Should a woman of reproductive age who is taking oral estradiol for hormone replacement stop the estradiol before beginning gonadotropin‑based controlled ovarian hyperstimulation for IVF, and how many days in advance?

Oral Estradiol and Ovarian Stimulation for IVF

Women taking oral estradiol for hormone replacement should discontinue it at least 2 weeks before starting gonadotropin-based controlled ovarian hyperstimulation for IVF, though some may require up to 4 months for complete normalization of pituitary-ovarian function. 1

Rationale for Discontinuation

Interference with Ovarian Response

• Exogenous estradiol suppresses the hypothalamic-pituitary-ovarian axis through negative feedback, which directly counteracts the goal of ovarian stimulation protocols that rely on releasing the hypothalamus and pituitary from estrogen negative feedback 2
• Oral estradiol maintains artificially elevated estrogen levels that can mask the natural hormonal fluctuations needed for optimal follicular recruitment and development during controlled ovarian hyperstimulation 1

Impact on Follicular Development

• Studies demonstrate that exogenous estrogen exposure alters follicular steroidogenesis and maturational processes, potentially affecting oocyte quality and quantity 3
• The presence of exogenous estradiol may interfere with accurate assessment of ovarian reserve and response to gonadotropin stimulation 1

Recommended Washout Period

Minimum Duration

• At least 2 weeks of discontinuation is required for basic normalization of pituitary-ovarian function 1
• This allows clearance of exogenous estradiol and restoration of endogenous hormonal feedback mechanisms 1

Extended Washout for Comprehensive Assessment

• For women with prolonged oral estradiol exposure, up to 4 months may be necessary for complete normalization of androgen/SHBG profiles and comprehensive hormonal assessment 1
• Longer exposure to hormonal contraceptives or hormone replacement may require extended washout periods 1

Clinical Considerations

• Use barrier contraception during the washout period if pregnancy prevention is needed, as women remain at risk of pregnancy even with irregular cycles 1
• The duration of prior estradiol use should be documented, as this influences the optimal washout period 1

Alternative Approaches During Stimulation

Aromatase Inhibitors as Adjuncts

• If estrogen modulation is needed during stimulation (such as in hormone-sensitive conditions), letrozole can be used alongside gonadotropins without reducing mature oocyte yield or fertilization capacity 4
• Letrozole antagonizes high estrogen levels during stimulation without the suppressive effects of exogenous estradiol 4
• Tamoxifen represents another option for estrogen antagonism during stimulation, though data are less robust than for letrozole 4

Common Pitfalls to Avoid

• Do not continue oral estradiol during ovarian stimulation, as this fundamentally contradicts the mechanism of controlled ovarian hyperstimulation 2
• Do not assume a brief washout (less than 2 weeks) is sufficient, particularly in women with prolonged estradiol exposure 1
• Do not confuse pre-treatment protocols with continuation of hormone replacement: while some IVF protocols use luteal phase estradiol priming (E2/ANT protocol), this is a specific, timed intervention distinct from ongoing hormone replacement therapy 5
• Recognize that estradiol pre-treatment protocols used for IVF cycle scheduling (starting in the luteal phase of the preceding cycle) are different from ongoing hormone replacement and are discontinued before gonadotropin stimulation begins 6, 5