Switching from Oral to Injectable Estradiol
Start injectable estradiol at ≤5 mg weekly (subcutaneous or intramuscular) when transitioning from oral estradiol, then titrate based on serum levels to avoid supraphysiologic concentrations. 1, 2
Recommended Starting Dose
Begin with 5 mg or less of estradiol cypionate or valerate weekly (either subcutaneous or intramuscular route), as current guideline-recommended starting doses of 2-10 mg weekly are too high and consistently produce supraphysiologic levels. 1
Among patients who achieved guideline-recommended estradiol concentrations (not supraphysiologic), the median dose was only 4.0 mg weekly (interquartile range 3.0-5.0 mg), demonstrating that lower doses are more appropriate. 2
There is no significant difference in estradiol concentrations achieved between intramuscular versus subcutaneous administration, nor between estradiol valerate versus cypionate, so route and ester type can be chosen based on patient preference. 2
Discontinuation of Oral Estradiol
Stop oral estradiol on the same day you administer the first injectable dose to avoid a gap in estrogen coverage, as injectable estradiol begins working immediately and transdermal formulations avoid first-pass hepatic metabolism that oral preparations undergo. 3
No washout period is necessary when switching between these formulations, as both deliver 17β-estradiol systemically.
Monitoring and Titration Strategy
Check serum estradiol levels 3-4 days after injection (mid-cycle timing) during the initial titration phase, as estradiol concentrations vary significantly based on timing within the injection cycle. 2
The dose and timing relative to last injection are the most significant factors affecting estradiol concentrations, making it critical to document when blood is drawn relative to the injection. 2
Titrate the dose to keep estradiol levels within the guideline-recommended physiologic range (typically 100-200 pg/mL), avoiding supraphysiologic concentrations that occur with higher doses. 1, 2
Most patients on current guideline-recommended doses achieve supraphysiologic concentrations (>200 pg/mL), which is why starting conservatively at ≤5 mg weekly is essential. 2
Endometrial Protection Considerations
If the patient has an intact uterus, continue or add progestogen for endometrial protection, using either 200 mg of oral or vaginal micronized progesterone daily for 12-14 days every 28 days in a sequential regimen. 4
This progestogen requirement applies regardless of whether estrogen is delivered orally, transdermally, or by injection. 4, 3
Common Pitfalls to Avoid
Avoid starting at doses ≥10 mg weekly, as this consistently leads to supraphysiologic estradiol levels across most of the injection cycle, increasing risks without additional benefit. 1
Do not assume that oral and injectable estradiol are dose-equivalent; injectable formulations bypass first-pass hepatic metabolism and are significantly more potent on a milligram-per-milligram basis. 3
Avoid checking estradiol levels immediately before the next injection (trough levels), as this timing may underestimate average exposure and lead to inappropriate dose escalation. 2
Do not overlook the need for progestogen in patients with an intact uterus, as estradiol by any route stimulates the endometrium and requires opposition. 4, 3