What are the risks of unopposed estrogen therapy (hormone replacement therapy, HRT)?

From the Guidelines

Unopposed estrogen therapy poses significant health risks, including endometrial cancer, blood clots, stroke, and gallbladder disease, and should be avoided in women with an intact uterus. The primary concern with unopposed estrogen is the increased risk of endometrial hyperplasia and endometrial cancer, as estrogen stimulates the growth of the uterine lining without the balancing effect of progesterone 1. This can lead to abnormal thickening of the endometrium and potentially cancerous changes over time. Women taking unopposed estrogen have a higher risk of developing endometrial cancer compared to those not using hormone therapy. Other risks include increased chances of blood clots, stroke, and gallbladder disease.

Risks Associated with Unopposed Estrogen

• Endometrial cancer: The risk of endometrial cancer is increased in women taking unopposed estrogen, particularly in those with an intact uterus 1.
• Blood clots: Unopposed estrogen increases the risk of blood clots, including deep vein thrombosis and pulmonary embolism 1.
• Stroke: The risk of stroke is also increased in women taking unopposed estrogen 1.
• Gallbladder disease: Unopposed estrogen may increase the risk of gallbladder disease, including cholecystitis 1.

Recommendations

For women who have not had a hysterectomy, it is recommended to take a progestogen (either progesterone or progestin) along with estrogen therapy to protect the uterine lining 1. The progestogen causes regular shedding of the endometrium, preventing excessive buildup. Women who have had a hysterectomy can safely take estrogen alone since they no longer have a uterus at risk. The typical regimen for women with an intact uterus includes daily estrogen (such as 0.5-1mg estradiol) plus either cyclic progesterone (such as 200mg micronized progesterone for 12-14 days each month) or continuous daily progesterone to prevent these risks.

Clinical Considerations

Clinicians should develop a shared decision-making approach to preventing chronic diseases in perimenopausal and postmenopausal women, considering individual risk factors and preferences in selecting effective interventions for reducing the risk of chronic diseases 1.

From the FDA Drug Label

An increased risk of endometrial cancer has been reported with the use of unopposed estrogen therapy in a woman with a uterus. The reported endometrial cancer risk among unopposed estrogen users is about 2 to 12 times 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 the use of estrogens for less than 1 year. The greatest risk appears associated with prolonged use, with increased risks of 15- to 24-fold for 5 to 10 years or more, and this risk has been shown to persist for at least 8 to 15 years after estrogen therapy is discontinued

The risks of unopposed estrogen include:

• Endometrial cancer: 2 to 12 times greater risk than non-users, dependent on duration and dose of treatment
• Venous thromboembolism (VTE): increased risk, particularly in the first 2 years of treatment 2 The use of unopposed estrogen therapy is associated with an increased risk of endometrial cancer and VTE. It is essential to weigh these risks against the potential benefits of therapy and to consider alternative treatments, such as adding a progestin to reduce the risk of endometrial hyperplasia. Clinical surveillance and adequate diagnostic measures are crucial for women using estrogen-alone or estrogen plus progestin therapy 2.

From the Research

Risks of Unopposed Estrogen

The use of unopposed estrogen has been associated with several risks, including:

• Increased risk of endometrial cancer, with a relative risk ranging from 1.8 to 36 for estrogen use of 5 years or longer 3
• Risk of endometrial hyperplasia and potentially endometrial cancer, especially in women with anovulatory cycles, obesity, and insulin resistance 4
• Increased risk of endometrial cancer with long-term use of unopposed estrogens, with a relative risk of 22.0 for women who used conjugated estrogens alone for 5 or more years 5

Factors Influencing Risk

Several factors can influence the risk of endometrial cancer associated with unopposed estrogen use, including:

• Duration of use: longer duration of use is associated with a higher risk of endometrial cancer 3, 5
• Dose: all dose levels of conjugated estrogens have been shown to increase the risk of endometrial cancer substantially 3
• Type of estrogen preparation: no differences have been found between oral synthetic estrogens and conjugated estrogens with respect to cancer risk 3
• Recency of use: risk consistently decreases with increasing time since cessation of use, although some residual excess risk may remain long after estrogens have been discontinued 3

Reducing Risk

The risk of endometrial cancer associated with unopposed estrogen use can be reduced by:

• Adding progestins to the therapy, which can protect the endometrium against the proliferative effects of estrogens 4, 6
• Using progestins continuously, which has been shown to reduce the risk of endometrial cancer relative to non-users 6
• Minimizing the duration of use, as shorter durations of use have been associated with a lower risk of endometrial cancer 3, 7