Does exogenous estradiol (estrogen) cause cancer?

From the Guidelines

Exogenous estradiol can potentially increase the risk of certain cancers, particularly hormone-sensitive cancers such as breast cancer and endometrial cancer. The relationship between exogenous estradiol and cancer risk is complex and depends on multiple factors, including dose, duration of use, route of administration, age at initiation, and individual risk factors 1.

Key Factors Influencing Cancer Risk

• Dose and duration of exogenous estradiol use
• Route of administration (oral vs. transdermal)
• Age at initiation of hormone therapy
• Individual risk factors, such as family history of cancer
• Presence of an intact uterus, which increases the risk of endometrial cancer when using estrogen-only therapy

According to a recent study published in 2025, there is limited prospective clinical data to inform the risk of hormone therapy on the progression of hormone-sensitive cancers 1.

Current Evidence and Recommendations

• The study suggests that exogenous estradiol can promote estrogen-dependent breast cancer recurrence, but the evidence is not conclusive 1.
• Another study published in 2010 found that hormone replacement therapy containing estradiol was associated with a small increased risk of breast cancer, particularly when combined with progestin and used for extended periods 1.
• The Women's Health Initiative study found that estrogen-only therapy actually decreased breast cancer risk in women who had undergone hysterectomy, while combined estrogen-progestin therapy increased risk 1.

In clinical practice, individualized risk assessment and regular monitoring are essential for women considering hormone therapy, and the decision to use exogenous estradiol should be made on a case-by-case basis, taking into account the patient's unique goals, risk factors, and medical history.

Considerations for Clinical Practice

• Patients should be informed of the potential risks and benefits of exogenous estradiol use
• Regular monitoring for cancer risk and other potential side effects is crucial
• Alternative therapies or dose adjustments may be considered to minimize cancer risk while still addressing the patient's medical needs.

From the FDA Drug Label

The use of unopposed estrogens in women with intact uteri has been associated with an increased risk of endometrial cancer The reported endometrial cancer risk among unopposed estrogen users is about 2- to 12- fold greater than in non-users, and appears dependent on duration of treatment and on estrogen dose. Estrogens increase the chances of getting cancer of the uterus. Estrogens may increase the risk of certain types of cancer, including cancer of the breast or uterus. The most important randomized clinical trial providing information about breast cancer in estrogen plus progestin users is the WHI substudy of daily CE (0.625 mg) plus MPA (2.5 mg). After a mean follow-up of 5. 6 years, the estrogen plus progestin substudy reported an increased risk of invasive breast cancer in women who took daily CE plus MPA. The WHI estrogen plus progestin substudy reported a statistically non-significant increased risk of ovarian cancer.

Exogenous estradiol (estrogen) may increase the risk of certain types of cancer, including:

• Endometrial cancer: The risk is increased in women with intact uteri, and is dependent on duration of treatment and estrogen dose.
• Breast cancer: The risk is increased in women taking estrogen plus progestin, and may also be increased in women taking estrogen alone.
• Ovarian cancer: The risk is not statistically significant, but may still be increased.

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From the Research

Exogenous Estradiol and Cancer Risk

• The relationship between exogenous estradiol (estrogen) and cancer risk is complex, with evidence suggesting that high levels of estrogen are associated with an increased risk of certain types of cancer, including breast and endometrial cancer 3, 4, 5.
• A study published in the Journal of the Endocrine Society found that higher estradiol levels significantly increase the risk of ovarian cancer and ER-positive breast cancer 3.
• Another study published in Best practice & research. Clinical endocrinology & metabolism found that exposure to higher levels of both exogenous and endogenous hormone is associated with breast cancer risk 4.
• However, a review published in Climacteric : the journal of the International Menopause Society suggested that estrogens require additional factors such as stromal factors or progestogens to increase the ratio of proliferation/apoptosis for initiation of replication errors and consequent mutations to occur, and that certain estrogen metabolites can even have carcinoprotective effects 6.

Specific Cancers and Exogenous Estradiol

• Breast Cancer: High levels of estrogen have been associated with an increased risk of breast cancer, particularly ER-positive breast cancer 3, 4.
• Endometrial Cancer: Exogenous estrogen has been linked to an increased risk of endometrial cancer, although the relationship is complex and may depend on the presence of progestogens 5, 7.
• Ovarian Cancer: Higher estradiol levels have been found to significantly increase the risk of ovarian cancer 3.
• Other Cancers: The relationship between exogenous estradiol and other types of cancer, such as liver cancer, is less clear and requires further research 5.