Does oral estradiol (estrogen) therapy increase the risk of cancer in women?

From the Guidelines

Taking oral estradiol can increase a woman's risk of certain cancers, but the relationship is complex. Estradiol can increase the risk of endometrial (uterine) cancer when taken alone, which is why it's typically combined with progesterone for women who still have a uterus. This combination helps protect the uterine lining. Breast cancer risk may also increase slightly with estradiol use, particularly with longer-term treatment (over 5 years) 1. The risk appears higher when estradiol is combined with certain progestins. However, the absolute increase in cancer risk is generally small, especially for women under 60 who start hormone therapy near menopause. The risk varies based on factors like age, personal and family medical history, duration of use, and whether estradiol is used alone or with progesterone.

Some key points to consider:

• The U.S. Food and Drug Administration (FDA)–approved indications for hormone therapy in postmenopausal women are limited to the treatment of menopausal symptoms and the prevention of osteoporosis 1.
• A black box warning indicates that estrogen with or without progestin should be prescribed at the lowest effective dose and for the shortest duration of use consistent with treatment goals and risks for the individual woman 1.
• The cancer risk must be weighed against potential benefits of estradiol, which include relief from menopausal symptoms like hot flashes and prevention of bone loss 1.
• Women considering estradiol should discuss their individual risk factors with their healthcare provider to make an informed decision 1.

The most recent and highest quality study on this topic is from the U.S. Preventive Services Task Force (USPSTF) recommendation statement, which concludes that the chronic disease prevention benefits of combined estrogen and progestin do not outweigh the harms in most postmenopausal women, and that the benefits of estrogen-only therapy are unlikely to outweigh the harms in most postmenopausal women who have had a hysterectomy 1.

From the FDA Drug Label

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. Long-term continuous administration of estrogen, with and without progestin, in women with and without a uterus, has shown an increased risk of endometrial cancer, breast cancer, and ovarian cancer.

• Cancer Risk: Taking oral estradiol may increase a woman's risk of cancer, including endometrial cancer, breast cancer, and ovarian cancer.
• Key Considerations: The risk of cancer is a significant concern when taking oral estradiol, and women should be closely monitored by their healthcare provider while taking this medication 2, 2, 2.

From the Research

Cancer Risk Associated with Oral Estradiol

• The risk of cancer associated with oral estradiol use is a complex issue, with various studies providing insights into the benefits and risks of hormone replacement therapy (HRT) 3, 4, 5.
• Unopposed long-term estrogen therapy, such as oral estradiol, increases the risk of developing endometrial hyperplasia, endometrial cancer, and possibly breast cancer 3.
• The addition of a progestin to estrogen therapy can reduce the risk of endometrial cancer, but its effect on breast cancer risk is still controversial 3, 4.
• Some studies suggest that the risk of breast cancer may not increase with short-term use of estrogen alone, but may increase with long-term use of combined estrogen and progestin therapy 4, 5.

Specific Cancers and Oral Estradiol Use

• Endometrial Cancer: Unopposed estrogen therapy increases the risk of endometrial cancer, but this risk can be reduced by adding a progestin to the regimen 3, 6.
• Breast Cancer: The risk of breast cancer associated with oral estradiol use is still unclear, with some studies suggesting an increased risk with long-term use of combined estrogen and progestin therapy 4, 5.
• Other Cancers: There is limited evidence on the association between oral estradiol use and other types of cancer, such as ovarian or cervical cancer.

Factors Influencing Cancer Risk

• Duration of Use: The risk of cancer associated with oral estradiol use may increase with longer duration of use 3, 4.
• Type of Estrogen: The type of estrogen used, such as estradiol or conjugated equine estrogens, may influence the risk of cancer 7.
• Addition of Progestin: The addition of a progestin to estrogen therapy can reduce the risk of endometrial cancer, but its effect on breast cancer risk is still unclear 3, 4.