What are the risks of using topical estrogen alone in patients with an intact uterus?

From the Guidelines

Topical estrogen alone should not be used in patients with an intact uterus due to the increased risk of endometrial cancer, as recommended by the ESMO-ESGO-ESTRO consensus conference in 2016 1. When considering the use of topical estrogen in patients with a uterus, it is essential to prioritize the risk of endometrial cancer. According to the US Preventive Services Task Force, unopposed estrogen therapy increases the risk of endometrial cancer, with a relative risk of 2.3 (95% CI, 2.1 to 2.5) compared to nonusers 1. Some key points to consider:

• The risk of endometrial cancer increases with the duration of unopposed estrogen use, with a relative risk of 9.5 for 10 years of use 1.
• The ESMO-ESGO-ESTRO consensus conference recommends that unopposed estrogen treatment should not be started or should be discontinued in women with a uterus in situ, with a level of evidence III and a strength of recommendation A 1.
• The consensus among voters was 100% in favor of this recommendation, highlighting the importance of avoiding unopposed estrogen therapy in patients with an intact uterus 1. It is crucial to weigh the benefits of topical estrogen therapy against the potential risks, particularly in patients with a uterus. While low-dose vaginal estrogen products may have minimal systemic absorption, the risk of endometrial cancer cannot be ignored. Some essential considerations:
• Any unusual vaginal bleeding should prompt immediate medical evaluation, as this could indicate endometrial stimulation requiring further assessment.
• Clinical evidence and practice guidelines support the safety of low-dose vaginal estrogen products when used as directed, but the risk of endometrial cancer remains a concern.
• The package inserts for these medications contain warnings about endometrial cancer risk, emphasizing the need for caution when prescribing topical estrogen therapy to patients with an intact uterus.

From the FDA Drug Label

The use of unopposed estrogens in women who have a uterus is 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. Most studies show no significant increased risk associated with use of estrogens for less than one year The greatest risk appears associated with prolonged use, with increased risks of 15- to 24-fold for five to ten years or more and this risk has been shown to persist for at least 8 to 15 years after estrogen therapy is discontinued.

The use of topical estrogen alone in patients who still have a uterus increases the risk of endometrial cancer. This risk is dependent on the duration of treatment and the dose of estrogen. Prolonged use of unopposed estrogens is associated with a higher risk of endometrial cancer, with increased risks of 15- to 24-fold for five to ten years or more.

• Key points:
  • Increased risk of endometrial cancer with unopposed estrogen use
  • Risk dependent on duration and dose of estrogen
  • Prolonged use associated with higher risk
  • Risk persists for at least 8 to 15 years after discontinuation of estrogen therapy 2, 3, 3

From the Research

Topical Estrogen Use Alone in Patients with a Uterus

• The use of unopposed estrogen, either endogenous or therapeutic, can induce endometrial hyperplasia and potentially endometrial cancer (EC) 4.
• Studies have shown that progestogen, including levonorgestrel intrauterine device, can prevent or treat hyperplasia, atypical hyperplasia, and even well-differentiated EC 4.
• The use of unopposed estrogen in women with intact uteri is still prevalent, despite the known increased incidence of endometrial hyperplasia, and can have economic consequences 5.
• Progestin therapy is the recommended fertility-sparing management of atypical endometrial hyperplasia or early-stage endometrial cancer in reproductive-aged women 6.
• Hormone therapy, including progestins, has been used as a fertility-preserving treatment for well-selected stage I, grade 1 endometrial cancer in young women, with high remission rates 7.
• The risk of endometrial hyperplasia and cancer can be decreased with the use of oral contraceptive pills or progesterone-containing intrauterine devices 8.
• The definitive and curative treatment for endometrial intraepithelial neoplasia (EIN) remains hysterectomy, but nonsurgical treatment modalities may be considered in certain cases, such as fertility-sparing treatments or medical comorbidities 8.

Risks and Considerations

• Unopposed estrogen use can lead to endometrial hyperplasia and cancer, especially in women with risk factors such as obesity, chronic anovulation, and polycystic ovarian syndrome 4, 8.
• The use of progestin and metformin therapy may be associated with lower relapse rates and similar remission, clinical pregnancy, and live birth rates compared to progestin therapy alone 6.
• The role of hormones, such as gonadotropin-releasing hormone analogs, selective estrogen receptor modulators, and aromatase inhibitors, in the treatment of endometrial hyperplasia and cancer is still being explored 7.