Estrogen Therapy in Menopause: Does It Increase or Decrease Breast Cancer Risk?
💡 Menopause is not just a natural process, but a transformation accompanied by serious medical implications.
While menopause is a natural phase in women's lives, it can significantly reduce quality of life with many problems it brings, such as hot flashes, night sweats, osteoporosis, sarcopenia, cardiometabolic problems, and neuropsychiatric effects.
Although these women are often defined as "healthy individuals," they are in fact "real patients" experiencing significant clinical issues.
👩⚕️ For women who have had a hysterectomy or are planning to, estrogen-alone therapy should be carefully evaluated for both symptom control and long-term health benefits.
However, should this treatment be a routine approach for every postmenopausal woman? This question is a topic that needs to be carefully discussed with scientific evidence. In this article, we will focus on a recent meta-analysis study published on April 23, 2024, in the journal Breast Cancer Research and Treatment, to examine the effects of estrogen therapy on breast cancer risk.
🔍 A Light Amidst Conflicting Findings: Does Estrogen Alone Reduce Breast Cancer Risk?
A long-debated topic: Does estrogen-alone therapy (without progestin) increase or decrease breast cancer risk?
While observational studies mostly present findings indicating an increase, the most impactful randomized controlled trial, the Women’s Health Initiative (WHI), showed the opposite, namely a significant reduction in risk.
📊 A New Meta-Analysis: Over 14,000 Women, Strong Data
✔️ This meta-analysis, published in 2024, was conducted to clarify previous conflicting results.
- Total of 10 randomized controlled studies
- Total of 14,282 postmenopausal women
- 591 new breast cancer cases were evaluated
- The largest data was provided by the WHI study
The study was conducted by Rowan Chlebowski and his team. The aim was to show the true effect of estrogen-alone use on breast cancer incidence (annual new case frequency). We will delve into the details in the following sections.
📘 Summary of the Meta-Analysis
This meta-analysis, published in 2024 and including 10 randomized controlled studies such as WHI (Women’s Health Initiative), examined the effect of estrogen-alone hormone therapy on breast cancer risk.
- Total Participants: 14,282 women
- Total Breast Cancer Cases: 591
- Median Follow-up Period: 7.2 – 16.2 years
- Covered Treatment Formulations: Conjugated equine estrogen (CEE), estradiol, estrone sulfate
📊 Key Findings – What Do They Mean?
In this study, women receiving estrogen therapy were compared to women receiving placebo (i.e., fake treatment containing no real drug). The goal was to determine which group had a lower risk of developing breast cancer.
- 🔹 In the total of 9 smaller studies:
Breast cancer was observed in only 1.2% of women taking estrogen, while this rate was 2.2% in women taking placebo.
👉 This suggests that estrogen could reduce the risk by approximately 35% (however, this difference is not statistically definitive). - 🔹 In 5 estradiol (a type of estrogen) studies:
Only the risk ratio was given: The risk of developing breast cancer was found to be 37% lower.
👉 However, this result is also borderline; more data may be needed to make a definitive decision. - 🔹 Combined result of all studies:
Breast cancer occurred in 3.6% of women receiving estrogen therapy, while it occurred in 4.7% of the placebo group.
👉 In other words, overall, estrogen therapy reduced breast cancer risk by 23%.
📌 This difference was found to be statistically significant (P = 0.002), meaning the probability of it occurring by chance is very low.
🤔 So, Why Is It So Controversial?
Because some large observational cohort studies (e.g., Million Women Study) report completely opposite results: an increase of 22% in breast cancer risk with long-term estrogen use was observed.
However, this new meta-analysis only uses randomized controlled trials, and such studies are considered stronger evidence than observational studies.
Why might this difference arise?
- In randomized studies, estrogen therapy is mostly given to women who have had their uterus removed; the risk may be low because progestin is not added.
- In the WHI study, all participants were regularly followed up with mammography, reducing the risk of delayed diagnosis.
- The type of estrogen is important: CEE (conjugated equine estrogen) can initiate apoptosis (programmed cell death) in some tumors, which may be a different biological effect than estradiol.
⚰️ What Is the Effect on Breast Cancer Mortality?
The WHI study evaluated not only the incidence of breast cancer development but also mortality rates (loss of life):
- In 11.8 years of follow-up: The breast cancer-related mortality rate decreased by 40% in the CEE group (HR: 0.60, CI: 0.37–0.97, P = 0.04)
- A 56% reduction was observed in ER(+), PR(–) tumors with poor prognosis
📌 So, estrogen was found to be associated not only with fewer, but also with less aggressive breast cancers.
🧭 To Whom Should It Be Recommended, To Whom Should It Not Be Recommended?
✅ Suitable Patient Profile:
- Hysterectomized
- Those with severe vasomotor symptoms
- Those with additional risks such as osteoporosis, sarcopenia
- Those in the young postmenopausal period (50–59 years old)
⚠️ Groups Requiring Caution:
- Those with an intact uterus requiring progestin support
- Those at high risk for breast cancer
- Those who cannot undergo regular screening follow-up
📉 Why Are Different Results Obtained from Observational Studies?
While observational cohort studies show that estrogen-alone use increases breast cancer incidence and mortality, randomized studies like WHI have reported a significant reduction in both rates.
These differences can be explained by the high level of evidence provided by randomized studies and the influence of confounding factors (e.g., healthy user effect) in observational studies.
⏳ Treatment Duration and Age of Initiation: Is It Valid for Every Age Group?
Although there are differences in estrogen formulation, treatment duration, and participant age among studies, there is significant consistency in the designs of all studies, including WHI.
- In the 50–59 age group, breast cancer mortality significantly decreased with CEE-alone therapy
- Additionally, rates of coronary heart disease, other cancers, and all-cause mortality also statistically significantly decreased
💊 Comparison with Tamoxifen: What's the Difference with Estrogen?
In the meta-analysis, the role of estrogen in preventing breast cancer was also compared with tamoxifen:
- Tamoxifen: Provides a 42% reduction in ER(+) cancers, but does not affect ER(-) cancers and does not reduce mortality
- Estrogen: Is effective in broader tumor subgroups, and also has the potential to reduce breast cancer mortality
🧪 Conclusion: Science is Changing, Should Attitudes Change Too?
✅ For Whom Can Estrogen-Alone Therapy Be a Safe Option?
This comprehensive meta-analysis presents strong randomized clinical evidence that estrogen-alone therapy can reduce the incidence of breast cancer, especially for postmenopausal women who have had their uterus removed.
For these women whose quality of life is severely affected by menopausal symptoms, estrogen therapy is valuable not only for symptom control but also for its potential to reduce breast cancer risk.
⚠️ However: These results should not imply a routine hormone therapy recommendation for all postmenopausal women. The decision should be made based on individual risk factors, symptom severity, and overall health status, with a joint evaluation by gynecological and oncology specialists.
Overall, I find this study valuable. However, I approach its routine application for all postmenopausal women with reservation.
Chlebowski RT, Aragaki AK, Pan K, Mortimer JE, Johnson KC, Wactawski-Wende J, LeBoff MS, Lavasani S, Lane D, Nelson RA, Manson JE. Randomized trials of estrogen-alone and breast cancer incidence: a meta-analysis. Breast Cancer Res Treat. 2024 Jul;206(1):177-184. doi: 10.1007/s10549-024-07307-9. Epub 2024 Apr 23. PMID: 38653905.
