Abstract
Doctors and patients fear the risk of breast cancer when using hormone replacement therapy (HRT). This review focuses on the choice of progestogen for HRT in menopausal. The Women’s Health Initiative (WHI) has been the only large double-blind placebo-controlled study testing the risk of breast cancer (BC) using HRT. No increased risk using estrogen (E)-only was seen, there was a significant decrease in mortality due to BC after the use of HRT which persisted during the recent 18-year follow-up of the WHI. In contrast in the combined arm the risk increased. In about 20 observational studies using mostly medroxyprogesterone acetate (MPA) or estradiol-norethisterone acetate (NETA) an increased BC-risk was observed comparable with the WHI. Only for natural progestogen, progesterone and for dydrogesterone (retro-isomer of progesterone) was no increased risk seen for up to 5–8 years, when compared directly with other progestogens, but for longer treatment an increased risk cannot be excluded. In contrast, the mortality due to BC after use of E-only and combined HRT decreased in about a dozen observational studies, and was very recently confirmed in a Finnish study evaluating 490,000 women using estradiol (E2) plus different progestogens. There have been already more than 70 studies evaluating the risk of BC during HRT, and still there are many open questions. Therefore, this review covers our own and other experimental research which could answer important questions. Experimental research has demonstrated that certain synthetic progestogens, but not progesterone and to some extent also not dydrogesterone, can accelerate the proliferation of breast cancer cells in vitro and in animal studies via special cell membrane components which we recently also detected in patients with BC, and we found differences comparing all available synthetic progestogens. Derived from these mechanisms future research may provide screening for patients at risk and predict the prognosis of possible BC.
Funding source: Beijing Municipal Administration of Hospitals Clinical medicine, Development of special funding support
Award Identifier / Grant number: XMLX201710
Funding source: Beijing Municipal Science & Technology Commission
Award Identifier / Grant number: Z161100000516143
Funding statement: This case was supported by Beijing Municipal Administration of Hospitals Clinical medicine, Development of special funding support, code: XMLX201710; Capital’s Funds for Health Improvement and Research, code: 2016-2-2113; Beijing Municipal Science & Technology Commission, code Z161100000516143; Beijing Municipal Administration of Hospitals’ Ascent Plan, code: DFL20181401; Beijing Municipality Health Technology High-level Talent, code: 2014-2-016; SAFEA: Project for Key Foreign Experts, code: 20181100005; Beijing Nature Science Foundation Y181004.
Author Statement
Conflict of interest: The authors declare no conflict of interest.
Informed consent: Informed consent is not applicable.
Ethical approval: The conducted research is not related to either human or animals use.
References
[1] Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, et al. 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. J Am Med Assoc. 2002;288:321–33.10.1001/jama.288.3.321Suche in Google Scholar
[2] Anderson GL, Limacher M, Assaf AR, Bassford T, Beresford SA, Black H, et al. Women’s Health Initiative Steering Committee. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized controlled trial. J Am Med Assoc. 2004;291:701–12.Suche in Google Scholar
[3] Baber RJ, Panay N, Fenton A, (on behalf of the IMS Writing Group). 2016 IMS Recommendations on women’s midlife health and menopause hormone therapy. Climacteric. 2016;19:109–50.10.3109/13697137.2015.1129166Suche in Google Scholar
[4] Neves-E-Castro M, Birkhauser M, Samsioe G, Lambrinoudaki I, Palacios S, Borrego RS, et al. EMAS position statement: the ten point guide to the integral management of menopausal health. Maturitas. 2015;81:88–92.10.1016/j.maturitas.2015.02.003Suche in Google Scholar
[5] North American Menopause Society. The 2012 hormone therapy position statement of: the North American Menopause Society. Menopause. 2012;19:257–71.10.1097/gme.0b013e31824b970aSuche in Google Scholar
[6] German S3 Guideline on HRT (Ortmann O, on behalf of 19 German Societies). Hormonal therapy in peri- and postmenopause. Short version of interdisciplinary S3 guideline. Frauenarzt. 2009;10:840–51.Suche in Google Scholar
[7] Santen RJ, Allred DC, Ardoin SP, Archer DF, Boyd N, Braunstein GD, et al. Postmenopausal hormone therapy: an Endocrine Society scientific statement. J Clin Endocrinol Metab. 2010;95(Suppl. 1):s1–66.10.1210/jc.2009-2509Suche in Google Scholar
[8] NICE Guidelines. Menopause: diagnosis and management. Available from: https://www.nice.org.uk/guidance/ng23/resources/menopause-diagnosis-and-managment-1837330217413. Accessed: 12 Dec 2015.Suche in Google Scholar
[9] de Villiers T, Hall JE, Pinkerton J, Cerdas Perez S, Reese M, Yang C, et al. Revised global consensus statement on menopausal hormone therapy. Climacteric. 2016;19:313–5.10.1080/13697137.2016.1196047Suche in Google Scholar
[10] US Preventive Services Task Force, Grossman DC, Curry SJ, Owens DK, Barry MJ, Davidson KW, et al. Hormone therapy for the primary prevention of chronic conditions in postmenopausal women: US Preventive Services Task Force Recommendation Statement. J Am Med Assoc. 2017;318:2224–33.10.1001/jama.2017.18261Suche in Google Scholar
[11] Stefanick ML, Anderson GL, Margolis KL, Hendrix SL, Rodabough RJ, Paskett ED, et al. Effects of conjugated equine estrogens on breast cancer and mammography screening in postmenopausal women with hysterectomy. J Am Med Assoc. 2006;295:1647–57.10.1001/jama.295.14.1647Suche in Google Scholar
[12] Scarabin PY, Oger E, Plu-Bureau G (for the ESTHER Study Group). Differential association of oral and transdermal oestrogen replacement therapy with venous thromboembolism risk. Lancet. 2003;362:428–32.10.1016/S0140-6736(03)14066-4Suche in Google Scholar
[13] Canonico M, Plu-Bureau G, Lowe GD, Scarabin P-Y. Hormone replacement therapy and risk of venous thromboembolism in postmenopausal women: a systematic review and meta-analysis. Br Med J. 2008;336:1227–31.10.1136/bmj.39555.441944.BESuche in Google Scholar PubMed PubMed Central
[14] Renoux C, Dell-Aniello S, Suissa S. Hormone replacement therapy and the risk of venous thromboembolism: a population-based study. J Thrombosis Haemostasis. 2010;8:979–86.10.1111/j.1538-7836.2010.03839.xSuche in Google Scholar
[15] Simon JA, Laliberté F, Duh MS, Pilon D, Kahler KH, Nyirady J, et al. Venous thromboembolism and cardiovascular disease complications in menopausal women using transdermal versus oral estrogen therapy. Menopause. 2016;23:600–10.10.1097/GME.0000000000000590Suche in Google Scholar PubMed
[16] Renoux C, Dell’Aniello S, Garbe D, Suissa S. Transdermal and oral hormone replacement therapy and the risk of stroke: a nested case-control study. Br Med J. 2010;340:c2519.10.1136/bmj.c2519Suche in Google Scholar PubMed
[17] Speroff L. Transdermal hormone therapy and the risk of stroke and venous thrombosis. Climacteric. 2010;13:429–32.10.3109/13697137.2010.507111Suche in Google Scholar PubMed
[18] Canonico M, Carcaillon L, Plu-Bureau G, Oger E, Singh-Manoux A, Tubert-Bitter P, et al. Postmenopausal hormone therapy and risk of stroke. Impact of the route of estrogen administration and type of progestogen. Stroke. 2016;47:1734–41.10.1161/STROKEAHA.116.013052Suche in Google Scholar PubMed PubMed Central
[19] Canonico M, Scarabin P-Y. Oral versus transdermal estrogens and venous thromboembolism in postmenopausal women: what is new since 2003? Menopause. 2016;23:587–8.10.1097/GME.0000000000000665Suche in Google Scholar PubMed
[20] Mueck AO. Postmenopausal hormone replacement therapy and cardiovascular disease: the value of transdermal estradiol and micronized progesterone. Climacteric. 2012;15(Suppl 1):11–7.10.3109/13697137.2012.669624Suche in Google Scholar PubMed
[21] Mueck AO, Seeger H. Shapiro S. Risk of breast cancer during hormone replacement therapy: Mechanisms. Horm Mol Biol Clin Invest. 2010;3:329–39.10.1515/hmbci.2010.037Suche in Google Scholar
[22] Mueck AO, Ruan X. Benefits and risks during HRT – main safety issue breast cancer. Horm Mol Biol Clin Invest. 2011;5:105–16.10.1515/HMBCI.2011.014Suche in Google Scholar PubMed
[23] Manson JE, Aragaki AK, Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, et al. Menopausal Hormone Therapy and long-term all-cause and cause-specific mortality: the women’s health initiative randomized trials. J Am Med Assoc. 2017;318:927–38.10.1001/jama.2017.11217Suche in Google Scholar PubMed PubMed Central
[24] Manson JE, Kaunitz AM. Menopause management – Getting clinical care back on track. N Engl J Med. 2016;374:803–6.10.1056/NEJMp1514242Suche in Google Scholar PubMed
[25] Langer RD. The evidence base for HRT: what can we believe? Climacteric. 2017;20:91–6.10.1080/13697137.2017.1280251Suche in Google Scholar
[26] Sartorius CA, Melville MY, Hovland AR, Tung L, Takimoto GS, Horwitz KB. A third transactivation function (AF3) of human progesterone receptors located in the unique N-terminal segment of the B-isoform. Mol Endocrinol. 1994;8:1347–60.Suche in Google Scholar
[27] Mulac-Jericevic B, Mullinax RA, DeMayo FJ, Lydon JP, Conneely OM. Subgroup of reproductive functions of progesterone mediated by progesterone receptor-B isoform. Science. 2000;289:1751–4.10.1126/science.289.5485.1751Suche in Google Scholar
[28] Mulac-Jericevic B, Lydon JP, DeMayo FJ, Conneely OM. Defective mammary gland morphogenesis in mice lacking the progesterone receptor B isoform. Proc Natl Acad Sci USA. 2003;100:9744–9.10.1073/pnas.1732707100Suche in Google Scholar
[29] Lange CA, Richer JK, Horwitz KB. Hypothesis: progesterone primes breast cancer cells for cross-talk with proliferative or antiproliferative signals. Mol Endocrinol. 1999;13:829–36.10.1210/mend.13.6.0290Suche in Google Scholar
[30] Bergink EW, van Meel F, Turpijn EW, van der Vies J. Binding of progestagens to receptor proteins in MCF-7 cells. J Steroid Biochem. 1983;19:1563–70.10.1016/0022-4731(83)90371-0Suche in Google Scholar
[31] Kontula K, Janne O, Vihko R, de Jager E, de Visser J, Zeelen F. Progesteronebinding proteins: In vitro binding and biological activity of different steroidal ligands. Acta Endocrinol. 1975;78:574–92.10.1530/acta.0.0780574Suche in Google Scholar PubMed
[32] Ghatge R, Jacobsen B, Schittone S, Horwitz K. The progestational and androgenic properties of medroxyprogesterone acetate: gene regulatory overlap with dihydrotestosterone in breast cancer cells. Breast Cancer Res. 2005;7:R1036–50.10.1186/bcr1340Suche in Google Scholar PubMed PubMed Central
[33] Bray JD, Jelinsky S, Ghatge R, Bray JA, Tunkey C, Saraf K, et al. Quantitative analysis of gene regulation by seven clinically relevant progestins suggests a highly similar mechanism of action through progesterone receptors in T47D breast cancer cells. J Steroid Biochem Mol Biol. 2005;97:328–41.10.1016/j.jsbmb.2005.06.032Suche in Google Scholar PubMed
[34] Moore NL, Hickey TE, Butler LM, Tilley WD. Multiple nuclear receptor signalling pathways mediate the actions of synthetic progestins in target cells. Mol Cell Endocrinol. 2012;397:60–70.10.1016/j.mce.2011.09.019Suche in Google Scholar PubMed
[35] Jacobsen BM, Schittone SA, Richer JK, Horwitz KB. Progesterone-independent effects of human progesterone receptors (PRs) in estrogen receptor-positive breast cancer: PR isoform-specific gene regulation and tumor biology. Mol Endocrinol. 2005;19:574–87.10.1210/me.2004-0287Suche in Google Scholar PubMed
[36] Topper YJ, Freeman CS. Multiple hormone interactions in the developmental biology of the mammary gland. Physiol Rev. 1980;60:1049–106.10.1152/physrev.1980.60.4.1049Suche in Google Scholar
[37] Clarke CL, Sutherland RL. Progestin regulation of cellular proliferation. Endocr Rev. 1990;11:266–301.10.1210/edrv-11-2-266Suche in Google Scholar
[38] McManus MJ, Welsch CW. The effect of estrogen, progesterone, thyroxine, and human placental lactogen on DNA synthesis of human breast ductal epithelium maintained in athymic nude mice. Cancer. 1984;54:1920–7.10.1002/1097-0142(19841101)54:9<1920::AID-CNCR2820540924>3.0.CO;2-FSuche in Google Scholar
[39] Laidlaw IJ, Clarke RB, Howell A, Owen AW, Potten CS, Anderson E. The proliferation of normal human breast tissue implanted into athymic nude mice is stimulated by estrogen but not progesterone. Endocrinology. 1995;136:164–71.10.1210/endo.136.1.7828527Suche in Google Scholar
[40] Krämer EA, Seeger H, Krämer B, Wallwiener D, Mueck AO. The effect of progesterone, testosterone and synthetic progestogens on growth factor- and estradiol-treated human cancerous and benign breast cells. Eur J Obstet Gynecol Reprod. 2006;27:39–141.10.1016/j.ejogrb.2005.12.004Suche in Google Scholar
[41] van der Burg B, Kalkhoven E, Isbrücker L, de Laat SW. Effects of progestins on the proliferation of estrogen-dependent human breast cancer cells under growth factor-defined conditions. J Steroid Biochem Mol Biol. 1992;42:457–65.10.1016/0960-0760(92)90257-JSuche in Google Scholar
[42] Schoonen WG, Joosten JW, Kloosterboer HJ. Effects of two classes of progestins, pregnane and 19-nortestosterone derivatives, on cell growth of human breast tumor cells: 1.MCF-7 cell lines. J Steroid Biochem Mol Biol. 1995;55:423–37.10.1016/0960-0760(95)00215-4Suche in Google Scholar
[43] Cappelletti V, Miodini P, Fioravanti L, DiFronzo G. Effect of progestin treatment on estradiol- and growth factor-stimulated breast cancer cell lines. Anticancer Res. 1995;15:2551–6.Suche in Google Scholar
[44] Lippert C, Seeger H, Wallwiener D, Mueck AO. The effect of medroxyprogesterone acetate and norethisterone on the estradiol stimulated proliferation in MCF-7 cells: comparison of continuous combined versus sequential combined estradiol/progestin treatment. Eur J Gynaecol Oncol. 2001;22:331–5.Suche in Google Scholar
[45] Lobenhofer EK, Huper G, Iglehart JD, Marks JR. Inhibition of mitogen-activated protein kinase and phosphatidylinositol 3-kinase activity in MCF-7 cells prevents estrogen-induced mitogenesis. Cell Growth Differ. 2000;11:99–110.Suche in Google Scholar
[46] Santen RJ, Xinde Song R, McPherson R, Kumar R, Adam L, Jeng MH, et al. The role of mitogen-activated protein (MAP) kinase in breast cancer. J Steroid Biochem Mol Biol. 2002;80:239–56.10.1016/S0960-0760(01)00189-3Suche in Google Scholar
[47] Fu XD, Giretti MS, Goglia L, Flamini MI, Sanchez AM, Baldacci C, et al. Comparative actions of progesterone, medroxyprogesterone acetate, drospirenone and nestorone on breast cancer cell migration and invasion. BMC Cancer. 2008;8:166–71.10.1186/1471-2407-8-166Suche in Google Scholar
[48] Losel RM, Besong D, Peluso JJ, Wehling M. Progesterone receptor membrane component 1 – many tasks for a versatile protein. Steroids 2008;73:929–34.10.1016/j.steroids.2007.12.017Suche in Google Scholar
[49] Cahill MA. Progesterone receptor membrane component 1: an integrative review. J Steroid Biochem Mol Biol. 2007;105:16–36.10.1016/j.jsbmb.2007.02.002Suche in Google Scholar PubMed
[50] Crudden G, Loesel R, Craven RJ. Overexpression of the cytochrome p450 activator hpr6 (heme-1 domain protein/human progesterone receptor) in tumors. Tumour Biol. 2005;26:142–6.10.1159/000086485Suche in Google Scholar PubMed
[51] Neubauer H, Ma Q, Zhou J, Yu Q, Ruan X, Seeger H, et al. Possible role of PGRMC1 in breast cancer development. Climacteric 2013;16:509–13.10.3109/13697137.2013.800038Suche in Google Scholar PubMed
[52] Ruan X, Zhang Y, Mueck AO, Willibald M, Seeger H, Fehm T, et al. Increased expression of progesterone membrane component 1 is associated with aggressive phenotype and poor prognosis in ER-positive and – negative breast cancer. Menopause. 2017;24:203–9.10.1097/GME.0000000000000739Suche in Google Scholar PubMed
[53] Neubauer H, Adam G, Fehm T, Seeger H, Neubauer H, Solomayer E, et al. Membrane-initiated effects of progesterone on proliferation and activation of VEGF gene expression in human breast cancer cells. Climacteric. 2009;12:230–9.10.1080/13697130802635637Suche in Google Scholar PubMed
[54] Neubauer H, Yang Y, Seeger H, Fehm T, Tong X, Cahill MA, et al. The presence of a membrane-bound progesterone receptor sensitizes the estradiol-induced effect on the proliferation of human breast cancer cells. Menopause. 2011;18:845–50.10.1097/gme.0b013e31820e5ac5Suche in Google Scholar PubMed
[55] Ruan X, Neubauer H, Yang Y, Schneck E, Schultz S, Fehm T, et al. Progestogens and membrane-initiated effects on the proliferation of human breast cancer cells. Climacteric. 2012;15:467–72.10.3109/13697137.2011.648232Suche in Google Scholar PubMed
[56] Ruan X, Neubauer H, Schneck H, Schultz S, Fehm T, CaHill MA, et al. Nomegestrol acetate sequentially or continuously combined to estradiol did not negatively affect membrane-receptor associated progestogenic effects in human breast cancer cells. Gynecol Endocrinol. 2012;28:863–6.10.3109/09513590.2012.671396Suche in Google Scholar PubMed
[57] Schneck H, Ruan X, Seeger H, Cahill MA, Fehm T, Neubauer H, et al. Membrane-receptor initiated proliferative effects of dienogest in human breast cancer cells. Gynecol Endocrinol. 2013;29:160–3.10.3109/09513590.2012.730572Suche in Google Scholar PubMed
[58] Neubauer H, Ruan X, Schneck H, Seeger H, Cahill MA, Liang Y, et al. Overexpression of progesterone receptor membrane component 1: possible mechanism for increased breast cancer risk with norethisterone in hormone therapy. Menopause. 2013;20:504–10.10.1097/gme.0b013e3182755c97Suche in Google Scholar
[59] Zhou J, Yu Q, Chen R, Seeger H, Fehm T, Cahill MA, et al. Medroxyprogesterone acetate- driven increase in breast cancer risk might be mediated via cross-talk with growth factors in the presence of progesterone receptor membrane component-1. Maturitas. 2013;76:129–33.10.1016/j.maturitas.2013.06.013Suche in Google Scholar PubMed
[60] Zhang Y, Ruan X, Willibald M, Seeger H, Fehm T, Neubauer H, et al. May progesterone receptor membrane component 1 (PGRMC1) predict the risk of breast cancer? Gynecol Endocrinol. 2016;32:58–60.10.3109/09513590.2015.1078303Suche in Google Scholar PubMed
[61] Zhao Y, Ruan X, Wanga H, Lia X, Gua M, Wang L, Li Y, et al. The presence of membrane-bound progesterone receptor induces growth of breast cancer with norethisterone but not with progesterone: a xenograft model. Maturitas. 2017;102:26–33.10.1016/j.maturitas.2017.05.007Suche in Google Scholar PubMed
[62] Stanczyk FZ. Editorial. Can the increase in breast cancer observed in the estrogen plus progestin arm of the Women’s Health Initiative trial be explained by progesterone receptor membrane component 1? Menopause. 2011;18:833–4.10.1080/01650420903178136Suche in Google Scholar
[63] Willibald M, Bayer G, Stahlhut V, Poschmann G, Stühler K, Gierke B, et al. Progesterone Receptor Membrane Component 1 is Phosphorylated upon Progestin Treatment in Breast Cancer Cells. Oncotarget (advanced publications). Available from: www.impactjournals.com/oncotarget/. Accepted: 28 Jun 2017.10.18632/oncotarget.19819Suche in Google Scholar PubMed PubMed Central
[64] Seeger H, Ruan X, Neubauer H, Brucker S, Mueck A. Membrane-initiated effects of Serelys® on proliferation and apoptosis of human breast cancer cells. Gynecol Endocrinol. 2017; epub ahead (Nov 5, 2017).10.1080/09513590.2017.1407751Suche in Google Scholar PubMed
[65] Chlebowski RT, Hendrix SL, Langer RD, Stefanick ML, Gass M, Lane D, et al. Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women’s Health Initiative Randomized Trial. J Am Med Assoc. 2003;289:3243–53.10.1001/jama.289.24.3243Suche in Google Scholar PubMed
[66] Jones ME, Schoemaker MJ, Wright L, McFadden E, Griffin J, Thomas D, et al. Menopausal hormone therapy and breast cancer: what is the true size of the increased risk? Br J Cancer. 2016;115:607–15.10.1038/bjc.2016.231Suche in Google Scholar PubMed PubMed Central
[67] Asi N, Mohammed K, Haydour Q, Gionfriddo MR, Vargas OL, Prokop LJ, et al. Progesterone vs. synthetic progestins and the risk of breast cancer: a systematic review and meta-analysis. Systematic Rev. 2016;5:121–9.10.1186/s13643-016-0294-5Suche in Google Scholar PubMed PubMed Central
[68] de Lignières B, de Vathaire F, Fournier S, Urbinelli R, Allaert F, Le MG, et al. Combined hormone replacement therapy and risk of breast cancer in a French cohort study of 3175 women. Climacteric. 2002;5:332–40.10.1080/cmt.5.4.332.340Suche in Google Scholar
[69] Fournier A, Berrino F, Clavel-Chapelon F. Unequal risks for breast cancer associated with different hormone therapies: results from the E3N cohort study. Breast Cancer Res Treat. 2008;107:103–11.10.1007/s10549-007-9523-xSuche in Google Scholar PubMed PubMed Central
[70] Cordina-Duverger E, Truong T, Anger A, Sanchez M, Arveux P, Kerbrat P, et al. Risk of breast cancer by type of menopausal hormone therapy: a case-control study among post-menopausal women in France. PLoS One. 2013;11:1–9.10.1371/journal.pone.0078016Suche in Google Scholar PubMed PubMed Central
[71] Lyytinen H, Pukkala E, Ylikorkala O. Breast cancer risk in postmenopausal women using estradiol-progestogen therapy. Obstet Gynecol. 2009;113:65–73.10.1097/AOG.0b013e31818e8cd6Suche in Google Scholar PubMed
[72] Schneider C, Jick SS, Meier CR. Risk of gynecological cancers in users of estradiol/dydrogesterone or other HRT preparations. Climacteric. 2009;12:514–24.10.3109/13697130903075352Suche in Google Scholar PubMed
[73] Stute P, Wildt L, Neulen J. The impact of micronized progesterone on breast cancer risk: a systematic review. Climacteric. 2018;21:111–22.10.1080/13697137.2017.1421925Suche in Google Scholar PubMed
[74] 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;128:144–56.10.1002/ijc.25314Suche in Google Scholar PubMed
[75] Nanda K, Bastian LA, Schulz K. Hormone replacement therapy and the risk of death from breast cancer: a systematic review. Am J Obstet Gynecol. 2002;186:325–34.10.1067/mob.2002.121077Suche in Google Scholar PubMed
[76] Mikkola TS, Savolainen-Peltonen H, Tuomikoski P, Hoti F, Vattulainen P, Gissler M, et al. Reduced risk of breast cancer mortality in women using postmenopausal hormone therapy: a Finnish nationwide comparative study. Menopause. 2016;23:1199–203.10.1097/GME.0000000000000698Suche in Google Scholar PubMed
©2019 Walter de Gruyter GmbH, Berlin/Boston
