Short answer: in women with a BRCA1 or BRCA2 mutation who had their ovaries removed to reduce their cancer risk, an Israeli study published in 2026 in JAMA Network Open, with 919 participants followed for almost 9 years, found no increase in breast cancer with the use of hormone therapy after surgery (Regev-Sadeh et al., JAMA Netw Open 2026). Estrogen used alone was associated with a slightly lower risk for each year of use, especially in BRCA1. By contrast, the hormonal IUD used before surgery was associated with a higher risk. It is an observational study: it shows association, not causation, and the decision remains individual and made together with the care team.
Why this question matters
For health professionals
Carriers of pathogenic variants in BRCA1/2 have a cumulative risk by age 80 of 72% and 69% for breast cancer, and of 44% and 17% for ovarian cancer, respectively (Kuchenbaecker et al., JAMA 2017). Risk-reducing salpingo-oophorectomy is recommended after childbearing is complete, at ages 35–40 in BRCA1 and 40–45 in BRCA2 (Sessa et al., Ann Oncol 2023), and is associated with lower all-cause mortality (HR 0.32; 95% CI 0.24–0.42) (Kotsopoulos et al., JAMA Oncol 2024) and an 80% reduction in ovarian, fallopian tube and peritoneal cancer (Finch et al., J Clin Oncol 2014).
The cost is early surgical menopause. In the general population, bilateral oophorectomy before age 45 was associated with higher mortality (HR 1.67), especially without estrogen replacement (Rocca et al., Lancet Oncol 2006). Hormone therapy (HT) is the most effective treatment for vasomotor symptoms and prevents bone loss (NAMS, Menopause 2022), but in BRCA carriers the fear of increasing breast cancer risk limits its use, and there is still no specific international guideline (Regev-Sadeh et al., JAMA Netw Open 2026; Gordhandas et al., Gynecol Oncol 2019).
In plain language
People who inherit a change in the BRCA1 or BRCA2 genes have a much higher lifetime risk of breast and ovarian cancer. To reduce that risk, guidelines recommend removing the ovaries and fallopian tubes at around 35 to 45 years of age, once the woman has had the children she wants.
The surgery saves lives, but it brings on menopause all at once and earlier: hot flashes, insomnia, bone loss and other effects. Hormone replacement relieves this, but many women and doctors fear that it could increase breast cancer in particular. That is the question the study tried to answer.
The study, in numbers
For health professionals
Multicenter retrospective cohort (Clalit Health Services, Shaare Zedek and Sheba), with surgeries between 2000 and 2024 and at least 1 year of follow-up; 90% carried one of the 3 Ashkenazi founder variants. Women with prior cancer and with mastectomy before or up to 1 year after oophorectomy were excluded. The outcome was the first invasive breast cancer (ductal carcinoma in situ did not count). HT was modeled as a time-dependent covariate in Cox regression, adjusted for age at surgery, gene, parity, prior use of oral contraceptives, of the levonorgestrel intrauterine device (LNG-IUD), of HT before surgery, and family history (Regev-Sadeh et al., JAMA Netw Open 2026).
Among users, the mean duration was 5.1 years; 68% used a combined regimen and 31% estrogen alone; the oral route was the most common (54%), followed by the patch (19%).
In plain language
The researchers reviewed the medical records of three large health services in Israel and followed, for almost 9 years, women with BRCA who had had their ovaries removed and had no cancer at the time.
They then compared those who used hormone replacement with those who did not, taking into account differences between them (age, children, contraceptive use, family history). No one was randomly assigned to use it or not: the study only observed what happened.
What the study found
1. Using hormone therapy was not associated with more breast cancer
For health professionals
Ever use: combined HT, HR 1.06 (95% CI 0.67–1.68); estrogen alone, HR 0.89 (0.48–1.63). The results held in the subgroups by gene and by age at surgery (< 45 and ≥ 45 years). As expected, the baseline risk was lower in BRCA2 than in BRCA1 (HR 0.46; 0.32–0.65) (Regev-Sadeh et al., JAMA Netw Open 2026).
In plain language
Comparing those who used hormone replacement with those who did not, the number of breast cancer cases was similar. This held for BRCA1 and BRCA2 and for those who had surgery before or after age 45.
2. Estrogen alone: slightly lower risk for each year of use
For health professionals
In the duration analysis, each year of estrogen alone was associated with HR 0.90 (0.81–0.99) overall and 0.87 (0.77–0.98) in BRCA1; in BRCA2, 0.96 (0.82–1.12), not significant. Combined HT did not change the risk per year (HR 0.95; 0.89–1.01) (Regev-Sadeh et al., JAMA Netw Open 2026). The finding points in the same direction as the cohort by Kotsopoulos et al. with 872 BRCA1 carriers, in which the 10-year cumulative incidence was 12% with estrogen alone and 22% with estrogen plus progestogen (Kotsopoulos et al., JAMA Oncol 2018).
In plain language
In women who used estrogen alone, each year of use was associated with about 10% lower risk, and 13% lower in those with BRCA1. Note: estrogen alone is only used in people who no longer have a uterus (hysterectomy). Those who have a uterus need a progestogen alongside it, for the safety of the endometrium.
3. Combined HT for 5 years or more in those who had surgery before 45: a signal to watch
For health professionals
In the subgroup with oophorectomy before age 45, use of combined HT for ≥ 5 years had HR 2.38 (1.03–5.50) in the univariate analysis and 2.31 (0.99–5.40) after adjustment, at the borderline of significance (Regev-Sadeh et al., JAMA Netw Open 2026). In another Israeli cohort of 306 carriers, the higher risk with HT appeared in those who had surgery after age 45 (OR 3.43; 1.2–9.8) (Michaelson-Cohen et al., Eur J Cancer 2021); Kotsopoulos et al., however, did not observe this age effect (Kotsopoulos et al., JAMA Oncol 2018). The data by age are still inconsistent.
In plain language
In a smaller group, women who had surgery before age 45 and used combined replacement for 5 years or more, a signal of higher risk appeared. But the numbers were borderline, with no firm conclusion, and other studies show different results. It is a point that deserves more research.
4. Hormonal IUD used before surgery: association with higher risk
For health professionals
Prior use of the LNG-IUD was associated with HR 1.69 (1.09–2.61) overall and 2.00 (1.18–3.36) in BRCA1; in BRCA2, 1.26 (0.55–2.90), not significant. Prior oral contraceptive use did not change the risk (Regev-Sadeh et al., JAMA Netw Open 2026). In the general population, large cohorts also show a modest relative increase with the hormonal IUD: HR 1.13 in Sweden (Yi et al., Am J Obstet Gynecol 2024) and HR 1.4 in Denmark, with an estimated excess of 14 cases per 10,000 users within 5 years (Mørch et al., JAMA 2024). In pooled data from 4 prospective cohorts, hormonal contraceptive use was associated with HR 1.29 in BRCA1, with no association in BRCA2 (Phillips et al., J Clin Oncol 2025).
In plain language
Women who had used a hormonal IUD before surgery had more breast cancer during follow-up, especially those with BRCA1. This is an association, not proof that the IUD causes cancer, and it needs to be confirmed. No one should remove or change their IUD on their own: this is something to discuss with a doctor, also weighing the benefits of the method.
Why estrogen alone and progestogen may behave differently
Estrogen alone does not activate this pathway in the same way. Blocking RANKL reduced this proliferation in the laboratory and in mice; this has not yet been tested as prevention in women.
For health professionals
BRCA1 tumors are predominantly triple-negative. In normal breast tissue from BRCA1 carriers, RANK+ luminal progenitors are highly proliferative, and blocking RANKL with denosumab reduced progesterone-induced proliferation in laboratory models (Nolan et al., Nat Med 2016); in mice, inactivating the RANK/RANKL pathway delayed or prevented Brca1-driven tumors (Sigl et al., Cell Res 2016). In the general population, more than 20 years of follow-up of the WHI trials showed lower breast cancer incidence with estrogen alone (HR 0.78; 0.65–0.93) and higher incidence with estrogen plus medroxyprogesterone (HR 1.28; 1.13–1.45) (Chlebowski et al., JAMA 2020). These are data on biological plausibility and from women without BRCA; they do not replace clinical studies in carriers.
In plain language
One hypothesis scientists are studying: the progestogen (present in combined replacement and in the hormonal IUD) turns on a "switch" called RANKL in the breast, which makes some cells multiply more. In women with BRCA1, these cells appear to be more sensitive. Estrogen alone does not turn on this switch in the same way. So far, this has been seen in the laboratory and in animals.
What other studies had already shown
| Study | Who took part | Main result |
|---|---|---|
| Regev-Sadeh et al., 2026 | 919 BRCA1 or BRCA2 carriers after oophorectomy, Israel | HT with no increase in risk; estrogen alone HR 0.90 per year (0.87 in BRCA1); prior hormonal IUD HR 1.69 |
| Kotsopoulos et al., 2018 | 872 BRCA1 carriers after oophorectomy, international cohort | HT ever use HR 0.97; at 10 years, 12% breast cancer with estrogen alone and 22% with combined HT |
| Michaelson-Cohen et al., 2021 | 306 BRCA1 or BRCA2 carriers, Israel | No overall difference (OR 1.4); higher risk with HT in those who had surgery after age 45 (OR 3.43) |
| Marchetti et al., 2018 (meta-analysis) | 3 studies, 1,100 carriers | HT with no increase in risk (HR 0.98); trend favoring estrogen alone, not significant |
| WHI, Chlebowski et al., 2020 (clinical trial) | 27,347 postmenopausal women, no focus on BRCA | Estrogen alone HR 0.78; estrogen + progestogen HR 1.28 |
Table sources (Regev-Sadeh et al., JAMA Netw Open 2026; Kotsopoulos et al., JAMA Oncol 2018; Michaelson-Cohen et al., Eur J Cancer 2021; Marchetti et al., Crit Rev Oncol Hematol 2018; Chlebowski et al., JAMA 2020).
Limitations that weigh on interpretation
For health professionals
- Observational design: there is a risk of residual confounding even with multivariable adjustment.
- HT users were younger at surgery (43.5 vs 50.4 years) and had less family history of breast cancer (46% vs 54%), which may influence the results.
- Possible immortal time bias (mitigated by time-dependent modeling), recall bias, and selection bias from excluding missing data.
- No statistical power to compare routes, doses and formulations; 90% with Ashkenazi founder variants, which limits generalizability (Regev-Sadeh et al., JAMA Netw Open 2026).
In plain language
- The study observed rather than tested: those who used hormones may differ from those who did not in ways that were not measured.
- The users were younger and had fewer cases in the family.
- Almost all had a specific type of mutation, common in Israel; the results may not apply equally to all women with BRCA.
- It was not possible to compare pills, patches and gels, or different doses.
What this changes in practice
The study reinforces, with more data, what earlier reviews had already suggested: hormone therapy after oophorectomy does not appear to cancel out the risk-reducing benefit of surgery (Gordhandas et al., Gynecol Oncol 2019; Marchetti et al., Crit Rev Oncol Hematol 2018). The 2023 European guideline considers that it may be discussed to relieve symptoms, weighing its limits and risks (Sessa et al., Ann Oncol 2023). The authors also point out that, because estrogen alone is only suitable for those without a uterus, the question of whether or not to combine hysterectomy with oophorectomy becomes part of the pre-operative conversation (Regev-Sadeh et al., JAMA Netw Open 2026).
Questions that may help in the conversation with the care team:
- In my case, what are the benefits and risks of hormone therapy after surgery?
- Does it make sense to discuss removing the uterus at the same time, with hormone replacement in mind?
- For how long would it be considered, and how would breast follow-up be done?
- Is the contraceptive method I use today the most suitable for me?
In summary
- In 919 BRCA1 or BRCA2 carriers who had their ovaries removed, using hormone therapy was not associated with more breast cancer.
- Estrogen alone was associated with a slightly lower risk per year of use, especially in BRCA1; it is only used in those without a uterus.
- Combined HT for 5 years or more in those who had surgery before 45 showed a borderline signal that needs further study.
- The hormonal IUD used before surgery was associated with higher risk, mainly in BRCA1.
- It is an observational study: decisions remain individual and are made with the team that cares for each woman.
Frequently asked questions
Can a woman with BRCA use hormone replacement after having her ovaries removed?
The available studies, including the 2026 study with 919 carriers, did not show an increase in breast cancer with hormone therapy after surgery, and the European guideline considers that it may be discussed. The decision is individual and should be made with the team that cares for the patient.
Does hormone replacement increase breast cancer in people with BRCA1?
In the 2026 study, no. Estrogen alone was even associated with a slightly lower risk for each year of use in BRCA1. Combined therapy did not change the risk overall. These are observational data, which show association, not causation.
What about people with BRCA2?
In BRCA2, neither estrogen alone nor combined therapy significantly changed the risk of breast cancer in this study.
Why is estrogen alone not suitable for everyone?
In those who still have a uterus, estrogen alone increases the risk of endometrial cancer. That is why it is combined with a progestogen. Estrogen alone is only used by those who have already had the uterus removed.
Should people with BRCA have their hormonal IUD removed?
Not on their own. The study showed an association between prior use of the LNG-IUD and more breast cancer, especially in BRCA1, but it does not prove causation. The choice of method should be reviewed with a doctor, weighing benefits and risks.
At what age is removing the ovaries recommended for people with BRCA?
The European guideline (ESMO, 2023) recommends the surgery after childbearing is complete, at around 35 to 40 years in BRCA1 and 40 to 45 years in BRCA2. The exact timing is decided case by case.
References
- Regev-Sadeh S, Michaelson-Cohen R, Madorksy-Feldman D, et al. Hormone Therapy After Oophorectomy and Breast Cancer Risk in Women With BRCA Pathogenic Variant. JAMA Netw Open. 2026;9(4):e265648. doi:10.1001/jamanetworkopen.2026.5648
- Kotsopoulos J, Gronwald J, Karlan BY, et al. Hormone Replacement Therapy After Oophorectomy and Breast Cancer Risk Among BRCA1 Mutation Carriers. JAMA Oncol. 2018;4(8):1059-1065. doi:10.1001/jamaoncol.2018.0211
- Marchetti C, De Felice F, Boccia S, et al. 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. 2018;132:111-115. doi:10.1016/j.critrevonc.2018.09.018
- Michaelson-Cohen R, Gabizon-Peretz S, Armon S, et al. Breast cancer risk and hormone replacement therapy among BRCA carriers after risk-reducing salpingo-oophorectomy. Eur J Cancer. 2021;148:95-102. doi:10.1016/j.ejca.2021.02.007
- Gordhandas S, Norquist BM, Pennington KP, et al. Hormone replacement therapy after risk reducing salpingo-oophorectomy in patients with BRCA1 or BRCA2 mutations; a systematic review of risks and benefits. Gynecol Oncol. 2019;153(1):192-200. doi:10.1016/j.ygyno.2018.12.014
- Chlebowski RT, Anderson GL, Aragaki AK, et al. Association of Menopausal Hormone Therapy With Breast Cancer Incidence and Mortality During Long-term Follow-up of the Women’s Health Initiative Randomized Clinical Trials. JAMA. 2020;324(4):369-380. doi:10.1001/jama.2020.9482
- Kuchenbaecker KB, Hopper JL, Barnes DR, et al. Risks of Breast, Ovarian, and Contralateral Breast Cancer for BRCA1 and BRCA2 Mutation Carriers. JAMA. 2017;317(23):2402-2416. doi:10.1001/jama.2017.7112
- Finch AP, Lubinski J, Møller P, et al. Impact of Oophorectomy on Cancer Incidence and Mortality in Women With a BRCA1 or BRCA2 Mutation. J Clin Oncol. 2014;32(15):1547-1553. doi:10.1200/JCO.2013.53.2820
- Kotsopoulos J, Gronwald J, Huzarski T, et al. Bilateral Oophorectomy and All-Cause Mortality in Women With BRCA1 and BRCA2 Sequence Variations. JAMA Oncol. 2024;10(4):484-492. doi:10.1001/jamaoncol.2023.6937
- Rebbeck TR, Kauff ND, Domchek SM. Meta-analysis of Risk Reduction Estimates Associated With Risk-Reducing Salpingo-oophorectomy in BRCA1 or BRCA2 Mutation Carriers. J Natl Cancer Inst. 2009;101(2):80-87. doi:10.1093/jnci/djn442
- Sessa C, Balmaña J, Bober SL, et al. Risk reduction and screening of cancer in hereditary breast-ovarian cancer syndromes: ESMO Clinical Practice Guideline. Ann Oncol. 2023;34(1):33-47. doi:10.1016/j.annonc.2022.10.004
- Rocca WA, Grossardt BR, de Andrade M, et al. Survival patterns after oophorectomy in premenopausal women: a population-based cohort study. Lancet Oncol. 2006;7(10):821-828. doi:10.1016/S1470-2045(06)70869-5
- The 2022 Hormone Therapy Position Statement of The North American Menopause Society Advisory Panel. The 2022 hormone therapy position statement of The North American Menopause Society. Menopause. 2022;29(7):767-794. doi:10.1097/GME.0000000000002028
- Phillips KA, Kotsopoulos J, Domchek SM, et al. Hormonal Contraception and Breast Cancer Risk for Carriers of Germline Mutations in BRCA1 and BRCA2. J Clin Oncol. 2025;43(4):422-431. doi:10.1200/JCO.24.00176
- Yi H, Zhang N, Huang J, et al. Association of levonorgestrel-releasing intrauterine device with gynecologic and breast cancers: a national cohort study in Sweden. Am J Obstet Gynecol. 2024;231(4):450.e1-450.e12. doi:10.1016/j.ajog.2024.05.011
- Mørch LS, Meaidi A, Corn G, et al. Breast Cancer in Users of Levonorgestrel-Releasing Intrauterine Systems. JAMA. 2024;332(18):1578-1580. doi:10.1001/jama.2024.18575
- Nolan E, Vaillant F, Branstetter D, et al. RANK ligand as a potential target for breast cancer prevention in BRCA1-mutation carriers. Nat Med. 2016;22(8):933-939. doi:10.1038/nm.4118
- Sigl V, Owusu-Boaitey K, Joshi PA, et al. RANKL/RANK control Brca1 mutation-driven mammary tumors. Cell Res. 2016;26(7):761-774. doi:10.1038/cr.2016.69
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Physician (CRM-SC 32925 | CRM-BA 39586, Brazil). Sees patients by video consultation in Brazil and abroad. This content is educational, reviewed against the cited references, and does not replace a consultation.
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How video consultations workReviewed on October 31, 2026 by Dr. Diegomaier Nunes Neri — CRM-SC 32925 | CRM-BA 39586 (Brazil).