The breast and sex hormones

DOI

https://dx.doi.org/10.18565/aig.2021.12.58-66

Smetnik A.A., Rodionov V.V., Kometova V.V., Burmenskaya O.V., Dardyk M.V., Sencha A.N., Ermakova E.I., Ashrafyan L.A.
Academician V.I. Kulakov National Medical Research Center of Obstetrics, Gynecology, and Perinatology, Ministry of Health of the Russian Federation, Moscow, Russia

The breast is part of a woman’s reproductive system, a target organ for sex hormones, and a site of their local biosynthesis and metabolism. The risk of breast cancer (BC) in the presence of fibrocystic disease largely depends on the severity of breast tissue proliferative processes. Combined oral contraceptives (COCs) have some effect on the breast, which is usually levelled off by other positive effects of this type of therapy. The possible increase in BC risk, which is associated with menopausal hormone therapy (MHT), is small and similar to or lower than that related to decreased physical activity, obesity, and alcohol use. Micronized progesterone or dydrogesterone, as well as tibolone, bazedoxifene, and estrol, which are used in the therapy of menopausal disorders, may be associated with a lower BC risk. A family history of BC is not a contraindication to MHT. BRCA1/2 mutation carriers may benefit from MHT after risk-reducing salpingo-oophorectomy. BC is a contraindication to combined hormonal contraceptives, MHT, tibolone, and local hormone therapy.
Conclusion: Thus, thorough breast examination before and during therapy, selection of patients from the low-risk BC group, and choice of drugs without proven significant effect on BC risks are the key when prescribing COCs or MHT.

breast

fibrocystic disease

mastopathy

breast cancer

sex hormones

estrogens

progestogens

androgens

combined oral contraceptives

menopausal hormone therapy

BRCA1/2 gene mutations

Full text (in Russian)

Родионов В.В., Гайлиш Ю.П., Сметник А.А. Доброкачественные заболевания молочных желез. В кн.: Серов В.Н., Сухих Г.Т., Прилепская В.Н., Радзинский В.Е., ред. Руководство по амбулаторно-поликлинической помощи в акушерстве и гинекологии. 3-е изд. М.: ГЭОТАР-Медиа; 2018: 989-1008. [Rodionov V.V., Gailish Yu.P., Smetnik A.A. Benign breast disease. In: Serov V.N., Sukhikh G.T., Prilepskaya V.N. Radzinski V.E. ed. Outpatient Clinical Care Guide in Obstetrics and Gynecology. 3th ed. revised and supplemented. M.: GEOTAR-Media. 2018: 989-1008. (in Russian)].
Приказ МЗ РФ от 20 октября 2020 г. N 1130н "Об утверждении порядка оказания медицинской помощи по профилю "акушерство и гинекология". [Order of the Ministry of Health of the Russian Federation of October 20, 2020 No. 1130n "On approval of the procedure for the provision of medical care in the profile of" obstetrics and gynecology". (in Russian)].
Сметник В.П., Бурдина Л.М., Меских Е.В., Бурдина И.И. Методы лечения диффузных доброкачественных заболеваний молочной железы. В кн.: Харченко В.П., Рожковой Н.И., ред. Маммология. Национальное руководство. М.: ГЭОТАР-Медиа; 2009: 319-24. [Smetnik V.P., Burdina L.M., Meskih E.V., Burdina I.I. Methods of treatment of benign breast diseases. Mammology: National guidance. In: Harchenko V.P., Rozhkova N.I., ed. M.: GEOTAR-Media; 2009: 319-24. (in Russian)].
Kowalczyk W., Waliszczak G., Jach R., Dulinska-Litewka J. Steroid receptors in breast cancer: understanding of molecular function as a basis for effective therapy development. Cancers (Basel). 2021; 13(19): 4779. https://dx.doi.org/10.3390/cancers13194779.
Керчелаева С.Б., Сметник А.А., Беспалов В.Г. Мастопатия и профилактика рака молочной железы как междисциплинарная проблема. РМЖ. Мать и дитя. 2016; 15: 1018-25. [Kerchelaeva S.B., Smetnik A.A., Bespalov V.G. Mastopathy and prevention of breast cancer as an interdisciplinary problem. Breast cancer. Mother and child. 2016; 15: 1018-25. (in Russian)].
Беспалов В.Г., Травина М.Л. Фиброзно-кистозная болезнь и риск рака молочной железы (обзор литературы). Опухоли женской репродуктивной системы. 2015; 4: 58-70. [Bespalov V.G., Travina M.L. fibrocystic disease and the risk of breast cancer (literature review). Tumors of female reproductive system. 2015; 4: 58-70. (in Russian)].
Santen R.J., Mansel R. Benign breast disorders. N. Engl. J. Med. 2005; 353(3): 275-85. https://dx.doi.org/10.1016/j.ogc.2013.05.004.
Belachew E.B., Sewasew D.T. Molecular mechanisms of endocrine resistance in estrogen-receptor-positive breast cancer. Front. Endocrinol (Lausanne). 2021; 12: 599586. https://dx.doi.org/10.3389/fendo.2021.599586. eCollection 2021.
Castoria G., Migliaccio A., Giovannelli P., Auricchio F. Cell proliferation regulated by estradiol receptor: therapeutic implications. Steroids. 2010; 75(8-9): 524-7. https://dx.doi.org/10.1016/j.steroids.2009.10.007.
Maselli A., Pierdominici M., Vitale C., Ortona E. Membrane lipid rafts and estrogenic signalling: a functional role in the modulation of cell homeostasis. Apoptosis. 2015; 20(5): 671-8. https://dx.doi.org/10.1007/s10495-015-1093-5.
Titus-Ernstoff L., Longnecker M.P., Newcomb P.A., Dain B., Greenberg E.R., Mittendorf R. et al. Menstrual factors in relation to breast cancer risk. Cancer Epidemiol. Prev. Biomark. 1998; 7(9): 783-9.
Grimm S.L., Hartig S.M., Edwards D.P. Progesterone receptor signaling mechanisms. J. Mol. Biol. 2016; 428(19): 3831-49. https://dx.doi.org/10.1016/j.jmb.2016.06.020.
Cenciarini M.E., Proietti C.J. Molecular mechanisms underlying progesterone receptor action in breast cancer: Insights into cell proliferation and stem cell regulation. Steroids. 2019; 152: 108503. https://dx.doi.org/10.1016/j.steroids.2019.108503.
Mote P.A., Bartow S., Tran N., Clarke C.L. Loss of co-ordinate expression of progesterone receptors A and B is an early event in breast carcinogenesis. Breast Cancer Res. Treat. 2002; 72(2): 163-72. https://dx.doi.org/10.1023/a:1014820500738.
Kensler K.H., Beca F., Baker G.M., Heng Y.J., Beck A.H., Schnitt S.J. et al. Androgen receptor expression in normal breast Ttssue and subsequent breast cancer risk. NPJ Breast Cancer. 2018; 4: 33. https://dx.doi.org/10.1038/s41523-018-0085-3.
Garay J.P., Park B.H. Androgen receptor as a targeted therapy for breast cancer. Am. J. Cancer Res. 2012; 2(4): 434-45.
Fioretti F.M., Sita-Lumsden A., Bevan C.L., Brooke G.N. Revising the role of the androgen receptor in breast cancer. J. Mol. Endocrinol. 2014; 52(3): R257-65. https://dx.doi.org/10.1530/JME-14-0030.
Dietel M. Hormone replacement therapy (HRT), breast cancer and tumor pathology. Maturitas. 2010; 65(3): 183-9. https://dx.doi.org/10.1016/j.maturitas.2009.11.005.
Schneyer R., Lerma K. Health outcomes associated with use of hormonal contraception: breast cancer. Curr. Opin. Obstet. Gynecol. 2018; 30(6): 414-8. https://dx.doi.org/10.1097/GCO.0000000000000493.
Singletary S.E. Rating the risk factors for breast cancer. Ann. Surg. 2003; 237(4): 474-82. https://dx.doi.org/10.1097/01.SLA.0000059969.64262.87.
Anderson G.L., Chlebowski R.T., Rossouw J.E., Rodabough R.J., McTiernan A., Margolis K.L. et al. Prior hormone therapy and breast cancer risk in the Women's Health Initiative randomized trial of estrogen plus progestin. Maturitas. 2006; 55(2): 103-15. https://dx.doi.org/10.1016/j.maturitas.2006.05.004.
The NAMS 2017 Hormone Therapy Position Statement Advisory Panel. The 2017 hormone therapy position statement of The North American Menopause Society. Menopause. 2017; 24(7): 728-53. https://dx.doi.org/10.1097/GME.0000000000000921.
Baber R.J., Panay N., Fenton A.; IMS Writing Group. 2016 IMS Recommendations on women's midlife health and menopause hormone therapy. Climacteric. 2016; 19(2): 109-50. https://dx.doi.org/10.3109/13697137.2015.1129166.
Anderson G.L., Chlebowski R.T., Aragaki A.K., Kuller L.H., Manson J..E, Gass M. 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(5): 476-86. https://dx.doi.org/10.1016/S1470-2045(12)70075-X.
Fournier A., Berrino F., Clavel-Chapelon F. Unequal risks for breast cancer associated with different hormone replacement therapies: results from the E3N cohort study. Breast Cancer Res. Treat. 2008; 107(1): 103-11. https://dx.doi.org/10.1007/s10549-007-9523-x.
Cordina-Duverger E., Truong T., Anger A., Sanchez M., Arveux P., Kerbrat P., Guénel P. Risk of breast cancer by type of menopausal hormone therapy: a case-control study among post-menopausal women in France. PLoS One. 2013; 8(11): e78016. https://dx.doi.org/10.1371/journal.pone.0078016.
Lyytinen H., Pukkala E., Ylikorkala O. Breast cancer risk in postmenopausal women using estradiol-progestogen therapy. Obstet. Gynecol. 2009; 113(1): 65-73. https://dx.doi.org/10.1097/AOG.0b013e31818e8cd6.
Valdivia I., Campodónico I., Tapia A., Capetillo M., Espinoza A., Lavín P. Effect of tibolone and continuous combined hormone replacement therapy on mammographic breast density and breast histochemical markers in postmenopausal women. Fertil. Steril. 2004; 81(3): 617-23. https://dx.doi.org/10.1016/j.fertnstert.2003.07.041.
Bakken K., Fournier A., Lund E., Waaseth M., Dumeaux V., Clavel-Chapelon F. et al. Menopausal hormone therapy and breast cancer risk: impact of different treatments. The European Prospective Investigation into Cancer and Nutrition. Int. J. Cancer. 2011; 128(1): 144-56. https://dx.doi.org/10.1002/ijc.25314.
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): 1159-68. https://dx.doi.org/10.1016/S0140-6736(19)31709-X.
Hamoda H., Davis S.R., Cano A., Morris E., Davison S., Panay N. et al. BMS, IMS, EMAS, RCOG and AMS joint statement on menopausal hormone therapy and breast cancer risk in response to EMA Pharmacovigilance Risk Assessment Committee recommendations in May 2020. Post Reprod. Health. 2021; 27(1): 49-55. https://dx.doi.org/10.1177/2053369120983154.
Vinogradova Y., Coupland C., Hippisley-Cox J. Use of hormone replacement therapy and risk of breast cancer: nested case-control studies using the QResearch and CPRD databases. BMJ. 2020; 371: m3873. https://dx.doi.org/10.1136/bmj.m3873.
Сметник А.А., Сметник В.П., Киселев В.И. Опыт применения индол-3-карбинола в лечении заболеваний молочной железы и профилактике рака молочной железы. Акушерство и гинекология. 2017; 2: 106-12. [Smetnik A.A., Smetnik V.P., Kiselev V.I. Experience in management of breast diseases and breast cancer prevention with indol-3-carbinol. Akusherstvo i ginekologia/ Obstetrics and Gynecology. 2017; 2: 106-12. (in Russian)]. https://dx.doi.org/10.18565/aig.2017.2.106-12
Сметник А.А., Родионов В.В., Киселев В.И. Химиопрофилактика рака молочной железы у носительниц мутаций генов BRCA1/2. Medica mente. Лечим с умом. 2017; 3(2): 27-31. [Smetnik A.A., Rodionov V.V., Kiselev V.I. Chemoprophylaxis of breast cancer in carriers of BRCA1 / 2 gene mutations. Medica mente. 2017; 3(2): 27-31 (in Russian)].
Клинические рекомендации «Профилактика рака молочной железы и рака яичников у носителей мутаций генов BRCA1/BRCA2» (не утвержденные). [Clinical Recommendations "Prevention of breast and ovarian cancer in carriers of BRCA1/BRCA2 gene mutations" (not yet approved)). (in Russian)]. Available at: https://promisan.ru/storage/uploads/file/s/i/g/7frzhgbv/Protokol_BRCA.pdf
Famorca-Tran J., Roux G. The consequences of a BRCA mutation in women. J. Adv. Pract. Oncol. 2015; 6(3): 194-210. https://dx.doi.org/10.6004/jadpro.2015.6.3.2.
Cibula D., Gompel A., Mueck A.О., La Vecchia C., Hannaford P.C., Skouby S.O. et al. Hormonal contraception and risk of cancer. Hum. Reprod. Update. 2010; 16(6): 631-50. https://dx.doi.org/10.1093/humupd/dmq022.
Kotsopoulos J., Librach C.L., Lubinski J., Gronwald J., Kim-Sing C., Ghadirian P. et al. Infertility, treatment of infertility, and the risk of breast cancer among women with BRCA1 and BRCA2 mutations: a case-control study. Cancer Causes Control. 2008; 19(10): 1111-9. https://dx.doi.org/10.1007/s10552-008-9175-0.
Gronwald J., Glass K., Rosen B., Karlan B., Tung N., Neuhausen S.L. et al. Treatment of infertility does not increase the risk of ovarian cancer among women with a BRCA1 or BRCA2 mutation. Fertil. Steril. 2016; 105(3): 781-5. https://dx.doi.org/10.1016/j.fertnstert.2015.11.034.
Finch A., Narod S.A. Quality of life and health status after prophylactic salpingo-oophorectomy in women who carry a BRCA mutation: A review. Maturitas. 2011; 70(3): 261-5. https://dx.doi.org/10.1016/j.maturitas.2011.08.001.
Birrer N., Chinchilla C., Del Carmen M., Dizon D.S. Is hormone replacement therapy safe in women with a BRCA mutation? A systematic review of the contemporary literature. Am. J. Clin. Oncol. 2018; 41(3): 313-5. https://dx.doi.org/10.1097/COC.0000000000000269.
Nappi R.E., Cassani C., Rossi M., Zanellini F., Spinillo A. Dealing with premature menopause in women at high-risk for hereditary genital and breast cancer. Minerva Ginecol. 2016; 68(5): 602-12.
Сметник А.А., Родионов В.В., Кометова В.В. Коррекция климактерических расстройств у больных раком молочной железы: актуальные методы и перспективы. Акушерство и гинекология. 2020; 1(Прил.): 26-33. [Smetnik A.A. Rodionov V.V., Kometova V.V. Treatment of climacteric symptoms in patients with breast cancer: current methods and perspectives. Akusherstvo i ginekologia/ Obstetrics and Gynecxology. 2020; 1(Suppl.): 26-33. (in Russian)]. https://dx.doi.org/10.18565/aig.2020.1suppl.26-33
Umland E.M., Karel L., Santoro N. Bazedoxifene and conjugated equine estrogen: a combination product for the management of vasomotor symptoms and osteoporosis prevention associated with menopause. Pharmacotherapy. 2016; 36(5): 548-61. https://dx.doi.org/10.1002/phar.1749.
Santen R.J., Song Y., Wang J.P., Yue W. Preclinical breast effects of a tissue selective estrogen complex (TSEC) including conjugated estrogen with bazedoxifen. J. Steroid Biochem. Mol. Biol. 2017; 170: 61-4. https://dx.doi.org/10.1016/j.jsbmb.2016.05.008.
Smith C.L., Santen R.J., Komm B., Mirkin S. Breast-related effects of selective estrogen receptor modulators and tissue-selective estrogen complexes. Breast Cancer Res. 2014; 16(3): 212. https://dx.doi.org/10.1186/bcr3677.
Shim S., Park K.M., Chung Y.L., Kim M.R. Updates on therapeutic alternatives for genitourinary syndrome of menopause: hormonal and non-hormonal managements. J. Menopausal Med. 2021; 27(1): 1-7. https://dx.doi.org/10.6118/jmm.20034.
Apter D., Zimmerman Y., Beekman L., Mawet M., Maillard C., Foidart J.M., Coelingh Bennink H.J.T. Estetrol combined with drospirenone: an oral contraceptive with high acceptability, user satisfaction, well-being and favourable body weight control. Eur. J. Contracept. Reprod. Health Care. 2017; 22(4): 260-7. https://dx.doi.org/10.1080/13625187.2017.1336532.
Coelingh Bennink H.J.T., Verhoeven C., Zimmerman Y., Visser M., Foidart J.-M., Gemzell-Danielsson K. Pharmacokinetics of the fetal estrogen estetrol in a multiple-rising-dose study in postmenopausal women. Climacteric. 2017; 20(3): 285-9. https://dx.doi.org/10.1080/13697137.2017.1291608.
Singer C.F., Bennink H.J., Natter C., Steurer S., Rudas M., Moinfar F. et al. Antiestrogenic effects of the fetal estrogen estetrol in women with estrogen-receptor positive early breast cancer. Carcinogenesis. 2014; 35(11): 2447-51. https://dx.doi.org/10.1093/carcin/bgu144.

Received 08.12.2021

Accepted 15.12.2021

Antonina A. Smetnik, MD, Ph.D., Head of the Department of Gynecological Endocrinology, V.I. Kulakov National Medical Research Centre for Obstetrics, Gynecology and Perinatology, Ministry of Healthcare of the Russian Federation, +7(495)531-44-44, a_smetnik@oparina4.ru, https://orcid.org/0000-0002-0627-3902,
117997, Russia, Moscow, Ac. Oparina str., 4.
Valery V. Rodionov, Dr. Med. Sci., Head of the Department of Breast Pathology, V.I. Kulakov National Medical Research Centre for Obstetrics, Gynecology and Perinatology, Ministry of Healthcare of the Russian Federation, +7(495)531-44-44, v_rodionov@oparina4.ru, https://orcid.org/0000-0003-0096-7126,
117997, Russia, Moscow, Ac. Oparina str., 4.
Vlada V. Kometova, MD, Ph.D., Head of the Department of Oncopathology, V.I. Kulakov National Medical Research Centre for Obstetrics, Gynecology and Perinatology, Ministry of Healthcare of the Russian Federation, +7(495)531-44-44, v_kometova@oparina4.ru, https://orcid.org/0000-0001-9666-6875,
117997, Russia, Moscow, Ac. Oparina str., 4.
Olga V. Burmenskaya, Dr. Bio. Sci., Head of the Laboratory of Oncological Genetics, V.I. Kulakov National Medical Research Centre for Obstetrics, Gynecology and Perinatology, Ministry of Healthcare of the Russian Federation, +7(495)438-22-92, o_bourmenskaya@oparina4.ru, https://orcid.org/0000-0003-2842-3980,
117997, Russia, Moscow, Ac. Oparina str., 4.
Maria V. Dardyk, MD, Researcher at the Department of Oncopathology, V.I. Kulakov National Medical Research Centre for Obstetrics, Gynecology and Perinatology, Ministry of Healthcare of the Russian Federation, +7(495)531-44-44, m_dardyk@oparina4.ru, https://orcid.org/0000-0002-4489-7660,
117997, Russia, Moscow, Ac. Oparina str., 4.
Alexander N. Sencha, Dr. Med. Sci., Professor, Head of the Department of Visual Diagnostics, V.I. Kulakov National Medical Research Centre for Obstetrics, Gynecology and Perinatology, Ministry of Healthcare of the Russian Federation, +7(495)531-44-44, a_sencha@oparina4.ru, https://orcid.org/0000-0002-1188-8872,
117997, Russia, Moscow, Ac. Oparina str., 4.
Elena I. Ermakova, MD, Ph.D., Senior Researcher at the Department of Gynecological Endocrinology, V.I. Kulakov National Medical Research Centre for Obstetrics, Gynecology and Perinatology, Ministry of Healthcare of the Russian Federation, +7(495)531-44-44, e_ermakova@oparina4.ru, https://orcid.org/0000-0002-6629-051X,
117997, Russia, Moscow, Ac. Oparina str., 4.
Levon A. Ashrafyan, Dr. Med. Sci., Professor, Academician of the RAS, Head of the Institution of Oncogynecology and Mammology, V.I. Kulakov National Medical Research Centre for Obstetrics, Gynecology and Perinatology, Ministry of Healthcare of the Russian Federation, +7(495)531-44-44, l_ashrafyan@oparina4.ru,
https://orcid.org/0000-0001-6396-4948, 117997, Russia, Moscow, Ac. Oparina str., 4.

Authors’ contributions: Smetnik A.A., Rodionov V.V., Kometova V.V. – development of the concept and design of a review of publications on the topic of the article, data analysis, writing the text of the manuscript, approval of the manuscript for publication; Burmenskaya O.V., Dardyk M.V., Sencha A.N., Ermakova E.I., Ashrafyan L.A. – a review of publications on the topic of the article, data analysis.
Conflicts of interest: The authors declare that there are no conflicts of interest.
Funding: The investigation has been partially sponsored within the framework of the state assignment “Assessment of the individual risk of breast cancer in women with benign breast diseases (fibrocystic disease)” (State Registration No. R&D 121040600432-9).
For citation: Smetnik A.A., Rodionov V.V., Kometova V.V., Burmenskaya O.V., Dardyk M.V., Sencha A.N., Ermakova E.I., Ashrafyan L.A. The breast and sex hormones.
Akusherstvo i Ginekologiya/Obstetrics and Gynecology. 2021; 12: 58-66 (in Russian)
https://dx.doi.org/10.18565/aig.2021.12.58-66

The breast and sex hormones

Smetnik A.A., Rodionov V.V., Kometova V.V., Burmenskaya O.V., Dardyk M.V., Sencha A.N., Ermakova E.I., Ashrafyan L.A.

Keywords

References

About the Authors

Similar Articles