Estradiol Cypionate Injection
Product Overview
Estradiol cypionate is an esterified prodrug of estradiol, the most potent endogenous estrogen. Following intramuscular or subcutaneous injection, the cypionate (cyclopentylpropionate) ester undergoes gradual enzymatic hydrolysis at the depot site, releasing free estradiol that is chemically identical to the hormone produced by the ovaries. This pharmacokinetic profile supports sustained serum estradiol concentrations over several weeks, reducing injection frequency compared with daily oral or transdermal delivery.
Key Product Facts
Active ingredient: Estradiol cypionate (17β-estradiol cyclopentylpropionate)
Carrier oil: Grapeseed oil (Empower compounded formulation). Note: The commercial brand Depo-Estradiol (Pfizer) uses cottonseed oil.
Concentration: 10 mg/mL in a 5 mL multidose vial (Empower). Commercial Depo-Estradiol: 5 mg/mL.
Route: Intramuscular injection (FDA-approved route). Subcutaneous injection is also used off-label and is supported by pharmacokinetic data showing equivalent bioavailability.
Duration of action: Approximately 3 to 6 weeks depending on dose and individual metabolism. |
Dosing by Indication
Indication |
Dose Range |
Frequency |
Source |
Moderate to severe vasomotor symptoms (hot flashes) |
1 to 5 mg IM |
Every 3 to 4 weeks |
FDA label (Depo-Estradiol); GoodRx; PDR |
Hypoestrogenism due to hypogonadism |
1.5 to 2 mg IM |
Once monthly |
FDA label; GoodRx |
Adolescent hypogonadism (initiation) |
0.2 to 0.4 mg IM, titrated to 1.5–2 mg |
Once monthly |
PDR; MediVera |
Pharmacokinetic Profile
The cypionate ester markedly increases lipophilicity, creating a slow-release intramuscular depot. Following injection, estradiol cypionate is absorbed over several weeks. The FDA label for Depo-Estradiol reports that a single 5 mg injection produces estrogenic effects lasting approximately 3 to 4 weeks (measured by vaginal cornification), with vasomotor symptom relief observed within 1 to 5 days and maintained for an average of approximately 5 weeks.
However, serum estradiol levels are not flat across the injection interval. A 1980 pharmacokinetic study in premenopausal women (Oriowo et al.) found that a single 5 mg IM dose produced mean peak estradiol of approximately 337 pg/mL at 3.9 days post-injection, with mean levels of approximately 159 pg/mL over 11.8 days before declining. Clinicians should anticipate a peak-to-trough variation and counsel patients accordingly. Lower doses (1 to 2.5 mg) produce more moderate peaks and may offer a smoother pharmacokinetic profile at the cost of shorter duration.
Carrier Oil: Compounded vs. Commercial
The carrier oil differs between compounded and commercial formulations, which is clinically relevant for patients with allergies and may affect injection-site tolerability:
•
Empower Pharmacy (compounded): Estradiol cypionate 10 mg/mL in grapeseed oil. Grapeseed oil is a thinner, lower-viscosity vehicle associated with reduced injection-site irritation and lower allergenicity compared to cottonseed oil.
•
Depo-Estradiol (Pfizer, commercial): Estradiol cypionate 5 mg/mL in cottonseed oil with chlorobutanol preservative. Cottonseed oil has a longer track record in FDA-approved injectable hormone products but is associated with a higher (though still rare) rate of injection-site reactions.
Route of Administration
The FDA-approved route is intramuscular injection into the gluteal muscle. However, subcutaneous injection is increasingly used off-label. A Mayo Clinic study comparing subcutaneous and intramuscular administration of estradiol cypionate in gender-affirming hormone therapy found equivalent median estradiol levels between routes, with the subcutaneous group using a slightly lower median weekly dose (3 mg vs. 4 mg for valerate). Subcutaneous injection is generally considered easier, less painful, and may support better adherence. Empower’s compounded formulation is labeled for both IM and subcutaneous use.
Clinical Advantages
•
Less frequent dosing: Once every 3 to 4 weeks (or monthly) compared with daily oral tablets, daily topical creams, or twice-weekly patches. Reduces treatment burden and may improve adherence.
•
Bypasses first-pass hepatic metabolism: Parenteral estradiol avoids the hepatic effects of oral estrogen, including increased production of clotting factors, sex hormone-binding globulin (SHBG), and triglycerides. This may confer a more favorable thrombotic and metabolic risk profile.
•
Bioidentical estradiol: Releases 17β-estradiol identical to endogenous hormone. No conversion to equine estrogens or synthetic progestins is involved.
•
Alternative for patients with absorption challenges: Useful for women who have difficulty with other delivery methods, including those with dermatologic conditions limiting patch or cream use, gastrointestinal conditions affecting oral absorption, or lifestyle factors making daily application impractical.
Important: For women with an intact uterus, concomitant progesterone therapy is recommended to mitigate the risk of endometrial hyperplasia and carcinoma. Reevaluation at 3- to 6-month intervals is advised, using the lowest effective dose and considering periodic attempts at dose reduction or cessation once symptoms abate.
References
1. Depo-Estradiol [package insert]. New York, NY: Pfizer Inc. (Pharmacia & Upjohn Company LLC). Available at: DailyMed/FDA.gov.
2. Empower Pharmacy. Estradiol Cypionate Injection product page.
Estradiol Cypionate Injection
3. Oriowo MA, Landgren BM, Stenström B, Diczfalusy E. A comparison of the pharmacokinetic properties of three estradiol esters. Contraception. 1980;21(4):415–424.
4. Rothman MS, Hamnvik OPR, Davidge-Pitts C, et al. Revisiting injectable estrogen dosing recommendations for gender-affirming hormone therapy. Transgend Health. 2024. doi:10.1089/trgh.2023.0209.
5. Herndon JS, Maheshwari AK, Nippoldt TB, et al. Comparison of the subcutaneous and intramuscular estradiol regimens as part of gender-affirming hormone therapy. Endocr Pract. 2023;29(5):356–361.
6. GoodRx. Depo-Estradiol (estradiol cypionate): Uses, Side Effects & More.
https://www.goodrx.com/depo-estradiol/what-is
7. PDR (Prescribers’ Digital Reference). Depo-Estradiol.
Drug Summary
8. MediVera Compounding Pharmacy. Estradiol Cypionate: Indications, Clinical Considerations and Dosing.
Estradiol Cypionate - MediVera Compounding Pharmacy
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