Skip to main content

Hormone replacement therapy in BRCA mutation carriers: how shall we do no harm?

Hormones volume 22, pages 19–23 (2023)Cite this article

Abstract

Women with a BRCA mutation have an increased risk of developing breast and ovarian cancer. Bilateral salpingo-oophorectomy is the only effective strategy to reduce this risk. Risk-reducing bilateral salpingo-oophorectomy (RRSO) is recommended between the ages of 35 and 40 for women carriers of BRCA1 and between the ages of 40 and 45 for women carriers of BRCA1 and BRCA2 mutations. Most women undergo this procedure prior to their natural menopause subsequently developing an anticipated lack of hormones. This condition affects the quality of life and longevity, while it is more pronounced in women carrying a BRCA1 mutation compared to BRCA2 because they are likely to have surgery earlier. Hormone replacement therapy (HRT) is the only strategy able to significantly compensate for the loss of ovarian hormone production and counteract menopausal symptoms. There is strong evidence that short-term HRT use does not increase the risk of breast cancer among women with a BRCA1 mutation. Few data are available on BRCA2 mutation carriers. Therefore, BRCA mutation carriers require careful counseling about the outcomes of their RRSO, including menopausal symptoms and/or the fear associated with HRT use.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

USD 39.95

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Data Availability

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.

Abbreviations

RRBSO:

Risk-reducing bilateral salpingo-oophorectomy

HRT:

Hormone replacement therapy

HR:

Hazard ratio

CI:

Confidence interval

BC:

Breast cancer

RRSO:

Risk-reducing salpingo-oophorectomy

NCCN:

National Comprehensive Cancer Network

WHI:

Women’s Health Initiative

ESHRE:

European Society of Human Reproduction and Embryology

MWS:

Million Women Study

EC:

Endometrial cancer

OC:

Ovarian cancer

References 

  1. Massarotti C, Buonomo B, Dellino B, Campanella M, De Stefano C, Ferrari A, Anserini P,  Lambertini M, Peccatori FA (2022) Contraception and hormone replacement therapy inhealthy carriers of germline BRCA1/2 genes pathogenic variants: results from an Italian survey. Cancers (Basel) 19:205. https://doi.org/10.3390/cancers14143457

  2. Kuchenbaecker KB, Hopper JL, Barnes DR, Phillips KA, Mooij TM, Roos-Blom MJ, Jervis S, van Leeuwen FE, Milne RL, Andrieu N, Goldgar DE, Terry MB, Rookus MA, Easton DF, Antoniou AC, McGuffog L, Evans DG, Barrowdale D, Frost D, Adlard J, Ong KR, Izatt L, Tischkowitz M, Eeles R, Davidson R, Hodgson S, Ellis S, Nogues C, Lasset C, Stoppa-Lyonnet D, Fricker JP, Faivre L, Berthet P, Hooning MJ, van der Kolk LE, Kets CM, Adank MA, John EM, Chung WK, Andrulis IL, Southey M, Daly MB, Buys SS, Osorio A, Engel C, Kast K, Schmutzler RK, Caldes T, Jakubowska A, Simard J, Friedlander ML, McLachlan SA, Machackova E, Foretova L, Tan YY, Singer CF, Olah E, Gerdes AM, Arver B, Olsson H, Brca BC Consortium (2017) Risks of breast, ovarian, and contralateral breast cancer for BRCA1 and BRCA2 mutation carriers. JAMA 317:2402–2416. https://doi.org/10.1001/jama.2017.7112

    Article  CAS  PubMed  Google Scholar 

  3. Marchetti C, De Felice F, Palaia I, Perniola G, Musella A, Musio D, Muzii L, Tombolini V, Panici PB (2014) Risk-reducing salpingo-oophorectomy: a meta-analysis on impact on ovarian cancer risk and all cause mortality in BRCA 1 and BRCA 2 mutation carriers. BMC Womens Health 14:150. https://doi.org/10.1186/s12905-014-0150-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Rebbeck TR, Levin AM, Eisen A, Snyder C, Watson P, Cannon-Albright L, Isaacs C, Olopade O, Garber JE, Godwin AK, Daly MB, Narod SA, Neuhausen SL, Lynch HT, Weber BL (1999) Breast cancer risk after bilateral prophylactic oophorectomy in BRCA1 mutation carriers. J Natl Cancer Inst 91:1475–1479. https://doi.org/10.1093/jnci/91.17.1475

    Article  CAS  PubMed  Google Scholar 

  5. Eleje GU, Eke AC, Ezebialu IU, Ikechebelu JI, Ugwu EO, Okonkwo OO(2018) Risk‐reducing bilateral salpingooophorectomy in women with BRCA1 or BRCA2 mutations. Cochrane Database of Systematic Reviews 8:CD012464. https://doi.org/10.1002/14651858.CD012464.pub2

  6. Kotsopoulos J, Gronwald J, Karlan BY, Huzarski T, Tung N, Moller P, Armel S, Lynch HT, Senter L, Eisen A (2018) Hormone replacement therapy after oophorectomy and breast cancer risk among BRCA1 mutation carriers. JAMA Oncol 4:1059–1065

    Article  PubMed  PubMed Central  Google Scholar 

  7. Webber L, Davies M, Anderson R, Bartlett J, Braat D, Cartwright B, Cifkova R, de Muinck Keizer-Schrama S, Hogervorst E, Janse F, Liao L, Vlaisavljevic V, Zillikens C, Vermeulen N, European Society for Human R, POI Embryology Guideline Group on (2016) ESHRE guideline: management of women with premature ovarian insufficiency. Hum Reprod 31:926–37. https://doi.org/10.1093/humrep/dew027

    Article  CAS  PubMed  Google Scholar 

  8. Pacello P, Yela D, Rabelo S, Giraldo P, Benetti-Pinto C (2014) Dyspareunia and lubrication in premature ovarian failure using hormonal therapy and vaginal health. Climacteric 17:342–347

    Article  CAS  PubMed  Google Scholar 

  9. Manolagas SC, O’brien CA, Almeida M (2013) The role of estrogen and androgen receptors in bone health and disease. Nature Reviews Endocrinology 9:699

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Madalinska JB, van Beurden M, Bleiker EM, Valdimarsdottir HB, Hollenstein J, Massuger LF, Gaarenstroom KN, Mourits MJ, Verheijen RH, van Dorst EB, van der Putten H, van der Velden K, Boonstra H, Aaronson NK (2006) The impact of hormone replacement therapy on menopausal symptoms in younger high-risk women after prophylactic salpingo-oophorectomy. J Clin Oncol 24:3576–3582. https://doi.org/10.1200/JCO.2005.05.1896

    Article  PubMed  Google Scholar 

  11. Anderson GL, Limacher M, Assaf AR, Bassford T, Beresford SA, Black H, Bonds D, Brunner R, Brzyski R, Caan B, Chlebowski R, Curb D, Gass M, Hays J, Heiss G, Hendrix S, Howard BV, Hsia J, Hubbell A, Jackson R, Johnson KC, Judd H, Kotchen JM, Kuller L, LaCroix AZ, Lane D, Langer RD, Lasser N, Lewis CE, Manson J, Margolis K, Ockene J, O’Sullivan MJ, Phillips L, Prentice RL, Ritenbaugh C, Robbins J, Rossouw JE, Sarto G, Stefanick ML, Van Horn L, Wactawski-Wende J, Wallace R, Wassertheil-Smoller S, Women’s Health Initiative Steering C (2004) Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized controlled trial. JAMA 291:1701–1712. https://doi.org/10.1001/jama.291.14.1701

    Article  CAS  PubMed  Google Scholar 

  12. Beral V, C Million Women Study (2003) Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet 362:419–427. https://doi.org/10.1016/s0140-6736(03)14065-2

    Article  CAS  PubMed  Google Scholar 

  13. Gabriel C, Tigges-Cardwell J, Stopfer J, Erlichman J, Nathanson K, Domchek S (2009) Use of total abdominal hysterectomy and hormone replacement therapy in BRCA1 and BRCA2 mutation carriers undergoing risk-reducing salpingo-oophorectomy. Fam Cancer 8:23–28

    Article  CAS  PubMed  Google Scholar 

  14. Rebbeck TR, Friebel T, Wagner T, Lynch HT, Garber JE, Daly MB, Isaacs C, Olopade OI, Neuhausen SL, Eeles R (2005) Effect of short-term hormone replacement therapy on breast cancer risk reduction after bilateral prophylactic oophorectomy in BRCA1 and BRCA2 mutation carriers: the PROSE Study Group. J Clin Oncol 23:7804–7810

    Article  CAS  PubMed  Google Scholar 

  15. Buonomo B, Massarotti C, Dellino M, Anserini P, Ferrari A, Campanella M, Magnotti M, De Stefano C, Peccatori FA, Lambertini M (2021) Reproductive issues in carriers of germline pathogenic variants in the BRCA1/2 genes: an expert meeting. BMC Med 19:205. https://doi.org/10.1186/s12916-021-02081-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Marchetti C, De Felice F, Boccia S, Sassu C, Di Donato V, Perniola G, Palaia I, Monti M, Muzii L, Tombolini V, Benedetti Panici P (2018) Hormone replacement therapy after prophylactic risk-reducing salpingo-oophorectomy and breast cancer risk in BRCA1 and BRCA2 mutation carriers: a meta-analysis. Crit Rev Oncol Hematol 132:111–115. https://doi.org/10.1016/j.critrevonc.2018.09.018

    Article  CAS  PubMed  Google Scholar 

  17. Grady D, Gebretsadik T, Kerlikowske K, Ernster V, Petitti D (1995) Hormone replacement therapy and endometrial cancer risk: a meta-analysis. Obstet Gynecol 85:304–313

    Article  CAS  PubMed  Google Scholar 

  18. Lawton FG, Pavlik EJ (2022) Perspectives on Ovarian Cancer 1809 to 2022 and Beyond. Diagnostics 12:791

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Shu CA, Pike MC, Jotwani AR, Friebel TM, Soslow RA, Levine DA, Nathanson KL, Konner JA, Arnold AG, Bogomolniy F (2016) Uterine cancer after risk-reducing salpingo-oophorectomy without hysterectomy in women with BRCA mutations. JAMA Oncol 2:1434–1440

    Article  PubMed  PubMed Central  Google Scholar 

  20. Segev Y, Rosen B, Lubinski J, Gronwald J, Lynch HT, Moller P, Kim-Sing C, Ghadirian P, Karlan B, Eng C (2015) Risk factors for endometrial cancer among women with a BRCA1 or BRCA2 mutation: a case control study. Fam Cancer 14:383–391

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Bafunno D, Romito F, Lagattolla F, Delvino VA, Minoia C, Loseto G, Dellino M, Guarini A, Catino A, Montrone M, Longo V, Pizzutilo P, Galetta D, Giotta F, Latorre AC, Russo A, Lorusso V, Cormio C (2021) Psychological well-being in cancer outpatients during COVID-19. J BUON 26:1127–1134

    PubMed  Google Scholar 

  22. Vasta FM, Dellino M, Bergamini A, Gargano G, Paradiso A, Loizzi V, Bocciolone L, Silvestris E, Petrone M, Cormio G, Mangili G (2020) Reproductive outcomes and fertility preservation strategies in women with malignant ovarian germ cell tumors after fertility sparing surgery. Biomedicines 8:554. https://doi.org/10.3390/biomedicines8120554

  23. Daniele A, Divella R, Pilato B, Tommasi S, Pasanisi P, Patruno M, Digennaro M, Minoia C, Dellino M, Pisconti S, Casamassima P, Savino E, Paradiso AV (2021) Can harmful lifestyle, obesity and weight changes increase the risk of breast cancer in BRCA 1 and BRCA 2 mutation carriers? A mini review. Hered Cancer Clin Pract 19:45. https://doi.org/10.1186/s13053-021-00199-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Vimercati A, Dellino M, Crupano FM, Gargano G, Cicinelli E (2022) Ultrasonic assessment of cesarean section scar to vesicovaginal fold distance: an instrument to estimate pre-labor uterine rupture risk. J Matern Fetal Neonatal Med 35:4370–4374. https://doi.org/10.1080/14767058.2020.1849121

    Article  CAS  PubMed  Google Scholar 

  25. Daniele A, A Guarini, S Summa, M Dellino, G Lerario, S Ciavarella, P Ditonno, AV Paradiso, R Divella, P Casamassima, E Savino, MD Carbonara, and C Minoia (2021) Body composition change, unhealthy lifestyles and steroid treatment as predictor of metabolic risk in non-Hodgkin’s lymphoma survivors. J Pers Med 11. https://doi.org/10.3390/jpm11030215

  26. Dellino M, Carriero C, Silvestris E, Capursi T, Paradiso A, Cormio G (2020) Primary vaginal carcinoma arising on cystocele mimicking vulvar cancer. J Obstet Gynaecol Can 42:1543–1545. https://doi.org/10.1016/j.jogc.2020.03.007

    Article  PubMed  Google Scholar 

  27. Dellino M, E Cascardi, C Leoni, F Fortunato, A Fusco, R Tinelli, G Cazzato, S Scacco, A Gnoni, A Scilimati, V Loizzi, A Malvasi, A Sapino, V Pinto, E Cicinelli, G Di Vagno, G Cormio, V Chiantera, and AS Lagana (2022) Effects of oral supplementation with myo-inositol and D-chiro-Inositol on ovarian functions in female long-term survivors of lymphoma: results from a prospective case-control analysis. J Pers Med 12. https://doi.org/10.3390/jpm12091536

  28. Cascardi E, G Cazzato, A Daniele, E Silvestris, G Cormio, G Di Vagno, A Malvasi, V Loizzi, S Scacco, V Pinto, E Cicinelli, E Maiorano, G Ingravallo, L Resta, C Minoia, and M Dellino (2022) Association between cervical microbiota and HPV: could this be the key to complete cervical cancer eradication? Biology (Basel) 11. https://doi.org/10.3390/biology11081114

  29. Dellino M, E Cascardi, M Vinciguerra, B Lamanna, A Malvasi, S Scacco, S Acquaviva, V Pinto, G Di Vagno, G Cormio, R De Luca, M Lafranceschina, G Cazzato, G Ingravallo, E Maiorano, L Resta, A Daniele, and D La Forgia (2022) Nutrition as personalized medicine against SARS-CoV-2 infections: clinical and oncological options with a specific female groups overview. Int J Mol Sci 23. https://doi.org/10.3390/ijms23169136

  30. Silvestris E, Cormio G, Skrypets T, Dellino M, Paradiso AV, Guarini A, Minoia C (2020) Novel aspects on gonadotoxicity and fertility preservation in lymphoproliferative neoplasms. Crit Rev Oncol Hematol 151:102981. https://doi.org/10.1016/j.critrevonc.2020.102981

    Article  PubMed  Google Scholar 

  31. Silvestris E, S D'Oronzo, P Cafforio, A Kardhashi, M Dellino, and G Cormio (2019) In vitro generation of oocytes from ovarian stem cells (OSCs): in search of major evidence. Int J Mol Sci 20.https://doi.org/10.3390/ijms20246225

  32. Dellino M, Silvestris E, Loizzi V, Paradiso A, Loiacono R, Minoia C, Daniele A, Cormio G (2020) Germinal ovarian tumors in reproductive age women: fertility-sparing and outcome. Medicine (Baltimore) 99:e22146. https://doi.org/10.1097/MD.0000000000022146

    Article  CAS  PubMed  Google Scholar 

  33. Silvestris E, Dellino M, Cafforio P, Paradiso AV, Cormio G, D’Oronzo S (2020) Breast cancer: an update on treatment-related infertility. J Cancer Res Clin Oncol 146:647–657. https://doi.org/10.1007/s00432-020-03136-7

    Article  PubMed  Google Scholar 

  34. Bergamini A, Luisa FM, Dellino M, Erica S, Loizzi V, Bocciolone L, Rabaiotti E, Cioffi R, Sabetta G, Cormio G, Mangili G (2022) Fertility sparing surgery in sex-cord stromal tumors: oncological and reproductive outcomes. Int J Gynecol Cancer 32:1063–1070. https://doi.org/10.1136/ijgc-2021-003241

    Article  PubMed  Google Scholar 

  35. Viviani S, Dellino M, Ramadan S, Peracchio C, Marcheselli L, Minoia C, Guarini A (2022) Fertility preservation strategies for patients with lymphoma: a real-world practice survey among Fondazione Italiana Linfomi centers. Tumori 108:572–577. https://doi.org/10.1177/03008916211040556

    Article  PubMed  Google Scholar 

  36. Silvestris E, G De Palma, S Canosa, S Palini, M Dellino, A Revelli, and AV Paradiso (2020) Human ovarian cortex biobanking: a fascinating resource for fertility preservation in cancer. Int J Mol Sci 21.https://doi.org/10.3390/ijms21093245

  37. Casaubon JT, Kashyap S, Regan JP (2022) BRCA 1 and 2, in StatPearls. Treasure Island (FL)

  38. Najjar S, Allison KH (2022) Updates on breast biomarkers. Virchows Arch 480:163–176. https://doi.org/10.1007/s00428-022-03267-x

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Interdisciplinary Medicine (DIM), University of Bari “Aldo Moro”, 70124, Bari, Italy

    Vera Loizzi & Gennaro Cormio

  2. Oncology Unit IRCSS Istituto Tumori “Giovanni Paolo II”, 70124, Bari, Italy

    Vera Loizzi & Gennaro Cormio

  3. Obstetrics and Gynecology Unit, Department of Biomedical Sciences and Human Oncology, University of Bari, Bari, Italy

    Miriam Dellino, Marco Cerbone, Francesca Arezzo, Giulia Chiariello, Gianluca Raffaello Damiani & Ettore Cicinelli

  4. Clinic of Obstetrics and Gynecology, San Paolo” Hospital, ASL Bari, Bari, Italy

    Miriam Dellino

  5. Section of Pathology, Department of Emergency and Organ Transplantation (DETO), University of Bari “Aldo Moro”, Bari, Italy

    Gerardo Cazzato

  6. Department of Medical Sciences, University of Turin, 10124, Turin, Italy

    Eliano Cascardi

  7. Pathology Unit, FPO-IRCCS Candiolo Cancer Institute, 10060, Candiolo, Italy

    Eliano Cascardi

  8. Section of Gynecology and Obstetrics, Department of Interdisciplinar Medicine(DIM), University of Bari “Aldo Moro”, 70124, Bari, Italy

    Achiropita Lepera

Authors
  1. Vera Loizzi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Miriam Dellino
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Marco Cerbone
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Francesca Arezzo
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Giulia Chiariello
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Achiropita Lepera
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Gerardo Cazzato
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Eliano Cascardi
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Gianluca Raffaello Damiani
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Ettore Cicinelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Gennaro Cormio
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Miriam Dellino.

Ethics declarations

Ethics approval

The manuscript had ethical approval. The Ethical Review Board was obtained from the Ethics Committee of the Policlinico Bari, Italy, who approved the study protocol.

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher's note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Loizzi, V., Dellino, M., Cerbone, M. et al. Hormone replacement therapy in BRCA mutation carriers: how shall we do no harm?. Hormones 22, 19–23 (2023). https://doi.org/10.1007/s42000-022-00427-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s42000-022-00427-1

Keywords

  • BRCA
  • HRT
  • RRSO