Менопаузальная гормональная терапия: онкологические риски

Мусина Е.В., Коган И.Ю. Менопаузальная гормональная терапия: онкологические риски. Гинекология. 2020; 22 (3): 29–32. DOI: 10.26442/20795696.2020.3.200154

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Musina E.V., Kogan I.Yu. Menopausal hormone therapy: oncological risks. Gynecology. 2020; 22 (3): 29–32. DOI: 10.26442/20795696.2020.3.200154

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Аннотация

В обзорной статье представлен анализ литературы за последние 10 лет, о взаимосвязи менопаузальной гормональной терапии (МГТ) и рисков развития злокачественных заболеваний у женщин, в том числе и с факторами риска, такими как мутации в генах BRCA1/2. Основным сдерживающим фактором в назначении МГТ на сегодняшний день остается вопрос: есть ли связь между МГТ и развитием онкологической патологии, в связи с высокими показателями смертности от злокачественных новообразований̆, которые занимают 2-е место после сердечно-сосудистых заболеваний̆. Основная локализация опухолевого процесса, который останавливает назначение МГТ, – это рак молочной железы. В структуре заболеваемости злокачественными новообразованиями среди женского населения в России рак молочной железы занимает лидирующее место, с этим и связаны основные опасения по влиянию МГТ. Результаты крупных исследований достаточно неоднозначны и не дают ответа на все вопросы. Не стоит забывать и о других локализациях опухолевого процесса, на которые МГТ также может оказывать влияние, и о которых также нет однозначного ответа на вопрос о связи МГТ и рисков развития опухоли. Как для любой терапии, для МГТ есть свои противопоказания, которые тоже освещены в статье. Представлены и основные режимы приема МГТ и их взаимосвязь с рисками развития опухоли, влияние основных компонентов МГТ на процессы неопластической трансформации.

Ключевые слова: менопаузальная гормональная терапия, онкологические риски

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The review article presents an analysis of the literature over the past 10 years on the relationship of menopausal hormone therapy and the risks of developing malignant diseases in women, including risk factors, such as mutations in the BRCA1/2 genes. The main limiting factor in the appointment of menopausal hormone therapy today remains the question: is there a connection between MHT and the development of oncological pathology, due to the high mortality rates from malignant neoplasms, which occupy the 2nd place after cardiovascular diseases. The main localization of the tumor process, which stops the appointment of MHT, is breast cancer. In the structure of the incidence of malignant neoplasms among the female population in Russia, breast cancer occupies a leading place, and this is the main interest in the effect of MHT. The results of large-scale studies are rather ambiguous and do not answer all the questions. Do not forget about other localizations of the tumor process, which MHT can also influence, and about which, there is also no unequivocal answer to the question about the relationship of MHT and the risks of tumor development. As for any therapy, for MHT there are contraindications, which are also covered in the article. The main modes of taking menopausal hormone therapy and their relationship with the risks of tumor development are also presented. The influence of the main components of menopausal hormone therapy on the processes of neoplastic transformation.

Key words: menopausal hormonal therapy, oncological risks.

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Список литературы

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7. Fournier A, Mesrina S, Dossus L et al. Risk of breast cancer after stopping menopausal hormone therapy in the E3N cohort. Breast Cancer Res Treat 2014; 145 (2): 535–43.
8. 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. DOI: 10.1016/S0140-6736(19)31709-X
9. Manson JE, Chlebowski RT, Stefanick ML et al. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the women’s health initiative randomized trials. JAMA 2013; 31: 1353–68. DOI: 10.1001/jama.2013.278040
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[Ashrafian L.A., Kiselev V.I., Kuznetsov I.N. i dr. Molekuliarnaia onkobiologiia i perspektivy effektivnoi terapii. Onkologiia. 2016; 3: 80–7. DOI: 10.17116/onkolog20165280-87 (in Russian).]
16. Byrne C, Ursin G, Martin CF et al. Mammographic Density Change With Estrogen and Progestin Therapy and Breast Cancer Risk. J Natl Cancer Inst 2017; 109: 1–7. doi: 10.1093/jnci/djx001
17. Marjoribanks J, Farquhar C, Roberts H, Lethaby A. Long term hormone therapy for perimenopausal and postmenopausal women. Cochrane Database Sys Rev 2012; 7: CD004143. DOI: 10.1002/14651858.CD004143.pub4
18. NCCN – Evidence-Based Cancer Guidelines. https://www.nccn.org/
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22. Anderson GL, Chlebowski RT, Aragaki AK et al. Conjugated equine oestrogenand breast cancer incidence and mortality in postmenopausal women with hysterectomy: extended follow- up of the Women’s Health Initiative randomisedplacebo-controlled trial. Lancet Oncol 2012; 13: 476–86.
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[Paianidi Iu.G., Zhordania K.I. Menopauzal'naia gormonal'naia terapiia v onkologii. Rekomendatsii mezhdunarodnogo obshchestva po menopauze (IMS, 2016). Obzor. Onkoginekologiia. 2016; 3: 43–53 (in Russian).]
25. Yang Liu, Lan Ma, Xiaoling Yang et al. Menopausal hormone replacement therapy and the risk of ovarian cancer: a meta-analysis. Front Endocrinol 2019; 10: 801. DOI: 10.3389/fendo.2019.00801
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[Imianitov E.N. Fundamental'naia onkologiia v 2011 godu: obzor naibolee interesnykh otkrytiĭ. Prakt. onkologiia. 2012; 13 (1): 1–8 (in Russian).]
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[BRCA1/2. Prakticheskoe rukovodstvo dlia vrachei. RUSSCO. 2016; c. 12 (in Russian).]
28. Mehrgou A, Akouchekian M. The importance of BRCA1 and BRCA2 genes mutations in breast cancer development. Med J Islam Repub Iran 2016; 30: 369.
29. Ходорович О.С. Наследственная форма рака молочной железы. Методы профилактики. Вестн. РНЦРР МЗ РФ. 2012; 12. http://vestnik.rncrr.ru/vestnik/v12/papers/hodorovich_v12.
[Khodorovich O.S. Nasledstvennaia forma raka molochnoi zhelezy.
Metody profilaktiki. Vestn. RNTsRR MZ RF. 2012; 12. http://vestnik.rncrr.ru/vestnik/v12/papers/hodorovich_v12 (in Russian).]
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31. Mavaddat N, Peock S, Frost D et al. Cancer risks for BRCA1 and BRCA2 mutation carriers: results from prospective analysis of EMBRACE. J Natl Cancer Inst 2013; 105 (11): 812–22. DOI: org/10.1093/jnci/djt095
32. Kotsopoulos J, Huzarski T, Gronwald J et al. Bilateral Oophorectomy and Breast Cancer Risk in BRCA1 and BRCA2 Mutation Carriers.
J Natl Cancer Inst 2016; 109: 1–7. DOI: 10.1093/jnci/djw177
33. De Felice F, Marchetti C, Mussela A et al. Bilateral Risk-Reduction Mastectomy in BRCA1 and BRCA2 Mutation Carriers: A Meta-analysis. Ann Surg Oncol 2015; 22 (9): 2876–80.
34. Domchek SM, Friebel T, Neuhausen SL et al. PROSE Consortium. Is hormone replacement therapy (HRT) following risk-reducing salpingooophorectomy (RRSO) in BRCA1 (B1)- and BRCA2 (B2)-mutation carriers associated with an increased risk of breast cancer? [Abstract].
J Clin Oncol 2011; 29 (Suppl.). Abstract 1501.
35. Eisen A, Lubinski J, Gronwald J et al. Hereditary Breast Cancer Clinical Study Group. Hormone therapy and the risk of breast cancer in BRCA1 mutation carriers. J Natl Cancer Inst 2008; 100: 1361–7.
36. Nappi RE, Cassani C, Rossi M et al. Dealing with premature menopause in women at high-risk for hereditary genital and breast cancer. Minerva Ginecol 2016; 68 (5): 602–12.
37. Domchek S, Kaunitz AM. Use of Systemic Hormone Therapy in BRCA Mutation Carriers. NAMS Practice Pearl 2016; May 5: 1–4.
38. The 2017 Hormone therapy position statement of The North American Menopause Society. Menopause 2017; 24 (7): 728–53. DOI: 10.1097/GME.0000000000000921
39. Jaakkola S, Pukkala E, Lyytinen H et al. Postmenopausal estradiol-progestagen therapy and risk for uterine cervical cancer. Int J Cancer 2012; 131: 537–43.
40. Amitay EL et al. Postmenopausal hormone replacement therapy and colorectal cancer risk by molecular subtypes and pathways. Int J Cancer 2020.
41. Schwartz AG, Ray RM, Cote ML et al. Hormone Use, Reproductive History, and Risk of Lung Cancer The Women’s Health Initiative Studies.
J Thoracic Oncol 2015; 10 (7): 1004–13.
42. Stabile LP, Dacic S, Land SR. Combined Analysis of Estrogen Receptor β-1 and Progesterone Receptor Expression Identifies Lung Cancer Patients with Poor Outcome. Clin Cancer Res 2011; 1: 154–64. DOI: 10.1158/1078-0432.CCR-10-0992
43. De Giorgi V, Gori A, Savarese I et al. Role of BMI and hormone therapy in melanoma risk: a case–control study. J Cancer Res Clin Oncol 2017; 143 (7): 1191–7.
44. Botteri E, Støer NC, Sakshaug S et al. Menopausal hormone therapy and risk of melanoma: Do estrogens and progestins have a different role? Int J Cancer 2017; 141 (9): 1763–70.

________________________________________________

1. Menopause and menopause in women. Clinical recommendations. Moscow, 2016 (in Russian).
2. Baber RJ, Panay N, Fenton A, the IMS Writing Group. IMS Recommendations on women’s midlife health and menopause hormone therapy. Climacteric 2016; 19 (2): 109–50.
3. Neves-e-Castro M, Birkhäuser M, Samsioe G et al. EMAS position statement: The ten point guide to the integral management of menopausal health. Maturitas 2015; 81: 88–92.
4. Stuenkel CA, Davis SR, Gompel A et al. Treatment of symptoms of the menopause: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2015; 100 (11): 3975–4011.
5. Rossouw JE, Anderson GL, Prentice RL et al. 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: 321–32.
6. Мosekilde L et al. Danish Osteoporosis Prevention Study (DORS): project design and inclusion of 2000 normal perimenopausal women. Maturitas 1999; 31 (3): 207–19. DOI: 10.1016/s0378-5122(99)00006-7
7. Fournier A, Mesrina S, Dossus L et al. Risk of breast cancer after stopping menopausal hormone therapy in the E3N cohort. Breast Cancer Res Treat 2014; 145 (2): 535–43.
8. 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. DOI: 10.1016/S0140-6736(19)31709-X
9. Manson JE, Chlebowski RT, Stefanick ML et al. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the women’s health initiative randomized trials. JAMA 2013; 31: 1353–68.
DOI: 10.1001/jama.2013.278040
10. Stanczyk FZ, Hapgood JP, Winer S et al. Progestogens used in postmenopausal hormone therapy: differences in their pharmacological properties, intracellular actions, and clinical effects. Endocrine Rev 2013; 34 (2): 171–208. DOI: org/10.1210/er.2012-1008
11. Anderson GL, Chlebowski RT, Aragaki AK et al. Conjugated equine oestrogen and breast cancer incidence and mortality in postmenopausal women with hysterectomy: extended follow-up of the Women’s Health Initiative randomised placebo-controlled trial. Lancet Oncol 2012; 13: 476–86.
12. Baber R, Panay N. 2016 IMS Recommendations on women’s midlife health and menopause hormone therapy. Climacteric. 2016; 19: 109–50. DOI: org/10.3109/13697137.2015.1129166
13. Franco SS, Raveh-Amit H, Kobolák J et al. The crossroads between cancer stem cells and aging. BMC Cancer 2015; 15 (Suppl. 1): 1–15. DOI: org/10.1186/1471-2407-15-S1-S1
14. Lyu T, Jia N, Wang J et al. Expression and epigenetic regulation of angiogenesis-related factors during dormancy and recurrent growth of carcinoma. Epigenetics 2013; 8: 1330–46. DOI: 10.4161/epi.26675
15. Ashrafian L.A., Kiselev V.I., Kuznetsov I.N. i dr. Molekuliarnaia onkobiologiia i perspektivy effektivnoi terapii. Onkologiia. 2016; 3: 80–7.
DOI: 10.17116/onkolog20165280-87 (in Russian).
16. Byrne C, Ursin G, Martin CF et al. Mammographic Density Change With Estrogen and Progestin Therapy and Breast Cancer Risk. J Natl Cancer Inst 2017; 109: 1–7. doi: 10.1093/jnci/djx001
17. Marjoribanks J, Farquhar C, Roberts H, Lethaby A. Long term hormone therapy for perimenopausal and postmenopausal women. Cochrane Database Sys Rev 2012; 7: CD004143. DOI: 10.1002/14651858.CD004143.pub4
18. NCCN – Evidence-Based Cancer Guidelines. https://www.nccn.org/
19. Kuhl H, Schneider H. Progesterone – promoter or inhibitor of breast cancer. Climacteric 2013; 16 (Suppl. 1): 54–68.
20. Hirschberg AL, Tani E, Brismar K. Effects of drospirenone and norethisterone acetate combined with estradiol on mammographic density and proliferation of breast epithelial cells – A prospective randomized trial. Maturitas 2019; 126: 18–24. DOI: org/10.1016/j.maturitas.2019.04.205
21. Ruan Х, Neubauer H, Yang Y et al. Progestogens and membrane-initiated effects on the proliferation of human breast cancer cells. Climacteric 2012; 15: 467–72. DOI: org/10.3109/13697137.2011.648232
22. Anderson GL, Chlebowski RT, Aragaki AK et al. Conjugated equine oestrogenand breast cancer incidence and mortality in postmenopausal women with hysterectomy: extended follow- up of the Women’s Health Initiative randomisedplacebo-controlled trial. Lancet Oncol 2012; 13: 476–86.
23. Pérez-López FR, Chedraui P, Troyano-Luque JM. Peri- And Post-Menopausal Incidental Adnexal Masses and the Risk of Sporadic Ovarian Malignancy: New Insights and Clinical Management. Gynecol Endocrinol 2010; 26 (9): 631–43. DOI: 10.3109/09513590.2010.487611
24. Paianidi Iu.G., Zhordania K.I. Menopauzal'naia gormonal'naia terapiia v onkologii. Rekomendatsii mezhdunarodnogo obshchestva po menopauze (IMS, 2016). Obzor. Onkoginekologiia. 2016; 3: 43–53 (in Russian).
25. Yang Liu, Lan Ma, Xiaoling Yang et al. Menopausal hormone replacement therapy and the risk of ovarian cancer: a meta-analysis. Front Endocrinol 2019; 10: 801. DOI: 10.3389/fendo.2019.00801
26. Imianitov E.N. Fundamental'naia onkologiia v 2011 godu: obzor naibolee interesnykh otkrytiĭ. Prakt. onkologiia. 2012; 13 (1): 1–8 (in Russian).
27. BRCA1/2. Практическое руководство для врачей. RUSSCO. 2016; c. 12.
[BRCA1/2. Prakticheskoe rukovodstvo dlia vrachei. RUSSCO. 2016; c. 12 (in Russian).]
28. Mehrgou A, Akouchekian M. The importance of BRCA1 and BRCA2 genes mutations in breast cancer development. Med J Islam Repub Iran 2016; 30: 369.
29. Khodorovich O.S. Nasledstvennaia forma raka molochnoi zhelezy.
Metody profilaktiki. Vestn. RNTsRR MZ RF. 2012; 12. http://vestnik.rncrr.ru/vestnik/v12/papers/hodorovich_v12 (in Russian).
30. Temkin SM, Bergstrom J, Samimi G, Minasian L. Ovarian cancer prevention in high-risk women. Clin Obstet Gynecol 2017; 60: 738–57. DOI: 10.1097/GRF.0000000000000318
31. Mavaddat N, Peock S, Frost D et al. Cancer risks for BRCA1 and BRCA2 mutation carriers: results from prospective analysis of EMBRACE. J Natl Cancer Inst 2013; 105 (11): 812–22. DOI: org/10.1093/jnci/djt095
32. Kotsopoulos J, Huzarski T, Gronwald J et al. Bilateral Oophorectomy and Breast Cancer Risk in BRCA1 and BRCA2 Mutation Carriers.
J Natl Cancer Inst 2016; 109: 1–7. DOI: 10.1093/jnci/djw177
33. De Felice F, Marchetti C, Mussela A et al. Bilateral Risk-Reduction Mastectomy in BRCA1 and BRCA2 Mutation Carriers: A Meta-analysis. Ann Surg Oncol 2015; 22 (9): 2876–80.
34. Domchek SM, Friebel T, Neuhausen SL et al. PROSE Consortium. Is hormone replacement therapy (HRT) following risk-reducing salpingooophorectomy (RRSO) in BRCA1 (B1)- and BRCA2 (B2)-mutation carriers associated with an increased risk of breast cancer? [Abstract].
J Clin Oncol 2011; 29 (Suppl.). Abstract 1501.
35. Eisen A, Lubinski J, Gronwald J et al. Hereditary Breast Cancer Clinical Study Group. Hormone therapy and the risk of breast cancer in BRCA1 mutation carriers. J Natl Cancer Inst 2008; 100: 1361–7.
36. Nappi RE, Cassani C, Rossi M et al. Dealing with premature menopause in women at high-risk for hereditary genital and breast cancer. Minerva Ginecol 2016; 68 (5): 602–12.
37. Domchek S, Kaunitz AM. Use of Systemic Hormone Therapy in BRCA Mutation Carriers. NAMS Practice Pearl 2016; May 5: 1–4.
38. The 2017 Hormone therapy position statement of The North American Menopause Society. Menopause 2017; 24 (7): 728–53. DOI: 10.1097/GME.0000000000000921
39. Jaakkola S, Pukkala E, Lyytinen H et al. Postmenopausal estradiol-progestagen therapy and risk for uterine cervical cancer. Int J Cancer 2012; 131: 537–43.
40. Amitay EL et al. Postmenopausal hormone replacement therapy and colorectal cancer risk by molecular subtypes and pathways. Int J Cancer 2020.
41. Schwartz AG, Ray RM, Cote ML et al. Hormone Use, Reproductive History, and Risk of Lung Cancer The Women’s Health Initiative Studies.
J Thoracic Oncol 2015; 10 (7): 1004–13.
42. Stabile LP, Dacic S, Land SR. Combined Analysis of Estrogen Receptor β-1 and Progesterone Receptor Expression Identifies Lung Cancer Patients with Poor Outcome. Clin Cancer Res 2011; 1: 154–64. DOI: 10.1158/1078-0432.CCR-10-0992
43. De Giorgi V, Gori A, Savarese I et al. Role of BMI and hormone therapy in melanoma risk: a case–control study. J Cancer Res Clin Oncol 2017; 143 (7): 1191–7.
44. Botteri E, Støer NC, Sakshaug S et al. Menopausal hormone therapy and risk of melanoma: Do estrogens and progestins have a different role? Int J Cancer 2017; 141 (9): 1763–70.

Авторы

Е.В. Мусина*, И.Ю. Коган

ФГБНУ «Научно-исследовательский институт акушерства, гинекологии и репродуктологии им. Д.О. Отта», Санкт-Петербург, Россия
*E.musina@mail.ru

________________________________________________

Ekaterina V. Musina*, Igor Yu. Kogan

Ott Research Institute of Obstetrics, Gynecology and Reproductology, Saint Petersburg, Russia
*E.musina@mail.ru

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