Abstract
Background
The impact of hormones on the development of breast cancer is despite extensive studies, incompletely understood. Combined estrogen-progestogen treatment augments the risk for breast cancer beyond that of estrogen alone, according to numerous studies. The role of breast cell proliferation as a promoter in the development and growth of breast cancer is well recognized.
Materials and methods
Seventy-nine patients from three randomised trials were subject to a re-analysis of breast cell proliferation: (1) 22 women received continuous combined treatment with oral estradiol (E2) 2 mg/norethisterone acetate (NETA) 1 mg once daily for 3 months. (2) Thirty-seven women received 2 months of sequential treatment with oral conjugated equine estrogens (CEE) 0.625 mg daily combined with medroxyprogesterone acetate (MPA) 5 mg for 14/28 days of each cycle. (3) Twenty women received oral estradiol-valerate (E2V) 2 mg daily combined with levonorgestrel (LNG) intrauterine system (IUS), 20 μg/24 h for 2 months. Fine needle aspiration (FNA) (studies 1 and 3) and core needle biopsy (CNB) (study 2) were used for the assessment of breast cell proliferation.
Results
There were no baseline proliferation differences, but at the end of treatment there was a highly significant between-group difference for E2V/LNG IUS versus the other two groups (p = 0.0025). E2/NETA and CEE treatments gave a 4–7-old increase in proliferation during treatment (p = 0.04) and (p = 0.007), respectively, which was absent in the E2V/LNG group, showing a significant correlation with insulin-like growth factor binding protein-3 (IGFBP-3) serum levels.
Conclusion
E2V in combination with very low serum concentrations of LNG in the IUS gives no increase in proliferation in the normal breast.
Author Statement
Research funding: The previous randomised studies were supported by grants from the Swedish Cancer Society, the Swedish Research Council (project No. 5982), the Karolinska Institutet Research Funds, NV ORGANON, Besins International Healthcare and Leiras/Schering.
Conflict of interest: None declared.
Informed consent: Before participation in the study, all the women gave their written informed consent.
Ethical approval: All three studies were performed at the Karolinska University Hospital in Stockholm, Sweden and approved by the independent Ethics Committee and the Swedish Medical Products Agency; (IRB-2005/762-31) and (EU-2005/001016-51) [13], (IRB-97/264) [11] and (IRB-96/159) [16], respectively.
References
[1] Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, et al. 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.288.3.321Search in Google Scholar
[2] Beral V. Million Women Study Collaborators. Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet. 2003;362:419–27.10.1016/S0140-6736(03)14065-2Search in Google Scholar
[3] Santen RJ, Pinkerton J, McCartney C, Petroni GR. Risk of breast cancer with progestins in combination with estrogen as hormone replacement therapy. J Clin Endocrinol Metab. 2001;86:16–23.10.1210/jcem.86.1.7269Search in Google Scholar
[4] 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;108:103–11.10.1007/s10549-007-9604-xSearch in Google Scholar
[5] Gompel A, Malet C, Spritzer P, Lalardrie JP, Kuttenn F, Mauvais-Jarvis P. Progestin effect on cell proliferation and 17 beta-hydroxysteroid dehydrogenase-activity in normal human breast cells in culture. J Clin Endocrinol Metab. 1986;63:1174–80.10.1210/jcem-63-5-1174Search in Google Scholar
[6] Courtin A, Communal L, Vilasco M, Cimino D, Mourra N, de Bortoli M, et al. Glucocorticoid receptor activity discriminates between progesterone and medroxyprogesterone acetate effects in breast cells. Breast Cancer Res Treat. 2012;131:49–63.10.1007/s10549-011-1394-5Search in Google Scholar
[7] Longacre TA, Bartow SA. A correlative morphologic study of human breast and endometrium in the menstrual cycle. Am J Surg Pathol. 1986;10:382–93.10.1097/00000478-198606000-00003Search in Google Scholar
[8] Söderqvist G, Isaksson E, von Schoultz B, Carlström K, Tani E, Skoog L. Proliferation on breast epithelial cells in Healthy women during the menstrual cycle. Am J Obstet Gynecol. 1997;176:123–8.10.1016/S0002-9378(97)80024-5Search in Google Scholar
[9] Isaksson E, von Schoultz E, Odlind V, Söderqvist G, Csemiczky G, Carlström K, et al. Effects of oral contraceptives on breast proliferation. Breast Cancer Res Treat. 2001;65:163–9.10.1023/A:1006482418082Search in Google Scholar
[10] Hofseth LJ, Raafat AM, Osuch JR, Pathak DR, Slomski CA, Haslam SZ. Hormone replacement therapy with estrogen or estrogen plus medroxyprogesterone acetate is associated with increased epithelial proliferation in the normal postmenopausal breast. J Clin Endocrinol Metab. 1999;84:4559–65.10.1210/jcem.84.12.6194Search in Google Scholar
[11] Conner P, Söderqvist G, Skoog L, Gräser T, Walter F, Tani E, et al. Breast cell proliferation in postmenopausal women during HRT evaluated through fine needle aspiration cytology. Breast Cancer Res Treat. 2003;78:159–65.10.1023/A:1022987618445Search in Google Scholar
[12] Clavel-Chapelon F, Gerbouin-Rérolle P. The E3N study: breast cancer and risk factors. Ann Pathol. 2012;32:S34.10.1016/j.annpat.2012.09.007Search in Google Scholar PubMed
[13] Murkes D, Conner P, Leifland K, Tani E, Beliard A, Lundström E, et al. Effects of percutaneous estradiol-oral progesterone versus oral conjugated equine estrogens-medroxyprogesterone acetate on breast cell proliferation and bcl-2 protein in healthy women. Fertil Steril. 2011;95:1188–91.10.1016/j.fertnstert.2010.09.062Search in Google Scholar PubMed
[14] Cline JM, Soderqvist G, von Schoultz E, Skoog L, von Schoultz B. Effects of conjugated estrogens, medroxyprogesterone acetate, and tamoxifen on the mammary glands of macaques. Breast Cancer Res Treat. 1998;48:221–9.10.1023/A:1005984932268Search in Google Scholar
[15] Lundström E, Bygdeson M, Svane G, Azavedo E, von Schoultz B. Neutral effect of ultra-low-dose continuous combined estradiol and norethisterone acetate on mammographic breast density. Climacteric. 2007;10:249–56.10.1080/13697130701385805Search in Google Scholar PubMed
[16] Lundström E, Söderqvist G, Svane G, Azavedo E, Olovsson M, Skoog L, von Schoultz E, von Schoultz B. Digitized assessment of mammographic breast density in patients who received low-dose intrauterine levonorgestrel in continuous combination with oral estradiol valerate: a pilot study. Fertil Steril. 2006;85:989–95.10.1016/j.fertnstert.2005.09.026Search in Google Scholar PubMed
[17] Skoog L, Humla S, Isaksson S, Tani E. Immunocytochemical analysis of receptors for estrogen and progesterone in fine-needle aspirates from human breast carcinomas. Diagn Cytopathol. 1990;6:95–8.10.1002/dc.2840060205Search in Google Scholar PubMed
[18] Leifland K, Lagerstedt U, Svane G. Comparison of stereotactic fine needle aspiration cytology and core needle biopsy in 522 non-palpable breast lesions. Acta Radiol. 2003;44:387–91.10.1080/j.1600-0455.2003.00098.xSearch in Google Scholar
[19] Conner P, Skoog L, Söderqvist G. Breast epithelial proliferation in postmenopausal women evaluated through fine-needle-aspiration cytology. Climacteric. 2001;4:7–12.10.1080/cmt.4.1.7.12Search in Google Scholar
[20] Leifland K, Lundquist H, Lagerstedt U, Svane G. Comparison of pre-operative simultaneous stereotactic fine needle aspiration biopsy and stereotactic core needle biopsy in ductal carcinoma in situ of the breast. Acta Radiol. 2003;44:213–7.10.1034/j.1600-0455.2003.00026.xSearch in Google Scholar PubMed
[21] 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.0b013e31818e8cd6Search in Google Scholar PubMed
[22] Crandall C, Hovey K, Andrews C, Cauley J, Stefanick M, Shufelt C, et al. Comparison of clinical outcomes among users of oral and transdermal estrogen therapy in the Women’s Health Initiative Observational Study. Menopause. 2017;24:1145–53.10.1097/GME.0000000000000899Search in Google Scholar PubMed PubMed Central
[23] Franzén S, Zaijzek J. Aspiration biopsy in diagnosis of palpable lesions of the breast. Critical review of 3479 consecutive biopsies. Acta Radiol Ther Phys Biol. 1968;7:241–62.10.3109/02841866809133198Search in Google Scholar PubMed
[24] Lee K-W, Ma L, Yan X, Liu B, Zhang XK, Cohen P. Rapid apoptosis induction by IGFBP-3 involves an insulin-like growth factor dependent nucleomitochondrial translocation of RXRalpha/Nur77. J Biol Chem. 2005;280:16942–8.10.1074/jbc.M412757200Search in Google Scholar PubMed
[25] Mccarthy K, Laban C, Mcvittie CJ, Ogunkolade W, Khalaf S, Bustin S, et al. The expression and function of IGFBP-3 in normal and malignant breast tissue. Anticancer Res. 2009;29:3785–90.Search in Google Scholar
[26] Lindén Hirschberg A, Tani E, Brismar K, Lundström E. Effects of drospirenone and norethisterone acetate combined with estradiol on mammographic density and proliferation of breast epithelial cells – A prospective randomized trial. Maturitas. 2019;126:18–24.10.1016/j.maturitas.2019.04.205Search in Google Scholar PubMed
[27] Wang M, Wu X, Chai F, Zhang Y, Jiang J. Plasma prolactin and breast cancer risk: a meta-analysis. Sci Rep. 2016;6:25998.10.1038/srep25998Search in Google Scholar PubMed PubMed Central
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