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

From the Guidelines

Vaginal estrogen should not be used alone in patients who still have a uterus. This recommendation is based on the strongest and most recent evidence available, which emphasizes the importance of avoiding unopposed estrogen treatment in women with a uterus in situ to prevent endometrial hyperplasia and cancer 1. The evidence from the esmo-esgo-estro consensus conference on endometrial cancer, published in the Annals of Oncology in 2016, clearly states that unopposed oestrogen treatment should not be started or should be discontinued in women with a uterus in situ, with a consensus of 100% and a strength of recommendation of A 1. Key points to consider include:

• The risk of endometrial hyperplasia and cancer associated with unopposed estrogen use
• The importance of balancing the benefits of vaginal estrogen therapy for genitourinary symptoms of menopause with the potential risks to the endometrium
• The need for alternative approaches, such as combined estrogen and progestogen therapy, to mitigate these risks
• The importance of patient education on proper application techniques, frequency, and potential side effects, as well as the need for prompt evaluation in case of unexpected vaginal bleeding. In clinical practice, it is crucial to prioritize the safety and well-being of patients, and therefore, vaginal estrogen should not be used alone in patients with an intact uterus 1.

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 use of unopposed estrogens in women with intact uteri has been associated with an increased risk of endometrial cancer

The use of vaginal estrogen alone in patients who still have a uterus is associated with an increased risk of endometrial cancer.

• The risk of endometrial cancer is 2- to 12-fold greater than in non-users, and appears dependent on duration of treatment and on estrogen dose.
• Adding a progestin to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer 2, 2.

From the Research

Vaginal Estrogen Use Alone in Patients with a Uterus

• Vaginal estrogen use alone in patients who still have a uterus is associated with an increased risk of endometrial hyperplasia and potentially endometrial cancer 3, 4, 5, 6.
• Unopposed estrogen, either endogenous or therapeutic, can induce endometrial hyperplasia and potentially endometrial cancer 3.
• The addition of a progestogen to estrogen therapy has been shown to decrease or eliminate the endometrial risk associated with estrogen replacement therapy (ERT) 5, 6.
• Continuous combined therapy with estrogen and progestogen has been shown to be effective in reducing the risk of endometrial hyperplasia and cancer 4, 6.
• The type and dose of progestogen used can affect the risk of endometrial hyperplasia and cancer, with some progestogens being more effective than others in providing endometrial protection 7.

Risks Associated with Unopposed Estrogen

• Unopposed estrogen is associated with an increased risk of endometrial hyperplasia at all doses and durations of therapy between one and three years 6.
• The risk of endometrial hyperplasia with unopposed estrogen is higher than with combined estrogen and progestogen therapy 4, 6.
• Anovulatory cycles, obesity, and insulin resistance are major risk factors for endometrial cancer, and unopposed estrogen can increase this risk 3.

Importance of Progestogen in Combined Menopausal Hormone Therapy

• Progestogen is necessary for endometrial protection in combined menopausal hormone therapy (MHT) for women with an intact uterus 7.
• The choice of progestogen and its dose and regimen can affect the risk of endometrial hyperplasia and cancer 7.
• Most progestogens are available as oral formulations, but some are also available as transdermal formulations 7.