What is the risk of endometrial hyperplasia and cancer with the use of vaginal estrogens, such as estradiol (estrogen)?

Risk of Endometrial Hyperplasia and Cancer with Vaginal Estrogens

Vaginal estrogens do not substantially increase the risk of endometrial hyperplasia or cancer when used at low doses for genitourinary syndrome of menopause. 1

Safety Profile of Vaginal Estrogens

• Unlike systemic unopposed estrogen therapy (which increases endometrial cancer risk 2-12 times), low-dose vaginal estrogens have not been shown to significantly increase endometrial hyperplasia or cancer risk 2
• Data from clinical trials show no increased risk of endometrial hyperplasia and carcinoma in postmenopausal women using ultra-low-dose (10-microgram) estradiol vaginal tablets for 1 year 3
• The incidence rate of endometrial hyperplasia and carcinoma with vaginal estradiol was 0.52% per year in clinical trials, which falls within the background rate of 0-1% in postmenopausal women 3
• Vaginal estrogen preparations do not cause significant increases in serum estrogen levels, which is why they don't stimulate endometrial growth like systemic therapy 2

Comparison with Systemic Estrogen Therapy

• Unopposed systemic estrogen therapy increases endometrial cancer risk 10-30 fold if treatment continues for 5 years or more 4, 5
• Risk of endometrial cancer with systemic therapy increases dramatically with duration of use, reaching a relative risk of 9.5 for 10 years of use 5
• The elevated risk from systemic therapy remains for at least 5-8 years after discontinuation 5, 2
• In contrast, topical vaginal estrogen does not show an associated increase in serum estrogen levels 4

Clinical Evidence for Vaginal Estrogen Safety

• The 2018 Journal of Urology guidelines explicitly state: "Data do not show an increased risk of recurrence of breast cancer, endometrial hyperplasia or carcinoma in women who use vaginal estrogen for urogenital symptoms" 4
• This safety profile is attributed to minimal systemic absorption, as "there is no associated increase in serum estrogen" with vaginal preparations 4
• Clinical trials of ultra-low-dose estradiol vaginal tablets (10 micrograms) showed that 85.6% of women had atrophic endometrium after 52 weeks of treatment, confirming lack of endometrial stimulation 3

Practical Considerations

• Despite the favorable safety profile, clinical surveillance is still recommended for women using any form of estrogen therapy 2
• Abnormal vaginal bleeding should always prompt evaluation to rule out endometrial pathology, regardless of the type of estrogen therapy 2
• For women with an intact uterus using systemic estrogen therapy, progestogen must be added to protect against endometrial hyperplasia and cancer, but this is generally not necessary with low-dose vaginal estrogen preparations 5, 6
• Periodic examination with transvaginal ultrasound or endometrial biopsy for asymptomatic women using vaginal estrogens is not considered cost-effective 7

Special Considerations

• Women with a history of breast cancer who are experiencing severe genitourinary symptoms may use vaginal estrogen with caution, as data do not show an increased risk of breast cancer recurrence 4
• The risk-benefit profile of vaginal estrogens is particularly favorable compared to systemic therapy, especially for women concerned about endometrial safety 1
• Long-term studies (beyond 1 year) on endometrial safety of vaginal estrogens are limited, but available evidence suggests continued safety with prolonged use 1, 7