Almanac of Clinical MedicineAlmanac of Clinical MedicineАльманах клинической медицины2072-05052587-9294Moscow Regional Research and Clinical Institute (MONIKI)25710.18786/2072-0505-2015-37-100-104GYNECOLOGYГИНЕКОЛОГИЯАBNORMAL UTERINE BLEEDING DURING МENOPAUSAL HORMONAL THERAPYАНОМАЛЬНЫЕ МАТОЧНЫЕ КРОВОТЕЧЕНИЯ НА ФОНЕ МЕНОПАУЗАЛЬНОЙ ГОРМОНАЛЬНОЙ ТЕРАПИИZaydievaYa. Z.ЗайдиеваЯ. З.
Russian Federation

MD, PhD, Professor, Head of the Department of Gynecologic Endocrinology

д-р мед. наук, профессор, руководитель отделения гинекологической эндокринологии

Moscow Regional Scientific Research Institute for Obstetrics and GynecologyГБУЗ МО «Московский областной научно-исследовательский институт акушерства и гинекологии»15032015371001042202201622022016Copyright ©; 2015, Zaydieva Y.Z.Copyright ©; 2015, Зайдиева Я.З.2015Zaydieva Y.Z.Зайдиева Я.З.https://creativecommons.org/licenses/by/4.0https://almclinmed.ru/jour/article/view/257

Postmenopausal women using continuous combined estrogen/progestin therapy are likely to have irregular bleedings or spotting. Up to now, their causes remain unclear. Most investigators believe that a potential mechanism of abnormal bleedings during menopausal hormonal therapy could be a change in the ratio of pro- and anti-angiogenic factors, namely, of vascular endothelial growth factor to thrombospondin-1; alterations in metalloproteinases and their tissue inhibitors; changes in a tissue factor that is a mediator of endometrial hemostasis; as well as an increased number of endometrial leukocytes with predominance of uterine natural killer cells. As long as no link between bleeding discharge during continuous combined hormonal treatment and any of these  actors has been established, each and every of them is the subject of in vivo and in vitro investigations. At present, there are no  herapeutic methods to correct this complication of hormonal treatment. Patient monitoring to exclude neoplastic abnormalities in endometrium are of paramount importance.

У женщин в климактерии, принимающих комбинированную гормональную терапию в непрерывном режиме, нередко возникают эпизоды ациклических кровотечений из половых путей. Причины этого явления до сих пор не ясны. Большинство исследователей считают, что возможным механизмом аномальных кровотечений на фоне менопаузальной гормональной терапии служат изменение соотношения про- и антиангиогенных факторов сосудистого эндотелиального фактора роста и тромбоспондина-1, повреждения металлопротеиназ и их тканевых ингибиторов, изменения тканевого фактора – медиатора гемостаза в эндометрии, а также повышение уровня лейкоцитов в эндометрии с преобладанием естественных киллерных клеток. Поскольку взаимосвязь между возникновением кровянистых выделений на фоне непрерывного комбинированного режима гормональной терапии и этими факторами не установлена, каждый из них является предметом исследований in vivo и in vitro. В настоящее время отсутствуют терапевтические методы коррекции этого осложнения гормональной терапии. Важным представляется мониторинг пациенток с точки зрения исключения неопластических процессов в эндометрии.

climacteriumpostmenopausemenopausal hormonal therapyendometriumprogestogensangiogenesisabnormal uterine bleedingsклимактерийпостменопаузаменопаузальная гормональная терапияэндометрийпрогестагеныангиогенезаномальные маточные кровотечения1. de Villiers TJ, Gass ML, Haines CJ, Hall JE, Lobo RA, Pierroz DD, Rees M. Global consensus statement on menopausal hormone therapy. Climacteric. 2013;16(2):203–4.2. Archer DF, Dorin MH, Heine W, Nanavati N, Arce JC. Uterine bleeding in postmenopausal women on continuous therapy with estradiol and norethindrone acetate. Endometrium Study Group. Obstet Gynecol. 1999;94(3):323–9.3. Chlebowski RT, Hendrix SL, Langer RD, Stefanick ML, Gass M, Lane D, Rodabough RJ, Gilligan MA, Cyr MG, Thomson CA, Khandekar J, Petrovitch H, McTiernan A; WHI Investigators. Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women's Health Initiative Randomized Trial. JAMA. 2003;289(24):3243–53.4. Manson JE, Hsia J, Johnson KC, Rossouw JE, Assaf AR, Lasser NL, Trevisan M, Black HR, Heckbert SR, Detrano R, Strickland OL, Wong ND, Crouse JR, Stein E, Cushman M; Women's Health Initiative Investigators. Estrogen plus progestin and the risk of coronary heart disease. N Engl J Med. 2003;349(6):523–34.5. Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, Jackson RD, Beresford SA, Howard BV, Johnson KC, Kotchen JM, Ockene J; Writing Group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA. 2002;288(3):321–33.6. Archer DF, Lobo RA, Land HF, Pickar JH. A comparative study of transvaginal uterine ultrasound and endometrial biopsy for evaluating the endometrium of postmenopausal women taking hormone replacement therapy. Menopause. 1999;6(3):201–8.7. Archer DF. The effect of the duration of progestin use on the occurrence of endometrial cancer in postmenopausal women. Menopause. 2001;8(4):245–51.8. Lethaby A, Suckling J, Barlow D, Farquhar CM, Jepson RG, Roberts H. Hormone replacement therapy in postmenopausal women: endometrial hyperplasia and irregular bleeding. Cochrane Database Syst Rev. 2004;(3):CD000402.9. Archer DF, Dorin M, Lewis V, Schneider DL, Pickar JH. Effects of lower doses of conjugated equine estrogens and medroxyprogesterone acetate on endometrial bleeding. Fertil Steril. 2001;75(6):1080–7.10. Archer DF. Endometrial bleeding during hormone therapy: the effect of progestogens. Maturitas. 2007;57(1):71–6.11. American College of Obstetricians and Gynecologists. Ovarian, endometrial, and colorectal cancers. Obstet Gynecol. 2004;104(4):S77–84.12. Anderson GL, Judd HL, Kaunitz AM, Barad DH, Beresford SA, Pettinger M, Liu J, McNeeley SG, Lopez AM; Women's Health Initiative Investigators. Effects of estrogen plus progestin on gynecologic cancers and associated diagnostic procedures: the Women's Health Initiative randomized trial. JAMA. 2003;290(13):1739–48.13. Hulley S, Furberg C, Barrett-Connor E, Cauley J, Grady D, Haskell W, Knopp R, Lowery M, Satterfield S, Schrott H, Vittinghoff E, Hunninghake D; HERS Research Group. Noncardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/progestin Replacement Study follow-up (HERS II). JAMA. 2002;288(1):58–66.14. Anderson GL, Limacher M, Assaf AR, Bassford T, Beresford SA, Black H, Bonds D, Brunner R, Brzyski R, Caan B, Chlebowski R, Curb D, Gass M, Hays J, Heiss G, Hendrix S, Howard BV, Hsia J, Hubbell A, Jackson R, Johnson KC, Judd H, Kotchen JM, Kuller L, LaCroix AZ, Lane D, Langer RD, Lasser N, Lewis CE; Women's Health Initiative Steering Committee. Effects of conjugated equine estrogen in postmenopausalwomen with hysterectomy: the Women's Health Initiative randomized controlled trial. JAMA. 2004;291(14):1701–12.15. Lacey JV Jr, Brinton LA, Lubin JH, Sherman ME, Schatzkin A, Schairer C. Endometrial carcinoma risks among menopausal estrogen plus progestin and unopposed estrogen users in a cohort of postmenopausal women. Cancer Epidemiol Biomarkers Prev. 2005;14(7):1724–31.16. Lethaby A, Farquhar C, Sarkis A, Roberts H, Jepson R, Barlow D. Hormone replacement therapy in postmenopausal women: endometrial hyperplasia and irregular bleeding. Cochrane Database Syst Rev. 2000;(2):CD000402.17. Strom BL, Schinnar R, Weber AL, Bunin G, Berlin JA, Baumgarten M, DeMichele A, Rubin SC,Berlin M, Troxel AB, Rebbeck TR. Case-control study of postmenopausal hormone replacement therapy and endometrial cancer. Am J Epidemiol. 2006;164(8):775–86.18. Effects of hormone replacement therapy on endometrial histology in postmenopausal women. The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. The Writing Group for the PEPI Trial. JAMA. 1996;275(5):370–5.19. Weiderpass E, Adami HO, Baron JA, Magnusson C, Bergstrom R, Lindgren A, Correia N, Persson I. Risk of endometrial cancer following estrogen replacement with and without progestins. J Natl Cancer Inst. 1999;91(13):1131–7.20. Krikun G, Schatz F, Taylor R, Critchley HO, Rogers PA, Huang J, Lockwood CJ. Endometrial endothelial cell steroid receptor expression and steroid effects on gene expression. J Clin Endocrinol Metab. 2005;90(3):1812–8.21. Rowan JP, Simon JA, Speroff L, Ellman H. Effects of low-dose norethindrone acetate plus ethinyl estradiol (0.5 mg/2.5 microg) in women with postmenopausal symptoms: updated analysis of three randomized, controlled trials.Clin Ther. 2006;28(6):921–32.22. Simon JA, Liu JH, Speroff L, Shumel BS, Symons JP. Reduced vaginal bleeding in postmenopausal women who receive combined norethindrone acetate and low-dose ethinylestradiol therapy versus combined conjugated equine estrogens and medroxyprogesterone acetate therapy. Am J Obstet Gynecol. 2003;188(1):92–9.23. Speroff L, Rowan J, Symons J, Genant H, Wilborn W. The comparative effect on bone density, endometrium, and lipids of continuous hormones as replacement therapy (CHART study). A randomized controlled trial. JAMA. 1996;276(17):1397–403.24. Pickar JH, Archer DF. Is bleeding a predictor of endometrial hyperplasia in postmenopausal women receiving hormone replacement therapy? Menopause Study Group (United States, Italy, Netherlands, Switzerland, Belgium, Germany, and Finland. Am J Obstet Gynecol. 1997;177(5):1178–83.25. Pickar JH, Bottiglioni F, Archer DF. Amenorrhea frequency with continuous combined hormone replacement therapy: a retrospective analysis. Menopause Study Group. Climacteric. 1998;1(2):130–6.26. Charnock-Jones DS, Macpherson AM, Archer DF, Leslie S, Makkink WK, Sharkey AM, Smith SK. The effect of progestins on vascular endothelial growth factor, oestrogen receptor and progesterone receptor immunoreactivity and endothelial cell density in human endometrium. Hum Reprod. 2000;15 Suppl 3:85–95.27. Critchley HO, Brenner RM, Henderson TA, Williams K, Nayak NR, Slayden OD, Millar MR, Saunders PT. Estrogen receptor beta, but not estrogen receptor alpha, is present in the vascular endothelium of the human and nonhuman primate endometrium. J Clin Endocrinol Metab. 2001;86(3):1370–8.28. Lecce G, Meduri G, Ancelin M, Bergeron C, Perrot-Applanat M. Presence of estrogen receptor beta in the human endometrium through the cycle: expression in glandular, stromal, and vascular cells. J Clin Endocrinol Metab. 2001;86(3):1379–86.29. Hickey M, Dwarte D, Fraser IS. Superficial endometrial vascular fragility in Norplant users and in women with ovulatory dysfunctional uterine bleeding. Hum Reprod. 2000;15(7):1509–14.30. Hickey M, Pillai G, Higham JM, Sullivan M, Horncastle D, Doherty D, Stamp G. Changes in endometrial blood vessels in the endometrium of women with hormone replacement therapy-related irregular bleeding. Hum Reprod.2003;18(5):1100–6.31. Lockwood CJ, Runic R, Wan L, Krikun G, Demopolous R, Schatz F. The role of tissue factor in regulating endometrial haemostasis: implications for progestin-only contraception. Hum Reprod. 2000;15 Suppl 3:144–51.32. Mirkin S, Navarro F, Archer DF. Hormone therapy and endometrial angiogenesis. Climacteric. 2003;6(4):273–7.33. Vincent AJ, Salamonsen LA. The role of matrix metalloproteinases and leukocytes in abnormal uterine bleeding associated with progestin-only contraceptives. Hum Reprod. 2000;15 Suppl 3:135–43.34. Vincent AJ, Zhang J, Ostor A, Rogers PA, Affandi B, Kovacs G, Salamonsen LA. Decreased tissue inhibitor of metalloproteinase in the endometrium of women using depot medroxyprogesterone acetate: a role for altered endometrial matrix metalloproteinase/tissue inhibitor of metalloproteinase balance in the pathogenesis of abnormal uterine bleeding? Hum Reprod. 2002;17(5):1189–98.35. Whitehead MI, King RJ, McQueen J, Campbell S. Endometrial histology and biochemistry in climacteric women during oestrogen and oestrogen/progestogen therapy. J R Soc Med. 1979;72(5):322–7.36. Hickey M, Crewe J, Mahoney LA, Doherty DA, Fraser IS, Salamonsen LA. Mechanisms of irregular bleeding with hormone therapy: the role of matrix metalloproteinases and theirtissue inhibitors. J Clin Endocrinol Metab.2006;91(8):3189–98.37. Hickey M, Crewe J, Goodridge JP, Witt CS, Fraser IS, Doherty D, Christiansen FT, Salamonsen LA. Menopausal hormone therapy and irregular endometrial bleeding: a potential role for uterine natural killer cells. J Clin Endocrinol Metab. 2005;90(10):5528–35.38. Whitehead MI, Townsend PT, Pryse-Davies J, Ryder TA, King RJ. Effects of estrogens and progestins on the biochemistry and morphology of the postmenopausal endometrium. N Engl J Med. 1981;305(27):1599–605.39. Goldstein SR. The endometrial echo revisited: have we created a monster? Am J Obstet Gynecol. 2004;191(4):1092–6.