Are the health effects from estrogen therapy permanent?

Are Health Effects from Estrogen Therapy Permanent?

Most health effects from estrogen therapy are reversible and return to baseline after discontinuation, though the timeline varies by effect—bone protection is lost within years of stopping, cardiovascular benefits diminish rapidly, while some cancer risks decline quickly but endometrial cancer risk remains elevated long-term.

Reversible Effects That Diminish After Stopping

Bone Protection

• The protective effect against osteoporotic fractures is lost after discontinuation of hormone therapy 1, 2
• Bone loss resumes at postmenopausal rates once estrogen is stopped, with the greatest benefit seen in long-term current users 2
• This means the fracture risk reduction (approximately 30-50% during treatment) is not permanent and requires ongoing therapy to maintain 3

Cardiovascular Effects

• Cardiovascular disease risk reduction (20-40% during treatment) is greatest in long-term and current users, suggesting benefit diminishes after stopping 2
• The protective effects on lipid profiles and vascular function are not permanent and reverse when therapy is discontinued 4

Menopausal Symptoms

• Vasomotor symptoms (hot flashes) and genitourinary symptoms return if estrogen is stopped before natural resolution would have occurred 1, 3
• These effects are completely reversible and symptom-dependent 3

Effects That Persist or Change Slowly After Stopping

Breast Cancer Risk

• The increased breast cancer risk associated with combined estrogen-progestin therapy (26% increase, HR 1.26) declined rapidly after cessation of HRT in the WHI trial 1, 5
• However, the risk does not immediately return to baseline—there is a lag period during which some elevated risk persists 5
• For estrogen-only therapy, no significant increase in breast cancer risk was observed, and some studies suggest a protective effect that would theoretically reverse after stopping 1, 5

Endometrial Cancer Risk

• Unopposed estrogen increases endometrial cancer risk, and this risk remains elevated even after discontinuation 2
• This is one of the few truly persistent effects, with risk increasing with duration of use and not immediately reversing when therapy stops 2
• The addition of progestin prevents this increased risk during treatment 1, 3

Cognitive Effects

• The Women's Health Initiative Memory Study (WHIMS) found increased dementia risk during treatment, but whether this risk persists or reverses after stopping is not well-established 1

Physical Changes in Gender-Affirming Hormone Therapy Context

Irreversible Changes with Testosterone

• Voice deepening and increased body/facial hair are permanent changes that persist even after testosterone cessation 1

Reversible Changes with Estrogen

• Breast development, fat redistribution, and decreased muscle mass from feminizing hormone therapy are largely reversible if therapy is stopped 1

Critical Clinical Implications

Duration-Dependent Effects

• Post hoc analyses suggest increased probability of harm with longer duration of use and increasing age at initiation 1
• The FDA black box warning emphasizes using the lowest effective dose for the shortest duration consistent with treatment goals 1

Time-Sensitive Window for Benefits

• The most favorable risk-benefit profile exists for women under 60 or within 10 years of menopause onset 3
• Starting therapy many years after menopause (>10 years) is associated with less favorable outcomes and potentially increased harm 1, 3

Common Pitfalls to Avoid

• Do not assume bone protection continues after stopping HRT—women need alternative osteoporosis prevention strategies if they discontinue therapy 1, 2
• Do not reassure patients that all risks immediately disappear upon stopping—endometrial cancer risk remains elevated, and breast cancer risk declines gradually 5, 2
• Do not delay addressing the reversibility question until discontinuation—counsel patients upfront that most benefits require ongoing therapy 3

Monitoring After Discontinuation

• Women who stop HRT after long-term use should have bone density monitoring, as fracture risk returns to that of never-users 1, 2
• Cardiovascular risk assessment should be updated, as the protective effect is not permanent 2, 4
• Breast cancer surveillance should continue per standard guidelines, recognizing that any elevated risk from prior HRT use diminishes over time 5, 3