusoglu F, Erkkola R, Goulis DG, Kiesel L, Lopes P, Pines A, van Trotsenburg M, Lambrinoudaki I, Rees M. Topical estrogens and non-hormonal preparations for postmenopausal vulvovaginal atrophy: An EMAS clinical guide. Maturitas. 2021;148:55-61. https://doi.org/10.1016/j.maturitas.2021.04.005

13. National Institute for Health and Care Excellence. Menopause: diagnosis and management. NICE guideline [NG23]. Available at: https://www.nice.org.uk/guidance/NG23. Accessed: August 27, 2022.

14. Galhardo CL, Soares JM Jr, Simões RS, Haidar MA, Rodrigues de Lima G, Baracat EC. Estrogen effects on the vaginal pH, fl and cytology in late postmenopause after a long period without hormone therapy. Clin Exp Obstet Gynecol. 2006;33(2):85-98.

15. Russo E, Caretto M, Giannini A, Bitzer J, Cano A, Ceausu I, Chedraui P, Durmusoglu F, Erkkola R, Goulis DG, Kiesel L, Lambrinoudaki I, Hirschberg AL, Lopes P, Pines A, Rees M, van Trotsenburg M, Simoncini T. Management of urinary incontinence in postmenopausal women: An EMAS clinical guide. Maturitas. 2021;143:223-230. https://doi.org/10.1016/j.maturitas.2020.09.005

16. Cody JD, Jacobs ML, Richardson K, Moehrer B, Hextall A. Oestrogen therapy for urinary incontinence in post-menopausal women. Cochrane Database Syst Rev. 2012;10(10):CD001405. https://doi.org/10.1002/14651858.CD001405.pub3

17. 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

18. Kuhl H. Pharmacology of estrogens and progestogens: infl of different routes of administration. Climacteric. 2005;8 Suppl 1:3-63. https://doi.org/10.1080/13697130500148875

19. Lethaby A, Ayeleke RO, Roberts H. Local oestrogen for vaginal atrophy in postmenopausal women. Cochrane Database Syst Rev. 2016;2016(8):CD001500. https://doi.org/10.1002/14651858.CD001500.pub3

20. Mitchell CM, Reed SD, Diem S, Larson JC, Newton KM, Ensrud KE, LaCroix AZ, Caan B, Guthrie KA. Effi of Vaginal Estradiol or Vaginal Moisturizer vs Placebo for Treating Postmenopausal Vulvovaginal Symptoms: A Randomized Clinical Trial. JAMA Intern Med. 2018;178(5):681-690. https://doi.org/10.1001/jamainternmed.2018.0116

21. Pinkerton JV, Kaunitz AM, Manson JE. Not time to abandon use of local vaginal hormone therapies. Menopause. 2018;25(8):855-858. https://doi.org/10.1097/GME.0000000000001142

22. Griesser H, Skonietzki S, Fischer T, Fielder K, Suesskind M. Low dose estriol pessaries for the treatment of vaginal atrophy: a double-blind placebo-controlled trial investigating the effi of pessaries containing 0.2mg and 0.03mg estriol. Maturitas. 2012;71(4):360368. https://doi.org/10.1016/j.maturitas.2011.12.022

23. Archer DF, Constantine GD, Simon JA, Kushner H, Mayer P, Bernick B, Graham S, Mirkin S; REJOICE Study Group. TX-004HR vaginal estradiol has negligible to very low systemic absorption of estradiol. Menopause. 2017;24(5):510-516. https://doi.org/10.1097/GME.0000000000000790

24. Estradiol-containing (0.01% w/w) medicinal products for topical use. European Medicines Agency. 16 January 2020. Available at: https://www.ema.europa.eu/en/medicines/human/referrals/estradiol-containing-001-ww-medicinal-products-topical-use. Accessed: August 27, 2022.

25. Vagifem 10 micrograms vaginal tablets. Emc. Available at: https://www.medicines.org.uk/emc/product/5719/smpc. Accessed: August 27, 2022.

26. Archer DF, Constantine GD, Simon JA, Kushner H, Mayer P, Bernick B, Graham S, Mirkin S; REJOICE Study Group. TX-004HR vaginal estradiol has negligible to very low systemic absorption of estradiol. Menopause. 2017;24(5):510-516. https://doi.org/10.1097/GME.0000000000000790

27. Santen RJ, Mirkin S, Bernick B, Constantine GD. Systemic estradiol levels with low-dose vaginal estrogens. Menopause. 2020;27(3):361370. https://doi.org/10.1097/GME.0000000000001463

28. Kroll R, Archer DF, Lin Y, Sniukiene V, Liu JH. A randomized, multicenter, double-blind study to evaluate the safety and effi of estradiol vaginal cream 0.003% in postmenopausal women with dyspareunia as the most bothersome symptom. Menopause. 2018;25(2):133138. https://doi.org/10.1097/GME.0000000000000985

29. Bhupathiraju SN, Grodstein F, Stampfer MJ, Willett WC, Crandall CJ, Shifren JL, Manson JE. Vaginal estrogen use and chronic disease risk in the Nurses' Health Study. Menopause. 2018;26(6):603-610. https://doi.org/10.1097/GME.0000000000001284

30. Rahn DD, Carberry C, Sanses TV, Mamik MM, Ward RM, Meriwether KV, Olivera CK, Abed H, Balk EM, Murphy M; Society of Gynecologic Surgeons Systematic Review Group. Vaginal estrogen for genitourinary syndrome of menopause: a systematic review. Obstet Gynecol. 2014;124(6):1147-1156. https://doi.org/10.1097/AOG.0000000000000526

31. Potter N, Panay N. Vaginal lubricants and moisturizers: a review into use, effi , and safety. Climacteric. 2021;24(1):19-24. https://doi.org/10.1080/13697137.2020.1820478

32. De Seta F, Caruso S, Di Lorenzo G, Romano F, Mirandola M, Nappi RE. Effi and safety of a new vaginal gel for the treatment of symptoms associated with vulvovaginal atrophy in postmenopausal women: A double-blind randomized placebo-controlled study. Maturitas. 2021;147:34-40. https://doi.org/10.1016/j.maturitas.2021.03.002

33. Herbenick D, Reece M, Hensel D, Sanders S, Jozkowski K, Fortenberry JD. Association of lubricant use with women's sexual pleasure, sexual satisfaction, and genital symptoms: a prospective daily diary study. J Sex Med. 2011;8(1):202-12. https://doi.org/10.1111/j.1743-6109.2010.02067.x

34. Lee YK, Chung HH, Kim JW, Park NH, Song YS, Kang SB. Vaginal pH-balanced gel for the control of atrophic vaginitis among breast cancer survivors: a randomized controlled trial. Obstet Gynecol. 2011;117(4):922-927. https://doi.org/10.109AOG.0b013e3182118790

35. Nappi RE, Kotek M, Brešt'anský A, Giordan N, Tramentozzi E. Effectiveness of hyaluronate-based pessaries in the treatment of vulvovaginal atrophy in postmenopausal women. Climacteric. 2020;23(5):519-524. https://doi.org/10.1080/13697137.2020.1754386

36. Wilkinson EM, Łaniewski P, Herbst-Kralovetz MM, Brotman RM. Personal and Clinical Vaginal Lubricants: Impact on Local Vaginal Microenvironment and Implications for Epithelial Cell Host Response and Barrier Function. J Infect Dis. 2019;220(12):20092018. https://doi.org/10.1093/infdis/jiz412

37. Weiderpass E, Baron JA, Adami HO, Magnusson C, Lindgren A, Bergström R, Correia N, Persson I. Low-potency oestrogen and risk of endometrial cancer: a case-control study. Lancet. 1999;353(9167):1824-1828. https://doi.org/10.1016/S01406736(98)10233-7

38. Crandall CJ, Diamant A, Santoro N. Safety of vaginal estrogens: a systematic review. Menopause. 2020;27(3):339-360. https://doi.org/10.1097/GME.0000000000001468

39. Rueda C, Osorio AM, Avellaneda AC, Pinzón CE, Restrepo OI. The effi and safety of estriol to treat vulvovaginal atrophy in postmenopausal women: a systematic literature review. Climacteric. 2017;20(4):321-330. https://doi.org/10.1080/13697137.2017.1329291

40. Villa P, Tagliaferri V, Amar ID, Cipolla C, Ingravalle F, Scambia G, Ricciardi W, Lanzone A. Local ultra-low-dose estriol gel treatment of vulvo-vaginal atrophy: effi and safety of long-term treatment. Gynecol Endocrinol. 2020;36(6):535-539. https://doi.org/10.1080/09513590.2019.1702016

41. Crandall CJ, Hovey KM, Andrews CA, Chlebowski RT, Stefanick ML, Lane DS, Shifren J, Chen C, Kaunitz AM, Cauley JA, Manson JE. Breast cancer, endometrial cancer, and cardiovascular events in participants who used vaginal estrogen in the Women's Health Initiative Observational Study. Menopause. 2018;25(1):11-20. https://doi.org/10.1097/GME.0000000000000956

42. Collaborative Group on Hormonal Factors in Breast Cancer. Type and timing of menopausal hormone therapy and breast cancer risk: individual participant meta-analysis of the worldwide epidemiological evidence. Lancet. 2019;394(10204):1159-1168. https://doi.org/10.1016/S0140-6736(19)31709-X

43. Vinogradova Y, Coupland C, Hippisley-Cox J. Use of hormone replacement therapy and risk of venous thromboembolism: nested case-control studies using the QResearch and CPRD databases. BMJ. 2019;364:k4810. https://doi.org/10.1136/bmj.k4810

44. Crean-Tate KK, Faubion SS, Pederson HJ, Vencill JA, Batur P. Management of genitourinary syndrome of menopause in female cancer patients: a focus on vaginal hormonal therapy. Am J Obstet Gynecol. 2020;222(2):103-113. https://doi.org/10.1016/j.ajog.2019.08.043

45. Goss PE, Ingle JN, Pritchard KI, Robert NJ, Muss H, Gralow J, Gelmon K, Whelan T, Strasser-Weippl K, Rubin S, Sturtz K, Wolff AC, Winer E, Hudis C, Stopeck A, Beck JT, Kaur JS, Whelan K, Tu D, Parulekar WR. Extending Aromatase-Inhibitor Adjuvant Therapy to 10 Years. N Engl J Med. 2016;375(3):209-219. https://doi.org/10.1056/NEJMoa1604700

46. Santen RJ, Mirkin S, Bernick B, Constantine GD. Systemic estradiol levels with low-dose vaginal estrogens. Menopause. 2020;27(3):361370. https://doi.org/10.1097/GME.0000000000001463

47. Kendall A, Dowsett M, Folkerd E, Smith I. Caution: Vaginal estradiol appears to be contraindicated in postmenopausal women on adjuvant aromatase inhibitors. Ann Oncol. 2006;17(4):584-587. https://doi.org/10.1093/annonc/mdj127

48. Pavlović RT, Janković SM, Milovanović JR, Stefanović SM, Folić MM, Milovanović OZ, Mamillapalli C, Milosavljević MN. The Safety of Local Hormonal Treatment for Vulvovaginal Atrophy in Women With Estrogen Receptor-positive Breast Cancer Who Are on Adjuvant Aromatase Inhibitor Therapy: Meta-analysis. Clin Breast Cancer. 2019;19(6):e731-e740. https://doi.org/10.1016/j.clbc.2019.07.007

49. Hirschberg AL, Sánchez-Rovira P, Presa-Lorite J, Campos-Delgado M, Gil-Gil M, Lidbrink E, Suárez-Almarza J, Nieto-Magro C. Effi and safety of ultra-low dose 0.005% estriol vaginal gel for the treatment of vulvovaginal atrophy in postmenopausal women with early breast cancer treated with nonsteroidal aromatase inhibitors: a phase II, randomized, double-blind, placebo-controlled trial. Menopause. 2020;27(5):526-534. https://doi.org/0.1097/GME.0000000000001497

50. Sánchez-Rovira P, Hirschberg AL, Gil-Gil M, Bermejo-De Las Heras B, Nieto-Magro C. A Phase II Prospective, Randomized, Double-Blind, Placebo-Controlled and Multicenter Clinical Trial to Assess the Safety of 0.005% Estriol Vaginal Gel in Hormone ReceptorPositive Postmenopausal Women with Early Stage Breast Cancer in Treatment with Aromatase Inhibitor in the Adjuvant Setting. Oncologist. 2020;25(12):e1846-1854. https://doi.org/10.1634/theoncologist.2020-0417

51. Le Ray I, Dell'Aniello S, Bonnetain F, Azoulay L, Suissa S. Local estrogen therapy and risk of breast cancer recurrence among hormone-treated patients: a nested case-control study. Breast Cancer Res Treat. 2012;135(2):603-609. https://doi.org/10.1007/s10549012-2198-y

52. Rees M, Angioli R, Coleman RL, Glasspool R, Plotti F, Simoncini T, Terranova C. European Menopause and Andropause Society (EMAS) and International Gynecologic Cancer Society (IGCS) position statement on managing the menopause after gynecological cancer: focus on menopausal symptoms and osteoporosis. Maturitas. 2020;134:56-61. https://doi.org/10.1016/j.maturitas.2020.01.005

53. Aerts L, Enzlin P, Verhaeghe J, Poppe W, Vergote I, Amant F. Sexual functioning in women after surgical treatment for endometrial cancer: a prospective controlled study. J Sex Med. 2015;12(1):198209. https://doi.org/10.1111/jsm.12764

54. Chambers LM, Herrmann A, Michener CM, Ferrando CA, Ricci S. Vaginal estrogen use for genitourinary symptoms in women with a history of uterine, cervical, or ovarian carcinoma. Int J Gynecol Cancer. 2020;30(4):515-524. https://doi.org/10.1136/ijgc-2019-001034

55. Rousset-Jablonski C, Selle F, Adda-Herzog E, Planchamp F, Selleret L, Pomel C, Daraï E, Chabbert-Buffet N, Pautier P, Trémollières F, Guyon F, Rouzier R, Laurence V, Chopin N, Faure-Conter C, Bentivegna E, Vacher-Lavenu MC, Lhomme C, Floquet A, Treilleux I, Lecuru F, Gouy S, Kalbacher E, Genestie C, Thibault MR, Ferron G, Devouassoux M, Kurtz JE, Provansal M, Namer M, Joly F, Pujade-Lauraine E, Grynberg M, Querleu D, Morice P, Gompel A, Ray-Coquard I. Fertility preservation, contraception and menopause hormone therapy in women treated for rare ovarian tumours: guidelines from the French national network dedicated to rare gynaecological cancers. Eur J Cancer. 2019;116:35-44. https://doi.org/10.1016/j.ejca.2019.04.018

56. Aerts L, Enzlin P, Verhaeghe J, Poppe W, Vergote I, Amant F. Long-term sexual functioning in women after surgical treatment of cervical cancer stages IA to IB: a prospective controlled study. Int J Gynecol Cancer. 2014;24(8):1527-1534. https://doi.org/10.1097/IGC.0000000000000236

57. Aerts L, Enzlin P, Verhaeghe J, Vergote I, Amant F. Psychologic, relational, and sexual functioning in women after surgical treatment of vulvar malignancy: a prospective controlled study. Int J Gynecol Cancer. 2014;24(2):372-380. https://doi.org/10.1097/IGC.0000000000000035

58. Bodner K, Laubichler P, Kimberger O, Czerwenka K, Zeillinger R, Bodner-Adler B. Oestrogen and progesterone receptor expression in patients with adenocarcinoma of the uterine cervix and correlation with various clinicopathological parameters. Anticancer Res. 2010;30(4):1341-1345.

59. Martin JD, Hähnel R, McCartney AJ, De Klerk N. The influence of estrogen and progesterone receptors on survival in patients with carcinoma of the uterine cervix. Gynecol Oncol. 1986;23(3):329-335. https://doi.org/10.1016/0090-8258(86)90134-4