Hormonal Contraception in Breast Cancer Survivors: From Hormonal Physiology to Future Perspectives
Main Article Content
Abstract
For the millions of women who have successfully battled breast cancer, the question of contraception presents a unique and often complex challenge. Navigating the landscape of hormonal options requires a deep understanding of how cancer treatments have altered their bodies' hormonal physiology and a careful weighing of the risks and benefits. Contraceptive management in breast cancer patients also requires scientific evidence. This review discusses the interaction between sexual steroids and the mammary gland, bridging basic science with large studies such as the WHI and the Million Women Study, which have demonstrated the risks associated with combined hormonal therapy. Based on these data, hormone-containing contraceptives are contraindicated, and the copper intrauterine device (Cu-IUD) emerges as the main safe option. However, while non-hormonal methods have traditionally been the first line of defense, ongoing research and a shift towards personalized medicine are opening up new perspectives and potential future options for this growing population. The use of progestin-only methods, particularly the levonorgestrel-releasing intrauterine system (LNG-IUS), presents a more nuanced picture, and remains a matter of debate. Although it offers benefits such as endometrial protection in tamoxifen users, its oncological safety is still uncertain. Some studies suggest that the low levels of circulating progestin may not pose a significant risk of recurrence. As a future perspective, new molecules such as estetrol (E4) are emerging as promising alternatives due to their selective action profile. The conversation around hormonal contraception is evolving, and future researches will provide choices that align with patients’ individual needs and desires.
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How to Cite
PACHNICKI, Jan Pawel Andrade; DE ANDRADE, Giovana Galego Navarrete.
Hormonal Contraception in Breast Cancer Survivors: From Hormonal Physiology to Future Perspectives.
Medical Research Archives, [S.l.], v. 13, n. 8, aug. 2025.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/6856>. Date accessed: 05 dec. 2025.
doi: https://doi.org/10.18103/mra.v13i8.6856.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
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6. Schwarz EB, Hess R, Trussell J. Contraceptive options for women with cancer. J Gen Intern Med. 2009;24 Suppl 2:S401-S406.
7. Hickey M, Peate M, Saunders CM, Friedlander M. Breast cancer in young women: an overview. Hum Reprod Update. 2009;15(3):323-339.
8. Patel A, Schwarz EB, Sreedevi M, Roston A. Contraception for the medically complex patient. Contraception. 2012;86(3):191-198.
9. World Health Organization. Medical Eligibility Criteria for Contraceptive Use. 5th ed. World Health Organization; 2015.
10. Mallepell S, Krust A, Chambon P, Brisken C. Paracrine signaling through the epithelial estrogen receptor alpha is required for proliferation and morphogenesis in the mammary gland. Proc Natl Acad Sci U S A. 2006;103(7):2196-2201.
11. Brisken C, O'Malley BW. Hormone action in the mammary gland. Cold Spring Harb Perspect Biol. 2010;2(12):a003178.
12. Haslam SZ, Shyamala G. Progesterone receptors in normal mammary gland: receptor modulations in relation to differentiation. J Cell Biol. 1979;86(3):730-736.
13. Santen RJ, Brodie H, Simpson ER, Siiteri PK, Brodie AM. History of aromatase: saga of an important biological mediator and therapeutic target. Endocr Rev. 2009;30(4):343-375.
14. Inhoffen HH, Logemann W, Hohlweg W, Serini A. Untersuchungen in der Sexualhormon-Reihe. Ber Dtsch Chem Ges. 1938;71(5):1024-1032.
15. Vigo F, Lubianca JN, Corleta HV. Progestógenos: farmacologia e uso clínico. Rev Femina. 2011;39(3):127-137.
16. Topper YJ, Freeman CS. Multiple hormone interactions in the developmental biology of the mammary gland. Physiol Rev. 1980;60(4):1049-1106.
17. Graham JD, Clarke CL. Physiological action of progesterone in target tissues. Endocr Rev. 1997;18(4):502-519.
18. Humphreys RC, Lydon J, O'Malley BW, Rosen JM. Mammary gland development is mediated by both stromal and epithelial progesterone receptors. Mol Endocrinol. 1997;11(6):801-811.
19. 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 U S A. 2003;100(17):9744-9749.
20. Mulac-Jericevic B, Conneely OM. Reproductive tissue selective actions of progesterone receptors. Reproduction. 2004;128(2):139-146.
21. Ruan W, Monaco ME, Kleinberg DL. Progesterone stimulates mammary gland ductal morphogenesis by synergizing with and enhancing IGF-I. Endocrinology. 2004;145(7):3361-3368.
22. Shi HY, Lydon JP, Zhang M. Hormonal defect in maspin heterozygous mice reveals a role of progesterone in pubertal ductal development. Mol Endocrinol. 2004;18(9):2196-2207.
23. Coneely OM, Mulac-Jericevic B, DeMayo FJ, Lydon JP, O'Malley BW. Reproductive functions of progesterone receptors. Recent Prog Horm Res. 2002;57:1-32.
24. Pike MC, Key TJ. Oestrogens, progestagens, and the risk of breast cancer. Eur J Cancer Clin Oncol. 1988;24(1):29-43.
25. Wren BG. The effect of progestogens on breast tissue. Maturitas. 1988;10(1):3-9.
26. Lydon JP, Ge G, Kittrell FS, Medina D, O'Malley BW. Murine progesterone receptor A-form and B-form knockout mice reveal that progesterone action on mammary gland development is mediated by the B-form. Cancer Res. 1999;59(17):4276-4284.
27. Soyal SM, Ismail PM, Li J, Mulac-Jericevic B, Conneely OM, Lydon JP. The differing roles of progesterone receptors in the breast and uterus. Breast Cancer Res. 2002;4(5):191-196.
28. Chlebowski RT, Hendrix SL, Langer RD, et al. 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):3243-3253.
29. Beral V; Million Women Study Collaborators. Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet. 2003;362(9382):419-427.
30. Holmberg L, Anderson H; HABITS steering and data monitoring committees. HABITS (hormonal replacement therapy after breast cancer--is it safe?), a randomised comparison: trial stopped. Lancet. 2004;363(9407):453-455.
31. von Schoultz E, Rutqvist LE; Stockholm Breast Cancer Study Group. Menopausal hormone therapy after breast cancer: the Stockholm randomized trial. J Natl Cancer Inst. 2005;97(7):533-535.
32. Campagnoli C, Clavel-Chapelon F, Kaaks R, Peris C, Berrino F. Progestins and progesterone in hormone replacement therapy and the risk of breast cancer. J Steroid Biochem Mol Biol. 2005;96(2):95-108.
33. Lange CA, Yee D. Progesterone and breast cancer. Womens Health (Lond). 2008;4(2):151-162.
34. Mester J, Redeuilh G. Progesterone receptors: fifty years of research, what's new? Anticancer Agents Med Chem. 2008;8(8):872-885.
35. Beatson GT. On the treatment of inoperable cases of carcinoma of the mamma: suggestions for a new method of treatment, with illustrative cases. Lancet. 1896;2(3802):104-107.
36. Macdonald PC, Siiteri PK. The relationship between the extraglandular production of estrone and the occurrence of endometrial neoplasia. Gynecol Oncol. 1974;2(2-3):259-263.
37. Jensen EV, DeSombre ER, Jungblut PW. Estrogen receptors in hormone-responsive tissues and tumors. Proc Natl Acad Sci U S A. 1967;59(2):632-638.
38. Ali S, Coombes RC. Endocrine-responsive breast cancer and strategies for combating resistance. Nat Rev Cancer. 2002;2(2):101-112.
39. Deroo BJ, Korach KS. Estrogen receptors and human disease. J Clin Invest. 2006;116(3):561-570.
40. Hammond ME. Estrogen receptor, progesterone receptor and HER2 a 'ménage à trois' in breast cancer. Breast Cancer Res Treat. 2010;120 Suppl 1:S1-S6.
41. Backman T, Rauramo I, Jaakkola K, et al. Use of the levonorgestrel-releasing intrauterine system and breast cancer. Obstet Gynecol. 2005;106(4):813-817.
42. Trinh XB, Tjalma WA, Makar AP, Buytaert G, Weyler J, Van Dam PA. Use of the levonorgestrel-releasing intrauterine system in breast cancer patients. Fertil Steril. 2008;90(1):17-22.
43. Dinger J, Bardenheuer K, Moehner S. Levonorgestrel-releasing and copper intrauterine devices and the risk of breast cancer. Contraception. 2011;83(3):211-217.
44. Scapinelli A, Oliveira VM, Takagi MM, Aldrighi JM. Levonorgestrel-releasing intrauterine system and breast cancer risk. Rev Assoc Med Bras. 2010;56(6):615-617.
45. Fu Y, Zhuang Z. Long-term effects of levonorgestrel-releasing intrauterine system on tamoxifen-treated breast cancer patients: a meta-analysis. Int J Clin Exp Pathol. 2014;7(10):6419-6429.
46. Soini T, Hurskainen R, Grénman S, et al. Levonorgestrel-releasing intrauterine system and the risk of breast cancer: A nationwide cohort study. Acta Oncol. 2016;55(2):188-192.
47. Roberts H, Hickey M. The levonorgestrel-releasing intrauterine system for endometrial protection in women with breast cancer on adjuvant tamoxifen. Maturitas. 2016;89:1-2.
48. Black A, Guilbert E; Society of Obstetrician and Gynecologists of Canada. Canadian Contraception Consensus (Part 3 of 4): Chapter 8 - Progestin-Only Contraception. J Obstet Gynaecol Can. 2016;38(3):279-294.
49. Gérard C, Blanpain C, de Jésus I, et al. Estetrol is a natural estrogen with unique ERα-dependent actions in breast cancer cells. Mol Cell Endocrinol. 2016;422:93-101.
50. Benoit M, Coelingh Bennink HJ, Debrock S, et al. Estetrol acts as a selective nuclear estrogen receptor alpha modulator in the vagina. Hum Reprod. 2017;32(11):2203-2214.
51. Singer CF, Coelingh Bennink HJ, Natter C. The effect of estetrol on apoptosis and proliferation markers in human breast cancer tissue. Climacteric. 2021;24(2):152-158.
2. Giaquinto AN, Sung H, Newman LA, et al. Breast cancer statistics 2024. CA Cancer J Clin. 2024;74(6):477-495.
3. Kim J, Munster PN. Estrogens and breast cancer. Ann Oncol. 2025;36(2):134-148.
4. Byrne J, Mulvihill JJ, Myers MH, et al. Effects of treatment for childhood cancer on fertility. N Engl J Med. 1987;317(21):1315-1321.
5. McNaught J, Reid RL. Contraception for the woman with a medical condition: an evidence-based review. J Obstet Gynaecol Can. 2006;28(7):616-639.
6. Schwarz EB, Hess R, Trussell J. Contraceptive options for women with cancer. J Gen Intern Med. 2009;24 Suppl 2:S401-S406.
7. Hickey M, Peate M, Saunders CM, Friedlander M. Breast cancer in young women: an overview. Hum Reprod Update. 2009;15(3):323-339.
8. Patel A, Schwarz EB, Sreedevi M, Roston A. Contraception for the medically complex patient. Contraception. 2012;86(3):191-198.
9. World Health Organization. Medical Eligibility Criteria for Contraceptive Use. 5th ed. World Health Organization; 2015.
10. Mallepell S, Krust A, Chambon P, Brisken C. Paracrine signaling through the epithelial estrogen receptor alpha is required for proliferation and morphogenesis in the mammary gland. Proc Natl Acad Sci U S A. 2006;103(7):2196-2201.
11. Brisken C, O'Malley BW. Hormone action in the mammary gland. Cold Spring Harb Perspect Biol. 2010;2(12):a003178.
12. Haslam SZ, Shyamala G. Progesterone receptors in normal mammary gland: receptor modulations in relation to differentiation. J Cell Biol. 1979;86(3):730-736.
13. Santen RJ, Brodie H, Simpson ER, Siiteri PK, Brodie AM. History of aromatase: saga of an important biological mediator and therapeutic target. Endocr Rev. 2009;30(4):343-375.
14. Inhoffen HH, Logemann W, Hohlweg W, Serini A. Untersuchungen in der Sexualhormon-Reihe. Ber Dtsch Chem Ges. 1938;71(5):1024-1032.
15. Vigo F, Lubianca JN, Corleta HV. Progestógenos: farmacologia e uso clínico. Rev Femina. 2011;39(3):127-137.
16. Topper YJ, Freeman CS. Multiple hormone interactions in the developmental biology of the mammary gland. Physiol Rev. 1980;60(4):1049-1106.
17. Graham JD, Clarke CL. Physiological action of progesterone in target tissues. Endocr Rev. 1997;18(4):502-519.
18. Humphreys RC, Lydon J, O'Malley BW, Rosen JM. Mammary gland development is mediated by both stromal and epithelial progesterone receptors. Mol Endocrinol. 1997;11(6):801-811.
19. 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 U S A. 2003;100(17):9744-9749.
20. Mulac-Jericevic B, Conneely OM. Reproductive tissue selective actions of progesterone receptors. Reproduction. 2004;128(2):139-146.
21. Ruan W, Monaco ME, Kleinberg DL. Progesterone stimulates mammary gland ductal morphogenesis by synergizing with and enhancing IGF-I. Endocrinology. 2004;145(7):3361-3368.
22. Shi HY, Lydon JP, Zhang M. Hormonal defect in maspin heterozygous mice reveals a role of progesterone in pubertal ductal development. Mol Endocrinol. 2004;18(9):2196-2207.
23. Coneely OM, Mulac-Jericevic B, DeMayo FJ, Lydon JP, O'Malley BW. Reproductive functions of progesterone receptors. Recent Prog Horm Res. 2002;57:1-32.
24. Pike MC, Key TJ. Oestrogens, progestagens, and the risk of breast cancer. Eur J Cancer Clin Oncol. 1988;24(1):29-43.
25. Wren BG. The effect of progestogens on breast tissue. Maturitas. 1988;10(1):3-9.
26. Lydon JP, Ge G, Kittrell FS, Medina D, O'Malley BW. Murine progesterone receptor A-form and B-form knockout mice reveal that progesterone action on mammary gland development is mediated by the B-form. Cancer Res. 1999;59(17):4276-4284.
27. Soyal SM, Ismail PM, Li J, Mulac-Jericevic B, Conneely OM, Lydon JP. The differing roles of progesterone receptors in the breast and uterus. Breast Cancer Res. 2002;4(5):191-196.
28. Chlebowski RT, Hendrix SL, Langer RD, et al. 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):3243-3253.
29. Beral V; Million Women Study Collaborators. Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet. 2003;362(9382):419-427.
30. Holmberg L, Anderson H; HABITS steering and data monitoring committees. HABITS (hormonal replacement therapy after breast cancer--is it safe?), a randomised comparison: trial stopped. Lancet. 2004;363(9407):453-455.
31. von Schoultz E, Rutqvist LE; Stockholm Breast Cancer Study Group. Menopausal hormone therapy after breast cancer: the Stockholm randomized trial. J Natl Cancer Inst. 2005;97(7):533-535.
32. Campagnoli C, Clavel-Chapelon F, Kaaks R, Peris C, Berrino F. Progestins and progesterone in hormone replacement therapy and the risk of breast cancer. J Steroid Biochem Mol Biol. 2005;96(2):95-108.
33. Lange CA, Yee D. Progesterone and breast cancer. Womens Health (Lond). 2008;4(2):151-162.
34. Mester J, Redeuilh G. Progesterone receptors: fifty years of research, what's new? Anticancer Agents Med Chem. 2008;8(8):872-885.
35. Beatson GT. On the treatment of inoperable cases of carcinoma of the mamma: suggestions for a new method of treatment, with illustrative cases. Lancet. 1896;2(3802):104-107.
36. Macdonald PC, Siiteri PK. The relationship between the extraglandular production of estrone and the occurrence of endometrial neoplasia. Gynecol Oncol. 1974;2(2-3):259-263.
37. Jensen EV, DeSombre ER, Jungblut PW. Estrogen receptors in hormone-responsive tissues and tumors. Proc Natl Acad Sci U S A. 1967;59(2):632-638.
38. Ali S, Coombes RC. Endocrine-responsive breast cancer and strategies for combating resistance. Nat Rev Cancer. 2002;2(2):101-112.
39. Deroo BJ, Korach KS. Estrogen receptors and human disease. J Clin Invest. 2006;116(3):561-570.
40. Hammond ME. Estrogen receptor, progesterone receptor and HER2 a 'ménage à trois' in breast cancer. Breast Cancer Res Treat. 2010;120 Suppl 1:S1-S6.
41. Backman T, Rauramo I, Jaakkola K, et al. Use of the levonorgestrel-releasing intrauterine system and breast cancer. Obstet Gynecol. 2005;106(4):813-817.
42. Trinh XB, Tjalma WA, Makar AP, Buytaert G, Weyler J, Van Dam PA. Use of the levonorgestrel-releasing intrauterine system in breast cancer patients. Fertil Steril. 2008;90(1):17-22.
43. Dinger J, Bardenheuer K, Moehner S. Levonorgestrel-releasing and copper intrauterine devices and the risk of breast cancer. Contraception. 2011;83(3):211-217.
44. Scapinelli A, Oliveira VM, Takagi MM, Aldrighi JM. Levonorgestrel-releasing intrauterine system and breast cancer risk. Rev Assoc Med Bras. 2010;56(6):615-617.
45. Fu Y, Zhuang Z. Long-term effects of levonorgestrel-releasing intrauterine system on tamoxifen-treated breast cancer patients: a meta-analysis. Int J Clin Exp Pathol. 2014;7(10):6419-6429.
46. Soini T, Hurskainen R, Grénman S, et al. Levonorgestrel-releasing intrauterine system and the risk of breast cancer: A nationwide cohort study. Acta Oncol. 2016;55(2):188-192.
47. Roberts H, Hickey M. The levonorgestrel-releasing intrauterine system for endometrial protection in women with breast cancer on adjuvant tamoxifen. Maturitas. 2016;89:1-2.
48. Black A, Guilbert E; Society of Obstetrician and Gynecologists of Canada. Canadian Contraception Consensus (Part 3 of 4): Chapter 8 - Progestin-Only Contraception. J Obstet Gynaecol Can. 2016;38(3):279-294.
49. Gérard C, Blanpain C, de Jésus I, et al. Estetrol is a natural estrogen with unique ERα-dependent actions in breast cancer cells. Mol Cell Endocrinol. 2016;422:93-101.
50. Benoit M, Coelingh Bennink HJ, Debrock S, et al. Estetrol acts as a selective nuclear estrogen receptor alpha modulator in the vagina. Hum Reprod. 2017;32(11):2203-2214.
51. Singer CF, Coelingh Bennink HJ, Natter C. The effect of estetrol on apoptosis and proliferation markers in human breast cancer tissue. Climacteric. 2021;24(2):152-158.